HK1167864B - Substituted 2-acetamido-5-aryl-1,2,4-triazolones and use thereof - Google Patents
Substituted 2-acetamido-5-aryl-1,2,4-triazolones and use thereof Download PDFInfo
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The present application relates to novel, substituted 2-acetamido-5-aryl-1, 2, 4-triazolones, to processes for their preparation, to their use alone or in combination for the treatment and/or prophylaxis of diseases and to their use for the production of medicaments for the treatment and/or prophylaxis of diseases, more particularly for the treatment and/or prophylaxis of cardiovascular disorders.
The fluid content of the human body is governed by various physiological control mechanisms, the purpose of which is to keep the fluid content constant (volume homeostasis). During the process, the volumetric loading of the vascular system and the osmolarity of the plasma are continuously recorded by suitable receptors (baroreceptors and nose receptors). The information provided by these receptors to the relevant centers in the brain regulates drinking behavior and controls fluid excretion via the kidneys through humoral and neural signals. The peptide hormone antidiuretic hormone (otherwise known as vasopressin) has central importance in this process [ Schrier r.w., Abraham, w.t., New Engl. J. Med. 341, 577-585 (1999)]。
Antidiuretic hormones are produced in the suprafascial nucleus on the wall of the third ventricle (hypothalamus) and specialized endocrine neurons in n. Where the hormone is released into the bloodstream in response to a stimulus. Volume reduction, for example due to acute blood loss, severe sweating, prolonged thirst or diarrhea, is a stimulus leading to an enhanced excretion of hormones. Conversely, secretion of antidiuretic hormones is inhibited due to an increase in intravascular volume, for example due to increased fluid ingress.
Antidiuretic hormones exert their major effects by binding to three receptors, which are classified as V1a, V1b and V2 receptors and belong to the family of G protein-coupled receptors. The V1a receptor is located primarily on cells of vascular smooth muscle tissue. Their activation causes vasoconstriction and thus an increase in peripheral resistance and blood pressure. In addition, the V1a receptor can be detected in the liver. The V1b receptor (also known as the V3 receptor) is detectable in the central nervous system. Along with Corticotropin Releasing Hormone (CRH), antidiuretic hormone regulates the basal and stress-induced secretion of adrenocorticotropic hormone (ACTH) via the V1b receptor. The V2 receptor is located in the distal tubular epithelial tissue and in the epithelial tissue of the collecting tubule in the kidney. Their activation renders these epithelial tissues water permeable. This phenomenon is due to the introduction of Aquaporinen (a special water channel) in the luminal membrane of epithelial cells.
The importance of antidiuretic hormones for the reabsorption of water from the urine in the kidneys will be made clearer from the clinical picture of diabetes insipidus, which is caused by hormonal deficiencies, e.g. due to pituitary damage. Patients who suffer from this clinical phenomenon will excrete up to 20 litres of urine per 24 hours if they are not given a replacement hormone. This volume corresponds to about 10% of the initial urine. Because of its great importance for the reabsorption of water from the urine, antidiuretic hormone is also referred to synonymously as antidiuretic hormone (ADH). Logically, pharmacological inhibition of the effect of antidiuretic hormone/ADH on the V2 receptor results in increased urination. However, in contrast to the effects of other diuretics (thiazides and loop diuretics), V2 receptor antagonists cause increased water excretion without significantly increasing electrolyte excretion. This means that volume homeostasis can be restored without the need for processes that affect electrolyte homeostasis with the aid of V2 antagonist drugs. Thus, drugs with V2 antagonist activity appear to be particularly suitable for the treatment of all diseases associated with an overload of the body by water, but without an effective parallel increase in electrolytes. A significant electrolyte abnormality is measurable in clinical chemistry as Hyponatriämie (hyponatremia) (sodium concentration < 135 mmol/L); it is the most important electrolyte abnormality in hospital patients, with an incidence of about 5% or 250000 cases/year in the united states alone. If the plasma sodium concentration drops below 115 mmol/L, coma and death are imminent.
There is a distinction between high capacity (hypovolämische), general capacity (euvolämische) and high capacity hyponatremia depending on the following reasons. The form of Hyponatriämie with edema formation is clinically interesting. Typical examples of this are inappropriate ADH/antidiuretic hormone secretion Syndrome (SIAD), for example after craniocerebral trauma or as paraneolasie in carcinomas, and hypervolumic hyponatremia in liver cirrhosis, various renal diseases and cardiac insufficiency [ De Luca L. et al,Am. J. Cardiol. 96 (suppl.), 19L-23L (2005)]. In particular, patients with cardiac insufficiency-despite their relatively hyponatremia (hypernatriämie) and high-volume (Hypervolämie) -often show increased antidiuretic hormone levels, which are seen as a consequence of neurohumoral regulation which is generally disturbed in cardiac insufficiency conditions [ Francis g.s. et al,Circulation 82, 1724-1729 (1990)]。
the interfering neurohormonal regulation manifests itself mainly by an increase in sympathetic tone and inappropriate activation of the renin-angiotensin-aldosterone system. Although the inhibitory effect of these components by beta-blockers on the one hand and ACE inhibitors or angiotensin receptor blockers on the other hand is now an inherent part of the pharmacological treatment of cardiac insufficiency conditions, an inappropriate increase in the secretion of diuretic hormones in highly advanced cardiac insufficiency conditions is still not sufficiently treated today. In addition to the water retention mediated by the V2 receptor and the associated adverse hämodynamischen results in terms of increased reverse load, left ventricular emptying, pressure in the pulmonary vessels and stroke volume were also adversely affected by V1 a-mediated vasoconstriction. Furthermore, based on experimental data in animals, the direct overgrowth-promoting effect on the myocardium is also attributed to antidiuretic hormones. In contrast to the volume-expanded renal effect (which is mediated by activation of the V2 receptor), the direct effect on the myocardium is triggered by activation of the V1a receptor.
For these reasons, substances which inhibit the action of antidiuretic hormones at the V2 and/or at the V1a receptor appear to be suitable for the treatment of cardiac insufficiency. In particular, compounds having binding activity to the antidiuretic hormone receptors (V1a and V2) should both have desirable renal and hemodynamic effects and therefore provide a particularly desirable profile (profiler) for the treatment of patients with cardiac insufficiency. The provision of these conjugated antidiuretic hormone antagonists also appears to be justified, since a volume reduction mediated solely by the blockade of the V2 receptor can entail stimulation of the nose receptors and thus a further compensatory increase in antidiuretic hormone release. Thus, the deleterious effects of antidiuretic hormones, such as vasoconstriction and myocardial overgrowth, can be further enhanced in the absence of components that simultaneously block the V1a receptor [ Saghi p. et al,Europ. Heart J. 26, 538-543 (2005)]。
WO 99/54315 discloses substituted triazolones having neuroprotective activity and WO 2006/117657 describes triazolone derivatives as anti-inflammatory agents. Furthermore, EP 503548-A1 and EP 587134-A2 claim cyclic urea derivatives and their use for the treatment of thrombosis. Substituted triazolethiones as ion channel modulators are disclosed in WO 2005/097112. WO 2007/134862 describes substituted imidazol-2-ones and 1,2, 4-triazolones as antidiuretic hormone receptor antagonists for the treatment of cardiovascular disorders.
It is an object of the present invention to provide novel compounds which act as potent, selective antagonists of the dual V1a/V2 receptor and which are themselves suitable for the treatment and/or prevention of diseases, more particularly cardiovascular diseases.
The present invention provides compounds of general formula (I):
(I),
wherein
A is-C (R)6AR6B) - (O-O) -or-C (R)6AR6B)-C(R7AR7B)-*，
In the formula
Is at the connection to R3At the location of the connection to the other,
R6Ais hydrogen, (C)1-C4) An alkyl group or a trifluoromethyl group, or a salt thereof,
R6Bis hydrogen or (C)1-C4) An alkyl group, a carboxyl group,
R7Ais hydrogen, (C)1-C4) An alkyl group or a trifluoromethyl group, or a salt thereof,
R7Bis hydrogen or (C)1-C4) An alkyl group, a carboxyl group,
q is a group selected from the group consisting of CH and N,
R1is (C)1-C6) Alkyl radical (C)2-C6) Alkenyl (C)2-C6) Alkynyl or (C)3-C7) A cycloalkyl group,
wherein (C)1-C6) Alkyl radical (C)2-C6) Alkenyl and (C)2-C6) Alkynyl may be substituted by 1 to 3 substituents independently from each other selected from deuterium, halogen, cyano, oxo, hydroxy, trifluoromethyl, (C)3-C7) Cycloalkyl group, (C)1-C6) Alkoxy, trifluoromethoxy and phenyl,
wherein (C)3-C7) Cycloalkyl can be selected by 1 or 2 independently of one another from (C)1-C4) Alkyl, oxo, hydroxy, (C)1-C4) Substituted by the substituent in the alkoxy and the amino,
and
wherein (C)1-C6) Alkoxy can be selected from amino, hydroxy, (C) by 1 or 2 independently of one another1-C4) Alkoxy, hydroxycarbonyl and (C)1-C4) Substituted by the substituent in the alkoxy carbonyl group,
And
wherein the phenyl radical may be substituted by 1 to 3 substituents which are each independently selected from the group consisting of halogen, cyano, nitro, (C)1-C4) Alkyl, trifluoromethyl, hydroxy, hydroxymethyl, (C)1-C4) Alkoxy, trifluoromethoxy, (C)1-C4) Alkoxymethyl, hydroxycarbonyl, (C)1-C4) Alkoxycarbonyl, aminocarbonyl, mono (C)1-C4) Alkylaminocarbonyl and di- (C)1-C4) An alkyl amino carbonyl group,
and
wherein (C)3-C7) Cycloalkyl can be selected from fluorine, (C) by 1 or 2 independently of one another1-C4) Alkyl radical (C)1-C4) Alkoxy, hydroxy, amino and oxo,
R2is benzothienyl, phenyl, thienyl or furyl,
wherein benzothienyl, phenyl, thienyl and furyl can be selected from the group consisting of halogen, cyano, nitro, (C) by 1 to 3 substituents independently of one another1-C4) Alkyl, trifluoromethyl, hydroxy, (C)1-C4) Alkoxy and trifluoromethoxy,
R3is trifluoromethyl, hydroxy, trifluoromethoxy, (C)1-C4) Alkoxy group, (C)3-C7) Cycloalkoxy, nitro, amino, -NR8-C(=O)-R9，-NR10-SO2-R11，-SO2-NR12R13，-O-C(=O)-NR14R15，-NR16-C(=O)-NR17R18，-NR19-C(=O)-OR20，-S(=O)nR21，-O-SO2-NR24R25，–NR26-SO2-NR27R28or-NR30R31，
Wherein
R8Is hydrogen or (C)1-C4) An alkyl group, a carboxyl group,
R9is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
or
R8And R9Together with the atoms to which they are attached form a 5-to 7-membered heterocyclic ring,
wherein the 5-to 7-membered heterocyclic rings may be selected independently of one another from fluorine, (C) 1-C4) Alkyl and trifluoromethyl, substituted with 1 or 2 substituents,
R10is hydrogen or (C)1-C4) An alkyl group, a carboxyl group,
R11is (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
or
R10And R11Together with the atoms to which they are attached form a 5-to 7-membered heterocyclic ring,
wherein the 5-to 7-membered heterocyclic rings may be selected independently of one another from fluorine, (C)1-C4) Alkyl and trifluoromethyl, substituted with 1 or 2 substituents,
R12is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
R13is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
or
R12And R13Together with the nitrogen atom to which they are bonded form a 4-to 7-membered heterocyclic ring,
wherein the 4-to 7-membered heterocyclic ring may be selected independently of one another from fluorine, oxo, hydroxy, (C)1-C4) Alkyl and trifluoromethyl, substituted with 1 or 2 substituents,
R14is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
R15is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
or
R14And R15Together with the nitrogen atom to which they are bonded form a 4-to 7-membered heterocyclic ring,
wherein the 4-to 7-membered heterocyclic ring may be selected independently of one another from fluorine, oxo, hydroxy, (C)1-C4) Alkyl and trifluoromethyl, substituted with 1 or 2 substituents,
R16is hydrogen or (C)1-C4) An alkyl group, a carboxyl group,
R17is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
R18is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
or
R16And R17Together with the nitrogen atom to which they are bonded form a 5-to 7-membered heterocyclic ring,
Wherein the 5-to 7-membered heterocyclic ring may be selected independently of one another from the group consisting of fluoro, trifluoromethyl and (C)1-C4) 1 or 2 substituents in the alkyl group,
or
R17And R18Together with the nitrogen atom to which they are bonded form a 4-to 7-membered heterocyclic ring,
wherein the 4-to 7-membered heterocyclic ring may be selected independently of one another from fluorine, oxo, hydroxy, (C)1-C4) Alkyl and trifluoromethyl, substituted with 1 or 2 substituents,
R19is hydrogen or (C)1-C4) An alkyl group, a carboxyl group,
R20is (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
or
R19And R20Together with the atoms to which they are attached form a 5-to 7-membered heterocyclic ring,
wherein the 5-to 7-membered heterocyclic rings may be selected independently of one another from fluorine, (C)1-C4) Alkyl and trifluoromethyl, substituted with 1 or 2 substituents,
n is a number 0, 1 or 2,
R21is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
R24is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
R25is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
or
R24And R25Together with the nitrogen atom to which they are bonded form a 4-to 7-membered heterocyclic ring,
wherein the 4-to 7-membered heterocyclic ring may be selected independently of one another from fluorine, oxo, hydroxy, (C)1-C4) Alkyl and trifluoromethyl, substituted with 1 or 2 substituents,
R26is hydrogen or (C)1-C4) An alkyl group, a carboxyl group,
R27is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
R28is hydrogen, (C) 1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
or
R26And R27Together with the nitrogen atom to which they are bonded form a 5-to 7-membered heterocyclic ring,
wherein the 5-to 7-membered heterocyclic ring may be selected independently of one another from the group consisting of fluoro, trifluoromethyl and (C)1-C4) 1 or 2 substituents in the alkyl group,
or
R27And R28Together with the nitrogen atom to which they are bonded form a 4-to 7-membered heterocyclic ring,
wherein the 4-to 7-membered heterocyclic ring may be selected independently of one another from fluorine, oxo, hydroxy and (C)1-C4) 1 or 2 substituents in the alkyl group,
R30is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
R31is (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
or
R30And R31Together with the nitrogen atom to which they are bonded form a 4-to 7-membered heterocyclic ring,
wherein the 4-to 7-membered heterocyclic ring may be selected independently of one another from fluorine, oxo, hydroxy, (C)1-C4) Alkyl and trifluoromethyl, substituted with 1 or 2 substituents,
R4is phenyl, naphthyl or 5-to 10-membered heteroaryl,
wherein phenyl, naphthyl and 5-to 10-membered heteroaryl can be selected independently of one another from the group consisting of halogen, cyano, nitro, (C)1-C4) Alkyl, difluoromethyl, trifluoromethyl, hydroxy, (C)1-C4) Alkoxy, difluoromethoxy and trifluoromethoxy, substituted with 1-3 substituents,
R5is hydrogen, deuterium, trifluoromethyl or (C) 1-C4) An alkyl group, a carboxyl group,
R29is hydrogen or (C)1-C4) An alkyl group, a carboxyl group,
and their salts, solvates, and solvates of the salts.
The compounds according to the invention are compounds of the general formula (I) and their salts, solvates, and solvates of the salts; the compounds of the general formula illustrated below, which are encompassed by the general formula (1), and their salts, solvates, and solvates of the salts; and the compounds illustrated below as working examples and encompassed by the general formula (I), and their salts, solvates, and solvates of the salts; provided that the compounds described below encompassed by the general formula (I) are not already salts, solvates, and solvates of such salts.
Depending on their structure, the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers). The present invention thus includes enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and/or diastereomers, stereoisomerically homogeneous components can be separated in a known manner.
As long as the compounds according to the invention can exist in tautomeric forms, the invention encompasses all tautomeric forms.
Preferred in the context of the present inventionSalt (salt)Are physiologically acceptable salts of the compounds of the present invention. Also included are salts which-per se are not suitable for pharmaceutical applications-but which may be used, for example, for the isolation or purification of the compounds of the invention.
Physiologically acceptable salts of the compounds of the invention include acid addition salts of inorganic acids, carboxylic acids and sulfonic acids, examples being salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
Physiologically acceptable salts of the compounds of the invention also include salts with customary bases, such as, for example and with preference, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16C atoms, such as, for example and with preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine,N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
Within the scope of the inventionSolvatesAre those forms of the compounds of the present invention which form solid or liquid complexes by coordination with solvent molecules. Hydrates are a particular form of solvates in which the coordination is with water. Preferred solvates in the context of the present invention are hydrates.
In addition, the present invention also includes prodrugs of the invention. The term "prodrug" includes compounds which may be biologically or non-biologically active themselves, but which are converted (e.g., metabolized or hydrolyzed) to the compounds of the invention during the residence time in the body.
In the context of the present invention, unless otherwise specified, the substituents have the following definitions:
within the scope of the inventionAlkyl radicalIs a linear or branched alkyl group having 1 to 6 or 1 to 4 carbon atoms. For example and preferably, it includes the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, isopentyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3, 3-dimethylbutyl, 1-ethylbutyl and 2-ethylbutyl.
Within the scope of the inventionCycloalkyl radicalsIs a monocyclic saturated alkyl group having 3 to 7 or 3 to 6 carbon atoms. For example and preferably, it comprises the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Within the scope of the inventionAlkenyl radicalIs a linear or branched alkenyl group having 2 to 6 carbon atoms and one or two double bonds. Preference is given to straight-chain or branched alkenyl having 2 to 4 carbon atoms and one double bond. For example and preferably, it includes the following: vinyl, allyl, isopropenyl and n-but-2-en-1-yl.
Within the scope of the inventionAlkynyl radicalIs a linear or branched alkynyl group having 2 to 6 carbon atoms and a triple bond. For example and preferably, it comprises the following groups: ethynyl, n-prop-1-yn-1-yl, n-prop-2-yn-1-yl, n-but-2-yn-1-yl and n-but-3-yn-1-yl.
Within the scope of the inventionAlkoxy radicalIs a linear or branched alkoxy group having 1 to 6 or 1 to 4 carbon atoms. For example and preferably, it comprises the following groups: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy and tert-butoxy.
Within the scope of the inventionCycloalkoxy radical Is a monocyclic saturated cycloalkyl group having 3 to 7 carbon atoms, which is linked via an oxygen atom. For example and preferably, it comprises the following groups: cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and cycloheptyloxy.
Within the scope of the inventionAlkoxycarbonyl radicalIs a linear or branched alkoxy group having 1 to 6 carbon atoms and a carbonyl group attached to oxygen. For example and preferably, it includes the following: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
Within the scope of the inventionMonoalkylaminocarbonylIs an amino group attached via a carbonyl group and having a linear or branched alkyl substituent containing 1 to 4 carbon atoms. For example and preferably, it comprises the following groups: methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl and tert-butylaminocarbonyl.
Within the scope of the inventionDialkylaminocarbonyl radicalsIs an amino group which is linked via a carbonyl group and has 2 identical or different linear or branched alkyl substituents, each of which has 1 to 4 carbon atoms. For example and preferably, it comprises the following groups: n, N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-N-propylaminocarbonyl, N-N-butyl-N-methylaminocarbonyl and N-tert-butyl-N-methylaminocarbonyl.
Within the scope of the inventionHeterocyclic ringsIs a saturated or partially unsaturated heterocyclic ring having a total of 4 to 7 ring atoms, which includes from one to three ring heteroatoms selected from the N, O and/or S series, and is linked via a ring carbon atom or optionally a ring nitrogen atom. For example, it includes the following groups: azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, pyrazolidinyl, imidazolidinyl, piperazinyl, tetrahydropyrimidinyl,oxazolidinyl, morpholinyl, thiomorpholinyl, diazepanyl, tetrahydrofuranyl, tetrahydropyranyl,oxazinalkyl (oxazinanyl), oxazepinyl,
2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 2-oxoazepan-1-yl, 2-oxoimidazolidin-1-yl, 2-oxo-1, 3-Oxazolidin-3-yl, 2-oxotetrahydropyrimidin-1 (2H) -yl, 2-oxo-1, 3-Oxazinan-3-yl, 2-oxo-1, 3-azepan-1-yl, 2-oxo-1, 3-oxazepan-3-yl, 2, 3-dihydro-1H-pyrrol-1-yl, 2-oxo-2, 5-dihydro-1H-pyrrol-1-yl, 2-oxo-1, 3-Oxazolidinyl-3-yl, 2-oxo-1, 3-Oxazol-3 (2H) -yl, 2-oxoimidazolidin-1-yl, 2-oxo-2, 3-dihydro-1H-imidazol-1-yl, 1, 1-dioxy (Dioxido) -1, 2-thiazolidin-2-yl, 1, 1-dioxy (Dioxido) -1, 2-thiazinan (thiazinan) -2-yl, 1, 1-dioxy (Dioxido) -1, 2-thiadiazacycloheptan-2-yl, 1, 1-dioxy (Dioxido) -1,2, 5-thiadiazolidin-2-yl, 1, 1-dioxy (Dioxido) -1,2, 6-thiadiazinnan (thiadiazanyl) -2-yl and 1, 1-dioxy (Dioxido) -1,2, 7-thiadiazepan-2-yl. Preference is given to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, diazepanyl, oxazepinyl, 2-oxoimidazolidin-1-yl, 2-oxo-2, 3-dihydro-1H-pyrrol-1-yl, 2-oxo-2, 5-dihydro-1H-pyrrol-1-yl, 2-oxo-1, 3- Oxazolidin-3-yl, 1, 1-dioxy (Dioxido) -1,2, 5-thiadiazolidin-2-yl, 2-oxotetrahydropyrimidin-1 (2H) -yl, 2-oxo-1, 3-Oxazinan-3-yl, 2-oxo-1, 3-diazacycloHeptane-1-yl and 2-oxo-1, 3-oxazepan-3-yl.
Within the scope of the inventionHeteroaryl radicalIs a monocyclic or optionally bicyclic aromatic heterocycle (heteroaromatic) having a total of 5 to 10 ring atoms, which comprises up to three identical or different ring heteroatoms from the series N, O and/or S and is linked via a ring carbon atom or optionally via a ring nitrogen atom. For example, it includes the following groups: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl,azolyl radical, isoAn azole group, an isothiazolyl group, a triazolyl group,oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzimidazolylAzolyl, benzothiazolyl, benzotriazolyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinazolinyl, quinoxalinyl, 2, 3-naphthyridinyl, pyrazolo [3,4-b]A pyridyl group. Preference is given to monocyclic rings having up to three ring heteroatoms from the series N, O and/or S 5- Or 6- Membered heteroarylFor example, furyl, thienyl, thiazolyl,azolyl, isothiazolyl, iso-thiazolylAzolyl, pyrazolyl, imidazolyl, triazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl.
Within the scope of the inventionHalogen elementIncluding fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.
Within the scope of the inventionOxo radicalIs an oxygen atom attached to a carbon atom via a double bond.
If a group in a compound of the present invention is substituted, the group, unless otherwise specified, may be substituted one or more times. In the context of the present invention, it is suitable that their definitions are independent of one another for all radicals which occur more than once. Preference is given to substitution by one, two or three identical or different substituents. Very particular preference is given to substitution by one substituent.
Preferred in the context of the present invention are compounds of the general formula (I-B)
(I-B),
Wherein
A is-C (R)6AR6B) - (O-O) -or-C (R)6AR6B)-C(R7AR7B)-*，
Wherein
Is connected to R3At the location of the connection to the other,
R6Ais hydrogen, (C)1-C4) An alkyl group or a trifluoromethyl group, or a salt thereof,
R6Bis hydrogen or (C)1-C4) An alkyl group, a carboxyl group,
R7Ais hydrogen, (C)1-C4) An alkyl group or a trifluoromethyl group, or a salt thereof,
R7Bis hydrogen or (C) 1-C4) An alkyl group, a carboxyl group,
R1is (C)1-C6) Alkyl radical (C)2-C6) Alkenyl (C)2-C6) Alkynyl or (C)3-C7) A cycloalkyl group,
wherein (C)1-C6) Alkyl radical (C)2-C6) Alkenyl and (C)2-C6) Alkynyl may be substituted by 1 to 3 substituents which are each independently selected from halogen, cyano, oxo, hydroxy, trifluoromethyl, (C)3-C7) Cycloalkyl group, (C)1-C6) Alkoxy, trifluoromethoxy and phenyl,
wherein (C)3-C7) Cycloalkyl radicals may be chosen independently of one another from (C)1-C4) Alkyl, oxo, hydroxy, (C)1-C4) Alkoxy and amino substituted by 1 or 2 substituents,
and
wherein (C)1-C6) Alkoxy groups may be selected independently of one another from amino, hydroxy, (C)1-C4) Alkoxy, hydroxycarbonyl and (C)1-C4) Substituted by 1 or 2 substituents in the alkoxycarbonyl group,
and
wherein the phenyl radicals may be selected, independently of one another, from halogen, cyano, nitro, (C)1-C4) Alkyl, trifluoromethyl, hydroxy, hydroxymethyl, (C)1-C4) Alkoxy, trifluoromethoxy, (C)1-C4) Alkoxymethyl, hydroxycarbonyl, (C)1-C4) Alkoxycarbonyl, aminocarbonyl, mono (C)1-C4) Alkylaminocarbonyl and di- (C)1-C4) 1-3 substituents in the alkyl amino carbonyl group,
and
wherein (C)3-C7) Cycloalkyl radicals may be chosen, independently of one another, from fluorine, (C)1-C4) Alkyl radical (C)1-C4) Alkoxy, hydroxy, amino and oxo substituted by 1 or 2 substituents,
R2Is a phenyl, thienyl or furyl group,
wherein phenyl, thienyl and furyl can be selected independently of one another from the group consisting of halogen, cyano, nitro, (C)1-C4) Alkyl, trifluoromethyl, hydroxy, (C)1-C4) Alkoxy and 1-3 substituents of trifluoromethoxy,
R3is trifluoromethyl, hydroxy, nitro, amino, -NR8-C(=O)-R9，-NR10-SO2-R11，-SO2-NR12R13，-O-C(=O)-NR14R15，-NR16-C(=O)-NR17R18，-NR19-C(=O)-OR20or-S (= O)nR21，
Wherein
R8Is hydrogen or (C)1-C4) An alkyl group, a carboxyl group,
R9is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
R10is hydrogen or (C)1-C4) An alkyl group, a carboxyl group,
R11is (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
R12is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
R13is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
or
R12And R13Together with the nitrogen atom to which they are bonded form a 4-to 7-membered heterocyclic ring,
wherein the 4-to 7-membered heterocyclic ring may be selected independently of one another from fluorine, oxo, hydroxy and (C)1-C4) 1 or 2 substituents in the alkyl group,
R14is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
R15is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
or
R14And R15Together with the nitrogen atom to which they are bonded form a 4-to 7-membered heterocyclic ring,
wherein the 4-to 7-membered heterocyclic ring may be selected independently of one another from fluorine, oxo, hydroxy and (C)1-C4) 1 or 2 substituents in the alkyl group,
R16is hydrogen or (C)1-C4) An alkyl group, a carboxyl group,
R17is hydrogen, (C)1-C4) Alkyl or (C) 3-C7) A cycloalkyl group,
R18is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
or
R16And R17Together with the nitrogen atom to which they are bonded form a 5-to 7-membered heterocyclic ring,
wherein the 5-to 7-membered heterocyclic ring may be selected independently of each other from fluorine and (C)1-C4) 1 or 2 substituents in the alkyl group,
or
R17And R18With which they are bonded toThe nitrogen atoms together form a 4-to 7-membered heterocyclic ring,
wherein the 4-to 7-membered heterocyclic ring may be selected independently of one another from fluorine, oxo, hydroxy and (C)1-C4) 1 or 2 substituents in the alkyl group,
R19is hydrogen or (C)1-C4) An alkyl group, a carboxyl group,
R20is (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
or
R19And R20Together with the atoms to which they are attached form a 5-to 7-membered heterocyclic ring,
wherein the 5-to 7-membered heterocyclic ring may be selected independently of each other from fluorine and (C)1-C4) 1 or 2 substituents in the alkyl group,
n is a number 0, 1 or 2,
R21is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
R4is phenyl, naphthyl or 5-to 10-membered heteroaryl,
wherein phenyl, naphthyl and 5-to 10-membered heteroaryl can be selected independently of one another from the group consisting of halogen, cyano, nitro, (C)1-C4) Alkyl, difluoromethyl, trifluoromethyl, hydroxy, (C)1-C4) Alkoxy, difluoromethoxy and trifluoromethoxy, substituted with 1-3 substituents,
R5Is hydrogen, trifluoromethyl or (C)1-C4) An alkyl group, a carboxyl group,
and their salts, solvates, and solvates of the salts.
Preferred within the scope of the present invention are compounds of the general formula (I), in which
A is-C (R)6AR6B) - (O-O) -or-C (R)6AR6B)-C(R7AR7B)-*，
Wherein
Is connected to R3At the location of the connection to the other,
R6Ais hydrogen, methyl or trifluoromethyl,
R6Bis hydrogen or a methyl group, or a mixture thereof,
R7Ais hydrogen, methyl or trifluoromethyl,
R7Bis hydrogen or a methyl group, or a mixture thereof,
q is a group selected from the group consisting of CH and N,
R1is (C)1-C6) Alkyl radical (C)2-C6) Alkenyl or (C)3-C6) A cycloalkyl group,
wherein (C)1-C6) Alkyl and (C)2-C6) Alkenyl can be selected independently of one another from the group consisting of fluorine, chlorine, cyano, oxo, hydroxy, trifluoromethyl, (C)3-C6) Cycloalkyl group, (C)1-C4) Alkoxy, trifluoromethoxy and phenyl, substituted with 1-3 substituents,
wherein (C)3-C6) Cycloalkyl groups may be substituted with 1 or 2 substituents independently of one another selected from methyl, ethyl, oxo, hydroxy, methoxy, ethoxy and amino,
and
wherein the phenyl group may be substituted with a substituent selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, methoxymethyl, ethoxymethyl, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and aminocarbonyl,
And
wherein (C)3-C6) Ring (C)The alkyl group may be substituted with 1 or 2 substituents independently selected from fluorine, methyl, ethyl, methoxy, ethoxy, hydroxy, amino and oxo,
R2is benzothien-2-yl, phenyl or thienyl,
wherein benzothien-2-yl, phenyl and thienyl may be substituted, independently of one another, by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, hydroxyl, methoxy, ethoxy and trifluoromethoxy,
R3is trifluoromethyl, hydroxy, amino, -NR8-C(=O)-R9，-NR10-SO2-R11，-SO2-NR12R13，-O-C(=O)-NR14R15，-NR16-C(=O)-NR17R18，-NR19-C(=O)-OR20，-S(=O)nR21，-O-SO2-NR24R25or-NR26-SO2-NR27R28-，
Wherein
R8Is hydrogen or a methyl group, or a mixture thereof,
R9is (C)1-C4) An alkyl group, a carboxyl group,
or
R8And R9Together with the atoms to which they are attached form a 5-to 7-membered heterocyclic ring,
R10is hydrogen or a methyl group, or a mixture thereof,
R11is (C)1-C4) An alkyl group, a carboxyl group,
or
R10And R11Together with the atoms to which they are attached form a 5-to 7-membered heterocyclic ring,
R12is (C)1-C4) An alkyl group, a carboxyl group,
R13is (C)1-C4) An alkyl group, a carboxyl group,
R14is hydrogen or (C)1-C4) An alkyl group, a carboxyl group,
R15is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
or
R14And R15Together with the nitrogen atom to which they are bonded form a 4-to 7-membered heterocyclic ring,
R16is hydrogen or (C)1-C4) An alkyl group, a carboxyl group,
R17is hydrogen or (C)1-C4) An alkyl group, a carboxyl group,
R18is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
or
R16And R17Together with the nitrogen atom to which they are bonded form a 5-to 7-membered heterocyclic ring,
R19is hydrogen or a methyl group, or a mixture thereof,
R20Is (C)1-C4) An alkyl group, a carboxyl group,
or
R19And R20Together with the atoms to which they are attached form a 5-to 7-membered heterocyclic ring,
n is a number 0, 1 or 2,
R21is (C)1-C4) An alkyl group, a carboxyl group,
R24 is hydrogen or a methyl group, or a mixture thereof,
R25is hydrogen or a methyl group, or a mixture thereof,
R26is hydrogen or a methyl group, or a mixture thereof,
R27is hydrogen or (C)1-C4) An alkyl group, a carboxyl group,
R28is hydrogen or (C)1-C4) An alkyl group, a carboxyl group,
or
R26And R27Together with the nitrogen atom to which they are bonded form a 5-to 7-membered heterocyclic ring,
R4is a phenyl group, and the phenyl group,
wherein phenyl may be substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy,
R5is hydrogen, deuterium, trifluoromethyl, methyl or ethyl,
R29is hydrogen or a methyl group, or a mixture thereof,
and their salts, solvates, and solvates of the salts.
Preferred within the scope of the present invention are compounds of the general formula (I-B), in which
A is-C (R)6AR6B) - (O-O) -or-C (R)6AR6B)-C(R7AR7B)-*，
In the formula
Is connected to R3At the location of the connection to the other,
R6Ais hydrogen, methyl or trifluoromethyl,
R6Bis hydrogen or a methyl group, or a mixture thereof,
R7Ais hydrogen, methyl or trifluoromethyl,
R7Bis hydrogen or a methyl group, or a mixture thereof,
R1is (C)1-C6) Alkyl radical (C)2-C6) Alkenyl or (C)3-C6) A cycloalkyl group,
wherein (C)1-C6) Alkyl and (C)2-C6) Alkenyl can be selected independently of one another from the group consisting of fluorine, chlorine, cyano, oxo, hydroxy, trifluoromethyl, (C) 3-C6) Cycloalkyl group, (C)1-C4) Alkoxy, trifluoromethoxy and phenyl, substituted with 1-3 substituents,
wherein (C)3-C6) Cycloalkyl groups may be substituted with 1 or 2 substituents independently of one another selected from methyl, ethyl, oxo, hydroxy, methoxy, ethoxy and amino,
and
wherein the phenyl group may be substituted with a substituent selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, methoxymethyl, ethoxymethyl, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and aminocarbonyl,
and
wherein (C)3-C6) Cycloalkyl groups may be substituted independently of one another by 1 or 2 substituents selected from the group consisting of fluorine, methyl, ethyl, methoxy, ethoxy, hydroxy, amino and oxo,
R2is a phenyl group or a thienyl group,
wherein phenyl and thienyl may be substituted with 1 or 2 substituents independently selected from the group consisting of fluoro, chloro, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy and trifluoromethoxy,
R3is a trifluoromethyl group, a hydroxyl group, an amino group,-NR8-C(=O)-R9，-NR10-SO2-R11，-SO2-NR12R13，-O-C(=O)-NR14R15，-NR16-C(=O)-NR17R18or-NR19-C(=O)-OR20，
In the formula
R8Is hydrogen or a methyl group, or a mixture thereof,
R9is (C)1-C4) An alkyl group, a carboxyl group,
R10is hydrogen or a methyl group, or a mixture thereof,
R11is (C)1-C4) An alkyl group, a carboxyl group,
R12is (C)1-C4) An alkyl group, a carboxyl group,
R13is (C)1-C4) An alkyl group, a carboxyl group,
R14is hydrogen or (C) 1-C4) An alkyl group, a carboxyl group,
R15is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
or
R14And R15Together with the nitrogen atom to which they are bonded form a 4-to 6-membered heterocyclic ring,
R16is hydrogen or (C)1-C4) An alkyl group, a carboxyl group,
R17is hydrogen or (C)1-C4) An alkyl group, a carboxyl group,
R18is hydrogen, (C)1-C4) Alkyl or (C)3-C7) A cycloalkyl group,
or
R17And R18Together with the nitrogen atom to which they are bonded form a 4-to 6-membered heterocyclic ring,
R19is hydrogen or a methyl group, or a mixture thereof,
R20is (C)1-C4) An alkyl group, a carboxyl group,
or
R19And R20Together with the atoms to which they are attached form a 5-or 6-membered heterocyclic ring,
R4is a phenyl group, and the phenyl group,
wherein phenyl may be substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy,
R5is hydrogen, trifluoromethyl, methyl or ethyl,
and their salts, solvates, and solvates of the salts.
Particularly preferred within the scope of the present invention are compounds of the general formula (I), in which
A is-C (R)6AR6B) - (O-O) -or-C (R)6AR6B)-C(R7AR7B)-*，
Wherein
Is connected to R3At the location of the connection to the other,
R6Ais hydrogen or a trifluoromethyl group, or a salt thereof,
R6Bis a hydrogen atom, and is,
R7Ais a hydrogen atom, and is,
R7Bis a hydrogen atom, and is,
q is a group of N which is a group of,
R1is (C)2-C4) Alkyl radical (C)2-C4) An alkenyl group or a cyclopropyl group, in which,
wherein (C)2-C4) Alkyl and (C)2-C4) Alkenyl may be substituted by 1 or 2 substituents independently of one another selected from fluorine, oxo, hydroxy and trifluoromethyl,
R2Is a phenyl group, and the phenyl group,
wherein the phenyl group may be substituted by a substituent selected from fluorine or chlorine,
R3is hydroxy, -amino, -NR8-C(=O)-R9，-NR10-SO2-R11，-SO2-NR12R13，-O-C(=O)-NR14R15，-NR16-C(=O)-NR17R18，-NR19-C(=O)-OR20，-S(=O)nR21or-NR26-SO2-NR27R28-，
Wherein
R8Is a hydrogen atom, and is,
R9is a methyl group, and the compound is,
R10is a hydrogen atom, and is,
R11is a methyl group or an ethyl group,
R12is a methyl group, and the compound is,
R13is a methyl group, and the compound is,
R14is hydrogen or a methyl group, or a mixture thereof,
R15is a hydrogen, a methyl or ethyl radical,
R16is a hydrogen atom, and is,
R17is hydrogen or a methyl group, or a mixture thereof,
R18is a hydrogen, a methyl or ethyl radical,
or
R16And R17Together with the nitrogen atom to which they are bonded form a 2-oxoimidazolidin-1-yl or 2-oxotetrahydropyrimidin-1 (2H) -yl ring,
R19is a hydrogen atom, and is,
R20is a methyl group or an ethyl group,
or
R19And R20Together with the atom to which they are attached form 2-oxo-1, 3-Oxazolidin-3-yl or 2-oxo-1, 3-An oxazinane-3-yl ring,
n is the number 0 or 2 and,
R21is a methyl group, and the compound is,
R26is a hydrogen atom, and is,
R27is a hydrogen atom, and is,
R28is a hydrogen atom, and is,
R4is a radical of the formula
Wherein
# is linked to-C (R)5)(AR3) The point of attachment on the N-is,
R22is hydrogen, cyano, methyl, trifluoromethoxyFluorine, chlorine, trifluoromethyl and methoxy,
R23is hydrogen, cyano, methyl, trifluoromethoxy, fluoro, chloro, trifluoromethyl and methoxy,
wherein the group R22And R23At least one of which is not hydrogen,
R5is hydrogen or a methyl group, or a mixture thereof,
R29is a hydrogen atom, and is,
and their salts, solvates, and solvates of the salts.
Further particularly preferred within the scope of the present invention are compounds of the general formula (I), in which
A is-C (R)6AR6B) - (O-O) -or-C (R)6AR6B)-C(R7AR7B)-*，
Wherein
Is connected to R3At the location of the connection to the other,
R6Ais hydrogen or a trifluoromethyl group, or a salt thereof,
R6Bis a hydrogen atom, and is,
R7Ais a hydrogen atom, and is,
R7Bis a hydrogen atom, and is,
q is a group of N which is a group of,
R1is (C)2-C4) Alkyl radical (C)2-C4) An alkenyl group or a cyclopropyl group, in which,
wherein (C)2-C4) Alkyl and (C)2-C4) Alkenyl may be substituted by 1 or 2 substituents independently of one another selected from fluorine, oxo, hydroxy and trifluoromethyl,
R2is a phenyl group, and the phenyl group,
wherein the phenyl group may be substituted by a substituent selected from fluorine or chlorine,
R3is trifluoromethyl, hydroxy, amino, -NR8-C(=O)-R9，-NR10-SO2-R11，-SO2-NR12R13，-O-C(=O)-NR14R15，-NR16-C(=O)-NR17R18，-NR19-C(=O)-OR20，-S(=O)nR21or-NR26-SO2-NR27R28-，
Wherein
R8Is a hydrogen atom, and is,
R9is a methyl group, and the compound is,
R10is a hydrogen atom, and is,
R11is a methyl group or an ethyl group,
R12is a methyl group, and the compound is,
R13is a methyl group, and the compound is,
R14is hydrogen or a methyl group, or a mixture thereof,
R15is a hydrogen, a methyl or ethyl radical,
R16is a hydrogen atom, and is,
R17is hydrogen or a methyl group, or a mixture thereof,
R18is a hydrogen, a methyl or ethyl radical,
or
R16And R17Together with the nitrogen atom to which they are bonded form a 2-oxoimidazolidin-1-yl or 2-oxotetrahydropyrimidin-1 (2H) -yl ring,
R19is a hydrogen atom, and is,
R20 is a methyl group or an ethyl group,
or
R19And R20Together with the atom to which they are attached form 2-oxo-1, 3-Oxazolidin-3-yl or 2-oxo-1, 3-An oxazinane-3-yl ring,
n is the number 0 or 2 and,
R21is a methyl group, and the compound is,
R26is a hydrogen atom, and is,
R27Is a hydrogen atom, and is,
R28is a hydrogen atom, and is,
R4is a radical of the formula
Wherein
# is linked to-C (R)5)(AR3) The point of attachment on the N-is,
R22are hydrogen, fluorine, chlorine, trifluoromethyl and methoxy,
R23are hydrogen, fluorine, chlorine, trifluoromethyl and methoxy,
wherein the group R22And R23At least one of which is not hydrogen,
R5is hydrogen or a methyl group, or a mixture thereof,
R29is a hydrogen atom, and is,
and their salts, solvates, and solvates of the salts.
More particularly preferred within the scope of the present invention are compounds of the general formula (I), in which
A is-C (R)6AR6B) - (O-O) -or-C (R)6AR6B)-C(R7AR7B)-*，
Wherein
Is connected to R3At the location of the connection to the other,
R6Ais hydrogen or a trifluoromethyl group, or a salt thereof,
R6Bis a hydrogen atom, and is,
R7Ais a hydrogen atom, and is,
R7Bis a hydrogen atom, and is,
q is a group of N which is a group of,
R1is 3,3, 3-trifluoroprop-1-en-1-yl, 3,3, 3-trifluoropropyl or 1,1, 1-trifluoroprop-2-ol-3-yl,
R2is a phenyl group, and the phenyl group,
wherein the phenyl group may be substituted by a substituent selected from fluorine or chlorine,
R3is hydroxy, -amino, -NR8-C(=O)-R9，-NR10-SO2-R11，-SO2-NR12R13，-O-C(=O)-NR14R15，-NR16-C(=O)-NR17R18，-NR19-C(=O)-OR20，-S(=O)nR21or-NR26-SO2-NR27R28-，
Wherein
R8Is a hydrogen atom, and is,
R9is a methyl group, and the compound is,
R10is a hydrogen atom, and is,
R11is a methyl group or an ethyl group,
R12is a methyl group, and the compound is,
R13is a methyl group, and the compound is,
R14is hydrogen or a methyl group, or a mixture thereof,
R15is a hydrogen, a methyl or ethyl radical,
R16is a hydrogen atom, and is,
R17is hydrogen or a methyl group, or a mixture thereof,
R18is a hydrogen, a methyl or ethyl radical,
or
R16And R17Together with the nitrogen atom to which they are bonded form a 2-oxoimidazolidin-1-yl or 2-oxotetrahydropyrimidin-1 (2H) -yl ring,
R19Is a hydrogen atom, and is,
R20is a methyl group or an ethyl group,
or
R19And R20Together with the atom to which they are attached form 2-oxo-1, 3-Oxazolidin-3-yl or 2-oxo-1, 3-An oxazinane-3-yl ring,
n is the number 0 or 2 and,
R21is a methyl group, and the compound is,
R26 is a hydrogen atom, and is,
R27is a hydrogen atom, and is,
R28is a hydrogen atom, and is,
R4is a radical of the formula
In the formula
# is linked to-C (R)5)(AR3) The attachment site on the N-terminus of the polypeptide,
R22are hydrogen, fluorine, chlorine and trifluoromethyl,
R23are hydrogen, fluorine, chlorine and trifluoromethyl,
wherein the group R22And R23At least one of which is not hydrogen,
R5is hydrogen or a methyl group, or a mixture thereof,
R29is a hydrogen atom, and is,
and their salts, solvates, and solvates of the salts.
Particularly preferred within the scope of the present invention are compounds of the general formula (I-B), in which
A is-C (R)6AR6B) - (O-O) -or-C (R)6AR6B)-C(R7AR7B)-*，
Wherein
Is connected to R3At the location of the connection to the other,
R6Ais hydrogen or a trifluoromethyl group, or a salt thereof,
R6Bis a hydrogen atom, and is,
R7Ais thatThe presence of hydrogen in the presence of hydrogen,
R7Bis a hydrogen atom, and is,
R1is (C)2-C4) Alkyl radical (C)2-C4) An alkenyl group or a cyclopropyl group, in which,
wherein (C)2-C4) Alkyl and (C)2-C4) Alkenyl may be substituted by 1 or 2 substituents independently of one another selected from fluorine, hydroxy, oxo and trifluoromethyl,
R2is a phenyl group, and the phenyl group,
wherein the phenyl group may be substituted with a substituent selected from fluorine and chlorine,
R3is trifluoromethyl, hydroxy, amino, -NR8-C(=O)-R9，-NR10-SO2-R11，-O-C(=O)-NR14R15or-NR 16-C(=O)-NR17R18，
Wherein
R8Is a hydrogen atom, and is,
R9is a methyl group, and the compound is,
R10is a hydrogen atom, and is,
R11is a methyl group or an ethyl group,
R14is hydrogen or a methyl group, or a mixture thereof,
R15is a hydrogen, a methyl or ethyl radical,
R16is a hydrogen atom, and is,
R17is hydrogen or a methyl group, or a mixture thereof,
R18is a hydrogen, a methyl or ethyl radical,
R4is a radical of the formula
Wherein
# is linked to-C (R)5)(AR3) The position of the connection on the N-is,
R22is hydrogen, cyano, methyl, trifluoromethoxy, fluoro, chloro, trifluoromethyl and methoxy,
R23is hydrogen, cyano, methyl, trifluoromethoxy, fluoro, chloro, trifluoromethyl and methoxy,
wherein the group R22And R23At least one of which is not hydrogen,
R5is hydrogen or a methyl group, or a mixture thereof,
and their salts, solvates, and solvates of the salts.
Particularly preferred within the scope of the present invention are furthermore compounds of the formula (I-B), in which
A is-C (R)6AR6B) - (O-O) -or-C (R)6AR6B)-C(R7AR7B)-*，
Wherein
Is connected to R3At the location of the connection to the other,
R6Ais hydrogen or a trifluoromethyl group, or a salt thereof,
R6Bis a hydrogen atom, and is,
R7Ais a hydrogen atom, and is,
R7Bis a hydrogen atom, and is,
R1is (C)2-C4) Alkyl radical (C)2-C4) An alkenyl group or a cyclopropyl group, in which,
wherein (C)2-C4) Alkyl and (C)2-C4) Alkenyl may be substituted by 1 or 2 substituents independently of one another selected from fluorine, hydroxy, oxo and trifluoromethyl,
R2is a phenyl group, and the phenyl group,
wherein the phenyl group may be substituted with a substituent selected from fluorine and chlorine,
R3Is trifluoromethyl, hydroxy, amino, -NR8-C(=O)-R9，-NR10-SO2-R11，-O-C(=O)-NR14R15or-NR16-C(=O)-NR17R18，
Wherein
R8Is a hydrogen atom, and is,
R9is a methyl group, and the compound is,
R10is a hydrogen atom, and is,
R11is a methyl group or an ethyl group,
R14is hydrogen or a methyl group, or a mixture thereof,
R15is a hydrogen, a methyl or ethyl radical,
R16is a hydrogen atom, and is,
R17is hydrogen or a methyl group, or a mixture thereof,
R18is a hydrogen, a methyl or ethyl radical,
R4is a radical of the formula
Wherein
# is linked to-C (R)5)(AR3) To the N-atomThe position of the grafting site is shown,
R22are hydrogen, fluorine, chlorine, trifluoromethyl and methoxy,
R23are hydrogen, fluorine, chlorine, trifluoromethyl and methoxy,
wherein the group R22And R23At least one of which is not hydrogen,
R5is hydrogen or a methyl group, or a mixture thereof,
and their salts, solvates, and solvates of the salts.
More particularly preferred within the scope of the present invention are compounds of the general formula (I-B), in which
A is-C (R)6AR6B) - (O-O) -or-C (R)6AR6B)-C(R7AR7B)-*，
Wherein
Is connected to R3At the location of the connection to the other,
R6Ais hydrogen or a trifluoromethyl group, or a salt thereof,
R6Bis a hydrogen atom, and is,
R7Ais a hydrogen atom, and is,
R7Bis a hydrogen atom, and is,
R1is 3,3, 3-trifluoroprop-1-en-1-yl, 3,3, 3-trifluoropropyl or 1,1, 1-trifluoroprop-2-ol-3-yl,
R2is a phenyl group, and the phenyl group,
wherein the phenyl group may be substituted with a substituent selected from fluorine and chlorine,
R3is hydroxy, -amino, -NR8-C(=O)-R9，-NR10-SO2-R11，-O-C(=O)-NR14R15or-NR16-C(=O)-NR17R18，
Wherein
R8Is a hydrogen atom, and is,
R9is a methyl group, and the compound is,
R10is a hydrogen atom, and is,
R11is a methyl group or an ethyl group,
R14is hydrogen or a methyl group, or a mixture thereof,
R15is a hydrogen, a methyl or ethyl radical,
R16Is a hydrogen atom, and is,
R17is hydrogen or a methyl group, or a mixture thereof,
R18is a hydrogen, a methyl or ethyl radical,
R4is a radical of the formula
Wherein
# is linked to-C (R)5)(AR3) The attachment site on the N-terminus of the polypeptide,
R22is hydrogen, fluorine, chlorine or trifluoromethyl,
R23is hydrogen, fluorine, chlorine or trifluoromethyl,
wherein the group R22And R23At least one of which is not hydrogen,
R5is hydrogen or a methyl group, or a mixture thereof,
and their salts, solvates, and solvates of the salts.
Within the scope of the inventionPreferred are compounds of formula (I) wherein R2Is p-chlorophenyl.
Also preferred within the scope of the present invention are compounds of the formula (I), in which
R2Is a phenyl group or a thienyl group,
wherein the phenyl and thienyl groups may be substituted with a substituent selected from the group consisting of fluoro, chloro, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy and trifluoromethoxy.
Also preferred within the scope of the present invention are compounds of the formula (I) wherein R1Is 3,3, 3-trifluoroprop-1-en-1-yl.
Also preferred within the scope of the present invention are compounds of the formula (I) wherein R1Is 3,3, 3-trifluoropropyl.
Also preferred within the scope of the present invention are compounds of the formula (I) wherein R1Is 1,1, 1-trifluoropropan-2-ol-3-yl.
Also preferred within the scope of the present invention are compounds of the formula (I), in which
R1Is (C)2-C4) Alkyl or (C)2-C4) An alkenyl group which is a radical of an alkylene group,
wherein (C)2-C4) Alkyl and (C)2-C4) The alkenyl group may be substituted with 1 or 2 substituents independently selected from fluorine, hydroxy, oxo and trifluoromethyl.
Also preferred within the scope of the present invention are compounds of the formula (I) wherein R1Is cyclopropyl.
Also preferred within the scope of the present invention are compounds of the formula (I), in which
R3is-O-C (= O) -NR14R15or-NR16-C(=O)-NR17R18，
Wherein
R14Is hydrogen or a methyl group, or a mixture thereof,
R15is a hydrogen, a methyl or ethyl radical,
R16is a hydrogen atom, and is,
R17is hydrogen or a methyl group, or a mixture thereof,
R18is hydrogen, methyl or ethyl.
Also preferred within the scope of the present invention are compounds of the formula (I), in which
R3is-NR10-SO2-R11，
Wherein
R10Is hydrogen and
R11is methyl or ethyl.
Also preferred within the scope of the present invention are compounds of the formula (I), in which
R3Is a hydroxyl group or an amino group.
Also preferred within the scope of the present invention are compounds of the formula (I), in which
R3is-NR16-C(=O)-NR17R18or-NR19-C(=O)-OR20，
Wherein
R16And R17Together with the nitrogen atom to which they are bonded form a 2-oxoimidazolidin-1-yl or 2-oxotetrahydropyrimidin-1 (2H) -yl ring,
R19and R20Together with the atom to which they are attached form 2-oxo-1, 3-Oxazolidin-3-ylOr 2-oxo-1, 3-An oxazinan-3-yl ring.
Also preferred within the scope of the present invention are compounds of the formula (I), in which
R3is-NR16-C(=O)-NR17R18or-NR19-C(=O)-OR20，
Wherein
R16And R17Together with the nitrogen atom to which they are bonded form a 2-oxoimidazolidin-1-yl ring,
R19and R20Together with the atom to which they are attached form 2-oxo-1, 3-Oxazolidin-3-yl ring.
Also preferred within the scope of the present invention are compounds of the general formula (I) wherein A is-CH2-CH2-。
Also preferred within the scope of the present invention are compounds of the general formula (I) wherein A is-CH2-。
Also preferred within the scope of the present invention are compounds of formula (I) wherein Q is N.
Also preferred within the scope of the present invention are compounds of formula (I) wherein Q is CH.
Also preferred within the scope of the present invention are compounds of the formula (I) wherein R5Is hydrogen, trifluoromethyl, methyl or ethyl.
Also preferred within the scope of the present invention are compounds of the formula (I) wherein R5Is hydrogen.
Also preferred within the scope of the present invention are compounds of the formula (I) wherein R5Is methyl.
Also preferred within the scope of the present invention are compounds of the formula (I) wherein R5Is trifluoromethyl, methyl or ethyl.
Also preferred within the scope of the present invention are compounds of the formula (I) wherein R29Is hydrogen.
Also preferred within the scope of the present invention are compounds of the formula (I) wherein R 29Is methyl.
The radical definitions given in each combination and preferred combination of radicals, respectively, are optionally replaced by radical definitions in other combinations, independently of the combination with the particular radical given.
Very particular preference is given to combinations of two or more of the abovementioned preferred ranges.
The invention further provides a process for preparing the compounds of the general formula (I) according to the invention, characterized in that
[A] A compound of the general formula (II)
(II),
Wherein Q, R1And R2Each as defined above, is capable of,
coupled to compounds of the formula (III) by activation of the carboxylic acid function in an inert solvent
(III),
Wherein A, R3，R4，R5And R29Each as defined above, is capable of,
or
[B] A compound of the general formula (IV):
(IV),
wherein Q, R1And R2Each as defined above, is capable of,
reacting with a compound of formula (V) in an inert solvent in the presence of a base
(V),
Wherein A, R3，R4，R5And R29Each as defined above, is capable of,
and
X1is a leaving group, such as halogen, methanesulfonate or toluenesulfonate,
the resulting compounds of general formula (I) are then optionally converted into their solvates, salts and/or solvates of the salts with the corresponding (I) solvent and/or (ii) base or acid.
Inert solvents for process step (II) + (III) → (I) are, for example, ethers such as diethyl ether, bis Alkanes, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1, 2-dichloroethane, trichloroethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulfoxide, N-dimethylformamide, N' -Dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP). It is likewise possible to use mixtures of such solvents. Dichloromethane, tetrahydrofuran, dimethylformamide or mixtures of these solvents are preferred.
