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WO2017012579A1 - Composés d'indole substitués, méthodes d'utilisation et utilisations de ceux-ci - Google Patents

Composés d'indole substitués, méthodes d'utilisation et utilisations de ceux-ci Download PDF

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Publication number
WO2017012579A1
WO2017012579A1 PCT/CN2016/090985 CN2016090985W WO2017012579A1 WO 2017012579 A1 WO2017012579 A1 WO 2017012579A1 CN 2016090985 W CN2016090985 W CN 2016090985W WO 2017012579 A1 WO2017012579 A1 WO 2017012579A1
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Prior art keywords
group
compound
och
alkyl
alkoxy
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English (en)
Chinese (zh)
Inventor
金传飞
梁海平
张英俊
张
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Sunshine Lake Pharma Co Ltd
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Sunshine Lake Pharma Co Ltd
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Priority to CN201680002185.7A priority Critical patent/CN106795160B/zh
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Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the technical field of medicines, and in particular relates to compounds, compositions and methods and uses thereof for treating central nervous system dysfunction.
  • the invention describes substituted anthraquinone compounds which may act as serotonin reuptake inhibitors and/or 5-HT 1A receptor agonists.
  • Serotonin a neurotransmitter that transmits signals in the brain and nervous system, plays an important role in central nervous system (CNS) dysfunction, especially anxiety, depression, aggression, and impulsive emotions. character of. Antagonizing or stimulating certain types of serotonin receptors can effectively modulate central nervous system dysfunction. To date, at least 14 serotonin receptors have been identified. These receptors can be divided into different families, which are classified as 5-HT 1 , 5-HT 2 , 5-HT 3 , 5-HT 4 , 5-HT 5 , 5-HT 6 and 5-HT 7 , respectively. Different subtypes are distinguished by a, b, and c.
  • Depression is the most important of all indications associated with serotonin dysfunction, as depression has become the fourth most burdensome disease in humans, according to the World Health Organization. It is estimated that by 2020, the disability-adjusted life expectancy of depression will leap to the second place in all diseases. (Bromet E, Andrade LH, Hwang I, et al., Cross-national epidemiology of DSM-IV major depressive episode. BMCMed. 2011, 9:90).
  • TCAs tricyclic antidepressants
  • MAOIs monoamine oxidase inhibitors
  • SSRIs selective serotonin reuptake inhibitors
  • SSRIs Traditional SSRIs treatment increases the serotonin content by inhibiting the reuptake of serotonin and regulating its transport.
  • the use of SSRIs also activates the 5-HT 1A autoreceptor of the presynaptic membrane, resulting in a decrease in the release of serotonin and a decrease in the concentration of synaptic serotonin.
  • SSRIs cause desensitization of 5-HT 1A autoreceptors, and the activation effect is restrained, thereby exerting a normal regulatory effect.
  • 5-HT 1A autoreceptor is an important reason for delaying the efficacy of SSRIs (Celada P, Puig M, Amargos-Bosch M, et al., The therapeutic role of 5-HT 1A and 5) -HT 2A receptors in depression. J Psychiatry Neurosci, 2004, 29(4): 252-65). Therefore, overcoming the negative feedback effect of 5-HT 1A autoreceptor antagonists has the prospect of enhancing and accelerating clinical anti-depression.
  • a 5-HT 1A receptor agonist or partial agonist acts directly on the postsynaptic serotonin receptor to increase serotonin neurotransmission in the SSRI latency phase.
  • Feiger and Wilcox demonstrated that buspirone and gepirone are clinically effective 5-HT 1A partial agonists (Feiger, A. Psychopharmacol. Bull. 1996, 32: 659-65).
  • the addition of buspirone to standard SSRI treatments resulted in significant improvements in patients who had previously not responded to standard treatment for depression (Dimitriou, EJ Clin. Psychopharmacol., 1998, 18: 465-9).
  • the present invention provides a novel compound having selective serotonin reuptake inhibitory activity and/or 5-HT 1A receptor agonistic activity, and has good clinical application prospects.
  • the compounds of the invention have better pharmacological, pharmacological and/or toxicological properties than existing analogous compounds.
  • the present invention relates to a novel class of substituted indole compounds which have strong binding affinity to a 5-HT transporter (SERT) and which selectively inhibit 5-HT reuptake, and which are also associated with 5-HT 1A receptors. It has strong binding affinity and can effectively agonize 5-HT 1A receptor, so it can be used to prepare drugs for treating central nervous system (CNS) dysfunction, and the compound of the present invention has stable properties, good safety, pharmacodynamics and Pharmacokinetic advantages, such as good brain plasma ratio, good bioavailability or good metabolic stability, have good clinical application prospects.
  • SERT 5-HT transporter
  • CNS central nervous system
  • the compounds of the present invention selectively inhibit serotonin reuptake and/or have an agonistic effect on 5-HT 1A receptors, and can be used for the preparation of central nervous system (CNS) dysfunction, such as depression and anxiety. , a drug for bipolar disorder.
  • CNS central nervous system
  • the invention also provides methods of preparing such compounds and pharmaceutical compositions containing such compounds.
  • the invention relates to a compound which is a compound of formula (I) or a stereoisomer, tautomer, oxynitride, solvate, metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • each of R 1 , R a , R b , X, W, V, U, m, n and r has the meaning as described in the present invention.
  • X is CR 2 or N; W is CR 3 or N; V is CR 4 or N; U is CR 5 or N;
  • the precondition is that at most two of X, W, V and U are N at the same time;
  • R 2 , R 3 , R 4 and R 5 have the meanings indicated in the present invention.
  • each of R 1 and R a is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, C 1 -C 6 alkyl, C 1- C 6 haloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy, wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkane
  • the oxy group and the C 1 -C 6 haloalkoxy group are each independently optionally substituted by one or more R w ; and each R w has the meaning as described herein.
  • m is 0, 1, 2 or 3.
  • n 0, 1, 2, 3 or 4.
  • r is 0, 1 or 2.
  • p is 1, 2, 3 or 4.
  • each of R 1 and R a is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy or C 1 -C 4 haloalkoxy, wherein said C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 The alkoxy group and the C 1 -C 4 haloalkoxy group are each independently optionally substituted by one or more R w ; and each R w has the meaning as described herein.
  • each of R 1 and R a is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, methyl, ethyl, n-propyl Base, isopropyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, -CF 3 or -OCF 3 .
  • the compound of the present invention is a stereoisomer, tautomer, oxynitride, solvate, metabolism of a compound having one of the following structures or a compound having one of the following structures a product, a pharmaceutically acceptable salt or a prodrug thereof:
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed herein.
  • the invention relates to a pharmaceutical composition further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
  • the pharmaceutical composition of the present invention further comprises a medicament for treating central nervous system dysfunction, wherein the medicament for treating central nervous system dysfunction is an antidepressant, an anxiolytic, and an emotional stabilizer.
  • Lithium salt drugs atypical antipsychotics, antiepileptic drugs, anti-Parkinson's disease drugs, drugs as selective serotonin reuptake inhibitors and/or 5-HT 1A receptor agonists, central nervous stimulants , a nicotinic antagonist or any combination thereof.
  • the medicament for treating central nervous system dysfunction of the present invention is amitriptyline, desipramine, mirtazapine, bupropion, and rebaudioside.
  • the invention relates to the use of a compound or composition disclosed herein for the manufacture of a medicament for the prevention, treatment or amelioration of central nervous system dysfunction.
  • the medicament is for preventing, treating or ameliorating central nervous system dysfunction in a mammal; in another embodiment, the medicament is for preventing, treating or ameliorating central nervous system dysfunction in a human .
  • the central nervous system dysfunction refers to depression, anxiety, mania, schizophrenia, bipolar disorder, sleep disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress Obstacle, dyskinesia, sexual dysfunction, musculoskeletal pain, cognitive impairment, memory disorder, Parkinson's disease, Huntington's disease, phobia, substance abuse or addiction, drug addiction withdrawal symptoms or premenstrual tension synthesis disease.
  • the invention relates to the use of a compound or composition disclosed herein for the manufacture of a medicament for inhibiting serotonin reuptake.
  • the invention relates to the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament for the partial activating of a 5-HT 1A receptor.
  • the invention relates to a process for the preparation, isolation and purification of a compound of formula (I).
  • the results of the biological test indicate that the compound of the present invention has strong affinity for the human 5-HT transporter (SERT); and also has strong binding affinity for the 5-HT 1A receptor; therefore, the compound provided by the present invention can be used as a better choice.
  • SERT human 5-HT transporter
  • a serotonin reuptake inhibitor and/or a 5-HT 1A receptor agonist are included in the compound of the present invention.
  • any of the embodiments of any of the aspects of the invention may be combined with other embodiments as long as they do not contradict each other. Furthermore, in any of the embodiments of any of the aspects of the present invention, any of the technical features may be applied to the technical features in other embodiments as long as they There will be no contradictions.
  • subject refers to an animal. Typically the animal is a mammal, including a human. Subjects, for example, also refer to primates (eg, humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In one embodiment, the subject is a primate. In another embodiment, the subject is a human.
  • patient refers to a person (including adults and children) or other animal. In some embodiments, “patient” refers to a human.
  • stereoisomer refers to a compound that has the same chemical structure but differs in the way the atoms or groups are spatially aligned. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotomers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • (-) or l indicates that the compound is left-handed.
  • Compounds prefixed with (+) or d are dextrorotatory.
  • a particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as a mixture of enantiomers.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as the (R)-, (S)- or (R, S)-configuration presence.
  • each asymmetric atom has at least 50% enantiomeric excess in the (R)- or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the compounds of the invention may be one of the possible isomers or mixtures thereof, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms) The form exists.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have a cis or trans configuration.
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography, depending on the difference in physicochemical properties of the components. Method and / or step crystallization.
  • racemate of any of the resulting end products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art by known methods, for example, by obtaining the diastereomeric salts thereof. Separation. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert) E.
