WO2008067712A1 - Composés à structure de cyclopentane, procédé de préparation et utilisations médicales de ceux-ci - Google Patents

Composés à structure de cyclopentane, procédé de préparation et utilisations médicales de ceux-ci Download PDF

Info

Publication number
WO2008067712A1
WO2008067712A1 PCT/CN2007/002975 CN2007002975W WO2008067712A1 WO 2008067712 A1 WO2008067712 A1 WO 2008067712A1 CN 2007002975 W CN2007002975 W CN 2007002975W WO 2008067712 A1 WO2008067712 A1 WO 2008067712A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkoxy
halogen atom
substituted
alkyl
Prior art date
Application number
PCT/CN2007/002975
Other languages
English (en)
Chinese (zh)
Inventor
Mingwei Wang
Qing Liu
Na Li
Original Assignee
Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences filed Critical Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
Publication of WO2008067712A1 publication Critical patent/WO2008067712A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40—Thiophene-2-carboxylic acid
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to a class of compounds having a substituted cyclopropane structure, a process for the preparation thereof, and as a glucagon like peptide-1 receptor (Glucagon like peptide) 1 receptor, GLP-1R ) modulators in the prevention and / or treatment of metabolic disorders (including but not limited to diabetes, insulin resistance and obesity, etc.), cardiovascular diseases, neurodegenerative diseases (such as Alzheimer's disease) Medical use.
  • metabolic disorders including but not limited to diabetes, insulin resistance and obesity, etc.
  • cardiovascular diseases including but not limited to diabetes, insulin resistance and obesity, etc.
  • neurodegenerative diseases such as Alzheimer's disease
  • 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.
  • 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 and disease is the lack of absolute insulin secretion.
  • the clinical treatment is supplemented with insulin.
  • Lord 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. After the sulfonylurea hypoglycemic agent binds to the receptor of the pancreatic ⁇ -cell membrane, it closes the 4-electrode channel and blocks the potassium ion efflux, leading to depolarization of the cell membrane, causing the Ca 2+ channel to open, causing extracellular calcium influx. The increase in intracellular calcium concentration triggers the release of insulin.
  • 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.
  • glibenclamide excellent Hypoglycemic
  • gliclazide domecon
  • glipizide mepyridin
  • gliclazone sucgar level.
  • 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.
  • hypoglycemic agents mainly include Thiazolidinediones (such as troglitazone, rosiglitazone, pioglitazone, etc.), ⁇ 3-adrenergic receptor modulators, glucagon receptor antagonists, and fatty acids.
  • Metabolic interference drugs such as ⁇ -glucosidase inhibitors (such as acarbose, voglibose, miglitol, etc.) and aldose reductase inhibitors.
  • GLP-1 R belongs to type B G protein-coupled receptor (GPCR).
  • GLP-1 gutagonal peptide-1
  • the gutagonal 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 NY Acad 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. Acute injection of GLP-1 can be used in cardiac hypertrophy.
  • GLP-1 drugs such as the GLP-1 derivative developed by Danovo Nordisk of Denmark (trade name Limglutide; 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 last year and is expected to exceed $1 billion in sales this year.
  • GLP-1 and its peptide analogs there have been no reports of successful development of non-peptide small molecule GLP-1R agonists.
  • An object of the present invention is to provide a compound represented by the following formula I and a pharmaceutically acceptable salt thereof; another object of the present invention is to provide a process for producing a compound represented by the following formula I; It is still another object of the invention to provide a pharmaceutical composition comprising a compound represented by the following formula I; A further object of the present invention is to provide a compound represented by the following Formula I as a glucagon-like peptide-1 receptor modulator in the prevention and/or treatment of metabolic disorders including, but not limited to, diabetes, insulin resistance and Obesity), cardiovascular disease and neurodegenerative diseases
  • the present invention provides a glucagon-like peptide-1 receptor modulator, which increases the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases ( Members of drugs such as Alzheimer's disease).
  • the present invention relates to a compound represented by the following formula I, or a pharmaceutically acceptable salt thereof, and all stereo and optical isomers thereof, or a prodrug having the same pharmacological action thereto, an ester thereof, a solvate thereof or Metal complexes:
  • X and Y are each (CH 2 ) n and n is 0-2, oxygen, sulfur or nitrogen.
  • substituents hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; amide; carboxamide; sulfhydryl; Ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; Unsubstituted pyrrolyl;
  • R 2 , R 3 are each independently any of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • the compound of the above formula I is a ring, characterized in that when X, Y are (CH 2 ) n and n is 0-2, oxygen, sulfur or nitrogen, it is:
  • R 4 is any one of the following substituents: H; an alkyl group; any one, two or three substituted ( ⁇ - ⁇ 6 containing an alkoxy group including a halogen atom, C r C 6 or a hydroxyl group) alkyl; C 2 -C 6 alkenyl group; a halogen atom includes any containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; any one, two or three substituted C 2 -C 6 alkynyl groups including a ?