Suitable condensing agents for the amidation in process step (II) + (III) → (I) include, for example, carbodiimides such as N, N '-diethyl-, N, N' -dipropyl-, N, N '-diisopropyl-, N, N' -Dicyclohexylcarbodiimide (DCC) or N- (3-dimethylaminoisopropyl) -N '-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as N, N' -Carbonyldiimidazole (CDI), 1,2-AzoleCompounds such as 2-ethyl-5-phenyl-1, 2-Azole-3 sulfate or 2-tert-butyl-5-methyl-isoAzolePerchlorates, acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline, or isobutyl chloroformate, propanephosphonic anhydride, diethyl cyanophosphonate, bis- (2-oxo-3- Oxazolidinyl) phosphoryl chloride, benzotriazol-1-yloxy-tris (dimethylamino) phosphoniumHexafluorophosphate, benzotriazol-1-yloxy-tris (pyrrolidino) phosphonium saltHexafluorophosphate (PyBOP), O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethylureaTetrafluoroborate (TBTU), O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethylureaHexafluorophosphate (HBTU), 2- (2-oxo-1- (2H) -pyridinyl) -1,1,3, 3-tetramethylureaTetrafluoroborate (TPTU), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylureaHexafluorophosphate (HATU) or O- (1H-6-chlorobenzotriazol-1-yl) -1,1,3, 3-tetramethylureaTetrafluoroborates (TCTU), optionally in combination with further auxiliaries, such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), and, as bases, alkali metal carbonates, for example sodium or potassium carbonates or bicarbonates, or organic bases, such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine or N, N-diisopropylethylamine. Preferably, EDC in combination with HOBt or TBTU is used in the presence of N, N-diisopropylethylamine.
The condensation reaction (II) + (III) → (I) is generally carried out at a temperature of from-20 ℃ to +60 ℃ and preferably from 0 ℃ to +40 ℃. The reaction can be carried out at atmospheric pressure, at elevated pressure or at reduced pressure (for example 0.5 to 5 bar). This operation is generally carried out at atmospheric pressure.
Inert solvents for process step (IV) + (V) → (I) are, for example, halogenated hydrocarbons, such as methylene chloride, chloroform, tetrachloromethane, trichloroethylene or chlorobenzene, ethers, such as diethyl ether, diethyl etherAlkane, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether,hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, N-dimethylformamide, dimethyl sulfoxide, N' -Dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP) or pyridine. It is likewise possible to use mixtures of the solvents listed. Preferably, acetonitrile, acetone or dimethylformamide is used.
As base for process step (IV) + (V) → (I), customary inorganic or organic bases are suitable. These preferably include alkali metal hydroxides, for example lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates, for example lithium, sodium, potassium, calcium or cesium carbonate, alkali metal alcoholates, for example sodium or potassium methylate, sodium or potassium ethylate or sodium or potassium tert-butylate, alkali metal hydrides, for example sodium or potassium hydride, amides, for example sodium amide, lithium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine, pyridine, 1, 5-diazabicyclo [4.3.0 ]Non-5-ene (DBN), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU) or 1, 4-diazabicyclo [2.2.2]Octane (DABCO)®). Preferably, potassium carbonate or cesium carbonate is used.
Here, the base is used in an amount of from 1 to 5 mol, preferably from 1 to 2.5 mol, based on 1mol of the compound of the formula (IV). The reaction is generally carried out at a temperature in the range from 0 ℃ to +100 ℃, preferably from +20 ℃ to +80 ℃. The reaction can be carried out at atmospheric pressure, at elevated pressure or at reduced pressure (for example 0.5 to 5 bar). This operation is generally carried out at atmospheric pressure.
The preparation of the compounds of the invention can be illustrated by the following synthetic reaction schemes:
reaction scheme
1
Alternatively, wherein A is-CH2-or-CH2-CH2The compounds of the general formula (I) can also be prepared by reducing compounds of the general formula (XV) in an inert solvent in the presence of a suitable reducing agent,
(XV),
wherein Q, R1，R2，R4，R5And R29Each as defined above, is capable of,
and
T1is hydrogen or (C)1-C4) -an alkyl group,
to give a compound of the general formula (I-A):
(I-A),
wherein Q, R1，R2，R4，R5And R29Each as defined above, is capable of,
and, optionally, further modification of compound (I-a) according to reactions and methods known to those skilled in the art, such as nucleophilic and electrophilic substitutions, oxidation, reduction, hydrogenation, transition metal-catalyzed coupling reactions, elimination, alkylation, amination, esterification, ester cleavage, etherification, ether cleavage, and the introduction and removal of temporary protecting groups.
Suitable inert solvents for process step (XV) → (I-A) here are alcohols, such as methanol, ethanol, n-propanol or isopropanol, or ethers, such as diethyl ether, diethyl etherAlkanes, tetrahydrofuran, ethylene glycol dimethyl ether, dimethoxyethane or diethylene glycol dimethyl ether, or halogenated hydrocarbons such as methylene chlorideChloroform, carbon tetrachloride or 1, 2-dichloroethane, or other solvents such as dimethylformamide. It is likewise possible to use mixtures of the solvents listed. Preference is given to using dimethoxyethane and tetrahydrofuran.
Suitable reducing agents for process step (XV) → (I-a) include boron hydrides, such as sodium borohydride, sodium triacetoxyborohydride, lithium borohydride or sodium cyanoborohydride, aluminum hydrides, such as lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride or diisobutyl aluminum hydride, diborane or borane-tetrahydrofuran complexes.
The reaction (XV) → (I-A) is generally carried out at a temperature in the range of from 0 ℃ to +60 ℃, preferably from 0 ℃ to +40 ℃.
The compounds of formula (II) can be reacted to N by base-induced alkylation of compounds of formula (IV)2-substituted compound (VII) and obtained by subsequent ester hydrolysis (see scheme 2):
reaction scheme
2
The compounds of the formula (VII) in which Q is N can additionally also be obtained from the literature known N- (alkoxycarbonyl) arylthioamides of the formula (IX) [ see, for example, m. Arnswald, w.p. Neumann,J. Org. Chem. 58 (25), 7022-7028 (1993); E.P. Papadopoulos, J. Org. Chem. 41 (6), 962-965 (1976)]preparation, this is achieved by reaction between a compound of general formula (IX) and a hydrazino ester of general formula (VIII) and subsequent alkylation at the N-4 position of triazolone (X) (scheme 3):
reaction scheme
3
Compounds of the general formula (IV) wherein Q is N can be prepared starting from carbohydrazides of the general formula (XI) by reaction thereof with isocyanates of the general formula (XII) or nitrophenylcarbamates of the general formula (XIII) and subsequent base-induced cyclization of the intermediate hydrazine carboxamide (XIV) (scheme 4):
reaction scheme
4
Wherein R is1Corresponding to the substituent CH2CH(OH)CF3The compound of (1) is initially reacted from isocyanatoalkyl acetates (XIIa) and (XI) according to scheme 4 to give (XIVa). Subsequent basic cyclization gives triazolone (IVa). CF (compact flash)3The introduction of the group is achieved by reaction of (IVa) with trifluoroacetic anhydride in pyridine. The resulting ketone (IVb) can be converted into (IVc) by reduction (scheme 5):
reaction scheme
5
Compounds of the general formula (II) wherein Q is CH are obtainable by reaction between alpha-amino ketones of the general formula (XVI) and isocyanates of the general formula (XVII) and subsequent ester hydrolysis (scheme 6). The compounds of the general formula (XVI) can themselves be synthesized in a manner known in the literature from α -bromoketones of the general formula (XVIII) and amino esters of the general formula (XIX) (scheme 7):
Reaction scheme
6
Reaction scheme
7
The compounds of the formulae (III), (V), (VI), (VIII), (IX), (XI), (XII), (XIIa), (XIII), (XVII), (XIX) and (XX) are each obtained by various commercial routes known in the literature or can be prepared analogously to methods known in the literature or by the methods described in the experimental part of the description.
The other compounds of the invention can also, if desired, be obtained starting from compounds of the general formula (I) obtained according to the process described above, via the substituents, in particular in R1And R3Nominally listed) of the functional group. These transformations are carried out according to conventional methods known to those skilled in the art and include, for example, reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, eliminations, alkylations, aminations, esterifications, ester fragmentations, etherifications, ether fragmentations, in particular carboxamide formation, and the introduction and removal of temporary protecting groups.
The invention further comprises compounds of the general formula (III):
(III),
in the formula
A is-C (R)6AR6B) - (O-O) -or-C (R)6AR6B)-C(R7AR7B)-*，
Wherein
Is connected to R3At the location of the connection to the other,
R6AIs hydrogen or a trifluoromethyl group, or a salt thereof,
R6Bis a hydrogen atom, and is,
R7Ais a hydrogen atom, and is,
R7Bis a hydrogen atom, and is,
q is a group of N which is a group of,
R3is hydroxy, -amino, -NR8-C(=O)-R9，-NR10-SO2-R11，-SO2-NR12R13，-O-C(=O)-NR14R15，-NR16-C(=O)-NR17R18，-NR19-C(=O)-OR20，-S(=O)nR21or-NR26-SO2-NR27R28-，
Wherein
R8Is a hydrogen atom, and is,
R9is a methyl group, and the compound is,
R10is a hydrogen atom, and is,
R11is a methyl group or an ethyl group,
R12is a methyl group, and the compound is,
R13is a methyl group, and the compound is,
R14is hydrogen or a methyl group, or a mixture thereof,
R15is a hydrogen, a methyl or ethyl radical,
R16is a hydrogen atom, and is,
R17is hydrogen or a methyl group, or a mixture thereof,
R18is a hydrogen, a methyl or ethyl radical,
or
R16And R17 Together with the nitrogen atom to which they are bonded form a 2-oxoimidazolidin-1-yl or 2-oxotetrahydropyrimidin-1 (2H) -yl ring,
R19is a hydrogen atom, and is,
R20is a methyl group or an ethyl group,
or
R19And R20Together with the atom to which they are attached form 2-oxo-1, 3-Oxazolidin-3-yl or 2-oxo-1, 3-An oxazinane-3-yl ring,
n is the number 0 or 2 and,
R21is a methyl group, and the compound is,
R26is a hydrogen atom, and is,
R27is a hydrogen atom, and is,
R28is a hydrogen atom, and is,
R4is a radical of the formula
In the formula
# is linked to-C (R)5)(AR3) The position of the connection on the N-is,
R22are hydrogen, fluorine, chlorine and trifluoromethyl,
R23are hydrogen, fluorine, chlorine and trifluoromethyl,
wherein the group R22And R23Is not at least one ofThe presence of hydrogen in the presence of hydrogen,
R5is hydrogen or a methyl group, or a mixture thereof,
R29is hydrogen.
The invention further includes compounds of the general formula (V):
(V),
in the formula
A is-C (R)6AR6B) - (O-O) -or-C (R)6AR6B)-C(R7AR7B)-*，
Wherein
Is connected to R3At the location of the connection to the other,
R6Ais hydrogen or a trifluoromethyl group, or a salt thereof,
R6Bis a hydrogen atom, and is,
R7Ais a hydrogen atom, and is,
R7BIs a hydrogen atom, and is,
q is a group of N which is a group of,
R3is hydroxy, -amino, -NR8-C(=O)-R9，-NR10-SO2-R11，-SO2-NR12R13，-O-C(=O)-NR14R15，-NR16-C(=O)-NR17R18，-NR19-C(=O)-OR20，-S(=O)nR21or-NR26-SO2-NR27R28-，
Wherein
R8Is a hydrogen atom, and is,
R9is a methyl group, and the compound is,
R10is a hydrogen atom, and is,
R11is a methyl group or an ethyl group,
R12is a methyl group, and the compound is,
R13is a methyl group, and the compound is,
R14is hydrogen or a methyl group, or a mixture thereof,
R15is a hydrogen, a methyl or ethyl radical,
R16is a hydrogen atom, and is,
R17is hydrogen or a methyl group, or a mixture thereof,
R18is a hydrogen, a methyl or ethyl radical,
or
R16And R17Together with the nitrogen atom to which they are bonded form a 2-oxoimidazolidin-1-yl or 2-oxotetrahydropyrimidin-1 (2H) -yl ring,
R19is a hydrogen atom, and is,
R20is a methyl group or an ethyl group,
or
R19And R20Together with the atom to which they are attached form 2-oxo-1, 3-Oxazolidin-3-yl or 2-oxo-1, 3-An oxazinane-3-yl ring,
n is the number 0 or 2 and,
R21is a methyl group, and the compound is,
R26is a hydrogen atom, and is,
R27is a hydrogen atom, and is,
R28is a hydrogen atom, and is,
R4is a radical of the formula
Wherein
# is linked to-C (R)5)(AR3) The position of the connection on the N-is,
R22are hydrogen, fluorine, chlorine and trifluoromethyl,
R23are hydrogen, fluorine, chlorine and trifluoromethyl,
wherein the group R22And R23At least one of which is not hydrogen,
R5is hydrogen or a methyl group, or a mixture thereof,
R29is hydrogen.
The present invention further includes the following compounds:
5- (4-chlorophenyl) -4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -2, 4-dihydro-3H-1, 2, 4-triazol-3-one.
The compounds according to the invention have valuable pharmacological properties and can be used for the prophylaxis and/or treatment of various diseases and disease-inducing conditions in the human and animal body.
The compounds according to the invention are potent selective bis V1a/V2 receptor antagonists which inhibit anti-diuretic hormone activity in vitro and in vivo.
The compounds according to the invention are particularly suitable for the prophylaxis and/or treatment of cardiovascular diseases. In this respect, the following may be mentioned, for example and preferably, as target indications: acute and chronic cardiac insufficiency, arterial hypertension, coronary heart disease, stable and unstable angina pectoris, myocardial ischemia, myocardial infarction, shock, arteriosclerosis, atrial and ventricular arrhythmias, transient and ischemic attacks, stroke, inflammatory cardiovascular diseases, peripheral and cardiovascular diseases, peripheral circulation disorders, pulmonary hypertension of the arteries, spasms of the coronary and peripheral arteries, thrombosis, thromboembolic diseases, edema formation such as pulmonary edema, cerebral edema, nephrogenic edema or cardiac insufficiency-related edema, and restenosis, for example after thrombolytic therapy, Percutaneous Transluminal Angioplasty (PTA), transluminal coronary angioplasty (PTCA), heart transplantation and bypass surgery.
In the sense of the present invention, the term cardiac insufficiency also includes more specific or related forms of diseases, such as right heart insufficiency, left heart insufficiency, general insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, congenital ventricular defect, heart valve defect, cardiac insufficiency with heart valve defect, mitral stenosis, mitral insufficiency, aortic stenosis, aortic insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary stenosis, pulmonary insufficiency, combined heart valve defect, myocarditis (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic cardiac insufficiency, alcoholism cardiomyopathy, cardiac storage diseases, cardiac insufficiency and cardiac diastolic and systolic cardiac insufficiency.
Furthermore, the compounds according to the invention are suitable as diuretics for the treatment of edematous diseases and electrolyte disorders, in particular hypercapacitative hyponatremia and hyponatremia normovolema.
The compounds according to the invention are also suitable for the prophylaxis and/or treatment of polycystic kidney disease (PCKD) and of syndromes which are deficient in ADH secretion (antidiuretic hormone secretion dysfunction syndrome, SIADH).
In addition, the compounds according to the invention can be used for the prevention and/or treatment of cirrhosis, ascites, diabetes and diabetic complications, such as neuropathy and nephropathy, acute and chronic renal failure and chronic renal insufficiency.
Furthermore, the compounds according to the invention are suitable for the prophylaxis and/or treatment of central nervous disorders such as anxiety disorders and depression, glaucoma and cancer, in particular lung tumors.
Furthermore, the compounds according to the invention can be used for the prevention and/or treatment of inflammatory diseases, asthma diseases, chronic-obstructive airways diseases (COPD), pain disorders, prostatic hypertrophy, incontinence, cystitis, overactive bladder diseases, kidney diseases such as pheochromocytoma and renal stroke, domestic diseases such as Crohn's disease and diarrhea, or menstrual disorders such as dysmenorrhea, or endometriosis.
An additional object of the present invention is the use of the compounds according to the invention for the treatment and/or prevention of diseases, in particular of the above-mentioned diseases.
A further object of the present invention is the use of the compounds of the invention in a method for the treatment and/or prophylaxis of acute and chronic cardiac insufficiency, high and normal volume hyponatremia, cirrhosis of the liver, ascites, oedema, and symptoms of inadequate ADH secretion (antidiuretic hormone secretion dysfunction syndrome, SIADH).
An additional object of the present invention is the use of the compounds according to the invention for the production of medicaments for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases.
An additional object of the present invention is a method for the treatment and/or prevention of diseases, in particular of the above-mentioned diseases, using an effective amount of at least one compound according to the invention.
The compounds according to the invention can be used alone or, if necessary, in combination with other active substances. An additional object of the invention is a medicament containing at least one compound according to the invention and one or more further active substances, in particular for the treatment and/or prophylaxis of the abovementioned diseases. As active substances suitable for this purpose in combination, mention may be made, for example and preferably, of the following:
Organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, heartache, vaso-sensitivity or SIN-1, and inhaled NO;
diuretics, especially cyclic diuretics and thiazides and thiazide diuretics;
positive inotropic active compounds, such as cardiac glycosides (digoxin), and beta-adrenergic and dopaminergic agonists, such as isoproterenol, epinephrine, norepinephrine, dopamine, and dobutamine;
compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and/or cyclic adenosine monophosphate (cAMP), for example inhibitors of Phosphodiesterase (PDE) 1, 2, 3, 4 and/or 5, in particular PDE 5 inhibitors such as viagra (sildenafil), alda (vardenafil) and rhinoceros (tadalafil), and PDE 3 inhibitors such as thalidone and fenpropiophenone;
natriuretic peptides such as "atrial natriuretic peptide" (ANP), "B-type natriuretic peptide" or "brain natriuretic peptide" (BNP, nesiritide), "C-type natriuretic peptide" (CNP) and kidney-derived natriuretic peptide (urodizatin);
calcium sensitizers, such as and preferably levosimendan (levosimendan);
NO-and blood-independent activators of guanylate cyclase, particularly the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;
NO-independent, but blood-dependent stimulators of guanylate cyclase, such as guanylate cyclase agonists (riociguat) and the compounds described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451, among others;
an inhibitor of Human Neutrophil Elastase (HNE), such as sevelalestat or DX-890;
compounds which inhibit the signal transduction cascade, such as tyrosine kinase inhibitors, in particular sorafenib (sorafenib), imatinib (imatinib), gefitinib (gefitinib) and erlotinib (erlotinib);
compounds which influence the energy metabolism of the heart, such as and preferably etomoxir, dichloroacetate, ranolazine or trimethoprim;
drugs having an antithrombotic effect, such as and preferably platelet aggregation inhibitors, anticoagulants or fibrinolytic (fibrinolytic) substances;
blood pressure lowering active substances such as and preferably calcium antagonists, angiotensin AII antagonists, ACE inhibitors, inhibitors of anti-oxidants (vasopeptidase), inhibitors of neutral endopeptidase, endothelin antagonists, renin inhibitors, alpha receptor blockers, beta receptor blockers, mineralocorticoid receptor antagonists and rho-kinase inhibitors; and/or
Active substances which improve fat metabolism, such as and preferably thyroid receptor agonists, cholesterol synthesis inhibitors such as and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric gallic acid adsorbents, gallic acid reabsorption inhibitors and lipoprotein (a) antagonists.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with (co-administered with) diuretics, such as, and preferably, furosemide, bumetanide, torsemid, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylchlorothiazide, polythiazide, trichlorthiazide, chloroacetone, indapamide, toluquinazolone, quinazolone, acetazolamide, dichloramide, glycerol, isosorbide, mannitol, amiloride or triamcinolone acetonide.
Drugs having an antithrombotic effect are understood as preferably meaning compounds selected from platelet aggregation inhibitors, anticoagulants or fibrinolytic substances.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with platelet aggregation inhibitors, such as and preferably aspirin, clopidogrel, ticlopidine or dipyridamole.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with thrombin inhibitors, for example and preferably ximegatran (ximelagatran), melagatran (melagatran), bivalirudin (bivalirudin) or clexase (clexane).
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPIIb/IIIa antagonist, for example and preferably tirofiban (tirofiban) or abciximab (abciximab).
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a factor Xa inhibitor, such as, and preferably, rivaroxaban (BAY 59-7939), DU-176b, apixaban (apixaban), omixaban (otamixaxban), fidaxaban (fidaxaban), rizaxaban (razaxaban), fondaparinux (fondaparinux), epixaparin (idraparinux), PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or a Low Molecular Weight (LMW) heparin derivative.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, for example and preferably coumarin.
Blood pressure lowering agents are understood as preferably referring to compounds selected from the following: calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasoactive peptidase inhibitors, inhibitors of neutral endopeptidase, endothelin antagonists, renin inhibitors, alpha receptor blockers, beta receptor blockers, mineralocorticoid receptor antagonists, rho-kinase inhibitors and diuretics.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium antagonist, such as and preferably nifedipine, amlodipine, verapamil or diltiazem.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin AII antagonist, such as and preferably losartan (losartan), candesartan (candisartan), valsartan (valsartan), telmisartan (telmisartan), or emblosartan (embusartan).
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin ACE antagonist, such as and preferably enalapril (enalapril), captopril (captopril), lisinopril (lisinopril), ramipril (ramipril), delapril (delapril), fosinopril (fosinopril), quinapril (quinapril), perindopril (perindopril) or perindopril (trandopril).
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with vasoactive peptidase inhibitors or Neutral Endopeptidase (NEP) inhibitors.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelin antagonist, such as and preferably bosentan (bosentan), darussan (daursentan), ambrisentan (ambrisentan) or sitaxsentan (sitaxsentan).
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with renin inhibitors, for example and preferably aliskiren (aliskiren), SPP-600 or SPP-800.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an alpha-1 receptor blocker, for example and preferably prazosin.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a beta-receptor blocker, for example and preferably propranolol, atenolol, timolol, propranolol, pentabutandin, clodronol, propranolol, nadolol, meindolol, carbazolol, mestranol, metoprolol, ditalol, thalidomide, bisoprolol, quinolol, esmolol, labetalol, cadiolol, adaprolol (adaprolol), landiolol (landiolol), nebivolol (nebivolol), epanolol (epanolol) or bucindolol.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a mineral corticoid receptor antagonist, for example and preferably spironolactone, eplerenone, canrenone or potassium pernolide.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with rho-kinase inhibitors, such as and preferably fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049-.
Fat metabolism-modifying agents are understood as preferably referring to compounds selected from the following: CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, polymeric gallic acid adsorbents, gallic acid reabsorption inhibitors, lipase inhibitors and lipoprotein (a) antagonists.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, such as and preferably Dacetrapib (dalcetrapib), BAY 60-5521, anacetrapib or CETP-vaccine (CETi-1).
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thyroid receptor agonist, for example and preferably D-tetraiodothyronine (D-thyroxine), 3,5,3' -triiodothyronine (T3), CGS 23425 or axitrome (CGS 26214).
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor selected from statins (statins), for example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, for example and preferably BMS-188494 or TAK-475.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACAT inhibitor, for example and preferably avasimibe (avasimibe), melinamide (melinamide), antipab (pactamide), eflucimibe or SMP-797.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an MTP inhibitor, such as and preferably impliptatide, BMS-201038, R-103757 or JTT-130-.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-gamma agonist, for example and preferably pioglitazone or rosiglitazone (rosiglitazone).
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-delta agonist, for example and preferably GW-501516 or BAY 68-5042.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with cholesterol absorption inhibitors, for example and preferably ezetimibe (ezetimibe), tiquinane (tiqueside) or pamaquide (pamaquoside).
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, for example and preferably orlistat (orlistat).
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a polymeric gallic acid adsorbent, e.g. and preferably cholestyramine, colestipol, colesevolvam, cholestagel or colestimid.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an inhibitor of gallic acid reabsorption, such as, and preferably, an ASBT (= IBAT) inhibitor, such as AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635-.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipoprotein (a) antagonist, for example and preferably gemcabene calcium (CI-1027) or niacin.
Further objects of the invention are medicaments which comprise at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable additives, and the use of the medicaments for the above-mentioned purposes.
The compounds according to the invention can act systemically and/or locally. For this purpose, they can be administered in a suitable manner, for example orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally or otically or as an implant or stent.
For these administration routes, the compounds according to the invention can be administered in a suitable administration form.
For oral administration, those administration forms which act according to the prior art, which release the compounds of the invention rapidly and/or in a modified manner, contain the compounds of the invention in crystalline and/or amorphized and/or dissolved form, for example tablets (uncoated or coated tablets, for example with a gastric-resistant or delayed-dissolving or insoluble coating which controls the release of the compounds of the invention), tablets or films/flakes which disintegrate rapidly in the oral cavity, films/lyophilisates, capsules (for example hard or soft gelatin capsules), dragees, granules, powders, emulsions, suspensions, aerosols or solutions.
Parenteral administration can be carried out omitting an absorption step (e.g., intravenous, intra-arterial, intracardiac, intraspinal or intralumbar administration) or including an absorption step (e.g., intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal administration). Suitable administration forms for parenteral administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilized powders or sterile powders.
For other routes of administration, for example, inhalation formulations (including powder inhalers and nebulizers), nasal drops, solutions or sprays; lingually, sublingually or buccally administered tablets, films/wafers or capsules, suppositories, oral or ocular preparations, vaginal capsules, aqueous suspensions (lotions, oscillatable mixtures), lipophilic suspensions, ointments, creams, transdermal dosage forms (e.g. patches), emulsions, slurries, foams, dusting powders, implants or stents are suitable.
Oral or parenteral administration, especially oral and intravenous administration, is preferred.
The compounds according to the invention can be converted into the administration forms described. This can be carried out in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable additives. Such additives include carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifying and dispersing agents or wetting agents (e.g. sodium lauryl sulphate, polyoxysorbitan oleate), binders (e.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin), stabilisers (e.g. antioxidants such as, for example, ascorbic acid), colours (e.g. inorganic pigments such as iron oxides) and flavouring or odour modifiers.
In general, in order to achieve effective results in parenteral administration, it has been found advantageous to administer a dose of about 0.001-10 mg/kg, preferably about 0.01-1 mg/kg of body weight. In oral administration, the dose is about 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg and quite particularly preferably 0.1 to 10 mg/kg of body weight.
Nevertheless, deviations from this amount are sometimes required, i.e. depending on the body weight, the route of administration, the individual response to the active substance, the nature of the formulation and the time or interval of administration. It is therefore sufficient in some cases to cope with this with less than the above-mentioned minimum amount, while in other cases the upper limit must be exceeded. If administered in larger amounts, these need to be divided into several administrations a day.
The following practical examples are provided to illustrate the present invention. The present invention is not limited to these examples.
Unless otherwise indicated, the percentages stated in the following tests and examples are percentages by weight, parts are parts by weight, and the solvent ratio, dilution ratio and concentration information on the liquid/liquid solution are each based on volume.
A. Examples
Abbreviations：
BOC tert-butoxycarbonyl
CI chemical ionization (in MS)
DCI direct chemical ionization (in MS)
DME 1, 2-dimethoxyethane
DMF dimethyl formamide
DMSO dimethyl sulfoxide
EDC N' - (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride
eq. equivalent
ESI electrospray ionization (in MS)
GC/MS gas chromatography-coupled mass spectrometry
sat, saturated
h hours
HOBt 1-hydroxy-1H-benzotriazole hydrate
HPLC high pressure, high performance liquid chromatography
HV high vacuum
LC/MS liquid chromatography-coupled mass spectrometry
Lithium LDA diisopropylamide
LiHMDS lithium hexamethyldisilazane
min(s) min
MS mass spectrometry
MTBE methyl tert-butyl ether
NMR nuclear magnetic resonance spectroscopy
rac racemates/racemates
RfRetention factors (on silica gel in thin layer chromatography)
RT Room temperature
RtRetention time (in HPLC)
THF tetrahydrofuran
TMOF Proformic acid trimethyl ester
UV ultraviolet spectroscopy
v/v (of solution) volume-to-volume ratio.
LC/MS ， HPLC And GC/MS method of producing a composite material：
Method of producing a composite material 1 ：MS instrument type: micromass ZQ; HPLC instrument type: waters Alliance 2795; a chromatographic column: phenomenex Synergi 2.5. mu.MAX-RP 100A Mercury, 20 mm. times.4 mm; mobile phase A: 1 l of water + 0.5 ml of 50% strength formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% strength formic acid; gradient: 0.0 min 90% a → 0.1 min 90% a → 3.0 min 5% a → 4.0 min 5% a → 4.01 min 90% a; flow rate: 2 ml/min; oven: 50 ℃; and (4) UV detection: 210 nm.
Method of producing a composite material 2 ：MS instrument type: waters (Micromass) Quattro Micro; HPLC instrument type: agilent 1100 series; a chromatographic column: thermo Hypersil GOLD 3 μ 20 x 4 mm; eluent A: 1 l of water + 0.5 ml of 50% strength formic acid; eluent B: 1 l acetonitrile + 0.5 ml 50% strength formic acid; gradient: 0.0 min 100% a → 3.0 min 10% a → 4.0 min 10% a → 4.01 min 100% a (flow 2.5 ml) → 5.00 min 100% a; oven: 50 ℃; flow rate: 2 mL/min; and (4) UV detection: 210 nm.
Method of producing a composite material 3 ：The instrument comprises the following steps: micromass Quattro Premier with Waters UPLC Acquity; a chromatographic column: thermo Hypersil GOLD 1.9 μ, 50X 1 mm; eluent A: 1 l of water + 0.5 ml of 50% strength formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% strength formic acid; gradient: 0.0 min 90% a → 0.1 min 90% a → 1.5 min 10% a → 2.2 min 10% a; oven: 50 ℃; flow rate: 0.33 ml/min; and (4) UV detection: 210 nm.
Method of producing a composite material 4 ：The instrument comprises the following steps: watersACQUITY SQD UPLC System; a chromatographic column: waters Acquity UPLC HSS T31.8 μ 50 × 1 mm; eluent A: 1 l of water + 0.25 ml of 99% strength formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% strength formic acid; gradient: 0.0 min 90% a → 1.2 min 5% a → 2.0 min 5% a; oven: 50 ℃; flow rate: 0.40 ml/min; and (4) UV detection: 210-400 nm.
Method of producing a composite material 5 ；The instrument comprises the following steps: waters ACQUITY SQD UPLC System; a chromatographic column: waters Acquity UPLC HSS T31.8 μ 50 × 1 mm; eluent A: 1 l of water + 0.25 ml of 99% strength formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% strength formic acid; gradient: 0.0 min 90% a → 1.2 min 5% a → 2.0 min 5% a; oven: 50 ℃; flow rate: 0.40 ml/min; and (4) UV detection: 210-400 nm.
Method of producing a composite material 6 ：MS instrument type: micromass ZQ; HPLC instrument type: HP 1100 series; UV DAD; a chromatographic column: phenomenex Gemini 3 mu, 30 mm multiplied by 3.0 mm; eluent A: 1 l of water + 0.5 ml of 50% strength formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% strength formic acid; gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; flow rate: 0.0 min 1 ml/min, 2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50 ℃; and (4) UV detection: 210 nm.
Method of producing a composite material 7 ：MS instrument type: waters ZQ; HPLC instrument type: agilent 1100 series; UV DAD; a chromatographic column: thermo Hypersil GOLD 3 μ 20 mm x 4 mm; eluent A: 1 l of water + 0.5 ml of 50% strength formic acid; eluent B: 1 l acetonitrile + 0.5 ml 50% strength formic acid; gradient: 0.0 min 100% a → 3.0 min 10% a → 4.0 min 10% a → 4.1 min 100% flow rate: 2.5 ml/min; oven: 55 ℃; the flow rate is 2 ml/min; and (4) UV detection: 210 nm.
Method of producing a composite material 8 ( Chiral preparation HPLC) ：With the selection agent Poly- (N-methacryloyl-D-leucine-dicyclopropylmethylamide)) A basic chiral stationary silica gel phase; a chromatographic column: 670 mm x 40 mm, flow rate: 80 ml/min, temperature: 24 ℃; UV detector 260 nm. Eluent: isohexane/ethyl acetate 30: 70.
Method of producing a composite material 8a ：Eluent: isohexane/ethyl acetate 10:90 (v/v); flow rate: 50 ml/min.
Method of producing a composite material 9 ( Chiral analysis HPLC) ：A chiral stationary silica gel phase based on the selector Poly- (N-methacryloyl-D-leucine-dicyclopropylmethylamide); a chromatographic column: 250 mm x 4.6 mm, eluent ethyl acetate 100%, flow rate: 1 ml/min, temperature: 24 ℃; UV detector 265 nm.
Method of producing a composite material 10 ( Preparation property HPLC) ：A chromatographic column: from-Sil 120 ODS-4HE, 10 μm, SNo. 3331, 250 mm x 30 mm. 0.1% aqueous formic acid, eluent B: acetonitrile; flow rate: 50 ml/min program: 0-3 minutes: 10% of B; 3-27 minutes: gradient-95% B; 27-34 minutes: 95% of B; 34.01-38 minutes: 10% of B.
Method of producing a composite material 11 ( Chiral preparation HPLC) ：Stationary phase Daicel Chiralcel OD-H, 5 μm, column: 250 mm multiplied by 20 mm; temperature: RT; and (4) UV detection: 230 nm. Various eluents:
method of producing a composite material 11a ：Eluent: isohexane/isopropanol 70:30 (v/v); flow rate: 20 ml/min
Method of producing a composite material 11b ：Eluent: isohexane/isopropanol 50:50 (v/v); flow rate: 18 ml/min
Method of producing a composite material 11c ：Eluent: isohexane/methanol/ethanol 70:15: 15; (v/v/v); flow rate: 20 ml/min
Method of producing a composite material 11d ：Eluent: isohexane/isopropanol 75:25 (v/v); flow rate: 15 ml/min
Method of producing a composite material 12 ( Chiral analysis HPLC) ：Stationary phase Daicel Chiralcel OD-H, column: 250 mm × 4 mm; flow rate: 1 ml/min; temperature: RT; and (4) UV detection: 230 nm. Various eluents:
method of producing a composite material 12a ：Eluent: isohexane/isopropanol 1:1 (v/v);
method of producing a composite material 12b ：Eluent: isohexane/methanol/ethanol 70:15:15 (v/v/v)
Method of producing a composite material 12c ：Eluent: isohexane/isopropanol 75:25 (v/v);
method of producing a composite material 13 ( Chiral preparation HPLC) ：A chiral stationary silica phase based on the selector poly (N-methacryloyl-D-leucine-dicyclopropylmethylamide); a chromatographic column: 600 mm x 30 mm, eluent: step gradient ethyl acetate/methanol 1:1 (0-17 min) → ethyl acetate (17.01 min-21 min) → ethyl acetate/methanol 1:1(21.01 min-25 min); flow rate: 80 ml/min, temperature: 24 ℃; UV detector: 265 nm.
Method of producing a composite material 13a ：Same as method 13, but eluent: 0-5.08 min isohexane/ethyl acetate 10:90, then ethyl acetate 100%
Method of producing a composite material 13b ：Eluent: 100% Ethyl acetate
Method of producing a composite material 14 ( Chiral analysis HPLC) ：Same as method 9, but flow rate: 2 ml/min.
Method of producing a composite material 15 ( Chiral preparation HPLC) ：A chiral stationary silica gel phase based on the selector Poly- (N-methacryloyl-L-isoleucine-3-pentylamide); a chromatographic column: 430 mm x 40 mm, flow rate: 80 ml/min, temperature: 24 ℃; UV detector: 260 nm. Various eluents:
Method of producing a composite material 15a ：100% Ethyl acetate
Method of producing a composite material 15b ；Isohexane/ethyl acetate 10:90
Method of producing a composite material 16 ( Chiral analysis HPLC) ：A chiral stationary silica gel phase based on the selector Poly- (N-methacryloyl-L-isoleucine-3-pentylamide); a chromatographic column: 250 mm x 4.6 mm, eluent 100% ethyl acetate, flow rate: 2 ml/min, temperature: 24 ℃; UV detector 265 nm.
Method of producing a composite material 17 ( Chiral preparation HPLC) ：A chiral stationary silica gel phase based on the selector Poly- (N-methacryloyl-L-leucine- (+) -3-pinane methylamide); a chromatographic column: 600 mm x 30 mm, flow rate: 80 ml/min, temperature: 24 ℃; UV detector 265 nm. Various eluents:
method of producing a composite material 17a ：Isohexane/ethyl acetate 20:80
Method of producing a composite material 17b ：Isohexane/ethyl acetate 30:70
Method of producing a composite material 17c ：Isohexane/ethyl acetate 50:50
Method of producing a composite material 17d ：100% Ethyl acetate
Method of producing a composite material 17e ：Isohexane/ethyl acetate 40:60
Method of producing a composite material 17f ：Isohexane/ethyl acetate 10:90
Method of producing a composite material 18 ( Chiral analysis HPLC) ：A chiral stationary silica gel phase based on the selector poly (N-methacryloyl-L-leucine- (+) -3-pinane methylamide); a chromatographic column: 250 mm x 4.6 mm, temperature: 24 ℃; UV detector 265 nm.
Method of producing a composite material 18a ：Eluent: isohexane/ethyl acetate 50:50, flow rate: 2 ml/min.
Method of producing a composite material 18b ：Eluent: 100% ethyl acetate, flow rate: 2 ml/min.
Method of producing a composite material 18c ：Eluent: 100% ethyl acetate, flow rate: 1 ml/min.
Method of producing a composite material 19 ( Preparation property HPLC) ：A chromatographic column Grom-Sil 120 ODS-4HE 10 μm, 250 mm x 30 mm; eluent: a = water, B = acetonitrile; gradient: 0.0 min 10% B, 3 min 10% B, 30 min 95% B, 42 min 95% B, 42.01 min 10% B, 45 min 10% B; flow rate: 50 ml/min; column temperature: room temperature; and (4) UV detection: 210 nm.
Method of producing a composite material 20 ( Preparation property HPLC) ：A chromatographic column: reprosil C18, 10 μm, 250 mm x 30 mm; eluent A: 0.1% aqueous formic acid, eluent B: methanol; flow rate: 50 ml/min.; the procedure is as follows: 0-4.25 minutes: 90% A/10% B; 4.26-4.5 min: gradient-60% B; 4.5-11.5 min: gradient-80% B; 11.51-17 minutes: gradient-100% B; 17.01-19.5 min 100% B; gradient-40% B from 19.51 to 19.75; 19.76-20.51 min: 60% A/40% B.
Method of producing a composite material 21 ( Chiral preparation HPLC) ：Stationary phase Daicel Chiralpak AS-H, 5 μm, column: 250 mm multiplied by 20 mm; temperature: RT; and (4) UV detection: 230 nm; flow rate: 20 ml/min; various eluents:
method of producing a composite material 21a ：Eluent: isohexane/isopropanol 65:35
Method of producing a composite material 21b ：Eluent: isohexane/isopropanol 50: 50; flow rate 20 ml/min
Method of producing a composite material 22 ( Chiral analysis HPLC) ：Stationary phase Daicel Chiralpak AD-H5 μm, column: 250 mm × 4 mm; and (4) UV detection: 220 nm; flow rate: 1 ml/min; eluent: isohexane/isopropanol 50: 50.
Method of producing a composite material 23 ( Preparation property HPLC) ：A chromatographic column: YMC ODS C18, 10 μm, 250 mm. times.30 mm; eluent A: 0.1% aqueous formic acid, eluent B: methanol; flow rate: 50 ml/min.; the procedure is as follows: 0-4.25 minutes: 90% A/10% B; 4.26-4.5 min: gradient-60% B; 4.5-11.5 min: gradient-80% B; gradient-100% B over 11.51-17 min; 17.01-19.5 min 100% B; gradient-40% B from 19.51 to 19.75; 19.76-20.51 min: 60% A/40% B.
Method of producing a composite material 24 ( Chiral preparation HPLC) ：Chiral stationary silica gel phase based on the selector Poly- (N-methacryloyl-L-leucine-tert-butylamide) on an irregular (graded) vinyl silica gel column; 250 mm x 20 mm, flow rate: 45 ml/min, temperature: RT; UV detector 260 nm. Various eluents:
method of producing a composite material 24a ：Isohexane/ethyl acetate 10:90
Method of producing a composite material 24b ：Isohexane/ethylEthyl acid ester 20:80
Method of producing a composite material 25 ( Chiral analysis HPLC) ：Chiral stationary silica gel phase based on the selector Poly- (N-methacryloyl-L-leucine-tert-butylamide) on an irregular (graded) vinyl silica gel column; 250 mm x 4 mm, flow rate: 1.5 ml/min, temperature: RT; UV detector 260 nm. Various eluents:
Method of producing a composite material 25a ：Isohexane/ethyl acetate 20:80
Method of producing a composite material 25b ：Isohexane/ethyl acetate 30:70
Method of producing a composite material 26 ( Chiral preparation HPLC) ：Stationary phase Daicel Chiralpak AD-H, 5 μm, column: 250 mm multiplied by 20 mm; temperature: RT; and (4) UV detection: 230 nm; flow rate: 20 ml/min; various eluents:
method of producing a composite material 26a ：Isohexane/isopropanol 65:35 (v/v)
Method of producing a composite material 26b ：Isohexane/isopropanol 80:20 (v/v)
Method of producing a composite material 26c ：Isohexane/isopropanol 50:50 (v/v)
Method of producing a composite material 26d ：Isohexane/ethanol 65:35 (v/v)
Method of producing a composite material 26e ：Isohexane/ethanol 50:50 (v/v)
Method of producing a composite material 27 ( Chiral analysis HPLC) ：Stationary phase Daicel Chiralpak AD-H, 5 μm, column: 250 mm x 4 mm; temperature: 30 ℃; and (4) UV detection: 230 nm; flow rate: 1 ml/min; various eluents:
method of producing a composite material 27a ：Isohexane/isopropanol 50:50 (v/v)
Method of producing a composite material 27b ：Isohexane/isopropanol 60:40 (v/v)
Method of producing a composite material 27c ：Isohexane/isopropanol/20% trifluoroacetic acid 75:24:1 (v/v/v)
Method of producing a composite material 27d ：Isohexane/ethanol 50:50 (v/v)
Method of producing a composite material 28 ( Chiral preparation HPLC) ：A chiral stationary silica gel phase based on the selector Poly- (N-methacryloyl-L-leucine- (+) -3-pinane methylamide); a chromatographic column: 600 mm x 40 mm, temperature: RT; UV detector 265 nm; eluent: isohexane/isopropanol 80:20 (v/v); flow rate: 50 ml/min.
Method of producing a composite material 29 ( Chiral preparation HPLC) ：Chiral stationary phase based on selection agent Poly- (N-methacryloyl-D-valine-3-pentylamide) on spherical hydrosulfuryl silica gel; a chromatographic column: 250 mm x 20 mm, temperature: RT; UV detector 260 nm; eluent: isohexane/isopropanol 60:40 (v/v); flow rate: 20 ml/min.
Method of producing a composite material 30 ( Chiral preparation HPLC) ：Chiral stationary phase based on selection agent Poly- (N-methacryloyl-D-valine-3-pentylamide) on spherical hydrosulfuryl silica gel; a chromatographic column: 250 mm x 4 mm, temperature: RT; UV detector 260 nm; eluent: isohexane/isopropanol 60:40 (v/v); flow rate: 1.5 ml/min.
Method of producing a composite material 31 (LC-MS) ：MS instrument type: waters ZQ; HPLC instrument type: agilent 1100 series; UV DAD; a chromatographic column: thermo Hypersil GOLD 3 μ 20 mm x 4 mm; eluent A: 1 l of water + 0.5 ml of 50% strength formic acid; eluent B: 1 l acetonitrile + 0.5 ml 50% strength formic acid; gradient: 0.0 min 100% a → 3.0 min 10% a → 4.0 min 10% a → 4.1 min 100% flow rate: 2.5 ml/min; oven: 55 ℃; the flow rate is 2 ml/min; and (4) UV detection: 210 nm.
Method of producing a composite material 32 ( Preparation property HPLC) ：A chromatographic column: reprosil C18, 10 μm, 250 mm x 40 mm; eluent A: 0.1% aqueous formic acid, eluent B: acetonitrile; flow rate: 50 ml/min.; the procedure is as follows: 0-6 minutes: 90% A/10% B; 6-40 minutes: gradient-95% B; 40-53 minutes: 5% A/95% B; 53.01-54 min: gradient-10% B; 54.01-57 min: 90% A/10% B.
Method of producing a composite material 33 ( Chiral preparation HPLC) ：A chiral stationary phase based on the selection agent poly (N-methacryloyl-D-leucine-dicyclopropylmethylamide) on a spherical vinyl silica gel; a chromatographic column: 670 mm x 40 mm, flow rate: 80 ml/min, temperature: 24 ℃; UV detector 265 nm; eluent: 0-7.75 minutes: 100% ethyl acetate; 7.76 min-12.00 min: 100% methanol; 12.01 min-16.9 min: 100% ethyl acetate.
Method of producing a composite material 34 ：Chiral analytical HPLC under SFC (supercritical fluid chromatography) conditions: a chiral stationary phase based on the selection agent poly (N-methacryloyl-D-leucine-dicyclopropylmethylamide) on a spherical vinyl silica gel; a chromatographic column: 250 mm x 4.6 mm, temperature: 35 ℃, eluent: CO 22Methanol 67: 33; pressure: 120 bar, flow rate: 4 ml/min, UV detector 250 nm.
Starting compounds and intermediates:
example 1A
Ethyl N- ({2- [ (4-chlorophenyl) carbonyl ] hydrazino } carbonyl) glycinate
A suspension of 12.95 g (75.9 mmol) of 4-chlorobenzohydrazide in 50 ml of dry THF is introduced at 50 ℃ and a solution of 10.0 g (77.5 mmol) of ethyl 2-isocyanatoacetate in 100 ml of dry THF is added dropwise. A solution is formed first and then a precipitate is generated. After the end of the addition, the mixture was stirred at 50 ℃ for a further 2 hours and then left to stand at room temperature overnight. The crystals are isolated by filtration, washed with a little ether and then dried in HV. This gives 21.43 g (89% of theory) of the title compound.
LC/MS [ method 1]: Rt = 1.13 min; m/z = 300 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 10.29 (s, 1H), 8.21 (s, 1H), 7.91 (d, 2H), 7.57 (d, 2H), 6.88 (br.s, 1H), 4.09 (q, 2H), 3.77 (d, 2H), 1.19 (t, 3H)。
Example 2A
[3- (4-chlorophenyl) -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl ] acetic acid
21.43 g (67.93 mmol) of the compound from example 1A were admixed with 91 ml of 3N aqueous sodium hydroxide solution and then heated at reflux overnight. After cooling to room temperature, the mixture was adjusted to a pH of 1 by slow addition of about 20% strength hydrochloric acid. The precipitated solid was isolated by filtration, washed with water, and then dried at 60 ℃ under reduced pressure. Yield: 17.55 g (90% of theory, about 88% purity).
LC/MS [ method 1]: Rt = 0.94 min; m/z = 254 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 13.25 (br.s, 1H), 12.09 (s, 1H), 7.65-7.56 (m, 4H), 4.45 (s, 2H)。
Example 3A
5- (4-chlorophenyl) -4- (3,3, 3-trifluoro-2-oxopropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one (or, hydrated form: 5- (4-chlorophenyl) -4- (3,3, 3-trifluoro-2, 2-dihydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one)
5 g (16.36 mmol) of the compound from example 2A were dissolved in 200 ml of pyridine under argon and admixed with 17.18 g (81.8 mmol) of trifluoroacetic anhydride. The temperature was increased to about 35 ℃. After 30 minutes, the pyridine was removed on a rotary evaporator and the residue was diluted with 1.5L of 0.5N hydrochloric acid. The mixture was heated to 70 ℃ and then filtered while hot. The solid was washed with a small amount of water. The whole filtrate was extracted three times with ethyl acetate. The combined organic phases were washed with water, then with saturated aqueous sodium bicarbonate solution, then with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent was removed on a rotary evaporator. The residue is dried under HV. Yield: 3.56 g (68% of theory) of the title compound in hydrated form.
LC/MS [ method 1]: Rt = 1.51 min; m/z = 306 (M+H)+And 324 (M + H)+ (Ketone and hydrate)
1H NMR (DMSO-d6, 400 MHz): δ = 12.44 (s, 1H), 7.72 (d, 2H), 7.68 (br.s, 2H), 7.61 (d, 2H), 3.98 (s, 2H)。
Example 4A
5- (4-chlorophenyl) -4- (3,3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one
3.56 g (11 mmol) of the compound from example 3A are dissolved in 100 ml of methanol and admixed with 3.75 g (99 mmol) of sodium borohydride under ice cooling (gas evolution). After 1.5 hours, 200 ml of 1M hydrochloric acid were slowly added. The methanol was removed on a rotary evaporator and the residue was diluted with 500 ml of water and then extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent was removed on a rotary evaporator. The residue is dried under HV. This gives 3.04 g (90% of theory) of the title compound.
LC/MS [ method 2 ]]: Rt = 1.80 min; m/z = 308 (M+H)+。
1H NMR (DMSO-d6, 400 MHz): δ = 12.11 (s, 1H), 7.75 (d, 2H), 7.62 (d, 2H), 6.85 (d, 1H), 4.34-4.23 (m, 1H), 3.92 (dd, 1H), 3.77 (dd, 1H)。
Example 5A
[3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoro-2-hydroxypropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid methyl ester
3.04 g (9.9 mmol) of the compound from example 4A are dissolved in 100 ml of acetonitrile and admixed with 1.07 g (9.9 mmol) of methyl chloroacetate, 2.73 g (19.8 mmol) of potassium carbonate and a small spoon of potassium iodide. The reaction mixture was heated at reflux for 1 hour, cooled to room temperature, and then filtered. The filtrate is freed of volatile constituents on a rotary evaporator and the residue is then dried in HV. Yield: 3.70 g (89% of theory) of the title compound in about 90% purity.
LC/MS [ method 3 ]]: Rt = 1.10 min; m/z = 380 (M+H)+。
1H NMR (DMSO-d6, 400 MHz): δ = 7.78 (d, 2H), 7.64 (d, 2H), 6.91 (d, 1H), 4.72 (s, 2H), 4.16-4.35 (m, 1H), 3.99 (dd, 1H), 3.84 (dd, 1H), 3.70 (s, 3H)。
Example 5A the racemic compound can be resolved into its enantiomers, example 6A and example 7A, by preparative HPLC on a chiral phase, which have already been described in WO 2007/134862.
A chromatographic column: a chiral silica gel phase based on the selector poly (N-methacryloyl-L-isoleucine-3-pentylamide), 430 mm by 40 mm; eluent: step gradient isohexane/ethyl acetate 1:1 → ethyl acetate → isohexane/ethyl acetate 1: 1; flow rate: 50 ml/min; temperature: 24 ℃; and (4) UV detection: 260 nm.
This gave, from 3.6 g of the racemic compound of example 5A (dissolved in 27 ml of ethyl acetate and 27 ml of isohexane and separated into three fractions by chromatography), 1.6 g of enantiomer 1 (which eluted first) (example 6A), and 1.6 g of enantiomer 2 (which eluted subsequently) (example 7A).
Example 6A
{3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetic acid methyl ester (enantiomer I)
The enantiomer eluting first in the racemate resolution of example 5A.
Rt = 3.21 min [ column: a chiral silica gel phase based on the selector poly (N-methacryloyl-L-isoleucine-3-pentylamide), 250 mm × 4.6 mm; eluent: isohexane/ethyl acetate 1: 1; flow rate: 1 ml/min; and (4) UV detection: 260 nm ].
Example 7A
{3- (4-chlorophenyl) -5-oxo-4- [ (2R) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetic acid methyl ester (enantiomer II)
The last eluting enantiomer from the racemate resolution of example 5A.
Rt = 4.48 min [ column: a chiral silica gel phase based on the selector poly (N-methacryloyl-L-isoleucine-3-pentylamide), 250 mm × 4.6 mm; eluent: isohexane/ethyl acetate 1: 1; flow rate: 1 ml/min; and (4) UV detection: 260 nm ].
Example 8A
{3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetic acid
The enantiomerically pure ester of example 6A (1.6 g, 4.21 mmol) was dissolved in 77 ml of methanol and admixed with 17 ml of 1M aqueous lithium hydroxide. The mixture was stirred at room temperature for 1 hour and then concentrated on a rotary evaporator. The residue is diluted with 100 ml of water and then acidified with 1N hydrochloric acid to a pH of 1-2. The precipitated product was isolated by filtration, washed successively with water and cyclohexane and then blotted dry. After further drying in HV, the title compound (1.1 g, 71% of theory) is obtained.
[α]D 20= 3.4 ° (methanol, c = 0.37 g/100 ml)
LC/MS [ method 1]: Rt = 1.51 min; m/z = 366 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 3.84 (dd, 1H), 4.00 (dd, 1H), 4.25 (m, 1H), 4.58 (s, 2H), 6.91 (d, 1H), 7.63 (d, 2H), 7.78 (d, 2H), 13.20 (br. s, 1H)。
Example 9A
{3- (4-chlorophenyl) -5-oxo-4- [ (2R) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetic acid
The title compound was obtained from example 7A in the same manner as in example 8A.
[α]D 20= 4.6 ° (methanol, c = 0.44 g/100 ml)
LC/MS [ method 1]: Rt = 1.53 min; m/z = 366 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 3.84 (dd, 1H), 4.00 (dd, 1H), 4.25 (m, 1H), 4.58 (s, 2H), 6.91 (d, 1H), 7.63 (d, 2H), 7.78 (d, 2H), 13.20 (br. s, 1H)。
Example 10A
{ (phenylsulfonyl) [3- (trifluoromethyl) phenyl ] methyl } carbamic acid tert-butyl ester
The amount of tert-butyl carbamate used was 4.49 g (38.29 mmol) and sodium benzenesulfinate 12.57 g (76.57 mmol) were introduced into 110 ml of methanol/water (1:2) and then admixed successively with 10 g (57.43 mmol) of 3- (trifluoromethyl) benzaldehyde and 2.87 ml (76.09 mmol) of formic acid. The mixture was stirred at room temperature for 30 hours. The precipitated product was isolated by filtration, washed successively with water and diethyl ether and then blotted dry. Further drying in HV gave 11.2 g (47% of theory) of the title compound.
1H-NMR (400 MHz, DMSO-d6): δ = 8.86 (d, 1H), 8.14 (s, 1H), 7.99 (d, 1H), 7.88 (d, 2H), 7.80 (d, 1H), 7.71-7.77 (m, 1H), 7.59-7.70 (m, 3H), 6.25 (d, 1H), 1.18 (s, 9H)。
Example 11A
{ (E) - [3- (trifluoromethyl) phenyl ] methylidene } carbamic acid tert-butyl ester
The amount used of 10.88 g (78.73 mmol) of potassium carbonate is dried thermally in HV, cooled to RT under argon and admixed with 127 ml of THF and with 5.45 g (13.12 mmol) of the sulfonyl compound from example 10A. The mixture was stirred under argon at reflux for 16 hours. The mixture was cooled to room temperature and then filtered through Celite (Celite). The latter was rinsed with THF. The entire filtrate is freed of volatile constituents on a rotary evaporator and then in HV to give 3.63 g (100% of theory) of the title compound.