  • tautomer or "tautomeric form” refers to structural isomers having different energies that are interconvertible by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • proton transfer such as keto-enol isomerization and imine-ene Amine isomerization.
  • “Pharmaceutically acceptable” means a compound, material, composition, and/or dosage form that, within the scope of sound medical judgment, is suitable for contact with a patient's tissue without undue toxicity, irritation, allergies, or reasonable The benefits/risk ratios are commensurate with other problems and complications and are effectively used for the intended use.
  • the compounds of the invention may be optionally substituted with one or more substituents, such as the compounds of the above formula, or, as in the examples, specific examples, subclasses, and ones encompassed by the invention Class of compounds.
  • substituents of the present invention include, but are not limited to, D, F, Cl, N 3 , -CN, -OH, -SH, -NH 2 , alkyl, alkoxy, alkylthio, alkylamino , cycloalkyl, heterocyclic, aryl, heteroaryl and the like.
  • C 1 -C 6 alkyl refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • linking substituents are described.
  • the Markush variable recited for that group is understood to be a linking group.
  • the definition of the Markush group for the variable is "alkyl” or "aryl”
  • the “alkyl” or “aryl” respectively represent the attached An alkylene group or an arylene group.
  • halogen and “halo” are used interchangeably herein and refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • alkyl or "alkyl group” as used herein, denotes a saturated straight or branched monovalent hydrocarbon group containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally selected The ground is replaced by one or more substituents described herein.
  • the alkyl group contains from 1 to 6 carbon atoms; in another embodiment, the alkyl group contains from 1 to 4 carbon atoms; and in one embodiment, the alkyl group contains 1 - 3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH) (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), and the like.
  • alkylene denotes a saturated divalent hydrocarbon radical derived from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon. Unless otherwise specified, an alkylene group contains from 1 to 12 carbon atoms. In one embodiment, the alkylene group contains 1-6 carbon atoms; in another embodiment, the alkylene group contains 1-4 carbon atoms; in yet another embodiment, the alkylene group The group contains 1-3 carbon atoms; also in one embodiment, the alkylene group contains 1-2 carbon atoms. Such examples include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylidene (-CH(CH 3 )CH 2 -) and the like.
  • alkenyl denotes a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, wherein at least one site of unsaturation, i.e., has a carbon-carbon sp 2 double bond, wherein the alkenyl group
  • the group may be optionally substituted with one or more substituents described herein, including the positioning of "cis” and “trans”, or the positioning of "E” and "Z”.
  • the alkenyl group contains 2 to 6 carbon atoms; in another embodiment, the alkenyl group contains 2 to 4 carbon atoms.
  • alkynyl means a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, wherein at least one site of unsaturation, i.e., has a carbon-carbon sp triple bond, wherein the alkynyl group It may be optionally substituted with one or more of the substituents described herein.
  • the alkynyl group contains 2 to 6 carbon atoms; in another embodiment, the alkynyl group contains 2 to 4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), and the like. .
  • alkoxy denotes an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains from 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; In another embodiment, the alkoxy group contains from 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains from 1 to 3 carbon atoms.
  • the alkoxy group can be optionally substituted with one or more substituents described herein.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propyloxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butyl Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ), and so on.
  • alkylamino or “alkylamino” includes “N-alkylamino” and "N,N-dialkylamino", wherein the amino groups are each independently substituted with one or two alkyl groups, Wherein the alkyl group has the meaning as described herein.
  • Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N, N - Diethylamino and the like.
  • the alkylamino group is optionally substituted with one or more substituents described herein.
  • haloalkyl denotes an alkyl, alkenyl or alkoxy group substituted by one or more halogen atoms, wherein alkyl, alkenyl and alkoxy
  • the group has the meaning as described herein, and such examples include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.
  • cycloalkyl denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring carbon atoms.
  • the cycloalkyl group contains from 3 to 10 ring carbon atoms; in another embodiment, the cycloalkyl group contains from 3 to 8 ring carbon atoms; in yet another embodiment, the cycloalkyl group comprises 3- 6 ring carbon atoms.
  • Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the cycloalkyl group can be optionally substituted with one or more substituents described herein.
  • heterocyclyl and “heterocycle” are used interchangeably herein to refer to a monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring atoms wherein at least one ring atom of the ring is selected from the group consisting of nitrogen and sulfur. And oxygen atoms, the ring may be fully saturated or contain one or more degrees of unsaturation, but none of the aromatic rings.
  • the sulfur atom of the ring can be optionally oxidized to an S-oxide.
  • the nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound.
  • heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrroline, 3-pyrrolyl , pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Pentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl , dioxoal
  • Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, a sulfolane group, a thiomorpholino 1,1-dioxide, and the like.
  • the heterocyclyl group is optionally substituted with one or more substituents described herein.
  • heteroatom refers to O, S, N, P, and Si, including any form of oxidation states of N, S, and P; forms of primary, secondary, tertiary, and quaternary ammonium salts; or nitrogen atoms in heterocycles. a form in which hydrogen is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like in N-substituted pyrrolidinyl) NR).