  • 3 ⁇ 4 containing pigment comprising atoms, C r C 4 alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carbonamide group, a mercapto group, Yue thio, ethylthio in Any one, two or three substituted pyranyl groups; containing an alkyl group including a halogen atom, d-, a nitro group, a carboxyl group, Any one, two or three substituted thienyl groups including an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a fluorenyl group, an ethylthio group; containing a halogen atom, C r C Any one, two or three substituted pyrrole groups of 4 alkyl, nitro, carboxyl, aldehyde,
  • R 6 and R 7 are each independently a substituent of any of the following: H; an alkyl group of C!-Ce; any one, two or three containing an alkoxy group including a prime atom, d- or a hydroxyl group.
  • C r C 6 alkyl substituted C r C 6 alkyl; C 2 -C 6 alkenyl; any one, two or three substituted C 2 -C 6 containing a halogen atom, d-alkoxy or hydroxy group Alkenyl; C 2 -C 6 alkynyl; any one, two or three substituted C 2 -C 6 alkynyl group including a halogen atom, a C 6 alkoxy group or a hydroxyl group; C 3 -C 6 cycloalkyl; includes any halogen atom-containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl; aryl; benzyl a furanyl group; a pyrenyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, C r C
  • 3 ⁇ 4 containing pigment comprising atoms, C r C 6 alkoxy or hydroxy, including any one, two three or substituted C r C 6 alkanoyl; C 2 -C 6 alkenyl group; a pigment contain any atoms including, C r C 6 alkoxy or hydroxy, including one, Two or three substituted C 2 -C 6 alkenoyl groups; C 2 -C 6 alkynyl groups; any one, two or three containing a halogen atom, a hydroxyl group of C r C 6 or a hydroxyl group Substituted
  • C r C 6 alkanoyl include a halogen atom contain any, -C 6 alkoxy or hydroxy, including one, two or three substituents of C r C 6 alkanoyl; C r C 6 alkenoyl ;!
  • 3 ⁇ 4 comprise any pigment containing atoms, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; and comprising Any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; 3 ⁇ 4 atom, any C r C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl group; a formyl adamantane, substituted adamantane Yue group; aroyl Benzyl; furanoyl; pyranoyl; thiophene acyl; pyrroyl; Is (CH 2 ) classroom, n is 0-2, 0, S or H; or R 2
  • R n and R 12 are each independently a substituent of any of the following: H; an alkyl group of dC 6 ; any one, two or three containing an alkoxy group including a ? 3 atom, a C 6 alkoxy group or a hydroxyl group; a substituted alkyl group of dC 6 ; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C containing an alkoxy group including a halogen atom, C r C 6 or a hydroxyl group ; 6 alkenyl; C 2 -C 6 alkynyl group; a halogen atom includes contain any C, C r C 6 alkoxy or hydroxy, including one, two or three substituents 2 -C 6 alkynyl group of a cycloalkyl group of C r C 6 ; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom
  • C r C 4 Any one, two or three substituted thienyl groups including a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; Any one or two of an atom, a C, a C 4 alkyl group, a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, and an ethylthio group.
  • R 2 and R 3 are respectively: Wherein R 5 is any one of the following substituents: H; d-alkyl; any one, two or three substituted Ci-alkyl groups including a halogen atom, an alkoxy group of d- or a hydroxyl group ; (3 ⁇ 4- (36 alkenyl group; a halogen atom include any containing, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 An alkynyl group of -C 6 ; any one, two or three substituted C 2 -C 6 alkynyl groups including a prime atom, an alkoxy group of d- or a hydroxyl group; a C 3 -C 6 naphthenic group; Any one, two or three substituted C 3 -C 6 naphthenes containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl
  • One, two or three substituted pyranyl groups Any one, two or three substitutions of a halogen atom, an alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group a thienyl group; containing an alkyl group including a cyclin atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethyl thio group Any one, two or three substituted pyrrolyl groups; an alkanoyl group of Ci-C 6 ; any one, two or three substituted groups including a halogen atom
  • R 6 and R 7 are each independently a substituent of any of the following: H; an alkyl group of C r C 6 ; any one or two containing an alkoxy group including a prime atom, C r C 6 or a hydroxyl group.
  • a three-substituted alkyl group of dC 6 a C 2 -C 6 alkenyl group; any one, two or three substituted 3 ⁇ 4- ⁇ 6 groups including a halogen atom, an alkoxy group of CC 6 or a hydroxyl group; alkenyl; C 2 -C 6 alkynyl group; a halogen atom includes any containing, C r C 6 alkoxy or hydroxy inner one, two or three substituents of C 2 -C 6 alkynyl group; a C a 3- C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; an aryl group; a benzyl group ; furanyl; pyranyl; thienyl; pyrrolyl; pyridyl; containing a halogen atom
  • Substituted furanyl containing an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group Any one, two or three substituted pyranyl groups; containing an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carbon amide Any one, two or three substituted thienyl groups including a thiol group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, - an nitro group, a carboxy group, an aldehyde
