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WO2013000108A1 - Composés hétérocycliques azoles, procédés de préparation, compositions pharmaceutiques et leurs utilisations - Google Patents

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

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Publication number
WO2013000108A1
WO2013000108A1 PCT/CN2011/076402 CN2011076402W WO2013000108A1 WO 2013000108 A1 WO2013000108 A1 WO 2013000108A1 CN 2011076402 W CN2011076402 W CN 2011076402W WO 2013000108 A1 WO2013000108 A1 WO 2013000108A1
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Prior art keywords
methyl
dihydro
fluorobenzylthio
trifluoromethylbiphenyl
cyclopenta
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Ceased
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PCT/CN2011/076402
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English (en)
Chinese (zh)
Inventor
沈建华
王逸平
王凯
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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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Application filed by Shanghai Institute of Materia Medica of CAS filed Critical Shanghai Institute of Materia Medica of CAS
Priority to PCT/CN2011/076402 priority Critical patent/WO2013000108A1/fr
Priority to PCT/CN2012/000661 priority patent/WO2013000267A1/fr
Priority to US14/129,199 priority patent/US20140171431A1/en
Priority to EP12804554.9A priority patent/EP2725024A4/fr
Priority to CN201280030865.1A priority patent/CN103619831B/zh
Publication of WO2013000108A1 publication Critical patent/WO2013000108A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D403/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • Azole heterocyclic compound, preparation method thereof, pharmaceutical composition and use thereof is Azole heterocyclic compound, preparation method thereof, pharmaceutical composition and use thereof
  • the present invention relates to the field of medicinal chemistry, and in particular to novel azole heterocyclic compounds and preparation methods 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 Applications.
  • Background of the invention
  • Atherosclerosis is the pathophysiological basis of cardiovascular and cerebrovascular diseases.
  • the formation of thrombus after rupture of atheromatous plaques and vascular occlusion 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 current standard drug regimen is: statins modulate blood lipids, antihypertensive drugs to control blood pressure, and take drugs that resist platelet aggregation.
  • statins modulate 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 the blood paddle that promotes inflammation and causes atherosclerosis.
  • Zalewski A reported (Arterioscler Thromb Vase Biol, 2005, 25 (5): 923-931) lipoprotein-associated phospholipase 2 eight (eight 2 ⁇ 1) during the formation of pro-inflammatory effects and the ox-LDL induced atherosclerosis It plays an important role in mediating the above biological effects of ox-LDL.
  • Lp-PLA 2 is also called plasma platelet activating factor (PAF acetylhydrolase, which contains 441 amino acids with a relative molecular mass of 45 kD.
  • PAF acetylhydrolase plasma platelet activating factor
  • 70% of 1 ⁇ 1 ⁇ 2 in human blood paddles binds to LDL, 30% Lp-PLA 2 binds to high-density lipoprotein (HDL), which means that it is easily transported along with LDL to the site of damage in the vessel wall.
  • HDL high-density lipoprotein
  • Lp-PLA 2 can hydrolyze PAF, PAF-like phospholipids and oxidatively modified Phosphatidylcholine, etc.
  • Lp-PLA 2 has strong specificity for the short strand residues of the sn-2 position of phospholipids. When the residue at position sn-2 is acetyl, it has the maximum hydrolytic activity, and the phospholipid substrate with the long-chain fatty acid at the sn-2 position has no enzymatic activity.
  • Site-directed mutagenesis identifies Ser-273, Asp in Lp-PLA 2 -296 and His-351 constitute the center of its enzyme activity.
  • Lp-PLA 2 inhibitor may reduce the occurrence of the aforementioned inflammatory response, and is a new, non-lipid-lowering strategy for the treatment of 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 Drags 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 can be used as a quantitative diagnostic indicator to alert patients with low LDL levels but with potential cardiovascular risk.
  • ARIC Atherosclerosis Risk in Comnmnities
  • Lp-PLA 2 is a risk factor for predicting disease recurrence.
  • a study using coronary angiography indicated that for every one standard deviation of Lp-PLA 2 levels, the incidence of coronary heart disease increased by 30% in four years. This effect of Lp-PLA 2 is independent of traditional risk factors and C-reactive protein (CRP).
  • CRP C-reactive protein
  • Lp-PLA 2 inhibitors may be used for other diseases that exhibit endothelial dysfunction such as diabetes, hypertension, angina, and reperfusion in ischemic areas.
  • Lp-PLA 2 is expressed in activated inflammatory cells (macrophages, lymphocytes, neutrophils, eosinophils, etc.), and thus Lp-PLA 2 inhibitors can be used in the treatment of conditions associated with inflammatory cells, Such as psoriasis and a variety of airway inflammatory diseases including asthma, chronic bronchitis.
  • 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 [3 lactam derivatives which are An irreversible, acetylation inhibitor of Lp-PLA 2 CTew et al, Biochemistry, 37, 10087, 1998).
  • Smit line 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 clinical stage of the flood season.
  • An object of the present invention is to provide a pharmaceutically acceptable azole heterocyclic compound represented by the formula (I) or ( ⁇ ), a cis-trans isomer, an enantiomer thereof and a diastereomer thereof. , a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a process for the preparation of the compound of the formula (I).
  • Another object of the present invention is to provide a use of the compound of the formula (I) or (II) as an Lp-PLA 2 inhibitor, thereby preparing a disease for preventing, treating or ameliorating the activity associated with Lp-PLA 2 enzyme activity.
  • Use of the drug such as atherosclerosis, stroke, myocardial infarction, angina pectoris, myocardial ischemia, reperfusion injury, coronary heart disease, diabetes, asthma, psoriasis, rheumatoid arthritis, acute and chronic inflammatory diseases .
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising one or more effective therapeutic doses of a compound of the formula (I) or (A) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt Accepted accessories.
  • Another object of the present invention is to provide a method for preventing, treating or ameliorating a disease associated with Lp-PLA 2 enzyme activity, comprising the azole heterocyclic compound of the present invention, a cis-trans isomer thereof, and an enantiomeric A conformation, diastereomer, racemate, solvate, hydrate, or a pharmaceutically acceptable salt thereof, or a composition according to the invention.
  • an azole heterocyclic compound represented by the formula (I) or ( ⁇ ) a cis-trans isomer, an enantiomer, a diastereomer thereof, a racemic Body, hydrate, solvate, or pharmaceutically acceptable
  • T is a four to six dollar fat ring, or a benzene ring
  • R is a sulfhydryl group
  • X is CH or N
  • Y is a phenyl ring and is optionally substituted with one or more substituents selected from the group consisting of:
  • W is selected from the following six structures of af:
  • R 1 is selected from H, , C 3 .12 1 ⁇ 2 alkenyl, d. 12 1 ⁇ 2 fluorenyl, -NR 4 R 5 substituted C 2 _ 4 fluorenyl, 4
  • R 2 is selected from H' , -COR 4 , -COOR 4 ,
  • R 3 may be in the ortho, meta or para position, is selected from H, halogen atom, alkyl with the d_ s, partially or fully halogenated alkyl with d_ s;
  • R 4 , R 5 are each independently selected from g H, C 3 -7 cyclodecyl, C s linear or branched fluorenyl, optionally substituted by -COOR 9 , -NR 9 R 10 '-OR 9 '-COR 9 , substituted by a benzene ring, a benzyl group, an aromatic and a non-aromatic heterocyclic ring, optionally a halogen atom Replaced by the sulfhydryl group of C s ; or
  • R 4 , R 5 and its attached N together form a 5-8 membered non-aromatic heterocyclic ring which may comprise another hetero atom selected from N, 0, S, and optionally a halogen atom, a group, -NR"R 12 , -OR 11 , substituted by oxo, benzyl; the thiol group of the _ s is optionally substituted by -COOR 4 ;
  • R s , R 7 , R s are each independently selected from the group consisting of a fluorenyl group, a hydroxy-substituted C M fluorenyl group, a benzyl group, which is optionally substituted with a fluorenyl group of a halogen atom;
  • R 9 , R 1Q are each independently selected as g H, C s thiol; or
  • R 9 , R 1Q together with the N to which it is bonded constitutes a 5-8 membered non-aromatic heterocyclic ring, and the heterocyclic ring may comprise another hetero atom selected from N, 0, S;
  • R 11 ' R 12 are each independently selected as g H, d. s fluorenyl.
  • Halo represents a halogen atom.
  • T is a five-membered aliphatic ring, or a benzene ring
  • X is CH or in another preferred embodiment, in the formula (I): when T is five When the aliphatic ring is a member, X is N; when T is a benzene ring, X is CH.
  • Y is a fluorine atom-substituted benzene
  • Y is "4-fluorophenyl", "2,3-difluorophenyl”.
  • w is selected from the five structures a - e ,
  • R 1 and R 2 are as described above.
  • R 1 is a fluorenyl group of 4 substituted by ⁇ r3 or -NR 4 R 5 .
  • R 1 is "(4-trifluoromethylbiphenyl-4-yl)methyl".
  • R 2 is -C0R 4 , -CONR 4 R 5 , cyclopropyl, sulfhydryl group of C 5 , and the fluorenyl group is -NR 4 R 5 , -OR 4 ,
  • R 2 is selected from "NN-dimethylamino", “N-(2-diethylamino)ethylamino", methyl-N-(2-diethylamino)ethylamino", "dimethyl Aminomethyl", “diethylaminomethyl”, “(tetrahydropyrrole small)methyl", “(N-methyl-p-fluorobenzamide)methyl", “isopropyl", “cyclopropyl””,”(3-diethylamino)propyl”,”(4-diethylamino)butyl",”hydroxymethyl”,”(1-hydroxy)ethyl”,”(p-fluorobenzylthio))methyl",”(N-methylisopropylamino)methyl”,”[(1-ethylpyrrole-2-yl)methylamino]methyl",”(N-ethylpiperazine-1-yl)methyl",methyl-(2-dimethylamino)ethylamino]
  • the compound is selected from the group consisting of:
  • Methyl N- ⁇ 3-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[pyrimidin-1(5H>yl]methyl-4- Methyl (p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-5-yl ⁇ methylaminoacetate;
  • a pharmaceutical composition comprising one or more effective therapeutic doses a hydrate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
  • the composition further comprises one or more drugs selected from the group consisting of: a hypolipidemic agent, an anti-arterial Atherosclerosis, hypoglycemic agents, anti-angina drugs, anti-inflammatory drugs, antihypertensive drugs or lipid-lowering proteins Drugs.
  • an azole heterocyclic compound, a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a solvate thereof, hydrated according to the invention Use of a substance, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for an Lp-PLA 2 inhibitor.
  • the disease comprises atherosclerosis, stroke, coronary heart disease, diabetes, asthma, psoriasis, rheumatoid arthritis, acute and chronic inflammatory diseases.
  • a method for preventing, treating or ameliorating a disease associated with Lp-PLA 2 enzymatic activity comprising administering an azole heterocyclic compound, a cis-trans isomer thereof, a pair of the invention
  • the disease comprises atherosclerosis, stroke, coronary heart disease, diabetes, asthma, psoriasis, rheumatoid arthritis, acute and chronic inflammatory diseases.
  • a process for the preparation of a compound, a hydrate, or a pharmaceutically acceptable salt thereof characterized in that one of the following Reaction Scheme 1 - Reaction Scheme 4 is employed:
  • the compound of the formula (I) (i.e., compound 6) can be produced by the method shown in Reaction Scheme 1: wherein R 13 is C 1 .
  • the thiol group, the definition of TXYR 2 is as described above;
  • compound 1 Amidation of compound 1 to compound 2; compound 2 produces compound 3 under the action of a dehydrating reagent; compound 3 is reacted with hydroxylamine hydrochloride under the action of a base to prepare compound 4; compound 4 is catalyzed by boron trifluoride diethyl ether with R 2 CHO reaction produces compound 5, the reaction is carried out in an aprotic solvent; compound 5 is reacted with R 13 CH 2 CHO under the catalysis of boron trifluoride etherate to obtain compound 6;
  • the compound of the formula (I) (ie, compound 10) can be prepared by the method shown in Scheme 2.
  • R 14 is methyl or ethyl, and Halo, TW, Y are as defined above;
  • compound 7 is condensed with a cyclic fluorenone carboxylate R14 °3 ⁇ 4 ⁇ in the presence of a dehydrating agent to form compound 8; compound 8 forms a compound 9 under the action of Me 3 SiNCS; Compound 9 is reacted with Y ⁇ Halo in a polar solvent to form compound 10;
  • the compound 11 and the aqueous formaldehyde solution are co-heated to form the compound 12; under the action of a base, the compound 12 and Y ⁇ Halo in a polar solvent to form a compound 14;
  • the compound 11 is first reacted with Y ⁇ Halo to form a compound 13, and then co-heated with an aqueous formaldehyde solution to form a compound 14;
  • the compound of the formula (I) can be converted by a functional group to form another compound of the formula (I), and such a functional group is converted as shown in Reaction Scheme 4:
  • compounds of formula (I) is the compound 15, wherein R 15 3 ⁇ 4 H, d_ s a group embankment, R 16 is alkyl with the d_ s And the fluorenyl group is optionally substituted by NR 4 R 5 or a phenyl group, which is optionally substituted by a halogen atom, R 13 is a fluorenyl group, L is NR 4 , 0 or S, Z is CH, N or 0, T, X, Y, R 1 , R 4 , R 5 , R 6 , R 7 , R s are as defined above;
  • Compound 15 is formed under the action of a chlorinating reagent to form compound 16; compound 16 is reacted with R 16 LH under the action of a base to obtain compound 17;
  • Substituted as used in the present invention means replaced by one or more groups.
  • groups When a plurality of groups are selected from the same series of candidate substituents, they may be the same or different.
  • the "fat ring” described in the present invention represents a cyclic hydrocarbon group having 3 to 12 carbon atoms, and may contain an unsaturation, preferably a 4-6 membered aliphatic ring such as cyclopentanyl or cyclopentene.
  • mercapto and the like “decyloxy” as used in the present invention include all branched and straight chain isomers of a specific number of carbon atoms, preferably C 12 fluorenyl, more preferably d s fluorenyl. More preferably, it is a C 14 fluorenyl group, and a fluorenyl group is further preferable.
  • Representative examples are, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl.
  • alkenyl group represents all branched and straight-chain aliphatic hydrocarbon chains having one to five double bonds at a specific number of carbon atoms.
  • Representative examples are but not limited to: vinyl, propylene.
  • cycloalkyl as used in the present invention 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.
  • non-aromatic heterocyclic ring as used in the present invention, unless specifically defined, represents a saturated monocyclic ring system having 2 to 10 carbon atoms and having one to four hetero atoms selected from g, 0, and S. Representative examples are, but are not limited to, aziridine, thiazine, azetidinium, tetrahydrofuran, pyrrolidine, piperidine, piperazine, morpholine and the like.
  • aromatic heterocyclic ring represents a monocyclic ring system having 4 to 10 ring-forming atoms, containing one to four hetero atoms (selected from N, 0, S) and obeying the Hiickel rule.
  • Representative examples are, but are not limited to, pyridine, pyrimidine, pyrazole, furan, thiophene, thiazole, pyrazine.
  • halogen as used in the present invention includes fluorine, chlorine, bromine and iodine unless specifically defined.
  • substitution on the benzene ring or the heterocyclic ring in the present invention means that it can occur at any position which is not substituted by hydrogen and other atoms.
  • 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.
  • the partial compound represented by the formula (I) or (II) of the present invention itself is in the form of a salt, such as when R 2 is a fluorenyl Halo r5
  • “Pharmaceutically acceptable salt” means that the compound of formula 0) 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, but not limited to, when R 2 is a fluorenyl group and is substituted with -NR 4 R 5 to form a pharmaceutically acceptable salt with a suitable acid.
  • the suitable acid may be a mineral acid or an organic acid.
  • Representative examples of pharmaceutically acceptable salts include, but are not limited to: hydrochloride, sulfate, hydrobromide, methanesulfonate, nitric acid, phosphate, acetate, oxalate, succinate, Tartrate, maleate, arginine, etc.
  • a pharmaceutically acceptable salt can be formed 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 crystallization solvent containing a different chemical amount and a compound represented by the formula ⁇ or (II) or a pharmaceutically acceptable salt thereof in all crystal forms are within the scope of the present invention.
  • Some of the compounds of the present invention have one or more chiral centers, such as, but not limited to, when w is a structure, and thus may exist as a racemate, a racemic mixture, an enantiomer, a diastereomer, Various forms such as diastereomeric mixtures. All such isomeric forms of the compounds of the formula (I) or (II) are within the scope of the invention.
  • a part of the compound represented by the formula ⁇ or (II) may exist in the form of a cis-trans isomer, such as but not limited to when R 1 is an alkenyl group, and thus one isomer and two cis-trans isomers Mixtures are all within the scope of the invention.
  • the compound represented by Formula 1 or (II) may have a rotamer due to the restriction of free rotation of a certain group, and thus a certain form of rotamer and a mixture of a plurality of rotamers are also Within the scope of the invention of this patent.
  • 'solvate' is used herein to describe a molecular complex comprising a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, such as ethanol.
  • solvent molecules such as ethanol.
  • 'hydrate' is used when the solvent is water.
  • T is preferably a five-membered aliphatic ring, or a benzene ring;
  • X is CH or N
  • T when T is a five-membered aliphatic ring, X is N; when T is a benzene ring, X is CH; Y is preferably a halogen atom-substituted benzene ring, more preferably a fluorine atom-substituted benzene ring, most Preferred is "4-fluorophenyl", "2,3-difluorophenyl";
  • R 1 is most preferably "(4-trifluoromethylbiphenyl-4-yl)methyl"
  • Methyl N- ⁇ 3-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[pyrimidin-1(5H>yl]methyl-4- Methyl (p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-5-yl ⁇ methylaminoacetate;
  • the compounds of the present invention are potent inhibitors of lipoprotein-associated phospholipase A 2 and are potentially useful for clinical treatment, particularly for the treatment and prevention of acute and chronic coronary heart disease, such as peripheral vascular and cerebrovascular atherosclerosis. This type of event is caused; that is, the present invention provides a compound of the formula (I) or ( ⁇ ) which can be used for clinical treatment.
  • the compound represented by the formula (I) or (II) 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. , high blood pressure, angina pectoris and ischemic reperfusion.
  • Lyso-PC lysophosphatidylcholine
  • the compounds of the formula (I) or (II) 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, These conditions also include ischemia, rheumatoid arthritis, stroke, brain inflammatory diseases (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 formula (I) or (II) of the present invention can be treated Applications in conditions associated with inflammatory cell activation, such as psoriasis and a variety of airway inflammatory diseases including asthma and chronic bronchitis.
  • the present invention provides formula (I) or (II) use of a compound represented by further treated by inhibition of Lp-PLA 2 enzyme activity of Lp-PLA 2 activation and associated diseases.
  • 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) or (II) of the present invention can also be used in combination with the following drugs in the treatment of the above diseases: hypolipidemic drugs, antiatherogenic drugs, hypoglycemic agents, anti-angina drugs, anti-inflammatory drugs Medicine, antihypertensive drugs or lipid-lowering proteins & drugs.
  • drugs for example, statins that inhibit cholesterol synthesis, antioxidants, probucol, insulin sensitizers, calcium channel antagonists, or non-steroidal anti-inflammatory drugs.
  • the compound of the formula (I) or (II) of the present invention can be used in combination with a cholesterol lowering drug such as a statin.
  • a cholesterol lowering drug such as a statin.
  • Statins are HMG-CoA reductase inhibitors such as atorvastatin, swastatin, pravastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, and the like. Both drugs can be taken at the same time or separately as recommended by your doctor.
  • the compound of the formula (I) or (II) of the present invention can be used in combination with a hypoglycemic agent or an insulin sensitizer.
  • the combined insulin sensitizer is preferably a PPAR-gamma 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) or (II), and a pharmaceutically acceptable adjuvant.
  • the pharmaceutically acceptable excipient is a pharmaceutically acceptable carrier, a sputum or a sustained release agent, and the like.
  • the compounds and pharmaceutical compositions provided herein may be in various forms, such as tablets, capsules, powders, troches, 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 safe or effective amount (e.g., 0.1 to 99.9% by weight, preferably 1 to 90 parts by weight) of the compound of the formula (I) or (II) or a pharmaceutically acceptable compound thereof. a salt; and a balance of a pharmaceutically acceptable excipient wherein the total weight of the composition is 100 parts by weight.
  • the pharmaceutical compositions of the present invention comprise from 0.1 to 99.9% by weight based on the total weight. /. a compound of the formula (I) or (II) or a pharmaceutically acceptable salt thereof, preferably from 1 to 90% by weight, based on the total weight; and the balance of a pharmaceutically acceptable excipient, wherein the group The total weight of the compound was 100% by weight.
  • a preferred ratio of the compound of the formula (I) or (II) to a pharmaceutically acceptable carrier, a scorpion or a sustained release agent is that the formula (I) as an active ingredient accounts for more than 60% by weight of the total weight, and the remainder is 0-% by weight. 40%, the amount of the remaining portion is preferably from 1 to 20%, most preferably from 1 to 10%.
  • the compound of the formula (I) or ( ⁇ ) or the pharmaceutical composition comprising the compound of the formula (I) or (II) may be used clinically in mammals, including humans and animals, and the route of administration may include oral, nasal inhalation. , transdermal absorption, pulmonary administration 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 filled or liquid 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 hydrazine.
  • 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 parenteral 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. Preparation
  • the compound of the present invention can be produced by the method shown in Reaction Scheme 1, 2, 3 or 4. Unless special
  • the compound of the formula (I) (i.e., compound 6) can be produced by the method shown in Reaction Scheme 1: wherein R 13 is C 1 .
  • the definition of thiol, T, X, Y, R 2 is the same as above;
  • Compound 1 can be purchased or prepared by methods known in the literature (e.g., WO03016287, WO03042206, the entire disclosure of which is incorporated herein by reference).
  • Amidation of compound 1 to form compound 2 one method of this process is that compound 1 firstly forms an acid chloride and then undergoes amination, the acylating reagent is thionyl chloride or oxalyl chloride, and the ammoniating reagent is a large excess of concentrated ammonia or ammonia.
  • reaction solvent includes aprotic solvent such as DCM, DCE, acetonitrile, THF; reaction temperature is between -15'C and O'C; and another method is direct reaction with inorganic ammonium salt in the presence of condensing agent
  • the condensing agent used includes dicyclohexylcarbodiimide (DCC), diethyl azodicarboxylate/triphenylphosphine, carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide hydrochloride/1-hydroxy-benzo-triazole (EDCI/HOBt), 0-(lH-benzotriazol-1-yl)-NNN', N'-tetramethyl Isourea boron tetrafluoride (TBTU) or the like; the inorganic ammonium salt such as ammonium chloride, ammonium carbonate, ammonium hydrogencarbonate or the
  • the compound 2 is dehydrated to form the compound 3;
  • the dehydrating agent is preferably trifluoroacetic anhydride or phosphorus oxychloride; optionally, an organic base such as pyridine or triethylamine is added to the reaction; and the reaction solvent includes an aprotic solvent such as DCM, DCE or THF. Most preferred are DCM, THF, and the reaction temperature is between -40 ° C and room temperature.
  • Compound 3 is reacted with hydroxylamine hydrochloride under the action of excess alkali to prepare compound 4;
  • the base used is an organic base or an inorganic base such as triethylamine, potassium carbonate, sodium hydroxide, etc.;
  • the reaction is carried out in a polar solvent such as methanol or ethanol. , DMF, water, etc. or a mixed solvent thereof;
  • the reaction temperature is from O'C to 60'C, preferably room temperature.
  • compound 4 Under the catalysis of boron trifluoride diethyl ether, compound 4 is reacted with one equivalent of R 2 CHO to form compound 5; boron trifluoride ether is used in an amount of more than 1 equivalent, usually 2 equivalents; and the reaction solvent is most usually diethyl ether or THF.
  • the temperature is between O'C and 40 'C, preferably room temperature.
  • the compound 5 is reacted with R 13 CH 2 CHO to obtain the compound 6 under the catalysis of boron trifluoride diethyl ether; the boron trifluoride ether is used in an amount of more than 1 equivalent, usually 2 equivalents; the reaction solvent is most usually diethyl ether or THF;
  • the reaction is carried out in the presence of a dehydrating agent, including a molecular sieve, toluene azeotrope, Si(OEt) 4, etc.; the reaction solvent includes methanol, ethanol, toluene, acetic acid, etc.; the reaction temperature is between O'C and 140 'C, preferably the reflux temperature of the solvent used.
  • a dehydrating agent including a molecular sieve, toluene azeotrope, Si(OEt) 4, etc.
  • the reaction solvent includes methanol, ethanol, toluene, acetic acid, etc.
  • the reaction temperature is between O'C and 140 'C, preferably the reflux temperature of the solvent used.
  • Compound 8 is condensed with isocyanate to form compound 9; the isocyanate includes Me 3 SiNCS, 0 0
  • Compound 9 is reacted with Y ⁇ Halo to form compound 10; more than one equivalent of an organic base or an inorganic base such as triethylamine, DBU, DIPEA, potassium carbonate, sodium carbonate or the like is added to the reaction; optionally, a catalyst such as potassium iodide or tetra is added.
  • the reaction solvent includes acetonitrile, acetone, DME, DCM, DCE, EA, ethanol, methanol, THF, etc.; the reaction temperature is from O'C to 80 'C, preferably the reflux temperature of the solvent used.
  • Compound 11 is prepared by the method described in Compound 9;
  • the compound 11 is co-heated with a large excess of aqueous formaldehyde solution to form the compound 12; the reaction is carried out in a pressure-tight container or a reflux condenser; the reaction is carried out without a solvent or in a dioxane; the reaction temperature is between 100' C to 160 ° C ; compound 12 is reacted with Y ⁇ Halo to form compound 14; reaction conditions are described with reference to the preparation of compound 10 from compound 9;
  • Reaction route 4 the compound of the formula (I) can be converted by a functional group to form another compound of the formula (I), and some examples of such functional group conversion are shown in Reaction Scheme 4. It is to be noted that these examples are only a part, but not all, of the conversion of the functional groups in the present invention, and thus do not limit the preparation method of the compound of the present invention in any way. Further examples of functional group transformations will be given in the preparation of the specific example compounds.
  • R 2 is a-hydroxy substituted indenyl
  • the compound of formula (I) is compound 15, wherein 1 15 is H, an indenyl group, R 16 is an indenyl group, and the fluorenyl group is optionally NR 4 R 5 or phenyl substituted, the phenyl group is optionally substituted by a halogen atom, R 13 is a fluorenyl group, L is NR 4 , 0 or 3, Z is CH, N or 0, T, X, Y, R 1 , R 4 , R 5 , R 6 , R 7 , R s have the same definitions as above;
  • Compound 15 is chlorinated to give compound 16; the chlorinating reagent is 30 1 2 or PC1 3 ; the reaction is carried out in a non-polar solvent such as DCM, DCE, CC, Et 2 0; the reaction temperature is between O'C and room temperature;
  • Compound 16 is reacted with R 1S LH under the action of a base to obtain compound 17;
  • the base used includes an inorganic base such as NaH, n-BuLi, KOBu-t, K 2 CO 3 or an organic base such as triethylamine, DIPEA, DBU or DMAP;
  • the reaction solvent is selected from THF, CH 3 CN, DME, DMF, EtOH, MeOH or HOBu-t depending on the base used; the reaction temperature is between -80 ° C and 80 ° C ;
  • Compound 15 is oxidized to compound 18; the reaction conditions are extensively described in the reference book, such as Comprehensive Org. Syn., Vol. 7, pp 251-327; in the present invention, the preferred oxidizing agent is activated manganese dioxide in an amount of at least a compound. 5 equivalents of 15; the reaction solvent is dioxane or chloroform; the temperature is between room temperature and 80'C, preferably 50-70 'C;
  • the reducing agent in the present invention is a borohydride such as NaBH 4 , NaBH 3 CN/TXOPr-i) 4 or NaBH(OAc) 3 ;
  • the reaction solvent includes DCM, DCE, THF, EtOH, MeOH, etc.; From 0 to 80'C, preferably at room temperature;
  • Compound 18 is condensed with H 2 NNR 4 R 5 in a suitable solvent to form compound 21;
  • the reaction solvent is DCM, DCE, THF, EtOH or MeOH; optionally, a water absorbing agent such as molecular sieve or anhydrous magnesium sulfate is added; 0 ° C to room temperature;
  • the compound i.e., compound 28
  • R 1 , R 2 are as defined above;
  • Compound 23 can be purchased or prepared by methods known in the literature. CTetrahedron Letters 2001, ⁇ 2, 315-317); Compound 23 is condensed with hydroxylamine hydrochloride under the action of a base to form compound 24; the base used includes an organic base or 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 O'C and 40'C ;
  • Compound 24 is chlorinated to the compound 25 by an equivalent amount of NCS;
  • the reaction solvent includes THF, DMF, etc.;
  • the reaction temperature is between O'C and 60 'C;
  • Compound 25 is dehydrochlorinated under the action of a base to form a dipolar ionic intermediate 26, and then
  • the base used is an organic base such as triethylamine, DIPEA or DBU;
  • the reaction solvent includes THF, DMF, etc.;
  • the reaction temperature is between -40 ° C and room temperature;
  • Compound 27 is decomposed by hydrazine hydrate to give compound 28; the reaction is carried out in a polar solvent such as THF, methanol or ethanol; the reaction temperature is from O'C to 80'C, preferably 50-60'C ;
  • Compound 29 reacts with DPPA under the action of a base to form compound 30;
  • the base used is an organic base such as triethylamine, DIPEA, DBU or DMAP, most preferably DBU and DMAP; and the reaction solvent includes THF, CH 3 CN, DME, etc. a non-protic solvent, most preferably THF;
  • the reaction temperature is between O'C and 100 'C, preferably the reflux temperature of the solvent used;
  • Compound 30 is subjected to hydrogenation reduction or Staudinger reaction (Gololobov, YG Sixty years of Staudinger reaction. Tetrahedron 1981, 37: 437) to obtain compound 7; the hydrogenation reduction catalyst is palladium on carbon, and the reaction is carried out in methanol, ethanol, EA or THF.
  • the temperature is between O'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 31 is condensed with a formic acid derivative under the action of a strong base to form compound 32, and then reduced by NaBH 4 to obtain compound 29;
  • the strong base includes n-BuLi, s-BuLi, LDA, NaHMDS, etc., preferably n-BuLi ; derivative of the acid such as DMF, methyl or ethyl; and the reaction solvent is THF; reaction temperature between -80 ° C to room temperature;
  • Compound 33 is co-heated with a large excess of aqueous formaldehyde to directly form compound 29, and the reaction conditions are referred to Compound 12 describes the preparation of compound 14;
  • the compound 34 is co-heated with a large excess of aqueous formaldehyde to directly form the compound 29, and the reaction conditions are as described with reference to the preparation of the compound 14 from the compound 12;
  • Compound 35 is condensed with a formic acid derivative under the action of a strong base to form compound 36, and then reduced by NaBH 4 to obtain compound 29;
  • the strong base includes n-BuLi, s-BuLi, LDA, NaHMDS, etc., and most preferably n-BuLi ;
  • the carboxylic acid derivatives such as DMF, ethyl or by methyl; and
  • the reaction solvent is THF; reaction temperature between -80 ° C to room temperature.
  • R 1 - NCS is condensed with '' -V and MHMH 2 to form compound 37;
  • the base used is an inorganic base such as potassium carbonate, sodium carbonate or sodium hydroxide;
  • the solvent is a strong polar protic solvent such as water or ethanol or The mixed solvent;
  • the reaction temperature is the reflux temperature of the solvent used.
  • the above intermediate compound 31 can be produced by the method shown in Reaction Scheme 8; wherein R 1 and R 2 are as defined above;
  • R is condensed with TosMIC to form compound 31; the base used includes NaH,
  • An inorganic base such as KOBu-t, K 2 C0 3 or Cs 2 C0 3 or an organic base such as pyridine, triethylamine, DIPEA or DBU, or Used directly as a base
  • the reaction solvent includes THF, CH 3 CN, DME, DMF, EtOH, MeOH, HOBu-t or a mixed solvent thereof
  • the reaction temperature is between 0 and 80 ° C ;
  • R ⁇ NH HCl and KSCN are first co-heated to form compound 39, and then oxidative desulfurization is used to prepare compound 31; the condensation reaction is carried out in acetonitrile or HOBu-t, and acetic acid or propionic acid is added, and the reaction temperature is between 50 and 100'.
  • C Oxidative Desulfurization Reaction Conditions The description of Compound 38 prepared from Compound 37 is referred to.
  • R 2 is the same as above;
  • Compound 41 is first oxidized to Compound 42 and the oxidizing conditions are preferably active manganese dioxide or Swern oxidation (AJ Mancuso, SL. Huang, D. Swern. J. Org. Chem., 1978, 43, 2480); The use of manganese dioxide is described with reference to the preparation of compound 18 from compound 15; the preferred reagent for Swern oxidation in the present invention is oxalyl chloride/DMSO/NEt 3 combination; compound 42 and HNR 4 R 5 are reacted by reductive amination to give compound 44, reaction Conditions are described with reference to the preparation of compound 19 from compound 18.
  • the oxidizing conditions are preferably active manganese dioxide or Swern oxidation (AJ Mancuso, SL. Huang, D. Swern. J. Org. Chem., 1978, 43, 2480); The use of manganese dioxide is described with reference to the preparation of compound 18 from compound 15; the preferred reagent for Swern oxidation in the present invention
  • the compound 41 is first chlorinated to the compound 43, and the reaction conditions are as described with reference to the preparation of the compound 16 from the compound 15; the compound 43 is condensed with HNR 4 R 5 under the action of a base to give a compound 44, the base used is triethylamine, DIPEA, DBU or potassium carbonate may be added with KI as a catalyst, a reaction solvent such as acetonitrile, DCM, DCE, THF or acetone, and the reaction temperature is from room temperature to 90 ° C, preferably the reflux temperature of the solvent used.
  • Trifluoromethanesulfonic anhydride (4.3 ml, 26 mmol, 1.3 eq.) was dissolved in 100 ml of dichloromethane, protected with nitrogen and placed in a -40 ° C low temperature reactor. Pyridine (2.5 ml, 30 mmol, 1.5 eq.) was added dropwise with a syringe. A precipitate appeared and stirred vigorously. Methyl p-hydroxyphenylacetate (3.32 g, 20 mmol, 1 equivalent) was dissolved in 40 ml of dichloromethane and added to the reaction flask using a syringe, and the addition was completed in 5 min.
  • the intermediate A5 (10 mmol) was suspended in 20 ml of dry THF, and then evaporated, evaporated, and evaporated. Reaction was continued to room temperature, quenched with saturated aqueous NaHC0 3. The EA was extracted twice, and the organic phase was combined, washed twice with brine, dried and purified by column chromatography.
  • the intermediate A10 was used as a raw material and prepared according to the method of A4. ⁇ -NMR (d 6 -DMSO, 300 MHz)
  • the intermediate A12 was used as a raw material and prepared according to the method of A6.
  • the intermediate A13 was used as a raw material, and it was prepared by the method of A7.
  • Example 8 —(E)-l-[5-n-heptyl-4-(l-n-octene)-4,5-dihydro-1,2,4-oxadiazol-3-yl]methyl -2-p-fluorobenzylthio-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one
  • the compound of Example 1 (1 eq.) and octanal (2 eq.) were placed in dry THF. Under a nitrogen atmosphere, a solution of boron trifluoride diethyl ether (3 eq.) was added, and the reaction was carried out at room temperature for 2 h, about half of the starting material was converted, and the reaction time was not increased.
  • Example 19 1_ ⁇ _(2-morpholineethyl)-5-(p-trifluoromethylbiphenyl-4-yl)-4,5-dihydro-l,2,4-oxadiazol-3-yl Lmethyl-2-(2,3-difluorobenzylthio)-6,7-dihydro-lH-cyclopentyl ⁇ d]pyrimidin-4(5H)-one
  • Example 20 1- ⁇ 4- ⁇ -(octyl-1-yl)-ethyl b-(p-trifluoromethylbiphenyl-4-yl)-4,5-dihydro-1,2,4 - oxadiazol-3-yl ⁇ methyl-2-(4-fluorobenzyl-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one
  • Example 21 4- ⁇ 3-[2-(2,3-difluorobenzylthio)-5,6-trimethylene-4-oxo-4H-pyrimidin-1-yl]methyl-5- ( Ethyl p-trifluoromethylbiphenyl-4-yl)-4,5-dihydro-1,2,4-oxadiazol-4-ylindazin-1-carboxylate
  • Example 22 —4- ⁇ 3-[2-(4-fluorobenzylthio)-5,6-trimethylene-4-oxo-4H-pyrimidin-1-yl]methyl 5-(p-trifluoro Ethyl methylbiphenyl-4-yl)-4,5-dihydro-1,2,4-oxadiazol-4-yl ⁇ -pyridin-1-carboxylate
  • Example 23 ——1- ⁇ 4-12-(cyclopropyl-1-yl)-ethyl 5-(p-trifluoromethylbiphenyl-4-yl)-4,5-dihydro-1,2,4 - umoxazol-3-yl ⁇ methyl-2-(2,3-di-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one
  • Example 46 fluorobenzyl bromide 6 ⁇ l was refluxed for 1.5 h in 1.5 ml of acetone, and most of the reaction was monitored by TLC. The reaction was stopped, and the solid was precipitated after standing in the refrigerator for a while, collected by filtration, and dried to obtain 10 mg of a white powder.
  • Example 48 1-[1-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-dimethylaminomethyl-1H-imidazol-2-yl]methyl-2-(4-fluorobenzyl) Thio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one-hydrochloride
  • Example 46 100 mg (1 equivalent) was dissolved in 1.5 ml of isopropanol, placed in an ice bath, 15 ⁇ l (about 1.1 equivalents) of concentrated hydrochloric acid was added, stirred for 20 min, 5 ml of diethyl ether was added, and the mixture was placed in a refrigerator to precipitate a white solid. , dried to 80mg.
  • Example 50 The compound of Example 50 was dissolved in 3 ml of ethanol in an ice bath, and 0.5 ml of a 10% aqueous NaOH solution was added thereto, followed by a reaction at room temperature for 2 hours, and the TLC detection was completed. 15 ml of ice water was added to the flask, and the H value was adjusted to 5-6 with concentrated hydrochloric acid, and the precipitate was collected by filtration and dried to yield 60 mg. !
  • Example 52 N,N-Dimethyl- ⁇ 2-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro- ff-cyclopenta[rf]pyrimidine -1(5H)-yl]methyl-1-(p-trifluoro-5-ylindolecarboxamide
  • Example 51 Compound 40mg, EDCI 18mg, HOBt 13mg, dimethylamine hydrochloride 8mg, DIPEA 17 ⁇ 1 was reacted in 5ml DCM for 4h at room temperature, washed twice with ammonium chloride saturated solution, dried anhydrous NaS0 4 to prepare TLC, 20mg White solid.
  • Example 54 1-[1-(p-Trifluoromethylbiphenyl-4-yl)methyl-1H-benzoimidazol-2-yl]methyl-2-(4-fluorobenzylthio)-5- (1-methyl-1H-pyrazole-4
  • 5-phenylbutyric acid (3.28 g, 20 mmol) was dissolved in 20 ml of anhydrous methanol, and 2 ml of concentrated sulfuric acid was added dropwise with stirring. There is an exotherm, then reflux for 4h, stop. Most of the solvent was distilled off under reduced pressure, and 30 ml of ice water was added to the residue, and neutralized with a 10% sodium hydroxide solution. 60 m of dichloromethane was extracted three times, and the organic phases were combined, dried over magnesium sulfate, and evaporated to dryness.
  • the drying tube was sealed with water vapor, and a flask containing 100 ml of THF was charged with 22.8 g (0.1 mol, 1 equivalent) of p-bromobenzylamine and 17.5 ml (3.3 equivalent) of triethylamine, and placed in an ice bath. Dissolved in 25ml THF is added dropwise 6ml (l eq.) CS 2, 3 0 minutes dropwise to give a white emulsion, then at room temperature for 1 hour. Then, 20.9 g (ll equivalent) of p-toluenesulfonyl chloride was added in portions in an ice bath.
  • the D14 and D15 synthesized above were refluxed in 200 ml of ethanol for 2 h, and a large amount of white precipitate appeared. Most of the ethanol was distilled off under reduced pressure, and 200 ml of water and 20.7 g (1.5 eq.) of potassium carbonate were added to the residue, followed by reflux for 1 h. After cooling, put it in an ice bath, adjust the pH value of hydrochloric acid to 8-9, and precipitate a large amount of white solid. If there is a yellow solid, add a small amount of methylene chloride and stir it. Collect it by filtration, wash it several times, and wash off the dichloromethane. The color, after drying, gave 25 g of a white solid.
  • Example 62 N-methyl, N- ⁇ 3-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[rf]pyrimidin-1 (5H )-yl 1 methyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-5-ylindole methylaminoacetate 120 mg intermediate D25 (1 equivalent), 4-fluorobenzyl bromide 28 ⁇ l (1.1 eq.), anhydrous potassium carbonate 55 mg (2 eq.) was refluxed in 3 ml of acetone for 1 h, and the reaction was completed.
  • the preparation method is the same as that of D15 except that "methyl butyrate” is used instead of "methyl hydroxyacetate”.
  • Example 65 I-Methyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-3-yl]methyl-2-(4- Fluorobenzylthio) - 5-(1-methyl-1H-pyrazol-4-yl)methyl-pyrimidin-4(1H)-one
  • Example 68 —1-[5-Cyclopropyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-ff-l,2,4-triazol-3-yl]methyl-2 -(4-fluorobenzylthio)-6,7-dihydro-1

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Abstract

L'invention propose des composés hétérocycliques azoles de la formule (I) ou de la formule (II), leurs procédés de préparation, leurs compositions pharmaceutiques et leur utilisation dans la préparation de médicaments pour traiter des maladies associées à l'enzyme Lp-PLA2, les définitions pour chaque substituant étant les mêmes que celles définies dans la description.
PCT/CN2011/076402 2011-06-27 2011-06-27 Composés hétérocycliques azoles, procédés de préparation, compositions pharmaceutiques et leurs utilisations Ceased WO2013000108A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
PCT/CN2011/076402 WO2013000108A1 (fr) 2011-06-27 2011-06-27 Composés hétérocycliques azoles, procédés de préparation, compositions pharmaceutiques et leurs utilisations
PCT/CN2012/000661 WO2013000267A1 (fr) 2011-06-27 2012-05-15 Composé hétérocyclique azole, procédé de préparation, composition pharmaceutique et utilisation
US14/129,199 US20140171431A1 (en) 2011-06-27 2012-05-15 Azole heterocyclic compound, preparation method, pharmaceutical composition and use
EP12804554.9A EP2725024A4 (fr) 2011-06-27 2012-05-15 Composé hétérocyclique azole, procédé de préparation, composition pharmaceutique et utilisation
CN201280030865.1A CN103619831B (zh) 2011-06-27 2012-05-15 唑类杂环化合物、其制备方法、药物组合物和用途

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103951620A (zh) * 2014-02-27 2014-07-30 江南大学 一种1-烷基-1h-咪唑-2-甲醛的合成方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000066567A1 (fr) * 1999-05-01 2000-11-09 Smithkline Beecham Plc Composes pyrimidinones
WO2000068208A1 (fr) * 1999-05-05 2000-11-16 Smithkline Beecham Plc Derives pyrimidinones destines au traitement de l'atherosclerose
WO2002030904A1 (fr) * 2000-10-10 2002-04-18 Smithkline Beecham P.L.C. Derives pyridinone permettant de traiter l'atherosclerose

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000066567A1 (fr) * 1999-05-01 2000-11-09 Smithkline Beecham Plc Composes pyrimidinones
WO2000068208A1 (fr) * 1999-05-05 2000-11-16 Smithkline Beecham Plc Derives pyrimidinones destines au traitement de l'atherosclerose
WO2002030904A1 (fr) * 2000-10-10 2002-04-18 Smithkline Beecham P.L.C. Derives pyridinone permettant de traiter l'atherosclerose

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103951620A (zh) * 2014-02-27 2014-07-30 江南大学 一种1-烷基-1h-咪唑-2-甲醛的合成方法

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