  • aryl denotes a monocyclic, bicyclic and tricyclic carbocyclic ring system containing from 6 to 14 ring atoms, or from 6 to 12 ring atoms, or from 6 to 10 ring atoms, wherein at least one ring is aromatic .
  • the aryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the aryl group.
  • aryl can be used interchangeably with the terms "aromatic ring” or "aromatic ring”. Examples of the aryl group may include a phenyl group, a naphthyl group, an anthracene, and the like.
  • the aryl group can be optionally substituted with one or more substituents described herein.
  • heteroaryl denotes a monocyclic, bicyclic, and tricyclic ring system having 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring is aromatic, and At least one ring contains one or more heteroatoms.
  • a heteroaryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of a heteroaryl group.
  • heteroaryl can be used interchangeably with the terms “heteroaryl ring” or “heteroaromatic compound”.
  • the heteroaryl group is optionally substituted with one or more substituents described herein.
  • the 5-10 membered heteroaryl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N; in another embodiment, the heteroaryl group is lower 5-6 membered heteroaryl.
  • heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (eg 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-thi
  • a ring system formed by a substituent attached to a central ring represents a substituent on the ring (such as the ring B in formula a) which may be substituted or any reasonable The location can be replaced.
  • the formula a represents that any position on the B ring that may be substituted may be substituted by the substituent R, as shown in formula b, formula c and formula d.
  • protecting group refers to a substituent that is typically used to block or protect a particular functionality when reacted with other functional groups.
  • protecting group of an amino group refers to a substituent attached to an amino group to block or protect the functionality of an amino group in a compound.
  • Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl. (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc).
  • a "hydroxy protecting group” refers to a substituent of a hydroxy group used to block or protect the functionality of a hydroxy group.
  • Suitable protecting groups include trialkylsilyl, acetyl, benzoyl and benzyl.
  • Carboxy protecting group means a substituent of a carboxy group used to block or protect the functionality of a carboxy group.
  • Typical carboxy protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane Ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(diphenyl Phosphine) ethyl, nitroethyl, and the like.
  • a general description of protecting groups can be found in Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 and Kocienski et al., Protecting Groups, Thieme, Stuttgart, 2005.
  • prodrug denotes a compound which is converted in vivo to a compound of formula (I). Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue.
  • the prodrug-like compound of the present invention may be an ester.
  • the ester may be used as a prodrug such as a phenyl ester, an aliphatic (C 1-24 ) ester, an acyloxymethyl ester, or a carbonate. , carbamates and amino acid esters.
  • a compound of the invention comprises a hydroxyl group, i.e., it can be acylated to give a compound in the form of a prodrug.
  • Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxy group on the parent.
  • Metal product refers to a product obtained by metabolism of a specific compound or a salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such a product may be obtained by administering a compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like. Accordingly, the invention includes metabolites of a compound, including metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.
  • the "pharmaceutically acceptable salt” as used in the present invention means an organic salt and an inorganic salt of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, mineral acid salts formed by reaction with amino groups, hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or by other methods described in the literature, such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3 -Phenylpropionate
  • Salts obtained by appropriate bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates quaternary ammonium salts formed from any of the compounds comprising a group of N. Water soluble or oil soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -C 8 sulfonate and aromatic sulfonate.
  • suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -C 8 sulfonate and aromatic sulfonate.
  • Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine or mixtures thereof.
  • hydrate means that the solvent molecule is an association formed by water.
  • hydrate can be used.
  • a molecule of the compound of the invention may be combined with a water molecule, such as a monohydrate; in another embodiment, a molecule of the invention may be combined with more than one water molecule, such as dihydrate. In yet another embodiment, a molecule of the compound of the invention may be combined with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the compounds in a non-hydrated form.
  • any disease or condition as used in the present invention refers to ameliorating a disease or condition (ie, slowing or preventing or alleviating the progression of a disease or at least one of its clinical symptoms).
  • “treating” refers to alleviating or ameliorating at least one body Parameters, including physical parameters that may not be perceived by the patient.
  • “treating” refers to modulating a disease or condition from the body (eg, stabilizing a detectable symptom) or physiologically (eg, stabilizing the body's parameters) or both.
  • “treating” refers to preventing or delaying the onset, onset, or exacerbation of a disease or condition.
  • terapéuticaally effective amount means that when administered to a subject to treat a disease, the amount of the compound is sufficient to effect treatment of the disease.
  • the “therapeutically effective amount” can vary with the compound, the disease and severity, and the condition, age, weight, sex, etc. of the subject to be treated.
  • the indole compound of the present invention can be used as a selective serotonin reuptake inhibitor and/or a 5-HT 1A receptor agonist for a human center
  • the treatment of nervous system dysfunction such as depression, anxiety, and bipolar disorder, has potential uses.
  • stereochemistry of any particular chiral atom when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated within the invention, and as disclosed herein are included in the present invention. .
