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WO2012129792A1 - Composés de pyrimidinone, leurs procédés de préparation, leurs compositions pharmaceutiques et leurs utilisations - Google Patents

Composés de pyrimidinone, leurs procédés de préparation, leurs compositions pharmaceutiques et leurs utilisations Download PDF

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Publication number
WO2012129792A1
WO2012129792A1 PCT/CN2011/072302 CN2011072302W WO2012129792A1 WO 2012129792 A1 WO2012129792 A1 WO 2012129792A1 CN 2011072302 W CN2011072302 W CN 2011072302W WO 2012129792 A1 WO2012129792 A1 WO 2012129792A1
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Prior art keywords
reaction
compound
oxo
dihydro
cyclopenta
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Chinese (zh)
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王凯
沈建华
王逸平
王文义
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a novel class of pyrimidinone compounds and a process for the preparation thereof, pharmaceutical compositions containing the compounds as active ingredients, and their use in the preparation of a medicament for treating diseases associated with Lp-PLA 2 enzyme activity Application in .
  • Atherosclerosis is the pathophysiological basis of cardiovascular and cerebrovascular diseases.
  • the formation of thrombus after rupture of atheromatous plaques leads to vascular occlusion, which is the main cause of cardiovascular events. Therefore, prevention and treatment of atherosclerosis is an important issue that needs to be solved urgently in the medical field.
  • the standard clinical drug regimen is: statins regulate blood lipids, antihypertensive drugs to control blood pressure, and take drugs that resist platelet aggregation.
  • Oxidized low-density lipoprotein (ox-LDL) is a risk factor present in plasma that promotes inflammation and causes atherosclerosis.
  • Zalewski A et al. (Arterioscler Thromb Vase Biol, 2005, 25(5): 923-931) pro-inflammatory effects of lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) in ox-LDL and atherogenesis It plays an important role in mediating the above biological effects of ox-LDL.
  • Lp-PLA 2 is a member of the PLA 2 superfamily and belongs to VD type PLA 2 .
  • Lp-PLA 2 also known as plasma platelet-activating factor acetylhydrolase, contains 441 amino acids with a relative molecular mass of 45 kD. 70% of Lp-PLA 2 in human plasma binds to LDL, and 30% of Lp-PLA 2 binds to high-density lipoprotein (HDL), which means that it is easily transported to the site of damage caused by LDL into the vessel wall. .
  • Lp-PLA 2 can hydrolyze PAF, PAF-like phospholipids, and oxidatively modified phosphatidylcholines.
  • Lp-PLA 2 has strong specificity for the short strand residues of the phosphonium at the sn-2 position, and has the maximum hydrolytic activity when the sn-2 residue is an acetyl group, and the phospholipid of a long chain fatty acid at the sn-2 position.
  • the substrate has no enzymatic activity.
  • Site-directed mutagenesis Ser-273, Asp-296 and His-351 in Lp-PLA 2 have been identified to constitute the center of their enzyme activity.
  • Lp-PLA 2 maps atherosclerosis.
  • the long strand of the sn-2 position of the component lecithin of LDL is shortened by oxidative modification, and enters the arterial intima to become a substrate of Lp-PLA 2 .
  • Lp-PLA 2 hydrolyzes it to hydrolyze it, producing lysophosphatidylcholine (Lyso-PC) and oxidized free fatty acid (OX-NEFA), both of which have a strong pro-inflammatory effect.
  • cytokines such as Interferon expression, activation of leukocytes, induction of oxidative stress, induction of cell membrane permeability and apoptosis.
  • Lp-PLA 2 inhibitor may reduce the occurrence of the aforementioned inflammatory response, and is a new, non-lipid-lowering strategy for atherosclerosis.
  • Selective inhibitors of Lp-PLA 2 were observed in humans to significantly reduce ox-NEFA production and ox-LDL-induced apoptosis in macrophages (Rosenson RS, Vracar-Grabar M, Helenowski I. Cardiovasc Drugs Ther 2008 22:55-8).
  • Experiments performed on animal models also support the role of Lp-PLA 2 inhibitors, and Wilensky et al. (Wilensky RL, Shi Y, Mohler ER, et al.
  • Lp-PLA 2 is predictive of coronary heart disease events independent of traditional risk factors and C-reactive protein. For every one standard deviation of Lp-PLA 2 levels, the incidence of coronary heart disease events will increase by 22%. The risk of developing one-fifth of the highest Lp-PLA 2 levels is twice the lowest of the lowest level.
  • Lp-PLA 2 should be used as a diagnostic indicator to alert patients with low LDL levels but at high risk of coronary heart disease.
  • "Rotterdam study” (Oei HH, van der Meer IM, Hofman A, et al. Circulation 2005; 111 : 570-5) studies of 7,983 people with no history of coronary heart disease and older than 55 years of age indicate widespread Among the population, regardless of the level of cholesterol, Lp-PLA 2 is an early warning factor for coronary heart disease events and an early warning factor in ischemic cerebral palsy.
  • Lp-PLA 2 is also a risk factor for predicting the periodic occurrence of the disease.
  • One study pointed out (Brilakis ES, McConnell JP, Lennon RJ, Elesber AA, Meyer JG, Berger PB. Eur Heart J 2005; 26: 137-144), elevated Lp-PLA 2 levels in patients undergoing coronary angiography With a standard deviation, the incidence of coronary heart disease events will increase by 30%. This effect of Lp-PLA 2 is independent of traditional risk factors.
  • Lp-PLA 2 inhibitors may improve this condition.
  • Lp-PLA 2 inhibitors may be used for treatment.
  • Lp-PLA 2 in activated inflammatory cells (macrophages, lymphocytes, neutrophils, eosinophils, etc.)
  • Lp-PLA 2 inhibitors can therefore be used in the treatment of conditions associated with inflammatory cells, such as psoriasis.
  • Lp-PLA 2 inhibitors may be universally applicable to any process involving the hydrolysis of lipids into the two inflammatory traits with the participation of Lp-PLA 2 . This includes the aforementioned atherosclerosis, diabetes, hypertension, angina pectoris, rheumatoid arthritis, stroke, myocardial infarction, reperfusion, acute and chronic inflammatory diseases.
  • Patent applications W096/13484, W096/19451, WO97/02242, W097/21765, W097/21766, WO97/41098 and WO97/41099 disclose a series of monocyclic beta lactam derivatives which are Lp- A non-reversible, acetylation inhibitor of PLA 2 (Tew et al, Biochemistry, 37, 10087, 1998).
  • SmithKline Beecham pic has developed a class of potent reversible inhibitors of Lp-PLA 2 (WO 99/24420, WO 01/60805, WO 02/30911, WO 03/016287, WO 03/042179, WO 03/042206, WO 08 /048867, etc., characterized by a pyrimidinone or pyridone group in the structure.
  • Lp-PLA 2 inhibitor Darapladib (SB480848) is in the phase III clinical stage.
  • An object of the present invention is to provide a pharmaceutically acceptable pyrimidinone compound represented by the formula (I), an enantiomer, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically thereof thereof Acceptable salt.
  • Another object of the present invention is to provide a pyrimidinone compound of the formula (I), an enantiomer thereof, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof Preparation.
  • a further object of the present invention is to provide a pyrimidinone compound represented by the formula (I), an enantiomer thereof, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof
  • a medicament for the preparation of an Lp-PLA 2 inhibitor thereby for use in the preparation of a medicament for preventing, treating or ameliorating a disease associated with Lp-PLA 2 enzyme activity, such as atherosclerosis, stroke , myocardial infarction, angina pectoris, myocardial ischemia, reperfusion injury and other coronary heart disease, diabetes, rheumatoid arthritis, acute and chronic inflammatory diseases.
  • It is still another object of the present invention to provide a pharmaceutical composition comprising one or more effective therapeutic doses of a pyrimidinone compound of the formula (I), an enantiomer thereof, a diastereomer A body, a racemate and a mixture, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
  • the pyrimidinone compound provided by the present invention or a pharmaceutically acceptable salt thereof is represented by the formula (I):
  • (IA: IB: 1 and R 3 are each independently selected from the group consisting of: a straight or branched alkyl group of ⁇ , _ 1 () , a cycloalkyl group of C, a hydroxyl group, -NR 4 R 5 , , Or five to seven yuan aromatic or non-aromatic heterocyclic ring containing one to three nitrogen atoms, and not necessarily be d_ 3 alkyl substituents;
  • R 2 is an alkyl group of H or d 3 ;
  • R 1 —(CH 2 )m and R 2 together with the N to which they are bonded constitute a five- to seven-membered non-aromatic heterocyclic ring, and the non-aromatic heterocyclic ring is optionally substituted by an alkyl group of d_ 3 or —NR 4 R 5 , For example, but not limited to "4-dimethylaminopiperidinyl";
  • R 4 and R 5 are each independently selected from: an alkyl group of H or d 3 ;
  • R 6 may be in the para, para or meta position, selected from H, a halogen atom, d_ 4
  • R 7 is selected from H, a halogen atom, an alkyl group of d 2 or an alkyl group of d 2 substituted by three halogen atoms.
  • Substituted as used in the present invention means replaced by one or more groups. When a plurality of substituents are selected from the same series of candidate substituents, they may be the same or different.
  • the phrase "independently” as used in the present invention means that a plurality of defined groups can be selected from the same series of candidate groups, and they do not affect each other, that is, they may be the same or different.
  • the "effective therapeutic dose” as used in the present invention means that the disease, disorder, side effect, and the like of the subject receiving the dose are cured, improved, effectively prevented, or the incidence thereof is significantly lowered as compared with the subject not receiving the dose. In addition, it also includes an effective dose that enhances normal physiological function.
  • mercapto as used in the present invention includes all branched and straight chain isomers of a specific number of carbon atoms. Representative examples are, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl.
  • cycloalkyl group represents a non-aromatic, saturated, cyclic aliphatic hydrocarbon group at a specific number of carbon atoms.
  • Representative examples are, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • halogen as used in the present invention includes fluorine, chlorine, bromine and iodine unless specifically defined.
  • the pyrimidinone compound represented by the formula (I) may exist in the form of a pharmaceutically acceptable salt, which is a particularly important part within the scope of the present invention.
  • “Pharmaceutically acceptable salt” means that the compound of formula (I) retains the desired biological activity and has minimal toxic side effects.
  • the pharmaceutically acceptable salt can be obtained directly during the preparation and purification of the compound, or it can be obtained indirectly by reacting the free acid or free base of the compound with another suitable base or acid.
  • some of the compounds of the present invention contain a basic functional group such as R-NR 5 to form a pharmaceutically acceptable salt with a suitable acid.
  • the suitable acid may be a mineral acid or an organic acid.
  • pharmaceutically acceptable salts include, but are not limited to: hydrochloride, sulfate, hydrobromide, methanesulfonate, nitric acid, phosphate, acetate, oxalate, succinate, Tartrate, maleate, arginine, etc.
  • Some of the compounds of the present invention contain an acidic functional group such as R ⁇ -OH to form a pharmaceutically acceptable salt with a suitable base.
  • the suitable base may be an inorganic base or an organic base.
  • pharmaceutically acceptable salts include, but are not limited to, salts formed with inorganic ions, such as sodium salts, potassium salts, lithium salts, calcium salts, aluminum salts, zinc salts, ammonium salts, and the like; Salts such as methylamine salt, ethylamine salt, triethylamine salt, meglumine salt, tromethamine salt and the like.
  • a part of the compound of the present invention or a pharmaceutically acceptable salt thereof is crystallized or recrystallized from water or an organic solvent, and the solvent may be used in the crystal.
  • different crystallization conditions may result in different crystal forms of the compound. Therefore, a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof containing a different chemical amount of the crystallization solvent and all the crystal forms is within the scope of the present invention.
  • the compound of the formula (I) of the present invention has one or more chiral centers, and thus may exist as a racemate, a racemic mixture, an enantiomeric monomer, a diastereomeric monomer, or a non- Enantiomeric mixtures and other forms.
  • tautomers such as, but not limited to, H, and thus a tautomer and a mixture of a plurality of tautomers are within the scope of the present invention.
  • the compound represented by the formula (I) may have a rotamer due to the restriction of free rotation of a certain group, and thus a certain form of rotamer and Mixtures of multiple rotamers are also within the scope of the invention.
  • R 3 is preferably -
  • R is especially chosen as H, .
  • Linear or branched alkyl, C 3 -7 cyclodecyl or -NR 4 R 5 ; m 0-2 integer;
  • R 4 and R 5 are each independently preferably an alkyl group
  • R 6 has the same definition as above.
  • R 1 and R 3 are each independently preferably Or -NR 4 R 5 ;
  • R 2 is preferably H or methyl
  • n is preferably 1 or 2;
  • n 0-2;
  • R 4 and R 5 are each independently preferably an alkyl group
  • R 6 has the same definition as above.
  • R 3 is preferably p-trifluoromethylbiphenyl-4-yl
  • R ⁇ CH ⁇ m- is preferably a linear or branched alkyl group of H, CM, cyclopropylmethyl or -CH 2 CH 2 NR 4 R 5 ;
  • R 4 and R 5 are each independently preferably methyl or ethyl. Most preferably ethyl;
  • R 1 and R 3 are each independently preferably ⁇ 0 ⁇ R or -N R 4 R 5 ;
  • R 2 is preferably H or methyl
  • n is preferably 1 or 2;
  • n 0-2;
  • R 4 and R 5 are each independently preferably methyl or ethyl
  • R 7 is preferably a methyl group substituted with a halogen atom, a methyl group or a halogen atom, and most preferably -CF 3 .
  • the pyrimidinone compound represented by the formula (I) may specifically be:
  • the compounds of the present invention are potent inhibitors of lipoprotein-associated phospholipase A2 and are potentially useful for clinical treatment, particularly for the treatment and prevention of acute and chronic coronary heart disease, such as by peripheral vascular and cerebrovascular atherosclerosis.
  • This type of event that is, the present invention provides a compound of the general formula (I) which can be used for clinical treatment.
  • the compound represented by the formula (I) of the present invention can inhibit the formation of lysophosphatidylcholine (Lyso-PC), and thus can be generally applied to diseases associated with endothelial dysfunction, such as atherosclerosis, diabetes, hypertension, Angina and ischemic reperfusion. Furthermore, the compounds of the formula (I) can be generally applied to any condition involving the hydrolysis of oxidized lipids with the participation of Lp-PLA 2 , in addition to atherosclerosis, diabetes, etc. Ischemia, rheumatoid arthritis, stroke, brain inflammatory disease (such as Alzheimer's disease), myocardial infarction, reperfusion injury, sepsis, acute and chronic inflammatory diseases.
  • Lp-PLA 2 is expressed in activated inflammatory cells (macrophages, lymphocytes, neutrophils, eosinophils, etc.), and thus the compounds of the general formula (I) of the present invention can be treated and inflammatory cell activation Applications in related conditions such as psoriasis.
  • the present invention provides the use of a compound represented by the general formula (I) for the treatment of a disease associated with activation of Lp-PLA 2 by inhibiting the enzymatic activity of Lp-PLA 2 .
  • diseases may be associated with the following events: activation of inflammatory cells; formation of lysophosphatidylcholine and oxidized free fatty acids; Lp-PLA 2 catalyzed lipid oxidation; endothelial cell dysfunction.
  • the compound of the formula (I) of the present invention can be used in combination with the following drugs in the treatment of the above diseases: hypolipidemic Medicine, anti-atherosclerotic drugs, hypoglycemic agents, anti-angina drugs, anti-inflammatory drugs, antihypertensive drugs or drugs that inhibit phospholipase A.
  • a statin that inhibits cholesterol synthesis an antioxidant probucol, an insulin sensitizer, a calcium channel antagonist, or a non-anti-inflammatory drug.
  • the compound of the formula (I) of the present invention is used in combination with a cholesterol lowering drug, such as a statin.
  • a statin is an HMG-CoA reductase inhibitor such as atorvastatin, swastatin, pravastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, and the like. You can take both drugs at the same time or at different times as recommended by your doctor.
  • the compound of the formula (I) of the present invention can be used in combination with a hypoglycemic agent or an insulin sensitizer.
  • the insulin sensitizer used in combination is preferably a PPA- ⁇ agonist such as rosiglitazone or pioglitazone.
  • the compounds of the invention are typically administered in the form of a standard pharmaceutical composition. That is, the present invention provides a pharmaceutical composition comprising one or more effective therapeutic doses of a compound of the formula (I), and a pharmaceutically acceptable adjuvant.
  • the pharmaceutically acceptable excipient is a pharmaceutically acceptable carrier, excipient or sustained release agent, and the like.
  • the compounds and pharmaceutical compositions provided herein may be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions, aerosols, and the like, and may be presented in a suitable solid or liquid carrier or In the diluent.
  • the pharmaceutical compositions of the invention may also be stored in a suitable injectable or drip sterilizing device. Odorants, flavoring agents and the like may also be included in the pharmaceutical composition.
  • the pharmaceutical composition contains a safely effective amount (e.g., 0.1 to 99.9 parts by weight, preferably 1 to 90 parts by weight) of the compound of the formula (I) or a pharmaceutically acceptable salt thereof; A quantity of a pharmaceutically acceptable excipient wherein the total weight of the composition is 100 parts by weight.
  • the pharmaceutical composition of the present invention contains the compound of the formula (I) or a pharmaceutically acceptable salt thereof in an amount of from 0.1 to 99.9% by weight, based on the total weight, preferably from 1 to 90% by weight, based on the total weight; A pharmaceutically acceptable excipient wherein the total weight of the composition is 100% by weight.
  • a preferred ratio of the compound of the formula (I) to a pharmaceutically acceptable carrier, excipient or sustained release agent is that the formula (I) as the active ingredient accounts for more than 60% by weight of the total weight, and the balance is 0-40% by weight of the total weight, the rest
  • the amount of the moiety is preferably from 1 to 20%, most preferably from 1 to 10%.
  • the compound of the formula (I) or the pharmaceutical composition comprising the compound of the formula (I) of the present invention can be used clinically in mammals, including humans and animals, and the administration route can include oral, nasal inhalation, transdermal absorption, and pulmonary administration. Medicine or gastrointestinal tract.
  • a preferred route of administration is oral. It is preferably in a unit dosage form, and each dose contains the active ingredient of 0.01 mg to 200 mg, preferably 0.5 mg to 100 mg, once or in divided doses. Regardless of the method of administration, the optimal dosage for the individual should be based on the specific treatment. Usually starting with a small dose, gradually increase the dose until the most appropriate dose is found.
  • the pharmaceutical composition of the present invention can be administered orally and intravenously, intramuscularly or subcutaneously.
  • Preferred pharmaceutical compositions are solid compositions, especially tablets and solid filling or liquids, from the standpoint of ease of preparation and administration. Filled capsules. Oral administration of the pharmaceutical composition is preferred.
  • the solid carrier includes: starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin
  • the liquid carrier includes: sterile water, polyethylene glycol, nonionic surfactant and edible oil (such as corn oil). , peanut oil and sesame oil, etc., as long as it is suitable for the characteristics of the active ingredient and the particular mode of administration required.
  • Adjuvants which are usually used in the preparation of pharmaceutical compositions may also be advantageously included, for example, flavoring agents, coloring agents, preservatives and antioxidants such as vitamin E, vitamin C, BHT and BHA.
  • Injectable formulations include, but are not limited to, sterile, injectable, aqueous, oily solutions, suspensions, emulsions and the like. These formulations may also be formulated with parenterally suitable diluents, dispersing agents, wetting agents, suspending agents and the like. Such injectable formulations can be sterilized by filtration in a filter that traps bacteria. These formulations may also be formulated with a bactericide which is dissolved or dispersed in an injectable medium or by other methods known in the art.
  • the compound of the present invention can be produced by one of the methods represented by Reaction Scheme 1 or Scheme 2. Unless otherwise defined, the definition of each substituent in the reaction scheme is the same as in the general formula (I). Reaction route 1
  • compound 1 Under the action of a base, compound 1 is condensed with hydroxylamine hydrochloride to form compound 2;
  • the base used includes an organic base and an inorganic base such as triethylamine, potassium carbonate, sodium hydroxide, etc.;
  • the reaction is carried out in a polar solvent such as methanol, Ethanol, DMF, water, etc. or a mixed solvent thereof; the reaction temperature is between 0 ° C and 30 ° C.
  • the compound 2 is chlorinated to the compound 3 by an equivalent amount of NCS; the reaction solvent includes THF, DMF, etc.; and the reaction temperature is from 0 ° C to 60 ° C.
  • Compound 3 is dehydrochlorinated under the action of a base to form a 1,3-dipole ion, and then added with ethyl acrylate to form compound 4;
  • the base used is an organic base such as triethylamine, DIPEA, DBU, etc.; THF, DMF, etc.; reaction temperature between -40 ° C to room temperature.
  • the catalyst used in the reaction is palladium/carbon in an amount of 10% to 20% by mass of the compound 4; the reaction is carried out in a polar solvent such as methanol or ethanol; the reaction temperature is between 0 ° C Up to 80 ° C, the best room temperature.
  • Compound 5 reacts with DPPA under the action of a base to form compound 6;
  • the base used is an organic base such as triethylamine, DIPEA, DBU, DMAP, etc., most preferably DBU and DMAP; and
  • the reaction solvent includes THF, CH 3 CN, DME
  • the equipolar aprotic solvent is preferably THF; the reaction temperature is between 0 ° C and 100 ° C, preferably the reflux temperature of the solvent used.
  • Compound 6 is subjected to a hydrogenation reduction reaction or a Staudinger reaction to obtain a compound 7 (Gololobov, Y. G. Sixty years of Staudinger reaction. Tetrahedron 1981, 37: 437); the catalyst used for the hydrogenation reduction reaction is palladium.
  • the reaction is carried out in methanol, ethanol, EA or THF, the reaction temperature is between 0 ° C and 80 ° C, preferably room temperature; the reagent used in the Staudinger reaction is an excess of Ph 3 P, and the reaction is in THF-H 2 0 In progress, the temperature is between 0 ° C and 50 ° C.
  • R 8 is methyl or ethyl
  • the reaction is carried out in the presence of a dehydrating agent comprising molecular sieves, toluene azeotrope, Si(OEt) 4 or the like
  • the reaction solvent includes methanol, ethanol, toluene, acetic acid, etc.
  • the reaction temperature is from 0 ° C to 140 ° C, preferably the reflux temperature of the solvent used.
  • Compound 8 is condensed with more than one equivalent of isocyanate to form compound 9; the isocyanate includes
  • Compound 9 is reacted with p-fluorobenzyl bromide or p-fluorobenzyl chloride to form compound 10; more than one equivalent of an organic or inorganic base such as triethylamine, DBU, DIPEA, potassium carbonate, sodium carbonate, etc. is added to the reaction; Such as potassium iodide, tetrabutylammonium iodide, etc.; the reaction solvent includes acetonitrile, acetone, DME, DCM, DCE, EA, ethanol, methanol, THF, etc.; reaction temperature is between 0 ° C and 80 ° C, the best for use The reflux temperature of the solvent.
  • an organic or inorganic base such as triethylamine, DBU, DIPEA, potassium carbonate, sodium carbonate, etc.
  • the reaction solvent includes acetonitrile, acetone, DME, DCM, DCE, EA, ethanol, methanol, THF, etc.
  • Compound 10 and R 1 - (CH 2 ) m -LG are prepared under the action of a strong base, and LG represents a leaving group including a halogen atom, a trifluoromethylsulfonate (-OTf), a methanesulfonate (- OMs), etc., most preferably Cl, B, I;
  • the strong base includes NaH, n-BuLi, KOBu-t, etc., most preferably NaH;
  • the reaction solvent includes THF, DMF;
  • the reaction temperature is between -80 ° C to Room temperature, preferably from 0 ° C to room temperature.
  • R 8 is methyl or ethyl
  • the hydrochloride salt of compound 12 at least one is required.
  • Equivalent organic base such as triethylamine, DIPEA
  • the reaction is carried out in the presence of a dehydrating agent, including molecular sieve, toluene azeotrope, Si(OEt) 4, etc.
  • the reaction solvent includes methanol, ethanol, toluene, acetic acid, etc.
  • the reaction temperature is between 0 ° C and 140 ° C, preferably the reflux temperature of the solvent used.
  • Compound 13 is condensed with greater than one equivalent of isocyanate to form compound 14; the isocyanate includes
  • Compound 14 is reacted with p-fluorobenzyl bromide or p-fluorobenzyl chloride to form compound 15; more than one equivalent of an organic or inorganic base such as triethylamine, DBU, DIPEA, potassium carbonate, sodium carbonate, etc. is added to the reaction; Such as potassium iodide, tetrabutylammonium iodide, etc.; the reaction solvent includes acetonitrile, acetone, DME, DCM, DCE, EA, ethanol, methanol, THF, etc.; reaction temperature is between 0 ° C and 80 ° C, the best for use The reflux temperature of the solvent.
  • an organic or inorganic base such as triethylamine, DBU, DIPEA, potassium carbonate, sodium carbonate, etc.
  • the reaction solvent includes acetonitrile, acetone, DME, DCM, DCE, EA, ethanol, methanol, THF, etc.
  • Compound 15 undergoes alkaline hydrolysis to give compound 16;
  • the base used is an inorganic strong base such as LiOH, NaOH, KOH;
  • the reaction is carried out in an aqueous polar solvent including methanol, ethanol, dioxane, DMF, DMSO Isopropanol, THF, etc., preferably methanol or ethanol;
  • the reaction temperature is between 0 ° C and 50 ° C; after the hydrolysis reaction is completed, the reaction solution is subjected to acidification to precipitate the free compound 16, and acidification is usually carried out using hydrochloric acid and acetic acid.
  • Compound 16 and ( eH2 ) m or its hydrochloride form compound 17 under the action of a condensing agent;
  • the condensing agent used includes dicyclohexylcarbodiimide (DCC), diethyl azodicarboxylate/triphenyl Phosphorus, carbonyl diimidazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride/1-hydroxy-benzo-triazole (EDCI/-(lH-benzo) Triazol-1-yl)-AWN', N'-tetramethylisourea boron tetrafluoride (TBTU) / organic base, etc.; when used For the hydrochloride, at least one equivalent of an organic base such as triethylamine or DIPEA is required; the reaction solvent includes non-alcoholic solvents such as DCM, DCE, acetonitrile, THF, toluene, DMF
  • the above compound 12 can be produced by one of two methods shown in Reaction Scheme 3 and Reaction Scheme 4. Hydrogenation reduction
  • compound 18 is condensed with sodium pyruvate to form compound 19; the reaction is carried out in methanol, ethanol, water, DCM or a mixed solvent thereof; the reaction temperature is between 0 ° C and 30 ° C; It is purchased or prepared as known in the literature.
  • Compound 19 is prepared by esterification to produce compound 20; the acid catalyst in the reaction is formed in situ from acetyl chloride and ethanol; the reaction solvent is toluene; and the reaction temperature is between 0 ° C and 110 ° C.
  • the catalyst is palladium/carbon in an amount of 10% to 20% by mass of the compound 20; the reaction is carried out in a low polar solvent such as EA; and the reaction temperature is between 0 ° C and 80 ° C, The best is room temperature.
  • Compound 21 reacts with DPPA under the action of a base to form compound 22; the base used is an organic base such as triethylamine, DIPEA, DBU, DMAP, etc., most preferably DBU and DMAP; and the reaction solvent includes THF, CH 3 CN, DME, etc.
  • a polar aprotic solvent most preferably THF; the reaction temperature is between 0 ° C and 100 ° C, most preferably the reflux temperature of the solvent used.
  • Compound 22 is subjected to a hydrogenation reduction reaction or a Staudinger reaction to obtain a compound 23 (Gololobov, YG Sixty years of Staudinger reaction. Tetrahedron 1981, 37: 437); the catalyst for the hydrogenation reduction reaction is palladium/carbon, and the reaction is carried out in methanol, ethanol, EA, THF.
  • the reaction temperature is between 0 ° C and 80 ° C, preferably room temperature; the reagent used for the Staudinger reaction is an excess of Ph 3 P, and the reaction is carried out in THF-H 2 0 at a temperature between 0 ° C and 50 ° C. .
  • Compound 12 can be prepared by the method shown in Scheme 4: wherein R 6 is as defined above.
  • Diethyl 2-acetamidomalonate is condensed with ( GH2 ) n
  • the base used includes NaH, KOBu-t, sodium ethoxide, etc., preferably sodium ethoxide;
  • reaction solvents include ethanol, DME, THF, DMF, etc., most commonly ethanol; reaction temperature is between 0 ° C and 80 ° C.
  • the compound 24 is hydrolyzed by 1 equivalent of NaOH, and then decarboxylated by heating to form the compound 25; the hydrolysis reaction is carried out in an aqueous alcohol solution at a reaction temperature of from 0 ° C to room temperature; and the decarboxylation reaction is refluxed in toluene.
  • Compound 25 is acid hydrolyzed to prepare compound 26; the reaction is carried out under reflux in dilute hydrochloric acid.
  • Compound 26 undergoes an esterification reaction involving thionyl chloride to form compound 24; the reaction is carried out under reflux in ethanol.
  • the numbering of the synthetic intermediate of the present invention begins with the English letters "A, B, C", such as the intermediate "A8"; and the final “example” begins with the word “example 18".
  • A6 2-[4-(p-trifluoromethylbiphenyl-4-yl)-1-ethoxy-1-pyrene-2-yl]amino-1-cyclopentenecarboxylate
  • the product obtained in the previous step was dissolved in 10 ml of absolute ethanol, and 195 ⁇ l of ethyl cyclopentanone-2-carboxylate and 590 ⁇ l of tetraethyl silicate were added, and the reaction was refluxed under nitrogen for 10 h.
  • the mixture was directly stirred into silica gel, and after spinning, it was separated by flash column chromatography to obtain 0.51 g of oil.
  • the dried DMF was heated at 140 ° C for 4 h, and the reaction was completed by TLC. After cooling, the flask was placed in an ice bath, and saturated with sodium bicarbonate solution was added dropwise. Then, 20 ml of EA and 10 ml of water were added and stirred for 10 min. The EA phase was separated, and the aqueous phase was extracted once with 10 ml of EA, and the organic phases were combined.
  • the above gum was dissolved in 3 ml of ethanol, and ice-bath, 0.5 ml of 10% aqueous NaOH solution was added dropwise, and the reaction was completed at room temperature for 2 hours. 20 ml of ice water was added to the flask, and the pH was adjusted to about 5 with 6N hydrochloric acid to precipitate a white precipitate. Add 5 ml of EA - stir for 10 min, collect the precipitate by filtration, wash with water, wash with EA, and dry to give 186 mg.
  • Example 2 monomethyl-TV-dimethylaminoethyl _ 2 _[ (2 _ p-fluorobenzylthio) _ 4 _ oxo_6, 7 _ dihydro _ 4 / _ cyclopentamethylpyrimidine -1(5H)-yl]-4-(p-trifluoro-4-yl)butanamide
  • A10 was suspended in 15 ml of anhydrous diethyl ether, placed in an ice bath, and 370 ⁇ l of phosphorus tribromide was added in portions, and then reacted at room temperature for 2 hours.
  • the flask was placed in an ice bath, and the mixture was diluted with a saturated aqueous solution of sodium hydrogen carbonate.
  • the organic phase was separated, and the aqueous phase was extracted with diethyl ether.
  • the organic phase was combined and dried over magnesium sulfate. .
  • A14 3-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopentamethylpyrimidine -1(5H)-yl]propionic acid
  • Example 7 1-[3-(p-trifluoromethylbiphenyl-4-yl)-l-(4-dimethylaminopiperidin-1-yl)-1-oxopropan-2-yl] -2-p-fluorobenzylthio-6,7-dihydro-1H-cyclopenta[-4(5H)-one
  • B2 2.0g was placed in 15 ml of 6N hydrochloric acid and refluxed for 5 h. The water was evaporated to dryness under reduced pressure, and then water was taken twice with toluene to give a solid residue as B3-4-diethylamino-2-aminobutyric acid salt.
  • the preparation method was the same as that of A7, except that the reaction was completed, and the sodium carbonate saturated solution was used instead of the sodium hydrogencarbonate saturated solution to quench.
  • 550 mg of the target product was obtained from 2.5 g of B5.
  • the preparation method was the same as that of A8, and 660 mg of the target product was obtained from 1.0 g of B6.
  • 'H-NMR (CDC1 3 , 300 MHz) ⁇ .92/1.13 (2x t, 9 ⁇ ), 2.07 (m, 2 ⁇ ), 2.25 (m, 1H), 2.46 (m, 8H), 2.86 (m, 3H) , 4.16 (m, 2H), 4.49 (q, 2H), 4.95/5.47 (2x m, 1H), 6.97 (t, 2H), 7.35 (m, 2H)
  • the solid was dissolved in 30 ml of DMF, and 0.5 g of NCS was first added to initiate the reaction, and the remaining 3.5 g of NCS was added in portions, and the rate of addition was such that the temperature of the solution did not exceed 40 ° C, and the reaction was stopped for 0.5 h.
  • the reaction solution was dissolved in 200ml EA, washed 5 times with a small amount of brine several times, dried MgS0 4, the solvent was evaporated to dryness to give C2, 8.0g solid.
  • the preparation method was the same as A8 except that C9 was substituted for A7.
  • 'H-NMR (CDC1 3 , 300 MHz, ca 3:1 rotamer) 52.05 (m, 2H), 2.70/2.44 (2x m, 4H), 2.86/2.96 (2x m, 1H), 3.05/3.26 (2x m, 1H), 4.50 (m, 2H), 5.40/4.90 (2x t, 1H), 5.00/5.04 (2x dd, 1H), 7.07/6.79 (2x s, 1H, -NH-), 6.95/ 6.99 (2x t, 2H), 7.34 (m, 4H), 7.63 (d, 2H), 7.65 (d, 2H), 7.70 (d, 2H).
  • Example 30 one (s) - trans -1-[2-oxo-1-p-fluorobenzyl
  • Substrates were detected using tritiated platelet activating factor ([ 3 H] PAF, Perkinelmer, Lot NET910).
  • the reaction was carried out in a 200 ⁇ l system (50 mmol/L hydroxyethylpiperazineethanesulfonic acid (HEPES) and B 150 mmol/L sodium chloride (NaCl), pH 7.4).
  • HEPES hydroxyethylpiperazineethanesulfonic acid
  • NaCl sodium chloride
  • the reaction was carried out at 37 ° C for 10 minutes, followed by vortexing by adding 600 ⁇ l of CHCl 3 /MeOH (2:1) to terminate the reaction. After standing for a while, it was centrifuged at 12,000 x g for 15 minutes, and the aqueous layer was transferred to a new tube, vortexed by adding 200 ⁇ l of chloroform, and allowed to stand or centrifuge for 2 minutes. The supernatant of the ⁇ aqueous layer was taken for determination of radioactivity.
  • Reaction buffer 180 170 170 Test compound 10 Dimethyl sulfoxide (solvent) 10 10
  • Inhibition rate 1- (test tube DPM value - blank tube DPM value) control tube DPM value - blank tube DPM value)
  • Example 3 NT 26 NT
  • Example 9 NT 91 34
  • Example 19 NT 27 NT
  • Example 20 NT 33 NT
  • Example 21 NT 72 ⁇
  • Example 25 99 93 67
  • Example 26 98 90 44
  • Example 27 99 96.0 76.8
  • Example 28 53.1 NT NT
  • Example 29 48.8 NT NT
  • Example 30 90 88.7 32.2
  • Example 31 91 73.2 ⁇
  • Example 32 90 69.4 ⁇
  • Example 33 93 78.6 13.3
  • Example 34 96 78.5 16.3
  • Example 39 80.4 21.8 1.6

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Abstract

L'invention concerne des composés de pyrimidinone représentés par la formule générale (I), leurs procédés de préparation, des compositions pharmaceutiques comprenant ce type de composés en tant que composants actifs et leurs utilisations dans la fabrication de médicaments pour le traitement de maladies associées à l'activité de l'enzyme Lp-PLA2. Dans la formule (I), la définition de chaque substituant est telle que décrite dans la description.
PCT/CN2011/072302 2011-03-30 2011-03-30 Composés de pyrimidinone, leurs procédés de préparation, leurs compositions pharmaceutiques et leurs utilisations Ceased WO2012129792A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104725279A (zh) * 2015-02-12 2015-06-24 威海迪素制药有限公司 一种N-Boc-联苯丙氨酸衍生物的制备方法
CN115477578A (zh) * 2022-10-18 2022-12-16 中国人民解放军61699部队 一种壬酰氯的纯化方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002030911A1 (fr) * 2000-10-10 2002-04-18 Smithkline Beecham P.L.C. Derives de pyrimidinone et leur utilisation dans le traitement de l'atherosclerose
WO2003016287A2 (fr) * 2001-08-14 2003-02-27 Smithkline Beecham P.L.C. Nouveaux procedes
CN1418199A (zh) * 2000-02-16 2003-05-14 史密斯克莱·比奇曼公司 作为ldl－pla2抑制剂的嘧啶－4－酮衍生物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1418199A (zh) * 2000-02-16 2003-05-14 史密斯克莱·比奇曼公司 作为ldl－pla2抑制剂的嘧啶－4－酮衍生物
WO2002030911A1 (fr) * 2000-10-10 2002-04-18 Smithkline Beecham P.L.C. Derives de pyrimidinone et leur utilisation dans le traitement de l'atherosclerose
WO2003016287A2 (fr) * 2001-08-14 2003-02-27 Smithkline Beecham P.L.C. Nouveaux procedes

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104725279A (zh) * 2015-02-12 2015-06-24 威海迪素制药有限公司 一种N-Boc-联苯丙氨酸衍生物的制备方法
CN104725279B (zh) * 2015-02-12 2018-03-02 威海迪素制药有限公司 一种N‑Boc‑联苯丙氨酸衍生物的制备方法
CN115477578A (zh) * 2022-10-18 2022-12-16 中国人民解放军61699部队 一种壬酰氯的纯化方法
CN115477578B (zh) * 2022-10-18 2024-04-26 中国人民解放军61699部队 一种壬酰氯的纯化方法

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