MS [DCI]: m/z = 274 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 8.95 (s, 1H), 8.26 (s, 1H), 8.23 (d, 1H), 8.01 (d, 1H), 7.80 (t, 1H), 1.52 (s, 9H)。
Example 12A
{ 2-Nitro-1- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester
3.6 g (13.17 mmol) of the compound from example 11A are introduced into 26 ml of nitromethane and admixed with 0.69 ml (3.95 mmol) of N, N-diisopropylethylamine. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and then washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution twice each, dried over sodium sulfate and then concentrated on a rotary evaporator. The residue (about 5 g) was dissolved in 15 ml of isopropanol under reflux. After cooling, the precipitated product was isolated by filtration, washed with a small amount of isopropanol and then blotted dry. After further drying in HV, the title compound is obtained: 2.26 g (51% of theory).
LC/MS [ method 3 ]]: Rt = 1.33 min; ES-: m/z = 333 (M-H)-
1H-NMR (400 MHz, DMSO-d6): δ = 7.88 (d, 1H), 7.78 (s, 1H), 7.70 (t, 2H), 7.59-7.65 (m, 1H), 5.31-5.44 (m, 1H), 4.97 (dd, 1H), 4.72-4.82 (m, 1H), 1.36 (s, 9H)。
Example 13A
2-nitro-1- [3- (trifluoromethyl) phenyl ] ethylamine hydrochloride
340 mg (1.02 mmol) of the mixture from example 12A are reacted at room temperature with 6.8 ml of hydrogen chloride in bisThe 4N solution formed in the alkane was combined and then stirred for 1 hour. The reaction mixture is concentrated under reduced pressure and dried in HV. This gives 274 mg (99% of theory) of the title compound.
LC/MS [ method 4 ]]: Rt = 0.54 min; m/z = 235 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 8.98 (br.s, 3H), 8.05 (s, 1H), 7.92 (d, 1H), 7.83 (d, 1H), 7.72 (t, 1H), 5.17-5.36 (m, 3H)。
Example 14A
{ (phenylsulfonyl) [2- (trifluoromethyl) phenyl ] methyl } carbamic acid tert-butyl ester
The title compound (4.09 g, 34% of theory) was obtained from 5.00 g (28.7 mmol) of 2- (trifluoromethyl) benzaldehyde in the same manner as in example 10A.
1H-NMR (400 MHz, DMSO-d6): δ = 8.88 (d, 1H), 8.20 (d, 1H), 7.79-7.88 (m, 5H), 7.68 (q, 3H), 6.32 (d, 1H), 1.19 (s, 9H)。
Example 15A
{ (E) - [2- (trifluoromethyl) phenyl ] methylidene } carbamic acid tert-butyl ester
The title compound was obtained from 4.09 g (9.85 mmol) of the compound of example 14A in the same manner as in example 11A: 2.61 g (97% of theory).
MS [DCI]: m/z = 274 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 9.02 (br.s, 1H), 8.25 (br.s, 1H), 7.90-7.97 (m, 1H), 7.85 (dd, 2H), 1.52 (s, 9H)。
Example 16A
{ 2-Nitro-1- [2- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester
The title compound was obtained from 1.50 g (5.49 mmol) of the compound of example 15A in the same manner as in example 12A: 1.54 g (84% of theory).
LC/MS [ method 5 ]]: Rt = 1.13 min; ES-: m/z = 333 (M-H)-
1H-NMR (400 MHz, DMSO-d6): δ = 8.04 (d, 1H), 7.80 (d, 1H), 7.70-7.77 (m, 2H), 7.55 (t, 1H), 5.72 (t, 1H), 4.77 (dd, 1H), 4.62-4.71 (m, 1H), 1.33 (s, 9H)。
Example 17A
2-nitro-1- [2- (trifluoromethyl) phenyl ] ethylamine hydrochloride
From 770 mg (2.30 mmol) of the compound of example 16A in the same manner as in example 13A, the title compound was obtained: 656 mg (quantitative, slightly contaminated).
LC/MS [ method 2 ]]: Rt = 0.99 min; m/z = 235 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 9.22 (br.s, 3H), 8.11 (d, 1H), 7.83-7.91 (m, 2H), 7.70 (t, 1H), 5.32-5.41 (m, 1H), 5.14-5.21 (m, 2H)。
Example 18A
[ (2, 3-dichlorophenyl) (phenylsulfonyl) methyl ] carbamic acid tert-butyl ester
The title compound was obtained from 5.00 g (28.6 mmol) of 2, 3-dichlorobenzaldehyde in the same manner as in example 10A: 2.22 g (19% of theory)
1H-NMR (400 MHz, DMSO-d6): δ = 8.93 (d, 1H), 7.96 (d, 1H), 7.84 (d, 2H), 7.76 (d, 2H), 7.63-7.71 (m, 2H), 7.51 (t, 1H), 6.60 (d, 1H), 1.21 (s, 9H)。
Example 19A
[ (E) - (2, 3-dichlorophenyl) methylidene ] carbamic acid tert-butyl ester
The title compound was obtained from 2.22 g (5.33 mmol) of the compound of example 18A in the same manner as in example 11A: 1.38g (94% of theory).
MS [DCI]: m/z = 274 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 9.11 (s, 1H), 8.01 (d, 1H), 7.92 (d, 1H), 7.52 (t, 1H), 1.52 (s, 9H)。
Example 20A
{ 2-Nitro-1- [2- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester
The title compound was obtained from 1.38g (5.03 mmol) of the compound of example 19A in the same manner as in example 12A: 865 mg (51% of theory).
LC/MS [ method 5 ]]: Rt = 1.17 min; m/z = 333 (M-H)-
1H-NMR (400 MHz, DMSO-d6): δ = 8.07 (d, 1H), 7.64 (d, 1H), 7.50 (d, 1H), 7.44 (t, 1H), 5.74 (t, 1H), 4.87 (d, 1H), 4.62 (t, 1H), 1.34 (s, 9H)。
Example 21A
1- (2, 3-dichlorophenyl) -2-nitroethylamine hydrochloride
From 430 mg (1.28 mmol) of the compound of example 20A in the same manner as in example 13A, the title compound was obtained: 363 mg (quantitative, 90% purity).
LC/MS [ method 6 ]]: Rt = 0.54/0.61 min; m/z = 234 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 9.03 (br.s, 3H), 7.81 (d, 1H), 7.78 (dd, 1H), 7.54 (t, 1H), 5.45 (dd, 1H), 5.22-5.28 (m, 2H)。
Example 22A
{ 2-amino-1- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester
248 mg (1.04 mmol) of the compound from example 12A are added to methanol and then admixed with 20 mg of palladium (10% on activated carbon). Hydrogenation was carried out overnight at atmospheric pressure and at room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. This gives 300 mg (88% of theory) of the title compound.
LC/MS [ method 5 ]]: Rt = 0.74 min; m/z = 305 (M+H)+
1H-NMR (400 MHz, DMSO-d6) δ = 7.51-7.72 (m, 4H), 7.44 (d, 1H), 4.50 (d, 1H), 2.63-2.77 (m, 2H), 1.63 (br. s, 2H), 1.36 (s, 9H).
Example 23A
{2- (carboxamido) -1- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester
75 mg (0.25 mmol) of the compound from example 22A are added to 1.5 ml of THF and admixed in small portions with 43.25 mg (0.26 mmol) of 4-nitrophenyl formate at 0 ℃. The mixture was stirred at 0 ℃ for 2 hours and then at room temperature overnight. The solvent was removed on a rotary evaporator and the residue was taken up in DMSO and purified by preparative HPLC (method 10). This gives 66 mg (81% of theory) of the title compound.
LC/MS [ method 2 ]]: Rt = 2.01 min; m/z = 333 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 8.08 (br.s, 1H), 7.97 (s, 1H), 7.51-7.66 (m, 5H), 4.71 (d, 1H), 3.40 (dt, 1H), 3.22-3.29 (m, 1H), 1.36 (s, 9H)。
Example 24A
N- { 2-amino-2- [3- (trifluoromethyl) phenyl ] ethyl } carboxamide hydrochloride
66 mg (0.2 mmol) of the compound from example 23A are introduced into 1.5 ml of dichloromethane and then reacted at room temperature with 1.56 ml of hydrogen chloride in dichloromethaneFormation in alkanesThe 4N solution of (1) was blended. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture is freed of volatile constituents on a rotary evaporator and then dried in HV. This gives 50 mg (94% of theory) of the title compound.
LC/MS [ method 2 ]]: Rt = 0.90 min; m/z = 233 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 8.56 (br.s, 3H), 8.19 (br.s, 1H), 8.01 (s, 1H), 7.91 (s, 1H), 7.76-7.81 (m, 2H), 7.70 (d, 1H), 4.51 (t, 1H), 3.50-3.71 (m, 2H)。
Example 25A
{2- (acetylamino) -1- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester
75 mg (0.25 mmol) of the compound from example 22A are added together with 60. mu.L (0.35 mmol) of N, N-diisopropylethylamine to 2.5 ml of dichloromethane and then admixed at room temperature with 21. mu.L (0.30 mmol) of acetyl chloride. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and then washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and then saturated aqueous sodium chloride solution each twice, dried over sodium sulfate and the solvent was removed on a rotary evaporator. Further drying in HV yields 88 mg of the title compound (100% of theory).
LC/MS [ method 4 ]]: Rt = 0.98 min; m/z = 347 (M+H)+。
Example 26A
N- { 2-amino-2- [3- (trifluoromethyl) phenyl ] ethyl } acetamide hydrochloride
70 mg (72% of theory) of the title compound are obtained from example 25A in the same manner as in example 13A.
LC/MS [ method 5 ]]: Rt = 0.46 min; m/z = 247 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 8.59 (br.s, 3H), 8.11 (t, 1H), 7.90 (s, 1H), 7.75-7.80 (m, 2H), 7.70 (d, 1H), 4.48 (d, 1H), 3.54-3.63 (m, 1H), 3.43-3.51 (m, 1H), 1.78 (s, 3H)。
Example 27A
{2- [ (ethylsulfonyl) amino ] -1- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester (racemate)
A solution of the compound from example 22A (100 mg, 0.33 mmol) in 2 ml of pyridine was combined at room temperature with 62. mu.L of ethanesulfonyl chloride (0.66 mmol) and the resulting mixture was stirred for 1 hour. Then an additional 16. mu.L (0.17 mmol) of ethanesulfonyl chloride was added. The mixture was stirred for another 1 hour, diluted with ethyl acetate, and then extracted by successively shaking twice each with 1M hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated on a rotary evaporator, and the residue is dried in HV. This gives 114 mg (88% of theory) of the title compound.
LC/MS [ method 3 ]]: Rt = 1.24 min; m/z = 297 (M+H-BOC)+
1H-NMR (400 MHz, DMSO-d6): δ = 7.69 (br.s, 1H), 7.55-7.66 (m, 3H), 7.49 (br.d, 1H), 7.16 (br. t, 1H), 4.67-4.75 (m, 1H), 3.12-3.38 (m, 2H), 2.81-2.99 (m, 2H), 1.38 (s, 9H), 1.10 (t, 3H)。
The title compound can be resolved into its two enantiomers by chromatography on a chiral phase (method 15a) -see examples 28A and 29A.
Example 28A
{2- [ (ethylsulfonyl) amino ] -1- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester (enantiomer I)
The first eluting enantiomer from the chromatographic separation enantiomer resolution of example 27A was obtained by method 15 a.
Chiral analytical HPLC [ method 16]: Rt = 1.35 min。
Example 29A
{2- [ (ethylsulfonyl) amino ] -1- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester (enantiomer II)
The final eluted enantiomer from the enantiomeric resolution of the chromatographic separation of example 27A was resolved by method 15 a.
Chiral analytical HPLC [ method 16]: Rt = 4.02 min。
Example 30A
{2- [ (methylsulfonyl) amino ] -1- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester (racemate)
A solution of the compound from example 22A (100 mg, 0.33 mmol) in 2 ml of pyridine was admixed at room temperature with 66. mu.L (0.66 mmol) of methanesulfonyl chloride and stirred for 1 hour. The mixture was diluted with ethyl acetate and then extracted successively with 1M hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution each with shaking twice. The organic phase is dried over sodium sulfate and concentrated on a rotary evaporator, and the residue is dried in HV. This gives 121 mg (96% of theory) of the title compound.
LC/MS [ method 5 ]]: Rt = 1.04 min; ESI pos.: m/z = 297 (M+H-BOC)+, ESI neg.: m/z = 381 (M-H)-,
1H-NMR (400 MHz, DMSO-d6): δ = 7.68 (br.s, 1H), 7.55-7.66 (m, 3H), 7.50 (br.d, 1H), 7.15 (br. t, 1H), 4.67-4.75 (m, 1H), 3.13-3.27 (m, 2H), 2.80 (s, 3H), 1.36 (s, 9H)。
The title compound can be resolved into its two enantiomers-see examples 31A and 32A-by chromatography on chiral phase (method 15 a).
Example 31A
{2- [ (methylsulfonyl) amino ] -1- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester (enantiomer I)
The first eluting enantiomer from the chromatographic separation enantiomer resolution of example 30A was obtained by method 15 a.
Chiral analytical HPLC [ method 16]: Rt = 1.74 min。
Example 32A
{2- [ (methylsulfonyl) amino ] -1- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester (enantiomer II)
The final eluting enantiomer from the chromatographic enantiomeric resolution of example 30A was resolved by method 15 a.
Chiral analytical HPLC [ method 16]: Rt = 3.47 min。
Example 33A
{ 2-amino-1- [2- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester
In a continuous flow hydrogenation apparatus (H-Cube, obtained from Thales Nano, Budapest, type HC-2-SS), 770 mg (2.30 mmol) of a solution of the compound of example 16A in 135 ml of methanol are hydrogenated (conditions: Laraney nickel box, flow rate of 1 ml/min, 45 ℃ C., hydrogen atmosphere). The resulting solution is concentrated on a rotary evaporator and the residue is dried briefly in HV. This gives 669 mg (95% of theory) of the title compound.
LC/MS [ method 2 ]]: Rt = 1.39 min; m/z = 305(M+H)+
1H-NMR (400 MHz, DMSO-d6) δ = 7.57-7.68 (m, 3H), 7.51 (br.d, 1H), 7.43 (t, 1H), 4.77 (br.s, 1H), 2.66 (dd, 1H), 2.58 (m, 1H), 1.51 (br. s, 2H), 1.35 (s, 9H).
Example 34A
{2- [ (ethylsulfonyl) amino ] -1- [2- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester (racemate)
A solution of the compound from example 33A (100 mg, 0.33 mmol) in 2 ml of pyridine was combined at room temperature with 62. mu.L of ethanesulfonyl chloride (0.66 mmol) and the resulting mixture was stirred for 1 hour. Then another 16. mu.L (0.66 mmol) of ethanesulfonyl chloride was added. The mixture was stirred for another 1 hour, diluted with ethyl acetate, and then extracted by successively shaking twice each with 1M hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated on a rotary evaporator, and the residue is dried in HV. This gives 113 mg (87% of theory) of the title compound.
LC/MS [ method 3 ]]: Rt = 1.24 min; m/z = 297 (M+H-BOC)+
1H-NMR (400 MHz, DMSO-d6): δ =7.75 (d, 1H), 7.65-7.71 (m, 2H), 7.44-7.50 (m, 2H), 7.31 (br. t, 1H), 4.95-5.05 (m, 1H), 3.03-3.18 (m, 2H), 2.84-3.03 (m, 2H), 1.35 (s, 9H), 1.12 (t, 3H)。
The title compound can be resolved into its two enantiomers-see examples 35A and 36A-by chromatography on chiral phase (method 15A).
Example 35A
{2- [ (ethylsulfonyl) amino ] -1- [2- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester (enantiomer I)
The first eluting enantiomer from the chromatographic enantiomeric resolution of example 34A was obtained by method 15 a.
Chiral analytical HPLC [ method 16]: Rt = 1.65 min。
Example 36A
{2- [ (ethylsulfonyl) amino ] -1- [2- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester (enantiomer II)
The final eluting enantiomer from the chromatographic enantiomeric resolution of example 34A was resolved by method 15 a.
Chiral analytical HPLC [ method 16]: Rt = 2.86 min。
Example 37A
{2- [ (methylsulfonyl) amino ] -1- [2- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester (racemate)
By the same preparation as in example 30A, 119 mg (95% of theory) of the title compound are obtained from the compound of example 33A (100 mg, 0.33 mmol).
LC/MS [ method 5 ]]: Rt = 1.01 min; ESI pos: m/z = 283 (M+H-BOC)+, ESI neg: m/z = 381 (M-H)-
1H-NMR (400 MHz, DMSO-d6): δ = 7.73 (d., 1H), 7.65-7.73 (m, 2H), 7.44-7.53 (m, 2H), 7.27 (br. t, 1H), 4.98-5.08 (m, 1H), 3.04-3.18 (m, 2H), 2.84 (s, 3H), 1.35 (s, 9H)。
The title compound can be resolved into its two enantiomers-see examples 38A and 39A-by chromatography on a chiral phase (method 15 a).
Example 38A
{2- [ (methylsulfonyl) amino ] -1- [2- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester (enantiomer I)
The first eluting enantiomer from the chromatographic enantiomeric separation resolution of example 37A was obtained by method 15 a.
Chiral analytical HPLC [ method 16 ]: Rt = 2.04 min。
Example 39A
{2- [ (methylsulfonyl) amino ] -1- [2- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester (enantiomer II)
The final eluting enantiomer from the chromatographic enantiomeric resolution of example 37A was resolved by method 15 a.
Chiral analytical HPLC [ method 16]: Rt = 7.41 min。
Example 40A
[ 2-amino-1- (2, 3-dichlorophenyl) ethyl ] carbamic acid tert-butyl ester
A solution of 440 mg (1.31mmol) of the compound according to example 20A in 100 ml of methanol was hydrogenated in a continuous flow hydrogenation apparatus (H-Cube, from Thales Nano, Budapest, type HC-2-SS) (conditions: Lannel nickel box, flow rate of 1 ml/min, 40 ℃, hydrogen atmosphere). The resulting solution is concentrated on a rotary evaporator and the residue is dried briefly in HV. This gives 370 mg (91% of theory) of the title compound.
LC/MS [ method 5 ]]: Rt = 0.76 min; m/z = 305 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 7.55 (br.d, 1H) 7.51 (dd, 1H), 7.31-7.39 (m, 2H), 4.81-4.89 (m, 1H), 2.72 (dd, 1H), 2.59 (d, 1H), 1.66 (br. s, 2H), 1.36 (s, 9H)。
Example 41A
{1- (2, 3-dichlorophenyl) -2- [ (ethylsulfonyl) amino ] ethyl } carbamic acid tert-butyl ester (racemate)
By using the same method as in example 27A, 101 mg (78% of theory) of the title compound is obtained from 100 mg of the compound of example 40A (0.33 mmol).
LC/MS [ method 3 ]]: Rt = 1.21 min; ESI pos: m/z = 297 (M+H-BOC)+; ESI neg: m/z = 395 (M-H)-
1H-NMR (400 MHz, DMSO-d6): δ = 7.56 (dd, 1H), 7.52 (br.d, 1H), 7.46 (dd, 1H), 7.39 (t, 1H), 7.29 (br. t, 1H),. 5.02-5.11 (m, 1H), 3.04-3.22 (m, 2H), 2.86-3.02 (m, 2H), 1.36 (s, 9H), 1.14 (t, 3H)。
The title compound can be resolved into its two enantiomers-see examples 42A and 43A-by chromatography on chiral phase (method 15 a).
Example 42A
{1- (2, 3-dichlorophenyl) -2- [ (ethylsulfonyl) amino ] ethyl } carbamic acid tert-butyl ester (enantiomer I)
The first eluting enantiomer from the chromatographic enantiomeric resolution of example 41A was obtained by method 15 a.
Chiral analytical HPLC [ method 16]: Rt = 1.94 min。
Example 43A
{1- (2, 3-dichlorophenyl) -2- [ (ethylsulfonyl) amino ] ethyl } carbamic acid tert-butyl ester (enantiomer II)
The final eluting enantiomer from the chromatographic enantiomeric resolution of example 41A was obtained by method 15 a.
Chiral analytical HPLC [ method 16]: Rt = 3.67 min。
Example 44A
{1- (2, 3-dichlorophenyl) -2- [ (methylsulfonyl) amino ] ethyl } carbamic acid tert-butyl ester (racemate)
According to the same preparation method as example 30A, 113 mg (90% of theory) of the title compound is obtained from the compound of example 40A (100 mg, 0.33 mmol).
LC/MS [ method 5 ]]: Rt = 1.05 min; ESI pos: m/z = 283 (M+H-BOC)+, ESI neg: m/z = 381 (M-H)-
1H-NMR (400 MHz, DMSO-d6): δ = 7.56 (dd, 1H), 7.53 (br.d, 1H), 7.47 (dd, 1H), 7.39 (t, 1H), 7.24 (t, 1H), 5.05-5.15 (m, 1H), 3.05-3.23 (m, 2H), 2.85 (s, 3H), 1.38 (s, 9H)。
The title compound can be resolved into its two enantiomers-see examples 45A and 46A-by chromatography on chiral phase (method 15A).
Example 45A
{1- (2, 3-dichlorophenyl) -2- [ (methylsulfonyl) amino ] ethyl } carbamic acid tert-butyl ester (enantiomer I)
The first eluting enantiomer from the chromatographic enantiomeric resolution of example 44A was obtained by method 15 a.
Chiral analytical HPLC [ method 16]: Rt = 1.88 min。
Example 46A
{1- (2, 3-dichlorophenyl) -2- [ (methylsulfonyl) amino ] ethyl } carbamic acid tert-butyl ester (enantiomer II)
The final eluting enantiomer from the enantiomeric resolution of the chromatographic separation of example 44A was obtained by method 15 a.
Chiral analytical HPLC [ method 16]: Rt = 10.30 min。
Example 47A
N- { 2-amino-2- [3- (trifluoromethyl) phenyl ] ethyl } methanesulfonamide hydrochloride (enantiomer II)
A solution of 57 mg (0.15 mmol) of the compound from example 32A in 2 ml of dichloromethane and 2 ml of hydrogen chloride in bisThe 4N solution formed in the alkane was combined and then stirred at room temperature for 2 hours. The volatile components are removed on a rotary evaporator. The residue is admixed with 5 ml of dichloromethane, the components are stirred together, and the mixture is then concentrated again on a rotary evaporator and then dried in HV. This gave 52 mg (quantitative) of the title compound in 85% purity.
LC/MS [ method 3 ]]: Rt = 0.55 min; ESI pos.: m/z = 283 (M+H)+
The same procedure was used to prepare examples 48A-58A:
example 59A
{ 2-hydroxy-1- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester
A solution of 4.00 g (12.5 mmol) of N-tert-butoxycarbonyl-2- (3-trifluoromethylphenyl) -DL-glycine and 2.1 ml (15 mmol) of triethylamine in 50 ml of THF was cooled to 0 ℃ and 1.79 ml (13.8 mmol) of isobutyl chloroformate was added dropwise and the mixture was combined. The resulting thick suspension was stirred at 0 ℃ for an additional 1 hour and then filtered into a cold flask. The solid was washed with a small amount of TH and the entire filtrate was slowly added dropwise to an ice-cooled suspension of sodium borohydride (1.42 g, 37.6 mmol) in 6 ml of water (vigorous gassing). The mixture is stirred vigorously at 0 ℃ for a further 1 hour and then admixed with 5 ml of 1N hydrochloric acid and then extracted three times with ethyl acetate. The organic phase is washed with 1N aqueous sodium hydroxide solution and then twice with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (method 10). This gives 2.00 g of the title compound (52% of theory).
LC/MS [ method 5 ]]: Rt = 1.02 min; m/z = 328 (M+Na)+, 206 (M+H-BOC)+。
1H NMR (DMSO-d6, 00 MHz): δ = 7.65 (s, 1H), 7.51-7.62 (m, 3H), 7.37 (br. d, 1H), 4.86 (t, 1H), 4.57-4.66 (m, 1H), 3.46-3.58 (m, 2H), 1.37 (s, 9H)。
Example 60A
Carbamic acid 2-amino-2- [3- (trifluoromethyl) phenyl ] ethyl ester hydrochloride
A solution of 1.00 g (3.28 mmol) of the compound of example 59A in 20 ml of acetonitrile is cooled to-15 ℃ and then admixed with 399. mu.L (4.59 mmol) of chlorosulfonyl isocyanate. After 10 minutes, 18 ml of water were added and the mixture was heated at 60 ℃ for 2 hours. After cooling to room temperature, the solution was made basic (pH 9-10) by addition of saturated aqueous sodium bicarbonate solution, then extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed on a rotary evaporator. To achieve complete deprotection of the amino groups, the residue was reacted with 15 ml of hydrogen chloride in bisThe 4M solution formed in the alkane was combined and the mixture was stirred at room temperature for 5 minutes and then concentrated on a rotary evaporator. Drying of the residue in HV gave 785 mg (84% of theory) of the title compound.
LC/MS [ method 4 ]]: Rt = 0.44 min; m/z = 249 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 8.80 (br.s, 3H), 7.97 (s, 1H), 7.88 (d, 1H), 7.80 (d, 1H), 7.70 (t, 1H), 6.61 (br. s, 2H), 4.63-4.73 (m, 1H), 4.26-4.38 (m, 2H)。
Example 61A
2-amino-2- [2- (trifluoromethyl) phenyl ] ethanolic hydrochloride
An amount of 500 mg (2.28 mmol) of (2-trifluoromethylphenyl) -DL-glycine was added in portions under argon to a ice-water-cooled solution of 1M borane-THF complex in THF (9.13 ml, 9.13 mmol). After 10 minutes, the cooling bath was removed and the mixture was stirred at room temperature for 4 hours. For the work-up, the pH was adjusted to acidity by addition of 1N hydrochloric acid, THF was removed on a rotary evaporator, the remaining aqueous solution was neutralized with 1N aqueous sodium hydroxide solution and then adjusted to basicity with saturated aqueous sodium bicarbonate solution. It was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed on a rotary evaporator. The crude amino alcohol obtained is reacted with 15 ml of hydrogen chloride in a solvent The 4M solution formed in the alkane was combined and then stirred for 5 minutes. The solution was then concentrated on a rotary evaporator. Drying the residue in HV to obtainThe title compound (550 mg, quantitative) was reacted further without purification.
LC/MS [ method 2 ]]: Rt = 0.78 min; m/z = 206 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.71 (br.s, 3H), 7.92 (d, 1H), 7.78-7.86 (m, 2H), 7.64 (t, 1H), 5.75 (t, 1H), 4.42 (dd, 1H), 3.64-3.77 (m, 2H)。
Example 62A
{ 2-hydroxy-1- [2- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester
367 mg (1.52 mmol) of the compound from example 61A are dissolved in 20 ml of bisAlkane and 20 ml of a 5% strength aqueous solution of sodium hydrogencarbonate were admixed with 356. mu.L (1.55 mmol) of Di-tert-butyl dicarbonate (Di-tert. -butyl carbonate), and the mixture was stirred at room temperature overnight. It was extracted five times with ethyl acetate. The combined organic phases were dried over sodium sulfate and then concentrated on a rotary evaporator. This residue corresponds to the title compound (338 mg, 73% of theory).
LC/MS [ method 2 ]]: Rt = 2.01 min; m/z = 306 (M+H)+
1H NMR (DMSO-d6400 MHz) (rotamers) (. delta. = 7.61-7.71 (m, 3H), 7.37-7.48 (m, 2H), 4.90-5.01 (m, 2H), 3.35-3.50 (m, 2H), 1.35 (br.s. about.7.5H) + 1.10 (br.s, 1.5H).
Example 63A
Carbamic acid 2-amino-2- [2- (trifluoromethyl) phenyl ] ethyl ester hydrochloride
A solution of 570 mg (1.87 mmol) of the compound of example 62A in 100 ml of acetonitrile is cooled to-15 ℃ and admixed with 325. mu.L (3.73 mmol) of chlorosulfonyl isocyanate. After 10 minutes, 50 ml of water were added and the mixture was heated at 60 ℃ for 4 hours. After cooling to room temperature, the solution was made basic (pH 9-10) by addition of saturated aqueous sodium bicarbonate solution, then extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed on a rotary evaporator. To achieve complete deprotection of the amino groups, the residue was reacted with 15 ml of hydrogen chloride in bis The 4M solution formed in the alkane was combined and the mixture was stirred at room temperature for 5 minutes and then the volatile components were removed on a rotary evaporator. This residue corresponds to the title compound (630 mg, quantitative).
LC/MS [ method 4 ]]: Rt = 0.34 min; m/z = 249 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ =8.97 (br.s, 3H), 8.06 (d, 1H), 7.80-7.87 (m, 2H), 7.66 (t, 1H), 6.64 (br.s, 2H), 4.64 (br.s, 1H), 4.37 (dd, 1H), 4.27 (dd, 1H)。
Example 64A
[ (1R) -1- (3-chlorophenyl) -2-hydroxyethyl ] carbamic acid tert-butyl ester
166 mg (95% of theory) of the title compound are obtained in the same manner as in example 62A from 134 mg (0.644 mmol) of (2R) -2-amino-2- (3-chlorophenyl) ethane-1-ol.
LC/MS [ method 1]: Rt = 1.10 min; m/z = 272 (M+H-BOC)+。
Example 65A
Carbamic acid 2-amino-2- (3-chlorophenyl) ethyl ester hydrochloride
In the same manner as in example 60A, from 166 mg (0.61 mmol) of the compound of example 64A, 200 mg of the title compound was obtained and then further used as a crude product.
LC/MS [ method 4 ]]: Rt = 0.30 min; m/z = 215 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 8.71 (br.s, 3H), 7.66 (s, 1H), 7.46-7.54 (m, 3H), 6.62 (br. s, 2H), 4.52-4.62 (m, 1H), 4.22-4.32 (m, 2H)。
Example 66A
2-amino-2- (2-chlorophenyl) ethanol
The amount of 4.00 g (21.6 mmol) of (2-chlorophenyl) -DL-glycine was added in portions under argon to a solution of ice-water-cooled 1M borane-THF complex in THF (64.7ml, 64.7 mmol). After 10 minutes, the cooling bath was removed and the mixture was stirred at room temperature for 4 hours. For the post-treatment, several pieces of ice were slowly added until the gas evolution was complete. The mixture was made alkaline by addition of 1N aqueous sodium hydroxide solution and then extracted three times with MTBE. The combined organic phases were dried over sodium sulfate and then concentrated on a rotary evaporator. The crude title compound obtained (3.00 g, 77% of theory) was reacted further without additional purification.
LC/MS [ method 4 ]]: Rt = 0.22 min; m/z = 172 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 7.64 (d, 1H), 7.37 (d, 1H), 7.32 (t, 1H), 7.24 (t, 1H), 4.87 (br.s, 1H), 4.26-4.32 (m, 1H), 3.53 (dd, 1H), 3.20 (dd, 1H), 2.08 (br. s, 2H)。
Example 67A
[1- (2-chlorophenyl) -2-hydroxyethyl ] carbamic acid tert-butyl ester
2.3 g (13.4 mmol) of the compound from example 66A are stirred with 3.69 ml (16 mmol) of di-tert-butyl dicarbonate in 100 ml of acetonitrile. Ethyl acetate and saturated aqueous sodium bicarbonate were then added. The phases were separated and the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases are washed successively with water (2 times) and saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue is dried in HV. The resulting crude title compound (4.2 g) was reacted in example 68A without additional purification.
LC/MS [ method 6 ]]: Rt = 2.02 min; m/z = 272 (M+H)+
1H NMR (DMSO-d6, 400 MHz) (rotamers): δ = 7.43 (dd, 1H), 7.39 (dd, 1H), 7.36 (br.d, 1H), 7.32 (td, 1H), 7.25 (td, 1H), 4.94-5.02 (m, 1H), 4.91 (t, 1H), 3.46-3.54 (m, 1H), 3.35-3.43 (m, 1H), 1.36 (br. s, 7.5 H) + 1.16 (br. s, 1.5 H)。
Example 68A
2-amino-2- (2-chlorophenyl) ethyl carbamate hydrochloride
The title compound (1.10 g, 69% of theory, over 2 stages) was obtained from 2.00 g (7.36 mmol) of the compound of example 67A in the same manner as in example 63A.
LC/MS [ method 4 ]]: Rt = 0.28 min; m/z = 215 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.76 (br.s, 3H), 7.75 (d, 1H), 7.57 (dd, 1H), 7.41-7.53 (m, 2H), 6.64 (br.s, 2H), 4.82-4.92 (m, 1H), 4.27 (qd [ABX], 2H)。
Example 69A
(2R) -2-amino-2- [3- (trifluoromethyl) phenyl ] propane-1-ol hydrochloride
A1M solution (37.1 ml, 37.1 mmol) of the borane-tetrahydrofuran complex formed in THF was cooled to 0 ℃ under argon. 2.5 g (9.27 mmol) of (2R) -2-amino-2- [3- (trifluoromethyl) phenyl ] propionic acid was added thereto, and, after removing the cooling bath, the mixture was stirred at room temperature for 4 hours. For work-up, it is carefully acidified with 1N hydrochloric acid. THF was removed on a rotary evaporator. The aqueous phase was made basic with saturated aqueous sodium bicarbonate solution and then extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and then concentrated on a rotary evaporator. The resulting crude product (2.4 g) was reacted further without purification.
LC/MS [ method 2 ]]: Rt = 0.93 min; m/z = 218 (M+H)+。
Example 70A
{ (2R) -1-hydroxy-2- [3- (trifluoromethyl) phenyl ] propan-2-yl } carbamic acid tert-butyl ester
2.032 g (9.27 mmol) of the compound from example 69A are dissolved in 50 ml of dichloromethane and 10ml of bisIn an alkane, the resulting solution was then admixed with 2.17 ml (9.45 mmol) of di-tert-butyl dicarbonate. The mixture was stirred at room temperature overnight and then freed from volatile constituents on a rotary evaporator. The residue is dried in HV and then purified by preparative HPLC (method 10). This gives 2.69 g (91%, theoretical in 2 stages) of the title compound.
LC/MS [ method 5 ]]: Rt = 1.09 min; m/z = 342 (M+Na)+。
1H NMR (DMSO-d6400 MHz) (rotamers) (. delta. = 7.50-7.64 (m, 5H), 6.92 (br. s, 1H), 4.97 (br. t, 1H), 3.43-3.54 (m [ AB ])]3H), 1.58 (s, 3H), 1.34 +1.00 (2 br. s, total 9H).
Example 71A
Carbamic acid (2R) -2-amino-2- [3- (trifluoromethyl) phenyl ] propyl ester hydrochloride
A solution of 520 mg (1.63 mmol) of the compound from example 70A in 10ml of acetonitrile is cooled to-15 ℃ and admixed with 198. mu.L (2.28 mmol) of chlorosulfonyl isocyanate. After 10 minutes, 18 ml of water were added and the mixture was heated at 60 ℃ overnight. After cooling to room temperature, the solution was made basic by addition of saturated aqueous sodium bicarbonate solution and then extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed on a rotary evaporator. To achieve complete deprotection of the amino groups, the residue was reacted with 5ml of hydrogen chloride in bis The 4M solution formed in the alkane was combined and the mixture was stirred at room temperature for 5 minutes and then concentrated on a rotary evaporator. Drying of the residue in HV gave the title compound (440 mg, 90% of theory).
LC/MS [ method 4 ]]: Rt = 0.47 min; m/z = 263 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 8.80 (br.s, 3H), 7.97 (s, 1H), 7.88 (d, 1H), 7.80 (d, 1H), 7.70 (t, 1H), 6.61 (br. s, 2H), 4.63-4.73 (m, 1H), 4.26-4.38 (m, 2H)。
Example 72A
(2R) -2- [ (tert-butoxycarbonyl) amino ] -2- (2-chlorophenyl) propanoic acid
In an amount of 500 mg (2.11 mmol) of (2R) -2-amino-2- [2- (chloromethyl) phenyl ] -methyl ester]Propionic acid was dissolved in 10 ml of 5% strength sodium bicarbonate solution and then admixed with 10 ml of diThe alkyl was blended and then with 511. mu.L (2.22 mmol) of di-tert-butyl dicarbonate. The mixture was stirred overnight, carefully adjusted to a pH of 2 with 1N hydrochloric acid and then extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and then concentrated on a rotary evaporator. The residue (322 mg, 51% of theory) corresponds to the title compound and can be reacted further as such.
LC/MS [ method 3 ]]: Rt = 1.08 min; m/z = 322 (M+Na)+。
Example 73A
[ (2R) -2- (2-chlorophenyl) -1-hydroxypropan-2-yl ] carbamic acid tert-butyl ester
110 mg (77% of theory) of the title compound are obtained from 150 mg (0.5 mmol) of the compound of example 72A in the same manner as in example 59A.
LC/MS [ method 4 ]]: Rt = 0.98 min; m/z = 286 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 7.44 (d, 1H), 7.32 (d, 1H), 7.17-7.29 (m, 2H), 6.79 (br. s, 1H), 4.96 (br. t, 1H), 3.60-3.82 (m, 2H), 1.64 (s, 3H), 1.33 (s, 9H)。
Example 74A
(2R) -2-amino-2- (2-chlorophenyl) propane-1-ol hydrochloride
In the same manner as in example 47A, by reacting hydrogen chloride with hydrogen chlorideA4N solution in an alkane was treated to obtain 49 mg (about 85% purity) of the title compound from 55 mg (0.19 mmol) of the compound of example 73A. It can participate in the reaction without purification.
LC/MS [ method 5 ]]: Rt = 0.28 min; m/z = 186 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.63 (br.s, 3H), 7.52 (d, 1H), 7.34-7.49 (m, 3H), 5.69 (br.s, 1H), 4.11 (dd, 1H), 3.83 (dd, 1H), 1.70 (s, 3H)。
Example 75A
(2R) -2-amino-2- (2-chlorophenyl) propyl carbamate
A solution of 55 mg (0.19 mmol) of the compound from example 73A in 2 ml of acetonitrile is admixed in 3 portions at room temperature over a period of 20 minutes with 39. mu.L (0.42 mmol) of chlorosulfonyl isocyanate. After a further 10 minutes, 2 ml of water were added and the mixture was heated at 60 ℃ for 2 hours. After cooling to room temperature, the solution was made basic by addition of 2N aqueous sodium bicarbonate solution and then extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and then concentrated on a rotary evaporator. Drying of the residue in HV gave the title compound (34 mg, 77% of theory, 90% pure) as lightly contaminated, which was itself available for further reaction as such.
1H NMR (DMSO-d6, 400 MHz): δ = 7.76 (dd, 1H), 7.38 (dd, 1H), 7.32 (td, 1H), 7.26 (td, 1H), 6.27-6.51 (br. s, 2H), 4.36 (d, 1H), 4.24 (d, 1H), 2.11-2.42 (br.s, 2H), 1.48 (s, 3H)。
Example 76A
{3- (4-chlorophenyl) -5-oxo-4- [ (1E) -3,3, 3-trifluoroprop-1-en-1-yl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetic acid methyl ester
280 mg (0.74 mmol) of the compound from example 7A are added at room temperature together with 108.1 mg (0.89 mmol) of 4-dimethylaminopyridine in 5.3 ml of pyridine, admixed with several portions of 0.31 ml (1.84 mmol) of trifluoromethanesulfonic anhydride and stirred for 12 hours. Pyridine was removed on a rotary evaporator and the residue was taken up in acetonitrile and 1N hydrochloric acid. The product was purified by preparative HPLC (method 10). This gives 230 mg (86% of theory) of the title compound.
LC/MS [ method 4 ]]: Rt = 1.14 min; m/z = 362 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 7.68 (s, 4H), 7.18 (d, 1H), 6.85 (dd, 1H), 4.78 (s, 2H), 3.72 (s, 3H)。
Example 77A
{3- (4-chlorophenyl) -5-oxo-4- [ (1E) -3,3, 3-trifluoroprop-1-en-1-yl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetic acid
260 mg (0.72 mmol) of the compound from example 76A are dissolved in 5 ml of methanol and admixed with 2.87 ml (2.87 mmol) of 1M aqueous lithium hydroxide solution. The mixture was stirred at room temperature for 1 hour, then acidified with 1N hydrochloric acid, and diluted with DMSO. The entire solution was purified by preparative HPLC (method 10). This gives 215 mg (86% of theory) of the title compound.
LC/MS [ method 4 ]]: Rt = 1.03 min; m/z = 348 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 13.31 (br. s, 1H), 7.68 (s, 4H), 7.19 (dd, 1H), 6.79-6.92 (m, 1H), 4.64 (s, 2H)。
Example 78A
3-amino-3- [3- (trifluoromethyl) phenyl ] propane-1-ol hydrochloride
2.57 ml (2.57 mmol) of a 1M borane-THF complex solution are introduced with ice cooling and under argon and admixed with 150 mg (0.64 mmol) of 3-amino-3- [3- (trifluoromethyl) phenyl ] propionic acid. After 10 minutes, the cooling bath was removed and the mixture was stirred at room temperature for 4 hours. Under ice-cooling, 1 ml of a 3N aqueous sodium hydroxide solution was added dropwise, and the mixture was stirred overnight. The reaction solution was acidified with 1N hydrochloric acid. The THF is removed on a rotary evaporator and the aqueous solution obtained is purified by preparative HPLC (method 10). This gives 160 mg (97% of theory) of the title compound.
LC/MS [ method 1]: Rt = 1.08 min; m/z = 220 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.19 (s, 1H), 7.90 (s, 1H), 7.80 (d, 1H), 7.74 (d, 1H), 7.66 (t, 1H), 4.42 (dd, 1H), 3.40 (dt, 1H), 3.25 (ddd, 1H), 2.04-2.16 (m, 1H), 1.87-1.97 (m, 1H)。
Example 79A
{ (1S) -3-hydroxy-1- [2- (trifluoromethyl) phenyl ] propyl } carbamic acid tert-butyl ester
6 ml (6 mmol) of a 1M borane-THF complex solution were introduced with ice cooling and under argon and admixed with (S) -Boc-2- (trifluoromethyl) - β -phenylalanine (500 mg, 1.50 mmol). The mixture was stirred at 0 ℃ for 1 hour. To remove excess borane, several pieces of ice were added. After the gas evolution was complete, saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The aqueous phase was acidified with 1N HCl and then extracted twice with ethyl acetate. The combined organic phases are washed with 1N hydrochloric acid and then with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dried in HV and corresponds to the title compound (340 mg, 71% of theory).
LC/MS [ method 3 ]]: Rt = 1.15 min; m/z = 220 (M+H-BOC)+。
Examples
80A
(3S) -3-amino-3- [2- (trifluoromethyl) phenyl ] propane-1-ol hydrochloride
150 mg (0.47 mmol) of the compound from example 79A in 3 ml of hydrogen chloride in dioxaneThe 4N solution formed in the alkane was stirred for 20 minutes. The volatile components are removed on a rotary evaporator and the residue is then dried in HV. This gives 140 mg (87% of theory) of the title compound.
LC/MS [ method 3 ]]: Rt = 1.15 min; m/z = 220 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.69 (br.s, 3H), 7.98 (d, 1H), 7.73-7.89 (m, 2H), 7.62 (t, 1H), 4.59 (br.s, 1H), 3.61-3.81 (m, 1H), 3.40-3.48 (m, 2H), 2.10-2.22 (m, 1H), 1.92-2.02 (m, 1H)。
Examples
81A
Carbamic acid (3S) -3-amino-3- [2- (trifluoromethyl) phenyl ] propyl ester hydrochloride
190 mg (90% of theory) of the title compound are obtained from 180 mg (0.70 mmol) of the compound of example 79A in the same manner as in example 63A.
LC/MS [ method 2 ]]: Rt = 0.97 min; m/z = 263 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.72 (br.s, 3H), 7.99 (d, 1H), 7.80-7.87 (m, 2H), 7.65 (t, 1H), 6.50 (br.s, 2H), 4.48-4.60 (m, 1H), 3.77-3.93 (m, 2H), 2.29-2.39 (m, 1H), 2.12-2.23 (m, 1H)。
Examples
82A
3- [ (tert-butoxycarbonyl) amino ] -3- (2, 3-dichlorophenyl) propionic acid
The amount of 3-amino-3- (2, 3-dichlorophenyl) propionic acid 1.50 g (6.41 mmol) was suspended in 45 ml of bisAlkane and 45 ml of 5% strength aqueous sodium hydrogencarbonate solution, the suspension being admixed at room temperature with 1.40 g (6.41 mmol) of di-tert-butyl dicarbonate. The mixture was stirred at room temperature for 16 hours. For the work-up, the suspension is admixed with about 50 ml of ethyl acetate with stirring. The precipitate was filtered off with suction. After phase separation of the mother liquor, the aqueous phase is carefully adjusted to a pH of 1 with 1N hydrochloric acid and then extracted once with about 50 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. This gives 1.68 g (79% of theory) of the target compound.
LC-MS [ method 3 ]] Rt = 1.18 min; MS [ESIneg]: m/z = 332 (M-H)-
The following compounds were obtained analogously:
example 85A
[1- (2, 3-dichlorophenyl) -3-hydroxypropyl ] carbamic acid tert-butyl ester
430 mg (1.29 mmol) of the compound from example 82A are suspended in 5 ml of THF and cooled to 0 ℃ and the suspension is admixed with 179. mu.L (1.29 mmol) of triethylamine and with 184. mu.L (1.42 mmol) of isobutyl chloroformate and stirred at 0 ℃ for 1 hour. The suspension was then filtered through a plug's (Seitz) frit into a cooled flask, and the remaining solid was washed with a small amount of THF. The filtrate was slowly added dropwise to a solution of 146 mg (3.86 mmol) of sodium borohydride in 0.5 ml of water under ice-cooling, followed by stirring at 0 ℃ for 1 hour. For work-up, the reaction mixture is admixed with about 10 ml of saturated aqueous sodium bicarbonate solution and then extracted with 50 ml of ethyl acetate. The organic phase was washed once with saturated aqueous sodium bicarbonate solution and once with saturated aqueous sodium chloride solution. They were dried over sodium sulfate, filtered and concentrated on a rotary evaporator. This gives 419 mg (95% of theory) of the target compound.
LC-MS [ method 3 ]] Rt = 1.20 min; MS [ESIpos]: m/z = 342 (M+Na)+
The following compounds were obtained analogously:
examples
87A
[1- (2-fluorophenyl) -3-hydroxypropyl ] carbamic acid tert-butyl ester
580 mg (1.95 mmol) of the compound from example 84A are dissolved in 5 ml of 1, 2-dimethoxyethane and the solution obtained is mixed successively at room temperature with 110.7 mg (2.93 mmol) of sodium borohydride and 16.5 mg (0.39 mmol) of lithium chloride. The mixture was then stirred at 85 ℃ for 16 hours. For the work-up, it was admixed with 15 ml of saturated aqueous sodium potassium tartrate solution and then extracted three times with 10 ml of ethyl acetate each time. The combined organic phases are dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The crude product is purified by chromatography on silica gel (elution: cyclohexane/ethyl acetate 1: 1). This gives 383 mg (73% of theory) of the target compound.
LC-MS [ method 4 ]] Rt = 0.91 min; MS [ESIpos]: m/z = 270 (M+H)+
1H-NMR (400 MHz, CDCl3): δ = 1.44 (s, 9H), 1.83-2.06 (m, 2H), 3.01 (br.s, 1H), 3.68 (br.s, 2H), 4.98-5.14 (m, 1H), 5.20-5.37 (m, 1H), 7.00-7.09 (m, 1H), 7.09-7.16 (m, 1H), 7.22-7.34 (m, 2H)。
Example 88A
Carbamic acid 3-amino-3- (2, 3-dichlorophenyl) propyl ester
From 612 mg of the compound of example 85A, 572 mg (quantitative) of the title compound was obtained in the form of a crude product in the same manner as in example 63A.
1H NMR (DMSO-d6, 400 MHz): δ = 8.58 (br.s, 3H), 7.72 (dd, 2H), 7.53 (t, 1H), 6.53 (br.s, 2H), 4.75-4.87 (m, 1H), 3.92 (dt, 1H), 3.73-3.80 (m, 1H), 2.22-2.32 (m, 1H), 2.07-2.19 (m, 1H)。
Examples
89A
Carbamic acid 3-amino-3- (2-fluorophenyl) propyl ester hydrochloride
Starting from 380 mg of the compound of example 87A, 268 mg (76% of theory) of the target compound are obtained in the same manner as in example 63A.
1H-NMR (400 MHz, DMSO-d6): δ = 2.05-2.21 (m, 1H), 2.25-2.40 (m, 1H), 3.62-3.75 (m, 1H), 3.81-3.93 (m, 1H), 4.50-4.66 (m, 1H), 6.53 (br.s, 2H), 7.23-7.37 (m, 2H), 7.41-7.52 (m, 1H), 7.62-7.75 (m, 1H), 8.64 (br.s, 3H)。
Examples
90A
3-amino-3- (2, 3-dichlorophenyl) propan-1-ol
800 mg (2.50 mmol) of the compound from example 85A are dissolved in 20 ml of dichloromethane and then mixed at 0 ℃ with 1.92 ml (25.0 mmol) of trifluoroacetic acid and stirred at room temperature for 1 hour. The mixture was stripped of solvent and trifluoroacetic acid on a rotary evaporator. The crude product is taken up in 20 ml of toluene and concentrated again under reduced pressure on a rotary evaporator. Purification was performed by chromatography on silica gel. The non-polar impurities can be separated by elution with ethyl acetate. Elution with dichloromethane/methanol/26% strength ammonia solution (10:1:0.1) gives 673 mg (79% of theory) of the expected compound.
LC-MS [ method 3 ] ] Rt = 0.50 min; MS [ESIpos]: m/z = 220 (M+H)+。
Examples
91A
2-amino-2- [3- (trifluoromethyl) phenyl ] ethanol trifluoroacetate salt
277mg (0.91 mmol) of the compound of example 59A were dissolved in 10 ml of dichloromethane and then mixed with 0.7 ml (9.1 mmol) of trifluoroacetic acid at 0 ℃ and then stirred at room temperature for 1 hour. The mixture was concentrated on a rotary evaporator. The crude product is taken up in 20 ml of toluene and concentrated again under reduced pressure on a rotary evaporator. The crude product was purified by preparative HPLC [ method 19 ]. This gives 124 mg (43% of theory) of the target compound.
LC-MS [ method 5 ]] Rt = 0.40 min; MS [ESIpos]: m/z = 206 (M+H)+(free base)
1H-NMR (400 MHz, MeOD): δ = 3.82 (dd, 2H), 3.94 (dd, 1H), 4.49 (dd, 1H), 7.64-7.71 (m, 1H), 7.71-7.79 (m, 2H), 7.84 (s, 1H)。
Examples
92A
2-amino-2- (2, 3-difluorophenyl) ethanol hydrochloride
103 mg (0.38 mmol) of the compound from example 86A are dissolved in 2 ml of dichloromethane and the solution is reacted at room temperature with 1.73 ml of hydrogen chloride in dichloromethaneThe 4M solution formed in the alkane was combined and then stirred at room temperature for 2 hours. The mixture is concentrated on a rotary evaporator and the residue is then dried in HV. This gives 79 mg (100% of theory) of the target compound.
LC-MS [ method 4 ]] Rt = 0.22 min; MS [ESIpos]: m/z = 173 (M+H)+ (free base).
Examples
93A
(3RS) -3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -3- (2-fluorophenyl) propionic acid methyl ester
50 mg (0.14 mmol) of the compound from example 8A are dissolved in 1 ml of DMF and admixed with 34 mg (0.18 mmol) of EDC and with 22 mg (0.16 mmol) of HOBt and stirred at room temperature for 10 minutes. Then, 35 mg (0.15 mmol) of methyl 3-amino-3- (2-fluorophenyl) propionate hydrochloride and 20. mu.L (0.15 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 16 hours. For the work-up, the reaction mixture is admixed with 10 ml of water and then extracted twice with 10 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The crude product was purified by preparative HPLC [ method 19 ]. This gives 47 mg (63% of theory) of the target compound.
LC-MS [ method 3 ]] Rt = 1.22 min; MS [ESIpos]: m/z = 545 (M+H)+
1H-NMR (400 MHz, CDCl3) δ = 2.80-2.96 (m, 2H), 3.53 and 3.58 (2s, 3H), 3.93-4.12 (m, 2H), 4.44-4.82 (m, 3H), 5.05 (t, 1H), 5.56-5.67 (m, 1H), 6.98-7.24 (m, 3H), 7.27-7.37 (m, 2H), 7.47-7.64 (m, 3H), 7.70 (d, 2H). (partial resolution of the double signal group for the mixture of diastereomers).
Example 94A
{3- (4-chlorophenyl) -5-oxo-4- [ (3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetic acid
400 mg (1.05 mmol) of the compound of example 5A were reacted in the same manner as in example 8A. This gives 328 mg (85% of theory) of the title compound.
LC/MS [ method 6 ]]: Rt = 2.01 min; m/z = 366 (M+H) +。
Example 95A
Amino [3- (trifluoromethyl) phenyl ] acetate acid salt
The amount used was 1.00 g (3.13 mmol) of N-tert-butoxycarbonyl-2- (3-trifluoromethylphenyl) -DL-glycine and 15.7 ml of hydrogen chloride in bisThe 4N solution in the alkane was mixed and then stirred at room temperature overnight. The volatile components are removed on a rotary evaporator. The residue is dried in HV. This gives 795 mg (99% of theory) of the title compound.
LC/MS [ method 2 ]]: Rt = 0.79 min; m/z = 220 (M+H)+。
Example 96A
2- (dibenzylamino) -2- [3- (trifluoromethyl) phenyl ] ethanol
A solution of 1.48 ml (12.4 mmol) of benzyl bromide in 5 ml of ethanol is added dropwise at room temperature to an initial solution of 795 mg of the compound from example 95A (3.11 mmol) and 2.15 g (15.5 mmol) of potassium carbonate in 20 ml of ethanol and 5 ml of water. The resulting mixture was heated at reflux overnight. After cooling to room temperature, the solvent was removed on a rotary evaporator. The residue was combined with 250 ml of water and then extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue (1.72 g) contained a mixture of N, N-dibenzylamino acid (Rt = 2.66 min), ethyl N, N-dibenzylamino acid (Rt = 3.21 min) and benzyl N, N-dibenzylamino acid (Rt = 3.32 min) according to LC-MS (method 2).
The mixture was dissolved in 50 ml of diethyl ether and then added to a 1M solution of lithium aluminium hydride in THF (12.9 ml, 12.9 mmol) under argon, which was subsequently cooled with ice water. The ice bath was then removed and the reaction mixture was heated at reflux for 1 hour. After cooling to room temperature, the excess hydride is decomposed with a few drops of water. The mixture was stirred with sodium sulfate for several minutes and then filtered. The filtrate was concentrated on a rotary evaporator. Drying of the residue in HV gave the title compound (730 mg, 28% of theory).
LC/MS [ method 2 ]]: Rt = 2.72 min; m/z = 386 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 7.59-7.70(m, 4H), 7.29-7.38 (m, 8H), 7.20-7.26 (m, 2H), 4.69 (t, 1H), 3.94-4.05 (m, 2H), 3.72-3.82 (m, 3H), 3.30 (d, 1H) (probably 1H, below the water signal at 3.32 ppm).
Example 97A
2- (dibenzylamino) -2- [3- (trifluoromethyl) phenyl ] acetaldehyde
A 2M solution of oxalyl dichloride in dichloromethane was diluted with 10 ml of dichloromethane under an argon atmosphere and then cooled to-78 ℃. A solution of 221. mu.L (3.11 mmol) of DMSO in 2 ml of dichloromethane was added dropwise thereto. After 10 minutes, a solution of 600 mg (1.56 mmol) of the compound from example 96A in 10 ml of dichloromethane is added dropwise. The mixture was stirred at-78 ℃ for 15 minutes and then admixed with 868. mu.L (6.22 mmol) of triethylamine. After a further 10 minutes, the cooling bath was removed and the mixture was warmed to room temperature and then mixed with 20 ml of water and 200 ml of dichloromethane. The aqueous phase is separated off for purification. The organic phase is washed twice with water and then with 5% strength aqueous sodium hydrogencarbonate solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue is dried in HV. The title compound (600 mg, quantitative) was immediately reacted further as crude product.