  • stereochemistry is indicated by a solid wedge or dashed line indicating a particular configuration, then the stereoisomers of the structure are defined and defined herein.
  • Nitrogen oxides of the compounds of the invention are also included within the scope of the invention.
  • the corresponding nitrogen-containing basic substance can be oxidized by using a usual oxidizing agent (for example, hydrogen peroxide) at elevated temperature, in the presence of an acid such as acetic acid, or by reacting with a peracid in a suitable solvent, for example, in methylene chloride.
  • a usual oxidizing agent for example, hydrogen peroxide
  • the oxynitride of the compound of the present invention is prepared by reacting with peracetic acid in ethyl acetate or methyl acetate or by reacting with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.
  • the compound of the formula (I) may exist in the form of a salt.
  • the salt refers to a pharmaceutically acceptable salt.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal treated therewith.
  • the salt is not necessarily a pharmaceutically acceptable salt, and may be used to prepare and/or purify a compound of formula (I) and/or to isolate a compound of formula (I). The intermediate of the enantiomer.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety by conventional chemical methods.
  • such salts can be obtained by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base such as a hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg or K.
  • a suitable base such as a hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg or K.
  • the free base form of these compounds is prepared by reaction with a stoichiometric amount of a suitable acid. This type of reaction is usually carried out in water or an organic solvent or a mixture of the two.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • any structural formula given by the present invention is also intended to indicate that these compounds are not isotopically enriched and isotopically enriched.
  • Isotopically enriched compounds have the structure depicted by the general formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • Exemplary isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the invention relates to an intermediate for the preparation of a compound of formula (I).
  • the invention provides a pharmaceutical composition comprising a compound of the invention.
  • the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or a combination thereof.
  • the pharmaceutical composition may be in the form of a liquid, solid, semi-solid, gel or spray.
  • compositions, formulations and administrations of the compounds of the invention are provided.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a single stereoisomer thereof, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof .
  • the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally other therapeutic and/or prophylactic ingredients.
  • Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel HC et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro ARet Al., Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe RC, Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.
  • compositions of the invention may exist in free form for treatment or, if appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or can be provided directly or indirectly to a patient in need thereof. Any additional adduct or derivative of the compound or its metabolite or residue.
  • compositions disclosed herein can be prepared and packaged in bulk form in which a safe and effective amount of a compound of the invention can be extracted and then administered to a patient in the form of a powder or syrup.
  • the pharmaceutical compositions disclosed herein can be prepared and packaged in unit dosage form, wherein each physically discrete unit contains a safe and effective amount of a compound of the invention.
  • the pharmaceutical compositions disclosed herein can generally contain, for example, from 0.5 mg to 1 g, or from 1 mg to 700 mg, or from 5 mg to 100 mg of the compounds disclosed herein.
  • pharmaceutically acceptable excipient means a pharmaceutically acceptable material, mixture or vehicle that is associated with the administration of a dosage form or pharmaceutical composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions which would greatly reduce the efficacy of the compounds disclosed herein when administered to a patient and result in a pharmaceutical composition that is not pharmaceutically acceptable Interaction.
  • each excipient must be pharmaceutically acceptable, for example, of sufficiently high purity.
  • Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen. In addition, pharmaceutically acceptable excipients can be selected based on their particular function in the composition.
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents , solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, Preservatives, stabilizers, surfactants and buffers.
  • excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents , solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents,
  • compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. A description of some common methods in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the present invention is directed to a process for preparing a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, the process comprising Mix various ingredients.
  • Pharmaceutical compositions comprising the compounds disclosed herein can be prepared, for example, by mixing at ambient temperature and atmospheric pressure.
  • dosage forms include those suitable for the following routes of administration: (1) oral administration, for example, tablets, capsules, caplets, pills, tablets, powders, syrups, elixirs, suspensions, Solution, emulsion, sachet and cachet; (2) parenteral administration, such as sterile solutions, suspensions and reconstituted powders; (3) transdermal administration, such as transdermal patches (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes , sprays, foams and gels.
  • routes of administration include those suitable for the following routes of administration: (1) oral administration, for example, tablets, capsules, caplets, pills, tablets, powders, syrups, elixirs, suspensions, Solution, emulsion, sachet and cachet; (2) parenteral administration, such as sterile solutions, suspensions and reconstituted powders; (3)
  • the compounds disclosed herein can be formulated into oral dosage forms. In another embodiment, the compounds disclosed herein may be formulated in an inhaled dosage form. In another embodiment, the compounds disclosed herein may be formulated for nasal administration. In yet another embodiment, the compounds disclosed herein can be formulated in a transdermal dosage form. In still another embodiment, the compounds disclosed herein may be formulated for topical administration.
  • the pharmaceutical composition provided by the present invention can be provided as a compressed tablet, a developed tablet, a chewable tablet, a fast-dissolving tablet, a reconstituted tablet, or an enteric coated tablet, a sugar-coated tablet or a film-coated tablet.
  • the pharmaceutical composition provided by the present invention may be provided in a soft capsule or a hard capsule, which may be prepared from gelatin, methylcellulose, starch or calcium alginate.