  • any C r C 6 alkoxy or hydroxy, including one, two or three substituents of the group C r C 6 alkenyl; C 2 - C 6 alkynyl group; a halogen atom-containing include, dC any of the 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkynyl group; a cycloalkyl group of C 3 -C 6; include halogen atom-containing alkyl, C 6 R & lt C Any one, two or three substituted C 3 -C 6 cycloalkane groups such as an oxy group or a hydroxy group; adamantyl formyl group, substituted adamantyl decanoyl group; aroyl group; benzyl group; furoyl group; Nor formyl; thiophene acyl; pyrrolyl acyl; (CH 2 ) n , n is 0-2,
  • R 9 and R 10 are each independently a substituent of any of the following: H; Includes atoms of any element containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of c r c 6 alkyl; C 2 -C 6 alkenyl group; a halogen atom-containing include, Any one, two or three substituted c 2 -c 6 alkenyl groups such as alkoxy or hydroxy of c r c 6 ;
  • C 2 -C 6 alkynyl group; a halogen atom include any containing, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of (3 2 - (6 alkynyl; C 3 - a C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, a C 6 alkoxy group or a hydroxyl group; an aryl group; a benzyl group; a furanyl group; a pyrenyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group
  • R 13 is any one of the following substituents: H; an alkyl group of dC 6 ; any one, two or three substituted C r C 6 containing a halogen atom, an alkoxy group of d- or a hydroxyl group alkyl; - (: 6 alkenyl group; a halogen atom includes any containing, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl; any one, two or three substituted ( 2- ( 6 alkynyl; C 3 -C 6 ring) containing a aryl group or a hydroxy group including a aryl group or a d-Cs alkyl; optionally include a halogen atom-containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C r C 6 cycloalkyl; ary
  • C r C 6 alkanoyl includes any pigment containing atoms, alkoxy or hydroxy dC 6, including one, two or three substituents of C r C 6 alkanoyl;
  • R 2 and R 3 are respectively:
  • R 5 is any of the following substituent groups: H; C r to C 6 alkyl; contain any include halogen atoms, alkoxy or hydroxy CrC 6 inner one, two or three substituents of (C6 to alkyl; - (: 6 alkenyl group; comprising comprising 3 ⁇ 4 atom, any C r C 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkenyl group; a!
  • a C 2 -C 6 alkynyl group any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group or a hydroxyl group; a C 3 -C 6 ring Any one, two or three substituted C 3 -C 6 naphthenes containing a halogen atom, an alkoxy group of -C 6 or a hydroxyl group; Aryl; benzyl; furyl; pyranyl; thienyl; pyrrolyl; pyridyl; containing arginyl, Cr C alkyl, nitro, carboxy, aldehyde, alkoxy, amine, Any one, two or three substituted aryl groups including an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, C r C 4 ,
  • R 6 and R 7 are each independently a substituent of any of the following: H; -alkyl; any one, two or three substituted Cs including a pertiny alkoxy group or a hydroxyl group of dC 6 C 6 alkyl R < C 2 -C 6 alkenyl group; and one, two or three substituents include a halogen atom contain any, dC 6 alkoxy or hydroxy, including a C 2 -C 6 alkenyl group of ; C 2 -C 6 alkynyl group; a halogen atom include any containing, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkynyl group of; C 3 - a C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, an alkoxy group or a hydroxyl group
  • (2 - (6 alkenyl; containing pigment include 3 ⁇ 4 atoms, C r C 6 alkoxy or hydroxy inner any one, two or three substituents of a C 2 -C 6 Alkenyl; C 2 -C 6 alkynyl; any one, two or three substituted (including 2 -( 6 alkynyl; C) including a halogen atom, a C 6 alkoxy group or a hydroxyl group a 3- C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; an aryl group; a benzyl group ; furanyl; pyranyl; thienyl; pyrrolyl; pyridyl; containing an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an
  • 3 ⁇ 4 containing pigment comprising atoms, - alkoxy or hydroxy arbitrary inner one, two or three substituents of C 2 -C 6 alkynyl group of; C 3 -C 6 cycloalkyl group; a halogen atom includes any containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl group ugly; adamantane formyl, Substituting adamantyl formyl; aroyl; benzoyl; furoyl; pyranoyl; thiophene acyl; pyrrolidinyl; Is (CH 2 ) n , n is 0-2, O, S or NH; or R 2 , R 3 are:
  • R 9 and R 10 are each independently a substituent of any of the following: H; an alkyl group of dC 6 ; Includes atoms of any element containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C r C 6 alkyl; C 2 -C 6 alkenyl group; a halogen atom-containing include, any C r C 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkenyl; C 2 -C 6 alkynyl group; a halogen atom include containing, C r C 6 Any one, two or three substituted C 2 -C 6 alkynyl groups such as alkoxy or hydroxy; C 3 -C 6 cycloalkyl; containing alkoxy groups including a halogen atom, d- or Any one, two or three substituted C 3 -C 6 cycloalkyl groups such as hydroxy; aryl; benz
  • Ru, R 15 are each independently a substituent of any of the following: H; an alkyl group of dC 6 ; any one, two or three containing an alkoxy group or a hydroxyl group including a 3 ⁇ 4 atom, a C 6 atom Substituted C r C 6 alkyl; C 2 -C 6 alkenyl; contains included!
  • R 2 and R 3 are respectively: Wherein R 5 is any of the following substituent groups: H; C r C 6 alkyl group; a halogen atom-containing optionally include, Cr alkoxy or hydroxy group including one, two or three substituents of C r C 6 An alkyl group; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C 6 fluorenyl groups containing a halogen atom, an alkoxy group of C r C 6 or a hydroxyl group; a C 2 -C 6 alkynyl group; Any one, two or three substituted C 2 -C 6 alkynyl groups including a prime atom, an alkoxy group of -C 6 or a hydroxyl group; a cycloalkyl group of C r C 6 ; containing a halogen atom, Any one, two or three substituted C 3 -C 6 cycloalkyl groups such as alkoxy or hydroxy
  • Three substituted furanyl; containing pigment atoms include, dC 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio in Any one, two or three substituted pyranyl groups; containing an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group Any one, two or three substituted thienyl groups including a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group Any one, two or three substituted pyrrolyl
  • R 6 and R 7 are each independently a substituent of any of the following: H; d-alkyl; any one, two or three containing a 3 ⁇ 4 atom, an alkoxy group or a hydroxyl group of d- Substituted ( ⁇ -( 6 alkyl; C 2 -C 6 alkenyl; any one, two or three substituted C 2 -C containing a prime atom, dC 6 alkoxy or hydroxy group) 6 alkenyl; C 2 -C 6 alkynyl group; a!
  • 3 ⁇ 4 containing pigment comprising atoms, C r C 6 alkoxy or hydroxy inner any one, two or three substituents of a C 2 -C 6 Alkynyl; C 3 -C 6 cycloalkyl; any one, two or three substituted C r C 6 cycloalkyl groups including a halogen atom, an alkoxy group or a hydroxyl group; an aryl group; a furanyl group; a pyrenyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carbon group amide groups, a mercapto group, Yue thio, ethylthio, including one, two or three aryl group substituents
  • aryl groups containing an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methyl group, Any one, two or three substituted pyridyl groups including an ethylthio group; containing an alkyl group including a halogen atom, - a nitro group, a carboxy group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group Any one, two or three substituted furanyl groups including a mercapto group, a methylthio group, an ethylthio group; an alkyl group including a pertinar atom, C r C 4 , a nitro group, a carboxyl group, a keto group,
  • C r C 6 alkanoyl includes any pigment containing atoms, C r C 6 alkoxy or hydroxy, including one, two or three substituents of d- alkanoyl; C 2 -C 6 alkenyl group of ; optionally include a halogen atom-containing, C R & lt C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; comprising comprising!
  • R 9 and R 10 are each independently from any of the following substituents: H; an alkyl group; any one, two or three substitutions including a sulfonate atom, a C 6 alkoxy group or a hydroxy group. a d-alkyl group; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C 6 groups including a halogen atom, an alkoxy group of C r C 6 or a hydroxyl group; normalization group; C 2 -C 6 alkynyl group; a halogen atom include any containing, C r C 6 alkoxy or hydroxy inner one, two or three substituents of C 2 -C 6 alkynyl group; a C a 3- C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, an alkoxy group or a hydroxyl group; an aryl
  • a three-substituted furyl group containing an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, a group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group Any one, two or three substituted pyranyl groups; containing an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, Any one, two or three substituted thienyl groups including a thiol group or an ethylthio group; containing a halogen atom, a dC ⁇ alkyl group, a nitro group, a carboxyl
  • any hydroxy or C r C 6 alkoxy inner one, two or three substituents of C r C 6 alkanoyl; C 2 -C 6 alkenyl group; a comprises containing a halogen atom, C Any one of alkoxy or hydroxy groups of r C 6 , Two or three substituted C 2 -C 6 alkenoyl groups; C 2 -C 6 alkynyl groups; containing any one, two or three including a halogen atom, a decyloxy group of Ci-C 6 or a hydroxyl group Substituted
  • 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 present invention also provides a medicament comprising the above compound for preventing and/or treating metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurological regressions. ( ⁇ mouth Alzheimer's disease) and so on.
  • the invention relates to methods of preventing and/or treating metabolic disorders, including but not limited to diabetes, insulin resistance and obesity, cardiovascular diseases and neurodegenerative diseases such as 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 modulates the glucagon-like peptide-1 receptor or a pharmaceutically acceptable salt thereof for preventing or treating the above Disease or symptom.
  • a compound that selectively modulates the glucagon-like peptide-1 receptor or a pharmaceutically acceptable salt thereof for preventing or treating the above Disease or symptom.
  • the above metabolic disorders including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease), etc.
  • administering an effective amount of a compound represented by the following formula I Or a pharmaceutically acceptable salt thereof, and all of its stereo and optical isomers, or prodrugs, esters, solvates or metal complexes thereof having the same pharmacological effects for prevention or treatment:
  • X and Y are each (CH 2 ) n and n is 0-2, oxygen, sulfur or nitrogen.
  • substituents hydrogen; Alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; amide; carboxamide; fluorenyl; alkylthio; ether; thioether; Substituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl;
  • R 2 , R 3 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • 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 formula I:
  • substituents hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; amide; carboxamide; fluorenyl; Sulfhydryl; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; Or unsubstituted pyrrolyl;
  • R 2 , R 3 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • the present invention provides a kit comprising the above combined preparation.
  • the present invention still further provides the use of the above combined preparation for the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease).
  • metabolic disorders including but not limited to diabetes, insulin resistance and obesity
  • cardiovascular diseases including but not limited to diabetes, insulin resistance and obesity
  • neurodegenerative diseases such as Alzheimer's disease.
  • To achieve selective stimulation of the glucagon-like peptide-1 receptor improve the patient's symptoms and quality of life.
  • metabolic disorder 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 development 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, is a progressive degenerative disease of the nervous system. Clinically manifested as chronic impaired intelligence and chronic loss of memory.
  • cardiac 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.
  • 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 (TLC), gel electrophoresis. And high performance liquid chromatography (HPLC) or sufficiently pure also means that even further purification does not alter the physicochemical properties detectable by the material, such as enzymatic activity and biological activity.
  • 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. To produce a prodrug, 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. By virtue of knowledge of pharmacokinetics and metabolism of the drug in the body, once the pharmaceutically active compound is known, one skilled in the art can design a prodrug of the compound. [See
  • composition refers to any mixture. It can be a solution, suspension, liquid, powder, ointment, aqueous, non-aqueous or any combination thereof.
  • union refers to any combination of two or more.
  • object includes humans and animals, for example, dogs, cats, cows, pigs, rodents, and the like.
  • the present invention provides a modulator of glucagon-like peptide-1 receptor function, which increases the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, Members of the drug such as insulin resistance and obesity;), cardiovascular disease and neurodegenerative diseases such as Alzheimer's disease.
  • the present invention relates to a compound represented by the following formula I, or a pharmaceutically acceptable salt thereof, and all stereo and optical isomers thereof, or a prodrug having the same pharmacological action thereto, an ester thereof, a solvate thereof or Metal complex.
  • X and Y are each (CH 2 ) n and n is 0-2, oxygen, sulfur or nitrogen.
  • substituents hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; amide; carboxamide; sulfhydryl; Ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; Unsubstituted pyrrolyl;
  • R 2 , R 3 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or not Substituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • the compounds of the invention may be a specific stereoisomer, such as the R- or S-configuration, or mixtures thereof, for example, a racemic mixture.
  • Compounds contemplated herein include all classes of pharmaceutically active compounds, or solutions or mixtures thereof. Also included are hydration types thereof, such as aqueous solutions, hydrolysates or ionized products of these compounds; and these compounds may contain varying amounts of bound water molecules.
  • the compounds of the invention may be prepared or synthesized according to any suitable method. Preferably, the compound is prepared by the synthetic procedure 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, streptoic acid, etc.
  • organic acids such as citric acid, acetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, etc.
  • An alkylsulfonic acid such as methanesulfonic acid, ethylsulfonic acid or the like
  • an arylsulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid can be used.
  • the present invention relates to methods for preventing and/or treating metabolic disorders including, but not limited to, diabetes, insulin resistance and obesity, cardiovascular diseases and neurodegenerative diseases such as 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 which 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 metabolic disorder is caused by administering an effective amount of the compound represented by the following formula I or a pharmaceutically acceptable salt thereof, and all of the stereo and optical isomers thereof, or the same pharmacological action therewith.
  • X and Y are each (CH 2 ) n and n is 0-2, oxygen, sulfur or nitrogen.
  • substituents hydrogen; alkane; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; amide; carboxamide; sulfhydryl; Ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; Unsubstituted pyrrolyl;
  • R 2 , R 3 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl. Any subject can be controlled by this method, preferably a mammal, more preferably a human.
  • the method can be used to control metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease).
  • a preferred disease or condition is any disease or condition caused or accompanied by insulin secretion and/or dysfunction.
  • metabolic disorders including but not limited to diabetes, islets
  • the compounds of the invention may be used alone or in combination with other therapeutic agents for diabetes, including insulin sensitizers, which are already on the market or to be marketed.
  • Any suitable metabolic disorder (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.
  • the above-mentioned diabetes therapeutic agents including insulin sensitizers
  • Suitable diabetes treatments include the use of insulin sensitizers in combination.
  • 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.
  • in vivo substances such as glycated hemoglobin, enzymes, antigens, antibodies, nucleic acids or other pathological and clinical markers, and related symptoms.
  • in vivo substances such as glycated hemoglobin, enzymes, antigens, antibodies, nucleic acids or other pathological and clinical markers, and related symptoms.
  • international patent WO 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 one or more therapeutic agents for diabetes include insulin sensitizers.
  • such a combination comprises a compound of the present invention or a pharmaceutically acceptable salt thereof, and all of its stereo and optical isomers, or a prodrug having the same pharmacological action thereto, an ester thereof, a solvate thereof or Metal complexes and one or more therapeutic agents for diabetes include insulin sensitizers, which are represented by the following general formula I:
  • X and Y are respectively (C3 ⁇ 4) n and n is 0-2, oxygen, sulfur or nitrogen.
  • substituents hydrogen; alkane; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; amide; carboxamide; sulfhydryl; Ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; Unsubstituted pyrrolyl;
  • R 2 , R 3 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • Any suitable therapeutic agent for diabetes 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 metabolic disorder including but not limited to diabetes, insulin resistance, and obesity
  • cardiovascular disease cardiovascular disease
  • a method of sexually transmitted diseases which comprises administering an effective amount of the above combined preparation, or a pharmaceutically acceptable salt thereof, to a subject in need and willingness to receive treatment or prevention, thereby treating or preventing the above-mentioned diseases or symptoms .
  • a kit 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 the prevention and treatment of a metabolic disorder (including However, it is not limited to instructions for use such as diabetes, insulin resistance and obesity, cardiovascular diseases and neurodegenerative diseases such as Alzheimer's disease.
  • a kit is provided comprising the combination described above and the use of the combination to prevent metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular disease and neurodegenerative Instructions for use of diseases such as Alzheimer's disease.
  • 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 that can be used in the present invention include, but do not It is limited to the contents set forth in U.S. Patent Nos. 5,736,154, 6,197,801, B1, 5,741,511, 5,886,039, 5,941,868, 6,258,374, and 5,686,102.
  • 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 present invention may be in accordance with conventional pharmaceutical mixing techniques with pharmaceutical carriers or excipients such as ⁇ -cyclodextrin and 2-hydroxypropyl- ⁇ -bad dextrins. 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 to 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.
  • the preferred pharmaceutical form is with sterile saline, dextrose solution, buffered Solution, or other pharmaceutically acceptable sterile liquid combination.
  • 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. Instructions for use by a doctor or patient may optionally be included.
  • the genetic method detects the agonistic effect of a compound on GLP-1R.
  • the GLP-1 concentration gradient was 10, 1, 0.1, 0.01, 0.001, 0.0001 nM, and the luciferase activity induced by ⁇ was 100%, and the EC 50 value of GLP-1 was measured to be 0.07 nM.
  • Figure 2. Reporter gene method to detect the antagonism of exendin 9 _ 39 on GLP-1.
  • the concentration of GLP-1 was 0.05 nM, and the concentration gradient of exendin 9-39 was 10000, 1000, 100, 10, 1, 0.1, 0 nM, and the activity of exendin 9-39 was set to 100%. The test showed exendin.
  • the GLP-1 concentration gradient was 1000, 200, 40, 8, 1.6, 0.32, 0.064, 0 nM.
  • GLP-1 specifically binds GLP-1R to the 125 1 standard GLP-1 with an IC 5Q value of 0.66 nM.
  • the color pan column is ZORBAX SB-C18 (2.1 X 150 mm, 3.5 ⁇ )
  • the mobile phase is acetonitrile/water
  • the flow rate is 0.2 ml/min
  • the detection wavelength is 254 ⁇ .
  • Example 1 The melting point was measured using an IA6304 melting point apparatus; NMR was measured by Varian Mercury-300 and Varian Mercury Plus 400 nuclear magnetic resonance spectrometer (solvent was CDC1 3 , CD 3 OD or DMSO-d 6 ); ESI-MS was performed by AB Mariner mass spectrometer It was measured that EI was measured by a Firmigan MAT95 spectrometer.
  • the materials used in the synthesis are commercially available products unless otherwise specified. The following specific examples are intended to further illustrate the invention but are not intended to limit the invention.
  • Example 1 The melting point was measured using an IA6304 melting point apparatus; NMR was measured by Varian Mercury-300 and Varian Mercury Plus 400 nuclear magnetic resonance spectrometer (solvent was CDC1 3 , CD 3 OD or DMSO-d 6 ); ESI-MS was performed by AB Mariner mass spectrometer It was measured that EI was measured by a Firmigan MAT95 spectrometer.
  • the materials used in the synthesis are commercial
  • the above amide (leq) was dissolved in methanol, a few drops of concentrated sulfuric acid was added dropwise, and the mixture was heated under reflux for 8 hours to give an ester. The above ester and thionyl chloride were reacted by heating for 2 hours to obtain a cyclic compound.
  • Example 2 The starting acid (leq) was dissolved in methanol, a few drops of concentrated sulfuric acid was added dropwise, and the mixture was heated under reflux for 8 hours to obtain an ester.
  • the above ester (2 eq) was heated to 1.80 ° C under the protection of nitrogen, and the compound phenyldiazonium (leq) was slowly added dropwise at a rate to maintain the reaction temperature of 180 ° C - 190 ° C. Cool to give an orange residue.
  • An appropriate amount of 10% diethyl ether/n-pentane was added and filtered to obtain a compound having a substituted cyclopropane structure.
  • the above compound having a substituted cyclopropane structure is dissolved in decyl alcohol, and a sodium hydroxide solution is added thereto, followed by heating to obtain a product.
  • the same method yields the following products:
  • Example 3 The raw material acid (leq) was dissolved in methanol, a few drops of concentrated sulfuric acid was added dropwise, and the mixture was heated under reflux for 8 hours to obtain an ester.
  • the above ester (2 eq) was heated to 180 ° C under the protection of nitrogen, and the compound phenyldiazonium (leq) was slowly added dropwise at a rate to maintain the reaction temperature of 180 ° C - 190 ° C. Cool to give an orange residue.
  • An appropriate amount of 10% acetamino/n-pentane was added and filtered to obtain a compound having a substituted cyclopropane structure.
  • GLP-1R is a G protein-coupled receptor.
  • the Get subunit of the 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 pre-insulin gene, cAMP binds to the response element to initiate transcription of the pre-insulin gene, thereby stimulating insulin expression and secretion (Diabetes, 2000, Vol.
  • the human embryonic kidney cell line (HEK 293) stably transfected with GLP-1R receptor gene expression vector and luciferase reporter gene expression vector regulated by cAMP response element was used to detect its response to the test compound (Celliology) , 1992, Vol. 89:8641-8645; Proc. Natl. Acad. Sci. USA 1987, Vol. 84:3434-3438 ). Samples that induce fluorescein ⁇ reporter gene expression when screened for compounds, It has GLP-1R agonistic activity.
  • Test materials and instrument cell lines HEK 293/GLP-lR+Luc cell line stably expressed by GLP-1R and luciferase (self-built by National New Drug Screening Center) Fetal bovine serum (GIBCO) DMEM medium (GIBCO) Steady-GloTM Luciferase Assay System (Promega)
  • Forma CO2 incubator Forma
  • HEK293/GLP1R+Luc cells were incubated at 20,000/100 ⁇ /well into 96-well culture plates at 37 in DMEM medium containing 10% fetal bovine serum and 500 g/ml G418. C was cultured overnight. The GLP-1 standard was diluted to a concentration gradient and then added to the above 96-well microplate in ⁇ /well. At 37. C, cultured for 6 hours under 5% C0 2 conditions. Luciferase activity was measured by the Steady-GloTM Luciferase Assay System Kit and the Victor 2 reader was used for readings.
  • DMEM medium (GIBCO)
  • HEK293/GLP1R+Luc cells were incubated at 20,000/100 ⁇ /well into 96-well culture plates at 37 in DMEM medium containing 10% fetal bovine serum and 500 g/ml G418. C cultured Night. Dilute Exendin 9-39 to a concentration gradient and then add 1 ⁇ M/well to the 96-well microplate at 37. Incubate for 10 minutes at C, 5% C0 2 , then add 0.05 nM GLP-1 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.
  • Exendin 9 . 3 dose-dependently inhibited reporter gene expression induced by GLP-1 (Table 2, Figure 2) with an IC 5Q value of 68.22 nM, indicating that its biological activity is mediated by GLP-1R. Table 2.
  • the method for detecting a reporter gene is a method for indirectly determining the level of intracellular cAMP concentration. In order to determine that the active compound can actually increase the intracellular cAMP concentration, directly by cAMP test The test kit is functionally verified.
  • Test materials and instrument cell lines HEK 293/GLP-lR+Luc cell line stably expressed by GLP-1R and luciferase (self-built by National New Drug Screening Center) cAMP test kit (Applied Biosystems) Forma carbon dioxide incubator ( Forma) Victor 2 Plate Reader (Wallac) cAMP Standard (kit comes with Applied Biosystems) 3.2 Test-risk method
  • HEK 293 cells were inserted into a 96-well culture plate at 20,000 / lOOul / well, cultured overnight at 37 ° C, GLP-1 was diluted with disulfoxide, and added to the above 96-well microplate in lul / well. Incubate for 15 min at 37 ° C, 5% CO 2 . Intracellular cAMP levels were measured by cAMP-Screen DirectTM Systerm kit instructions.
  • GLP-1 dose-dependently induces intracellular cAMP production (Table 3, Figure 3) with an EC 5() value of 0.079 nM, suggesting that it acts as a GLP-1R agonist and plays a role in GLP-1R signaling. effect.
  • Table 3 Induction of intracellular cAMP by GLP-1 (% response to 10 nM GLP-1
  • HEK 293/GLP1R+Luc cell line self-built by National New Drug Screening Center
  • Labeling compound 125 1 labeled GLP-1 (Amersham Biosciences)
  • GLP-1 specifically binds receptors to the 125 1 standard GLP-1 (Table 4, Figure 4), IC 5 . The value is 0.66 nM. Table 4. Binding viability test of GLP-1 to GLP-1R

Abstract

L'invention concerne des composés à structure de cyclopentane substitué représentés par la formule générale I, un procédé de préparation de ceux-ci, et leurs utilisations en tant que type de régulateurs d'accepteurs glucagons-1 dans la prévention et/ou le traitement de troubles métaboliques (notamment, entre autres le diabète, la résistance à l'insuline et l'adipose), de l'angiocardiopathie et de maladies neurodégénératives (telles que la maladie d'Alzheimer).
PCT/CN2007/002975 2006-12-05 2007-10-17 Composés à structure de cyclopentane, procédé de préparation et utilisations médicales de ceux-ci WO2008067712A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNA2006101191073A CN101195584A (zh) 2006-12-05 2006-12-05 一类具有取代环丙烷结构的化合物、制备方法及其医学用途
CN200610119107.3 2006-12-05

Publications (1)

Publication Number Publication Date
WO2008067712A1 true WO2008067712A1 (fr) 2008-06-12

Family

ID=39491651

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2007/002975 WO2008067712A1 (fr) 2006-12-05 2007-10-17 Composés à structure de cyclopentane, procédé de préparation et utilisations médicales de ceux-ci

Country Status (2)

Country Link
CN (1) CN101195584A (fr)
WO (1) WO2008067712A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107698417B (zh) * 2017-09-21 2020-08-25 宁波九胜创新医药科技有限公司 一种含炔基环丙化合物的制备方法
CN112745319B (zh) * 2019-10-30 2022-06-17 中国科学院上海药物研究所 一类取代三环结构的化合物、其制备方法及用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1626521A (zh) * 2003-12-12 2005-06-15 中国科学院上海药物研究所 一类胰高血糖样肽－1 受体激动剂及其制备方法和用途
CN1884278A (zh) * 2005-06-24 2006-12-27 中国科学院上海药物研究所 一类胰高血糖样肽－1受体调节剂、制备方法和用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1626521A (zh) * 2003-12-12 2005-06-15 中国科学院上海药物研究所 一类胰高血糖样肽－1 受体激动剂及其制备方法和用途
CN1884278A (zh) * 2005-06-24 2006-12-27 中国科学院上海药物研究所 一类胰高血糖样肽－1受体调节剂、制备方法和用途

Also Published As

Publication number Publication date
CN101195584A (zh) 2008-06-11

Similar Documents

Publication Publication Date Title
WO2008119238A1 (fr) Composés hétérocycliques substitués à cinq éléments, leur méthode de préparation et leur utilisation en médecine
US9458118B2 (en) Sodium channel modulators for the treatment of pain and diabetes
WO2009129696A1 (fr) Type de modulateurs positifs de transduction de signalisation de récepteur, procédés de préparation et utilisations de ceux-ci
WO2007009389A2 (fr) Derives de propanamide substitues, preparation et utilisation de ces derives
JP2016504282A (ja) ジヒドロピラゾールｇｐｒ４０モジュレーター
CA2613155C (fr) Regulateurs de recepteurs de peptide-1 de type glucagon, procedes de preparation et d'utilisation de ceux-ci
CN100453533C (zh) 一类胰高血糖样肽－1受体激动剂及其制备方法和用途
US20170304306A1 (en) SELECTIVE NaV1.7 INHIBITORS FOR THE TREATMENT OF DIABETES
WO2008067712A1 (fr) Composés à structure de cyclopentane, procédé de préparation et utilisations médicales de ceux-ci
WO2008067709A1 (fr) Composés de cyclobutane substitués, procédés de préparation et leurs utilisations pharmaceutiques
WO2008067713A1 (fr) Composés à structure de cyclopentane, leurs procédés de préparation et leurs utilisations médicales
WO2008067711A1 (fr) Composés à structure du cycle à 4 éléments substitués et leurs utilisations en tant que médicament
WO2008067710A1 (fr) Composés de cyclohexane substitués, procédés de préparation et utilisations médicales correspondants
CN112745319B (zh) 一类取代三环结构的化合物、其制备方法及用途
WO2008119248A1 (fr) Méthode de préparation d'une réaction photochimique de composés cycliques à quatre éléments
CN107805213A (zh) 苯硫乙酸类衍生物、其制备方法及其作为药物的用途
WO2007009353A1 (fr) Composes thiazol-4-one substitues, leurs procedes de fabrication et leur utilisation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07816589

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07816589

Country of ref document: EP

Kind code of ref document: A1