LC/MS [ method 6 ]]: Rt = 3.18 min; m/z = 384 (M+H)+。
Example 98A
3- (dibenzylamino) -1,1, 1-trifluoro-3- [3- (trifluoromethyl) phenyl ] propan-2-ol
300 mg (0.78 mmol) of the compound from example 97A are dissolved in 5 ml of THF, cooled to 0 ℃ and admixed with 183. mu.L (1.17 mmol) of (trifluoromethyl) trimethylsilane and then with 39. mu.L (39. mu. mol) of tetra-n-butylammonium fluoride in 1M solution of THF. The cooling bath was removed and the mixture was stirred at room temperature overnight. After 2 ml of 1N hydrochloric acid was added, it was stirred for another 30 minutes. THF was removed on a rotary evaporator and the product was purified by preparative chromatography (method 10). This gives 168mg (47% of theory) of the title compound as a mixture of diastereomers (ratio approx. 3:2)
LC/MS [ method 4 ]]: Rt= 1.43 min + 1.45 min (ratio 3: 2); m/z = 454 (M + H) in each case+
1H NMR (DMSO-d6, 400 MHz): δ = 7.52-7.77 (m, 4H), 7.38-7.41 (m, 8H), 7.22-7.30 (m, 2H), 6.33 (d, 0.4 H Diast.1), 6.22 (d, 0.6H Diast.2), 4.97-5.09 (m, 0.6H Diast.2), 4.88-4.99 (0.4 H, Diast. 1), 4.03 (d, 0.8H, Diast.1), 3.97 (d, 1.2 H, Diast.2), 3.94 (d, 0.6H, Diast.2), 3.91 (d, 0.4H, Diast.1), 3.03 (d, 0.8H, Diast.1), 3.87 (d, 1.2H, Diast.2)。
Example 99A
3-amino-1, 1, 1-trifluoro-3- [3- (trifluoromethyl) phenyl ] propan-2-ol
In a continuous flow hydrogenation apparatus (H-Cube, obtained from Thales Nano, Budapest, type HC-2-SS), 168mg (0.37 mmol) of a solution of the compound from example 98A in 50 ml of methanol are hydrogenated (conditions: Pd (OH))2C-box, flow rate of 1 ml/min, RT, standard hydrogen pressure). The reaction mixture is concentrated on a rotary evaporator and the residue is taken up in HV Dried briefly. The title compound (93 mg, 92% of theory) was obtained.
LC/MS [ method 4 ]]: Rt= 0.63 min + 0.65 min (ratio 2:3), each M/z = 274 (M + H)+
1H NMR (DMSO-d6, 400 MHz): δ = 7.79 (s, 0.4H Diast.1), 7.76 (s, 0.6H Diast.2), 7.72 (d, 0.4H Diast.1), 7.67 (d, 0.6H Diast.2), 7.50-7.64 (m, 2H), 6.40 (br. d, 1H), 4.03-4.21 (m, 2H)。
Example 100A
{ 2-Nitro-1- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester (non-racemic enantiomeric mixture)
9.75 ml (56 mmol) of N, N-diisopropylethylamine were slowly added dropwise at room temperature under argon to a suspension of 20.35 g (56 mmol) of zinc (II) trifluoromethanesulfonate in 300 ml of nitromethane, and the mixture was stirred for 1 hour. The yellow suspension is then mixed with 13.9 g (84 mmol) of (1R,2S) - (-) -2- (N-methylamino) -1-phenylpropan-1-ol [ (-) -N-methylephedrine ] and 18.4 g of molecular sieves, then stirred for 1 hour and then cooled to-20 ℃. 51.0 g (186.6 mmol) of the compound from example 11A was charged in the dropping funnel, and 75 ml of nitromethane was added. The initial solution spontaneously warmed to about 40 ℃ and precipitate formation began to proceed. The entire contents of the dropping funnel were then immediately added as one portion to the cooled zinc (II) trifluoromethanesulfonate/(-) -N-methylephedrine mixture (without temperature control). The reaction mixture was stirred in the cooling bath (-20 ℃) for a further 5 hours and then overnight, the temperature being slowly raised to-0 ℃. The post-treatment was performed similarly to the modification 1 of the process. The crude product was purified by using a short silica gel adsorption column (eluent dichloromethane/ethanol 100: 2). The fractions containing the product are combined, the solvent is removed on a rotary evaporator and the residue is dried in HV. The solid obtained is stirred at room temperature with 200 ml of n-pentane, separated again by filtration and dried in HV. This gives 32.4 g of the title compound (about 82% purity according to LC-MS, 43% of theory).
Wherein 5 g of the product was purified via HPLC [ method 20 ]. This gave 3.87 g of the title compound.
LC/MS [ method 5 ]]: Rt = 1.15 min; (ES neg.): m/z = 333 (M-H)-。
1H-NMR (400 MHz, DMSO-d6): δ = 1.36 (s, 9H), 4.77 (dd, 1H), 4.97 (dd, 1H), 5.34-5.44 (m, 1H), 7.59-7.66 (m, 1H), 7.66-7.74 (m, 2H), 7.78 (br. s, 1H), 7.89 (br. d, 1H)。
Example 101A
{ 2-amino-1- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester
(mixture of non-racemic enantiomers)
3.87 g (11.2 mmol) of the compound from example 100A are hydrogenated in 230 ml of methanol with 5 ml of a Raney nickel suspension (50% in water) under a hydrogen pressure of 3 bar for 3 hours. The reaction mixture was filtered through celite, then washed with methanol, and the filtrate was freed of solvent on a rotary evaporator. The residue is dried in HV. This gives 3.50 g (99% of theory) of the title compound.
LC/MS [ method 4 ]]: Rt = 0.76 min; m/z = 305 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 1.37 (s, 9H), 2.64-2.76 (m, 2H), 3.33 (s, 2H), 4.45-4.55 (m, 1H), 7.44 (br. d, 1H), 7.51-7.64 (m, 4H)。
Example 102A
{1- [3- (trifluoromethyl) phenyl ] ethane-1, 2-diyl } biscarbamic acid tert-butyl-methyl ester (mixture of non-racemic enantiomers)
500 mg (1.64 mmol) of the compound of example 101A together with 320. mu.L (2.30 mmol) of triethylamine are added to dichloromethane, cooled with ice and then 152. mu.L (1.97 mmol) of methyl chloroformate are added. The ice bath was removed and the mixture was stirred for an additional 1 hour. The solvent was removed on a rotary evaporator and the residue was purified by preparative HPLC [ method 20 ]. The product fractions are combined, the solvent is removed on a rotary evaporator and the residue is dried in HV. This gives 428 mg (72% of theory) of the title compound.
LC/MS [ method 2 ]]: Rt = 2.27 min; m/z = 363 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 1.36 (s, 9H), 3.19-3.26 (m, 2H), 3.46 (br. s, 3H), 4.64-4.76 (m, 1H), 7.18 (br. t, 1H), 7.49 (br. d, 1H), 7.53-7.65 (m, 4H)。
Example 103A
{1- [3- (trifluoromethyl) phenyl ] ethane-1, 2-diyl } biscarbamic acid tert-butyl-ethyl ester (non-racemic enantiomeric mixture)
A solution of 500 mg (1.64 mmol) of the compound from example 101A and 321. mu.L (2.30 mmol) of triethylamine in 15 ml of dichloromethane is cooled to 0 ℃ and then mixed with 189. mu.L (1.97 mmol) of ethyl chloroformate. The ice bath was removed and the mixture was stirred for an additional 1 hour. Volatile constituents are removed on a rotary evaporator and the residue is purified by preparative HPLC [ method 20 ]. The product fractions were combined and the solvent was then removed on a rotary evaporator. The residue is dried in HV. This gives 527 mg (85% of theory) of the title compound.
LC/MS [ method 2 ]]: Rt = 2.37 min; m/z = 377 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 1.08 (t, 3H), 1.35 (s, 9H), 3.18-3.27 (m, 2H), 3.85-3.97 (m, 2H), 4.65-4.77 (m, 1H), 7.13 (br. t, 1H), 7.48 (br. d, 1H), 7.52-7.64 (m, 4H)。
Example 104A
{2- [ (ethylcarbamoyl) amino ] -1- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester (mixture of non-racemic enantiomers)
A solution of 500 mg (1.64 mmol) of the compound from example 101A in 15 ml of dichloromethane is mixed at 0 ℃ with 260. mu.L (3.29 mmol) of ethyl isocyanate. The ice bath was removed and the reaction mixture was stirred for an additional 1 hour. All volatile constituents were then removed on a rotary evaporator. The residue was purified by preparative HPLC [ method 23 ]. The product fractions were freed of solvent on a rotary evaporator. Drying of the residue in HV gave 546 mg (89% of theory) of the title compound.
LC/MS [ method 2 ]]: Rt = 2.16 min; m/z = 376 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 0.95 (t, 3H), 1.35 (s, 9H), 2.91-3.04 (m, 2H), 3.08-3.19 (m, 1H), 3.21-3.31 (m, 1H), 4.57-4.66 (m, 1H), 5.88 (br. t, 1H), 5.96 (br. t, 1H), 7.48-7.64 (m, 5H)。
Example 105A
{1- [3- (trifluoromethyl) phenyl ] ethane-1, 2-diyl } biscarbamic acid 2-bromoethyl-tert-butyl ester (non-racemic enantiomeric mixture)
272 mg (0.89 mmol) of the compound from example 101A and 171. mu.L (0.98 mmol) of N, N-diisopropylethylamine in 3 ml of acetonitrile are admixed by dropwise addition of a solution of 106. mu.L (0.98 mmol) of 2-bromoethyl chloroformate in 2 ml of acetonitrile. For work-up, ethyl acetate and saturated aqueous sodium bicarbonate solution were added after 10 minutes. The organic phase is separated, washed again with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and freed of volatile constituents on a rotary evaporator. Drying of the residue in HV gave 352 mg (82% of theory) of the title compound.
LC/MS [ method 4 ]]: Rt = 1.15 min; m/z = 455/457 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 1.36 (s, 9H), 3.25 (t, 2H), 3.56 (t, 2H), 4.09-4.28 (m, 2H), 4.66-4.79 (m, 1H), 7.39 (br. t, 1H), 7.45-7.69 (m, 5H)。
Example 106A
{2- (2-oxo-1, 3-)Oxazolidin-3-yl) -1- [3- (trifluoromethyl) phenyl]Ethyl } carbamic acid tert-butyl ester (non-racemic enantiomeric mixture)
A solution of 352 mg (0.77 mmol) of the compound from example 105A in 10 ml of DMF is admixed with 34 mg (0.85 mmol) of sodium hydride (60% in mineral oil). The reaction mixture was stirred at room temperature overnight. For purification, 2 ml of 1N hydrochloric acid are added and the entire mixture is purified by preparative HPLC [ method 23 ]. The product fractions were combined and the solvent was then removed on a rotary evaporator. Drying of the residue in HV gave 242 mg (84% of theory) of the title compound.
LC/MS [ method 3]]: Rt = 1.19 min; m/z = 275 (M+H-BOC)+。
1H-NMR (400 MHz, DMSO-d6): δ = 1.37 (s, 9H), 3.34-3.44 (m, 2H), 3.45-3.62 (m, 2H), 4.12-4.23 (m, 2H), 4.85-4.95 (m, 1H), 7.55-7.66 (m, 3H), 7.69 (d, 1H), 7.78 (br. s., 1H)。
Example 107A
{2- (2-oxoimidazolidin-1-yl) -1- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester (non-racemic enantiomeric mixture)
An ice-cooled solution of 302 mg (0.99 mmol) of the compound from example 101A in 10 ml of dichloromethane is mixed by dropwise addition of 99. mu.L (1.09 mmol) of 2-bromoethyl isocyanate. After 10 minutes, the ice bath was removed and the mixture was stirred for an additional 5 minutes. All volatile components were removed on a rotary evaporator. The residue was taken up in 5 ml of anhydrous THF and admixed with 44 mg of sodium hydride (60% in mineral oil, 1.09 mmol) while cooling with ice. After 2 hours, 1 ml of 1M hydrochloric acid was added and the reaction mixture was freed of solvent on a rotary evaporator. The aqueous residue was dissolved in DMSO and then purified by preparative HPLC [ method 23 ]. The product fractions were freed of solvent on a rotary evaporator. Drying of the residue in HV gave 210 mg (38% of theory) of the title compound.
LC/MS [ method 4] Rt = 0.84 +0.99 min, M/z = 374 (M + H) +.
1H-NMR (400 MHz, DMSO-d6): δ = 1.36 (br. s., 9H), 3.09-3.18 (m, 2H), 3.18-3.32 (m, 4H), 4.74-4.86 (m, 1H), 6.25-6.39 (br. s, 1H), 7.44-7.76 (m, 5H)。
Example 108A
{2- (methylsulfinyl) -1- [2- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester (racemic mixture of diastereomers)
780 μ L (11.0 mmol) of dimethyl sulfoxide in 30 ml of THF were mixed by slowly adding 6.9 ml of an n-butyllithium solution (1.6M in hexane, 11.0 mmol) at-78 ℃. The resulting suspension is stirred at-78 ℃ for 30 minutes and then added to a solution of 1g (3.66 mmol) of the compound from example 15A in 30 ml of THF (precooled to-78 ℃). The reaction mixture was stirred at-78 ℃ for a further 30 minutes and then slowly warmed to room temperature. After 30 minutes at room temperature, it was again cooled to-20 ℃ and the reaction was stopped by adding 20 ml of a 10% strength aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate. The organic phase is separated, washed twice with water and once with saturated aqueous sodium chloride solution, dried over sodium sulfate and freed from volatile constituents on a rotary evaporator. The residue was purified by preparative HPLC [ method 20 ]. The product fractions were freed of solvent on a rotary evaporator. Drying of the residue in HV gave 952 mg (74% of theory) of the title compound as a mixture of diastereomers.
LC/MS [ method 5 ]]: Rt = 0.92 + 0.95 min; m/z = 352 (M+H)+。
Example 109A
{2- (methylthio) -1- [2- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester (racemate)
400 mg (1.14 mmol) of the compound from example 108A and 567 mg (2.16 mmol) of triphenylphosphine are dissolved in 14 ml of tetrachloromethane. The reaction mixture was stirred at reflux temperature overnight and then the solvent was removed on a rotary evaporator. The residue was purified by preparative HPLC [ method 20 ]. The product fractions were freed of solvent on a rotary evaporator. Drying in HV gave 340 mg (85% of theory) of the title compound.
LC/MS [ method 4 ]]: Rt = 1.20 min; m/z = 336 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 1.36 (s, 9H), 2.08 (s, 3H), 2.62 (dd, 1H), 2.71 (dd, 1H), 5.04-5.14 (m, 1H), 7.47 (t, 1H), 7.58 (br. d, 1H), 7.64-7.72 (m, 2H), 7.76 (br. d, 1H)。
Example 110A
[ (2-chlorophenyl) (phenylsulfonyl) methyl ] carbamic acid tert-butyl ester
The amounts 2.78 g (23.7 mmol) of tert-butyl carbamate and 7.79 g (47.4 mmol) of the sodium benzenesulfinate salt were introduced at room temperature into 55 ml of methanol/water (1:2) and then mixed with 5 g (35.6 mmol) of 2-chlorobenzaldehyde and then with 1.78 ml (47.1 mmol) of formic acid. The mixture was stirred at room temperature for 2 days. The precipitated white solid was obtained by suction filtration, and washed twice with water and diethyl ether. Drying in HV gave 5.77 g (42% of theory) of the title compound.
1H-NMR (400 MHz, DMSO-d6): δ = 1.21 (s, 9H), 6.54 (d, 1H), 7.42-7.58 (m, 3H), 7.62-7.70 (m, 2H), 7.73-7.79 (m, 1H), 7.82 (d, 2H), 7.92-8.03 (m, 1H), 8.87 (d, 1H)。
Example 111A
[ (E) - (2-chlorophenyl) methylene ] carbamic acid tert-butyl ester
An amount of 12.53 g (90.7 mmol) of potassium carbonate was heated in HV and then cooled in an argon atmosphere. The amount of 140 ml of anhydrous THF and 5.77 g (15.1 mmol) of the compound from example 110A were added and the mixture was stirred under argon at reflux temperature for 16 h. After cooling to room temperature, the reaction mixture was filtered through celite. The solid was washed with a small amount of THF. The entire filtrate was freed of solvent on a rotary evaporator. The oily residue is dried in HV. This gives 3.55 g (98% of theory) of the title compound.
1H-NMR (400 MHz, DMSO-d6): δ = 1.52 (s, 9H), 7.47-7.53 (m, 1H), 7.61-7.69 (m, 2H), 8.05 (d, 1H), 9.10 (s, 1H)。
Example 112A
[1- (2-chlorophenyl) -2-nitroethyl ] carbamic acid tert-butyl ester (racemate)
The amount of 16 ml (295.41 mmol) of nitromethane was mixed with 436. mu.L (2.50 mmol) of N, N-diisopropylethylamine and the yellow solution was stirred at room temperature for 1 hour. Then 2.0 g (8.34 mmol) of the compound from example 111A were added and the mixture was stirred at room temperature overnight. All volatile components were removed on a rotary evaporator. The residue was dissolved in 9 ml of isopropanol with boiling heating and the solution was then cooled to 0 ℃. The precipitated white solid was obtained by suction filtration and then washed with a small amount of cold isopropanol. Drying in HV gave 1.18 g (47% of theory) of the title compound.
The mother liquor was concentrated under reduced pressure and the residue was purified by preparative HPLC [ method 23 ]. The product fractions are freed of solvent on a rotary evaporator and then dried in HV. This gives a further 0.90 g (36% of theory) of the title compound.
LC/MS [ method 2 ]]: Rt = 2.30 min; m/z = 301 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 1.35 (s, 9H), 4.62 (dd, 1H), 4.81 (dd, 1H), 5.73 (dt, 1H), 7.32-7.44 (m, 2H), 7.49 (dd, 1H), 7.54 (dd, 1H), 8.00 (d, 1H)。
Example 113A
[ 2-amino-1- (2-chlorophenyl) ethyl ] carbamic acid tert-butyl ester
The title compound was obtained from 1.0g (3.33 mmol) of the compound of example 112A in the same manner as in example 33A: 993 mg (quantitative).
LC/MS [ method 4 ]]: Rt = 0.68 min; m/z = 271 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 1.36 (s, 9H), 1.65 (br. s., 2H), 2.58 (dd, 1H), 2.72 (dd, 1H), 4.79-4.87 (m, 1H), 7.24 (dt, 1H), 7.32 (t, 1H), 7.35-7.40 (m, 2H), 7.45 (br. d, 1H)。
Example 114A
[2- (carbamoylamino) -1- (2-chlorophenyl) ethyl ] carbamic acid tert-butyl ester
A solution of 330mg (1.15 mmol) of the compound from example 113A in 12 ml of water/methanol (1:1) is mixed at room temperature with 279 mg (3.44 mmol) of potassium cyanate. The mixture was heated at 40 ℃ for 1 hour, then mixed with 1.15 ml of 1M hydrochloric acid (1.15 mmol) and stirred at room temperature overnight. An additional 93 mg (1.14 mmol) of potassium cyanate were added and the mixture was stirred at room temperature for a further 3 hours. The entire reaction mixture was purified by preparative HPLC [ method 10 ]. The product fractions were freed of solvent on a rotary evaporator. Drying of the residue in HV gave 292 mg (80% of theory) of the title compound.
LC/MS [ method 4 ]]: Rt = 0.86 min; m/z = 314 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 1.35 (s, 9H), 3.03-3.13 (m, 1H), 3.19-3.29 (m, 1H), 4.84-4.94 (m, 1H), 5.56 (br. s, 2H), 6.01-6.08 (m, 1H), 7.26 (dt, 1H), 7.33 (t, 1H), 7.37-7.43 (m, 2H), 7.52 (br. d, 1H)。
Example 115A
{1- (2-chlorophenyl) -2- [ (methylsulfonyl) amino ] ethyl } carbamic acid tert-butyl ester
A solution of 330mg (1.15 mmol) of the compound from example 113A in 7 ml of pyridine is mixed at room temperature with 177. mu.L (2.29 mmol) of methanesulfonyl chloride. After 1 hour, the volatile constituents were removed on a rotary evaporator. The residue was purified by preparative HPLC [ method 23 ]. The product fractions were freed of solvent on a rotary evaporator. Drying of the residue in HV gave 312 mg (78% of theory) of the title compound.
LC/MS [ method 4 ]]: Rt = 0.96 min; m/z = 349 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 1.37 (s, 9H), 2.82 (s, 3H), 3.08 (ddd, 1H), 3.14-3.23 (m, 1H), 5.01-5.10 (m, 1H), 7.21 (t, 1H), 7.29 (dt, 1H), 7.35 (br. t, 1H), 7.41 (dd, 1H), 7.44 (br. d, 1H), 7.50 (dd, 1H)。
Example 116A
{1- (2-chlorophenyl) -2- [ (ethylsulfonyl) amino ] ethyl } carbamic acid tert-butyl ester
From 330 mg (1.15 mmol) of the compound of example 113A and 217. mu.L (2.29 mmol) of ethanesulfonyl chloride, 263 mg (63% of theory) of the title compound are obtained in the same manner as in example 115A.
LC/MS [ method 4 ]]: Rt = 1.01 min; m/z = 363 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 1.14 (t, 3H), 1.37 (s, 9H), 2.84-3.00 (m, 2H), 3.07 (ddd, 1H), 3.12-3.22 (m, 1H), 4.99-5.08 (m, 1H), 7.23-7.31 (m, 2H), 7.32-7.38 (m, 1H), 7.41 (dd, 1H), 7.42 (br. d, 1H), 7.49 (dd, 1H)。
Example 117A
[1- (2-chlorophenyl) -2- (methylsulfonyl) ethyl ] carbamic acid tert-butyl ester
A solution of 1 g (10.6 mmol) of (methylsulfonyl) methane in 30 ml of THF was cooled to-78 deg.C, and then 6.65 ml of an n-butyllithium solution (1.6M in hexane, 10.6 mmol) were slowly added and mixed. After 30 minutes at-78 ℃ the suspension obtained is added to a solution of 850 mg (3.55 mmol) of the compound from example 111A in 20 ml of THF (precooled to-78 ℃). The reaction mixture was stirred at-78 ℃ for 30 minutes and then slowly warmed to room temperature. After 30 minutes, it was again cooled to-20 ℃ and the reaction was stopped by adding 20 ml of a 10% strength aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate. The organic phase was separated, washed twice with water and once with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and the solvent is removed on a rotary evaporator. The residue is stirred with 10 ml of methanol/water (10:1) and the solid is filtered off with suction. The pale yellow solid is stirred with 20 ml of pentane/isopropanol 5:1 and then filtered off with suction again. Drying in HV gave 800 mg (55% of theory) of the title compound (82% purity according to LC/MS).
LC/MS [ method 3 ]]: Rt = 1.08 min; m/z = 234 (M+H-BOC)+。
1H-NMR (400 MHz, DMSO-d6): δ = 1.36 (s, 9H), 3.01 (s, 3H), 3.19-3.28 (m, 1H), 3.43-3.55 (m, 1H), 5.47-5.54 (m, 1H), 7.28-7.35 (m, 1H), 7.38 (t, 1H), 7.45 (d, 1H), 7.51 (d, 1H), 7.82 (br. d, 1H)。
Example 118A
[1- (2-chlorophenyl) -2- (methylsulfinyl) ethyl ] carbamic acid tert-butyl ester
(racemic diastereomer mixture)
The title compound was obtained from 850 mg (3.55 mmol) of the compound of example 111A in the same manner as in example 108A: 697 mg (62% of theory).
LC/MS [ method 4 ]]: Rt = 0.87 + 0.88 min; m/z = 318 (M+H)+。
1H-NMR (400 MHz, DMSO-d6) δ = 1.36 (s, 9H), 2.55 (br. s., "1.5H" (3H first diastereomer)), 2.64 (s, "1.5H" (3H second diastereomer)), 2.81-3.15 (m, 2H), 5.22-5.38 (m, 1H), 7.31 (br. t, 1H), 7.35-7.50 (m, 3H), 7.54 (br. d, 1H), 7.75-7.87 (m, 1H).
Example 119A
[1- (2-chlorophenyl) -2- (methylthio) ethyl ] carbamic acid tert-butyl ester (racemate)
In the same manner as in example 109A, 100 mg (0.32 mmol) of the compound of example 118A was reduced. This gives 44 mg (45% of theory) of the title compound.
LC/MS [ method 5 ]]: Rt = 1.20 min; m/z = 302 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 1.37 (s, 9H), 2.11 (s, 3H), 2.59-2.72 (m, 2H), 5.05-5.17 (m, 1H), 7.27 (dt, 1H), 7.35 (t, 1H), 7.41 (dd, 1H), 7.49 (dd, 1H), 7.57 (br. d, 1H)。
Example 120A
{2- (methylsulfonyl) -1- [2- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester
From 1.03 g (11.0 mmol) of (methylsulfonyl) methane and 1.0 g (3.7 mmol) of the compound from example 15A, 1.11 g (82% of theory) of the title compound are obtained in the same manner as in example 117A.
LC/MS [ method 3]]: Rt = 1.12 min; m/z = 268 (M+H-BOC)+。
1H-NMR (400 MHz, DMSO-d6): δ = 1.35 (s, 9H), 2.99 (s, 3H), 3.19 (br. d, 1H), 3.58 (dd, 1H), 5.53 (br. t, 1H), 7.50 (t, 1H), 7.67-7.80 (m, 3H), 7.85 (br. d, 1H)。
Example 121A
{2- (methylsulfonyl) -1- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester
535 mg (27% of theory) of the title compound are obtained from 1.50 g (15.9 mmol) of (methylsulfonyl) methane and 1.45 g (5.31 mmol) of the compound of example 11A by using the same method as example 117A.
LC/MS [ method 4 ]]: Rt = 1.02 min; m/z = 368 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 1.36 (s, 9H), 2.99 (s, 3H), 3.48-3.64 (m, 2H), 5.17 (m, 1H), 7.56-7.70 (m, 3H), 7.70-7.78 (m, 2H)。
Example 122A
{2- (dimethylaminosulfonyl) -1- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester
676 mg (5.49 mmol) of N, N-dimethylmethanesulfonamide in 10 ml of THF were admixed by slowly adding 3.43 ml (5.49 mmol) of a 1.6M solution of N-butyllithium in hexane at-78 ℃. After 30 minutes at-78 ℃ the colorless solution obtained is added to a solution of 500 mg (1.83 mmol) of the compound from example 11A in 10 ml of THF (precooled to-78 ℃). The reaction mixture was stirred at-78 ℃ for a further 30 minutes and then slowly warmed to room temperature. After 30 minutes, it was again cooled to-20 ℃ and the reaction was stopped by adding 5 ml of a 10% strength aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate, then washed twice with water and once with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and the solvent is then removed on a rotary evaporator. The residue was purified by preparative HPLC [ method 23 ]. The product fractions were freed of solvent on a rotary evaporator. Drying of the residue in HV gave 296 mg (41% of theory) of the title compound.
LC/MS [ method 3 ]]: Rt = 1.28 min; m/z = 297 (M+H-BOC)+。
1H-NMR (400 MHz, DMSO-d6): δ = 1.36 (s, 9H), 2.76 (s, 6H), 3.33 (dd, 1H), 3.53 (dd, 1H), 5.01-5.11 (m, 1H), 7.56-7.69 (m, 4H), 7.71 (br. s, 1H)。
Example 123A
[1- (2, 3-dichlorophenyl) ethane-1, 2-diyl ] biscarbamic acid tert-butyl-methyl ester
A solution of 192mg (0.63 mmol) of the compound from example 40A in 5.7 ml of dichloromethane is mixed together at room temperature with 123. mu.L (0.88 mmol) of triethylamine and then with 58. mu.L (0.75 mmol) of methyl chloroformate. The reaction mixture was stirred at room temperature overnight and then all volatile constituents were removed on a rotary evaporator. The residue was dissolved in DMSO and then purified by preparative HPLC [ method 20 ]. The product fractions are freed of solvent on a rotary evaporator and then dried in HV. This gives 167 mg (73% of theory) of the title compound.
LC/MS [ method 3 ]]: Rt = 1.22 min; m/z = 263 (M+H-BOC)+。
1H-NMR (400 MHz, DMSO-d6): δ = 3.14-3.27 (m, 2H), 3.48 (s, 3H), 5.07 (br. q, 1H), 7.13-7.21 (m, 1H), 7.32-7.38 (m, 1H), 7.38-7.44 (m, 1H), 7.47 (br. d, 1H), 7.53 (dd, 1H)。
Example 124A
[1- (2, 3-dichlorophenyl) ethane-1, 2-diyl ] biscarbamic acid tert-butyl-ethyl ester
184 mg (78% of theory) of the title compound are prepared in the same manner as in example 123A from 192mg (629. mu. mol) of the compound of example 40A and 72. mu.L (755. mu. mol) of ethyl chloroformate.
LC/MS [ method 3 ]]: Rt = 1.29 min; ES+: m/z = 277 (M+H-BOC)+。ES-: m/z = 375 (M-H)-
1H-NMR (400 MHz, DMSO-d6): δ = 7.31-7.57 (m, 4H), 7.12 (br. t., 1H), 5.07 (q, 1H), 3.88-3.98 (m, 2H), 3.12-3.28 (m, 2H), 1.35 (m, 9H), 1.10 (t, 3H)。
Example 125A
[2- (carbamoylamino) -1- (2, 3-dichlorophenyl) ethyl ] carbamic acid tert-butyl ester
192mg (0.63 mmol) of the compound from example 40A are introduced into 11 ml of water/methanol 1:2 and admixed successively at room temperature with 0.63 ml (0.63 mmol) of 1M hydrochloric acid and 166 mg (2.05 mmol) of potassium cyanate. The reaction mixture was stirred at room temperature overnight and then methanol was removed on a rotary evaporator. The residue was dissolved in DMSO and then purified by preparative HPLC [ method 20 ]. The product fractions were concentrated on a rotary evaporator. Drying of the residue in HV gave 177 mg (73% of theory) of the title compound.
LC/MS [ method 3 ]]: Rt = 1.05 min; m/z = 348 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 1.34 (s, 9H), 3.04-3.19 (m, 1H), 3.19-3.30 (m, 1H), 4.86-4.99 (m, 1H), 5.57 (br. s., 2H), 6.02-6.16 (br.m, 1H), 7.31-7.42 (m, 2H), 7.47-7.57 (m, 1H), 7.61 (d, 1H)。
Example 126A
{1- (2, 3-dichlorophenyl) -2- [ (ethylcarbamoyl) amino ] ethyl } carbamic acid tert-butyl ester
A solution of 192 mg (0.63 mmol) of the compound from example 40A in 5.7 ml of dichloromethane is mixed at room temperature with 100. mu.L (1.26 mmol) of ethyl isocyanate. The reaction mixture was stirred at room temperature overnight and then the solvent was removed on a rotary evaporator. The residue was dissolved in DMSO and then purified by preparative HPLC [ method 20 ]. The product fractions were freed of solvent on a rotary evaporator. Drying of the residue in HV gave 173 mg (73% of theory) of the title compound.
LC/MS [ method 3 ]]: Rt = 1.16 min; m/z = 276 (M+H-BOC)+。
1H-NMR (400 MHz, DMSO-d6): δ = 0.96 (t, 3H), 1.34 (s, 9H), 2.89-3.07 (m, 2H), 3.07-3.19 (m, 1H), 3.23-3.32 (m, 2H), 4.88-4.99 (m, 1H), 5.88-6.01 (m, 2H), 7.31-7.43 (m, 2H), 7.48-7.56 (m, 1H), 7.60 (br. d, 1H)。
Example 127A
3-amino-3- [3- (trifluoromethyl) phenyl ] propan-1-ol
10.9 ml (10.94 mmol) of borane-tetrahydrofuran complex (1M in THF) were introduced with ice cooling and under argon. 850 mg (3.65 mmol) of 3-amino-3- [3- (trifluoromethyl) phenyl ] propionic acid are then added. After 5 minutes, the cooling bath was removed and the mixture was stirred at room temperature overnight and at reflux for 4 hours. After cooling to room temperature, several pieces of ice were added until the gas evolution was complete. The mixture was made basic with 1M aqueous sodium hydroxide, diluted with water to a volume of about 150 ml and then extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. Drying in HV gave 744 mg (85% of theory) of the title compound in 92% purity.
LC/MS [ method 4 ]]: Rt = 0.45 min; m/z = 220 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 7.71 (s, 1H), 7.60-7.67 (m, 1H), 7.49-7.58 (m, 2H), 4.55 (br.s, 1H), 3.97-4.04 (dd, 1H), 3.34-3.50 (m, 2H), 2.00 (br. s., 2H), 1.59-1.78 (m, 2H)。
Example 128A
{ 3-hydroxy-1- [3- (trifluoromethyl) phenyl ] propyl } carbamic acid tert-butyl ester
A solution of 744 mg (3.39 mmol) of the compound from example 127A in 30 ml of dichloromethane is mixed with 1.56 ml (6.79 mmol) of di-tert-butyl dicarbonate and stirred at room temperature for 3 hours. For work-up, the reaction mixture is diluted with 100 ml of ethyl acetate and washed twice by successively washing with 1M hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution each. The organic phase is dried over sodium sulfate and the solvent is then removed on a rotary evaporator. The residue was purified by preparative HPLC [ method 23 ]. The product fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 870 mg (80% of theory) of the title compound.
LC/MS [ method 5 ]]: Rt = 1.03 min; m/z = 320 (M+H)+。
1H-NMR (400 MHz, DMSO-d6) Delta = 7.52-7.67 (m, 4H), 7.49 (d, 1H), 4.70 (q, 1H), 4.53 (t, 1H), 3.35-3.45 (m, 1H), 3.23-3.30 (m, 1H), 1.79-1.90 (m, 1H), 1.64-1.78 (m, 1H), 1.44 (s, 9H).
Example 129A
Carbamic acid 3-amino-3- [3- (trifluoromethyl) phenyl ] propyl ester
827 mg (2.59 mmol) of the compound of example 128A are added to 100 ml of acetonitrile. 676. mu.L (7.77 mmol) of chlorosulfonyl isocyanate in 10 ml of acetonitrile was added dropwise at-15 ℃. After 5 minutes, 50 ml of water were added and the mixture was heated at 60 ℃ overnight. The reaction mixture was mixed with saturated aqueous sodium bicarbonate solution, and then extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed on a rotary evaporator. Drying of the residue in HV gave 678 mg (quantitative) of the title compound.
LC/MS [ method 2 ]]: Rt = 1.06 min; m/z = 263 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 7.72 (s, 1H), 7.64 (d, 1H), 7.51-7.61 (m, 2H), 6.43 (br. s, 2H), 3.90-4.01 (m, 2H), 3.82 (dt, 1H), 3.30 (s, 2H), 1.73-1.93 (m, 2H)。
Example 130A
Amino [3- (difluoromethyl) phenyl ] acetic acid ethyl ester
The amount used was 1.0 g (4.83 mmol) of 3- (difluoromethyl) phenyl bromide, 1.42 g (5.31 mmol) of ethyl N- (diphenylmethylene) glycinate, 0.19 ml (0.193 mmol) of a 1M solution of tri-tert-butylphosphine in toluene, 55 mg (0.10 mmol) of palladium bis (dibenzylideneacetone) (0), 3.08 g (14.49 mmol) of potassium phosphate and 6.04 ml (18.11 mmol) of 3M hydrochloric acid in argon were heated to 100 ℃ in 20 ml of degassed toluene and stirred at this temperature overnight. A further 0.19 ml (0.193 mmol) of tri-tert-butylphosphine (1M solution in toluene) and 55 mg (0.10 mmol) of bis (dibenzylideneacetone) palladium (0) are added and the mixture is stirred at 100 ℃ for a further 24 hours. The mixture was cooled to room temperature and filtered through celite. The celite was washed with a small amount of toluene, and the filtrate was freed from the solvent under reduced pressure. For elimination of the protecting groups, the residue was dissolved in 50 ml of acetonitrile and mixed with 15 ml of 3M hydrochloric acid. After 2 hours, the acetonitrile fraction was removed on a rotary evaporator. The aqueous residue was diluted with water to a volume of about 150 ml and then washed three times with diethyl ether. The aqueous phase was adjusted to a pH of 9 by using 2M aqueous sodium carbonate solution and then extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. Drying in HV gave 265 mg (6.46% of theory) of the title compound in a purity of about 27%, which was reacted further without further purification.
LC/MS [ method 3]]: Rt = 0.63 min; m/z = 230 (M+H)+。
Example 131A
[ (tert-Butoxycarbonyl) amino ] [3- (difluoromethyl) phenyl ] acetic acid ethyl ester
265 mg (1.16 mmol) of the compound from example 130A are stirred together with 505 mg (2.31 mmol) of di-tert-butyl dicarbonate in 10.2 ml of dichloromethane at room temperature for 3 hours. The solvent was then removed on a rotary evaporator. The residue was purified by preparative HPLC [ method 20, and again by method 23 ]. The product fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 62 mg (29% of theory) of purity of about 49%.
LC/MS [ method 2 ]]: Rt = 2.42 min; m/z = 330 (M+H)+。
Example 132A
{1- [3- (difluoromethyl) phenyl ] -2-hydroxyethyl } carbamic acid tert-butyl ester
11.97 mg (0.28 mmol) of lithium chloride and 10.68 mg (0.28 mmol) of sodium borohydride are stirred together in 0.25 ml of ethanol at room temperature for 15 minutes. The mixture is then cooled to 0 ℃ and a solution of 62 mg (about 0.09 mmol, 49% purity) of the compound from example 131A in 0.25 ml of tetrahydrofuran is added dropwise. The mixture was stirred at room temperature overnight. For the work-up, it was cooled with ice-water and then adjusted to pH 2 using 1M hydrochloric acid. The reaction mixture was purified by preparative HPLC [ method 20 ]. The product fractions are freed of solvent on a rotary evaporator and then dried in HV. This gives 56 mg (about 45% purity, 93% of theory) of the title compound.
1H-NMR (400 MHz, DMSO-d6): δ = 1.36 (br. s, 9H), 3.45-3.56 (m, 2H), 4.49-4.64 (m, 1H), 4.82 (t, 1H), 7.01 (t, JH-F = 56 Hz, 1H), 7.18-7.53 (m, 4H)。
Example 133A
({2- [ (tert-butoxycarbonyl) amino ] -2- [3- (trifluoromethyl) phenyl ] ethyl } aminosulfonyl) carbamic acid tert-butyl ester
A solution of 110 mg (1.48 mmol) of tert-butanol in 2 ml of dichloromethane was cooled to 0 ℃ and mixed dropwise with a solution of 129. mu.L (1.48 mmol) of chlorosulfonyl isocyanate in 2 ml of dichloromethane. The mixture was stirred at room temperature for 1 hour. A solution of 820. mu.L is aspirated in a syringe and then added dropwise to a solution of 90 mg (296. mu. mol) of the compound of example 22A in 2 ml of dichloromethane. Then 103. mu.L of N, N-diisopropylethylamine were added and the reaction mixture was stirred at room temperature for another 2 hours. The volatile constituents were removed on a rotary evaporator. The residue was dissolved in a small amount of acetonitrile and then admixed with 1 ml of 1M hydrochloric acid, and the solution obtained was purified by preparative HPLC [ method 23 ]. The product-containing fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 111 mg (76% of theory) of the title compound.
LC/MS [ method 5 ]]: Rt = 1.16 min; m/z = 484 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 1.36 (s, 9H), 1.41 (s, 9H), 3.08-3.23 (m, 2H), 4.70-4.82 (m, 1H), 7.50 (br. d, 1H), 7.54-7.72 (m, 5H), 10.91 (br. s, 1H)。
Example 134A
N- { 2-amino-2- [3- (trifluoromethyl) phenyl ] ethyl } sulphonyldiamide
100 mg (0.20 mmol) of a solution of the compound from example 133A in 2 ml of dichloromethane and 2 ml of hydrogen chloride in bis The 4M solution in the alkane was combined and the mixture was stirred at room temperature for 2 hours. It was diluted with ethyl acetate and then mixed with 10% strength aqueous sodium bicarbonate. The aqueous alkaline phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed on a rotary evaporator. The residue was the title compound (53 mg, 92% of theory).
1H-NMR (400 MHz, DMSO-d6): δ = ca. 2.66 (br. s, 2H), 2.86-2.99 (m, 1H), 2.99-3.12 (m, 1H), 4.09 (dd, 1H), 6.60 (br. s, 3H), 7.52-7.64 (m, 2H), 7.68 (br. d, 1H), 7.75 (br. s, 1H)。
Example 135A
{ 2-hydroxy-1- [3- (trifluoromethyl) phenyl ] ethyl } methylcarbamic acid tert-butyl ester
An amount of 438 ml of borane-tetrahydrofuran complex (1M solution in THF, 438 mmol) was introduced and cooled with ice. 35 g (110 mmol) of N-Boc-2- (3-trifluoromethylphenyl) -DL-glycine were then added in several portions. The reaction mixture was stirred at room temperature for 2 hours and then carefully mixed with several pieces of ice. After the end of the gas evolution, the solvent was removed on a rotary evaporator. The aqueous residue was mixed with saturated sodium bicarbonate solution and then extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed on a rotary evaporator. The residue was dissolved in acetonitrile and 2.5% strength aqueous sodium bicarbonate. Then, 25.18 ml (109.62 mmol) of di-tert-butyl dicarbonate was added, and the mixture was stirred at room temperature for 3 hours. Acetonitrile was removed on a rotary evaporator. The residue was extracted three times with ethyl acetate, dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. The residue was again mixed with 438 ml of borane-tetrahydrofuran complex (1M solution in THF, 438 mmol) and stirred at 70 ℃ for 3 hours. It is worked up again by reacting excess hydrogen chloride in the second reactor A 4N solution in alkane was added to the fully worked up mixture, which was stirred overnight. After this time, the solvent was removed on a rotary evaporator. The residue was dried in HV and once more mixed with 400 ml of borane-tetrahydrofuran complex (1M solution in THF, 400 mmol) and then stirred overnight. It is then worked up and reacted again, as described above, with 25.18 ml (109.62 mmol) of di-tert-butyl dicarbonate. The crude product obtained after work-up was purified by preparative HPLC. Drying in HV gave 10.2 g (29% of theory) of the title compound.
LC/MS [ method 3 ]]: Rt = 1.24 min; m/z = 220 (M+H-BOC)+。
1H-NMR (400 MHz, DMSO-d6) δ = 7.53-7.68 (m, 4H), 5.20 (br.s, 0.5H (rotamer)), 5.04 (t, 1H), 5.03 (br. s,0.5H (rotamer)), 3.77-3.98 (m, 2H), 2.60-2.83 (br.s, 3H), 1.37 (br. s, 9H).
Example 136A
{2- (aminosulfonyloxy) -1- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester
The amount of 171. mu.L (1.97 mmol) of chlorosulfonyl isocyanate was mixed with 74. mu.L (1.97 mmol) of anhydrous formic acid at 0 ℃ under vigorous stirring under argon. After the addition, the reaction mixture solidified within seconds. Dichloromethane was added in an amount of 2 ml. The reaction mixture was then stirred at 0 ℃ for a further 1 hour and then at room temperature for 8 hours. After which it is cooled again to 0 ℃ and then mixed with 400 mg (1.31 mmol) of the compound of example 59A and 159. mu.L (1.97 mmol) of pyridine in 2 ml of dichloromethane. The cooling bath was removed and the reaction mixture was stirred at room temperature overnight. For the work-up, 5 ml of water and 5 ml of ethyl acetate were added. After 10 minutes, the mixture was diluted with 100 ml of ethyl acetate, then washed twice with water and once with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and the solvent is then removed on a rotary evaporator. The residue was purified by preparative HPLC [ method 10 ]. The product fractions were freed of solvent on a rotary evaporator. Drying in HV gave 260 mg (52% of theory) of the title compound.
LC/MS [ method 3 ]]: Rt = 1.21 min; ESIneg.:m/z = 383 (M-H)-。
H-NMR (400 MHz, DMSO-d6): δ = 7.67 (s, 5H), 7.55 (s, 2H), 4.96 (d, 1H), 4.08-4.18 (m, 2H), 1.21-1.44 (m, 9H)。
Example 137A
{ 2-amino-2- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid ethyl ester hydrochloride
(mixture of non-racemic enantiomers)
527 mg (1.40 mmol) of the compound from example 103A in 9.6 ml of dichloromethane are dissolved at room temperature in 9.4 ml (37 mmol) of hydrogen chloride in dichloromethaneThe 4M solution formed in the alkane was mixed and then stirred for 1 hour. All volatile constituents were then removed on a rotary evaporator. Drying of the residue in HV gave 437 mg (94% of theory) of the title compound.
LC/MS [ method 2 ]]: Rt = 1.31 min; m/z = 277 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 1.09 (t, 3H), 3.38-3.59 (m, 2H), 3.95 (q, 2H), 4.41-4.51 (m, 1H), 7.31 (br. t, 1H), 7.64-7.72 (m, 1H), 7.73-7.81 (m, 2H), 7.87 (br. s, 1H), 8.56 (br. s, 3H)。
The following examples were prepared in the same manner as in example 137A. The yield is in each case higher than 94% of theory:
example 158A
5- (4-chlorophenyl) -4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -2, 4-dihydro-3H-1, 2, 4-triazol-3-one
1.08 g (3.3 mmol) of the compound from example 3A are dissolved in 11 ml of N, N-dimethylacetamide. The solution was saturated with argon by removing atmospheric oxygen using reduced pressure. To this solution was added 21 mg (0.033 mmol) of the ruthenium complex RuCl (p-isopropylphenylmethane) [ (S, S) -Ts-DPEN) ] (CAS number 192139-90-5) under argon. A mixture of 0.63 ml (16.6 mmol) of formic acid and 0.27 ml (1.91 mmol) of triethylamine is then added and the resulting mixture is stirred at room temperature for 48 hours in the absence of air. For the work-up, the mixture is introduced into 10 ml of 0.1N hydrochloric acid and then extracted twice with 20 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by chromatography on silica gel (eluent: 1: cyclohexane/ethyl acetate 3:1, 2: cyclohexane/ethyl acetate 1: 1). This gives 830 mg (81% of theory) of the target compound.
The enantiomeric excess was 96% ee by chromatography using method 27 c.
(S) -enantiomer Rt = 5.73 min
(R) -enantiomer Rt = 6.82 min。
Example 159A
[ (tert-butoxycarbonyl) amino ] (3-chloro-2-fluorophenyl) acetic acid
An amount of 5 g (24.56 mmol) of 3-chloro-2-fluoro-DL-phenylglycine was suspended in the di-tert-butyl etherTo the alkane, 147 ml of a 5% strength aqueous sodium bicarbonate solution were then added. 5.36 g (24.56 mmol) of di-tert-butyl dicarbonate are then added. The suspension was stirred at room temperature overnight. Ethyl acetate was added to the white suspension, the components were stirred together and the precipitate was filtered off with suction. And extracting the mother liquor. The aqueous phase was extracted once more with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated on a rotary evaporator. Drying in HV gave 0.59 g (7.7% of theory) of the title compound.
The aqueous phase was acidified with 1M HCl and then extracted twice with ethyl acetate. The extract was dried over sodium sulfate, filtered and concentrated on a rotary evaporator. Drying in HV gave 5.05 g (65.4% of theory) of the title compound.
LC/MS [ method 2 ]]: Rt = 2.08 min; m/z = 204 (M+H)+。
Example 160A
[1- (3-chloro-2-fluorophenyl) -2-hydroxyethyl ] carbamic acid tert-butyl ester
2 g (6.59 mmol) of the compound from example 159A are dissolved in 20 ml of THF under argon. The solution is then cooled to 0 ℃ and 0.918 ml (6.59 mmol) triethylamine and 0.94 ml (7.24 mmol) isobutyl chloroformate are added dropwise. The reaction mixture was then stirred at 0 ℃ for 1 hour. Thereafter, the suspension was filtered through a plug (Seitz) frit into a cooled flask, washed with a small amount of THF. A solution of 747 mg (19.76 mmol) of sodium borohydride in 3 ml of water was added to the second flask, and the mixture was cooled with ice. The filtrate was slowly added dropwise with vigorous stirring. After 1 hour, the batch was carefully mixed with saturated aqueous sodium bicarbonate. It was then extracted with 30 ml of ethyl acetate. The organic phase was washed once more with saturated aqueous sodium bicarbonate solution and once with saturated aqueous sodium chloride solution. It was then dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. Drying in HV gave 1.74 g (75% of theory) of the title compound in approximately 83% purity.
LC/MS [ method 5 ]]: Rt = 0.99 min; m/z = 290 (M+H)+。
1H-NMR (400 MHz, CDCl3): δ = 1.43 (s, 9H), 1.90-1.98 (m, 1H), 3.78-3.93 (m, 2H), 5.01-5.12 (m, 1H), 5.32-5.42 (m, 1H), 7.08 (t, 1H), 7.23 (t, 1H), 7.30-7.37 (m, 1H)。
Example 161A
2-amino-2- (3-chloro-2-fluorophenyl) ethanol hydrochloride
1.74 g (6.01 mmol) ofThe compound of example 160A was added to 20 ml of dichloromethane. 22 ml (88.00 mmol) of hydrogen chloride in bis (N-bromosuccinimide) were added4M solution formed in an alkane. After stirring at room temperature for 1 hour, the reaction mixture is evaporated to dryness on a rotary evaporator and dried in HV. This gives 1.38 g (88% of theory) of the title compound in approximately 87% purity.
LC/MS [ method 5 ]]: Rt = 0.27 min; m/z = 190 (M+H)+。
Example 162A
Carbamic acid 2-amino-2- (3-chloro-2-fluorophenyl) ethyl ester hydrochloride
243 mg (0.84 mmol) of the compound of example 160A are introduced under argon into 10 ml of acetonitrile. Then 102. mu.L (1.17 mmol) of chlorosulfonyl isocyanate was added dropwise at-15 ℃. After 30 minutes, the reaction solution was mixed with 20 ml of water and heated at 60 ℃ overnight. The reaction mixture was cooled and introduced into a saturated aqueous sodium bicarbonate solution. It was then extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and the solvent is removed on a rotary evaporator. The residue is dissolved in 4 ml of dichloromethane and then reacted with 4 ml of hydrogen chloride in dichloromethaneThe 4M solution formed in the alkane was mixed. A precipitate formed immediately. After a subsequent stirring time of 10 minutes, the batch is freed of the solvent on a rotary evaporator. Drying in HV gave 219 mg (77% of theory) of the title compound in 79% purity.
LC/MS [ method 5 ]]: Rt = 0.27 min; m/z = 233 (M+H)+。
Example 163A
N-allyl-2- (2-bromo-4-chlorobenzoyl) hydrazinecarboxamide
An amount of 10.0 g (40.1 mmol) of 2-bromo-4-chlorobenzohydrazide was suspended in 100 ml of THF at 50 ℃ and then mixed with a solution of 3.59 ml (40.9 mmol) of allyl isocyanate in 50 ml of THF. Stirring was continued at 50 ℃ for 16 hours. The batch is then cooled to room temperature and diluted with 50 ml of diethyl ether. The precipitated solid is filtered off with suction, washed with a little ether and dried in HV. This gives 11.30 g (85% of theory) of the title compound.
LC/MS [ method 6 ]]: Rt = 1.81 min; m/z = 332 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 3.69 (t, 2H), 5.04 (d, 1H), 5.16 (d, 1H), 5.76-5.88 (m, 1H), 6.45 (t, 1H), 7.58 (s, 2H), 7.84 (s, 1H), 8.10 (s, 1H), 10.07 (s, 1H)。
Example 164A
4-allyl-5- (2-bromo-4-chlorophenyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one
11.3 g (33.98 mmol) of the compound from example 163A were dissolved in 61 ml (183.47 mmol) of 3M aqueous sodium hydroxide solution and then heated under reflux for 36 hours. The batch was then cooled, the fine precipitate removed by filtration and the filtrate was combined with 28 ml (169.88 mmol) of semi-concentrated hydrochloric acid under ice cooling to pH 10. The batch is filtered off with suction and the product is dissolved from the precipitate with methanol. Methanol was removed on a rotary evaporator. The residue is dried in HV. This gives 9.78 g (69% of theory) of the title compound in 75% purity.
LC/MS [ method 2 ]]: Rt= 1.88 min, M/z = 314 and 316 (M + H)+。
1H-NMR (400 MHz, CDCl3): δ = 4.19 (d, 2H), 4.93 (d, 1H), 5.09 (d, 1H), 5.64-5.74 (m, 1H), 7.32 (d, 1H), 7.39-7.44 (m, 1H), 7.72 (s, 1H), 9.45 (br. s., 1H)。
Example 165A
[ 4-allyl-3- (2-bromo-4-chlorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid methyl ester
9.78 g (about 23.32 mmol, purity 75%) of the compound from example 164A are dissolved in 75 ml of acetonitrile. Then 3.55 g (25.65 mmol) of potassium carbonate and 2.46 ml (27.98 mmol) of methyl chloroacetate were added. The mixture was stirred at reflux for 5 hours. After cooling, it was filtered with suction. The filtrate was slightly concentrated on a rotary evaporator, then diluted with 30 ml of ethyl acetate and washed with 30 ml each of 1M hydrochloric acid and saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and the solvent is removed on a rotary evaporator. The residue is purified by chromatography on silica gel (elution: cyclohexane/ethyl acetate 2: 1). This gives 7.1 g (79% of theory) of the title compound.
LC/MS [ method 6 ]]: Rt = 2.37 min; m/z = 386 (M+H)+。
Example 166A
[ 4-allyl-3- (2-bromo-4-chlorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid
4 g (10.35 mmol) of the compound from example 156A are dissolved in 30 ml of methanol and then mixed with 15.5 ml (15.52 mmol) of a 1M lithium hydroxide solution. The mixture was stirred at room temperature for 2 hours. The solvent was then removed on a rotary evaporator. The residue was diluted with 100 ml of water, washed with 20 ml of ethyl acetate and then acidified with 1M hydrochloric acid. It was extracted again with 50 ml of ethyl acetate. The organic phase is dried over sodium sulfate, filtered, concentrated on a rotary evaporator and dried in HV. This gives 3.61 g (94% of theory) of the title compound.
LC/MS [ method 3 ]]: Rt= 0.99 min, M/z = 372 and 374 (M + H)+。
1H-NMR (400 MHz, CDCl3): δ = 4.21 (d, 2H), 4.72 (s, 2H), 4.94 (d, 1H), 5.09 (d, 1H), 5.63-5.76 (m, 1H), 7.31-7.43 (m, 2H), 7.71 (s, 1H)。
Example 167A
2- [ (5-chloro-2-thienyl) carbonyl ] -N- (2-methoxyethyl) hydrazinecarboxamide
An amount of 3.1 g (17.55 mmol) of 5-chlorothiophene-2-carbohydrazide is essentially finely suspended in 30 ml of dry THF at 50 ℃. A solution of 1.81 g (17.90 mmol) of 1-isocyanato-2-methoxyethane in 30 ml of THF is then added dropwise. The mixture was stirred at 50 ℃ for 2.5 hours. After cooling to room temperature, the solvent was removed on a rotary evaporator and the residue was mixed with diethyl ether. The crystals are filtered off with suction, washed with diethyl ether and dried in HV. This gives 4.87 g (100% of theory) of the title compound.