  • compositions provided herein can be provided in liquid and semisolid dosage forms including emulsions, solutions, suspensions, elixirs, and syrups.
  • Dosage unit formulations for oral administration can be microencapsulated as appropriate. It may also be prepared as a composition for prolonged or sustained release, for example by coating or embedding the particulate material in a polymer, wax or the like.
  • the oral pharmaceutical compositions provided herein can also be provided in the form of liposomes, micelles, microspheres or nanosystems.
  • the micellar dosage form can be prepared by the method described in U.S. Pat. No. 6,350,458.
  • compositions provided herein can be provided as non-effervescent or effervescent granules and powders to reconstitute a liquid dosage form.
  • the pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents.
  • the pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.
  • Colorants and flavoring agents can be used in all of the above dosage forms.
  • the compounds disclosed herein can also be combined with soluble polymers as targeted drug carriers.
  • compositions provided herein can be formulated as immediate or modified release dosage forms, including delayed-, sustained-release, pulse-, controlled-, targeted-, and programmed release forms.
  • compositions provided herein can be formulated with other active ingredients that do not impair the intended therapeutic effect, or with a substance that complements the intended effect.
  • compositions provided by the present invention can be administered parenterally by injection, infusion or implantation for topical or systemic administration.
  • Parenteral administration as used in the present invention includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.
  • compositions provided herein can be formulated into any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and in liquids prior to injection.
  • dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see Remington: The Science and Practice of Pharmacy, on).
  • compositions provided by the present invention may be formulated for administration in single or multiple doses.
  • the single dose formulation is packaged in an ampoule, vial or syringe.
  • the multi-dose parenteral formulation must contain an antimicrobial agent at a bacteriostatic or fungistatic concentration. All parenteral formulations must be sterile, as is known and practiced in the art.
  • compositions disclosed herein can be formulated into any dosage form suitable for inhalation administration to a patient, such as a dry powder, aerosol, suspension or solution composition.
  • compositions suitable for transdermal administration can be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time.
  • the active ingredient can be delivered from the patch by ion permeation as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the compounds and pharmaceutical compositions provided by the present invention are useful for the preparation of a medicament for preventing, treating or ameliorating central nervous system dysfunction in mammals, including humans, and for preparing serotonin reuptake and/or agonism.
  • 5-HT 1A receptor drug 5-HT 1A receptor drug.
  • the amount of the compound in the composition of the present invention can effectively and selectively detect the reuptake of serotonin and agonize the 5-HT 1A receptor, and the compound of the present invention can be used as a therapeutic human center.
  • Neurological (CNS) dysfunction drugs such as depression and anxiety.
  • the compounds of the invention may be used, but are in no way limited to, the administration of an effective amount of a compound or composition of the invention to a patient to prevent, treat or ameliorate central nervous system dysfunction.
  • the central nervous system dysfunction disease responsive to serotonin receptor regulation further includes, but is not limited to, depression, anxiety, mania, schizophrenia, sleep disorder, bipolar disorder, obsessive concept With behavioral disorders, panic disorder, post-traumatic stress disorder, dyskinesia, sexual dysfunction, musculoskeletal pain, cognitive impairment, memory impairment, Parkinson's disease, Huntington's disease, phobia, substance abuse or addiction, Drug addiction withdrawal symptoms and premenstrual tension syndrome.
  • the compounds and pharmaceutical compositions of the present invention are also useful in veterinary treatment of pets, introduced species of animals, and mammals in farm animals. Other examples of animals include horses, dogs, and cats.
  • the compounds of the invention include pharmaceutically acceptable derivatives thereof.
  • the methods of treatment disclosed herein comprise administering to a patient in need thereof a safe and effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
  • Embodiments of the present disclosure include methods of treating the above mentioned diseases by administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention.
  • a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein can be administered by any suitable route of administration, including systemic administration and topical administration.
  • a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein can be administered at a time, or several times at different time intervals, over a specified period of time, depending on the dosage regimen. For example, administration once, twice, three times or four times a day. It can be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for the disclosed compounds or pharmaceutical compositions comprising the compounds disclosed herein depend on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, as determined by the skilled artisan.
  • suitable dosage regimens of the disclosed compounds or pharmaceutical compositions comprising the compounds of the present invention including the duration of implementation of the regimen, depend on the condition being treated, the severity of the condition being treated, the age of the subject being treated, and Body shape
  • the medical history of the patient being treated, the nature of the concurrent therapy, the desired therapeutic effect, etc. are within the knowledge and experience of the skilled person.
  • the dosage regimen for the adjustment may be required for individual patient responses to the dosage regimen, or for individual patient needs to change over time.
  • the compounds disclosed herein can be administered simultaneously with, or before or after, one or more other therapeutic agents.
  • the compounds of the invention may be administered separately or in combination with other therapeutic agents by the same or different routes of administration.
  • a prodrug of a compound disclosed herein is a functional derivative which, when administered to a patient, ultimately releases the compound of the present invention in vivo.
  • a compound disclosed herein is administered in a prodrug form
  • one of skill in the art can practice one or more of the following: (a) altering the in vivo onset time of the compound; (b) altering the duration of in vivo action of the compound; Changing the in vivo delivery or distribution of the compound; (d) altering the in vivo solubility of the compound; and (e) overcoming the side effects or other difficulties faced by the compound.
  • Typical functional derivatives for the preparation of prodrugs including variants of compounds which are cleaved chemically or enzymatically in vivo. These variants comprising the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates are well known to those skilled in the art.
  • the compounds of the present invention can be prepared by the methods described herein, unless otherwise stated, wherein the substituents are as defined for formula (I).
  • the following reaction schemes and examples are provided to further illustrate the contents of the present invention.
  • Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by refluxing with sodium metal.
  • Anhydrous dichloromethane and chloroform were obtained by reflux drying of calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were previously dried over anhydrous sodium sulfate.
  • reaction is generally carried out under a positive pressure of nitrogen or argon or on a dry solvent (unless otherwise indicated), the reaction bottle is stoppered with a suitable rubber stopper, and the substrate is driven through a syringe.
  • the glassware is dry.
  • the column is a silica gel column.
  • Silica gel 300-400 mesh was purchased from Qingdao Ocean Chemical Plant.
  • MS mass spectrometry
  • the pure compound was detected by UV using an Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50/80 mm DAC) at 210 nm / 254 nm.
  • the compound represented by the formula ( 5 ) can be produced by the method described in the synthesis scheme 1: First, the compound ( 1 ) is reacted under the action of POCl 3 to obtain the compound ( 2 ), and then the compound ( 2 ) and piperazine-1-carboxylic acid. The tert-butyl ester is reacted under the action of a base to obtain the compound ( 3 ), and finally the compound ( 3 ) is decarboxylated in a solution of trifluoroacetic acid in dichloromethane or ethyl acetate in ethyl acetate, followed by potassium carbonate or carbonic acid. Under the action of a base such as sodium, a nucleophilic substitution reaction with the compound ( 4 ) gives the target compound ( 5 ).
  • a base such as sodium
  • the compound represented by the formula ( 11 ) and the formula ( 12 ) can be produced by the method described in Synthetic Scheme 2: First, the compound ( 2 ) is reacted under the action of an oxidizing agent such as mCPBA or OXONE to obtain a compound ( 6 ), the compound ( 6 ). The compound ( 7 ) is obtained by reacting in acetic anhydride; then the compound ( 7 ) and the compound ( 8 ) are reacted under the action of a base to obtain a compound ( 9 ), and the compound ( 9 ) is further reacted with piperazine-1-carboxylic acid tert-butyl ester in a base.
  • an oxidizing agent such as mCPBA or OXONE
  • the reaction of the reaction gives the compound ( 10 ); the final compound ( 10 ) is deprotected from the Boc protecting group in a solution of trifluoroacetic acid in dichloromethane or ethyl acetate in ethyl acetate, followed by an alkali such as potassium carbonate or sodium carbonate. Under the action, a nucleophilic substitution reaction with the compound ( 4 ) gives the target compound ( 11 ). Compound ( 11 ) is subjected to hydrolysis of an ester to give another target compound ( 12 ).
  • the compound represented by the formula ( 15 ) can be produced by the method described in Synthesis Scheme 3: first, the compound ( 9 ) is subjected to aminolysis under the action of an aminating agent such as ammonia methanol solution to obtain a compound ( 13 ), and then the compound ( 13 ) is The piperazine-1-carboxylic acid tert-butyl ester is reacted under the action of a base to obtain a compound ( 14 ), and finally the compound ( 14 ) is deprotected from the Boc protecting group in a solution of trifluoroacetic acid in dichloromethane or ethyl acetate in ethyl acetate. Further, a nucleophilic substitution reaction with the compound ( 4 ) by a base such as potassium carbonate or sodium carbonate gives the target compound ( 15 ).
  • an aminating agent such as ammonia methanol solution
  • a base such as potassium carbonate or sodium carbonate
  • 1,6-Naphthyridin-5(6H)-one (3.00 g, 20.53 mmol) was added to phosphorus oxychloride (40 mL).
  • the reaction liquid was elevated in temperature, refluxed for 24 hours, and then cooled to room temperature, and then phosphorus oxychloride was distilled off under reduced pressure. Ice water (20 mL) was added to the reaction mixture, and the pH was adjusted to 8 to 9 with sodium carbonate solid.
  • the mixture was filtered and the filtrate was extracted with dichloromethane (20 mL ⁇ 5).
  • the organic phase was dried over anhydrous sodium sulfate EtOAcjjjjjjjjj g, 91.1%).
  • the title compound of this step was prepared according to the method of the step 3 of Example 1, that is, 4-(1,6-naphthyridin-5-yl)piperazine-1-carboxylic acid tert-butyl ester (400 mg, 1.27 mmol) and hydrogen chloride in ethyl acetate
  • the ester solution (4M, 2 mL) was obtained in methylene chloride (10 mL).
  • EtOAc EtOAc EtOAc EtOAc (EtOAc: EtOAc (21 mg, 0.13 mmol) and sodium carbonate (405 mg, 3.82 mmol) were obtained from EtOAc (EtOAc) (EtOAc)
  • EtOAc EtOAc
  • the title compound of this step is prepared according to the method of the step 3 of Example 1, that is, 4-(2-(2-ethoxy-2-oxoethoxy)-1,6-naphthyridin-5-yl)piperazine
  • the title compound of this step is prepared according to the method of the step 3 of Example 1, that is, 4-(2-(2-ethoxy-2-oxoethoxy)-1,6-naphthyridin-5-yl)piperazine
  • Example A Evaluation of the affinity of compounds for CHO cell transfected humanized 5-HT transporters
  • the incubated samples were quickly filtered through a 96-well cell harvester (Unifilter, Packard) under vacuum conditions through a glass fiber filter (GF/B, Packard) pre-impregnated with 0.3% PEI and using ice-cold 50 mM Tris-HCl and Rinse several times with 150 mM NaCl.
  • the filter was dried and the residual radioactivity was calculated in a scintillation counter (Topcount, Packard) using scintillation fluid (Microscint 0, Packard).
  • the experimental results are expressed as a percentage inhibition of radioligand-specific binding relative to the control group.
  • the standard reference compound was imipramine, and a competitive curve was obtained by a series of experimental tests to calculate the IC 50 .
  • the compounds of the invention IC on human 5-HT transporter (the SERT) 50 values less than 10 nM
  • the compounds of the invention IC on human 5-HT transporter (the SERT) 50 The value is less than 1 nM; specifically, the compound prepared in Example 1 of the present invention has an IC 50 value of 2.03 nM, and the compound prepared in Example 2 of the present invention has an IC 50 value of 0.61 nM.
  • Example B h5-HT 1A receptor binding affinity test
  • Human membrane was homogenized (36 ⁇ g protein), 0.3 nM [ 3 H]8-OH-DPAT (Perkin-Elmer) and buffer (50 mM Tris-HCl (pH 7.4), 10 mM MgSO at 22 °C. 4 , 0.5 mM EDTA, 2 ⁇ g / ml aprotinine) in a mixed system, with or without the addition of test compounds, for a total of 60 minutes.
  • buffer 50 mM Tris-HCl (pH 7.4), 10 mM MgSO at 22 °C. 4 , 0.5 mM EDTA, 2 ⁇ g / ml aprotinine
  • the standard reference compound was 8-OH-DPAT, and 10 ⁇ M 8-OH-DPAT was added to the mixed system of the above conditions for measurement of non-specific binding value.
  • a competitive curve was obtained by testing the data of a series of concentrations of 8-OH-DPAT in different experiments.
  • the incubated samples were quickly filtered through a 96-well cell harvester (Unifilter, Packard) under vacuum conditions through a glass fiber filter (GF/B, Packard) pre-impregnated with 0.3% PEI and repeated using ice-cold 50 mM Tris-HCl. Rinse several times. The filter was dried and the residual radioactivity was calculated in a scintillation counter (Topcount, Packard) using scintillation fluid (Microscint 0, Packard). The experimental results are expressed as a percentage inhibition of radioligand-specific binding relative to the control group.
  • the binding assay of [ 3 H]8-OH-DPAT (0.3 nM) to the 5-HT 1A receptor in human HEK-293 cells was performed by a scintillation proximity assay of the membrane.
  • the test compound needs to be tested at least three times at a concentration exceeding 6 log, and the data is subjected to nonlinear regression analysis by a Hill equation curve to obtain an IC 50 value, which is then calculated by the Cheng Prusoff equation to obtain a Ki value.
  • the compound of the invention binds to the h5-HT 1A receptor with a Ki value of less than 15 nM, and in other embodiments, the compound of the invention binds to the h5-HT 1A receptor with a Ki value of less than 1 nM;
  • the compound prepared in Inventive Example 1 had a Ki value of 0.31 nM, and the compound prepared in Example 2 of the present invention had a Ki value of 13.2 nM.
  • the experimental results show that the compound of the present invention has strong binding affinity to the 5-HT 1A receptor.

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Abstract

Des composés d'indole substitués, des méthodes d'utilisation et des utilisations de ceux-ci sont divulgués. La présente invention concerne en particulier des nouveaux composés d'indole et des compositions pharmaceutiques comprenant les composés, pour l'inhibition de la réabsorption de la 5-hydroxytryptamine et/ou l'excitation d'un récepteur 5-HT1A. L'invention concerne également des procédés de préparation de ces composés et compositions pharmaceutiques, et leurs utilisations dans le traitement d'un dysfonctionnements du système nerveux central.
PCT/CN2016/090985 2015-07-23 2016-07-22 Composés d'indole substitués, méthodes d'utilisation et utilisations de ceux-ci Ceased WO2017012579A1 (fr)

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