WO2022057930A1 - Composé de benzimidazole ayant un effet d'inhibition de lipase endothéliale, et utilisation - Google Patents

Composé de benzimidazole ayant un effet d'inhibition de lipase endothéliale, et utilisation Download PDF

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WO2022057930A1
WO2022057930A1 PCT/CN2021/119412 CN2021119412W WO2022057930A1 WO 2022057930 A1 WO2022057930 A1 WO 2022057930A1 CN 2021119412 W CN2021119412 W CN 2021119412W WO 2022057930 A1 WO2022057930 A1 WO 2022057930A1
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alkyl
aryl
compound
nmr
400mhz
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孙雅泉
张立洁
曹金明
杨康
李琛瑀
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盐城师范学院
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Definitions

  • the invention belongs to the technical field of medicine, in particular to a benzimidazole compound with endothelial lipase inhibitory effect and application thereof.
  • Cardiovascular disease is a common major health risk, and atherosclerosis is the leading cause of heart attack and stroke.
  • Atherosclerosis is a complex disease involving many cell types and molecular factors (Ross, R., Nature, 362(6423):801-809 (1993)).
  • Epidemiological studies have shown an inverse relationship between high-density protein (HDL) content and atherosclerosis risk, with HDL self-tissue transporting endogenous cholesterol to the liver and mediating selective cholesterol-producing tissue (Gordon, DJ et al. N.Eng.J.Med., 321(19):1311-1316(1989)).
  • HDL high-density protein
  • HDL metabolism is affected by several members of the phospholipase and triglyceride (TG) lipase protein family, which hydrolyze triglycerides, phospholipids (PL) and cholesterol lipids (CE) to generate fatty acids for intestinal absorption, energy produced or stored.
  • TG lipases lipoprotein lipase (LPL) affects the metabolism of HDL cholesterol by hydrolyzing triglycerides in triglyceride-rich lipoproteins, transferring lipids and lipoproteins to HDL, and is responsible for Hydrolysis of chylomicrons and very low density lipoproteins (VLDL) in muscle and adipose tissue.
  • VLDL very low density lipoproteins
  • Liver esterase hydrolyzes HDL triglycerides and phospholipids to generate smaller lipid-consuming HDL particles and plays a role in HDL cholesterol absorption (Jin, W. et al., Trends Endocrinol. Metab., 13(4). ): 174-178 (2002); Wong, H. et al., J. Lipid Res., 43: 993-999 (2002)).
  • Endothelial esterases also known as EDL, EL, LIPG, endothelial-derived lipases, and endothelial-derived lipases
  • EDL Endothelial esterase
  • EL endothelial-derived lipases
  • endothelial-derived lipases endothelial-derived lipases
  • endothelial lipase also exhibits in vitro triglyceride lipase activity and was found to hydrolyze HDL more efficiently than other lipoproteins (McCoy, MG et al. J. Lipid Res., 43: 921-929 (2002)).
  • Overexpression of the human endosebase gene in mouse liver significantly reduces HDL cholesterol and plasma concentrations of its major protein lipoprotein AI (apoA-I) (Jaye, M. et al. Nat. Genet., 21:424-428 (1999) )).
  • apoA-I major protein lipoprotein AI
  • the first object of the present invention is to provide a benzimidazole compound with endothelial lipase inhibitory effect and a tautomeric form and a physiologically tolerated salt thereof, wherein the structure of the benzimidazole compound is as shown in the general formula (I ) as shown:
  • R2 is selected from substituted aryl, arylalkyl, haloalkyl, wherein the substituent in substituted aryl is ortho- or meta-substituted halogen, C1-C8 alkyl, C3-C6 cycloalkyl, -ORc, nitro group in ortho position; or, if R3 is -C(O)RaRb, then R2 is selected from ortho, meta or para substituted aryl, ortho, meta Or para-substituted aromatic heterocyclic group, arylalkyl, haloalkyl, wherein the substituted aryl or the substituent in the aromatic heterocyclic ring is selected from halogen, C1-C8 alkyl, -ORc, nitro; R4, R5 , R6 are independently selected from H, -ORc, C1-C8 alkyl, cyano; R' is ortho, meta or para substituted H, halogen,
  • R2 is selected from unsubstituted or substituted aryl, unsubstituted or substituted aromatic heterocyclyl, C3-C6 cycloalkyl, -ORc, C2-C8 alkyl, arylalkyl, haloalkyl, Wherein the substituent in the substituted aryl or aromatic heterocyclic group is selected from ortho, meta or para substituted halogen, C1-C8 alkyl, ORc, nitro; R3 is H, -C(O)RaRb, -ORc, C1-C8 alkyl, C3-C6 cycloalkyl; R4, R5, R6 are independently selected from H, -ORc, C1-C8 alkyl, cyano; R' is H, halogen, -ORc, C1-C8 alkyl; R" is ortho, meta or para substituted H, halogen, -ORc, C1-C8 alkyl; n is 2-4;
  • R2 is selected from unsubstituted or substituted aryl, unsubstituted or substituted aromatic heterocyclyl, C3-C6 cycloalkyl, -ORc, C2-C8 alkyl, arylalkyl, haloalkyl, Wherein the substituent in the substituted aryl or aromatic heterocyclic group is selected from ortho, meta or para substituted halogen, C1-C8 alkyl, ORc, nitro; R3 is H, -C(O)RaRb, -ORc, C1-C8 alkyl, C3-C6 cycloalkyl; R4, R5, R6 are independently selected from H, -ORc, C1-C8 alkyl, cyano; R' is H, halogen, -ORc, C1-C8 alkyl; R"' is ortho, meta or para substituted H, halogen, -ORc, C1-C8 alkyl;
  • Ra and Rb are independently selected from H, C1-C4 alkyl, and Rc is H, C1-C8 alkyl.
  • the arylalkyl group is a C1-C8 alkyl group containing an unsubstituted or substituted aryl group; the substituents in the substituted aryl group are selected from ortho-, meta- or para-substituted Halogen, C1-C8 alkyl, ORc, nitro.
  • the aromatic heterocyclic ring in the aromatic heterocyclic group can be selected from thiophene, furan and pyridine.
  • the benzimidazole compounds are specifically selected as the following compounds:
  • Another object of the present invention is to provide the use of a benzimidazole compound and its tautomeric form and a physiologically tolerated salt thereof in the preparation of a drug for inhibiting endothelial lipase, wherein the structural formula of the benzimidazole compound is as follows: As shown in (I),
  • R1 is hydrogen, (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C1-C6)alkoxy, (C1-C6)-alkylene-aryl, (C1-C6) )-alkylene-heterocycle, (C1-C6)-alkylene-(C3-C12)-cycloalkyl, (C8-C14)-bicycle, in which aryl, heterocycle, cycloalkyl or dicycle
  • the ring may be mono- or polysubstituted by the following preferred groups: halogen, (C1-C6)-alkyl, (C1-C3)-alkoxy, hydroxyl, (C1-C6)-alkylmercapto, amino, ( C1-C6)-Alkyloxy, Di-(C2-C12)Alkylamino, Mono-(C1-C6)-Alkylaminocarbonyl, Di-(C2-C8)-Alkylhydr
  • R2 is -(C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C3)-haloalkoxy, (C1-C6)-alkyleneamino, di-(C2-C12) -Alkylamino, -CO-(C1-C6)-Alkyl, -COOR7, -CO-NR8R9, -O-CONR8R9, -O-CO-(C1-C6)-Alkylene-CO-O-( C1-C6)-alkyl, -O-CO-(C1-C6)-alkylene-CO-OH or -O-CO-(C1-C6)-alkylene-CO-NR8R9, aryl, hetero Ring, -(C2-C12) cycloalkyl; wherein aryl, heterocycle, cycloalkyl or bicycle may be mono- or polysubstituted by the following preferred groups: halogen, (C1-
  • R3, R4, R5, R6 are identically or differently hydrogen, (C1-C6)-alkyl, (C3-C12)-cycloalkyl, (C1-C4)-alkylene-aryl, (C1-C4 )-alkylene-(C3-C12)-cycloalkyl, halogen, (C1-C6)-alkyl, (C1-C3)-alkoxy, hydroxyl, (C1-C6)-alkylmercapto, amino , (C1-C6)-alkyloxy, di-(C2-C12) alkylamino, mono-(C1-C6)-alkylaminocarbonyl, di-(C2-C8)-alkylhydrocarbonyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkylcarbonyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, pentafluorothio, (C1-C6)-al
  • R7 is hydrogen, (C1-C10) alkyl, (C1-C4) alkylene-CN, (C1-C4) alkylene-aryl, (C1-C4)-alkylene-heterocycle, (C1 -C4)-alkylene-(C3-C12)-cycloalkyl, (C8-C14)-bicycle, wherein aryl, heterocycle, cycloalkyl or bicycle can be mono- or bicyclic by the following preferred groups Polysubstituted: Halogen, (C1-C6)-Alkyl, (C1-C6)-Alkoxy, Hydroxyl, (C1-C6)-Alkylmercapto, Amino, (C1-C6)-Alkylamino, Di- (C2-C12)-Alkylamino, Mono-(C1-C6)-Alkylaminocarbonyl, Di-(C2-C8)-Alkylaminocarbonyl, (C1-C6)
  • R8, R9 are identically or differently hydrogen, (C1-C6)-alkyl, aryl, (C3-C12)-cycloalkyl, (C1-C4)-alkylene-aryl, (C1-C4) -Alkylene-(C3-C12)-cycloalkyl.
  • the present invention relates to compounds of formula I in the form of their salts, solvates, racemates, racemic mixtures and pure enantiomers, as well as their diastereomers and mixtures thereof.
  • the alkyl or alkylene groups in substituents R1, R2, R3, R4, R5, R6, R7, R8 and R9 may be straight or branched.
  • Halogen is fluorine, chlorine, bromine or iodine, especially fluorine or chlorine.
  • haloalkyl is an alkyl mono-, poly- or fully substituted with halogen; preferred halogens are fluorine and chlorine.
  • a cycloalkyl group refers to a saturated or partially unsaturated (with one or two double bond) ring system containing one or more rings and containing only carbon atoms, such as cyclopropyl cyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl or adamantyl.
  • the cycloalkyl group may be mono- or polysubstituted by the following suitable groups, for example: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO ( C1-C6) alkyl, CONH2, CONH(C1-C6) alkyl, CON[(C1-C6) alkyl]2, cycloalkyl, (C1-C10) alkyl, (C2-C6)-alkene base, (C2-C6)-alkynyl, O-(C1-C6)-alkyl, O-CO-(C1-C6)-alkyl, O-CO-(C1-C6)-aryl, O- CO-(C1-C6)-heterocycle; PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S-(C1-C6)-alkane base, S-(CH
  • a bicyclic ring is a partially unsaturated bicyclic ring system having 8-14 ring atoms and having only carbon atoms as ring atoms.
  • This definition includes ring systems containing a fused benzene ring core. Examples which may be mentioned are tetrahydronaphthyl, ⁇ - or ⁇ -tetralone, indanyl or indan-1-one groups.
  • Preferred bicyclic groups are tetrahydronaphthyl and indanyl.
  • Bicyclic groups may be mono- or polysubstituted by suitable groups such as F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH (C1-C6)-Alkyl, CON[(C1-C6)-Alkyl]2, Cycloalkyl, (C1-C10)Alkyl, (C2-C6)-Alkenyl, (C2-C6)- Alkynyl, O-(C1-C6)-Alkyl, O-CO-(C1-C6)-Alkyl, O-CO-(C1-C6)-Aryl, O-CO-(C1-C6)- Heterocycle; PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S-(C1-C6)-alkyl, S-(CH2) n-aryl, S
  • aryl or heterocyclic group can be replaced by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2 up to two substituted; or by C(NH)(NH2), NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, NH-CO -(C1-C6)-Alkyl, NH-COO-(C1-C6)-Alkyl, NH-CO-Aryl, NH-CO-Heterocycle, NH-COO-Aryl, NH-COO-Heterocycle , NH-CO-NH-(C1-C6)-alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, N(C1-C6)-alkyl-CO-(C1-C6-
  • the aryl or heterocyclyl group can be represented by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2, NH(C1-C6)-Alkyl, N((C1-C6)- Alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2 mono-substituted to tri-substituted.
  • Aryl groups refer to phenyl or naphthyl groups.
  • Aryl groups may be mono- or polysubstituted by suitable groups such as F, C, Br, I, CF3, NO2, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1 -C6)-Alkyl, CON[(C1-C6)-Alkyl]2, (C3-C10)-Cycloalkyl, (C1-C10)-Alkyl, (C2-C6)-Alkenyl, ( C2-C6)-alkynyl, O-(C1-C6)-alkyl, O-CO-(C1-C6)-alkyl, O-CO-(C1-C6)-aryl; PO3H2, SO3H, SO2 -NH2, SO2NH(C1-C6)-alkyl, SO2N[((C1-C6)-alkyl]2, S-(C1-C6)-alkyl, S-(CH2)n-aryl, S- (CH2)n-hetero
  • aryl or heterocyclic group can be replaced by F, CI, Br, OH, CF3, NO2, CN, OCF3, O-((C1-C6)-alkyl, (C1-C6)-alkyl, NH2 Disubstituted at most; or by C(NHNH2), NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, NH-CO- (C1-C6)-Alkyl, NH-COO(C1-C6)-Alkyl, NH-CO-Aryl, NH-CO-Heterocycle, NH-COO-Aryl, NH-COO-Heterocycle, NH -CO-NH-((C1-C6)-alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, N(C1-C6)-alkyl-CO-((C1-
  • a heterocycle is a mono- or bicyclic ring system having 5-12 ring atoms, wherein at least one atom in the ring system is a heteroatom selected from N, O and S.
  • the definition also includes ring systems in which a heterocycle is fused to a benzene ring core.
  • (C5-C7)-heterocycle is a monocyclic ring system;
  • (C8-C12)-heterocycle is a bicyclic ring system.
  • Suitable "heterocycle” or “heterocyclic groups” are azacinyl, benzimidazolyl, benzofuranyl, benzothienyl, benzothienyl, benzoxyl, benzothiazolyl, benzene Triazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbazolyl, quinazolinyl, quinoline Linyl, 4H-quinazinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazine base, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furanyl, imidazolidinyl, imid
  • Peridyl represents 2-, 3- and 4-pyridyl.
  • Thienyl represents 2- and 3-thienyl.
  • Furyl represents 2- and 3-furyl.
  • N-oxides of these compounds such as 1-oxo-2-, -3 or -4-pyridyl heterocyclic or heterocyclic groups which may be mono- or polysubstituted by suitable groups such as: F, C1, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6) alkyl, CONH2, CONH(C1-C6) alkyl, CON[(C1-C6) alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O-(C1-C6)-alkyl, wherein one, more or All hydrogens can be replaced by fluorine; PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S-(C1-C6)-alkyl, S -(CH2)n-Phenyl, SO
  • suitable groups such as
  • Heteroaryl is a mono- or bicyclic aromatic ring system having 5 to 12 ring atoms, wherein at least one atom in the ring system is a heteroatom selected from N, O and S.
  • the definition also includes ring systems in which a heteroaryl group is fused to a benzene ring.
  • heteroaryl rings or “heteroaryl groups” are benzimidazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzotriazolyl , benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, furanyl, furanyl, imidazolyl, 1H-indazolyl, indolyl, 1,2,3- oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridine base, pyrrolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazole base and thienyl.
  • Heteroaryl rings or heteroaryl groups may be mono- or polysubstituted with suitable groups, such as: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)alkyl, CONH2 , CONH(C1-C6) alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-blockyl , O-(C1-C6)-alkyl, wherein one or more or all hydrogens in the alkyl can be replaced by fluorine; PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[ (C1-C6)-Alkyl]2, S-(C1-C6)-Alkyl, S-(CH2)n-Phenyl, SO-(C1-C6)-Alkyl, SO-(CH2)n- Pheny
  • the benzimidazole compounds that can be used to prepare endothelial lipase inhibitory drugs are specifically selected from the following compounds:
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of this invention are salts of inorganic acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, Salts of ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid and tartaric acid, suitable Salts of pharmaceutically acceptable bases are ammonium, alkali metal (eg sodium and potassium) and alkaline earth metal (eg magnesium and calcium) and tromethamine (2-amino-2-
  • suitable Salts of pharmaceutically acceptable bases are ammonium, alkali metal (eg sodium and potassium) and alkaline earth metal (eg magnesium and calcium) and trome
  • Salts with non-pharmaceutically acceptable anions such as trifluoroacetate are also within the scope of the present invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for non-therapeutic uses such as in vitro application.
  • physiologically functional derivative refers to any physiologically tolerable derivative of a compound of formula (I), such as an ester, which, when administered to a mammal such as a human, is capable of (directly or indirectly) ) to form a compound of formula I or an active metabolite thereof.
  • Physiologically functional derivatives also include prodrugs of the compounds of the present invention, eg, as described in H. Okada et al., Chem. Pharm, Bull. 1994, 42, 57-61. These prodrugs can be metabolized in vivo to form the compounds of the invention, and these prodrugs can themselves be active or inactive.
  • the compounds of the present invention may also exist in various polymorphic forms, such as amorphous, crystalline and polymorphic forms. All polymorphic forms of the compounds of the present invention are encompassed within the framework of the present invention and are a further aspect of the present invention
  • the compounds of the invention of general formula I have a surprising inhibitory effect on endothelial lipase (EL).
  • EL endothelial lipase
  • a preferred substrate for EL is HDL, which has anti-atherosclerotic activity, and a reduction in HDL levels leads to the progression of atherosclerosis and its sequelae, such as coronary heart disease, and in addition to the development of metabolic syndrome and its sequelae, diabetes mellitus.
  • inhibition of EL generally results in the prevention of atherosclerotic conditions and indirectly reduces the prevalence of the disease in populations at increased risk of diabetes.
  • the compounds of formula I have improved solubility in aqueous media and at least as high activity as compared to compounds of similar structure.
  • Preferred compounds of the present invention also have improved metabolic stability compared to compounds of the prior art.
  • the compounds of the present invention show advantages in serum stability.
  • the compounds of the present invention are particularly suitable for the treatment and/or prevention of the following diseases:
  • Dyslipidemia and its sequelae such as atherosclerosis, coronary heart disease, cerebrovascular disease, etc., especially (but not limited to) those conditions characterized by one or more of the following factors: high plasma triglyceride concentrations, high Postprandial plasma triglyceride concentration; low HDL cholesterol concentration; low apolipoprotein A concentration; high LDL cholesterol concentration; low density LDL cholesterol particles; high apolipoprotein B concentration;
  • metabolic syndrome Various other conditions that may be associated with metabolic syndrome, such as: obesity (overweight), including central obesity; thrombotic, hypercoagulable and prothrombotic stages (arterial and venous); hypertension; Heart failure, such as but not limited to heart failure following myocardial infarction, hypertensive heart disease, or cardiomyopathy; diabetes, especially type 2 diabetes, including prevention of its associated sequelae (hyperglycemia, glucose intolerance, pancreatic ⁇ -cell loss, macrovascular and microvascular disorders)
  • Atherosclerosis such as, but not limited to, coronary arteriosclerosis, including angina pectoris or myocardial infarction, stroke; restenosis or reocclusion of blood vessels; chronic inflammatory bowel disease diseases, such as Crohn's disease and ulcerative colitis; pancreatitis; other inflammatory states; retinopathy; adipocyte tumors; adipocyte carcinomas, such as liposarcoma; , liver, biliary and pancreatic cancers, endocrine tumors, lung, kidney and urinary tract, reproductive tract cancers, prostate cancer, etc.; acute and chronic myeloproliferative diseases and lymphomas; angiogenesis; neurodegenerative diseases; Alzheimer's disease multiple sclerosis; Parkinson's disease; erythrosquamous skin diseases such as psoriasis; acne vulgaris; other skin diseases and dermatological conditions modulated by PPARs; eczema and neuroderma
  • atherosclerosis such as, but not limited to, coronary arterio
  • a daily dose generally ranging from 0.3 mg to 100 mg (usually 3 mg- 50 mg)/day/kg body weight, eg 3-10 mg/kg/day.
  • Intravenous doses may be, for example, 0.3 mg-1.0 mg/kg, which may suitably be used as an infusion of 10 ng-100 ng/kg/minute, and suitable infusion solutions for these purposes may contain, for example, 0.1 ng-10 mg per milliliter, Usually 1 ng-10 mg, a single dose may contain eg 1 mg-10 g of the active ingredient.
  • ampoules for injection may contain, for example, 1 mg-100 mg
  • single-dose formulations, such as tablets or capsules, which may be administered orally may contain, for example, 0.05-1000 mg, usually 0.5-600 g.
  • the compounds of the present invention can be used in the form of compounds of formula I for the treatment of the above-mentioned conditions, but they are preferably in the form of pharmaceutical combinations with a pharmaceutically acceptable carrier, which of course must be pharmaceutically acceptable, that is to say in combination with .
  • the carrier must of course be pharmaceutically acceptable, that is to say compatible with the other ingredients of the composition and not harmful to the patient's health.
  • Carriers can be solid, liquid and colloids, preferably with the compound formulated in a single dose, eg, as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient.
  • Other pharmaceutically active substances, including other compounds of the present invention may also be present.
  • the pharmaceutical compositions of the present invention can be prepared by one of the known methods of pharmacy, which essentially involve admixing the ingredients with pharmaceutically acceptable carriers and/or excipients.
  • oral eg sublingual
  • parenteral eg subcutaneous, intramuscular, intradermal or intravenous
  • Coated formulations and coated sustained release formulations are also encompassed within the scope of the present invention.
  • Acid- and gastric-resistant formulations are preferred.
  • Suitable gastro-resistant coatings include cellulose phthalate.
  • a tablet may be prepared by compressing or molding a powder or granules of the compound, optionally with one or more other ingredients.
  • Compressed tablets may be prepared by mixing the compound in a free-flowing form such as a powder or granules, optionally with binders, glidants, inert diluents and/or one (or more) surface active/dispersing agent(s) in a suitable It is prepared by mixing and tableting in a machine. Molded tablets may be made by molding in a suitable machine the powdered compound moistened with an inert liquid diluent.
  • compositions suitable for oral (sublingual) administration include lozenges containing a compound of formula I with a flavoring agent (usually sucrose) and acacia or tragacanth, and in an inert base such as gelatin and glycerol or sucrose. and gum arabic) containing pastilles of the compounds.
  • a flavoring agent usually sucrose
  • acacia or tragacanth in an inert base
  • an inert base such as gelatin and glycerol or sucrose. and gum arabic
  • compositions suitable for parenteral administration preferably comprise sterile aqueous preparations of the compounds of formula I, preferably in the blood of the target lover, etc. These preparations are preferably administered intravenously, but may also be administered by subcutaneous, intramuscular or intradermal injection
  • these formulations can preferably be prepared by mixing the compound with water and sterilizing the resulting solution with blood and the like.
  • the injectable compositions of the present invention generally contain 0.1 to 5% by weight of the active compound.
  • compositions suitable for rectal administration are preferably in the form of single-dose suppositories.
  • Such formulations may be prepared by admixing a compound of formula I with one or more conventional solid carriers such as cocoa butter and shaping the resulting mixture.
  • Suitable pharmaceutical compositions for topical application to the skin are preferably in the form of ointments, creams, lotions, pastes, sprays, aerosols or oils.
  • Useful carriers include petroleum ether, lanolin, polyethylene glycols, alcohols, and combinations of two or more of these.
  • the active ingredient is generally present at a concentration of 0.1-15% by weight, eg, 0.5-2%, by weight of the composition.
  • compositions suitable for transdermal administration may be in the form of a single patch suitable for prolonged intimate contact with the epidermis of a patient.
  • patches suitably contain the active ingredient in an optionally buffered aqueous solution dissolved and/or dispersed in an adhesive or dispersed in a polymer.
  • Suitable active ingredient concentrations are from about 1% to 35%, preferably 3% to 15%.
  • Particular means of releasing the active ingredient may be by electrotransport or iontophoresis, eg as described in Pharmaceutical Research, 2(6):318 (1986).
  • the compounds of the present invention may be administered alone or in combination with one or more other pharmacologically active active ingredients.
  • the compounds of the present invention can be administered together with active ingredients having pharmacological effects similar thereto.
  • active ingredients having pharmacological effects similar thereto are: blood sugar-lowering drugs, antidiabetic drugs, active ingredients for the treatment of dyslipidemia, anti-atherosclerotic drugs, anti-obesity drugs, anti-inflammatory active ingredients, active ingredients for the treatment of malignant tumors , antithrombotic active ingredients, active ingredients in the treatment of hypertension, active ingredients in the treatment of heart failure, active ingredients in the treatment and/prevention of complications caused by or related to diabetes, active ingredients in the treatment of neurodegenerative diseases, treatment of central Active ingredients for neurological disorders, active ingredients for the treatment of drug dependence, nicotine and alcohol dependence, analgesics.
  • the combination of active ingredients can be administered to the patient by administering the active ingredients separately or as a combination product in which the active ingredients are coexisted in one pharmaceutical formulation.
  • the active ingredients preferably include: sulfonylureas; biguanides; meglitinides; oxadiazolidinediones; thiazolidinediones; glucosidase inhibitors; glycogen phosphorylase inhibitors; Glucagon antagonist; glucokinase agonist; fructose-1,6-bisphosphatase inhibitor.
  • the general formula 1 can be synthesized by the following method, and all chemical raw materials can be purchased through commercial channels.
  • the synthetic method includes the following routes:
  • Or method 2 generate polysubstituted benzimidazoles by reacting 1H benzimidazole with R1X:
  • Or method four the reaction of o-amino-substituted aniline and carbonyl compound generates polysubstituted benzimidazole.
  • the corresponding o-amino-substituted aniline can be prepared by the reaction of o-nitro compounds and different amines according to the literature method to obtain the o-nitro-substituted aniline, and then reduced by the literature method to obtain the o-amino-substituted aniline:
  • the second method is to prepare benzimidazole derivatives by reacting o-phenylenediamine with carboxylic acid.
  • the fourth method is to generate polysubstituted benzimidazole by reacting o-nitro-substituted aniline with aldehyde.
  • phospholipase specific substrate 12- (4,4-difluoro5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-deca Monoacyl)-sn-glycero-3-phosphocholine (manufacturer Molecular Probes) to define the enzymatic activity and inhibitory effect of endothelial lipase.
  • Enzymatic hydrolysis of the A1 ester bond of this phospholipid releases the fluorescent dye Bodipy-labeled fatty acids, which can be detected after separation by thin-layer chromatography on TLC plates (silica gel 60, Merck), or directly in the reaction vessel by measuring fluorescence test.
  • the decrease in enzyme activity was a function of the concentration of inhibitor used.
  • the inhibitor concentration at which half of the maximal enzyme activity observed is referred to as the IC50.
  • the IC50 values of the compounds of each example are shown in Table 1:
  • Solubility in aqueous systems can be tested by different methods. Examples of suitable dissolution precipitation methods ("kinetic solubility”) and methods for studying the dissolution of solid samples until equilibrium (“thermodynamic solubility”) are established.
  • a solution of the test compound in DMSO (2.5 mM; 0.5 ⁇ l) was transferred to 200 uL of an aqueous assay solution (eg, phosphate buffered saline, 10x, 1 M, Sigma, adjusted to 10 mM, pH 7.4) in a 96-well titer plate, The turbidity was also measured with a turbidimeter (eg Nephelostar Galaxy, BMG Labtech) at the resulting theoretical concentration of the test compound of 6.25 uM.
  • the test compound concentration in the aqueous test solution was then increased to 12.5 ⁇ M by further addition of DMSO solution (2.5 mM; 0.5 ⁇ L), and the turbidity measurement was repeated.
  • DMSO solution (1uL, 2.5mM; 0.5 ⁇ L, 10mM; then 9 ⁇ 1 ⁇ L, 10mM; then 9 ⁇ 1 ⁇ L, 10mM was added between the completion of the two detection processes to obtain theoretical concentrations of 25 ⁇ M, 50 ⁇ M, 100uM, 150 ⁇ M, 200 ⁇ M, 250 ⁇ M, 300 ⁇ M, 350 ⁇ M, 400uM , 450uM and 500 ⁇ M and check for turbidity.
  • the turbidity value from the turbidimeter is plotted against the theoretical concentration of the test compound in the aqueous test solution. Once significant turbidity was detected at the theoretical concentration (eg, 5 times the control value for an aqueous test solution), the following concentration levels were used as solubility limits for the compounds to be tested in solution. Therefore, the maximum possible detection range is shown as values ⁇ 625uM, 6.25-500 ⁇ M and >500uM.
  • Preferred benzimidazoles exhibit a kinetic solubility in phosphate buffer (pH 7.4) of at least 12.5 ⁇ M; more preferably at least 50 ⁇ M, even more preferably at least 250 ⁇ M.
  • the overall UV absorbance obtained from the HPLC UV detector for serial dilutions of the test compound (500uM, 100uM, 50uM, 10uM and 1uM) in DMSO showed a linear correlation with concentration as a calibration line.
  • the test compound (500 ug) was shaken together with the aqueous test solution (250 uL) in a sealed vial (capacity: 1.5 mL) for 16 hours (Eppendorf thermoshaker, 1400 rpm, 25°C, covered and protected from light). The samples were then centrifuged at maximum speed and the supernatant was finally filtered. A sample of the filtered supernatant was directly analyzed with an HPLC UV detector (see above). Another sample was analyzed after dilution (1 vol of supernatant, 39 vol of test solution).
  • the concentration of the test compound in the undiluted supernatant was calculated from the bulk UV absorbance obtained for the supernatant samples according to the established calibration line and expressed as the solubility of the test compound in the respective aqueous test solutions.
  • aqueous test solutions are deionized water or aqueous phosphate buffers with various pH values (eg pH 1.2; pH 4.0; pH 6.8; pH 7.4; pH 9.0), which can be obtained from commercial solutions (Phosphate Buffered Saline, 10x, Sigma) was prepared by dilution and adjustment with phosphoric acid or sodium hydroxide solutions according to standard methods.
  • Preferred compounds of the invention exhibit solubility in phosphate buffer (pH 7.4) of at least 12.5 ⁇ M; more preferably at least 50 ⁇ M, even more preferably at least 250 ⁇ M.

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Abstract

La présente invention relève du domaine technique des médicaments. L'invention concerne un composé de benzimidazole ayant un effet d'inhibition de lipase endothéliale, et une utilisation. Le composé de benzimidazole selon la présente invention a un excellent effet d'inhibition sur la lipase endothéliale, peut traiter de manière efficace l'athérosclérose et les séquelles de celle-ci, telles que la coronaropathie, et favorise également le traitement du syndrome métabolique et des séquelles de celui-ci, tels que le diabète. Le composé de benzimidazole selon la présente invention a une bonne solubilité dans un milieu aqueux, une bonne activité biologique et une bonne stabilité métabolique, et a un avantage en ce qui concerne la stabilité du sérum.
PCT/CN2021/119412 2020-09-21 2021-09-18 Composé de benzimidazole ayant un effet d'inhibition de lipase endothéliale, et utilisation WO2022057930A1 (fr)

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