1H-NMR (400 MHz, DMSO-d6): δ = 3.14-3.21 (m, 2H), 3.28-3.36 (m, 5H), 6.52 (br. s., 1H), 7.22 (d, 1H), 7.70 (d, 1H), 7.97 (s, 1H), 10.24 (s, 1H)。
Example 168A
5- (5-chloro-2-thienyl) -4- (2-methoxyethyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one
4.85 g (17.46 mmol) of the compound from example 167A are dissolved in 17 ml (52.39 mmol) of aqueous 3M sodium hydroxide solution and then heated at reflux for 168 hours. During this time, 1.05 g of each (26.19 mmol, 104.76 mmol total) solid sodium hydroxide was added after 16, 40, 64 and 88 hours. The batch is acidified to pH 10 with 1M hydrochloric acid and the mixture is extracted twice with 30 ml of ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered, freed of solvent on a rotary evaporator and dried in HV. This gives 2.44 g (54% of theory) of the title compound.
1H-NMR (400 MHz, DMSO-d6): δ = 3.20 (s, 3H), 3.53 (t, 2H), 3.92 (t, 2H), 7.24 (d, 1H), 7.51 (d, 1H), 12.04 (s, 1H)。
Example 169A
[3- (5-chloro-2-thienyl) -4- (2-methoxyethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid ethyl ester
2.4 g (9.24 mmol) of the compound from example 168A are suspended together with 2.55 g (18.48 mmol) of potassium carbonate in 48 ml of acetonitrile. Then 1.08 ml (10.17 mmol) of ethyl chloroacetate were added and the mixture was heated at 80 ℃ under reflux for 4.5 hours. Another 113 mg (0.92 mmol) of ethyl chloroacetate was added, and the mixture was stirred at 80 ℃ for 2 hours. The suspension is filtered through a layer of silica gel, which is washed with ethyl acetate, the filtrate is concentrated on a rotary evaporator and dried in HV. This gives 3.24 g (100% of theory) of the title compound.
LC/MS [ method 6 ]]: Rt = 2.42 min; m/z = 346 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 1.21 (t, 3H), 3.30 (s, 3H), 3.55 (t, 2H), 3.99 (t, 2H), 4.15 (q, 2H), 4.65 (s, 2H), 7.27 (d, 1H), 7.58 (d, 1H)。
Example 170A
[3- (5-chloro-2-thienyl) -4- (2-methoxyethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid
3.2 g (9.25 mmol) of the compound from example 169A are dissolved in 28 ml of methanol. Then 2.82 ml of a 20% strength aqueous potassium hydroxide solution were added. The mixture was stirred at room temperature for 2 hours. The methanol fraction was concentrated on a rotary evaporator in half. The mixture is then diluted with water and extracted once with 15 ml of ethyl acetate. The aqueous phase is acidified with 920. mu.L of concentrated hydrochloric acid and then extracted twice with 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. Drying in HV gave 2.34 g (80% of theory) of the title compound.
LC/MS [ method 6 ]]: Rt = 2.05 min; m/z = 318 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 3.20 (s, 3H), 3.55 (t, 2H), 3.99 (t, 2H), 4.53 (s, 2H), 7.27 (d, 1H), 7.58 (d, 1H), 13.14 (br. s., 1H)。
Example 171A
3- [ (tert-Butoxycarbonyl) amino ] -3- (2-methoxyphenyl) propionic acid methyl ester
An amount of 1.0 g (4.10 mmol) of methyl 3-amino-3- (2-methoxyphenyl) propionate was suspended in 25 ml of di-methylAlkane and 27.5 ml of 5% strength aqueous sodium bicarbonate solution. Then 0.89 g (4.10 mmol) of di-tert-butyl dicarbonate was added. The mixture was stirred at room temperature overnight. The white suspension is admixed with 50 ml of water and then extracted three times with 25 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and the solvent was removed on a rotary evaporator. This gives 1.34 g (100% of theory) of the title compound.
LC/MS [ method 4 ]]: Rt = 1.06 min; m/z = 310 (M+H)+。
Example 172A
[ 3-hydroxy-1- (2-methoxyphenyl) propyl ] carbamic acid tert-butyl ester
1.34 g (4.33 mmol) of the compound from example 171A are dissolved in 10 ml of dimethoxyethane and then combined with 246 mg (6.50 mmol) of sodium borohydride and 37 mg (0.87 mmol) of lithium chloride. The mixture was heated at 85 ℃ for 16 hours. For the work-up, it was cooled to room temperature and carefully mixed with 10 ml of saturated aqueous sodium potassium tartrate solution. It was extracted three times with 20 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and the solvent was removed on a rotary evaporator. The crude product is purified by chromatography on silica gel (elution: cyclohexane/ethyl acetate 9:1, 7: 3). This gives 348 mg (29% of theory) of the title compound.
LC/MS [ method 2 ]]: Rt = 1.90 min; m/z = 282 (M+H)+。
Example 173A
3-amino-3- (2-methoxyphenyl) propane-1-ol hydrochloride
100 mg (0.36 mmol) of the compound from example 172A are dissolved in 2 ml of dichloromethane, and 1.63 ml (6.52 mmol) of hydrogen chloride in dichloromethane are added4M solution formed in an alkane. The yellow solution was then stirred at room temperature for 1 hour. The reaction mixture is evaporated to dryness on a rotary evaporator and then dried in HV. This gives 88 mg (100% of theory) of the title compound.
1H-NMR (400 MHz, DMSO-d6): δ = 1.90-2.11 (m, 2H), 3.28-3.44 (m, 2H), 3.83 (s, 3H), 4.52-4.61 (m, 1H), 4.76 (br. s., 1H), 7.02 (t, 1H), 7.09 (d, 1H), 7.40 (t, 2H), 8.21 (br. s., 3H)。
Example 174A
Carbamic acid 3-amino-3- (2-methoxyphenyl) propyl ester hydrochloride
242 mg (0.86 mmol) of the compound from example 172A were introduced under argon into 12 ml of acetonitrile and 105. mu.L (1.20 mmol) of chlorosulfonyl isocyanate were added dropwise at-15 ℃ for blending. The reaction mixture was stirred at-10 ℃ for 30 minutes. Then 12 ml of water were added and the mixture was stirred overnight at 60 ℃. The reaction mixture was cooled, made basic with saturated aqueous sodium bicarbonate solution, and then extracted three times with 10 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and the solvent is removed on a rotary evaporator. The residue was taken up in 6 ml of hydrogen chloride solutionThe 4M solution formed in the alkane was combined, the components were stirred together for 10 minutes and the mixture was concentrated on a rotary evaporator. The residue is dried in HV. This gives 186 mg (83% of theory) of the title compound.
1H-NMR (400 MHz, DMSO-d6): δ = 2.03-2.29 (m, 2H), 3.64-3.76 (m, 2H), 3.83 (s, 3H), 4.49-4.61 (m, 1H), 6.98-7.13 (m, 2H), 7.34-7.46 (m, 2H), 8.23 (br. s., 1H), 8.35 (br. s., 2H)。
Example 175A
2-amino-2- (2, 3-dichlorophenyl) ethanol
The amount of 1.0 g (4.54 mmol) of amino- (2, 3-dichlorophenyl) acetic acid and 18.18 ml (18.18 mmol) of borane-THF complex (1M solution in THF) are stirred together at room temperature until the reaction is complete. For the post-treatment, several pieces of ice were added. After the end of the evolution of gas, the mixture was adjusted to a pH of 9-10 with 1M aqueous sodium hydroxide solution and then extracted three times with tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. Drying in HV yields 880 mg (91% of theory) of the title compound.
LC/MS [ method 5 ]]: Rt= 0.39 min, M/z = 206 and 208 (M + H)+。
Example 176A
[3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid methyl ester
1.2 g (3.32 mmol) of the compound from example 76A, 150 mg of platinum on carbon (5%) and 150 ml of methanol are hydrogenated under standard hydrogen pressure. For the work-up, the catalyst is filtered off and the filtrate is concentrated on a rotary evaporator. The crude product was purified by preparative HPLC (method 20). The product fractions were combined and the solvent was then removed on a rotary evaporator. Drying in HV gave 890 mg (73% of theory) of the title compound.
LC/MS [ method 4 ]]: Rt = 1.00 min; m/z = 364 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 2.55-2.68 (m, 2H), 3.69 (s, 3H), 4.01 (t, 2H), 4.70 (s, 2H), 7.61-7.72 (m, 4H)。
Example 177A
[3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid
1.27 g (3.49 mmol) of the compound from example 176A are added to 200 ml of methanol and 100 ml of water. Then 6.98 ml (6.98 mmol) of 1M aqueous lithium hydroxide solution were added. The mixture was stirred at room temperature for 2 hours. For purification, 15 ml of 1N hydrochloric acid are added and the mixture is freed from methanol on a rotary evaporator. The residue is diluted with 100 ml of water and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and the solvent is removed on a rotary evaporator and then dried in HV. This gives 1.11 g (91% of theory) of the title compound.
LC/MS [ method 2 ]]: Rt = 1.92 min; m/z = 350 (M+H)+。
1H-NMR (400 MHz, DMSO-d6): δ = 2.55-2.68 (m, 2H), 4.01 (t, 2H), 4.56 (s, 2H), 7.61-7.72 (m, 4H), 13.12 (br. s., 1H)。
Example 178A
{ 2-hydroxy-1- [2- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester (enantiomer I)
52.8 g of the compound of example 62A were isolated by chiral preparative HPLC [ method 33 ]. The first eluting enantiomer (21g) was obtained according to chiral analytical HPLC (method 34) in 93% ee.
Chiral analytical HPLC [ method 34]: Rt = 1.74 min。
For the final eluting enantiomer see example 179A.
Example 179A
{ 2-hydroxy-1- [2- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester (enantiomer II)
The final eluting enantiomer (18.9 g, 99.7% ee) was obtained from the separation of 52.8 g of the compound of example 62A by method 33.
Chiral analytical HPLC [ method 34]: Rt = 2.48 min。
LC/MS [ method 3 ]]: Rt = 1.13 min; m/z = 206 (M-BOC)+。
1H-NMR (400 MHz, DMSO-d6): δ = 1.35 (s, 9H), 3.36-3.50 (m, 2H), 4.90-5.01 (m, 2H), 7.37-7.48 (m, 2H), 7.61-7.70 (m, 4H)。
Further separation of the mixed fractions under the same conditions gave an additional 4.0 g of the second enantiomer, having 99.5% ee.
Example 180A
Carbamic acid 2-amino-2- [2- (trifluoromethyl) phenyl ] ethyl ester hydrochloride (enantiomer II)
250 mg (0.82 mmol) of the compound from example 179A are introduced under argon into 9.76 ml of acetonitrile. At-15 deg.C, 100. mu.L (1.15 mmol) of chlorosulfonyl isocyanate was added dropwise. After 30 minutes, the reaction solution was mixed with 20 ml of water and heated at 60 ℃ overnight. The batch was cooled and introduced into a saturated aqueous sodium bicarbonate solution. It was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. Drying in HV gave 220 mg (100% of theory) of the title compound.
LC/MS [ method 4 ]]: Rt = 0.39 min; m/z = 249 (M+H)+。
Example 181A
[ (tert-butoxycarbonyl) amino ] (2, 3-dichlorophenyl) acetic acid
An amount of 500 mg (2.27 mmol) of amino (2, 3-dichlorophenyl) acetic acid was suspended in 5 ml of bisAlkane and 5% strength aqueous sodium bicarbonate. Then 522. mu.L (2.27 mmol) of di-tert-butyl dicarbonate was added. The batch was stirred overnight at room temperature. The reaction mixture was extracted twice with ethyl acetate. The aqueous phase was acidified with 1M HCl and then extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. Drying in HV gave 703 mg (94% of theory) of the title compound.
LC/MS [ method 5 ]]: Rt= 1.02 min, M/z = 318 and 320 (M-H)-。
Example 182A
[1- (2, 3-dichlorophenyl) -2-hydroxyethyl ] carbamic acid tert-butyl ester
702 mg (2.19 mmol) of the compound from example 181A are dissolved in 7 ml of THF under argon and then cooled to 0 ℃. Then 306. mu.L (2.19 mmol) of triethylamine and 313. mu.L (2.41 mmol) of isobutyl chloroformate were added dropwise. The suspension was stirred at 0 ℃ for 1 hour. It was filtered through a plug (Seitz) frit into a cooled flask, washing with a small amount of THF. The filtrate was slowly added dropwise to a solution of 249 mg (6.58 mmol) of sodium borohydride in 1.5 ml of water which had been cooled to 0 ℃. After 1 hour, the batch was carefully mixed with saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The organic phase was again washed with saturated aqueous sodium bicarbonate solution and once with saturated aqueous sodium chloride solution. It was dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. Drying in HV gave 537 mg (56% of theory) of the title compound in 70% purity.
LC/MS [ method 4 ]]: Rt= 1.02 min, M/z = 306 and 308 (M + H)+。
Example 183A
Carbamic acid 2-amino-2- (2, 3-dichlorophenyl) ethyl ester
290 mg (about 0.95 mmol) of the compound of example 182A are introduced into 5 ml of acetonitrile under argon. At-15 deg.C, 115. mu.L (1.33 mmol) of chlorosulfonyl isocyanate was added dropwise. After 30 minutes, the reaction solution was mixed with 20 ml of water and heated at 60 ℃ overnight. The reaction mixture was cooled and introduced into a saturated aqueous sodium bicarbonate solution. It was extracted twice with 20 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. Drying in HV gave 176 mg (66% of theory) of the title compound in 89% purity.
LC/MS [ method 2 ]]: Rt = 1.07 min; m/z = 249 (M+H)+。
Example 184A
Carbamic acid 2-amino-2- [3- (trifluoromethyl) phenyl ] ethyl ester
93 mg (0.31 mmol) of the compound from example 59A are introduced under argon into 4 ml of acetonitrile. 37. mu.L (0.43 mmol) of chlorosulfonyl isocyanate was added dropwise at-15 ℃. After 30 minutes, the reaction solution was mixed with 8 ml of water and heated at 60 ℃ overnight. The reaction mixture was cooled and introduced into a saturated aqueous sodium bicarbonate solution. It was extracted twice with 10 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. Drying in HV gave 66 mg (64% of theory) of the title compound in 73% purity.
LC/MS [ method 3 ]]: Rt = 0.50 min; m/z = 249 (M+H)+。
Example 185A
[4- (4-chlorophenyl) -2-oxo-3- (3,3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl ] acetic acid (mixture of enantiomers)
An amount of 1.0 g (3.75 mmol) methyl [4- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] acetate (prepared according to WO 2007/134862, example 323A) and 796 mg (4.13 mmol) of 3-bromo-1, 1, 1-trifluoropropan-2-ol were dissolved in 50 ml acetone, 1.47 g (4.50 mmol) of cesium carbonate were added at room temperature and the mixture was heated at reflux for 16H. For the work-up, it was cooled to room temperature and mixed with 50 ml of water. It was neutralized by addition of 1M hydrochloric acid and then extracted three times with 50 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC [ method 19 ]. This gives 171 mg (13% of theory) of the target compound.
LC-MS [ method 3 ]] Rt = 1.02 min; MS [ESIpos]: m/z = 365 (M+H)+。
Example 186A
Ethylcarbamic acid 2- [ (tert-butoxycarbonyl) amino ] -2- [2- (trifluoromethyl) phenyl ] ethyl ester (enantiomerically pure)
An amount of 379. mu.L (4.78 mmol) of ethyl isocyanate was added to a solution of 365 mg (1.20 mmol) of the compound from example 179A and 15 mg (0.12 mmol) of 4-dimethylaminopyridine in 7 ml of pyridine. The reaction mixture was stirred overnight at 50 ℃. After cooling to room temperature, the mixture was mixed with 0.5 ml of ammonia solution (35% strength in water). The volatile constituents were removed on a rotary evaporator. The residue was dissolved in a small amount of acetonitrile and 1N hydrochloric acid and separated by preparative HPLC [ method 20 ]. The product-containing fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 380 mg (84% of theory) of the title compound.
LC-MS [ method 4 ]] Rt = 1.09 min; MS [ESIpos]: m/z = 377 (M+H)+。
Example 187A
Ethylcarbamic acid 2-amino-2- [2- (trifluoromethyl) phenyl ] ethyl ester hydrochloride (enantiomerically pure)
345 mg (0.92 mmol) of the compound from example 186A with 10 ml of hydrogen chloride in diethyl etherThe 4N solution formed in the alkane was mixed and the mixture was stirred at room temperature for 30 minutes. All volatile constituents were then removed on a rotary evaporator. The residue (311 mg, 100% of theory) was the title compound.
LC-MS [ method 2 ]] Rt = 1.20 min; MS [ESIpos]: m/z = 277 (M+H)+
1H-NMR (500MHz, DMSO-d6): δ [ppm]= 1.00 (t, 3H), 2.93-3.06 (m, 2H), 4.28 (dd, 1H), 4.38 (dd, 1H), 4.62-4.70 (m, 1H), 7.12 (br. t, 1H), 7.67 (t, 1H), 7.80-7.88 (m, 2H), 7.98 (d, 1H), 8.84 (br. s., 3H)。
Example the following are:
example 1
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { 2-nitro-1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (mixture of diastereomers)
337 mg (0.92 mmol) of the compound from example 8A with 274 mg (1.01 mmol, 1.1 equivalents) of the compound from example 13A, 247 mg (1.29 mmol, 1.4 equivalents) of EDC and 174 mg (1.29 mmol, 1.4 equivalents) of HOBt are introduced together with 8 ml of DMF, and 192. mu.L (1.10 mmol, 1.2 equivalents) of N, N-diisopropylethylamine are then added. The mixture was stirred at room temperature for 1 hour and then purified by preparative HPLC (method 10). This gives 445 mg (81% of theory) of the title compound.
LC-MS [ method 2 ]]: Rt = 2.46 min; MS [ESIpos]: m/z = 582 (M+H)+
1H NMR (DMSO-d6400 MHz. delta. = 9.07 (d, 1H), 7.83 (s, 1H), 7.66-7.79 (m, 4H), 7.56-7.66 (m, 3H), 6.925 (d, 0.5H (1H, belonging to diastereomer I)), 6.91 (d, 0.5H (1H, belonging to diastereomer II)), 5.63-5.77 (m, 1H), 5.08 (dd, 1H), 4.95 (dd, 1H), 4.53 (s, 1H (2H, belonging to diastereomer I)), 4.43-4.61 (m [ AB ], B ] is]1H (2H, belonging to diastereomer II)), 4.18-4.37 (m, 1H), 3.96 (br. d, 1H), 3.83 (dd, J =14.7, 9.5 Hz, 1H).
The diastereoisomers of example 1 were separated by preparative chromatography on chiral phase (method 11 a): see example 2 and example 3.
Example 2
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { 2-nitro-1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer I)
The diastereomer eluted first from the separation of example 1 by method 11 a.
LC-MS [ method 2 ]]: Rt = 2.43 min; MS [ESIpos]: m/z = 582 (M+H)+
Analytical chiral HPLC [ method 12a ]]: Rt = 4.40 min。
Example 3
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { 2-nitro-1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer II)
The final eluted diastereomer from the separation of example 1 by method 11 a.
LC-MS [ method 2 ]]: Rt = 2.44 min; MS [ESIpos]: m/z = 582 (M+H)+
Analytical chiral HPLC [ method 12a ]]: Rt = 5.37 min。
Example 4
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { 2-nitro-1- [2- (trifluoromethyl) phenyl ] ethyl } acetamide (mixture of diastereomers)
880 mg (72% of theory) of the title compound are obtained in the same manner as in example 1 from 766 mg (2.09 mmol) of the compound of example 8A and 656 mg (2.30 mmol) of the compound of example 17A.
LC-MS [ method 5 ]]: Rt = 1.12 min; MS [ESIpos]: m/z = 582 (M+H)+
The diastereoisomers of example 4 were separated by preparative chromatography on chiral phase (method 11 b): see examples 5 and 6.
Example 5
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { 2-nitro-1- [2- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer I)
The first eluting diastereomer obtained from 880 mg of the diastereomer separation of the compound of example 4 by method 11b (419 mg).
LC-MS [ method 2 ]]: Rt = 2.40 min; MS [ESIpos]: m/z = 582 (M+H)+
Analytical chiral HPLC [ method 12a ]]: Rt = 4.20 min。
1H NMR (DMSO-d6, 400 MHz): δ = 9.20 (d, 1H), 7.82 (d, 1H), 7.80-7.71 (m, 4H), 7.63 (d, 2H), 7.58 (t, 1H), 6.92 (d, 1H), 6.02-5.94 (m, 1H), 4.92 (dd, 1H), 4.82 (dd, 1H), 4.49 (s, 2H), 4.32-4.19 (m, 1H), 3.95 (dd, 1H), 3.82 (dd, 1H)。
Example 6
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { 2-nitro-1- [2- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer II)
The final eluting diastereomer (417 mg) obtained from 880 mg diastereomer separation of the compound of example 4 by method 11 b.
LC-MS [ method 2 ]]: Rt = 2.39 min; MS [ESIpos]: m/z = 582 (M+H)+
Analytical chiral HPLC [ method 12a ]]: Rt = 5.64 min。
1H NMR (DMSO-d6, 400 MHz): δ = 9.20 (d, 1H), 7.82 (d, 1H), 7.80-7.70 (m, 4H), 7.62 (d, 2H), 7.58 (t, 1H), 6.90 (d , 1H), 6.00-5.93 (m, 1H), 4.92 (dd, 1H), 4.82 (dd, 1H), 4.48 (dd [AB], 2H), 4.31-4.20 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H)。
Example 7
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {1- [2, 3-dichlorophenyl ] -2-nitroethyl } acetamide (mixture of diastereomers)
638 mg (91% of theory) of the title compound are obtained in the same manner as in example 1 from 422 mg (1.16 mmol) of the compound of example 8A and 363 mg (1.27 mmol) of the compound of example 21A.
LC-MS [ method 5 ]]: Rt = 1.13 min; MS [ESIpos]: m/z = 582 (M+H)+
The diastereomer of example 7 was separated by preparative chromatography on chiral phase (method 11 c): see example 8 and example 9.
Example 8
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {1- [2, 3-dichlorophenyl ] -2-nitroethyl } acetamide (diastereomer I)
The first eluting diastereomer (181 mg) obtained from 630 mg of the diastereomer separation of the compound of example 7 by method 11 c.
LC-MS [ method 2 ]]: Rt = 2.44 min; MS [ESIpos]: m/z = 582 (M+H)+
Analytical chiral HPLC [ method 12b ]: Rt = 5.81 min。
1H NMR (DMSO-d6, 400 MHz): δ = 9.22 (d, 1H), 7.74 (d, 2H), 7.67-7.61 (m, 3H), 7.55 (dd, 1H), 7.43 (t, 1H), 6.91 (d, 1H), 6.04-5.97 (m, 1H), 5.01 (dd, 1H), 4.81 (dd, 1H), 4.58-4.47 (m[AB], 2H), 4.33-4.21 (m, 1H), 3.95 (dd, 1H), 3.82 (dd, 1H)。
Example 9
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {1- [2, 3-dichlorophenyl ] -2-nitroethyl } acetamide (diastereomer II)
The final eluting diastereomer obtained from 630 mg diastereomer separation of the compound of example 7 by method 11c (281 mg).
LC-MS [ method 2 ]]: Rt = 2.44 min; MS [ESIpos]: m/z = 582 (M+H)+
Analytical chiral HPLC [ method 12b]: Rt = 6.66 min。
1H NMR (DMSO-d6, 400 MHz): δ = 9.22 (d, 1H), 7.74 (d, 2H), 7.66 (d, 1H), 7.63 (d, 2H), 7.55 (dd, 1H), 7.44 (t, 1H), 6.90 (d, 1H), 6.04-5.96 (m, 1H), 5.01 (dd, 1H), 4.81 (dd, 1H), 4.58-4.47 (m[AB], 2H), 4.31-4.20 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H)。
Example 10
N- { 2-amino-1- [3- (trifluoromethyl) phenyl ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide hydrochloride (mixture of diastereomers)
45 mg (77. mu. mol) of the compound of example 1 and 40 mg (348. mu. mol) of indium powder were mixed with 42. mu.L of concentrated hydrochloric acid in 0.5 ml of THF, and the mixture was stirred at room temperature for 2 hours. The mixture was then purified by preparative HPLC (method 10). The product-containing fractions are admixed with 2 ml of 1N hydrochloric acid and then concentrated on a rotary evaporator. Drying in HV gave 21 mg (46% of theory) of the title compound as a mixture of diastereomers.
LC-MS [ method 5 ]]: Rt = 0.85 min; MS [ESIpos]: m/z = 552 (M+H)+。
Example 11
N- { 2-amino-1- [3- (trifluoromethyl) phenyl ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide hydrochloride (diastereomer I)
In a continuous flow hydrogenation apparatus (H-Cube, obtained from Thales Nano, Budapest, type HC-2-SS), 325 mg (0.56 mmol) of a solution of the compound of example 2 in 50 ml of methanol are hydrogenated (conditions: Laraney nickel box, flow rate of 1 ml/min, standard hydrogen pressure, 45 ℃). Methanol was removed on a rotary evaporator and the residue was purified by preparative HPLC (method 10). The product-containing fractions are admixed with 20 ml of 1N hydrochloric acid and then concentrated on a rotary evaporator. Drying in HV gave 266 mg (81% of theory) of the title compound.
LC-MS [ method 4 ]]: Rt = 0.90 min; MS [ESIpos]: m/z = 552 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.99 (d, 1H), 7.99-8.21 (m, 3H), 7.67-7.80 (m, 5H), 7.57-7.67 (m, 3H), 6.89 (d, 1H), 5.18-5.28 (m, 1H), 4.50-4.67 (m [AB], 2H), 4.21-4.34 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.13-3.28 (m, 2H)。
Example 12
N- { 2-amino-1- [3- (trifluoromethyl) phenyl ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide hydrochloride (diastereomer II)
In the same manner as in example 11, but at room temperature 316 mg (0.54 mmol) of the compound of example 3 are hydrogenated. This gives 180 mg (56% of theory) of the title compound.
LC-MS [ method 4 ]]: Rt = 0.89 min; MS [ESIpos]: m/z = 552 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 9.00 (d, 1H), 8.12 (br.s, 3H), 7.66-7.81 (m, 5H), 7.57-7.66 (m, 3H), 6.94 (d, 1H), 5.20-5.29 (m, 1H), 4.50-4.66 (m [AB], 2H), 4.20-4.33 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.13-3.28 (m, 2H)。
Example 13
N- { 2-amino-1- [2- (trifluoromethyl) phenyl ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide hydrochloride (diastereomer I)
In the same manner as in example 11, but at room temperature 415mg (0.71 mmol) of the compound of example 5 are hydrogenated in 100 ml of methanol. This gives 330 mg (79% of theory) of the title compound.
LC-MS [ method 6 ]]: Rt = 1.57 min; MS [ESIpos]: m/z = 552 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 9.11-9.18 (m, 1H), 8.24 (br.s, 3H), 7.87 (d, 1H), 7.71-7.78 (m, 4H), 7.60-7.65 (m, 2H), 7.55 (t, 1H), 6.93 (d, 1H), 5.44-5.53 (m, 1H), 4.66 (dd, 1H), 4.52 (d, 1H), 4.19-4.30 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.07-3.22 (m, 1H), 2.95-3.07 (m, 1H)。
Example 14
N- { 2-amino-1- [2- (trifluoromethyl) phenyl ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide hydrochloride (diastereomer II)
In the same manner as in example 11, but at room temperature 415mg (0.71 mmol) of the compound of example 6 are hydrogenated in 100 ml of methanol. This gives 330 mg (79% of theory) of the title compound.
LC-MS [ method 6 ]]: Rt = 1.56 min; MS [ESIpos]: m/z = 552 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 9.08-9.17 (m, 1H), 8.21 (br.s, 3H), 7.86 (d, 1H), 7.70-7.78 (m, 4H), 7.62 (d, 2H), 7.53-7.59 (m, 1H), 6.88 (d, 1H), 5.44-5.52 (m, 1H), 4.67 (d, 1H), 4.51 (d, 1H), 4.20-4.32 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.09-3.22 (m, 1H), 2.96-3.08 (m, 1H)。
Example 15
N- [ 2-amino-1- (2, 3-dichlorophenyl) ethyl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide hydrochloride (diastereomer I)
In the same manner as in example 11, but at room temperature, 180mg (0.31 mmol) of the compound of example 8 are hydrogenated in 50 ml of methanol. This gives 116 mg (64% of theory) of the title compound.
LC-MS [ method 6 ]]: Rt = 1.61 min; MS [ESIpos]: m/z = 552 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 9.15 (d, 1H), 8.23 (br.s, 3H), 7.75 (d, 2H), 7.57-7.66 (m, 4H), 7.42 (t, 1H), 6.93 (d, 1H), 5.53 (td, 1H), 4.52-4.68 (m, 2H), 4.19-4.31 (m, 1H), 3.96 (dd, 1H), 3.83 (dd, 1H), 3.06-3.18 (m, 2H)。
Example 16
N- [ 2-amino-1- (2, 3-dichlorophenyl) ethyl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide hydrochloride (diastereomer II)
In the same manner as in example 11, but at room temperature, 280mg (0.48 mmol) of the compound of example 9 are hydrogenated in 80 ml of methanol. This gives 177 mg (63% of theory) of the title compound.
LC-MS [ method 5 ]]: Rt = 0.84 min; MS [ESIpos]: m/z = 552 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 9.23 (d, 1H), 8.26 (br.s, 3H), 7.74 (d, 2H), 7.58-7.67 (m, 4H), 7.42 (t, 1H), 6.90 (d, 1H), 5.52 (q, 1H), 4.52-4.69 (m [AB], 2H), 4.22-4.33 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.08-3.18 (m, 2H)。
Example 17
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (carboxamido) -1- [2- (trifluoromethyl) phenyl ] ethyl } acetamide (mixture of diastereomers)
The title compound was obtained from 62 mg (0.17 mmol) of the compound of example 8A and 50 mg (0.19 mmol) of the compound of example 24A by using the method described in example 1: 80mg (82% of theory).
LC-MS [ method 5 ]]: Rt = 1.06 min; MS [ESIpos]: m/z = 580 (M+H)+
The diastereomer of example 17 was separated by preparative chromatography on chiral phase (method 17 a): see example 18 and example 19.
Example 18
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (carboxamido) -1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer I)
The first eluting diastereomer obtained from the isolation of 80mg of the compound of example 17 by method 17a (28 mg).
LC-MS [ method 4 ]]: Rt = 1.04 min; MS [ESIpos]: m/z = 580 (M+H)+
Analytical chiral HPLC method 18a]: Rt = 5.28 min
1H NMR (DMSO-d6, 400 MHz): δ = 8.72 (d, 1H), 8.17 (t, 1H), 7.99 (s, 1H), 7.75 (d, 2H), 7.69 (s, 1H), 7.55-7.68 (m, 5H), 6.92 (d, 1H), 5.00-5.08 (m, 1H), 4.51 (s, 2H), 4.21-4.35 (m, 1H), 3.96 (dd, 1H), 3.83 (dd, 1H), 3.46-3.55 (m, 1H), 3.32-3.40 (m, 1H)。
Example 19
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (carboxamido) -1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer II)
The final eluting diastereomer obtained from the separation of 80 mg of the compound of example 17 by method 17a (30 mg).
LC-MS [ method 4 ]]: Rt = 1.04 min; MS [ESIpos]: m/z = 580 (M+H)+
Analytical chiral HPLC [ method 18a ]]: Rt = 15.29 min
1H NMR (DMSO-d6, 400 MHz): δ = 8.73 (d, 1H), 8.16 (t, 1H), 7.99 (s, 1H), 7.74 (d, 2H), 7.69 (s, 1H), 7.56-7.67 (m, 5H), 6.89 (d, 1H), 5.00-5.08 (m, 1H), 4.45-4.56 (m [AB], 2H), 4.22-4.34 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.47-3.55 (m, 1H), 3.32-3.40 (m, 1H)。
Example 20
N- {2- (acetylamino) -1- [3- (trifluoromethyl) phenyl ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (mixture of diastereomers)
The title compound was obtained from 82 mg (0.22 mmol) of the compound of example 8A and 70 mg (0.25 mmol) of the compound of example 26A by using the method described in example 1: 110 mg (75% of theory).
LC-MS [ method 2 ]] Rt = 2.26 / 2.28 min; MS [ESIpos]: m/z = 594 (M+H)+
The two diastereomers were separated by preparative chromatography on chiral phase (method 17 e): see examples 21 and 22.
Example 21
N- {2- (acetylamino) -1- [3- (trifluoromethyl) phenyl ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (diastereomer I)
The first eluting diastereomer obtained from the separation of 110 mg of the compound of example 20 by method 17e (42 mg).
LC-MS [ method 4 ]]: Rt = 1.06 min; MS [ESIpos]: m/z = 594 (M+H)+
Analytical chiral HPLC [ method 18a ]]: Rt = 4.18 min
1H NMR (DMSO-d6, 400 MHz): δ = 8.67 (d, 1H), 8.01 (t, 1H), 7.76 (d, 2H), 7.54-7.68 (m, 6H), 6.94 (d, 1H), 4.96-5.04 (m, 1H), 4.45-4.56 (m [AB], 2H), 4.25-4.36 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.36-3.46 (m, 1H), 3.27-3.35 (m, 1H), 1.75 (s, 3H)。
Example 22
N- {2- (acetylamino) -1- [3- (trifluoromethyl) phenyl ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (diastereomer II)
The final eluting diastereomer obtained from the separation of 110 mg of the compound of example 20 by method 17e (43 mg).
LC-MS [ method 4 ]]: Rt = 1.08 min; MS [ESIpos]: m/z = 594 (M+H)+
Analytical chiral HPLC [ method 18a ]]: Rt = 9.35 min
1H NMR (DMSO-d6, 400 MHz): δ = 8.68 (d, 1H), 8.01 (t, 1H), 7.75 (d, 2H), 7.55-7.68 (m, 6H), 6.92 (d, 1H), 4.96-5.03 (m, 1H), 4.45-4.55 (m, 2H), 4.24-4.36 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.37-3.45 (m, 1H), 3.26-3.36 (m, 1H), 1.75 (s, 3H)。
Example 23
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- [ (methylsulfonyl) amino ] -1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer I)
A mixture of 52 mg of the compound from example 8A (0.14 mmol) and 27 mg (0.20 mmol) of HOBt in 2 ml of DMF is introduced, mixed with 38 mg (0.20 mmol) of EDC and stirred at room temperature for 20 minutes. Then 50 mg (0.16 mmol) of the compound of example 50A and 35. mu.L (0.20 mmol) of N, N-diisopropylethylamine are added and the reaction mixture is stirred further at room temperature overnight. The entire mixture was completely purified by preparative HPLC (method 10). This gives 68 mg (76% of theory) of the title compound.
LC-MS [ method 2 ]]: Rt = 2.32 min; MS [ESIpos]: m/z = 630 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.70 (d, 1H), 7.71-7.78 (m, 3H), 7.57-7.70 (m, 5H), 7.24 (t, 1H), 6.92 (d, 1H), 5.02-5.11 (m, 1H), 4.48-4.60 (m [AB], 2H), 4.23-4.34 (m, 1H), 3.96 (dd, 1H), 3.83 (dd, 1H), 3.25-3.33 (m, 2H), 2.86 (s, 3H)。
Example 24
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- [ (methylsulfonyl) amino ] -1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer II)
A mixture of 45 mg of the compound from example 8A (0.12 mmol) and 23 mg (0.17mmol, 1.4 equivalents) of HOBt in 1.7 ml of DMF is introduced, mixed with 33 mg (0.17mmol, 1.4 equivalents) of EDC and stirred at room temperature for 20 min. Then 43 mg (0.14 mmol, 1.1 equiv.) of the compound from example 47A and 30. mu.L (0.17mmol, 1.4 equiv.) of N, N-diisopropylethylamine are added and the reaction mixture is stirred further overnight at room temperature. The entire mixture was purified by preparative HPLC (method 10). This gives 51 mg (66% of theory) of the title compound.
LC-MS [ method 2 ]]: Rt = 2.30 min; MS [ESIpos]: m/z = 630 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.72 (d, 1H), 7.72-7.77 (m, 3H), 7.57-7.70 (m, 5H), 7.24 (t, 1H), 6.89 (d, 1H), 5.02-5.10 (m, 1H), 4.46-4.62 (m [AB], 2H), 4.22-4.32 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.25-3.31 (m, 2H), 2.86 (s, 3H)。
Example 25
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- [ (methylsulfonyl) amino ] -1- [2- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer I)
The title compound was obtained in the same manner as in example 24 from 54 mg (0.15 mmol) of the compound of example 8A and 52 mg (0.16 mmol) of the compound of example 53A: 73 mg (78% of theory).
LC-MS [ method 5 ]]: Rt = 1.07 min; MS [ESIpos]: m/z = 630 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.75 (d, 1H), 7.68-7.80 (m, 5H), 7.62 (d, 2H), 7.51 (t, 1H), 7.41 (t, 1H), 6.93 (d, 1H), 5.30-5.38 (m, 1H), 4.61 (d, 1H), 4.47 (d, 1H), 4.22-4.33 (m, 1H), 3.95 (dd, 1H), 3.82 (dd, 1H), 3.12-3.27 (m, 2H), 2.88 (s, 3H)。
Example 26
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- [ (methylsulfonyl) amino ] -1- [2- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer II)
The title compound was obtained in the same manner as in example 24 from 57 mg (0.16 mmol) of the compound of example 8A and 55 mg (0.17 mmol) of the compound of example 54A: 70 mg (71% of theory).
LC-MS [ method 5 ]]: Rt = 1.06 min; MS [ESIpos]: m/z = 630 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.76 (d, 1H), 7.70-7.80 (m, 5H), 7.61 (d, 2H), 7.52 (t, 1H), 7.41 (t, 1H), 6.89 (d, 1H), 5.29-5.37 (m, 1H), 4.62 (d, 1H), 4.46 (d, 1H), 4.21-4.34 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.13-3.27 (m, 2H), 2.88 (s, 3H)。
Example 27
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {1- (2, 3-dichlorophenyl) -2- [ (methylsulfonyl) amino ] ethyl } acetamide (diastereomer I)
The title compound was obtained in the same manner as in example 24 from 50 mg (0.14 mmol) of the compound of example 8A and 48 mg (0.15 mmol) of the compound of example 57A: 64 mg (74% of theory).
LC-MS (square)Method 5]: Rt = 1.08 min; MS [ESIpos]: m/z = 630 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.76 (d, 1H), 7.74 (d, 2H), 7.62 (d, 2H), 7.59 (dd, 1H), 7.51 (dd, 1H), 7.40 (t, 1H), 7.36 (t, 1H), 6.92 (d, 1H), 5.37 (td, 1H), 4.49-4.62 (m [AB], 2H), 4.22-4.34 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.25-3.33 (m, 1H), 3.17 (ddd, 1H), 2.90 (s, 3H)。
Example 28
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {1- (2, 3-dichlorophenyl) -2- [ (methylsulfonyl) amino ] ethyl } acetamide (diastereomer II)
The title compound was obtained in the same manner as in example 24 from 51 mg (0.14 mmol) of the compound of example 8A and 49 mg (0.15 mmol) of the compound of example 58A: 59 mg (67% of theory).
LC-MS [ method 5 ]]: Rt = 1.08 min; MS [ESIpos]: m/z = 630 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.77 (d, 1H), 7.74 (d, 2H), 7.58-7.64 (m, 3H), 7.51 (br.d, 1H), 7.42 (t, 1H), 7.36 (t, 1H), 6.89 (d, 1H), 5.37 (td, 1H), 4.46-4.64 (m [AB], 2H), 4.21-4.31 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.25-3.35 (m, 1H), 3.17 (ddd, 1H), 2.89 (s, 3H)。
Example 29
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- [ (ethylsulfonyl) amino ] -1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer I)
The title compound was obtained in the same manner as in example 24 from 40 mg (0.11 mmol) of the compound of example 8A and 40 mg (0.12 mmol) of the compound of example 48A: 57 mg (81% of theory).
LC-MS [ method 5 ]]: Rt = 1.11 min; MS [ESIpos]: m/z = 644 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.68 (d, 1H), 7.71-7.78 (m, 3H), 7.57-7.69 (m, 5H), 7.27 (t, 1H), 6.93 (d, 1H), 5.00-5.08 (m, 1H), 4.48-4.58 (m [AB], 2H), 4.23-4.34 (m, 1H), 3.96 (dd, 1H), 3.83 (dd, 1H), 3.27 (t, 2H), 2.94 (dd, 2H), 1.11 (t, 3H)。
Example 30
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- [ (ethylsulfonyl) amino ] -1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer II)
The title compound was obtained in the same manner as in example 24 from 40 mg (0.11 mmol) of the compound of example 8A and 40 mg (0.12 mmol) of the compound of example 49A: 56 mg (80% of theory).
LC-MS [ method 2 ]]: Rt = 2.35 min; MS [ESIpos]: m/z = 644 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.69 (d, 1H), 7.71-7.76 (m, 3H), 7.57-7.69 (m, 5H), 7.26 (t, 1H), 6.89 (d, 1H), 5.00-5.07 (m, 1H), 4.46-4.61 (m [AB], 2H), 4.21-4.33 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.27 (t, 2H), 2.90-2.98 (m, 2H), 1.10 (t, 3H)。
Example 31
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- [ (ethylsulfonyl) amino ] -1- [2- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer I)
The title compound was obtained in the same manner as in example 24 from 40 mg (0.11 mmol) of the compound of example 8A and 40 mg (0.12 mmol) of the compound of example 51A: 53 mg (75% of theory).
LC-MS [ method 5 ]]: Rt = 1.10 min; MS [ESIpos]: m/z = 644 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.74 (d, 1H), 7.68-7.79 (m, 5H), 7.62 (d, 2H), 7.51 (t, 1H), 7.46 (t, 1H), 6.93 (d, 1H), 5.27-5.35 (m, 1H), 4.43-4.63 (m [AB], 2H), 4.22-4.34 (m, 1H), 3.95 (dd, 1H), 3.82 (dd, 1H), 3.10-3.26 (m, 2H), 2.91-3.02 (m, 2H), 1.16 (t, 3H)。
Example 32
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- [ (ethylsulfonyl) amino ] -1- [2- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer II)
The title compound was obtained in the same manner as in example 24 from 40 mg (0.11 mmol) of the compound of example 8A and 40 mg (0.12 mmol) of the compound of example 52A: 51 mg (72% of theory).
LC-MS [ method 2 ]]: Rt = 2.31 min; MS [ESIpos]: m/z = 644 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.74 (d, 1H), 7.69-7.79 (m, 5H), 7.61 (d, 2H), 7.51 (t, 1H), 7.45 (t, 1H), 6.89 (d, 1H), 5.26-5.36 (m, 1H), 4.42-4.65 (m [AB], 2H), 4.20-4.32 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.10-3.25 (m, 2H), 2.90-3.02 (m, 2H), 1.15 (t, 3H)。
Example 33
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {1- (2, 3-dichlorophenyl) -2- [ (ethylsulfonyl) amino ] ethyl } acetamide (diastereomer I)
The title compound was obtained in the same manner as in example 24 from 40 mg (0.11 mmol) of the compound of example 8A and 40 mg (0.12 mmol) of the compound of example 55A: 54 mg (77% of theory).
LC-MS [ method 2 ]]: Rt = 2.35 min; MS [ESIpos]: m/z = 644 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.72 (d, 1H), 7.75 (d, 2H), 7.63 (d, 2H), 7.59 (dd, 1H), 7.50 (d, 1H), 7.36-7.43 (m, 2H), 6.92 (d, 1H), 5.31-5.39 (m, 1H), 4.49-4.61 (m [AB], 2H), 4.23-4.33 (m, 1H), 3.95 (dd, 1H), 3.82 (dd, 1H), 3.23-3.29 (m, 1H), 3.11-3.20 (m, 1H), 2.92-3.03 (m, 2H), 1.15 (t, 3H)。
Example 34
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {1- (2, 3-dichlorophenyl) -2- [ (ethylsulfonyl) amino ] ethyl } acetamide (diastereomer II)
The title compound was obtained in the same manner as in example 24 from 40 mg (0.11 mmol) of the compound of example 8A and 40 mg (0.12 mmol) of the compound of example 56A: 56 mg (80% of theory).
LC-MS [ method 2 ]]: Rt = 2.34 min; MS [ESIpos]: m/z = 644 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.74 (d, 1H), 7.74 (d, 2H), 7.62 (d, 2H), 7.60 (dd, 1H), 7.50 (d, 1H), 7.37-7.43 (m, 2H), 6.89 (d, 1H), 5.34 (td, 1H), 4.46-4.63 (m [AB], 2H), 4.21-4.33 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.23-3.30 (m, 1H), 3.11-3.21 (m, 1H), 2.92-3.03 (m, 2H), 1.15 (t, 3H)。
Example 35
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { 2-hydroxy-1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (mixture of diastereomers)
The compound of example 59A (300 mg, 0.98 mmol) was prepared by reaction with hydrogen chloride in bisThe 4N solution in the alkane is stirred together for 10 minutes to deprotect, and subsequently the volatile components are removed on a rotary evaporator and dried in HV. The residue obtained is dissolved in 3 ml of DMF and then admixed with 202. mu.L (1.16 mmol) of N, N-diisopropylethylamine. In a separate flask 327 mg of the compound from example 8A (0.89 mmol) are stirred at room temperature for 20 minutes with 257 mg (1.34 mmol) of EDC and 181 mg (1.34 mmol) of HOBt in 4.8 ml of DMF. This solution was added to a solution of the amino alcohol, and the mixture was then reacted at room temperature for 20 minutes. 1 ml of 1N hydrochloric acid are then added and the complete reaction mixture is purified by preparative HPLC (method 10). This gives 324 mg (66% of theory) of the title compound.
LC-MS [ method 5 ]]: Rt = 1.07 min; MS [ESIpos]: m/z = 553 (M+H)+
The two diastereomers were separated by preparative chromatography on chiral phase (method 17 b): see examples 36 and 37.
Example 36
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { 2-hydroxy-1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer I)
The first eluting diastereomer obtained from the separation of 315 mg of the compound of example 35 by method 17b (147 mg).
Analytical chiral HPLC [ method 18a ]]: Rt = 9.82 min。
1H NMR (DMSO-d6, 400 MHz): δ = 8.71 (d, 1H), 7.75 (d, 2H), 7.69 (s, 1H), 7.53-7.66 (m, 5H), 6.91 (d, 1H), 5.02 (t, 1H), 4.91-4.98 (m, 1H), 4.49-4.59 (m [AB], 2H), 4.21-4.33 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.62 (t, 2H)。
Example 37
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { 2-hydroxy-1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer II)
The final eluting diastereomer obtained from the separation of 315 mg of the compound of example 35 by method 17b (147 mg).
Analytical chiral HPLC [ method 18a ]]: Rt = 13.98 min
1H NMR (DMSO-d6, 400 MHz): δ = 8.72 (d, 1H), 7.74 (d, 2H), 7.69 (s, 1H), 7.52-7.66 (m, 5H), 6.89 (d, 1H), 5.02 (t, 1H), 4.91-4.98 (m, 1H), 4.49-4.60 (m [AB], 2H), 4.21-4.33 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.62 (t, 2H)。
Example 38
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { 2-hydroxy-1- [2- (trifluoromethyl) phenyl ] ethyl } acetamide (mixture of diastereomers)
278 mg (0.76 mmol) of the compound from example 8A are introduced together with 184 mg (0.76 mmol) of the compound from example 61A, 219 mg (1.14 mmol) of EDC and 154 mg (1.14 mmol) of HOBt in 18 ml of DMF and then admixed with 265. mu.L (1.52 mmol) of N, N-diisopropylethylamine. The mixture is stirred overnight at room temperature, admixed with 1 ml of 1N hydrochloric acid and then purified by preparative HPLC (method 10). This gives 310 mg (74% of theory) of the title compound.
LC-MS [ method 4 ]]: Rt = 1.03 min; MS [ESIpos]: m/z = 553 (M+H)+
The two diastereomers were separated by preparative chromatography on chiral phase (method 17 e): see examples 39 and 40.
Example 39
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { 2-hydroxy-1- [2- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer I)
The first eluting diastereomer (134 mg) obtained from the separation of 310 mg of the compound of example 38 by method 17 e. The product was purified by preparative HPLC (method 10) to remove solvent residues. This gave 99 mg of the title compound.
Analytical chiral HPLC [ method 18a ]]: Rt = 2.12 min
1H NMR (DMSO-d6, 400 MHz): δ = 8.79 (d, 1H), 7.73 (d, 2H), 7.64-7.71 (m, 3H), 7.61 (d, 2H), 7.44-7.51 (m, 1H), 6.89 (d, 1H), 5.17-5.24 (m, 1H), 5.14 (t, 1H), 4.52 (q [AB], 2H), 4.19-4.31 (m, 1H), 3.95 (dd, 1H), 3.82 (dd, 1H), 3.54-3.62 (m, 1H), 3.44-3.53 (m, 1H)。
Example 40
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { 2-hydroxy-1- [2- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer II)
The final eluting diastereomer obtained from the separation of 310 mg of the compound of example 38 by method 17e (156 mg). The product was also purified by preparative HPLC (method 10) to remove solvent residues. This gave 128 mg of the title compound.
Analytical chiral HPLC [ method 18a ]]: Rt = 5.59 min
1H NMR (DMSO-d6, 400 MHz): δ = 8.79 (d, 1H), 7.74 (d, 2H), 7.65-7.70 (m, 3H), 7.62 (d, 2H), 7.44-7.50 (m, 1H), 6.91 (d, 1H), 5.18-5.26 (m, 1H), 5.15 (t, 1H), 4.46-4.57 (m [AB], 2H), 4.20-4.33 (m, 1H), 3.95 (dd, 1H), 3.82 (dd, 1H), 3.54-3.62 (m, 1H), 3.44-3.53 (m, 1H)。
EXAMPLE 41
N- [1- (2-chlorophenyl) -2-hydroxyethyl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (mixture of diastereomers)
355 mg (0.97 mmol) of the compound from example 8A, 223 mg (1.17 mmol) of EDC and 166 mg (1.17 mmol) of HOBt are stirred in 5 ml of DMF and 10 ml of acetonitrile at room temperature for 20 minutes. This solution was added dropwise to a solution of the amino alcohol of example 66A (200 mg, 1.17 mmol) in 10 ml of acetonitrile, and the mixture was reacted at room temperature for 30 minutes. 1 ml of 1N hydrochloric acid are then added and the complete reaction mixture is purified by preparative HPLC (method 10). This gives 400 mg (77% of theory) of the title compound.
LC-MS [ method 3 ]]: Rt= 1.15 min + 1.16 min, in each case MS [ ESIpos [ ]]: m/z = 519 (M+H)+
The two diastereomers were separated by preparative chromatography on chiral phase (method 17 f): see examples 42 and 43.
Example 42
N- [1- (2-chlorophenyl) -2-hydroxyethyl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (diastereomer I)
The first eluting diastereomer (186 mg) obtained from the separation of 400 mg of the compound of example 41 by method 17 f. The product was also purified by preparative HPLC (method 10) to remove solvent residues. This gave 153 mg of the title compound.
Analytical chiral HPLC [ method 18b ]: Rt = 5.30 min
1H NMR (DMSO-d6, 400 MHz): δ = 8.75 (d, 1H), 7.74 (d, 2H), 7.62 (d, 2H), 7.46 (dd, 1H), 7.41 (dd, 1H), 7.25-7.36 (m, 2H), 6.89 (d, 1H), 5.24 (td, 1H), 5.09 (t, 1H), 4.48-4.60 (m [AB], 2H), 4.20-4.32 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.57-3.65 (m, 1H), 3.46-3.54 (m, 1H)。
Example 43
N- [1- (2-chlorophenyl) -2-hydroxyethyl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (diastereomer II)
The final eluting diastereomer obtained from the separation of 400 mg of the compound of example 41 by method 17f (209 mg). The product was also purified by preparative HPLC (method 10) to remove solvent residues. This gave 156 mg of the title compound.
Analytical chiral HPLC [ method 18b]: Rt = 6.94 min
1H NMR (DMSO-d6, 400 MHz): δ = 8.74 (d, 1H), 7.75 (d, 2H), 7.63 (d, 2H), 7.46 (dd, 1H), 7.41 (dd, 1H), 7.24-7.36 (m, 2H), 6.91 (d, 1H), 5.25 (td, 1H), 5.09 (t, 1H), 4.54 (s, 2H), 4.22-4.32 (m, 1H), 3.95 (dd, 1H), 3.82 (dd, 1H), 3.57-3.65 (m, 1H), 3.45-3.54 (m, 1H)。
Example 44
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { (2R) -1-hydroxy-2- [3- (trifluoromethyl) phenyl ] propan-2-yl } acetamide
151 mg (0.42 mmol) of the compound of example 8A are stirred together with 100 mg (0.46 mmol) of the compound of example 69A, 119 mg (0.62 mmol) of EDC and 84 mg (0.62 mmol) of HOBt in 4 ml of DMF at room temperature overnight, mixed with 1 ml of 1N hydrochloric acid and then purified completely by preparative HPLC (method 10). This gives 91 mg (39% of theory) of the title compound.
LC-MS [ method 1 ]] Rt = 2.04 min; MS [ESIpos]: m/z = 567 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.33 (s, 1H), 7.74 (d, 2H), 7.60-7.66 (m, 4H), 7.48-7.57 (m, 2H), 6.89 (d, 1H), 5.12 (t, 1H), 4.48-4.60 (m [AB], 2H), 4.20-4.32 (m, 1H), 3.95 (dd, 1H), 3.81 (dd, 1H), 3.55-3.66 (m, 2H), 1.62 (s, 3H)。
Example 45
(2R) -2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [3- (trifluoromethyl) phenyl ] propyl carbamate
76 mg (0.21 mmol) of the compound from example 8A are introduced together with 75 mg (0.25 mmol) of the compound from example 71A, 48 mg (0.25 mmol) of EDC and 36 mg (0.25 mmol) of HOBt in 2 ml of DMF, 73. mu.L (0.42 mmol) of N, N-diisopropylethylamine are added and the mixture is stirred at room temperature overnight. It is mixed with 1 ml of 1N hydrochloric acid and then purified completely by preparative HPLC (method 10). This gives 78 mg of the title compound (58% of theory).
LC-MS [ method 3 ]] Rt = 1.23 min; MS [ESIpos]: m/z = 610 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.58 (s, 1H), 7.74 (d, 2H), 7.69 (d, 1H), 7.57-7.66 (m, 4H), 7.54 (t, 1H), 6.87 (d, 1H), 6.40-6.75 (br.s, 2H), 4.50 (s, 2H), 4.22-4.32 (m, 1H), 4.22 (d, 1H), 4.16 (d, 1H), 3.95 (dd, 1H), 3.81 (dd, 1H), 1.68 (s, 3H)。
Example 46
Carbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [3- (trifluoromethyl) phenyl ] ethyl ester (mixture of diastereomers)
599 mg (1.64 mmol) of the compound of example 8A are introduced together with 750 mg (1.96 mmol) of the compound of example 60A, 377 mg (1.96 mmol) of EDC and 279 mg (1.96 mmol) of HOBt in 20ml of DMF, 570. mu.L (3.27 mmol) of N, N-diisopropylethylamine are added and the mixture is stirred at room temperature overnight. It is mixed with 5 ml of 1N hydrochloric acid and then purified completely by preparative HPLC (method 10). This gives 450 mg of the title compound (46% of theory).
LC-MS [ method 5 ] ] Rt = 1.06 min; MS [ESIpos]: m/z = 596 (M+H)+
The two diastereomers were separated by preparative chromatography on chiral phase (method 17 a): see examples 47 and 48.
Example 47
Carbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [3- (trifluoromethyl) phenyl ] ethyl ester (diastereomer I)
The first eluting diastereomer (209 mg) obtained from the separation of 400 mg of the compound of example 46 by method 17 a. The product was also purified by preparative HPLC (method 10) to remove solvent residues. This gave 169 mg of the title compound.
Analytical chiral HPLC [ method 18a ]]: Rt = 7.44 min。
1H NMR (DMSO-d6, 400 MHz): δ = 8.88 (d, 1H), 7.70-7.78 (m, 3H), 7.56-7.70 (m, 5H), 6.92 (d, 1H), 6.39-6.79 (br.s, 2H), 5.12-5.20 (m, 1H), 4.45-4.60 (m [AB], 2H), 4.22-4.34 (m, 1H), 4.06-4.17 (m, 2H), 3.96 (dd, 1H), 3.83 (dd, 1H)。
Example 48
Carbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [3- (trifluoromethyl) phenyl ] ethyl ester (diastereomer II)
The final eluting diastereomer obtained from the separation of 450 mg of the compound of example 46 by method 17a (190 mg). The product was also purified by preparative HPLC (method 10) to remove solvent residues. This gave 167 mg of the title compound.
Analytical chiral HPLC [ method 18a ]]: Rt = 17.99 min
1H NMR (DMSO-d6, 400 MHz): δ = 8.89 (d, 1H), 7.70-7.77 (m, 3H), 7.56-7.70 (m, 5H), 6.90 (d, 1H), 6.45-6.77 (br.s, 2H), 5.12-5.19 (m, 1H), 4.53 (s, 2H), 4.21-4.33 (m, 1H), 4.07-4.17 (m, 2H), 3.96 (dd, 1H), 3.83 (dd, 1H)。
Example 49
Carbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [2- (trifluoromethyl) phenyl ] ethyl ester (mixture of diastereomers)
428 mg (1.17 mmol) of the compound from example 8A are stirred with 269 mg (1.41 mmol) of EDC and 200 mg (1.41 mmol) of HOBt in 10 ml of DMF and 40 ml of acetonitrile at room temperature for 10 minutes. This solution is added dropwise to a solution of 400 mg (1.41 mmol) of the compound from example 63A and 408. mu.L (2.34 mmol) of N, N-diisopropylethylamine in 50 ml of acetonitrile, and the mixture is stirred at room temperature overnight. It is then mixed with 1 ml of 1N hydrochloric acid and then purified completely by preparative HPLC (method 10). This gives 580 mg of the title compound (83% of theory).
LC-MS [ method 2 ]] Rt = 2.24 min; MS [ESIpos]: m/z = 596 (M+H)+
The two diastereomers were separated by preparative chromatography on chiral phase (method 17 d): see examples 50 and 51.
Example 50
Carbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [2- (trifluoromethyl) phenyl ] ethyl ester (diastereomer I)
The first eluting diastereomer obtained from the separation of 580 mg of the compound of example 49 by method 17d (297 mg). The product was also purified by preparative HPLC (method 10) to remove solvent residues. This gave 239 mg of the title compound.
Analytical chiral HPLC [ method 18c ]]: Rt = 3.26 min。
1H NMR (DMSO-d6, 400 MHz): δ = 8.97 (d, 1H), 7.68-7.78 (m, 5H), 7.62 (d, 2H), 7.52 (t, 1H), 6.92 (d, 1H), 6.40-6.81 (2 br. s, 2H), 5.36-5.44 (m, 1H), 4.49 (s, 2H), 4.21-4.33 (m, 1H), 4.13 (dd, 1H), 3.91-4.01 (m, 2H), 3.81 (dd, 1H)。
Example 51
Carbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [2- (trifluoromethyl) phenyl ] ethyl ester (diastereomer II)
The final eluting diastereomer obtained from the separation of 580 mg of the compound of example 49 by method 17d (280 mg). The product was also purified by preparative HPLC (method 10). This gave 222 mg of the title compound.
Analytical chiral HPLC [ method 18c ]]: Rt = 4.49 min。
1H NMR (DMSO-d6, 400 MHz): δ = 8.98 (d, 1H), 7.69-7.79 (m, 5H), 7.62 (d, 2H), 7.49-7.56 (m, 1H), 6.90 (d, 1H), 6.40-6.81 (2 br. s, 2H), 5.35-5.42 (m, 1H), 4.43-4.55 (m [AB], 2H), 4.19-4.32 (m, 1H), 4.13 (dd, 1H), 3.92-4.01 (m, 2H), 3.82 (dd, 1H)。
Example 52
(2R) -2- (3-chlorophenyl) -2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] ethyl carbamate
183 mg (59% of theory) of the title compound are obtained from 203 mg (0.55 mmol) of the compound of example 8A and 153 mg (0.61 mmol) of the compound of example 65A in the same manner as in example 1.
LC-MS [ method 3 ]] Rt = 1.19 min; MS [ESIpos]: m/z = 562 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.79 (d, 1H), 7.76 (d, 2H), 7.63 (d, 2H), 7.43 (s, 1H), 7.29-7.41 (m, 3H), 6.92 (d, 1H), 6.41-6.80 (2 br. s, 2H), 5.02-5.11 (m, 1H), 4.43-4.59 (m, 2H), 4.22-4.34 (m, 1H), 4.02-4.15 (m, 2H), 3.96 (dd, 1H), 3.83 (dd, 1H)。
Example 53
Carbamic acid 2- (2-chlorophenyl) -2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] ethyl ester (mixture of diastereomers)
606 mg (1.66 mmol) of the compound from example 8A are stirred with 382 mg (1.99 mmol) of EDC and 283 mg (1.99 mmol) of HOBt in 5 ml of DMF and 10 ml of acetonitrile at room temperature for 10 minutes. This solution is added dropwise to a solution of 500 mg (1.99 mmol) of the compound from example 68A and 578. mu.L (3.31 mmol) of N, N-diisopropylethylamine in 10 ml of acetonitrile and the mixture is stirred for a further 30 minutes at room temperature. It is mixed with 1 ml of 1N hydrochloric acid and then purified completely by preparative HPLC (method 10). This gives 446 mg of the title compound (48% of theory).
LC-MS [ method 5 ]] Rt = 1.01 min; MS [ESIpos]: m/z = 562 (M+H)+
The two diastereomers were separated by preparative chromatography on chiral phase (method 17 f): see examples 54 and 55.
Example 54
Carbamic acid 2- (2-chlorophenyl) -2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] ethyl ester (diastereomer I)
The final eluting diastereomer (227 mg) obtained from the separation of 443 mg of the compound of example 53 by method 17 f. The product was also purified by preparative HPLC (method 10) to remove solvent residues. This gave 200 mg of the title compound.
Analytical chiral HPLC [ method 18b]: Rt = 1.77 min
1H NMR (DMSO-d6, 400 MHz): δ = 8.92 (d, 1H), 7.75 (d, 2H), 7.63 (d, 2H), 7.51 (dd, 1H), 7.44 (dd, 1H), 7.29-7.40 (m, 2H), 6.92 (d, 1H), 6.43-6.80 (2 br.s, 2H), 5.40-5.47 (m, 1H), 4.45-4.57 (m [AB], 2H), 4.21-4.32 (m, 1H), 4.00-4.12 (m, 2H), 3.96 (dd, 1H), 3.82 (dd, 1H)。
Example 55
Carbamic acid 2- (2-chlorophenyl) -2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] ethyl ester (diastereomer II)
The final eluting diastereomer (231 mg) obtained from the isolation of 443 mg of the compound of example 53 by method 17 f. The product was also purified by preparative HPLC (method 10) to remove solvent residues. This gave 202 mg of the title compound.
Analytical chiral HPLC [ method 18b]: Rt = 2.46 min
1H NMR (DMSO-d6, 400 MHz): δ = 8.93 (d, 1H), 7.74 (d, 2H), 7.62 (d, 2H), 7.51 (dd, 1H), 7.45 (dd, 1H), 7.30-7.40 (m, 2H), 6.90 (d, 1H), 6.44-6.79 (2 br.s, 2H), 5.38-5.46 (m, 1H), 4.52 (s, 2H), 4.21-4.32 (m, 1H), 4.00-4.12 (m, 2H), 3.96 (dd, 1H), 3.82 (dd, 1H)。
Example 56
(2R) -2- (2-chlorophenyl) -2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] propyl carbamate ester
42 mg (0.12 mmol) of the compound from example 8A are stirred with 32 mg (about 90% pure, 0.13 mmol) of the compound from example 75A, 26 mg (0.14 mmol) of EDC, 17 mg (0.14 mmol) of HOBt in 1.3 ml of DMF at room temperature for 1 hour. The mixture was then purified completely by preparative HPLC (method 10). This gives 42 mg of the title compound (63% of theory).
LC-MS [ method 4 ]] Rt = 1.01 min; MS [ESIpos]: m/z = 576 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.58 (s, 1H), 7.74 (d, 2H), 7.62 (d, 2H), 7.46 (dd, 1H), 7.37 (dd, 1H), 7.22-7.32 (br. s, 2H), 6.89 (d, 1H), 6.45-6.75 (m, 2H), 4.45 (s, 2H), 4.36-4.44 (m, 2H), 4.20-4.33 (m, 1H), 3.93 (dd, 1H), 3.80 (dd, 1H), 1.74 (s, 3H)。
Example 57
N- {2- (carbamoylamino) -1- [3- (trifluoromethyl) phenyl ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (diastereomer I)
266 mg (0.45 mmol) of the compound from example 11 are added to 6 ml of methanol/water 1:1 and admixed with potassium cyanate (110 mg, 1.36 mmol) at room temperature. The mixture was heated at 40 ℃ for 90 minutes. After complete reaction, the mixture was cooled to room temperature and then purified completely by preparative HPLC (method 10). Drying in HV gave 232 mg (84% of theory) of the title compound.
LC-MS [ method 4 ]]: Rt = 1.02 min; MS [ESIpos]: m/z = 595 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.78 (d, 1H), 7.76 (d, 2H), 7.54-7.66 (m, 6H), 6.94 (d, 1H), 6.09 (t, 1H), 5.60 (s, 2H), 4.87-4.95 (m, 1H), 4.49 (s, 2H), 4.25-4.38 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.29-3.38 (m, 1H), 3.19-3.27 (m, 1H)。
Example 58
N- {2- (carbamoylamino) -1- [3- (trifluoromethyl) phenyl ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (diastereomer II)
180 mg (0.31 mmol) of the compound from example 12 are added to 3 ml of methanol/water 1:1 and admixed with potassium cyanate (75 mg, 0.92 mmol) at room temperature. The mixture was heated at 40 ℃ for 90 minutes. The methanol was removed on a rotary evaporator and the aqueous residue was diluted with 20 ml of water. The precipitated solid is isolated by filtration, washed with a small amount of water and dried in HV. This gives 146 mg (76% of theory) of the title compound.
LC-MS [ method 4 ]]: Rt = 1.02 min; MS [ESIpos]: m/z = 595 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.79 (d, 1H), 7.77 (d, 2H), 7.54-7.66 (m, 6H), 6.94 (d, 1H), 6.08 (t, 1H), 5.59 (s, 2H), 4.88-4.95 (m, 1H), 4.41-4.56 (m [AB], 2H), 4.25-4.37 (m, 1H), 3.97 (dd, 1H), 3.84 (dd, 1H), 3.29-3.38 (m, 1H), 3.16-3.27 (m, 1H)。
Example 59
N- {2- (carbamoylamino) -1- [2- (trifluoromethyl) phenyl ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (diastereomer I)
The title compound (190 mg, 79% of theory) was obtained from 230mg (0.39 mmol) of the compound of example 13 in the same manner as in example 57.
LC-MS [ method 3 ]]: Rt = 1.17 min; MS [ESIpos]: m/z = 595 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.84 (d, 1H), 7.77 (d, 2H), 7.62-7.74 (m, 5H), 7.48 (t, 1H), 6.95 (d, 1H), 6.22 (t, 1H), 5.58 (s, 2H), 5.06-5.13 (m, 1H), 4.39-4.51 (m [AB], 2H), 4.25-4.37 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.21-3.27 (m, 2H)。
Example 60
N- {2- (carbamoylamino) -1- [2- (trifluoromethyl) phenyl ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (diastereomer II)
The title compound (41 mg, 81% of theory) was obtained from 50 mg (85. mu. mol) of the compound of example 14 in the same manner as in example 57, but at room temperature.
LC-MS [ method 2 ]]: Rt = 2.19 min; MS [ESIpos]: m/z = 595 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.84 (d, 1H), 7.76 (d, 2H), 7.60-7.72 (m, 5H), 7.48 (t, 1H), 6.93 (d, 1H), 6.23 (t, 1H), 5.59 (s, 2H), 5.05-5.12 (m, 1H), 4.45 (s, 2H), 4.25-4.37 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.15-3.34 (m, 2H)。
Example 61
N- [2- (carbamoylamino) -1- (2, 3-dichlorophenyl) ethyl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (diastereomer I)
The title compound (90 mg, 77% of theory) was obtained from 116mg (0.20 mmol) of the compound of example 15 in the same manner as in example 57.
LC-MS [ method 3 ]]: Rt = 1.19 min; MS [ESIpos]: m/z = 595 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.91 (d, 1H), 7.77 (d, 2H), 7.63 (d, 2H), 7.52-7.59 (m, 1H), 7.34-7.40 (m, 2H), 6.94 (d, 1H), 6.19 (t, 1H), 5.60 (s, 2H), 5.12-5.20 (m, 1H), 4.40-4.55 (q [AB], 2H), 4.25-4.37 (m, 1H), 3.97 (dd, 1H), 3.84 (dd, 1H), 3.28-3.37 (m, 1H), 3.19-3.28 (m, 1H)。
Example 62
N- [2- (carbamoylamino) -1- (2, 3-dichlorophenyl) ethyl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (diastereomer II)
The title compound (153 mg, 85% of theory) was obtained from 177mg (0.30 mmol) of the compound of example 16 in the same manner as in example 57.
LC-MS [ method 3 ]]: Rt = 1.20 min; MS [ESIpos]: m/z = 595 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.91 (d, 1H), 7.76 (d, 2H), 7.63 (d, 2H), 7.52-7.59 (m, 1H), 7.34-7.40 (m, 2H), 6.94 (d, 1H), 6.19 (t, 1H), 5.61 (s, 2H), 5.12-5.19 (m, 1H), 4.48 (s, 2H), 4.26-4.38 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.29-3.38 (m, 1H), 3.18-3.27 (m, 1H)。
Example 63
Carbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (1E) -3,3, 3-trifluoroprop-1-en-1-yl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [3- (trifluoromethyl) phenyl ] ethyl ester (racemate)
100 mg (0.29 mmol) of the compound from example 77A are added to 3 ml of DMF and admixed with 98.3 mg (0.35 mmol) of the compound from example 60A, 66.1 mg (0.35 mmol) of EDC, 49 mg (0.35 mmol) of HOBt and 75. mu.L (0.43 mmol) of N, N-diisopropylethylamine. The mixture is stirred at room temperature for 30 minutes, admixed with 1 ml of 1N hydrochloric acid and then purified by preparative HPLC (method 10). This gives 140 mg (84% of theory) of the title compound.
LC/MS [ method 5 ]]: Rt = 1.16 min; m/z = 578 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 8.90 (d, 1H), 7.73 (s, 1H), 7.57-7.69 (m, 7H), 7.18 (dq, 1H), 6.87 (dq, 1H), 5.09-5.27 (m, 1H), 4.47-4.68 (m [AB], 2H), 3.99-4.21 (m, 2H)。
The enantiomer of example 63 was separated by preparative chromatography on chiral phase (method 15 b): see example 64 and example 65.
Example 64
Carbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (1E) -3,3, 3-trifluoroprop-1-en-1-yl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [3- (trifluoromethyl) phenyl ] ethyl ester (enantiomer I)
The first eluting enantiomer (64 mg) obtained from the separation of 135 mg of the compound of example 63 by method 15 b.
Analytical chiral HPLC [ method 16 ]]: Rt = 1.50 min。
Example 65
Carbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (1E) -3,3, 3-trifluoroprop-1-en-1-yl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [3- (trifluoromethyl) phenyl ] ethyl ester (enantiomer II)
The last eluting enantiomer (62 mg) obtained from the separation of 135 mg of the compound of example 63 by method 15 b.
Analytical chiral HPLC [ method 16 ]]: Rt = 1.90 min。
Example 66
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { 3-hydroxy-1- [3- (trifluoromethyl) phenyl ] propyl } acetamide (mixture of diastereomers)
The title compound was obtained in the same manner as in example 24 from 100 mg (0.27 mmol) of the compound of example 8A and 84 mg (0.33 mmol) of the compound of example 78A: 112 mg (72% of theory).
LC-MS [ method 3 ]] Rt = 1.22 min; MS [ESIpos]: m/z = 567 (M+H)+
The diastereomer of example 66 was separated by preparative chromatography on chiral phase (method 8): see example 67 and example 68.
Example 67
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { 3-hydroxy-1- [3- (trifluoromethyl) phenyl ] propyl } acetamide (diastereomer I)
The first eluting diastereomer (50 mg) obtained from the chromatographic separation of 112 mg of the compound of example 66 by method 8.
Analytical chiral HPLC [ method 9 ]]: Rt = 3.25 min。
1H NMR (DMSO-d6, 400 MHz): δ = 8.71 (d, 1H), 7.73 (dd, 2H), 7.54-7.66 (m, 6H), 6.90 (d, 1H), 4.97-5.05 (m, 1H), 4.58 (t, 1H), 4.42-4.56 (m [AB], 2H), 4.21-4.33 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.32-3.47 (m, 2H), 1.77-1.96 (m, 2H)。
Example 68
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { 3-hydroxy-1- [3- (trifluoromethyl) phenyl ] propyl } acetamide (diastereomer II)
The final eluting diastereomer (47 mg) obtained from chromatographic separation of 112 mg of the compound of example 66 by method 8.
Analytical chiral HPLC [ method 9 ]]: Rt = 4.41 min。
1H NMR (DMSO-d6, 400 MHz): δ = 8.70 (d, 1H), 7.74 (dd, 2H), 7.53-7.66 (m, 6H), 6.92 (d, 1H), 4.98-5.08 (m, 1H), 4.59 (t, 1H), 4.49 (s, 2H), 4.21-4.33 (m, 1H), 3.95 (dd, 1H), 3.82 (dd, 1H), 3.32-3.47 (m, 2H), 1.77-1.96 (m, 2H)。
Example 69
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { (1S) -3-hydroxy-1- [2- (trifluoromethyl) phenyl ] propyl } acetamide
The title compound was obtained in the same manner as in example 49 from 167 mg (0.46 mmol) of the compound of example 8A and 140 mg (0.55 mmol) of the compound of example 80A: 152 mg (58% of theory).
LC-MS [ method 3 ]] Rt = 1.21 min; MS [ESIpos]: m/z = 567 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.75 (d, 1H), 7.74 (d, 2H), 7.64-7.70 (m, 3H), 7.62 (d, 2H), 7.41-7.50 (m, 1H), 6.90 (d, 1H), 5.20-5.28 (m, 1H), 4.57 (t, 1H), 4.40-4.55 (m [AB], 2H), 4.21-4.32 (m, 1H), 3.95 (dd, 1H), 3.81 (dd, 1H), 3.41-3.56 (m, 2H), 1.69-1.87 (m, 2H)。
Example 70
(3S) -3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -3- [2- (trifluoromethyl) phenyl ] propyl carbamate
The title compound was obtained in the same manner as in example 49 from 194 mg (0.53 mmol) of the compound of example 8A and 190 mg (0.64 mmol) of the compound of example 81A: 138 mg (43% of theory).
LC-MS [ method 5 ]] Rt = 1.04 min; MS [ESIpos]: m/z = 610 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.84 (d, 1H), 7.65-7.76 (m, 5H), 7.62 (d, 2H), 7.42-7.51 (m, 1H), 6.90 (d, 1H), 6.33-6.58 (br. s, 2H), 5.20-5.28 (m, 1H), 4.57 (t, 1H), 4.42-4.59 (m [AB], 2H), 4.01-4.08 (m, 1H), 3.86-3.99 (m, 2H), 3.82 (dd, 1H), 1.83-1.99 (m, 2H)。
Example 71
Carbamic acid 3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -3- (2, 3-dichlorophenyl) propyl ester (mixture of diastereomers)
The title compound was obtained in the same manner as in example 1 from 630 mg (1.72 mmol) of the compound of example 8A and 568 mg (1.90 mmol) of the compound of example 88A: 809 mg (77% of theory).
LC-MS [ method 3 ]] Rt = 1.22 + 1.23 min; MS [ESIpos]: m/z = 610 (M+H)+
The diastereomer of example 71 was separated by preparative chromatography on chiral phase (method 13): see example 72 and example 73.
Example 72
Carbamic acid 3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -3- (2, 3-dichlorophenyl) propyl ester (diastereomer I)
The first eluting diastereomer (270 mg) obtained from the chromatographic separation of 800 mg of the compound of example 71 by method 13.
LC-MS [ method 5 ]] Rt = 1.07 min; MS [ESIpos]: m/z = 610 (M+H)+
Analytical chiral HPLC [ method 14]: Rt = 5.61 min。
1H NMR (DMSO-d6, 400 MHz): δ = 8.83-8.90 (m, 1H), 7.75 (d, 2H), 7.63 (d, 2H), 7.54 (d, 1H), 7.44 (dd, 1H), 7.37 (t, 1H), 6.91 (d, 1H), 6.32-6.70 (br. s, 2H), 5.25-5.33 (m, 1H), 4.47-4.60 (m [AB], 2H), 4.20-4.34 (m, 1H), 3.88-4.04 (m, 3H), 3.82 (dd, 1H), 1.83-2.02 (m, 2H)。
Example 73
Carbamic acid 3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -3- (2, 3-dichlorophenyl) propyl ester (diastereomer II)
The final eluting diastereomer (270 mg) obtained from the chromatographic separation of 800 mg of the compound of example 71 by method 13.
LC-MS [ method 5 ]] Rt = 1.07 min; MS [ESIpos]: m/z = 610 (M+H)+
Analytical chiral HPLC [ method 14]: Rt = 14.96 min。
1H NMR (DMSO-d6, 400 MHz): δ = 8.87 (d, 1H), 7.74 (d, 2H), 7.62 (d, 2H), 7.55 (dd, 1H), 7.44 (dd, 1H), 7.38 (t, 1H), 6.90 (d, 1H), 6.34-6.69 (br.s, 2H), 5.24-5.32 (m, 1H), 4.44-4.62 (m [AB], 2H), 4.21-4.32 (m, 1H), 3.88-4.05 (m, 3H), 3.82 (dd, 1H), 1.83-2.02 (m, 2H)。
Example 74
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- [ (1R) -1- (2, 3-dimethylphenyl) -2-hydroxyethyl ] acetamide
50 mg (0.14 mmol) of the compound from example 8A, 39 mg (0.21 mmol) of EDC and 28 mg (0.21 mmol) of HOBt are stirred together in 1.2 ml of DMF at room temperature for 20 minutes and then admixed with 30 mg of (2R) -2-amino-2- (2, 3-dimethylphenyl) ethanol hydrochloride (0.15 mmol) and 31. mu.L (0.18 mmol) of N, N-diisopropylamine. The mixture was stirred at room temperature for 2 hours. Subsequently, the complete reaction mixture was purified by preparative HPLC (method 10). This gives 58 mg (81% of theory) of the title compound.
LC-MS [ method 5 ]]: Rt = 1.04 min; m/z = 513 (M+H)+
1H NMR (DMSO-d6,400 MHz): δ = 8.60 (d, 1H), 7.74 (d, 2H), 7.62 (d, 2H), 7.16 (dd, 1H), 7.01-7.08 (m, 2H), 6.89 (d, 1H), 5.08-5.16 (m, 1H), 4.94 (t, 1H), 4.41-4.56 (m [AB], 2H), 4.21-4.32 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.41-3.56 (m, 2H), 2.23 (s, 3H), 2.20 (s, 3H)。
Example 75
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- [ (1R) -1- (3-cyanophenyl) -2-hydroxyethyl ] acetamide
From 50 mg of the compound of example 8A (0.14 mmol) and 30 mg of (2R) -2-amino-2- (3-cyanophenyl) ethanol hydrochloride (0.15 mmol), 42 mg (60% of theory) of the title compound are obtained in the same manner as in example 74.
LC-MS [ method 5 ]]: Rt = 0.95 min; m/z = 510 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.68 (d, 1H), 7.79 (s, 1H), 7.70-7.77 (m, 3H), 7.68 (d, 1H), 7.62 (d, 2H), 7.54 (t, 1H), 6.90 (d, 1H), 5.03 (t, 1H), 4.87-4.94 (m, 1H), 4.56 (s, 2H), 4.22-4.33 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.58-3.64 (m, 2H)。
Example 76
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- [ (1R) -1- (3-chlorophenyl) -2-hydroxyethyl ] acetamide
54 mg (76% of theory) of the title compound are obtained in the same manner as in example 74 from 50 mg of the compound from example 8A (0.14 mmol) and 31 mg of (2R) -2-amino-2- (3-chlorophenyl) ethanol hydrochloride (0.15 mmol).
LC-MS [ method 5 ]]: Rt = 1.03 min; m/z = 519 (M+H)+
1H NMR (DMSO-d6,400 MHz): δ = 8.62 (d, 1H), 7.76 (d, 2H), 7.62 (d, 2H), 7.39 (s, 1H), 7.26-7.38 (m, 3H), 6.92 (d, 1H), 5.00 (t, 1H), 4.82-4.90 (m, 1H), 4.47-4.59 (m [AB], 2H), 4.21-4.35 (m, 1H), 3.96 (dd, 1H), 3.83 (dd, 1H), 3.55-3.63 (m, 2H)。
Example 77
N- [ (2R) -2- (2-chlorophenyl) -1-hydroxypropan-2-yl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide
33 mg (36% of theory) of the title compound are obtained in the same manner as in example 1 from 62 mg of the compound of example 8A (0.17 mmol) and 49 mg of the compound of example 74A (0.19 mmol).
LC-MS [ method 4 ]]: Rt = 1.02 min; m/z = 533 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.27 (s, 1H), 7.74 (d, 2H), 7.62 (d, 2H), 7.47 (dd, 1H), 7.33 (dd, 1H), 7.18-7.28 (m, 2H), 6.89 (d, 1H), 5.11 (t, 1H), 4.48 (s, 2H), 4.19-4.33 (m, 1H), 3.86-3.97 (m, 2H), 3.73-3.85 (m, 2H), 1.68 (s, 3H)。
Example 78
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {3,3, 3-trifluoro-2-hydroxy-1- [3- (trifluoromethyl) phenyl ] propyl } acetamide (mixture of diastereomers)
113 mg (0.31 mmol) of the compound from example 8A, 93 mg (0.34 mmol) of the amino alcohol from example 99A, 83 mg (0.43 mmol) of EDC and 59 mg (0.43 mmol) of HOBt are stirred together in 4.3 ml of DMF at room temperature for 2 hours. Subsequently, the reaction mixture was purified by preparative HPLC (method 10). This gives 162 mg (80% of theory) of the title compound as a mixture of 4 diastereomers.
LC-MS [ method 5 ]]: Rt = 1.14 min; MS [ESIpos]: m/z = 621 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ = 8.97 + 8.93 + 8.92 (3x d, 1H), 7.86 + 7.81 (2x s, 1H), 7.55-7.77 (m, 7H), 6.82-6.93 (5x d, 1.4H), 6.72 (d, 0.6H), 5.41 (br d, 0.4H), 5.15-5.21 (m, 0.6H), 4.42-4.66 (m, 2H), 4.20-4.40 (m, 2H), 3.92-4.01 (br d, 1H), 3.77-3.87 (2x dd, 1H)。
Example 79
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- [1- (2, 3-dichlorophenyl) -3-hydroxypropyl ] acetamide (mixture of diastereomers)
100 mg (0.27 mmol) of the compound from example 8A are dissolved in 4 ml of DMF and mixed with 68 mg (0.36 mmol) of EDC and with 44 mg (0.33 mmol) of HOBt and stirred at room temperature for 10 minutes. 66 mg (0.30 mmol) of the compound from example 90A are subsequently added and the mixture is stirred at room temperature for 16 hours. For the work-up, 10 ml of water were added and the mixture was extracted twice with 10 ml of ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The crude product was purified by preparative HPLC [ method 19 ]. This gives 44 mg (28% of theory) of the target compound.
LC-MS [ method 3 ]] Rt = 1.24 min; MS [ESIpos]: m/z = 567/569/571 (M+H)+
The diastereoisomeric mixture of example 79 was separated into diastereoisomers by preparative chromatography on chiral phase (method 11 d): see example 80 and example 81.
Example 80
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- [1- (2, 3-dichlorophenyl) -3-hydroxypropyl ] acetamide (diastereomer I)
The diastereomer eluted first from the separation of example 79.
Yield: 21 mg (14% of theory)
Rt= 4.04 min [ method 12c]
LC-MS [ method 5 ]] Rt = 1.07 min; MS [ESIpos]: m/z = 567/569/571 (M+H)+
1H-NMR (400 MHz, CDCl3): δ = 1.92-2.03 (m, 1H), 2.04-2.15 (m, 1H), 3.02 (br.s, 1H), 3.55-3.66 (m, 1H), 3.68-3.78 (m, 1H), 3.93-4.05 (m, 2H), 4.47-4.60 (m, 2H), 4.70 (d, 1H), 5.26 (d, 1H), 5.49 (td, 1H), 7.15-7.23 (m, 1H), 7.27-7.31 (m, 1H), 7.35-7.42 (m, 1H), 7.50 (d, 2H), 7.57-7.71 (m, 3H)。
Example 81
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- [1- (2, 3-dichlorophenyl) -3-hydroxypropyl ] acetamide (diastereomer II)
The final eluting diastereomer from the separation of example 79.
Yield: 20 mg (13% of theory).
Rt= 4.84 min method 12c]
LC-MS [ method 5 ]] Rt = 1.07 min; MS [ESIpos]: m/z = 567 (M+H)+
1H-NMR (400 MHz, CDCl3): δ = 1.88-2.00 (m, 1H), 2.04-2.15 (m, 1H), 3.05 (br.s, 1H), 3.54-3.68 (m, 1H), 3.70-3.81 (m, 1H), 3.91-4.06 (m, 2H), 4.51 (d, 1H), 4.54-4.62 (m, 1H), 4.69 (d, 1H), 5.22 (d, 1H), 5.49 (td, 1H), 7.10-7.23 (m, 2H), 7.37 (dd, 1H), 7.45 (d, 1H), 7.52 (d, 2H), 7.65 (d, 2H)。
Example 82
N- [1- (2-chlorophenyl) -3-hydroxypropyl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (mixture of diastereomers)
100 mg (0.27 mmol) of the compound from example 8A are dissolved in 1 ml of DMF and mixed with 79 mg (0.41 mmol) of EDC and 55 mg (0.41 mmol) of HOBt and stirred at room temperature for 10 minutes. 67 mg (0.30 mmol) of 3-amino-3- (2-chlorophenyl) propane-1-ol hydrochloride and 63. mu.L (0.38 mmol) of N, N-diisopropylethylamine were then added and the mixture was stirred at room temperature for 16 hours. For the work-up, 10 ml of water were added and the mixture was extracted twice with 10 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The crude product was purified by preparative HPLC [ method 19 ]. This gives 93 mg (64% of theory) of the target compound.
LC-MS [ method 3 ]] Rt = 1.16 min; MS [ESIpos]: m/z = 533/535 (M+H)+
The diastereoisomeric mixture of example 82 was separated into diastereoisomers by preparative chromatography on chiral phase (method 8 a): see example 83 and example 84.
Example 83
N- [1- (2-chlorophenyl) -3-hydroxypropyl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (diastereomer I)
The diastereomer eluted first from the separation of example 82.
Yield: 34 mg (23% of theory).
Rt= 2.00 min [ method 14 ]]
LC-MS [ method 6 ]] Rt = 2.21 min; MS [ESIpos]: m/z = 533/535 (M+H)+
1H-NMR (400 MHz, CDCl3): δ = 1.93-2.15 (m, 2H), 3.26 (br.s, 1H), 3.57-3.67 (m, 1H), 3.68-3.77 (m, 1H), 3.89-4.05 (m, 2H), 4.48-4.62 (m, 2H), 4.72 (d, 1H), 5.36-5.45 (m, 1H), 5.49 (td, 1H), 7.17-7.25 (m, 1H), 7.35 (d, 2H), 7.49 (d, 2H), 7.57 (d, 1H), 7.64 (d, 2H)。
Example 84
N- [1- (2-chlorophenyl) -3-hydroxypropyl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (diastereomer II)
The final eluting diastereomer from the separation of example 82.
Yield: 38 mg (26% of theory).
Rt= 2.92 min method 14]
LC-MS [ method 1 ]] Rt = 1.86 min; MS [ESIpos]: m/z = 533/535 (M+H)+
1H-NMR (400 MHz, CDCl3): δ = 1.90-2.15 (m, 2H), 3.56-3.68 (m, 1H), 3.69-3.79 (m, 1H), 3.87-4.06 (m, 2H), 4.50 (d, 1H), 4.53-4.63 (m, 1H), 4.70 (d, 1H), 5.48 (td, 1H), 7.16-7.23 (m, 2H), 7.30-7.40 (m, 2H), 7.51 (d, 2H), 7.65 (d, 2H)。
Example 85
2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [1- (2-chlorophenyl) -3-hydroxypropyl ] acetamide (racemate)
In the same manner as the compound in example 82, 30 mg (0.10 mmol) of [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid (for preparation, see WO 2007/134862, example 88A) was reacted. This gives 14 mg (30% of theory) of the target compound.
LC-MS [ method 3 ]] Rt = 1.12min; MS [ESIpos]: m/z = 461/463 (M+H)+
1H-NMR (400 MHz, CDCl3): δ = 0.67-0.79 (m, 2H), 0.97-1.09 (m, 2H), 1.92-2.15 (m, 2H), 2.67 (br.s, 1H), 2.99 (tt, 1H), 3.57-3.79 (m, 2H), 4.45-4.65 (m, 2H), 5.51 (td, 1H), 7.17-7.25 (m, 2H), 7.30-7.39 (m, 2H), 7.47 (d, 2H), 7.68 (d, 2H)。
Example 86
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- [ 3-hydroxy-1- (2-methylphenyl) propyl ] acetamide (mixture of diastereomers)
250 mg (0.68 mmol) of the compound from example 8A are dissolved in 5 ml of DMF and mixed with 170 mg (0.89 mmol) of EDC and with 111 mg (0.82 mmol) of HOBt and stirred at room temperature for 10 minutes. Then 124 mg (0.75 mmol) of 3-amino-3- (2-methylphenyl) propan-1-ol are added and the mixture is stirred at room temperature for 16 h. For the work-up, 10 ml of water were added and the mixture was extracted twice with 10 ml of ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The crude product was purified by preparative HPLC [ method 19 ]. This gives 181 mg (52% of theory) of the target compound.
LC-MS [ method 1 ]] Rt= 1.84 and 1.86 min, MS [ ESIpos]: m/z = 513 (M+H)+
The diastereoisomeric mixture of example 86 was separated into diastereoisomers by preparative chromatography on chiral phase (method 8 a): see example 87 and example 88.
Example 87
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- [ 3-hydroxy-1- (2-methylphenyl) propyl ] acetamide (diastereomer I)
The diastereomer eluted first from the separation of example 86.
Yield: 86 mg (25% of theory).
Rt= 1.80 min method 14]
LC-MS [ method 6 ]] Rt = 2.19 min; MS [ESIpos]: m/z = 513 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 1.65-1.91 (m, 2H), 2.32 (s, 3H), 3.33-3.48 (m, 2H), 3.81 (dd, 1H), 3.95 (dd, 1H), 4.20-4.34 (m, 1H), 4.35-4.57 (m, 3H), 5.06-5.18 (m, 1H), 6.90 (d, 1H), 7.11 (d, 2H), 7.14-7.21 (m, 1H), 7.31 (d, 1H), 7.62 (d, 2H), 7.74 (d, 2H), 8.59 (d, 1H)。
Example 88
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- [ 3-hydroxy-1- (2-methylphenyl) propyl ] acetamide (diastereomer II)
The final eluting diastereomer from the separation of example 86.
Yield: 87 mg (25% of theory).
Rt= 2.76 min [ method 14 ]]
LC-MS [ method 6 ]] Rt = 2.21 min; MS [ESIpos]: m/z = 513 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 1.68-1.89 (m, 2H), 2.32 (s, 3H), 3.34-3.49 (m, 2H), 3.82 (dd, 1H), 3.95 (dd, 1H), 4.20-4.33 (m, 1H), 4.45 (dd, 2H), 4.53 (t, 1H), 5.08-5.18 (m, 1H), 6.91 (d, 1H), 7.11 (d, 2H), 7.14-7.20 (m, 1H), 7.31 (d, 1H), 7.59-7.65 (m, 2H), 7.74 (d, 2H), 8.58 (d, 1H)。
Example 89
2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [ 3-hydroxy-1- (3-methoxyphenyl) propyl ] acetamide (racemate)
In the same manner as the compound of example 86, 30 mg (0.10 mmol) of [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid (for preparation see WO 2007/134862, example 88A) and 20 mg (0.11 mmol) of 3-amino-3- (3-methoxyphenyl) propan-1-ol were reacted. This gives 30 mg (63% of theory) of the target compound.
LC-MS [ method 3 ]] Rt = 1.08 min; MS [ESIpos]: m/z = 456 (M+H)+
1H-NMR (400 MHz, CDCl3): δ = 0.69-0.80 (m, 2H), 0.97-1.08 (m, 2H), 1.78-1.90 (m, 1H), 2.05-2.17 (m, 1H), 2.86 (br.s, 1H), 2.98 (tt, 1H), 3.57-3.74 (m, 2H), 3.77 (s, 3H), 4.55 (q, 2H), 5.20 (td, 1H), 6.75-6.84 (m, 2H), 6.87 (d, 1H), 7.04 (d, 1H), 7.21-7.25 (m, 1H), 7.46 (d, 2H), 7.67 (d, 2H)。
Example 90
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- (3,3, 3-trifluoro-1-phenylpropyl) acetamide (mixture of diastereomers)
In the same manner as the compound of example 86, 50 mg (0.14 mmol) of the compound of example 8A and 28 mg (0.15 mmol) of 3,3, 3-trifluoro-1-phenylpropan-1-amine were reacted. This gives 44 mg (59% of theory) of the target compound.
LC-MS [ method 3 ]] Rt = 1.30 min; MS [ESIpos]: m/z = 537 (M+H)+
1H-NMR (400 MHz, CDCl3): δ = 2.53-2.81 (m, 2H), 3.92-4.07 (m, 2H), 4.43-4.67 (m, 4H), 5.28-5.37 (m, 1H), 6.70 (dd, 1H), 7.27-7.40 (m, 5H), 7.46-7.56 (m, 4H)。
Example 91
N- [1- (3-chlorophenyl) -3-hydroxypropyl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (mixture of diastereomers)
48 mg (65% of theory) of the title compound are obtained in the same manner as for the compound of example 79 from 50 mg (0.14 mmol) of the compound of example 8A and 28 mg (0.15 mmol) of 3-amino-3- (3-chlorophenyl) propan-1-ol.
LC-MS [ method 1 ]] Rt= 1.89 and 1.90 min, MS [ ESIpos]: m/z = 533 (M+H)+
1H-NMR (400 MHz, CDCl3) δ = 1.78-1.91 (m, 1H), 2.00-2.15 (m, 1H), 3.14 (br.s, 0.5H), 3.25 (br.s, 0.5H), 3.54-3.74 (m, 2H), 3.89-4.06 (m, 2H), 4.43-4.74 (m, 3H), 5.10-5.22 (m, 1H), 5.28-5.40 (m, 1H), 7.10-7.30 (m, 4.5H), 7.42 (d, 0.5H), 7.46-7.53 (m, 2H), 7.64 (m, 2H) (partial resolution of signals of double recombination of diastereomer mixtures).
Example 92
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- [1- (2-fluorophenyl) -3-hydroxypropyl ] acetamide (mixture of diastereomers)
39 mg (0.07 mmol) of the compound from example 93A are dissolved in 2 ml of 1, 2-dimethoxyethane and the solution obtained is mixed successively at room temperature with 4.1 mg (0.11 mmol) of sodium borohydride and 0.6 mg (0.014 mmol) of lithium chloride. The mixture was then stirred at 85 ℃ for 16 hours. For the work-up, 10 ml of saturated aqueous sodium potassium tartrate solution were added and the mixture was extracted three times with 10 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The crude product was purified by preparative HPLC [ method 19 ]. This gives 19 mg (49% of theory) of the target compound.
LC-MS [ method 6 ]] Rt = 2.13 min; MS [ESIpos]: m/z = 517 (M+H)+
1H-NMR (400 MHz, CDCl3): δ = 1.92-2.11 (m, 2H), 3.55-3.76 (m, 2H), 3.89-4.07 (m, 2H), 4.43-4.77 (m, 3H), 5.31-5.44 (m, 1H), 6.98-7.15 (m, 2H), 7.17-7.39 (m, 2H), 7.46-7.54 (m, 2H), 7.59-7.68 (m, 2H)。
Example 93
Carbamic acid 3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -3- (2-fluorophenyl) propyl ester (mixture of diastereomers)
354 mg (0.97 mmol) of the compound from example 8A are dissolved in 3 ml of DMF and mixed with 260 mg (1.36 mmol) of EDC and 183 mg (1.36 mmol) of HOBt and stirred at room temperature for 10 minutes. 265 mg (1.07 mmol) of the compound from example 89A and 192. mu.L (1.16 mmol) of N, N-diisopropylethylamine were then added and the mixture was stirred at room temperature for 2 hours. For work-up, it is diluted with 5 ml of DMF and the crude product is purified directly by preparative HPLC [ method 19 ]. This gives 420 mg (77% of theory) of the target compound.
LC-MS [ method 5 ]] Rt = 0.99 min; MS [ESIpos]: m/z = 560 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 1.74-2.09 (m, 2H), 3.36-3.47 (m, 1H), 3.72-4.03 (m, 3H), 4.19-4.36 (m, 1H), 4.38-4.60 (m, 2H), 5.10-5.25 (m, 1H), 6.50 (br.s, 2H), 6.86-6.95 (m, 1H), 7.09-7.23 (m, 2H), 7.24-7.36 (m, 1H), 7.36-7.46 (m, 1H), 7.56-7.67 (m, 2H), 7.69-7.78 (m, 2H), 8.57-8.77 (m, 1H)。
Example 94
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- (3,3, 3-trifluoro-2-hydroxy-1-phenylpropyl) acetamide (mixture of diastereomers)
In the same manner as the compound of example 93, 100 mg (0.27 mmol) of the compound of example 8A and 73 mg (0.30 mmol) of 3-amino-1, 1, 1-trifluoro-3-phenylpropan-2-ol hydrochloride were reacted. This gives 102 mg (63% of theory) of the target compound as a mixture of diastereomers.
LC-MS [ method 2 ]] Rt = 2.29 min; MS [ESIpos]: m/z = 552 (M+H)+
1H-NMR (400 MHz, CDCl3): δ = 3.88-4.07 (m, 2H), 4.15-4.26 (m, 1H), 4.42-4.75 (m, 5H), 4.97-5.09 (m, 1H), 5.37 (dd, 1H), 7.15-7.41 (m, 5H), 7.44-7.53 (m, 2H), 7.56-7.65 (m, 2H)。
Example 95
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- [1- (2, 3-difluorophenyl) -2-hydroxyethyl ] acetamide (mixture of diastereomers)
128 mg (0.27 mmol) of the compound from example 8A are dissolved in 1 ml of DMF and mixed with 83 mg (0.43 mmol) of EDC and with 58 mg (0.43 mmol) of HOBt and stirred at room temperature for 10 minutes. 79 mg (0.37 mmol) of the compound from example 92A and 51. mu.L (0.37 mmol) of triethylamine are subsequently added and the mixture is stirred at room temperature for 16 hours. For the work-up, 10 ml of water were added and the mixture was extracted twice with 10 ml of ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The crude product was purified by preparative HPLC [ method 19 ]. This gives 118 mg (68% of theory) of the target compound.
LC-MS [ method 4 ]] Rt = 0.99 min; MS [ESIpos]: m/z = 521 (M+H)+
1H-NMR (400 MHz, CDCl3) δ = 3.13-3.25 (m, H), 3.45-3.52 (m, H), 3.58-3.70 (m, H), 3.74-3.83 (m, H), 3.83-4.10 (m, H), 4.46-4.57 (m, H), 4.58-4.78 (m, H), 5.25 (d, H), 5.29-5.40 (m, H), 5.62 (d, H), 6.95 (d, H), 6.99-7.16 (m, H), 7.48 (dd, H), 7.54 (d, H), 7.62 (d, H), 7.68 (d, H) (partial resolution of signals of double recombination of diastereomer mixtures). ).
Examples
96
2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 2-hydroxy-1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (racemate)
In the same manner as the compound of example 95, 48 mg (0.16 mmol) of [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid (for preparation see WO 2007/134862, example 88A) and 58 mg (0.18 mmol) of the compound of example 91A were reacted. This gives 61 mg (77% of theory) of the target compound.
LC-MS [ method 4 ]] Rt = 1.02 min; MS [ESIpos]: m/z = 481 (M+H)+
1H-NMR (400 MHz, CDCl3): δ = 0.72-0.82 (m, 2H), 0.99-1.09 (m, 2H), 2.36-2.45 (m, 1H), 3.00 (spt, 1H), 3.83-4.00 (m, 2H), 4.53-4.67 (m, 2H), 5.13-5.20 (m, 1H), 7.43-7.50 (m, 3H), 7.50-7.58 (m, 3H), 7.69 (d, 2H)。
Example 97
{2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid methyl ester (mixture of diastereomers)
393 mg (1.07 mmol) of the compound from example 8A, 353 mg (1.18 mmol) of the compound from example 138A, 247 mg (1.29 mmol) of EDC, 174 mg (1.29 mmol) of HOBt and 225. mu.L (1.29 mmol) of N, N-diisopropylethylamine are stirred in 13 ml of DMF at room temperature for 1 hour. The entire reaction solution was purified by preparative HPLC [ method 23 ]. The appropriate fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 416 mg (64% of theory) of the title compound as a mixture of diastereomers (ratio 20:78 according to analytical HPLC [ method 22 ]).
LC-MS [ method 5 ]] Rt = 1.09 min; MS [ESIpos]: m/z = 610 (M+H)+
The two diastereomers were separated by preparative HPLC on chiral phase [ method 21a ]: see example 98 and example 99.
Example 98
{2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid methyl ester (diastereomer I)
The first eluting diastereomer (51 mg, d.e. > 99.5%) obtained from chromatographic separation [ method 21a ] of 416 mg of the compound of example 97.
Chiral analytical HPLC [ method 22]] : Rt = 3.52 min。
LC-MS [ method 4 ]] Rt = 1.11 min; MS [ESIpos]: m/z = 610 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 3.22-3.40 (m, 2H), 3.47 (s, 3 H), 3.83 (dd, 1H), 3.96(dd, 1H), 4.22-4.35 (m, 1H), 4.51 (s, 2H), 5.02 (q, 1 H), 6.91 (d, 1 H), 7.26 (t, 1 H), 7.54-7.65 (m, 5H), 7.66 (s, 1H), 7.75 (d, 2H), 8.68 (d, 1H)。
Example 99
{2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid methyl ester (diastereomer II)
The final eluting diastereomer obtained from chromatographic separation of 416 mg of the compound of example 97 by method 21 a. The resulting product (238 mg, d.e. > 99.5%) was further purified by preparative HPLC [ method 20 ]. This gave 180 mg of the title compound.
Chiral analytical HPLC [ method 22 ]] : Rt = 4.81 min。
LC-MS [ method 5 ]] Rt = 1.11 min; MS [ESIpos]: m/z = 610 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 3.23-3.39 (m, 2H), 3.47 (s, 3 H), 3.83 (dd, 1H), 3.97 (dd, 1H), 4.21-4.33 (m, 1H), 4.44-4.57 (m, 2H [AB]), 5.01 (q, 1 H), 6.88 (d, 1 H), 7.26 (t, 1 H), 7.53-7.65 (m, 5H), 7.67 (s, 1H), 7.74 (d, 2H), 8.69 (d, 1H)。
Example 100
Ethyl {2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [3- (trifluoromethyl) phenyl ] ethyl } carbamate (mixture of diastereomers)
465 mg (1.27 mmol) of the compound from example 8A, 437 mg (1.40 mmol) of the compound from example 137A, 292 mg (1.52 mmol) of EDC, 206 mg (1.52 mmol) of HOBt and 266. mu.L (1.52 mmol) of N, N' -diisopropylethylamine are stirred in 15 ml of DMF at room temperature for 1 hour. The whole solution was purified by preparative HPLC [ method 23 ]. The appropriate fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 524 mg (66% of theory) of the title compound as a mixture of diastereomers (ratio 23: 74).
LC-MS [ method 5 ]] Rt = 1.15 min; MS [ESIpos]: m/z = 624 (M+H)+
The two diastereomers were separated by preparative HPLC on chiral phase [ method 21a ]: see example 101 and example 102.
Example 101
Ethyl {2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [3- (trifluoromethyl) phenyl ] ethyl } carbamate (diastereomer I)
The first eluting diastereomer (109 mg) obtained from the chromatographic separation of 520 mg of the compound of example 100 by method 21 a.
Chiral analytical HPLC [ method 22 ]] : Rt = 3.42 min。
LC-MS [ method 5 ]] Rt = 1.15 min; MS [ESIpos]: m/z = 624 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 1.08 (t, 3H), 3.23-3.40 (m, 2H), 3.79-3.99 (m, 4H), 4.22-4.33 (m, 1H), 4.51 (s, 2H), 5.02 (q, 1H), 6.91 (d, 1H), 7.21 (t, 1H), 7.53-7.68 (m, 6H), 7.75 (d, 2H), 8.68 (d, 1H)。
Example 102
Ethyl {2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [3- (trifluoromethyl) phenyl ] ethyl } carbamate (diastereomer II)
The final eluting diastereomer obtained from the chromatographic separation of 520 mg of the compound of example 100 by method 21 a. The resulting product (356 mg) was further purified by preparative HPLC [ method 20 ]. This gave 297 mg of the title compound.
Chiral analytical HPLC [ method 22 ]] : Rt = 4.31 min。
LC-MS [ method 5 ]] Rt = 1.15 min; MS [ESIpos]: m/z = 624 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 1.08 (t, 3H), 3.23-3.37 (m, 2H), 3.28-4.01 (m, 4H), 4.22-4.33 (m, 1H), 4.42-4.60 (m[AB], 2H), 5.01 (q, 1H), 6.88 (d, 1H), 7.21 (t, 1H), 7.50-7.68 (m, 6H), 7.73 (d, 2H), 8.69 (d, 1H)。
Example 103
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- [ (ethylcarbamoyl) amino ] -1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (mixture of diastereomers)
483 mg (1.32 mmol) of the compound from example 8A, 453 mg (1.45 mmol) of the compound from example 139A, 304 mg (1.59 mmol) of EDC, 214 mg (1.59 mmol) of HOBt and 276. mu.L (1.59 mmol) of N, N-diisopropylethylamine are stirred in 15.5 ml of DMF at room temperature overnight. Since the reaction was incomplete, 0.8 mmol each of EDC, HOBt and N, N-diisopropylethylamine were added and the mixture was stirred for a further 1 hour. The whole solution was purified by preparative HPLC [ method 23 ]. The appropriate fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 428 mg (52% of theory) of the title compound as a mixture of diastereomers (ratio 3.5:1 according to NMR).
LC-MS [ method 4 ]] Rt = 1.09 min; MS [ESIpos]: m/z = 623 (M+H)+
The two diastereomers were separated by preparative HPLC on chiral phase [ method 13a ]: see example 104 and example 105.
Example 104
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- [ (ethylcarbamoyl) amino ] -1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer I)
The first eluting diastereomer obtained from the chromatographic separation of 428 mg of the compound of example 103 by method 13a (333 mg).
Chiral analytical HPLC [ method 14]: Rt = 1.62 min。
1H NMR (400 MHz, DMSO-d6): δ = 0.92 (t, 3H), 2.88-3.00 (m, 2 H), 3.21-3.39 (m, 2H), 3.82 (dd, 1H), 3.97 (dd, 1H), 4.24-4.38 (m, 1H), 4.44-4.54 (m[AB], 2H), 4.87-4.98 (m, 1H), 5.95 (q, 2H), 6.91 (d, 1H), 7.53-7.66 (m, 6H), 7.76 (d, 2H), 8.79 (d, 1H)。
Example 105
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- [ (ethylcarbamoyl) amino ] -1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer II)
The final eluting diastereomer (100 mg) obtained from the chromatographic separation of 428 mg of the compound of example 103 by method 13 a.
Chiral analytical HPLC [ method 14] : Rt = 2.60 min。
1H NMR (400 MHz, DMSO-d6): δ = 0.91 (t, 3H), 2.83-3.00 (m, 2 H), 3.20-3.38 (m, 2H), 3.83 (dd, 1H), 3.97 (dd, 1H), 4.27-4.39 (m, 1H), 4.41-4.51 (m [AB], 2H), 4.89-4.96 (m, 1H), 5.95 (q, 2H), 6.95 (d, 1H), 7.54-7.66 (m, 6H), 7.77 (d, 2H), 8.79 (d, 1H)。
Example 106
N- [2- (carbamoylamino) -1- (2-chlorophenyl) ethyl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (mixture of diastereomers)
311 mg (0.85 mmol) of the compound from example 8A, 279 mg (0.94 mmol) of the compound from example 143A, 245 mg (1.28 mmol) of EDC, 173 mg (1.28 mmol) of HOBt and 193. mu.L (1.11 mmol) of N, N-diisopropylethylamine are stirred in 8 ml of DMF at room temperature for 2 hours. The whole solution was purified by preparative HPLC [ method 10 ]. The appropriate fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 182 mg (36% of theory) of the title compound as a mixture of diastereomers.
LC-MS [ method 4 ]] Rt= 0.97 and 0.98 min, MS [ ESIpos]: m/z = 561 (M+H)+
The two diastereomers were separated by preparative HPLC on chiral phase [ method 17d ]: see example 107 and example 108.
Example 107
N- [2- (carbamoylamino) -1- (2-chlorophenyl) ethyl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (diastereomer I)
The first eluting diastereomer obtained from the chromatographic separation of 120 mg of the compound of example 106 by method 17 d. The resulting product was further purified by preparative HPLC [ method 10 ]. This gave 40 mg of the title compound.
Chiral analytical HPLC [ method 18b] : Rt = 1.81 min。
LC-MS [ method 3 ]] Rt = 1.12 min; MS [ESIpos]: m/z = 561 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 3.15-3.25 (m, 1H), 3.26-3.36 (m, 1H), 3.84 (dd, 1H), 3.98 (dd, 1H), 4.24-4.37 (m, 1H), 4.39-4.55 (m[AB], 2H), 5.09-5.18 (m, 1H), 5.58 (s, 2H), 6.17 (t, 1H), 6.95 (d, 1H), 7.25-7.37 (m, 2H), 7.39-7.45 (m, 2H), 7.63 (d, 2H), 7.77 (d, 2H), 8.81 (d, 1H)。
Example 108
N- [2- (carbamoylamino) -1- (2-chlorophenyl) ethyl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (diastereomer II)
The final eluting diastereomer obtained from the chromatographic separation of 120 mg of the compound of example 106 by method 17 d. The resulting product (51 mg) was further purified by preparative HPLC [ method 10 ]. This gave 40 mg of the title compound.
