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WO2008067711A1 - Composés à structure du cycle à 4 éléments substitués et leurs utilisations en tant que médicament - Google Patents

Composés à structure du cycle à 4 éléments substitués et leurs utilisations en tant que médicament Download PDF

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Publication number
WO2008067711A1
WO2008067711A1 PCT/CN2007/002959 CN2007002959W WO2008067711A1 WO 2008067711 A1 WO2008067711 A1 WO 2008067711A1 CN 2007002959 W CN2007002959 W CN 2007002959W WO 2008067711 A1 WO2008067711 A1 WO 2008067711A1
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group
substituted
halogen atom
alkoxy
amide
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Chinese (zh)
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Mingwei Wang
Desu Chen
Na Li
Qing Liu
Jiayu Liao
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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

Definitions

  • the present invention relates to a class of compounds having a substituted four-membered ring structure as a modulator of Glucagon like peptide-1 receptor (GLP-1R) in the prevention and/or treatment of metabolic disorders (including Not limited to medical use such as diabetes, insulin resistance and obesity, cardiovascular disease and neurodegenerative diseases such as Alzheimer's disease.
  • metabolic disorders including Not limited to medical use such as diabetes, insulin resistance and obesity, cardiovascular disease and neurodegenerative diseases such as Alzheimer's disease.
  • Type 1 diabetes Disorders of glucose metabolism, especially diabetes, have become a major disease in modern society that seriously threatens human health and life. 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.
  • 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.
  • the potassium ion channel When the sulfonylurea-type hypoglycemic agent binds to the receptor of the pancreatic ⁇ -cell membrane, the potassium ion channel is closed, and the potassium ion efflux is blocked, resulting in depolarization of the cell membrane, causing the Ca 2+ channel to open, causing extracellular calcium influx, intracellular. When 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.
  • hypoglycemic agents mainly include Thiazolidinediones (such as troglitazone, rosiglitazone, pioglitazone, etc.), ⁇ 3-adrenergic receptor modulators, glucagon receptor antagonists, and fatty acids.
  • Thiazolidinediones such as troglitazone, rosiglitazone, pioglitazone, etc.
  • ⁇ 3-adrenergic receptor modulators such as glucagon receptor antagonists
  • glucagon receptor antagonists such as glucagon receptor antagonists
  • Metabolic interference drugs such as acarbose, voglibose, miglitol, etc.
  • aldose reductase inhibitors such as acarbose, voglibose, miglitol, etc.
  • GLP-1R Glucagon like peptide-1 receptor
  • GPCR G protein-coupled receptor
  • GLP-1 In vitro, GLP-1 promotes differentiation of embryonic stem cells into insulin Secreted beta-like cells (J Endocrinol. 2005, 186: 343-52). 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' Treatment of s disease (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.
  • GLP-1R has the effect of lowering blood pressure and dilating blood vessels.
  • Acute injection of 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 innovative drugs such as the GLP-1 derivative developed by Danovo Nordisk in Denmark (trade name Liraglutide; entering Phase III clinical trials) and Amylin Pharmaceuticals and Lilly in the United States.
  • the company's joint development of the GLP-1 analogue Exendin-4 (trade name Exenatide; has been approved for listing in April last year, this year's sales are expected to exceed $1 billion).
  • GLP-1 and its peptide analogs there have been no reports of successful development of non-peptide small molecule GLP-1R agonists. 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. Summary of the invention
  • the object of the present invention is to provide a compound having a substituted four-membered ring structure represented by the following formula I or II, and a pharmaceutically acceptable salt, ester, solvate, metal complex thereof or the same pharmacological action.
  • a prodrug another object of the present invention is to provide a pharmaceutical composition comprising a compound represented by the following formula I or hydrazine or a pharmaceutically acceptable salt, ester, solvate or metal complex thereof;
  • a further object of the present invention is to provide a compound represented by the following Formula I or II or a pharmaceutically acceptable salt, ester, solvate or metal complex thereof as a glucagon-like peptide-1 receptor modulator in the prevention And/or for medical use in the treatment of metabolic disorders including, but not limited to, diabetes, insulin resistance and obesity, cardiovascular diseases and neurodegenerative diseases such as Alzheimer's disease.
  • 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 having a substituted four-membered ring structure represented by the following formula I or II, or a pharmaceutically acceptable salt, ester, solvate, metal complex thereof or prodrug having the same pharmacological action:
  • the compounds include all stereo and optical isomers thereof.
  • n is 0-2; 0; S or NH.
  • R t and R 2 are each independently one of the following substituents: hydrogen; halogen; alkyl; cycloalkyl; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; Carboxamide; mercapto; thiol; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; a substituted or unsubstituted thienyl group; or a substituted or unsubstituted pyrrolyl group.
  • R 3 each independently of any of the following substituents: hydrogen; alkyl; cycloalkyl; decyloxy; amine; amine alkyl; amide; carboxamide; thiol; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • R 5 is any of the following substituent groups: H; C t - (6 groups of embankment; one, two or three substituents include a halogen atom contain any, dC ⁇ alkoxy or hydroxy embankment, including the dC An alkyl group of 6 ; ( 2 : 6 alkenyl; any one, two or three substituted C 2 -alkenyl groups including a halogen atom, a decyloxy group of dC 6 or a hydroxyl group; C 2 - ⁇ alkynyl; comprising any one, two or three substituents a C 2 -C 6 alkynyl group include a halogen atom, a hydroxyl group or a C 6 embankment of including; C 3 - C 6 cycloalkyl group; and includes any containing halogen, C "C e is a hydroxyl group or embankment, including one, two or three substituents of C 3 - C 6 cycloalky
  • R 3 and ⁇ are respectively:
  • substituents H; C 6 alkyl; or any one, two or three substituted d-C 6 including a halogen atom, d-( 6 alkoxy group or hydroxyl group) alkyl; C 2 - C 6 alkenyl; containing optionally include halogen atoms, C "embankment.
  • C 6 is alkoxy or hydroxy, including a C, two or three substituents of C 2 - C s alkenyl;
  • R 7 and R 8 are each independently a substituent of any of the following: H; d-alkyl; any one, two or three substituted groups including a halogen atom, an alkoxy group of CrC 6 or a hydroxyl group.
  • a fluorenyl group of CrC 6 a C 2 -C 6 alkenyl group; an alkenyl group containing any one, two or three substituted C 2 C s including a halogen atom, an alkoxy group of d- or a hydroxyl group; 2 - (: 6 alkynyl; any one, two or three substituted c 2 - () 6 alkynyl group including a halogen atom, d-C 6 alkoxy group or a hydroxyl group; c 3 - a cycloalkyl group of 6 6; a cycloalkyl group of any one, two or three substituted c 3 - c 6 having a halogen atom, an alkoxy group of d- or a hydroxyl group; an aryl group; a benzyl group; a pyranyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group;
  • CrC ⁇ alkyl nitro, carboxy, aldehyde, decyloxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio, any one, two or three substituted furans group; include a halogen atom-containing, - any (alkyl, nitro, carboxyl, acyloxy, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including a 4 , two or three substituted pyranyl groups; containing a halogen atom, d-C 4 fluorenyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, fluorenyl group, A Any one, two or three substituted thienyl groups including a thio group or an ethylthio group; containing an alkyl group including a
  • H is any one of the following substituents: H; C alkyl; any one, two or three substituted d ