WO2008119238A1 - Composés hétérocycliques substitués à cinq éléments, leur méthode de préparation et leur utilisation en médecine - Google Patents

Composés hétérocycliques substitués à cinq éléments, leur méthode de préparation et leur utilisation en médecine Download PDF

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WO2008119238A1
WO2008119238A1 PCT/CN2008/000513 CN2008000513W WO2008119238A1 WO 2008119238 A1 WO2008119238 A1 WO 2008119238A1 CN 2008000513 W CN2008000513 W CN 2008000513W WO 2008119238 A1 WO2008119238 A1 WO 2008119238A1
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group
alkoxy
alkyl
halogen atom
hydroxy
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Chinese (zh)
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Mingwei Wang
Qing Liu
Lilin Lin
Yueyun Zhang
Ling Zhou
Meiling Sun
Haoran Su
Yulin Hua
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Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
The National Center For Drug Screening
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/96—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/36—One oxygen atom
    • C07D263/40—One oxygen atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/46—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/54—Nitrogen and either oxygen or sulfur atoms

Definitions

  • the present invention relates to a class of substituted five-membered heterocyclic compounds and as a modulator of Glucagon-like peptide-1 receptor (GLP-1R) for the prevention and/or treatment of metabolic diseases ( Including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases [such as "Alzheimer's Disease” (AD), also known as Alzheimer's dementia] Medical use. BACKGROUND OF THE INVENTION Disorders of glucose metabolism, especially diabetes, have become a major disease that threatens human health and life in modern society. It is predicted that diabetes patients worldwide are increasing at a rate of 6% per year. By the end of 2006, there were 320 million patients (60 million in China, ranking second).
  • Diabetes is a group of clinical syndromes caused by the interaction of genetic and environmental factors. It is mainly divided into type 1 and type 2.
  • the basic pathophysiology of type 1 diabetes is absolute insulin secretion, and clinical treatment is mainly supplemented with insulin. It is also known as insulin-dependent diabetes.
  • Type 2 diabetes accounts for more than 95% of the diseased population. Clinical studies have found that most patients with type 2 diabetes can synthesize normal or even excess insulin, but the sensitivity of target cells to insulin is reduced (also known as "insulin resistance”), resulting in Relatively insufficient insulin, also known as non-insulin dependent diabetes. Insulin resistance is a key factor in the development and progression of type 2 diabetes.
  • Therapeutic drugs for type 2 diabetes include sulfonylureas, biguanides, other insulin sensitizers, and ancillary measures.
  • sulfonylurea hypoglycemic agent binds to the receptor of the pancreatic ⁇ -cell membrane, the potassium channel is blocked, and the potassium ion efflux is blocked, which leads to depolarization of the cell membrane, promotes the opening of the Ca 2+ channel, and causes extracellular calcium influx, intracellular.
  • the calcium ion concentration is increased, the release of insulin is triggered.
  • the biguanide hypoglycemic agent can suppress appetite, increase the binding of insulin to the receptor, promote the anaerobic glycolysis of glucose, inhibit tissue respiration, and inhibit hepatic gluconeogenesis. Mainly there are metformin, phenformin and butyl bismuth.
  • Other hypoglycemic agents mainly include thiazolidinediones
  • glucagon-like peptide-1 receptor belongs to the g-type coupled G protein-coupled receptor (GPCR).
  • GLP-1 gutagon-like peptide-1
  • the gutagon-like peptide-1 (GLP-1) released by the enteroendocrine cells is activated by highly specific binding to GLP-1R. It stimulates insulin secretion, inhibits the production of glucagon, and lowers postprandial blood glucose and maintains it at a constant level. Under physiological conditions, the effect of GLP-1 on insulin secretion is dependent on blood glucose concentration, and hypoglycemia does not occur due to sustained secretion. GLP-1 also promotes the proliferation and differentiation of beta cells, as well as neuromodulation, delays gastric emptying, and reduces appetite. In vitro, GLP-1 promotes the differentiation of embryonic stem cells into beta-like cells with insulin secretion (J Endocrinol.
  • GLP-1 acts on the central nervous system to promote cell survival and reduce apoptosis, reduce the neurotoxicity of ⁇ -amyloid peptide, inhibit the progression of neurodegenerative diseases, and promote learning and memory. Therefore, GLP-1 has recently been proposed for Alzheimer's disease. Treatment ( Ann N YAcad Sci, 2004, 1035: 290-315; Nat Med, 2003, 9: 1173-1179; Curr Alzheimer Res, 2005, 2: 377-385; J Pharmacol Exp Ther, 2002, 302: 881- 888). In addition, GLP-1 also plays an important role in the cardiovascular system. It has the effect of lowering blood pressure and dilating blood vessels.
  • GLP-1 can improve left ventricular systolic function in cardiac hypertrophy experiments. It also reduces myocardial cell damage in the presence of myocardial ischemia and reperfusion (J. Hypertens, 2003, 21: 1125-1135; Am J Physiol Endocrinol Metab, 2004, 287: E1209-E1215; Circulation, 2004, 110: 955-961; Diabetes, 2005, 54: 146-151). Due to the above-mentioned clear physiological effects, since the discovery of this target in the mid-1980s, the search for small molecule agonists of GLP-1R has been a research hotspot of many new drug development institutions in the world.
  • GLP-1 drugs such as the GLP-1 derivative developed by Danovo Nordisk, Denmark (trade name Liraglutide; entering Phase III clinical trials) and Amylin Pharmaceuticals and Eli Lilly and Company
  • GLP-1 analogue Exendin-4 trade name Exenatide; was approved for marketing in April 2005.
  • GLP-1 and its peptide analogs there are no reports of successful use of non-peptide small molecule GLP-1R agonists for clinical treatment. Due to the inconvenient oral administration of peptide drugs, the search for non-peptide GLP-1R modulators and the development of new anti-diabetic drugs with independent intellectual property rights are the common concerns of many new drug research institutions.
  • the object of the present invention is to provide a substituted five-membered heterocyclic compound represented by the following general formula and a pharmaceutically acceptable salt, ester, solvate, metal complex thereof or prodrug having the same pharmacological action
  • Another object of the present invention is to provide a pharmaceutical composition comprising a compound represented by the following formula or a pharmaceutically acceptable salt, ester, solvate or metal complex thereof;
  • metabolic diseases including but not Limited to diabetes, insulin resistance and obesity
  • cardiovascular disease and neurodegenerative diseases such as "Alzheimer's Disease (AD), also known as Alzheimer's dementia].
  • the present invention provides a glucagon-like peptide-1 receptor modulator, which increases the prevention and/or treatment of metabolic diseases (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases [eg Alzheimer's Disease (AD), also known as Alzheimer's dementia, is a member of the drug.
  • the present invention relates to a substituted five-membered heterocyclic compound represented by the following formula, or a pharmaceutically acceptable salt, ester, solvate, metal complex thereof or prodrug having the same pharmacological action:
  • the compounds include all geometric isomers thereof.
  • Z is CH, N
  • dC 6 alkyl include a halogen atom-containing, c r c 6 alkoxy or hydroxy, including any one, two or three substituents of c r c 6 alkyl; c 3 -c 6 cycloalkyl group; a halogen atom include containing, c r c 6 alkyl, c r c 6 alkoxy or hydroxy, including any one, two or three substituents of C 3 -C 6 cycloalkyl group; a phenyl group; comprising include a halogen atom, dC 6 alkyl, alkoxy or hydroxy dC 6 including any one, two or three substituted phenyl; benzyl;
  • R 2 , R 3 are a substituted or unsubstituted phenyl group; a substituted or unsubstituted pyridyl group; a substituted or unsubstituted furyl group; a substituted or unsubstituted pyranyl group; a substituted or unsubstituted thienyl group; Substituted pyrrolyl; substituted or unsubstituted indenyl; or substituted or unsubstituted naphthyl;
  • R 4 is any of the following substituent groups: H; a cyano group; sulfonylamino group; a hydroxyl group; a mercapto group; a halogen; acid; carboxylate; dC 6 alkyl; include a halogen atom-containing, dC 1-6 alkoxy group any hydroxy or including one, two or three substituents of C r C 6 alkyl group; a C r C 1-6 alkoxy group; a halogen atom-containing include, dC 6 alkyl group, an alkoxy group having 6 or dC a hydroxyl group, including any one, two or three alkoxy substituted dC 6; dC 6 alkylmercapto; contain any halogen atoms include, dc 6 alkyl, alkoxy or hydroxy dC including 6 One, two or three substituted ( ⁇ -0; alkylalkyl; C 2 -C 6 alkenyl; containing an alkyl
  • R 13 and R 14 are any one of the following substituents: H; cyano; sulfonylamino; hydroxy; fluorenyl; halogen; carboxylic acid; carboxylic acid ester; dC 6 alkyl; containing halogen atom, C r C any of the 6 alkoxy or hydroxy, including one, two or three substituents of C r C 6 alkyl group; a C r C 1-6 alkoxy group; a halogen atom-containing include, dC alkyl, C r 6 of any C 6 alkoxy or hydroxy, including one, two or three alkoxy substituted dC 6; dC 6 alkylmercapto; include a halogen atom-containing, dC 6 alkyl, C 6 R & lt C Any one, two or three substituted dC 6 alkyl fluorenyl groups such as alkoxy or hydroxy; C 2 -C 6 alkenyl; alkoxy group
  • R 15 and R 16 are each independently a substituent of any of the following: H; cyano; sulfonylamino; hydroxy; fluorenyl; halogen; carboxylic acid; carboxylic acid ester; dC 6 alkyl; containing halogen atom, dC any of the 6 alkoxy or hydroxy, including one, two or three substituents of C r C 6 alkyl; dC 1-6 alkoxy group; a halogen atom include alkyl containing, dC 6 alkyl, dC 6 alkoxy or hydroxy, including any one, two or three substituents dC 6 alkoxy; dC 6 alkylmercapto; include a halogen atom-containing, dC 6 alkyl, C r C 1-6 alkoxy group or Any one, two or three substituted dC 6 alkyl fluorenyl groups such as a hydroxyl group; a C 2 -C 6 alkenyl group
  • a C 2 -C 6 alkenyloxy group any one or two containing a halogen atom, a carboxyl group, a carboxylate group, a cyano group, an alkyl group of dC 6 , an alkoxy group of c r c 6 or a hydroxyl group; substituted three c 2 -c 6 alkenyl group; a C 2 -C 6 alkynyl group; the alkyl group include a halogen atom-containing, carboxyl, carboxylic ester group, a cyano group, 6 dC, dC 6 alkoxy Any one, two or three substituted c 2 -c 6 alkynyloxy groups including a hydroxy group; a benzyloxy group; an alkoxy group having a halogen atom, dC 6 , an alkoxy group or a hydroxyl group of dC 6 Any one, two or three substituted benzyloxy groups; phenoxy group;
  • R 4 is any of the following substituent groups: H; a cyano group; sulfonylamino group; a hydroxyl group; a mercapto group; a halogen; acid; carboxylate; dC 6 alkyl; include a halogen atom-containing, dC 1-6 alkoxy group any hydroxy or including one, two or three substituents of C r C 6 alkyl group; a C r C 1-6 alkoxy group; a halogen atom-containing include, dC 6 alkyl group, an alkoxy group having 6 or dC a hydroxyl
  • R 3 is: Wherein R 8 , R 9 and R 10 are any one of the following substituents: H; cyano; sulfonylamino; nitro; hydroxy; fluorenyl; halogen; dC 6 alkyl; containing halogen atom, C r C 6 any alkoxy or hydroxy, including one, two or three substituents of C r C 6 alkyl group; a C r C 1-6 alkoxy group; a halogen atom-containing comprising, a carboxyl group, a carboxylic acid ester group, a cyano group any dC alkyl, C r C 6 alkoxy or hydroxy 6 including one, two or three substituents of C r C 1-6 alkoxy group; a mercapto group C r C 6 alkyl; include halogen-containing atom, a carboxyl group, a carboxylic acid ester group, a cyano group, dC 6 alkyl, alk
  • R 2 is: Wherein R 13 and R 14 are any one of the following substituents: H; cyano; sulfonylamino; hydroxy; fluorenyl; halogen; carboxylic acid; carboxylic acid ester; dC 6 alkyl; containing halogen atom, C r C any of the 6 alkoxy or hydroxy, including one, two or three substituents of C r C 6 alkyl group; a C r C 1-6 alkoxy group; a halogen atom-containing include, dC alkyl, C r 6 of any C 6 alkoxy or hydroxy, including one, two or three alkoxy substituted dC 6; dC 6 alkylmercapto; include a halogen atom-containing, dC 6 alkyl, C 6 R & lt C alkoxy or hydroxy, including any one, two or three substituents of dC 6 alkylmercapto; dC 6 alkanoyloxy
  • R 3 is: Wherein R 8 , R 9 and R 10 are any one of the following substituents: H; cyano; sulfonylamino; nitro; hydroxy; fluorenyl; halogen; dC 6 alkyl; containing halogen atom, C r C 6 any alkoxy or hydroxy, including one, two or three substituents of C r C 6 alkyl group; a C r C 1-6 alkoxy group; a halogen atom-containing comprising, a carboxyl group, a carboxylic acid ester group, a cyano group any dC alkyl, C r C 6 alkoxy or hydroxy 6 including one, two or three substituents of C r C 1-6 alkoxy group; a mercapto group C r C 6 alkyl; include halogen-containing atom, a carboxyl group, a carboxylic acid ester group, a cyano group, dC 6 alkyl, alk
  • such a compound or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, either alone or in combination with a pharmaceutically acceptable carrier or excipient.
  • the invention also provides a medicament comprising the above compound for preventing and/or treating metabolic diseases (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases [eg "Alzheimer's Disease, AD", also known as Alzheimer's disease (Alzheimer's dementia)].
  • the invention relates to the prevention and/or treatment of metabolic diseases (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases [eg "Alzheimer's disease,”(Alzheimer's) Disease, AD), also known as Alzheimer's dementia, etc.
  • This method involves administering an effective amount of a selective, glucagon-like peptide to a subject in need or willingness to receive treatment or prevention.
  • a compound of a receptor or a pharmaceutically acceptable salt thereof for preventing or treating the above-mentioned diseases or symptoms.
  • the above-mentioned metabolic disorder disease including but not limited to diabetes, insulin resistance and obesity
  • cardiovascular diseases and neurodegenerative diseases eg "Alzheimer's disease,"(Alzheimer's) Disease, AD
  • a compound of a receptor or a pharmaceutically acceptable salt thereof for preventing or treating the above-mentioned diseases or symptoms.
  • the above-mentioned metabolic disorder disease including but not limited to diabetes, insulin resistance and obesity
  • Alzheimer's disease including but not limited to diabetes, insulin resistance and obesity, cardiovascular disease and neurodegenerative diseases [eg "Alzheimer's Disease” (Alzheimer's Disease, AD), also known as Alzheimer's disease
  • the compounds include all geometric isomers thereof.
  • Z is CH, N
  • dC 6 alkyl include a halogen atom-containing, c r c 6 alkoxy or hydroxy, including any one, two or three substituents of c r c 6 alkyl; c 3 -c 6 cycloalkyl group; a halogen atom include containing, c r c 6 alkyl, c r c 6 alkoxy or hydroxy, including any one, two or three substituents of C 3 -C 6 cycloalkyl group; a phenyl group; comprising include a halogen atom, dC 6 alkyl, alkoxy or hydroxy dC 6 including any one, two or three substituted phenyl; benzyl; R 2 , R 3 are a substituted or unsubstituted phenyl group; a substituted or unsubstituted pyridyl group; a substituted or unsubstituted furyl group; a substituted or unsubsti
  • the present invention relates to a combination preparation comprising a compound having a selective modulation of a glucagon-like peptide-1 receptor, particularly a function of activating the receptor, or a pharmaceutically acceptable salt thereof Or alone or in combination with a pharmaceutically acceptable carrier or excipient.
  • This compound has the structure of the following general formula:
  • a pharmacological prodrug, an ester thereof, a solvate thereof or a metal complex thereof where X is 0, S or NH;
  • Z is CH, N
  • dC 6 alkyl include a halogen atom-containing, c r c 6 alkoxy or hydroxy, including any one, two or three substituents of c r c 6 alkyl; c 3 -c 6 cycloalkyl group; a halogen atom include containing, c r c 6 alkyl, c r c 6 alkoxy or hydroxy, including any one, two or three substituents of C 3 -C 6 cycloalkyl group; a phenyl group; comprising include a halogen atom, dC 6 alkyl, alkoxy or hydroxy dC 6 including any one, two or three substituted phenyl; benzyl;
  • R 2 , R 3 are a substituted or unsubstituted phenyl group; a substituted or unsubstituted pyridyl group; a substituted or unsubstituted furyl group; a substituted or unsubstituted pyranyl group; a substituted or unsubstituted thienyl group; Substituted pyrrolyl; substituted or unsubstituted indenyl; or substituted or unsubstituted naphthyl.
  • the present invention provides a kit comprising the above combined preparation.
  • the invention further provides an application
  • the above combined preparations are useful for the prevention and/or treatment of metabolic diseases including but not limited to diabetes, insulin 4 and obesity, cardiovascular diseases and neurodegenerative diseases such as "Alzheimer's disease"
  • AD Alzheimer's Disease
  • AD also known as Alzheimer's dementia, etc.
  • metabolic disease refers to a related symptom and/or disease caused by metabolic disorders such as sugar, fat or protein caused by various causes.
  • diabetes refers to a multi-pathogenic metabolic disease characterized by chronic hyperglycemia accompanied by disorders of sugar, fat and protein metabolism caused by defects in insulin secretion and/or function.
  • insulin resistance refers to a decrease in the sensitivity of the surrounding tissues to insulin, and target tissues such as muscles and fats are resistant to insulin-induced glucose uptake. Insulin resistance is prevalent in type 2 diabetes, accounting for more than 90%, and is one of the main factors in the pathogenesis of type 2 diabetes.
  • obesity refers to an excess of body fat, a man weighing more than 25% of the ideal body weight or a woman weighing more than 30% of the ideal body weight. Genetic factors, hypothalamic disease, endocrine disorders, overeating and too little activity are all causes of obesity.
  • Alzheimer's Disease, AD also known as Alzheimer's dementia
  • cardiac loss As used herein, “cardiovascular disease” includes heart disease, pulmonary heart disease, hypertension, and hyperlipidemia. It has the characteristics of "high incidence, high mortality, high disability rate, high recurrence rate” and “more complications”.
  • an “effective amount” of a compound for treating a particular disease refers to an amount sufficient to ameliorate or to some extent alleviate the symptoms associated with the disease.
  • This dose can be administered in a single dose or in accordance with a therapeutic regimen. This dose cures the disease, but is typically administered to improve the condition. Repeated administration to improve symptoms may be desirable.
  • pharmaceutically acceptable salts, esters or other derivatives include any salt, ester or derivative which is readily prepared by those skilled in the art by known methods.
  • the compounds thus derived and produced can be administered to animals and humans without toxic effects.
  • the compound is either pharmaceutically active or a prodrug.
  • treatment means that the disease and symptoms are improved in any way, or other beneficial changes.
  • Treatment also includes the use of the compounds of the invention in medicine.
  • administration of a particular pharmaceutical composition to "improve" the symptoms of a particular disease means any reduction, whether permanent, temporary, prolonged, transient, can be attributed to or associated with the pharmaceutical composition.
  • Relevant application As used herein, “substantially pure” means sufficiently uniform that no impurities can be detected by standard analytical methods used by those skilled in the art to evaluate purity, such as thin layer chromatography.
  • substantially chemically pure compounds for purification are well known to those skilled in the art. However, a substantially chemically pure compound can be a stereoisomer or a mixture of isomers. In this case, further purification may increase the specific activity of the compound.
  • prodrug refers to a compound that is administered in vivo and which can be metabolized or converted to a biologically, pharmaceutically or therapeutically active form.
  • the pharmaceutically active compound will be modified to reproduce the active compound by metabolic processes.
  • Prodrugs can be designed to alter their metabolic stability, or precursors of transport properties, to mask their side effects or toxicity, to improve the taste of the drug, or to alter other properties.
  • composition refers to any mixture. It can be a solution, suspension, liquid, powder, ointment, aqueous, non-aqueous or any combination thereof.
  • joint refers to any combination between two or more.
  • object includes humans and animals, for example, dogs, cats, cows, pigs, rodents, etc. Experienced practitioners should understand that the subject is suitable and willing to be metabolically ill (including but not limited For diabetes, insulin resistance and obesity), cardiovascular disease and neurodegenerative diseases
  • AD Alzheimer's Disease
  • IUPAC-IUB committee promulgate biochemical nomenclature unless otherwise stated.
  • the present invention provides a modulator of glucagon-like peptide-1 receptor function, which increases the prevention and/or treatment of metabolic diseases including but not limited to diabetes, insulin Resistance and obesity), cardiovascular disease and neurodegenerative diseases [such as "Alzheimer's Disease” (AD), also known as Alzheimer's dementia].
  • the present invention relates to a compound having a substituted five-membered heterocyclic structure represented by the following formula, or a pharmaceutically acceptable salt, ester, solvate, metal complex thereof or prodrug having the same pharmacological action:
  • the compounds include all geometric isomers thereof.
  • Z is CH, N
  • R 2 , R 3 are a substituted or unsubstituted phenyl group; a substituted or unsubstituted pyridyl group; a substituted or unsubstituted furyl group; a substituted or unsubstituted pyranyl group; a substituted or unsubstituted thienyl group; Substituted pyrrolyl; substituted or unsubstituted indenyl; or substituted or unsubstituted naphthyl.
  • This compound was prepared by the synthetic method cited in Section F below. Further preferably, the compound or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, either alone or in combination with a pharmaceutically acceptable carrier or excipient.
  • the compounds of the invention may be prepared in the form of their pharmaceutically acceptable salts with any suitable acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
  • organic acids such as formic acid, acetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, etc.
  • a sulfonic acid such as methanesulfonic acid or ethylsulfonic acid
  • an arylsulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid can be used.
  • the present invention relates to the prevention and/or treatment of metabolic diseases (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases [eg "Alzheimer's disease”)
  • metabolic diseases including but not limited to diabetes, insulin resistance and obesity
  • cardiovascular diseases including but not limited to diabetes, insulin resistance and obesity
  • neurodegenerative diseases eg "Alzheimer's disease”
  • the method comprises administering to a subject in need or willing to receive treatment or prevention an effective amount of a compound that selectively agonizes the glucagon-like peptide-1 receptor or a pharmaceutically acceptable salt thereof for treating or preventing the above-mentioned diseases Or symptoms.
  • the above-mentioned disease is by administering an effective amount of a compound having a substituted five-membered heterocyclic structure represented by the following formula, or a pharmaceutically acceptable salt, ester, solvate, metal complex thereof or having the same pharmacological action.
  • Prodrugs to treat or prevent The compounds include all geometric isomers thereof.
  • ⁇ 0, S
  • ⁇ is CH, N;
  • dC 6 alkyl include a halogen atom-containing, c r c 6 alkoxy or hydroxy, including any one, two or three substituents of c r c 6 alkyl; c 3 -c 6 cycloalkyl group; a halogen atom include containing, c r c 6 alkyl, c r c 6 alkoxy or hydroxy, including any one, two or three substituents of C 3 -C 6 cycloalkyl group; a phenyl group; comprising include a halogen atom, dC 6 alkyl, alkoxy or hydroxy dC 6 including any one, two or three substituted phenyl; benzyl;
  • R 2 , R 3 are a substituted or unsubstituted phenyl group; a substituted or unsubstituted pyridyl group; a substituted or unsubstituted furyl group; a substituted or unsubstituted pyranyl group; a substituted or unsubstituted thienyl group; Substituted pyrrolyl; substituted or unsubstituted indenyl; or substituted or unsubstituted naphthyl. Any subject can be controlled by this method, preferably a mammal, more preferably a human.
  • the method can be used to prevent metabolic diseases (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases [such as "Alzheimer's Disease” (AD), also known as premature 't'Alzheimer's dementia], etc.
  • the preferred disease or condition is any disease or condition caused or accompanied by insulin secretion and/or dysfunction.
  • the invention may be used alone or in combination with other diabetes therapeutic agents already on the market or to be marketed, including insulin sensitizers. Compound. Any suitable metabolic disease (including but not limited to diabetes, insulin resistance, and obesity) therapeutic agents can be used in combination with the compounds of the present invention.
  • typical insulin sensitizers include rosiglitazone and pioglitazone.
  • the above insulin sensitizer is not administered when the compound of the invention is used. More preferably, the compound of the present invention is used to treat or prevent a disease or symptom caused by the use of the above-mentioned diabetes therapeutic agents (including insulin sensitizers) which have been marketed or will be marketed to produce drug resistance or side effects.
  • Diabetes treatments include a combination of insulin sensitizers.
  • it can be administered by intracavitary injection, subcutaneous injection, intravenous injection, intramuscular injection, intradermal injection, orally or topically with the compound of the present invention, or with a pharmaceutically acceptable salt thereof.
  • the method further comprises performing a diagnosis and prognostic assessment of the disease or condition of the subject to whom it is administered. Any suitable method can be used to diagnose and assess the relevant disease or condition and its prognosis.
  • Diagnosis and prognosis can be based on detecting and/or identifying any or all of the in vivo substances, such as glycated hemoglobin, enzymes, antigens, antibodies, nucleic acids or other pathological and clinical markers, and related symptoms.
  • a diagnostic or prognostic method disclosed in International Patent Publication No. WO 01/44815 and U.S. Patent No. 5,571,674 can be used.
  • the present invention also relates to a combination preparation comprising a compound which selectively modulates the function of the glucagon-like peptide-1 receptor, or a pharmacologically Acceptable salts, and therapeutic agents for one or more metabolic diseases include insulin sensitizers.
  • a combination comprises a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more therapeutic agents for metabolic diseases including an insulin sensitizer, the compound being represented by the following formula: And all of its geometric isomers, or prodrugs having the same pharmacological effects, esters thereof, solvates thereof or metal complexes thereof.
  • Z is CH, N
  • dC 6 alkyl include a halogen atom-containing, c r c 6 alkoxy or hydroxy, including any one, two or three substituents of c r c 6 alkyl; c 3 -c 6 cycloalkyl group; a halogen atom include containing, c r c 6 alkyl, c r c 6 alkoxy or hydroxy, including any one, two or three substituents of C 3 -C 6 cycloalkyl group; a phenyl group; comprising include a halogen atom, dC 6 alkyl, alkoxy or hydroxy dC 6 including any one, two or three substituted phenyl; benzyl;
  • R 2 , R 3 are a substituted or unsubstituted phenyl group; a substituted or unsubstituted pyridyl group; a substituted or unsubstituted furyl group; a substituted or unsubstituted pyranyl group; a substituted or unsubstituted thienyl group; Substituted pyrrolyl; substituted or unsubstituted indenyl; or substituted or unsubstituted naphthyl. Any suitable therapeutic agent for diabetes, including insulin sensitizers, can be used in the combination formulations of the invention.
  • one or more of the above-described diabetes therapeutic agents including insulin sensitizers may be included in the combined preparation of the present invention.
  • a method of treating or preventing a disease or condition caused or accompanied by insulin secretion and/or dysfunction is provided, the method comprising the need and acceptance
  • the subject to be treated or prevented is administered an effective amount of the above combined preparation, or a pharmaceutically acceptable salt thereof, to treat or prevent the above-mentioned diseases or symptoms.
  • kits comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, and the use of the above compound or a pharmaceutically acceptable salt thereof for controlling secretion and/or secretion by insulin Instructions for the use of a disease or condition caused by or associated with a dysfunction.
  • a kit comprising the combination described above and instructions for using the combination to treat or prevent a disease or condition caused or accompanied by insulin secretion and/or dysfunction.
  • the compounds of the invention are formulated for any suitable route of administration, for example, intraluminal, subcutaneous, intravenous, intramuscular Injection, intradermal injection, oral or topical medication.
  • the method can be administered by injection, in a single dose, in an ampoule, or in a multi-dose container with an additional buffer.
  • the formulations may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles.
  • the formulations may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in the form of a powder in the form of a suitable carrier, sterile non-pyrogenic water or other solvent.
  • the topical medicament of the present invention may be a foam, a gel, an ointment, an ointment, a transdermal patch, or a paste.
  • Pharmaceutical compositions and methods for administration which may be used in the present invention include, but are not limited to, those described in U.S. Patent Nos. 5,736,154, 6,197, 801 B1, 5,741, 511, 5, 886, 039, 5, 941, 868, 6, 258, 374 B1 and 5, 686, content.
  • the size of the dose to be treated or prevented will vary depending on the severity of the condition and the route of administration.
  • Dosage forms include tablets, troches, soy gums, dispersing agents, suspending agents, solutions, capsules, films and the like.
  • the compounds of the invention may be in accordance with conventional pharmaceutical mixing techniques with pharmaceutical carriers or excipients such as beta-cyclodextrin and 2-hydroxypropyl-beta-cyclodextrin. Tightly mixed.
  • a special carrier a local or parenteral route, may be employed.
  • parenteral dosage forms such as compositions for intravenous injection or infusion
  • similar pharmaceutical vehicles can be employed, water, glycols, oils, buffers, sugars, preservatives, liposomes, etc., which are well known to those skilled in the art. .
  • parenteral compositions include, but are not limited to, 5% w/v dextrose, physiological saline or other solutions.
  • the total dose of the compound of the present invention, alone or in combination with other preparations, can be administered in vial vials in a volume of from about 1 ml to about 2000 ml.
  • the amount of diluent will vary depending on the total dose administered.
  • the invention also provides a kit for achieving a therapeutic regimen.
  • the kit comprises an effective amount of a compound of the invention in a pharmaceutically acceptable form, alone or in combination with other agents, in one or more containers.
  • a preferred pharmaceutical form is in combination with sterile saline, dextrose solution, buffered solution, or other pharmaceutically acceptable sterile liquid.
  • the composition may be lyophilized or dried; in this case, the kit optionally further comprises a pharmaceutically acceptable solution, preferably a sterile solution, in a container to reconstitute the complex A solution for injection purposes is formed.
  • a pharmaceutically acceptable solution are physiological saline and dextrose solutions.
  • the kit of the invention further comprises a needle or syringe and/or a packaged alcohol pad for injection of the composition, preferably in sterile form.
  • F Preparation method When X is S, Y is 0, and Z is N, it is prepared by the following method:
  • alkyl group of H is an alkyl group of H; dC 6 ; an alkyl group containing one, two or three substituted C r C 6 including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; C 3 -C 6 naphthenic group; include a halogen atom-containing, dC 6 alkyl, alkoxy or hydroxy dC 6 including any one, two or three substituents of C 3 -C 6 cycloalkyl group; a phenyl group; a halogen atom-containing comprising, dC 6 alkyl, alkoxy or hydroxy dC 6 including any one, two or three substituted phenyl; benzyl;
  • R 2 , R 3 are a substituted or unsubstituted phenyl group; a substituted or unsubstituted pyridyl group; a substituted or unsubstituted furyl group; a substituted or unsubstituted pyranyl group; a substituted or unsubstituted thienyl group; Substituted pyrrolyl; substituted or unsubstituted indenyl; or substituted or unsubstituted naphthyl.
  • the final product ( ⁇ ) was tested by NMR. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1. Reporter gene method detects the agonistic effect of the compounds of the invention on GLP-1R.
  • the GLP-1 concentration gradient was 10, 1, 0.1, 0.01, 0.001, 0.0001 ⁇ , and the luciferase activity induced by hydrazine was 100%, and the EC 50 value of GLP-1 was determined to be 0.07 ⁇ .
  • the concentration gradient of the compound mwwl018 (SH17249) was 0, 0.3, 1, 3, 10, 30, 100, 300 ⁇ .
  • the concentration gradient of the compound mwwl018 (SH17249) was 0, 0.001, 0.01, 0.1, 1, 10, 100 ⁇ .
  • the results showed that the compound mwwl018 ( SH17249 ) specifically binds to the [ 125 1]-labeled GLP-1 and binds to the receptor in a dose-dependent manner. At the highest concentration of 100 ⁇ , it is equivalent to the [ 125 1] GLP.
  • the binding inhibition ratio of -1 was 43.2%.
  • GLP-1R is a G protein-coupled receptor.
  • GLP-1R binds to an agonist, the Ga subunit of G protein is activated to stimulate adenylate cyclase, resulting in elevated intracellular cAMP levels. Since the cAMP response element exists in the promoter region of the proinsulin gene, cAMP binds to the response element to initiate transcription of the pre-insulin gene, thereby stimulating insulin expression and secretion (Diabetes 2000, vol. 49: 1156-1164).
  • This experiment used a human embryonic kidney cell line (HEK 293) stably transfected with a GLP-1R receptor gene expression vector and a luciferase reporter gene expression vector regulated by a cAMP response element to detect its response to a test compound (Cell). Biology, 1992, 89:8641-8645; Proc. Natl. Acad. Sci. USA 1987, 84:3434-3438). A sample that induces expression of a luciferase reporter gene when screened for a compound is considered to have GLP-1R agonistic activity.
  • HEK293/GLP1R+Luc cells were incubated at 20,000/100 ⁇ /well into 96-well culture plates at 37 in DMEM medium containing 10% fetal calf serum and 500 ⁇ M ⁇ G418. C was cultured overnight. The GLP-1 standard and the compound mwwl018 (SHI 7249) and the like were diluted to a certain concentration gradient, and then added to the above 96-well microplate at 1 ⁇ M/well. At 37. C, cultured for 6 hours under 5% C0 2 conditions. Press Steady-Glo TM Luciferase Assay System kit instructions detected luciferase activity, Victor 2 plate reader was read.
  • Receptor binding activity test In order to determine the binding ability of the active compound to the receptor, a large amount of cells expressing GLP-1R were prepared, and [ 125 1]-labeled GLP-1 was used as a ligand, and the compound to be detected was simultaneously added. When the test compound is competitively bound to the 125 1 standard GLP-1, the isotope labeling on the cell membrane is reduced. The affinity of the compound for the receptor can be assessed accordingly (J Mol Endocrinol. 2000, 25:321-35; J Biomol Screen. 2000, 5:377-84). 2.1 Test materials and instruments:
  • HEK 293/GLP1R+Luc cell line self-built by the National New Drug Screening Center
  • Ii 4 conjugate [ 125 1] GLP-1 (Amersham Biosciences)

Abstract

L'invention concerne des composés hétérocycliques substitués à cinq éléments représentés par la formule générale mentionnée ci-après, et leurs sels acceptables d'un point de vue pharmaceutique, leurs esters, leurs solvates, leurs complexes métalliques ou leurs médicaments, et qui ont le même effet pharmacologique. L'invention concerne aussi leur utilisation comme récepteur de peptide 1 de type Glucagon dans la prophylaxie et/ou le traitement de troubles métaboliques, y compris, mais pas exclusivement, le diabète, l'insulinorésistance et l'obésité, les maladies cardio-vasculaires, les maladies neurodégénératives (telles que la maladie d'Alzheimer également connue sous le nom de démence d'Alzheimer) et autre.
PCT/CN2008/000513 2007-03-30 2008-03-14 Composés hétérocycliques substitués à cinq éléments, leur méthode de préparation et leur utilisation en médecine WO2008119238A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2009109998A1 (fr) * 2008-03-03 2009-09-11 Lupin Limited Nouveaux inhibiteurs de protéine tyrosine phosphatase - ib
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
DE102010015123A1 (de) 2010-04-16 2011-10-20 Sanofi-Aventis Deutschland Gmbh Benzylamidische Diphenylazetidinone, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2014064215A1 (fr) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la kinase tpl2 pour prévenir ou traiter le diabète et favoriser la survie de cellules β
WO2016151018A1 (fr) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique destinées à être utilisées dans le traitement du diabète
WO2021162665A1 (fr) * 2020-02-11 2021-08-19 Bahcesehir Universitesi Découverte basée sur la physique de nouveaux composés thérapeutiques de petite taille destinés à être utilisés en tant qu'inhibiteur de bcl-2

Families Citing this family (3)

* Cited by examiner, † Cited by third party
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EP3148541B1 (fr) * 2014-05-28 2020-09-02 Universität Bern Thiazolidinones en tant qu'inhibiteurs de l'absorption d'anandamide cellulaire et leur utilisation dans le traitement de troubles psychiatriques ou neurologiques et de l'inflammation, en particulier d'une neuro-inflammation
EP2952188A1 (fr) * 2014-06-03 2015-12-09 Universität Bern Thiazolidinones en tant qu'inhibiteurs de l'absorption d'anandamide cellulaire et leur utilisation dans le traitement de troubles psychiatriques ou neurologiques et de l'inflammation, en particulier d'une neuro-inflammation

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040171073A1 (en) * 2002-10-08 2004-09-02 Massachusetts Institute Of Technology Compounds for modulation of cholesterol transport
CN1657529A (zh) * 2004-02-20 2005-08-24 中国科学院上海药物研究所 2－取代亚胺噻唑烷衍生物，其制备工艺及药物组合物
WO2005082363A1 (fr) * 2004-02-20 2005-09-09 Board Of Regents, The University Of Texas System Composes de thiazolone permettant de traiter le cancer
CN1699354A (zh) * 2004-05-17 2005-11-23 中国科学院上海药物研究所 一类2,3,5－三取代－4－噻唑烷酮化合物及其药理用途
WO2006020680A2 (fr) * 2004-08-10 2006-02-23 Exelixis, Inc. Composes heterocycliques comme agents pharmaceutiques
CN1742010A (zh) * 2002-11-22 2006-03-01 史密丝克莱恩比彻姆公司 新的化学化合物
WO2007010281A2 (fr) * 2005-07-21 2007-01-25 Betagenon Ab Utilisation de derives et d'analogues de thiazole dans les troubles causes par les acides gras libres
WO2007032028A1 (fr) * 2005-09-16 2007-03-22 Torrent Pharmaceuticals Ltd. Thiazolinones et oxazolinones et leur utilisation en tant qu'inhibiteurs de ptp1b

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040171073A1 (en) * 2002-10-08 2004-09-02 Massachusetts Institute Of Technology Compounds for modulation of cholesterol transport
CN1742010A (zh) * 2002-11-22 2006-03-01 史密丝克莱恩比彻姆公司 新的化学化合物
CN1657529A (zh) * 2004-02-20 2005-08-24 中国科学院上海药物研究所 2－取代亚胺噻唑烷衍生物，其制备工艺及药物组合物
WO2005082363A1 (fr) * 2004-02-20 2005-09-09 Board Of Regents, The University Of Texas System Composes de thiazolone permettant de traiter le cancer
CN1699354A (zh) * 2004-05-17 2005-11-23 中国科学院上海药物研究所 一类2,3,5－三取代－4－噻唑烷酮化合物及其药理用途
WO2006020680A2 (fr) * 2004-08-10 2006-02-23 Exelixis, Inc. Composes heterocycliques comme agents pharmaceutiques
WO2007010281A2 (fr) * 2005-07-21 2007-01-25 Betagenon Ab Utilisation de derives et d'analogues de thiazole dans les troubles causes par les acides gras libres
WO2007032028A1 (fr) * 2005-09-16 2007-03-22 Torrent Pharmaceuticals Ltd. Thiazolinones et oxazolinones et leur utilisation en tant qu'inhibiteurs de ptp1b

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009109998A1 (fr) * 2008-03-03 2009-09-11 Lupin Limited Nouveaux inhibiteurs de protéine tyrosine phosphatase - ib
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
DE102010015123A1 (de) 2010-04-16 2011-10-20 Sanofi-Aventis Deutschland Gmbh Benzylamidische Diphenylazetidinone, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2014064215A1 (fr) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la kinase tpl2 pour prévenir ou traiter le diabète et favoriser la survie de cellules β
WO2016151018A1 (fr) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique destinées à être utilisées dans le traitement du diabète
WO2021162665A1 (fr) * 2020-02-11 2021-08-19 Bahcesehir Universitesi Découverte basée sur la physique de nouveaux composés thérapeutiques de petite taille destinés à être utilisés en tant qu'inhibiteur de bcl-2

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