Chiral analytical HPLC [ method 18b ] : Rt = 2.77 min。
LC-MS [ method 3 ]] Rt = 1.13 min; MS [ESIpos]: m/z = 561 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 3.15-3.25 (m, 1H), 3.26-3.36 (m, 1H), 3.83 (dd, 1H), 3.97 (dd, 1H), 4.26-4.38 (m, 1H), 4.42-4.53 (m [AB], 2H), 5.09-5.17 (m, 1H), 5.59 (s, 2H), 6.18 (t, 1H), 6.95 (d, 1H), 7.25-7.37 (m, 2H), 7.38-7.45 (m, 2H), 7.63 (d, 2H), 7.77 (d, 2H), 8.81 (d, 1H)。
Example 109
Carbamic acid 3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -3- [3- (trifluoromethyl) phenyl ] propyl ester (mixture of diastereomers)
945 mg (2.59 mmol) of the compound from example 8A, 743 mg (3.88 mmol) of EDC and 552 mg (3.88 mmol) of HOBt are stirred in 25 ml of DMF at room temperature for 20 minutes. The resulting solution was added dropwise to a solution of 678 mg (2.59 mmol) of the compound of example 129A in 75 ml of acetonitrile. After 30 minutes at room temperature, the acetonitrile was removed on a rotary evaporator. The remaining solution was mixed with 1 ml of 1M hydrochloric acid and then purified by preparative HPLC [ method 10 ]. The appropriate fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 1.18 g (75% of theory) of the title compound.
LC-MS [ method 2 ]] Rt = 2.27 min; MS [ESIpos]: m/z = 610 (M+H)+
The two diastereomers were separated from 180 mg of the resulting compound by preparative HPLC on chiral phase [ method 15a ]: see example 110 and example 111.
Example 110
Carbamic acid 3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -3- [3- (trifluoromethyl) phenyl ] propyl ester (diastereomer I)
The diastereomer eluted first obtained from the separation of 180 mg of the compound of example 109 by method 15 a. The isolated product was further purified by preparative HPLC [ method 10 ]. This gave 81 mg of the title compound.
Chiral analytical HPLC [ method 16]: Rt = 2.40 min
LC-MS [ method 5 ]] Rt = 1.07 min; MS [ESIpos]: m/z = 610 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 1.91-2.07 (m, 2H), 3.77-3.87 (m, 2H), 3.88-3.99 (m, 2H), 4.22-4.35 (m, 1H), 4.50 (s, 2H), 4.95-5.04 (m, 1H), 6.51 (br. s., 2H), 6.93 (d, 1H), 7.55-7.68 (m, 6H), 7.71-7.78 (m, 2H), 8.78 (d, 1H)。
Example 111
Carbamic acid 3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -3- [3- (trifluoromethyl) phenyl ] propyl ester (diastereomer II)
The final eluting diastereomer obtained from the separation of 180 mg of the compound of example 109 by method 15 a. The isolated product was further purified by preparative HPLC [ method 10 ]. This gave 68 mg of the title compound.
Chiral analytical HPLC [ method 16]: Rt = 3.28 min。
LC-MS [ method 4 ]] Rt = 1.05 min; MS [ESIpos]: m/z = 610(M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 1.90-2.07 (m, 2H), 3.76-4.03 (m, 4H), 4.20-4.34 (m, 1H), 4.41-4.60 (m [AB], 2H), 4.93-5.05 (m, 1H), 6.52 (br. s., 2H), 6.91 (d, 1H), 7.55-7.68 (m, 6H), 7.74 (d, 2H), 8.79 (d, 1H)。
Example 112
Carbamic acid 2- ({ [3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetyl } amino) -2- [3- (trifluoromethyl) phenyl ] ethyl ester (enantiomerically pure)
250 mg (0.43 mmol) of the compound of example 65 are hydrogenated in 37 ml of methanol at room temperature overnight in platinum (5% on carbon, 104 mg) under a hydrogen atmosphere (pressure = 1 atm). The catalyst is subsequently removed by filtration and the filtrate is purified by preparative HPLC [ method 20 ]. This gives 161 mg (64% of theory) of the title compound.
LC-MS [ method 2 ]] Rt = 2.34 min; MS [ESIpos]: m/z = 580 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 2.56-2.69 (m, 2H), 3.98 (t, 2H), 4.03-4.20 (m, 2H), 4.43-4.59 (m [AB], 2H), 5.06-5.22 (m, 1H), 6.57 (br. s., 2H), 7.55-7.75 (m, 8H), 8.85 (d, 1H)。
Example 113
[ methyl 2- ({ [3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetyl } amino) -2- (2, 3-dichlorophenyl) ethyl ] carbamate (racemate)
144 mg (0.41 mmol) of the compound from example 177A, 136 mg (0.45 mmol) of the compound from example 151A, 94 mg (0.50 mmol) of EDC, 67 mg (0.50 mmol) of HOBt and 86. mu.L (0.50 mmol) of N, N-diisopropylethylamine are stirred in 4.9 ml of DMF at room temperature for 1 hour. The whole solution was purified by preparative HPLC [ method 20 ]. The appropriate fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 173 mg (70% of theory) of the title compound.
LC-MS [ method 5 ]] Rt = 1.15 min; MS [ESIpos]: m/z = 594 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 2.54-2.68 (m, 2H), 3.21-3.36 (m, 2H), 3.50 (s, 3H), 3.98 (t, 2H), 4.44-4.56 (m [AB], 2H), 5.31 (q, 1H), 7.31 (br. t, 1H), 7.36 (t, 1H), 7.45 (dd, 1 H), 7.56 (dd, 1H), 7.61-7.69 (m, 4H), 8.67 (d, 1H)。
The two enantiomers were separated by preparative HPLC on chiral phase [ method 21b ]: see example 114 and example 115.
Example 114
Methyl [2- ({ [3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetyl } amino) -2- (2, 3-dichlorophenyl) ethyl ] carbamate (enantiomer 1)
The first eluting enantiomer (77 mg) obtained from 173 mg of the chromatographic separation of the enantiomers of the compound of example 113 by method 21 b. The product obtained was further purified by preparative HPLC [ method 20 ]. Drying in HV afforded 62 mg of the title compound as a white solid.
Chiral analytical HPLC [ method 22 ]]: Rt = 6.48 min。
Example 115
[2- ({ [3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetyl } amino) -2- (2, 3-dichlorophenyl) ethyl ] aminomethane acid ester (enantiomer 2)
The last eluting enantiomer (71 mg) obtained from 173 mg of the chromatographic separation of the enantiomers of the compound of example 113 by method 21 b. The product obtained was further purified by preparative HPLC [ method 20 ]. Drying in HV gave 60 mg of the title compound as a white solid.
Chiral analytical HPLC [ method 22 ]]: Rt = 11.02 min。
Example 116
Ethyl [2- ({ [3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetyl } amino) -2- (2, 3-dichlorophenyl) ethyl ] carbamate (racemate)
155 mg (0.44 mmol) of the compound from example 177A, 153 mg (0.49 mmol) of the compound from example 152A, 102 mg (0.53 mmol) of EDC, 72 mg (0.53 mmol) of HOBt and 93. mu.L (0.53 mmol) of N, N' -diisopropylethylamine are stirred in 5 ml of DMF at room temperature for 1 hour. The reaction solution was purified by preparative HPLC [ method 20 ]. The product fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 168 mg (62% of theory) of the title compound.
LC-MS [ method 5 ]] Rt = 1.20 min; MS [ESIpos]: m/z = 608 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 1.11 (t, 3H), 2.53-2.69 (m, 2H), 3.21-3.35 (m, 1H), 3.89-4.01 (m, 4H), 4.44-4.57 (m [AB], 2H), 5.31 (br. q, 1H), 7.26 (br. t, 1H), 7.36 (t, 1H), 7.44 (dd, 1H), 7.55 (dd, 1H), 7.60-7.68 (m, 4H), 8.67 (d, 1H)。
The two enantiomers were separated by preparative HPLC on chiral phase [ method 21b ]: see example 117 and example 118.
Example 117
Ethyl [2- ({ [3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetyl } amino) -2- (2, 3-dichlorophenyl) ethyl ] carbamate (enantiomer 1)
The first eluting enantiomer (67 mg) obtained from 168 mg of the chromatographic separation of the enantiomers of the compound of example 116 by method 21 b. The product obtained was further purified by preparative HPLC [ method 20 ]. Drying in HV afforded 54 mg of the title compound as a white solid.
Chiral analytical HPLC [ method 22 ]]: Rt = 5.36 min。
Example 118
Ethyl [2- ({ [3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetyl } amino) -2- (2, 3-dichlorophenyl) ethyl ] carbamate (enantiomer 2)
The final eluting enantiomer (71 mg) obtained from 168 mg of the chromatographic separation of the enantiomers of the compound of example 116 by method 21 b. The product obtained was further purified by preparative HPLC [ method 20 ]. Drying in HV gave 60 mg of the title compound as a white solid.
Chiral analytical HPLC [ method 22 ]]: Rt = 9.85 min。
Example 119
N- [2- (carbamoylamino) -1- (2, 3-dichlorophenyl) ethyl ] -2- [3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetamide (racemate)
162 mg (0.46 mmol) of the compound from example 177A, 145 mg (0.51 mmol) of the compound from example 153A, 107 mg (0.56 mmol) of EDC, 75 mg (0.56 mmol) of HOBt and 97. mu.L (0.56 mmol) of N, N' -diisopropylethylamine are stirred at room temperature in 5.4 ml of DMF overnight. The solution was diluted with 150 ml of ethyl acetate and then extracted twice with 1M hydrochloric acid and 1M aqueous sodium bicarbonate solution, respectively. The organic phase is dried over sodium sulfate and then freed of volatile constituents on a rotary evaporator. The residue was purified by preparative HPLC [ method 20 ]. The product fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 163 mg (61% of theory) of the title compound.
LC-MS [ method 5 ]] Rt = 1.04 min; MS [ESIpos]: m/z = 579 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 2.56-2.72 (m, 2H), 3.17-3.37 (m, 2H), 3.98 (t, 2H), 4.40-4.52 (m [AB], 2H), 5.11-5.18 (m, 1H), 5.56 (s, 2H), 6.14 (t, 1H), 7.32-7.39 (m, 2H), 7.52-7.57 (m, 1H), 7.61-7.66 (m, 2H), 7.66-7.71 (m, 2H), 8.93 (d, 1H)。
The two enantiomers were separated by preparative HPLC on chiral phase [ method 24a ]: see example 120 and example 121.
Example 120
N- [2- (carbamoylamino) -1- (2, 3-dichlorophenyl) ethyl ] -2- [3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetamide (enantiomer 1)
The first eluting enantiomer (61 mg) obtained from 160 mg of the chromatographic separation of the enantiomers of the compound of example 119 by method 24 a. The product obtained was further purified by preparative HPLC [ method 20 ]. Drying in HV gave 34 mg of the title compound.
Chiral analytical HPLC [ method 25a ]]: Rt = 4.28 min。
Example 121
N- [2- (carbamoylamino) -1- (2, 3-dichlorophenyl) ethyl ] -2- [3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetamide (enantiomer 2)
The final eluting enantiomer (81 mg) obtained from chromatographic separation of 160 mg of the enantiomer of the compound of example 119 by method 24 a. The product obtained was further purified by preparative HPLC [ method 20 ]. Drying in HV gave 39 mg of the title compound.
Chiral analytical HPLC [ method 25a ]]: Rt = 9.50 min。
Example 122
2- [3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- {1- (2, 3-dichlorophenyl) -2- [ (ethylcarbamoyl) amino ] ethyl } acetamide (racemate)
145 mg (0.42 mmol) of the compound from example 177A, 143 mg (0.46 mmol) of the compound from example 154A, 96 mg (0.50 mmol) of EDC, 67 mg (0.50 mmol) of HOBt and 87. mu.L (0.50 mmol) of N, N' -diisopropylethylamine are stirred in 4.9 ml of DMF at room temperature for 1 hour. The whole solution was purified by preparative HPLC [ method 20 ]. The product fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 150 mg (58% of theory) of the title compound.
LC-MS [ method 5 ]] Rt = 1.12 min; MS [ESIpos]: m/z = 607 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 0.92 (t, 3H), 2.57-2.71 (m, 2H), 2.86-2.99 (m, 2H), 3.19-3.38 (m, 2H), 3.98 (t, 2 H), 4.40-4.53 (m [AB], 2H), 5.13-5.20 (m, 1H), 5.93 (t, 1H), 6.02 (t, 1H), 7.32-7.39 (m, 2H), 7.50-7.58 (m, 1H), 7.61-7.72 (m, 4H), 8.91 (d, 1H)。
The two enantiomers were separated by preparative HPLC on chiral phase [ method 24b ]: see example 123 and example 124.
Example 123
2- [3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- {1- (2, 3-dichlorophenyl) -2- [ (ethylcarbamoyl) amino ] ethyl } acetamide (enantiomer 1)
The first eluting enantiomer obtained from the chromatographic separation of 160 mg of the enantiomer of the compound of example 122 by method 24 b. The product obtained was further purified by preparative HPLC [ method 20 ]. Drying in HV gave 55 mg of the title compound.
Chiral analytical HPLC [ method 25b]: Rt = 4.69 min。
Example 124
2- [3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- {1- (2, 3-dichlorophenyl) -2- [ (ethylcarbamoyl) amino ] ethyl } acetamide (enantiomer 2)
The final eluting enantiomer from chromatographic separation of 160 mg of the enantiomer of the compound of example 122 was obtained by method 24 b. The product obtained was further purified by preparative HPLC [ method 20 ]. Drying in HV gave 51 mg of the title compound.
Chiral analytical HPLC [ method 25b ]: Rt = 9.41 min。
Example 125
N- {1- (2-chlorophenyl) -2- [ (methylsulfonyl) amino ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (mixture of diastereomers)
298 mg (0.81 mmol) of the compound from example 8A, 304mg (0.90 mmol) of the compound from example 144A, 234 mg (1.22mmol) of EDC, 165 mg (1.22mmol) of HOBt and 184. mu.L (1.06mmol) of N, N' -diisopropylethylamine are stirred in 7.7 ml of DMF at room temperature for 2 hours. The whole solution was purified by preparative HPLC [ method 10 ]. The product fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 448 mg (90% of theory) of the title compound.
LC-MS [ method 4 ]] Rt = 1.02 min; MS [ESIpos]: m/z = 596 (M+H)+
The two diastereomers were separated by preparative HPLC on chiral phase [ method 17h ]: see example 126 and example 127.
Example 126
N- {1- (2-chlorophenyl) -2- [ (methylsulfonyl) amino ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (diastereomer I)
The diastereomer eluted first from the chromatographic separation of the diastereomer of 440 mg of the compound of example 125 by method 17 h. The product obtained was further purified by preparative HPLC [ method 20 ]. Drying in HV gave 141 mg of the title compound.
Chiral analytical HPLC [ method 18e]: Rt = 2.81 min。
LC-MS [ method 4 ]] Rt = 1.01 min; MS [ESIpos]: m/z = 596 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 2.87 (s, 3H), 3.11-3.20 (m, 1H), 3.25-3.35 (m, 1H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.22-4.34 (m, 1H), 4.46-4.64 (m[AB], 2H), 5.31-5.39 (m, 1H), 6.85 (d, 1H), 7.28-7.40 (m, 3H), 7.44 (d, 1 H), 7.54 (d, 1 H), 7.61 (d, 2H), 7.74 (d, 2H), 8.66 (d, 1H)。
Example 127
N- {1- (2-chlorophenyl) -2- [ (methylsulfonyl) amino ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (diastereomer II)
The final eluting diastereomer from 440 mg of the diastereomer chromatographic separation of the compound of example 125 was obtained by method 17 h. The product obtained was further purified by preparative HPLC [ method 20 ]. Drying in HV gave 102 mg of the title compound.
Chiral analytical HPLC [ method 18e]: Rt = 4.14 min。
LC-MS [ method 2 ]] Rt = 2.20 min; MS [ESIpos]: m/z = 596 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 2.88 (s, 3H), 3.11-3.19 (m, 1H), 3.25-3.33 (m, 1H), 3.83 (dd, 1H), 3.96 (br d, 1H), 4.23-4.34 (m, 1H), 4.55 (q, 2H), 5.32-5.40 (m, 1H), 6.88 (d, 1H), 7.29-7.34 (br t, 2H), 7.37 (t, 1H), 7.44 (d, 1H), 7.54 (d, 1H), 7.62 (d, 2H), 7.75 (d, 2H), 8.65 (d, 1H)。
Example 128
N- {1- (2-chlorophenyl) -2- [ (ethylsulfonyl) amino ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (mixture of diastereomers)
241 mg (0.66 mmol) of the compound from example 8A, 249mg (0.74 mmol) of the compound from example 145A, 189 mg (0.99mmol) of EDC, 133 mg (0.99mmol) of HOBt and 149. mu.L (0.99mmol) of N, N' -diisopropylethylamine are stirred in 6.2 ml of DMF at room temperature for 2 hours. The whole solution was purified by preparative HPLC [ method 10 ]. The product fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 375 mg (91% of theory) of the title compound.
LC-MS [ method 4 ]] Rt = 1.05 min; MS [ESIpos]: m/z = 610 (M+H)+
The two diastereomers were separated by preparative HPLC on chiral phase [ method 17g ]: see example 129 and example 130.
Example 129
N- {1- (2-chlorophenyl) -2- [ (ethylsulfonyl) amino ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (diastereomer I)
The first eluting diastereomer obtained from method 17g chromatographic separation of the diastereomer of 370 mg of the compound of example 128. The product obtained was further purified by preparative HPLC [ method 20 ]. Drying in HV gave 96 mg of the title compound as a white solid.
Chiral analytical HPLC [ method 18d]: Rt = 3.87 min。
LC-MS [ method 4 ]] Rt = 1.04 min; MS [ESIpos]: m/z = 610 (M+H)+
1H NMR (400 MHz, DMSO-d6) δ = 1.15 (t, 3H), 2.88-3.02 (m, 2H), 3.11-3.19 (m, 1H), 3.24-3.33 (m, 1H, hidden under a water signal), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.22-4.33 (m, 1H), 4.49 (d, 1H), 4.60 (d, 1H), 5.28-5.37 (m, 1H), 6.85 (d, 1H), 7.29-7.40 (m, 3H), 7.44 (d, 1H), 7.53 (d, 1H), 7.61 (d, 2H), 7.74 (d, 2H), 8.64 (d, 1H).
Example 130
N- {1- (2-chlorophenyl) -2- [ (ethylsulfonyl) amino ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (diastereomer II)
The final eluting diastereomer from method 17g obtained from 370 mg chromatographic separation of the diastereomer of the compound of example 128. The product obtained was further purified by preparative HPLC [ method 20 ]. Drying in HV gave 134 mg of the title compound.
Chiral analytical HPLC [ method 18d]: Rt = 5.08 min。
LC-MS [ method 4 ]] Rt = 1.05 min; MS [ESIpos]: m/z = 610(M+H)+
1H NMR (400 MHz, DMSO-d6) δ = 1.16 (t, 3H), 2.90-3.02 (m, 2H), 3.10-3.19 (m, 1H), 3.24-3.33 (m, 1H, hidden under a water signal), 3.83 (dd, 1H), 3.96 (br d, 1H), 4.23-4.34 (m, 1H), 4.48-4.61 (m [ AB [ 1H ])], 2H), 5.30-5.37 (m, 1H), 6.88 (d, 1H), 7.28-7.39 (m, 3H), 7.43 (d, 1H), 7.53 (d, 1H), 7.62 (d, 2H), 7.75 (d, 2H), 8.62 (d, 1H)。
Example 131
N- [1- (2-chlorophenyl) -2- (methylsulfonyl) ethyl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (mixture of diastereomers)
327 mg (0.89 mmol) of the compound from example 8A, 266 mg (0.98 mmol) of the compound from example 146A, 206 mg (1.07mmol) of EDC, 145 mg (1.07mmol) of HOBt and 187. mu.L (1.07mmol) of N, N' -diisopropylethylamine are stirred in 10.5 ml of DMF at room temperature for 1 hour. The whole solution was purified by preparative HPLC [ method 20 ]. The appropriate fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 354 mg (68% of theory) of the title compound.
LC-MS [ method 3 ]] Rt = 1.16 min; MS [ESIpos]: m/z = 581 (M+H)+
The two diastereomers were separated by preparative HPLC on chiral phase [ method 26a ]: see example 132 and example 133.
Example 132
N- [1- (2-chlorophenyl) -2- (methylsulfonyl) ethyl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (diastereomer I)
The first eluting diastereomer obtained from method 26a from the chromatographic separation of the diastereomer of 354 mg of the compound of example 131. The resulting product (163 mg) was further purified by preparative HPLC [ method 20 ]. Drying in HV gave 116 mg of the title compound.
Chiral analytical HPLC [ method 27a]: Rt = 4.06 min。
LC-MS [ method 5 ]] Rt = 1.03 min; MS [ESIpos]: m/z = 581 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 3.02 (s, 3H), 3.42 (m, 1H), 3.62 (dd, 1H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.20-4.33 (m, 1H), 4.51 (s, 2H), 5.72-5.80 (m, 1H), 6.89 (d, 1H), 7.31-7.42 (m, 2H), 7.47 (dd, 1H), 7.55 (dd, 1H), 7.60-7.65(m, 2H), 7.71-7.77 (m, 2H), 9.03 (d, 1H)。
Example 133
N- [1- (2-chlorophenyl) -2- (methylsulfonyl) ethyl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (diastereomer II)
The final eluting diastereomer obtained from the chromatographic separation of the diastereomer of 354 mg of the compound of example 131 by method 26 a. The product obtained was further purified by preparative HPLC [ method 20 ]. Drying in HV gave 131 mg of the title compound.
Chiral analytical HPLC [ method 27a]: Rt = 4.71 min。
LC-MS [ method 5 ]] Rt = 1.03 min; MS [ESIpos]: m/z = 581 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 3.02 (s, 3H), 3.42 (m, 1H), 3.62 (dd, 1H), 3.83 (dd, 1H), 3.96 (dd, 1H), 4.21-4.35 (m, 1H), 4.46-4.57 (m [AB], 2H), 5.74-5.81 (m, 1H), 6.91 (d, 1H), 7.31-7.42 (m, 2H), 7.46 (dd, 1H), 7.56 (dd, 1H), 7.60-7.66 (m, 2H), 7.72-7.78 (m, 2H), 9.03 (d, 1H)。
Example 134
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (methylsulfonyl) -1- [2- (trifluoromethyl) phenyl ] ethyl } acetamide (mixture of diastereomers)
438mg (1.20 mmol) of the compound of example 8A, 400 mg (1.32 mmol) of the compound of example 148A, 275 mg (1.44mmol) of EDC, 194 mg (1.44mmol) of HOBt and 250. mu.L (1.44mmol) of N, N' -diisopropylethylamine are stirred in 10.5 ml of DMF at room temperature for 1 hour. The whole solution was purified by preparative HPLC [ method 20 ]. The appropriate fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 594 mg (79% of theory) of the title compound.
LC-MS [ method 3 ]] Rt = 1.19 min; MS [ESIpos]: m/z = 615 (M+H)+
The two diastereomers were separated by preparative HPLC on chiral phase [ method 11e ]: see example 135 and example 136.
Example 135
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (methylsulfonyl) -1- [2- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer I)
The first eluting diastereomer (245 mg) obtained by method 11e from the chromatographic separation of the diastereomer of 594 mg of the compound of example 134. The product obtained was mixed with 10 ml of acetonitrile and 20 ml of water and then lyophilized.
Chiral analytical HPLC [ method 12a]: Rt = 5.11 min。
LC-MS [ method 4 ]] Rt = 1.04 min; MS [ESIpos]: m/z = 615 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 3.01 (s, 3H), 3.36 (dd, 1H), 3.67 (dd, 1H), 3.82 (dd, 1H), 3.95 (dd, 1H), 4.21-4.33 (m, 1H), 4.48 (s, 2H), 5.74-5.84 (m, 1H), 6.92 (d, 1H), 7.53 (t, 1H), 7.59-7.65 (m, 2H), 7.70-7.82 (m, 5H), 9.08 (d, 1H)。
Example 136
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (methylsulfonyl) -1- [2- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer II)
The final eluting diastereomer from the chromatographic separation of diastereomer of 594 mg of the compound of example 134 (225 mg) was obtained by method 11 e. The product obtained was mixed with 10 ml of acetonitrile and 20 ml of water and then lyophilized.
Chiral analytical HPLC [ method 12a]: Rt = 8.30 min。
LC-MS [ method 4 ]] Rt = 1.03 min; MS [ESIpos]: m/z = 615 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 3.01 (s, 3H), 3.36 (dd, 1H), 3.68 (dd, 1H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.20-4.31 (m, 1H), 4.44-4.53 (m[AB], 2H), 5.73-5.82 (m, 1H), 6.89 (d, 1H), 7.53 (t, 1H), 7.59-7.64 (m, 2H), 7.70-7.82 (m, 5H), 9.08 (d, 1H)。
Example 137
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (methylsulfonyl) -1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (mixture of diastereomers)
416mg (1.14 mmol) of the compound from example 8A, 380 mg (1.25 mmol) of the compound from example 149A, 262 mg (1.37mmol) of EDC, 184 mg (1.37mmol) of HOBt and 238. mu.L (1.37mmol) of N, N' -diisopropylethylamine are stirred in 13.4 ml of DMF at room temperature for 1 hour. The whole solution was purified by preparative HPLC [ method 23 ]. The appropriate fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 458 mg (65% of theory) of the title compound.
LC-MS [ method 4 ]] Rt = 1.06 min; MS [ESIpos]: m/z = 615 (M+H)+
The two diastereomers were separated by preparative HPLC on chiral phase [ method 26b ]: see example 138 and example 139.
Example 138
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (methylsulfonyl) -1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer I)
The first eluting diastereomer obtained from the chromatographic separation of 450 mg diastereomer of the compound of example 137 by method 26 b. The product obtained was further purified by preparative HPLC [ method 20 ]. Drying in HV gave 151 mg of the title compound.
Chiral analytical HPLC [ method 27a]: Rt = 3.61 min。
LC-MS [ method 5 ]] Rt = 1.07 min; MS [ESIpos]: m/z = 615 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 2.99 (s, 3H), 3.69 (d, 2H), 3.83 (dd, 1H), 3.96 (dd, 1H), 4.21-4.31 (m, 1H), 4.45-4.55 (m [AB], 2H), 5.48 (q, 1H), 6.89 (d, 1H), 7.57-7.80 (m, 8H), 8.99 (d, 1H)。
Example 139
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (methylsulfonyl) -1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer II)
The final eluting diastereomer from 450 mg of the compound of example 137 obtained by method 26b in the chromatographic separation of the diastereoisomers. The product obtained was further purified by preparative HPLC [ method 20 ]. Drying in HV gave 145 mg of the title compound.
Chiral analytical HPLC [ method 27a]: Rt = 4.40 min。
LC-MS [ method 5 ]] Rt = 1.08 min; MS [ESIpos]: m/z = 615 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 2.99 (s, 3H), 3.64-3.74 (m, 2H), 3.83 (dd, 1H), 3.96 (dd, 1H), 4.22-4.34 (m, 1H), 4.44-4.56 (m [AB], 2H), 5.45-5.53 (m, 1H), 6.91 (d, 1H), 7.57-7.80 (m, 8H), 8.98 (d, 1H)。
Example 140
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (dimethylaminosulfonyl) -1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (mixture of diastereomers)
221mg (0.60 mmol) of the compound from example 8A, 221mg (0.66 mmol) of the compound from example 150A, 174 mg (0.91mmol) of EDC, 122 mg (0.91mmol) of HOBt and 137. mu.L (0.79mmol) of N, N' -diisopropylethylamine are stirred in 5.7 ml of DMF at room temperature for 2 hours. The whole solution was purified by preparative HPLC [ method 10 ]. The product fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 337 mg (87% of theory) of the title compound.
LC-MS [ method 2 ]] Rt = 2.41 min; MS [ESIpos]: m/z = 644 (M+H)+
The two diastereomers were separated by preparative HPLC on chiral phase [ method 28 ]: see example 141 and example 142.
Example 141
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (dimethylaminosulfonyl) -1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer I)
The first eluting diastereomer obtained from the chromatographic separation of the diastereomer of 337 mg of the compound of example 140 by method 28. The resulting product (153 mg) was further purified by preparative HPLC [ method 20 ]. Drying in HV gave 120 mg of the title compound.
Chiral analytical HPLC [ method 18d]: Rt = 2.56 min。
LC-MS [ method 5 ]] Rt = 1.13 min; MS [ESIpos]: m/z = 644 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 2.75 (s, 6H), 3.48-3.63 (m, 2H), 3.83 (dd, 1H), 3.97 (dd, 1H), 4.20-4.33 (m, 1H), 4.49 (s, 2H), 5.33-5.41 (m, 1H), 6.90 (d, 1 H), 7.58-7.79 (m, 8H), 8.92 (d, 1H)。
Example 142
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (dimethylaminosulfonyl) -1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer II)
The final eluting diastereomer obtained from the chromatographic separation of the diastereomer of 337 mg of the compound of example 140 by method 28. The resulting product (160 mg) was further purified by preparative HPLC [ method 10 ]. Drying in HV afforded 129 mg of the title compound.
Chiral analytical HPLC [ method 18d]: Rt = 2.56 min。
LC-MS [ method 5 ]] Rt = 1.13 min; MS [ESIpos]: m/z = 644 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 2.76 (s, 6H), 3.48-3.63 (m, 2H), 3.83 (dd, 1H), 3.96 (dd, 1H), 4.21-4.34 (m, 1H), 4.42-4.55 (m [AB], 2H), 5.34-5.44 (m, 1H), 6.92 (d, 1H), 7.58-7.79 (m, 8H), 8.91 (d, 1H)。
Example 143
Carbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (1E) -3,3, 3-trifluoroprop-1-en-1-yl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [2- (trifluoromethyl) phenyl ] ethyl ester (enantiomerically pure)
A solution of 135 mg (0.23 mmol) of the compound from example 51 and 33 mg (0.27 mmol) of DMAP in 1.6 ml of pyridine is mixed by dropwise addition of 95. mu.L (0.57 mmol) of trifluoroacetic anhydride, and the mixture is stirred at room temperature for 3 days. 2 ml of 1N hydrochloric acid are subsequently added and the volatile constituents are removed on a rotary evaporator. The residue was dissolved in a small amount of DMSO and then purified by preparative HPLC [ method 10 ]. The product-containing fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 118 mg (90% of theory) of the title compound.
LC-MS [ method 4 ]] Rt = 1.13 min; MS [ESIpos]: m/z = 578 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 3.98 (dd, 1H), 4.14 (dd, 1H), 4.48-4.58 (m [AB], 2H), 5.36-5.45 (m, 1H), 6.40-6.77 (br. s., 2H), 6.84 (dq, 1H), 7.17 (dq, 1H), 7.52 (t, 1H), 7.61-7.76 (m, 7H), 8.98 (d, 1H)。
Example 144
Ethyl 2- ({ [3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetyl } amino) -2- [2- (trifluoromethyl) phenyl ] carbamate (enantiomerically pure)
A solution of 118 mg (0.20 mmol) of the compound of example 143 in 20 ml of methanol was hydrogenated at a temperature of 45 ℃ and a flow rate of 1 ml/min at standard pressure using a continuous flow hydrogenation unit (type H-Cube, Thales Nano, Budapest, HC-2-SS) equipped with a 5% Pt/C catalyst cartridge. Methanol was removed on a rotary evaporator and the residue was purified by preparative HPLC [ method 10 ]. This gives 31 mg (26% of theory) of the title compound.
LC-MS [ method 2 ]] Rt = 2.30 min; MS [ESIpos]: m/z = 580 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 2.51-2.69 (m, 2H), 3.93-4.01 (m, 3H), 4.12 (dd, 1H), 4.48 (s, 2H), 5.34-5.42 (m, 1H), 6.40-6.78 (br. s., 2H), 7.49-7.55 (m, 1H), 7.60-7.76 (m, 7H), 8.94 (d, 1H)。
Example 145
Ethylcarbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [2- (trifluoromethyl) phenyl ] ethyl ester (diastereoisomerically pure)
298 mg (0.81 mmol) of the compound from example 8A, 187 mg (0.98 mmol) of EDC and 132 mg (0.98 mmol) of HOBt are stirred in 5 ml of DMF for 10 minutes. The resulting solution was added dropwise to a solution of 280 mg (0.90 mmol) of the compound of example 187A and 156. mu.L (0.90 mmol) of N, N' -diisopropylethylamine in 10 ml of acetonitrile. The whole mixture was stirred at room temperature for 20 minutes, then mixed with 3 ml of 1N hydrochloric acid, and then purified by preparative chromatography [ method 10 ]. The product fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 420 mg (83% of theory) of the title compound.
LC-MS [ method 4 ]] Rt = 1.11 min; MS [ESIpos]: m/z = 624 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 0.98 (t, 3H), 2.90-3.04 (m, 2H), 3.82 (dd, 1H), 3.92-4.03 (m, 2H), 4.11-4.20 (m, 1H), 4.20-4.32 (m, 1H), 4.49 (s, 2H), 5.35-5.44 (m, 1H), 6.88 (d, 1H), 7.20 (t, 1H), 7.53 (t, 1H), 7.58-7.65 (m, 2H), 7.68-7.79 (m, 5H), 8.96 (d, 1H)。
Example 146
Ethylcarbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (1E) -3,3, 3-trifluoroprop-1-en-1-yl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [2- (trifluoromethyl) phenyl ] ethyl ester (enantiomerically pure)
A solution of 230 mg (0.37 mmol) of the compound from example 145 and 54mg (0.44 mmol) of DMAP in 5 ml of pyridine is mixed by dropwise addition of 155. mu.L (0.92 mmol) of trifluoroacetic anhydride, and the mixture is stirred at room temperature overnight. 2 ml of 1N hydrochloric acid are subsequently added and the volatile constituents are removed on a rotary evaporator. The residue was dissolved in a small amount of DMSO and then purified by preparative HPLC [ method 10 ]. The product-containing fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 168 mg (75% of theory) of the title compound.
LC-MS [ method 4 ]] Rt = 1.22 min; MS [ESIpos]: m/z = 606 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 0.98 (t, 3H), 2.92-3.04 (m, 2H), 3.99 (dd, 1H), 4.13-4.20 (m, 1H), 4.48-4.59 (m[AB], 2H), 5.37-5.45 (m, 1H), 6.85 (dq, 1H), 7.17 (dq, 1H), 7.23 (t, 1H), 7.50-7.56 (m, 1H), 7.60-7.77 (m, 7H), 8.99 (d, 1H)。
Example 147
Ethylcarbamic acid 2- ({ [3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetyl } amino) -2- [2- (trifluoromethyl) phenyl ] ethyl ester (enantiomerically pure)
A solution of 168 mg (0.28 mmol) of the compound of example 146 in 30 ml of methanol was hydrogenated at 70 ℃ and a flow rate of 1 ml/min at standard pressure using a continuous flow hydrogenation unit (type H-Cube, Thales Nano, Budapest, HC-2-SS) equipped with a 5% Pt/C catalyst cartridge. Methanol was removed on a rotary evaporator and the residue was purified by preparative HPLC [ method 20 ]. This gives 96 mg (55% of theory) of the title compound.
LC-MS [ method 5 ]] Rt = 1.16 min; MS [ESIpos]: m/z = 608 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 0.98 (t, 3 H), 2.55-2.65 (m, 2H), 2.91-3.03 (m, 2H), 3.94-4.02 (m, 3H), 4.10-4.19 (m, 1H), 4.47 (s, 2H), 5.35-5.43 (m, 1H), 7.21 (t, 1H), 7.52 (t, 1H), 7.59-7.68 (m, 4H), 7.68-7.76 (m, 3H), 8.94 (d, 1H)。
Example 148
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (2-oxo-1, 3-Oxazolidin-3-yl) -1- [3- (trifluoromethyl) phenyl]Ethyl acetamide (diastereomer)Mixture)
187 mg (0.51 mmol) of the compound from example 8A, 118 mg (0.61 mmol) of EDC and 87 mg (0.61 mmol) of HOBt are stirred for 5 minutes in 5 ml of DMF. The resulting solution is added dropwise to a solution of 175 mg (0.56 mmol) of the compound from example 140A and 89. mu.L (0.51 mmol) of N, N' -diisopropylethylamine in 5 ml of DMF. The whole mixture was stirred at room temperature for 2 hours and then mixed with 100 ml of 1N hydrochloric acid. Extraction was carried out with 500 ml of ethyl acetate. The organic phase is washed four times with water and once with saturated aqueous sodium chloride solution, then dried over sodium sulfate and freed of volatile constituents on a rotary evaporator. The residue was purified by preparative chromatography [ method 10 ]. The product fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 265 mg (83% of theory) of the title compound as a mixture of diastereomers (ratio about 3:1 according to NMR, ratio 77:23 according to chiral HPLC [ method 27a ]).
LC-MS [ method 4 ]] Rt = 1.09 min; MS [ESIpos]: m/z = 622 (M+H)+
The two diastereomers were separated by preparative HPLC on chiral phase [ method 26c ]: see example 149 and example 150.
Example 149
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (2-oxo-1, 3-Oxazolidin-3-yl) -1- [3- (trifluoromethyl) phenyl]Ethyl } acetamide (diastereomer I)
The first eluting diastereomer obtained by method 26c from the chromatographic separation of 265 mg diastereomer of the compound of example 148. The resulting product (192 mg) was further purified by preparative HPLC [ method 20 ]. Drying in HV gave 126 mg of the title compound.
Chiral analytical HPLC [ method 27a]: Rt = 3.75 min
LC-MS [ method 4 ]]: Rt = 1.09 min; MS [ESIpos]: m/z = 622 (M+H)+
1H-NMR (400 MHz, DMSO-d6): d = 3.42-3.52 (m, 3H), 3.57 (q, 1H), 3.83 (dd, 1H), 3.97 (dd, 1H), 4.16 (t, 2H), 4.21-4.35 (m, 1H), 4.51 (s, 2H), 5.24 (q, 1H), 6.89 (d, 1H), 7.57-7.64 (m, 3H), 7.64-7.69 (m, 1H), 7.69-7.78 (m, 3H), 7.80 (s, 1H), 8.81 (d, 1H)。
Example 150
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (2-oxo-1, 3-Oxazolidin-3-yl) -1- [3- (trifluoromethyl) phenyl]Ethyl } acetamide (diastereomer II)
The final eluting diastereomer obtained from the chromatographic separation of the diastereomer of 265 mg of the compound of example 148 by method 26 c. This gave 65 mg of the title compound in approximately 90% purity.
Chiral analytical HPLC [ method 27a ]: Rt = 6.01 min
LC-MS [ method 4 ]] Rt = 1.08 min; MS [ESIpos]: m/z = 622 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 3.43-3.53 (m, 3H), 3.57 (q, 1H), 3.83 (dd, 1H), 3.96 (dd, 1H), 4.17 (t, 2H), 4.22-4.33 (m, 1H), 4.43-4.58 (m, 2H), 5.24 (q, 1H), 6.90 (d, 1H), 7.57-7.69 (m, 4H), 7.69-7.78 (m, 3H), 7.80 (s, 1H), 8.80 (d, 1H)。
Example 151
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (2-oxoimidazolidin-1-yl) -1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (mixture of diastereomers)
182 mg (0.50 mmol) of the compound from example 8A, 115 mg (0.60 mmol) of EDC and 85 mg (0.60 mmol) of HOBt are stirred in 5 ml of DMF for 5 minutes. The solution obtained is added dropwise to a solution of 170 mg (0.55 mmol) of the compound from example 141A and 87. mu.L (0.50 mmol) of N, N' -diisopropylethylamine in 5 ml of DMF. The whole mixture was stirred at room temperature for 2 hours and then mixed with 100 ml of 1N hydrochloric acid. Extraction was carried out with 500 ml of ethyl acetate. The organic phase is washed four times with water and once with saturated aqueous sodium chloride solution, then dried over sodium sulfate and freed of volatile constituents on a rotary evaporator. The residue was purified by preparative chromatography [ method 10 ]. The product fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 168 mg (54% of theory) of the title compound as a mixture of diastereomers (ratio 72:25 according to chiral HPLC [ method 27a ]).
LC-MS [ method 4 ]] Rt = 1.08 min; MS [ESIpos]: m/z = 621 (M+H)+
The major diastereoisomers were separated in pure form by preparative HPLC [ method 26c ] on chiral phase (see example 152). The minor diastereomer (diastereomer 2) (Rt [ method 27a ] = 4.66 min) was not separated.
Example 152
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (2-oxoimidazolidin-1-yl) -1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer I)
The first eluting diastereomer obtained from method 26a from 168 mg of the chromatographic separation of diastereomer of the compound of example 151. Drying in HV gave 107 mg of the title compound.
Chiral analytical HPLC [ method 27a]: Rt = 3.87 min。
LC-MS [ method 4 ]] Rt = 1.08 min; MS [ESIpos]: m/z = 621 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 3.07-3.19 (m, 2H), 3.20-3.43 (m, 4H), 3.82 (dd, 1H), 3.97 (m, 1H), 4.25-4.36 (m, 1H), 4.49 (s, 2H), 5.08-5.15 (m, 1H), 6.37 (s, 1H), 6.90 (d, 1H), 7.56-7.70 (m, 5H), 7.72-7.78 (m, 3H), 8.70 (d, 1H)。
Example 153
N- [1- (2-chlorophenyl) -2- (methylthio) ethyl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (mixture of diastereomers)
53mg (0.14 mmol) of the compound from example 8A, 38 mg (0.16 mmol) of the compound from example 147A, 33 mg (0.17mmol) of EDC, 24 mg (0.17mmol) of HOBt and 30. mu.L (0.17mmol) of N, N' -diisopropylethylamine are stirred in 1.7 ml of DMF at room temperature for 1 hour. The solution is then acidified with 1N hydrochloric acid and the whole solution is purified by preparative HPLC [ method 20 ]. The product fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 70 mg of the title compound (87% of theory).
LC-MS [ method 5 ]] Rt = 1.16 min; MS [ESIpos]: m/z = 549 (M+H)+
1H NMR (400 MHz, DMSO-d6) δ = 2.09 (2s, 1 s/each diastereomer, 3H), 2.71-2.85 (m, 2H), 3.83 (dd, 1H), 3.96 (br d, 1H), 4.20-4.33 (m, 1H), 4.47-4.58 (m, 2H), 5.35-5.44 (m, 1H), 6.87-6.92 (m, interpreted as 1 d/each diastereomer, (6.89 + 6.90), 1H), 7.27-7.40 (m, 2H), 7.43 (br d, 1H), 7.52 (br d, 1H), 7.63 (2d, 2H), 7.74 (d, 2H), 8.82 (d, 1H).
Example 154
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (methylthio) -1- [2- (trifluoromethyl) phenyl ] ethyl } acetamide (mixture of diastereomers)
303mg (0.83 mmol) of the compound from example 8A, 248 mg (0.91 mmol) of the compound from example 142A, 191 mg (1.00mmol) of EDC, 135 mg (1.00mmol) of HOBt and 173. mu.L (1.00mmol) of N, N' -diisopropylethylamine are stirred in 9.8 ml of DMF at room temperature for 1 hour. The whole solution was purified by preparative HPLC [ method 20 ]. The appropriate fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 362 mg (73% of theory) of the title compound.
LC-MS [ method 3 ]] Rt = 1.33 min; MS [ESIpos]: m/z = 583 (M+H)+
The two diastereomers were separated by preparative HPLC on chiral phase [ method 29 ]: see example 155 and example 156.
Example 155
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (methylthio) -1- [2- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer I)
The first eluting diastereomer obtained from method 29 from a chromatographic separation of the diastereomer of 360 mg of the compound of example 154. The resulting product (148 mg) was further purified by preparative HPLC [ method 20 ]. Drying in HV gave 119 mg of the title compound.
Chiral analytical HPLC [ method 30]: Rt = 4.40 min。
LC-MS [ method 31] Rt = 2.53 min; MS [ESIpos]: m/z = 583 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 2.06 (s, 3H), 2.74-2.83 (m, 2H), 3.82 (dd, 1H), 3.95 (dd, 1H), 4.20-4.34 (m, 1H), 4.44-4.55 (m [AB], 2H), 5.32-5.41 (m, 1H), 6.92 (d, 1H), 7.50 (t, 1H), 7.60-7.65 (m, 2H), 7.67-7.78 (m, 5H), 8.86 (d, 1H)。
Example 156
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (methylthio) -1- [2- (trifluoromethyl) phenyl ] ethyl } acetamide (diastereomer II)
The final eluting diastereomer from 360 mg of the compound of example 154 was obtained by method 29. The resulting product (157 mg) was further purified by preparative HPLC [ method 20 ]. Drying in HV gave 108 mg of the title compound.
Chiral analytical HPLC [ method 30]: Rt = 5.97 min。
LC-MS [ method 31] Rt = 2.54 min; MS [ESIpos]: m/z = 583 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 2.06 (s, 3H), 2.73-2.84 (m, 2H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.20-4.32 (m, 1H), 4.43-4.56 (m [AB], 2H), 5.36 (q, 1H), 6.90 (d, 1H), 7.51 (t, 1H), 7.59-7.65 (m, 2H), 7.68-7.78 (m, 5H), 8.87 (d, 1H)。
Example 157
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {1- [3- (difluoromethyl) phenyl ] -2-hydroxyethyl } acetamide (mixture of diastereomers)
53mg (0.14 mmol) of the compound from example 8A, 39 mg (0.17mmol) of the compound from example 155A, 33 mg (0.17mmol) of EDC, 24 mg (0.17mmol) of HOBt and 30. mu.L (0.17mmol) of N, N' -diisopropylethylamine are stirred in 1.7 ml of DMF at room temperature for 1 hour. Due to the partial esterification of the product with reactant 8A, 0.5 ml of 1N aqueous lithium hydroxide solution was added and the mixture was stirred for 1 hour. It is subsequently acidified with 1N hydrochloric acid and the entire solution is purified by preparative HPLC [ method 20 ]. The product fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 362 mg (73% of theory) of the title compound.
LC-MS [ method 5 ]] Rt = 1.01 min; MS [ESIpos]: m/z = 535 (M+H)+
1H NMR (400 MHz, DMSO-d6) δ = 3.61 (t, 2H), 3.83 (dd, 1H), 3.96 (dd, 1H), 4.21-4.33 (m, 1H), 4.47-4.59 (m, 2H), 4.86-4.95 (m, 1H), 4.98 (t, 1H), 6.89 (t, 1H interpreted as 1d per diastereomer), 7.00 (dt, J = 3 Hz, 56 Hz, 1H), 7.42-7.55 (m, 4H), 7.59-7.66 (m, 2H), 7.74 (dd, 2H, interpreted as 1d per diastereomer), 8.66 (dd, 1H, interpreted as 1d per diastereomer).
Example 158
Sulfamic acid 3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -3- [3- (trifluoromethyl) phenyl ] propyl ester (mixture of diastereomers)
A solution of 27 mg (48. mu. mol) of the compound from example 66 in 0.5 ml of dry DMF and 100. mu.L of triethylamine is admixed by dropwise addition of a solution of 83 mg of sulfamoyl chloride in 2 ml of DMF. When reaction detection showed only 20% conversion, an additional 200 mg of sulfamoyl chloride was added as a solid. After 10 minutes, 2 ml of 1N hydrochloric acid are added and the entire reaction mixture is purified by preparative HPLC [ method 10 ]. The product fractions are freed of volatile constituents on a rotary evaporator and the residue is dried in HV. This gives 12mg (36% of theory) of the title compound in approximately 92% purity.
LC-MS [ method 3 ]] Rt= 1.25 and 1.26 min, MS [ ESIpos]: m/z = 646 (M+H)+
1H NMR (400 MHz, DMSO-d6) δ = 2.12 (q, 2H), 3.82 (dd, 1H), 3.92-4.04 (m, 2H), 4.04-4.13 (m, 1H), 4.22-4.32 (m, 1H), 4.44-4.59 (m, 2H), 4.98-5.07 (m, 1H), 6.91 (t, 1H is interpreted as 1d per diastereomer), 7.48 (s, 2H), 7.56-7.78 (m, 9H), 8.84 (dd, 1H is interpreted as 1d per diastereomer).
Example 159
Sulfamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [3- (trifluoromethyl) phenyl ] ethyl ester (mixture of diastereomers)
187 mg (0.51 mmol) of the compound from example 8A, 200 mg (approx. 90% purity, 0.56 mmol) of the compound from example 157A, 117 mg (0.61mmol) of EDC, 83 mg (0.61mmol) of HOBt and 107. mu.L (0.61mmol) of N, N' -diisopropylethylamine are stirred in 5.9 ml of DMF at room temperature for 1 hour. The solution is then acidified with 1N hydrochloric acid and the whole solution is purified by preparative HPLC [ method 10 ]. The product fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 215mg (60% of theory) of the title compound in approximately 90% purity.
LC-MS [ method 3 ]] Rt= 1.26 and 1.27 min, MS [ ESIpos]: m/z = 632 (M+H)+
1H NMR (400 MHz, DMSO-d6) δ = 3.83 (dd, 1H), 3.97 (br d, 1H), 4.18-4.34 (m, 3H), 4.51-4.63 (m, 2H), 5.28-5.35 (m, 1H), 6.91 (t (interpreted as 1d per diastereomer, 1H), 7.53-7.83 (m, 10H), 8.95 + 8.97 (1d per diastereomer, 1H).
Example 160
N- [2- (carbamoylamino) -1- (2, 3-dichlorophenyl) ethyl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (1E) -3,3, 3-trifluoroprop-1-en-1-yl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (enantiomerically pure)
The title compound (22 mg, 21% of theory) was obtained from 110mg (185. mu. mol) of the compound of example 62 in the same manner as in example 146.
LC-MS [ method 3 ]] Rt = 1.28 min; MS [ESIpos]: m/z = 577 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 3.19-3.38 (m, 2H), 4.45-4.60 (m, 2H), 5.14-5.23 (m, 1H), 5.54 (s, 2H), 6.14 (t, 1H), 6.85 (dq, 1H), 7.19 (dq, 1H), 7.33-7.42 (m, 2H), 7.55 (dd, 1H), 7.63-7.71 (m, 4H), 8.99 (d, 1H)。
Example 161
N- {2- (carbamoylamino) -1- [3- (trifluoromethyl) phenyl ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (1E) -3,3, 3-trifluoroprop-1-en-1-yl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (enantiomerically pure)
The title compound (15 mg, 18% of theory) was obtained from 87mg (146. mu. mol) of the compound of example 57 in the same manner as in example 146.
LC-MS [ method 4 ]] Rt = 1.09 min; MS [ESIpos]: m/z = 577 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 3.18-3.40 (m, 2H), 4.46-4.60 (m, 2H), 4.89-4.97 (m, 1H), 5.55 (s, 2H), 6.05 (t, 1H), 6.86 (dq, 1H), 7.19 (dq, 1H), 7.54-7.69 (m, 8H), 8.86 (d, 1H)。
Example 162
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (aminosulfonylamino) -1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (mixture of diastereomers)
62.2 mg (0.17 mmol) of the compound of example 8A, 53 mg (0.19 mmol) of the compound of example 134A, 39 mg (0.20 mmol) of EDC and 20 mg (0.20 mmol) of HOBt in 2 ml of DMF are stirred at room temperature overnight. 1 ml of 1N hydrochloric acid are subsequently added and the entire solution is purified by preparative HPLC [ method 20 ]. The product fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 84 mg of the title compound (78% of theory).
LC-MS [ method 5 ]] Rt = 1.03 min; MS [ESIpos]: m/z = 631 (M+H)+
1H-NMR (400 MHz, DMSO-d6) δ = 3.20 (br. t, 1H), 3.82 (dd, 1H), 3.96 (dt, interpreted as 1 dd per diastereomer, 1H), 4.21-4.34 (m, 1H), 4.45-4.62 (m, 2H), 5.05-5.14 (m, 1H,) 6.61-6.65 (m, 2H), 6.70-6.78 (m, 1H), 6.91 (dd, interpreted as 1d per diastereomer, 2H), 7.56-7.64 (m, 5H), 7.70 (br.s, 1H), 7.74-7.78 (m, 2H), 8.62-8.70 (t, 1H, interpreted as 1d per diastereomer).
Example 163
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { 2-hydroxy-1- [3- (trifluoromethyl) phenyl ] ethyl } -N-methylacetamide (mixture of diastereomers)
1.87 g (5.12 mmol) of the compound from example 8A, 1.18 mg (6.14 mmol) of EDC and 874 mg (6.14 mmol) of HOBt are stirred for 5 minutes in 100 ml of DMF. The resulting solution was added dropwise to a solution of 1.44 g (5.63 mmol) of the compound from example 156A and 892. mu.L (5.12 mmol) of N, N' -diisopropylethylamine in 50 ml of DMF. The whole mixture was stirred at room temperature for 1 hour and then mixed with 100 ml of 1N hydrochloric acid. Extraction was carried out with 500 ml of ethyl acetate. The organic phase is washed four times with water and once with saturated aqueous sodium chloride solution, then dried over sodium sulfate and freed of volatile constituents on a rotary evaporator. The residue was purified by preparative chromatography (method 20 and then again by method 32). The product fractions are freed of solvent on a rotary evaporator and the residue is dried in HV. This gives 637 mg (22% of theory) of the title compound as a diastereoisomeric mixture.
LC-MS [ method 4 ]] Rt = 1.08 min; MS [ESIpos]: m/z = 567 (M+H)+
The two diastereomers were separated by preparative HPLC on chiral phase [ method 26d ]: see example 164 and example 165.
Example 164
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { 2-hydroxy-1- [3- (trifluoromethyl) phenyl ] ethyl } -N-methylacetamide (diastereomer I)
The first eluting diastereomer obtained from the chromatographic separation of 200 mg diastereomer of the compound of example 163 by method 26 d. The resulting product (93 mg) was further purified by preparative HPLC [ method 20 ]. Drying in HV gave 80 mg of the title compound.
Chiral analytical HPLC [ method 27b]: Rt = 4.82 min。
LC-MS [ method 4 ]] Rt = 1.08 min; MS [ESIpos]: m/z = 567 (M+H)+
NMR showed two rotamers, a and B, in a ratio of about 2: 1:
1H NMR (400 MHz, DMSO-d6): δ = 2.64 (s, 3HB), 2.94 (s, 3HA), 3.77-4.04 (m, 4H), 4.21-4.33 (m, 1H), 4.78 (d, 1HA), 4.90 (d, 1HB), 4.91 (d, 1HA), 5.00 (d, 1HB), 5.05 (t, 1HA), 5.18-5.25 (m, 1HB), 5.28-5.33 (m, 1HB), 5.57 (t, 1HA), 6.89 (d, 1HA), 6.92 (d, 1HB), 7.55-7.72 (m, 6H), 7.76 (d, 2H)。
example 165
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { 2-hydroxy-1- [3- (trifluoromethyl) phenyl ] ethyl } -N-methylacetamide (diastereomer II)
The final eluting diastereomer obtained from chromatographic separation of 200 mg diastereomer of the compound of example 163 by method 26 d. The resulting product (96 mg) was further purified by preparative HPLC [ method 20 ]. Drying in HV gave 63 mg of the title compound.
Chiral analytical HPLC [ method 27b]: Rt = 6.60 min。
LC-MS [ method 4 ]] Rt = 2.54 min; MS [ESIpos]: m/z = 567 (M+H)+
NMR (at D)6-in DMSO) show two rotamers, a and B, in a ratio of about 2: 1:
1H NMR (400 MHz, DMSO-d6): δ = 2.63 (s, 3HB), 2.94 (s, 3HA), 3.81-4.03 (m, 4H), 4.21-4.33 (m, 1H), 4.78 (d, 1HA), 4.91 (d, 1HA), 4.90-5.03 (m [AB], 2HB), 5.05 (t, 1HA), 5.21 (t, 1HB), 5.31 (t, 1HB), 5.57 (t, 1HA), 6.89 (d, 1Hb), 6.91 (d, 1HA), 7.55-7.73 (m, 6H), 7.758 (d, 2HB), 7.764 (d, 2HA)。
Example 166
N- [1- (3-chloro-2-fluorophenyl) -2-hydroxyethyl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (mixture of diastereomers)
150 mg (0.39 mmol) of the compound from example 8A are dissolved in 1 ml of DMF and mixed with 87 mg (0.51 mmol) of EDC and with 68 mg (0.51 mmol) of HOBt and stirred at room temperature for 20 minutes. 115 mg (0.43 mmol) of the compound from example 161A and 60. mu.L (0.43 mmol) of triethylamine are subsequently added and the mixture is stirred at room temperature for 16 hours. For work-up, 100. mu.L of 1N hydrochloric acid are added and the crude product is purified directly by preparative HPLC [ method 19 ]. This gives 171 mg (82% of theory) of the target compound as a diastereoisomeric mixture.
LC-MS [ method 3 ]] Rt= 1.18 and 1.19 min, MS [ ESIpos]: m/z = 537 (M+H)+
1H-NMR (400 MHz, CDCl3) δ = 3.24 and 3.48 (2m, 1H), 3.58-3.68 (m, 1H), 3.73-3.81(2m, 1H), 3.83-4.16 (m, 3H), 4.47-4.77 (m, 3H), 5.28 and 5.62 (2d, 1H), 5.27-5.37 (m, 1H), 6.98 and 7.56 (2d, 1H), 7.01-7.10 (m, 1H), 7.12-7.22 (m, 1H), 7.29-7.37 (m, 1H), 7.46 and 7.49 (2d, 2H), 7.62 and 7.68 (2d, 2H). (partial resolution of the signals of the double recombination of the mixture of diastereomers).
The following compounds were obtained analogously:
example 187
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- [ 3-hydroxy-1- (2-methoxyphenyl) propyl ] acetamide (mixture of diastereomers)
134 mg (0.37 mmol) of the compound from example 8A are dissolved in 1 ml of DMF and mixed with 106 mg (0.55 mmol) of EDC and with 74 mg (0.55 mmol) of HOBt and stirred at room temperature for 20 minutes. 88 mg (0.40 mmol) of the compound from example 172A and 85. mu.L (0.51 mmol) of N, N-diisopropylethylamine are subsequently added and the mixture is stirred at room temperature for 16 hours. For work-up, 100. mu.L of 1N hydrochloric acid are added and the crude product is purified directly by preparative HPLC [ method 19 ]. This gives 77 mg (40% of theory) of the target compound as a diastereoisomeric mixture.
LC-MS [ method 4 ]] Rt = 0.99 min; MS [ESIpos]: m/z = 529 (M+H)+
1H NMR (400 MHz, DMSO-d6) δ = 1.70-1.87 (m, 2H), 3.35-3.45 (m, 2H), 3.78 (s, 3H), 3.80-3.86 (m, 1H), 3.92-4.01 (m, 1H), 4.22-4.33 (m, 1H), 4.40-4.56 (m, 3H), 5.16-5.26 (m, 1H), 6.86-6.99 (m, 3H), 7.16-7.31 (m, 2H), 7.59-7.68 (m, 2H), 7.71-7.79 (m, 2H), 8.42 (d, 1H). (partial resolution of the signals of the double recombination of the mixture of diastereomers).
Example 188
Carbamic acid 3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -3- (2-methoxyphenyl) propyl ester (mixture of diastereomers)
237 mg (0.65 mmol) of the compound from example 8A are dissolved in 2 ml of DMF and mixed with 174 mg (0.91 mmol) of EDC and with 123 mg (0.91 mmol) of HOBt and stirred at room temperature for 20 minutes. 186 mg (0.71 mmol) of the compound from example 174A and 129. mu.L (0.78 mmol) of N, N-diisopropylethylamine are then added and the mixture is stirred at room temperature for 16 hours. For work-up, 100. mu.L of 1N hydrochloric acid are added and the crude product is purified directly by preparative HPLC [ method 19 ]. This gives 123 mg (33% of theory) of the target compound as a diastereoisomeric mixture.
LC-MS [ method 5 ]] Rt = 1.01 min; MS [ESIpos]: m/z = 572 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 1.71-1.99 (m, 2 H), 3.78 (s, 3 H), 3.80-4.00 (m, 4 H), 4.22-4.34 (m, 1H), 4.40-4.60 (m, 2H), 5.14-5.31 (m, 1H), 6.46 (br. s., 2H), 6.85-7.01 (m, 3H), 7.16-7.33 (m, 2H), 7.59-7.67 (m, 2H), 7.69-7.80 (m, 2H), 8.38-8.54 (m, 1H). (partial resolution of the signals of the double recombination of the mixture of diastereomers).
The diastereoisomeric mixture was separated by preparative HPLC on chiral phase [ method 13a ]: see examples 189 and 190.
Example 189
Carbamic acid 3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -3- (2-methoxyphenyl) propyl ester (diastereomer I)
The diastereomer eluted first from the separation of example 188.
Yield: 33 mg (9% of theory).
Chiral analytical HPLC [ method 9]: Rt = 3.46 min
LC-MS [ method 5 ]] Rt = 1.01 min; MS [ESIpos]: m/z = 572 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 1.81-2.00 (m, 2 H), 3.79 (s, 3 H), 3.81-4.07 (m, 4 H), 4.22-4.35 (m, 1 H), 4.44-4.56 (m, 2 H), 5.17-5.29 (m, 1 H), 6.47 (br. s., 2 H), 6.87-7.01 (m, 3 H), 7.19-7.33 (m, 2 H), 7.63 (d, 2 H), 7.76 (d, 2 H), 8.50 (d, 1 H)。
Example 190
3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -3- (2-methoxyphenyl) propylcarbamate (diastereomer II)
The final eluting diastereomer from the separation of example 188.
LC-MS [ method 5 ]] Rt = 1.00 min; MS [ESIpos]: m/z = 572 (M+H)+
Chiral analytical HPLC [ method 9]: Rt = 3.83 min
Yield: 47 mg (12% of theory).
1H NMR (400 MHz, DMSO-d6): δ = 1.81-1.98 (m, 2 H), 3.78 (s, 3 H), 3.81-4.00 (m, 4 H), 4.21-4.34 (m, 1 H), 4.42-4.58 (m, 2 H), 5.17-5.26 (m, 1 H), 6.44 (br. s., 2 H), 6.87-7.00 (m, 3 H), 7.20-7.30 (m, 2 H), 7.62 (d, 2 H), 7.76 (d, 2 H), 8.48 (d, 1 H)。
Example 191
Carbamic acid 2- ({ [3- (4-chlorophenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetyl } amino) -2- [2- (trifluoromethyl) phenyl ] ethyl ester (enantiomer II)
An amount of 30 mg (0.08 mmol) of [3- (4-chlorophenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid (prepared according to WO2007/134862, example 154A) was dissolved in 1 ml of DMF, and the solution was then mixed with 21 mg (0.11 mmol) of EDC and with 15 mg (0.11 mmol) of HOBt, followed by stirring at room temperature for 20 minutes. 23 mg (0.09 mmol) of the compound from example 180A are subsequently added and the mixture is stirred at room temperature for 16 hours. For work-up, 50. mu.L of 1N hydrochloric acid are added and the crude product is purified directly by preparative HPLC [ method 19 ]. This gives 34 mg (69% of theory) of the target compound.
LC-MS [ method 4 ]] Rt = 1.09 min; MS [ESIpos]: m/z = 592 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 3.98 (dd, 1H), 4.13 (dd, 1H), 4.47-4.57 (m, 2H), 5.01 (s, 2H), 5.37-5.44 (m, 1H), 6.59 (br. s., 2H), 7.02-7.17 (m, 3H), 7.26-7.34 (m, 1H), 7.48-7.55 (m, 5H), 7.68-7.77 (m, 3H), 8.98 (d, 1H)。
The following compounds were obtained analogously:
example 202
Carbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- (2, 3-dichlorophenyl) ethyl ester (diastereomer I)
The first eluting diastereomer obtained from the separation of the mixture of diastereoisomers of example 199 by method 11 b.
Yield: 43 mg (32% of theory).
Chiral analytical HPLC [ method 12a]: Rt = 4.50 min
LC-MS [ method 4 ]] Rt = 1.05 min; MS [ESIpos]M/z = 596 and 598 (M + H)+
1H NMR (400 MHz, DMSO-d6): δ = 3.82 (dd, 1H), 3.95 (dd, 1H), 4.02-4.15 (m, 2H), 4.22-4.33 (m, 1H), 4.46-4.58 (m, 2H), 5.41-5.48 (m, 1H), 6.60 (s br., 2H), 6.91 (d, 1H), 7.39 (t, 1H), 7.45-7.50 (m, 1H), 7.56-7.66 (m, 3H), 7.74 (d, 2H), 8.99 (d, 1H)。
Example 203
Carbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- (2, 3-dichlorophenyl) ethyl ester (diastereomer II)
The final eluting diastereomer obtained from the separation of the mixture of diastereomers of example 199 by method 11 b.
Yield: 50 mg (41% of theory).
Chiral analytical HPLC [ method 12a]: Rt = 6.55 min
LC-MS (square)Method 4] Rt = 1.05 min; MS [ESIpos]M/z = 596 and 598 (M + H)+
1H NMR (400 MHz, DMSO-d6): δ = 3.82 (dd, 1H), 3.96 (dd, 1H), 4.02-4.16 (m, 2H), 4.22-4.29 (m, 1H), 4.47-4.57 (m, 2H), 5.40-5.48 (m, 1H), 6.60 (s br., 2H), 6.89 (d, 1H), 7.40 (t, 1H), 7.46-7.50 (m, 1H), 7.57-7.65 (m, 3H), 7.74 (d, 0H), 9.00 (d, 1H)。
Example 204
Carbamic acid 2- ({ [3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetyl } amino) -2- (2, 3-dichlorophenyl) ethyl ester (enantiomer I)
The first eluting enantiomer obtained from the separation of the mixture of enantiomers from example 201 by method 25.
Yield: 128 mg (36% of theory).
Chiral analytical HPLC [ method 27d]: Rt = 4.35 min
LC-MS [ method 3 ]] Rt = 1.24 min; MS [ESIpos]M/z = 580 and 582 (M + H)+
1H NMR (400 MHz, DMSO-d6): δ = 2.52-2.68 (m, 2H), 3.97 (t, 2H), 4.02-4.15 (m, 2H), 4.46-4.55 (m, 2H), 5.40-5.47 (m, 1H), 6.40-6.80 (m br., 2H), 7.38 (t, 1H), 7.47 (dd, 1H), 7.56-7.68 (m, 5H), 8.97 (d, 1H)。
Example 205
Carbamic acid 2- ({ [3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetyl } amino) -2- (2, 3-dichlorophenyl) ethyl ester (enantiomer II)
The final eluting enantiomer from the separation of the mixture of enantiomers of example 201 was obtained by method 25.
Yield: 135 mg (40% of theory).
Chiral analytical HPLC [ method 27d]: Rt = 5.04 min
LC-MS [ method 3 ]] Rt = 1.24 min; MS [ESIpos]M/z = 580 and 582 (M + H)+
1H NMR (400 MHz, DMSO-d6): δ = 2.52-2.68 (m, 2H), 3.97 (t, 2H), 4.02-4.15 (m, 2H), 4.46-4.55 (m, 2H), 5.40-5.47 (m, 1H), 6.40-6.80 (m br., 2H), 7.38 (t, 1H), 7.47 (dd, 1H), 7.56-7.68 (m, 5H), 8.97 (d, 1H)。
Example 206
Carbamic acid 2- ({ [4- (4-chlorophenyl) -2-oxo-3- (3,3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl ] acetyl } amino) -2- [3- (trifluoromethyl) phenyl ] ethyl ester (mixture of diastereomers)
An amount of 58 mg (0.11 mmol) of [4- (4-chlorophenyl) -2-oxo-3- (3,3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl ] acetic acid from example 184A was dissolved in 2 ml of DMF and the resulting solution was mixed with 28 mg (0.15 mmol) of EDC and with 20 mg (0.15 mmol) of HOBt and subsequently stirred at room temperature for 20 minutes. 42 mg (0.12 mmol) of the compound from example 183A are subsequently added and the mixture is stirred at room temperature for 16 hours. For work-up, 100. mu.L of 1N hydrochloric acid are added and the crude product is purified directly by preparative HPLC [ method 19 ]. This gives 13 mg (18% of theory) of the target compound.
LC-MS [ method 3 ]] Rt = 1.23 min; MS [ESIpos]: m/z = 595 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 3.74 (dd, 1H), 3.87 (dd, 1H), 4.05-4.15 (m, 2H), 4.19-4.28 (m, 1H), 4.32-4.39 (m, 2H), 5.12-5.21 (m, 1H), 6.59 (s br., 2H), 6.68-6.74 (m, 2H), 7.47-7.77 (m, 8H), 8.87 (d, 1H)。
Example 207
Carbamic acid 2- ({ [4- (4-chlorophenyl) -2-oxo-3- (3,3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl ] acetyl } amino) -2- [2- (trifluoromethyl) phenyl ] ethyl ester (mixture of diastereomers)
In the same manner as the compound of example 206, 58 mg (0.11 mmol) of [4- (4-chlorophenyl) -2-oxo-3- (3,3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl ] acetic acid from example 185A were reacted with 42 mg (0.12 mmol) of the compound of example 180A. This gives 12 mg (18% of theory) of the target compound.
LC-MS [ method 5 ]] Rt = 1.06 min; MS [ESIpos]: m/z = 595 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 3.73 (dd, 1H), 3.86 (dd, 1H), 3.98 (dd, 1H), 4.13 (dd, 1H), 4.19-4.27 (m, 1H), 4.27-4.38 (m, 2H), 5.37-5.45 (m, 1H), 6.59 (s br., 2H), 6.68-6.74 (m, 2H), 7.47-7.56 (m, 6H), 7.69-7.77 (m, 4H), 8.95 (d, 1H)。
B. Evaluation of pharmacological Activity
Abbreviations:
EDTA ethylene diamine tetraacetic acid
DMEM Dulbecco modified Eagle Medium
FCS fetal calf serum
HEPES 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid
SmGM smooth muscle cell growth medium
Tris-HCl 2-amino-2- (hydroxymethyl) -1, 3-propanediol hydrochloride
UtSMC uterine smooth muscle cells.
The pharmacological effects of the compounds of the invention can be revealed in the following assays:
B-1. in vitro cell assay for measuring anti-diuretic hormone receptor activity
The identification of agonists and antagonists of the human and rat V1a and V2 anti-diuretic hormone receptors and the quantitative analysis of the activity of the substances described herein were carried out using recombinant cell lines. These cells were originally derived from Hamster Ovary epithelial cells (Chinese Hamster Ovary, CHO K1, ATCC: American Type Culture Collection, Manassas, VA 20108, USA). The test cell lines constitutively expressed a modified form of the calpain-aequorin which-after recombination with the cofactor Coelenterazin-luminesced as the concentration of free calcium increased (Rizzuto R., Simpson A.W., Brini M., Pozzan T.; Nature 358 (1992) 325-327). In addition, the cells are stably transfected with either human or rat V1a or V2 receptors. For the Gs-coupled V2 receptor, the cell is stably transfected with other genes, which areHybrid Gα 16Protein coding (Amatruda T.T., Steele D.A., Slepak V.Z., Simon M.I., Proc. nat. Acad. Sci. USA 88 (1991), 5587-5591), independently or as a fusion gene. The resulting anti-diuretic hormone receptor test cells respond to stimulation by intracellular release of calcium ions of the recombinantly expressed anti-diuretic hormone receptor, which can be quantified by aequorin luminosity using a suitable luminometer (Milligan G., Marshall F., Rees S., Trends in Pharmaco. Sci.17 (1996) 235-237).
Test procedure:one day prior to the assay, cells were spotted in culture medium (DMEM, 10% FCS, 2mM glutamine, 10mM HEPES) in 384-well microtiter plates and maintained in cell culture vessels (96% humidity, 5% v/v carbon dioxide, 37 ℃). On the day of the assay, the culture medium was replaced with Tyrode solution (140 mM sodium chloride, 5 mM potassium chloride, 1 mM magnesium chloride, 2mM calcium chloride, 20 mM glucose, 20 mM HEPES), the latter additionally containing the cofactor Coelenterazin (50 μ M), and the microtiter plates were then incubated for an additional 3-4 hours. Test substances at various concentrations were added to the wells of the microtiter plate over 10-20 minutes, followed by addition of the agonist [ Arg8]Antidiuretic hormone, the resulting optical signal being immediately measured in a photometer. IC50 values were calculated using the GraphPad PRISM computer program (version 3.02).
The following table lists representative IC's of the compounds of the invention for cell lines transfected with human V1a or V2 receptors50The value:
table 1:
| example No. 2 | IC50 hV1a [µM] | IC50 hV2 [µM] |
| 2 | 0.0076 | 0.0026 |
| 10 | 0.0104 | 0.0063 |
| 14 | 0.001 | 0.0089 |
| 20 | 0.0015 | 0.0063 |
| 24 | 0.0045 | 0.0013 |
| 26 | 0.0009 | 0.0032 |
| 34 | 0.003 | 0.0015 |
| 39 | 0.0014 | 0.0078 |
| 44 | 0.044 | 0.0017 |
| 45 | 0.0055 | 0.0025 |
| 48 | 0.0052 | 0.0044 |
| 51 | 0.001 | 0.0085 |
| 53 | 0.0015 | 0.0049 |
| 57 | 0.0029 | 0.0022 |
| 60 | 0.0005 | 0.0045 |
| 62 | 0.0036 | 0.001 |
| 65 | 0.0168 | 0.0168 |
| 69 | 0.0016 | 0.0097 |
| 70 | 0.0016 | 0.0099 |
| 73 | 0.0108 | 0.0016 |
| 74 | 0.0216 | 0.0024 |
| 75 | 0.513 | 0.0592 |
| 78 | 0.0211 | 0.0304 |
| 87 | 0.0038 | 0.0058 |
| 89 | 2.88 | 0.29 |
| 90 | 0.0886 | 0.231 |
| 94 | 0.251 | 0.0723 |
| 95 | 0.0573 | 0.0192 |
| 96 | 0.0713 | 0.0402 |
| 112 | 0.0024 | 0.006 |
| 115 | 0.0035 | 0.0076 |
| 121 | 0.0009 | 0.0014 |
| 126 | 0.0018 | 0.0018 |
| 136 | 0.0039 | 0.024 |
| 141 | 0.036 | 0.0048 |
| 144 | 0.0014 | 0.0139 |
| 149 | 0.002 | 0.015 |
| 152 | 0.0022 | 0.0071 |
| 156 | 0.0019 | 0.01 |
| 157 | 0.0124 | 0.0051 |
| 159 | 0.0043 | 0.0018 |
| 163 | 0.594 | 0.0077 |
| 167 | 0.003 | 0.0054 |
| 168 | 0.087 | 0.076 |
| 172 | 0.091 | 0.136 |
| 182 | 0.304 | 0.028 |
| 184 | 0.072 | 0.0266 |
| 185 | 0.055 | 0.045 |
| 188 | 0.0082 | 0.0099 |
| 191 | 0.0023 | 0.0248 |
| 203 | 0.0027 | 0.0044 |
| 207 | 0.0033 | 0.101 |
B-2. Detection of antidiuretic hormones V1a In vitro cellular assays for the effects of receptor antagonists on modulation of genes prior to fibrosis
Cell line H9C2, which was isolated from rat heart tissue and was described as cardiomyocyte-Type (American Type Culture Collection ATCC number CRL-1446), endogenously expressed the anti-diuretic V1A receptor AVPR1A in high replicative numbers, whereas AVPR2 expression was undetectable. For the cellular analysis of the inhibition of AVPR1A receptor-dependent modulation of gene expression by receptor antagonists, the procedure was as follows:
H9C2 cells were seeded at a cell density of 100000 cells/well in 12-well microtiter plates for cell culture in 1.0 ml of Opti-MEM medium (Invitrogen Corp. Carlsbad CA, USA, Cat. number 11058-. After 24 hours, vehicle solution (negative control), antidiuretic hormone solution was added to each group of three wells (triplet): [ Arg8] -antidiuretic hormone acetate (Sigma Cat. number V9879) or test substance (dissolved in vehicle: water with 20% by volume of ethanol) and antidiuretic hormone solution. In cell culture, the final concentration of antidiuretic hormone was 0.05. mu.M. The test substance solution is added to the cell culture fluid in a small volume, and therefore the final concentration of 0.1% ethanol in the cell assay is not exceeded. After a culture period of 6 hours, the culture supernatant was aspirated, adherent cells were lysed in 250 μ L of RLT buffer (Qiagen, Ratingen, cat number 79216), and RNA was then isolated from the lysate by using RNeasy kit (Qiagen, cat number 74104). Followed by DNAse digestion (Invitrogen Cat. number 18068-015), cDNA synthesis (Promaga ImProm-II Reverse Transcription System Cat. number A3800) and RTPCR using pPCR MasterMix RT-QP2X-03-075 (obtained from Eurogentec, Seraing, Belgium). All procedures were performed according to the protocol of the test agent manufacturer. The Primer set for RTPCR was selected on the basis of the mRNA gene sequence (NCBI Genbank Entrez Nucleotide Data Base) by the Primer3Plus program using a probe with a 6-FAM-TAMRA marker. The RTPCR procedure for determining relative mRNA expression in cells of each assay batch was performed in a 96-well or 384-well microtiter plate format using the Applied Biosystems ABI Prism 7700 Sequence Detector according to the instrument instructions. Relative gene expression is represented by Δ - Δ Ct values obtained from the expression level of the reference ribosomal protein L-32 gene (Genbank acc. number NM — 013226) and the threshold Ct value for Ct = 35 [ Applied Biosystems, User Bulletin number 2 ABI Prism 7700 SDS December 11, 1997(10/2001 upgrade) ].
B-3. In vivo test to detect cardiovascular effects: blood pressure measurement for anesthetized rats ( Antidiuretic hormone "challenge" model )
Male Sprague-Dawley rats (250-350 g body weight) under ketamine/xylazine/pentobarbital injection anesthesia were inserted into the jugular and femoral veins polyethylene tubes (PE-50; Intramedic) preloaded with isotonic sodium chloride solution containing heparin (500 IU/ml) and then strapped (tied in). Injecting arginine-antidiuretic hormone via a venous access with a syringe; the test substance is injected via the second venous access. For the cystolic blood pressure determination, a pressure catheter (Millar SPR-3202F) was inserted into the carotid artery. The arterial cannula is connected to a pressure transducer which transmits its signal to a recording computer equipped with suitable recording software. In a typical experiment, experimental animals are administered a prescribed amount of arginine-antidiuretic hormone (30 ng/kg) in isotonic sodium chloride solution at 10-15 minute intervals with 3-4 consecutive bolus injections, and when the blood pressure again reaches the initial level, the substance to be tested is administered as a bolus in a suitable solvent, with subsequent infusions. After this, at regular time intervals (10-15 minutes), the same amount of antidiuretic hormone as the start is administered again. The blood pressure value is used as a basis for the measurement of the degree to which the test substance counteracts the blood pressure-raising effect of the antidiuretic hormone. Control animals received only solvent, not the test substance.
After intravenous administration, the compound of the present invention resulted in an inhibitory effect on the increase in blood pressure caused by arginine-antidiuretic hormone, as compared with the solvent control.
B-4. In vivo assay to detect this cardiovascular effect: diuresis studies in conscious rats in metabolic test cages
Wistar (Wistar) rats (220-400 g body weight) were kept free to eat (Altromin) and drink. During the course of the experiment, the animals each remained in a free drinking state for 4-8 hours in a metabolic test cage (Techniplast Deutschl and GmbH, D-82383 Hohenpei beta. enberg) suitable for rats of this body weight class. At the beginning of the experiment, the animals were fed the substance to be tested into the stomach in a suitable solvent of 1-3 ml volume/kg body weight using gastric tube feeding. Control animals received only solvent. The control and substance tests were performed in parallel on the same day. The control group and the substance-dose group each consisted of 4-8 animals. During the experiment, urine excreted by the animals was continuously collected in a receiver at the bottom of the cage. The volume of urine per unit time was determined separately for each animal and the concentration of excreted sodium and potassium ions in the urine was measured by the standard method of flame emission spectroscopy. To obtain a sufficient volume of urine, these animals were given a defined amount of water (typically 10 ml per kg body weight) by gastric tube feeding at the beginning of the experiment. The body weight of each animal was measured before the start of the experiment and after the end of the experiment.
After oral administration, the compounds of the invention result in increased urination compared to control animals, which is based primarily on increased excretion of water (aquaresis).
B-5. In vivo assay to detect cardiovascular effects: hemodynamic Studies for anesthetized dogs
Male or female hybrid dogs (Mongrels, Marshall BioResources, USA) weighing between 20-30 kg were anesthetized with pentobarbital (30 mg/kg iv, Narcoren, Merial, Germany) for surgical procedures and hemodynamic and functional research end points (terminiii). Coulonium chloride (Alloferin, ICN Pharmaceuticals, Germany, 3 mg/animal iv) was additionally used as a muscle relaxant. The dogs were inserted into a tube and an oxygen/ambient air mixture (40/60%) was introduced (about 5-6L/min). Aeration was performed using a Draeger ventilator (Sulla 808) and monitored using a carbon dioxide analyzer (ensstrm).
Anesthesia was maintained by continuous perfusion with pentobarbital (50 μ g/kg/min); fentanyl was used as an analgesic (10. mu.g/kg/hour). An alternative to pentobarbital is the use of isoflurane (1-2% by volume).
In a preliminary intervention, the dog was fitted with a cardiac pacemaker.
At a time 21 days prior to the first drug trial (i.e. start of experiment), cardiac pacemakers of Biotronik company (gloos) were implanted in subcutaneous skin bags and contacted with the heart via pacemaker electrodes which passed through the external jugular vein into the right ventricle under light irradiation.
Retrograde in femoral artery via sheath introducer (Avanti +; Cordis) by 7F biopsy forceps (Cordis) simultaneously with pacemaker implantation and after atraumatic passage through the aortic valve, there was defined damage to the mitral valve, monitored by echocardiography and irradiation. Thereafter, all access ports were removed and the dog spontaneously awakened from anesthesia.
On the other 7 days (i.e. 14 days before the first drug trial), the pacemaker was started and the heart was stimulated at a frequency of 220 shocks/minute.
Actual drug testing experiments were performed 14 and 28 days after the onset of pacemaker stimulation by using the following instruments:
bladder catheter for bladder relief and measuring urine flow
ECG leads connected to poles (for electrocardiography measurements)
The NaCl-filled fluidmatic PE-300 tube was inserted into the femoral artery. The tube was connected to a pressure transducer (Braun Melsungen, Melsungen, Germany) to measure the systemic blood pressure
A Millar Tip catheter (model 350 PC, Millar Instruments, Houston, USA) is inserted into the left atrium or into a port fixed in the carotid artery for measuring cardiac hemodynamics
Swan-Ganz catheter (CCOmbo 7.5F, Edwards, Irvine, USA) is inserted into the pulmonary artery via the jugular vein for measuring cardiac output, oxygen saturation, pulmonary arterial pressure and central venous pressure
Braun ü le placed in the cephalic vein for infusion of pentobarbital, for fluid replacement and for blood sampling (determination of the plasma level of a substance or other clinical blood values)
Braun ü le placed in the saphenous vein for infusion of fentanyl and for administration of substances
Perfusion with increasing doses of antidiuretic hormone (Sigma company), up to a dose of 4 mU/kg/min. This dose is then used to test a pharmacological substance.
If desired, the raw signal is amplified (Gould Amplifier, Gould Instrument Systems, Valley View, USA) or (Edwards View-Monitor, Edwards, Irvine, USA) and then input into a Ponemah system (DataSciences Inc, Minneapolis, USA) for evaluation. These signals were recorded continuously throughout the experimental time, further processed by the software by counting, and averaged over 30 seconds.
C. Illustrative examples of pharmaceutical compositions
The compounds of the invention are converted into pharmaceutical preparations in the following manner:
and (3) tablet preparation:
consists of the following components:
100 mg of a compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.
Tablet weight 212 mg. The diameter is 8 mm, and the curvature radius is 12 mm.
The production method comprises the following steps:
the mixture of the compound of the invention, lactose and starch is granulated with a 5% strength solution in water (m/m). After drying, the microparticles were mixed with magnesium stearate for 5 minutes. This mixture is compressed by using a conventional tablet press (see above for tablet forms). The instructional compressive force for compression was 15 kilonewtons (kN).
Suspension for oral administration:
consists of the following components:
1000 mg of a compound of the invention, 1000 mg of ethanol (96%), 400%mg of Rhodigel®(xanthan gum, available from FMC, Pennsylvania, USA) and 99 g of water.
A single dose of 100 mg of a compound of the invention is administered as a 10 ml oral suspension.
The production method comprises the following steps:
rhodigel is suspended in ethanol and the compound of the invention is then added to the suspension. Water was added with stirring. Stirring was continued for about 6 hours until swelling of the Rhodigel was complete.
Solution for oral administration:
Consists of the following components:
500 mg of a compound according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. A single dose of 100 mg of a compound of the invention corresponds to 20 g of an oral solution.
The production method comprises the following steps:
the compounds of the invention are suspended in a mixture of polyethylene glycol and polysorbate under agitation. The stirring operation is continued until the compound of the present invention is completely dissolved.
Intravenous injection
(i.v.)
Solutions of
:
The compounds of the invention are dissolved in a physiologically acceptable solvent (e.g., isotonic saline solution, 5% glucose solution and/or 30% PEG 400 solution) at a concentration below the saturation solubility. The solution is sterile filtered and dispensed into sterile, pyrogen-free injection containers.
Claims (31)
1. A compound of the general formula (I)
In the formula
A is-CH2，
Q is a group of N which is a group of,
R1is (C)2-C4) Alkyl radical (C)2-C4) An alkenyl group or a cyclopropyl group, in which,
wherein (A) and (B)C2-C4) Alkyl and (C)2-C4) Alkenyl may be substituted by 1 or 2 substituents independently of one another selected from fluorine, oxo, hydroxy and trifluoromethyl,
R2is a phenyl group, and the phenyl group,
wherein the phenyl group may be substituted by a substituent selected from fluorine or chlorine,
R3is-NR8-C(=O)-R9，-NR10-SO2-R11，-SO2-NR12R13，-O-C(=O)-NR14R15，-NR16-C(=O)-NR17R18，-NR19-C(=O)-OR20，-S(=O)nR21or-NR26-SO2-NR27R28-，
Wherein
R8Is a hydrogen atom, and is,
R9is a methyl group, and the compound is,
R10is a hydrogen atom, and is,
R11is a methyl group or an ethyl group,
R12is a methyl group, and the compound is,
R13is a methyl group, and the compound is,
R14is hydrogen or a methyl group, or a mixture thereof,
R15is a hydrogen, a methyl or ethyl radical,
R16is a hydrogen atom, and is,
R17is hydrogen or a methyl group, or a mixture thereof,
R18is a hydrogen, a methyl or ethyl radical,
or
R16And R17Together with the nitrogen atom to which they are bonded form a 2-oxoimidazolidin-1-yl or 2-oxotetrahydropyrimidin-1 (2H) -yl ring,
R19is a hydrogen atom, and is,
R20is a methyl group or an ethyl group,
or
R19And R20Together with the atom to which they are attached form 2-oxo-1, 3-Oxazolidin-3-yl or 2-oxo-1, 3-An oxazinane-3-yl ring,
n is the number 0 or 2 and,
R21is a methyl group, and the compound is,
R26is a hydrogen atom, and is,
R27is a hydrogen atom, and is,
R28is a hydrogen atom, and is,
R4is a radical of the formula
Wherein
# is linked to-C (R)5)(AR3) The point of attachment on the N-is,
R22is hydrogen, cyano, methyl, trifluoromethoxy, fluoro, chloro, trifluoromethyl and methoxy,
R23is hydrogen, cyano, methyl, trifluoromethoxy, fluoro, chloro, trifluoromethyl and methoxy,
Wherein the group R22And R23At least one of which is not hydrogen,
R5is hydrogen or a methyl group, or a mixture thereof,
R29is a hydrogen atom, and is,
and salts of the compounds.
2. A compound of formula (I) according to claim 1, wherein
In the formula
A is-CH2，
Q is a group of N which is a group of,
R1is (C)2-C4) Alkyl radical (C)2-C4) An alkenyl group or a cyclopropyl group, in which,
wherein (C)2-C4) Alkyl and (C)2-C4) Alkenyl groups may be selected independently of one another from fluorine, oxo, hydroxy and trisSubstituted by 1 or 2 substituents of fluoromethyl,
R2is a phenyl group, and the phenyl group,
wherein the phenyl group may be substituted by a substituent selected from fluorine or chlorine,
R3is-NR8-C(=O)-R9，-NR10-SO2-R11，-SO2-NR12R13，-O-C(=O)-NR14R15，-NR16-C(=O)-NR17R18，-NR19-C(=O)-OR20，-S(=O)nR21or-NR26-SO2-NR27R28-，
Wherein
R8Is a hydrogen atom, and is,
R9is a methyl group, and the compound is,
R10is a hydrogen atom, and is,
R11is a methyl group or an ethyl group,
R12is a methyl group, and the compound is,
R13is a methyl group, and the compound is,
R14is hydrogen or a methyl group, or a mixture thereof,
R15is a hydrogen, a methyl or ethyl radical,
R16is a hydrogen atom, and is,
R17is hydrogen or a methyl group, or a mixture thereof,
R18is a hydrogen, a methyl or ethyl radical,
or
R16And R17Together with the nitrogen atom to which they are bonded form a 2-oxoimidazolidin-1-yl or 2-oxotetrahydropyrimidin-1 (2H) -yl ring,
R19is a hydrogen atom, and is,
R20is a methyl group or an ethyl group,
or
R19And R20Together with the atom to which they are attached form 2-oxo-1, 3-Oxazolidin-3-yl or 2-oxo-1, 3-An oxazinane-3-yl ring,
n is the number 0 or 2 and,
R21is a methyl group, and the compound is,
R26is a hydrogen atom, and is,
R27is a hydrogen atom, and is,
R28is a hydrogen atom, and is,
R4is a radical of the formula
Wherein
# is linked to-C (R) 5)(AR3) The point of attachment on the N-is,
R22are hydrogen, fluorine, chlorine, trifluoromethyl and methoxy,
R23are hydrogen, fluorine, chlorine, trifluoromethyl and methoxy,
wherein the group R22And R23At least one of which is not hydrogen,
R5is hydrogen or a methyl group, or a mixture thereof,
R29is a hydrogen atom, and is,
and salts of the compounds.
3. A compound of formula (I) according to claim 1 or 2, wherein
In the formula
A is-CH2，
Q is a group of N which is a group of,
R1is 3, 3, 3-trifluoroprop-1-en-1-yl, 3, 3, 3-trifluoropropyl or 1, 1, 1-trifluoroprop-2-ol-3-yl,
R2is a phenyl group, and the phenyl group,
wherein the phenyl group may be substituted by a substituent selected from fluorine or chlorine,
R3is-NR8-C(=O)-R9，-NR10-SO2-R11，-SO2-NR12R13，-O-C(=O)-NR14R15，-NR16-C(=O)-NR17R18，-NR19-C(=O)-OR20，-S(=O)nR21or-NR26-SO2-NR27R28-，
Wherein
R8Is a hydrogen atom, and is,
R9is a methyl group, and the compound is,
R10is a hydrogen atom, and is,
R11is a methyl group or an ethyl group,
R12is a methyl group, and the compound is,
R13is a methyl group, and the compound is,
R14is hydrogen or a methyl group, or a mixture thereof,
R15is a hydrogen, a methyl or ethyl radical,
R16is a hydrogen atom, and is,
R17is hydrogen or a methyl group, or a mixture thereof,
R18is a hydrogen, a methyl or ethyl radical,
or
R16And R17Together with the nitrogen atom to which they are bonded form a 2-oxoimidazolidin-1-yl or 2-oxotetrahydropyrimidin-1 (2H) -yl ring,
R19is a hydrogen atom, and is,
R20is a methyl group or an ethyl group,
or
R19And R20Together with the atom to which they are attached form 2-oxo-1, 3-Oxazolidin-3-yl or 2-oxo-1, 3-An oxazinane-3-yl ring,
n is the number 0 or 2 and,
R21is a methyl group, and the compound is,
R26is a hydrogen atom, and is,
R27is a hydrogen atom, and is,
R28is a hydrogen atom, and is,
R4is a radical of the formula
Wherein
# is linked to-C (R)5)(AR3) The point of attachment on the N-is,
R22are hydrogen, fluorine, chlorine and trifluoromethyl,
R23are hydrogen, fluorine, chlorine and trifluoromethyl,
wherein the group R22And R23At least one of which is not hydrogen,
R5is hydrogen or a methyl group, or a mixture thereof,
R29is a hydrogen atom, and is,
and salts of the compounds.
4. A compound of the formula (I-B)
Wherein
A is-CH2，
R1Is (C)2-C4) Alkyl radical (C)2-C4) An alkenyl group or a cyclopropyl group, in which,
wherein (C)2-C4) Alkyl and (C)2-C4) Alkenyl is substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, hydroxy, oxo and trifluoromethyl,
R2is a phenyl group, and the phenyl group,
wherein the phenyl group is substituted with a substituent selected from fluorine and chlorine,
R3is-NR8-C(=O)-R9，-NR10-SO2-R11，-O-C(=O)-NR14R15or-NR16-C(=O)-NR17R18，
Wherein
R8Is a hydrogen atom, and is,
R9is a methyl group, and the compound is,
R10is a hydrogen atom, and is,
R11is a methyl group or an ethyl group,
R14is hydrogen or a methyl group, or a mixture thereof,
R15is a hydrogen, a methyl or ethyl radical,
R16is a hydrogen atom, and is,
R17is hydrogen or a methyl group, or a mixture thereof,
R18is a hydrogen, a methyl or ethyl radical,
R4is a radical of the formula
Wherein
# is linked to-C (R)5)(AR3) The point of attachment on the N-is,
R22is hydrogen, cyano, methyl, trifluoromethoxy, fluoro, chloro, trifluoromethyl and methoxy,
R23is hydrogen, cyano, methyl, trifluoromethoxy, fluoro, chloro, trifluoromethyl and methoxy,
wherein the group R22And R23At least one of which is not hydrogen,
R5is hydrogen or a methyl group, or a mixture thereof,
and salts thereof.
5. The compound of the formula (I-B) according to claim 4
Wherein
A is-CH2，
R1Is (C)2-C4) Alkyl radical (C)2-C4) An alkenyl group or a cyclopropyl group, in which,
wherein (C)2-C4) Alkyl and (C)2-C4) Alkenyl is substituted by 1 or 2 substituents independently selected from fluorine, hydroxy, oxo and trifluoromethyl,
R2is a phenyl group, and the phenyl group,
wherein the phenyl group is substituted with a substituent selected from fluorine and chlorine,
R3is-NR8-C(=O)-R9，-NR10-SO2-R11，-O-C(=O)-NR14R15or-NR16-C(=O)-NR17R18，
Wherein
R8Is a hydrogen atom, and is,
R9is a methyl group, and the compound is,
R10is a hydrogen atom, and is,
R11is a methyl group or an ethyl group,
R14is hydrogen or a methyl group, or a mixture thereof,
R15is a hydrogen, a methyl or ethyl radical,
R16is a hydrogen atom, and is,
R17is hydrogen or a methyl group, or a mixture thereof,
R18is a hydrogen, a methyl or ethyl radical,
R4is a radical of the formula
Wherein
# is linked to-C (R)5)(AR3) The point of attachment on the N-is,
R22are hydrogen, fluorine, chlorine, trifluoromethyl and methoxy,
R23are hydrogen, fluorine, chlorine, trifluoromethyl and methoxy,
wherein the group R22And R23At least one of which is not hydrogen,
R5is hydrogen or a methyl group, or a mixture thereof,
R29is a hydrogen atom, and is,
and salts of the compounds.
6. The compound of the formula (I-B) according to claim 4
Wherein
A is-CH2，
R1Is 3, 3, 3-trifluoroprop-1-en-1-yl, 3, 3, 3-trifluoropropyl or 1, 1, 1-trifluoroprop-2-ol-3-yl,
R2is a phenyl group, and the phenyl group,
wherein the phenyl group is substituted with a substituent selected from fluorine and chlorine,
R3is-NR8-C(=O)-R9，-NR10-SO2-R11，-O-C(=O)-NR14R15or-NR16-C(=O)-NR17R18，
Wherein
R8Is a hydrogen atom, and is,
R9Is a methyl group, and the compound is,
R10is a hydrogen atom, and is,
R11is a methyl group or an ethyl group,
R14is hydrogen or a methyl group, or a mixture thereof,
R15is a hydrogen, a methyl or ethyl radical,
R16is a hydrogen atom, and is,
R17is hydrogen or a methyl group, or a mixture thereof,
R18is a hydrogen, a methyl or ethyl radical,
R4is a radical of the formula
Wherein
# is linked to-C (R)5)(AR3) The point of attachment on the N-is,
R22is hydrogen, fluorine, chlorine or trifluoromethyl,
R23is hydrogen, fluorine, chlorine or trifluoromethyl,
wherein the group R22And R23At least one of which is not hydrogen,
R5is hydrogen or a methyl group, or a mixture thereof,
and salts thereof.
7. A compound of formula (I-B) according to claim 4, 5 or 6 wherein
A is-CH2，
R1Is a 3, 3, 3-trifluoropropyl group,
R2is a phenyl group, and the phenyl group,
wherein the phenyl group is substituted with a substituent selected from fluorine and chlorine,
R3is-O-C (= O) -NR14R15，
Wherein
R14Is hydrogen or a methyl group, or a mixture thereof,
R15is a hydrogen, a methyl or ethyl radical,
R4is a radical of the formula
Wherein
# is linked to-C (R)5)(AR3) The point of attachment on the N-is,
R22is hydrogen, fluorine, chlorine or trifluoromethyl,
R23is hydrogen, fluorine, chlorine or trifluoromethyl,
wherein the group R22And R23At least one of which is not hydrogen,
R5is hydrogen or a methyl group, or a mixture thereof,
and salts thereof.
8. A compound of the formula (I-B) according to claim 4, 5 or 6
Wherein
A is-CH2，
R1Is a 3, 3, 3-trifluoropropyl group,
R2is a phenyl group, and the phenyl group,
wherein the phenyl group is substituted with a substituent selected from fluorine and chlorine,
R3is-NR8-C(=O)-R9，
Wherein
R8Is a hydrogen atom, and is,
R9is a methyl group, and the compound is,
R4is a radical of the formula
Wherein
# is linked to-C (R)5)(AR3) The point of attachment on the N-is,
R22is hydrogen, fluorine, chlorine or trifluoromethyl,
R23is hydrogen, fluorine, chlorine or trifluoromethyl,
wherein the group R22And R23At least one of which is not hydrogen,
R5is hydrogen or a methyl group, or a mixture thereof,
and salts thereof.
9. A compound of the formula (I-B) according to claim 4, 5 or 6
Wherein
A is-CH2，
R1Is a 3, 3, 3-trifluoropropyl group,
R2is a phenyl group, and the phenyl group,
wherein the phenyl group is substituted with a substituent selected from fluorine and chlorine,
R3is-NR10-SO2-R11，
Wherein
R10Is a hydrogen atom, and is,
R11is a methyl group or an ethyl group,
R4is a radical of the formula
Wherein
# is linked to-C (R)5)(AR3) The point of attachment on the N-is,
R22is hydrogen, fluorine, chlorine or trifluoromethyl,
R23is hydrogen, fluorine, chlorine or trifluoromethyl,
wherein the group R22And R23At least one of which is not hydrogen,
R5is hydrogen or a methyl group, or a mixture thereof,
and salts thereof.
10. A compound of the formula (I-B) according to claim 4, 5 or 6
Wherein
A is-CH2，
R1Is a 3, 3, 3-trifluoropropyl group,
R2is a phenyl group, and the phenyl group,
wherein the phenyl group is substituted with a substituent selected from fluorine and chlorine,
R3is-NR16-C(=O)-NR17R18，
Wherein
R16Is a hydrogen atom, and is,
R17is hydrogen or a methyl group, or a mixture thereof,
R18is a hydrogen, a methyl or ethyl radical,
R4is a radical of the formula
Wherein
# is linked to-C (R) 5)(AR3) The point of attachment on the N-is,
R22is hydrogen, fluorine, chlorine or trifluoromethyl,
R23is hydrogen, fluorine, chlorine or trifluoromethyl,
wherein the group R22And R23At least one of which is not hydrogen,
R5is hydrogen or a methyl group, or a mixture thereof,
and salts thereof.
11. A compound of the formula (I-B) according to claim 4, 5 or 6
Wherein
R1Is 3, 3, 3-trifluoroprop-1-en-1-yl, 3, 3, 3-trifluoropropyl or 1, 1, 1-trifluoroprop-2-ol-3-yl,
R3is-O-C (= O) -NR14R15，
Wherein
R14Is hydrogen or a methyl group, or a mixture thereof,
R15is hydrogen, methyl or ethyl.
12. A compound of the formula (I-B) according to claim 4, 5 or 6
Wherein
R1Is 1, 1, 1-trifluoropropan-2-ol-3-yl,
R3is-O-C (= O) -NR14R15，
Wherein
R14Is hydrogen or a methyl group, or a mixture thereof,
R15is a hydrogen, a methyl or ethyl radical,
R22is hydrogen, fluorine, chlorine or trifluoromethyl, and
R23is hydrogen, fluorine, chlorine or trifluoromethyl,
wherein the group R22And R23Is not hydrogen.
13. A compound of the formula (I-B) according to claim 4, 5 or 6
Wherein
R1Is 3, 3, 3-trifluoroprop-1-en-1-yl, 3, 3, 3-trifluoropropyl or 1, 1, 1-trifluoroprop-2-ol-3-yl,
R3is NH-C (= O) -CH3。
14. A compound of the formula (I-B) according to claim 4, 5 or 6
Wherein
R1Is 1, 1, 1-trifluoropropan-2-ol-3-yl,
R3is NH-C (= O) -CH3，
R22Is hydrogen, fluorine, chlorine or trifluoromethyl, and
R23Is hydrogen, fluorine, chlorine or trifluoromethyl,
wherein the group R22And R23Is not hydrogen.
15. A compound of the formula (I-B) according to claim 4, 5 or 6
Wherein
R1Is 3, 3, 3-trifluoroprop-1-en-1-yl, 3, 3, 3-trifluoropropyl or 1, 1, 1-trifluoroprop-2-ol-3-yl, R3is-NR10-SO2-R11，
Wherein
R10Is a hydrogen atom, and is,
R11is methyl or ethyl.
16. A compound of the formula (I-B) according to claim 4, 5 or 6
Wherein
R1Is 1, 1, 1-trifluoropropan-2-ol-3-yl,
R3is-NR10-SO2-R11，
Wherein
R10Is a hydrogen atom, and is,
R11is a methyl group or an ethyl group,
R22is hydrogen, fluorine, chlorine or trifluoromethyl, and
R23is hydrogen, fluorine, chlorine or trifluoromethyl,
wherein the group R22And R23Is not hydrogen.
17. A compound of the formula (I-B) according to claim 4, 5 or 6
Wherein
R1Is 3, 3, 3-trifluoroprop-1-en-1-yl, 3, 3, 3-trifluoropropyl or 1, 1, 1-trifluoroprop-2-ol-3-yl, R3is-NR16-C(=O)-NR17R18，
Wherein
R16Is a hydrogen atom, and is,
R17is hydrogen or a methyl group, or a mixture thereof,
R18is hydrogen, methyl or ethyl.
18. A compound of the formula (I-B) according to claim 4, 5 or 6
Wherein
R1Is 1, 1, 1-trifluoropropan-2-ol-3-yl,
R3is-NR16-C(=O)-NR17R18，
Wherein
R16Is a hydrogen atom, and is,
R17is hydrogen or a methyl group, or a mixture thereof,
R18is a hydrogen, a methyl or ethyl radical,
R22is hydrogen, fluorine, chlorine or trifluoromethyl, and
R23is hydrogen, fluorine, chlorine or trifluoromethyl,
Wherein the group R22And R23Is not hydrogen.
19. A compound of the general formula (I-B), wherein the compound is selected from
Diastereomer I of 2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { 2-nitro-1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide,
a mixture of diastereomers of N- {2- (acetylamino) -1- [3- (trifluoromethyl) phenyl ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide,
diastereomer II of 2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- [ (methylsulfonyl) amino ] -1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide,
diastereomer II of 2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- [ (methylsulfonyl) amino ] -1- [2- (trifluoromethyl) phenyl ] ethyl } acetamide,
diastereomer II of 2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {1- (2, 3-dichlorophenyl) -2- [ (ethylsulfonyl) amino ] ethyl } acetamide,
(2R) -2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [3- (trifluoromethyl) phenyl ] propyl carbamate,
diastereomer II of 2- [3- (trifluoromethyl) phenyl ] ethyl carbamate ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [3- (trifluoromethyl) phenyl ] ethyl ester,
diastereomer II of 2- [2- (trifluoromethyl) phenyl ] ethyl carbamate ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [2- (trifluoromethyl),
diastereoisomeric mixture of 2- (2-chlorophenyl) -2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] ethyl carbamate,
diastereomer I of N- {2- (carbamoylamino) -1- [3- (trifluoromethyl) phenyl ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide,
diastereomer II of N- {2- (carbamoylamino) -1- [2- (trifluoromethyl) phenyl ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide,
N- [2- (carbamoylamino) -1- (2, 3-dichlorophenyl) ethyl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide (diastereomer II),
enantiomer II of 2- [3- (trifluoromethyl) phenyl ] ethyl carbamate, [ ({3- (4-chlorophenyl) -5-oxo-4- [ (1E) -3, 3, 3-trifluoroprop-1-en-1-yl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [3- (trifluoromethyl) phenyl ] ethyl ester,
enantiomerically pure carbamic acid 2- ({ [3- (4-chlorophenyl) -5-oxo-4- (3, 3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetyl } amino) -2- [3- (trifluoromethyl) phenyl ] ethyl ester,
enantiomer 2 of methyl [2- ({ [3- (4-chlorophenyl) -5-oxo-4- (3, 3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetyl } amino) -2- (2, 3-dichlorophenyl) ethyl ] carbamate,
enantiomer 2 of N- [2- (carbamoylamino) -1- (2, 3-dichlorophenyl) ethyl ] -2- [3- (4-chlorophenyl) -5-oxo-4- (3, 3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetamide,
diastereomer I of N- {1- (2-chlorophenyl) -2- [ (methylsulfonyl) amino ] ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide,
Diastereomer II of 2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (methylsulfonyl) -1- [2- (trifluoromethyl) phenyl ] ethyl } acetamide,
diastereomer I of 2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (dimethylaminosulfonyl) -1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide,
enantiomerically pure ethyl 2- ({ [3- (4-chlorophenyl) -5-oxo-4- (3, 3, 3-trifluoropropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetyl } amino) -2- [2- (trifluoromethyl) phenyl ] carbamate,
2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (2-oxo-1, 3-Oxazolidin-3-yl) -1- [3- (trifluoromethyl) phenyl]Ethyl } acetamide diastereomer I,
diastereomer I of 2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (2-oxoimidazolidin-1-yl) -1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide,
diastereomer II of 2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- (methylthio) -1- [2- (trifluoromethyl) phenyl ] ethyl } acetamide,
Diastereoisomeric mixture of sulfamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [3- (trifluoromethyl) phenyl ] ethyl ester,
carbamic acid 2- (3-chloro-2-fluorophenyl) -2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] ethyl ester,
enantiomer II of 2- ({ [3- (4-chlorophenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetyl } amino) -2- [2- (trifluoromethyl) phenyl ] ethyl carbamate,
diastereomer II of 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- (2, 3-dichlorophenyl) ethyl carbamate,
diastereoisomeric mixture of 2- ({ [4- (4-chlorophenyl) -2-oxo-3- (3, 3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl ] acetyl } amino) -2- [2- (trifluoromethyl) phenyl ] ethyl carbamate
And salts thereof.
20. A compound of the general formula (I-B), wherein the compound is
Diastereomer II of 2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- [ (methylsulfonyl) amino ] -1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide
And salts thereof.
21. A compound of the general formula (I-B), wherein the compound is
Diastereomer II of 2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- {2- [ (methylsulfonyl) amino ] -1- [2- (trifluoromethyl) phenyl ] ethyl } acetamide
And salts thereof.
22. A compound of the general formula (I-B), wherein the compound is
(2R) -2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [3- (trifluoromethyl) phenyl ] propyl carbamate
And salts thereof.
23. A compound of the general formula (I-B), wherein the compound is
Diastereomer II of 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [3- (trifluoromethyl) phenyl ] ethyl carbamate
And salts thereof.
24. A compound of the general formula (I-B), wherein the compound is
Diastereomer II of 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] -2- [2- (trifluoromethyl) phenyl ] ethyl carbamate
And salts thereof.
25. A compound of the general formula (I-B), wherein the compound is
Diastereoisomeric mixture of 2- (2-chlorophenyl) -2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetyl) amino ] ethyl carbamate
And salts thereof.
26. A compound of the general formula (I-B), wherein the compound is
Diastereomer II of N- [2- (carbamoylamino) -1- (2, 3-dichlorophenyl) ethyl ] -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3, 3, 3-trifluoro-2-hydroxypropyl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } acetamide,
and salts thereof.
27. A process for the preparation of compounds of the general formula (I) and/or of the general formula (I-B) as defined in claims 1 to 26, characterized in that
[A] A compound of the general formula (II)
Wherein Q, R1And R2Each as defined in claims 1-26,
coupled to compounds of the general formula (III) by activation of the carboxylic acid function in an inert solvent
Wherein A, R3，R4，R5And R29Each as defined in claims 1-26,
or
[B] A compound of the general formula (IV)
Wherein Q, R1And R2Each as defined in claims 1-26,
with a compound of the formula (V) in an inert solvent in the presence of a base
Wherein A, R3，R4，R5And R29Each as defined in claims 1-26,
and
X1is a leaving group, such as halogen, methanesulfonate or toluenesulfonate,
the resulting compounds of the general formula (I) and/or general formula (I-B) are then optionally converted into their salts with corresponding bases or acids.
28. Use of a compound of formula (I) and/or formula (I-B) as defined in any one of claims 1 to 26 for the manufacture of a medicament for the treatment and/or prophylaxis of acute and chronic cardiac insufficiency, hyponatremia with high and general capacity, chronic interstitial hepatitis, ascites, oedema and syndromes with insufficient ADH secretion, i.e. SIADH.
29. A medicament comprising a compound of formula (I) and/or formula (I-B) as defined in any one of claims 1 to 26 in association with inert, non-toxic, pharmaceutically suitable excipients.
30. A medicament comprising a compound of formula (I) and/or formula (I-B) as defined in any one of claims 1 to 26 in combination with one or more other active ingredients selected from the group consisting of diuretics, angiotensin AII antagonists, ACE inhibitors, beta-receptor blockers, mineral corticoid receptor antagonists, organic nitrates, NO donors and substances with inotropic activity.
31. A medicament according to claim 29 or 30 for the treatment and/or prevention of acute and chronic cardiac insufficiency, hyponatremia of high and general capacity, chronic interstitial hepatitis, ascites, oedema and syndromes with insufficient ADH secretion, i.e. SIADH.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102009013640 | 2009-03-18 | ||
| DE102009013640.1 | 2009-03-18 | ||
| DE102010001064A DE102010001064A1 (en) | 2009-03-18 | 2010-01-20 | Substituted 2-acetamido-5-aryl-1,2,4-triazolones and their use |
| DE102010001064.2 | 2010-01-20 | ||
| PCT/EP2010/001565 WO2010105770A1 (en) | 2009-03-18 | 2010-03-12 | Substituted 2-acetamido-5-aryl-1,2,4-triazolones and use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1167864A1 HK1167864A1 (en) | 2012-12-14 |
| HK1167864B true HK1167864B (en) | 2015-07-24 |
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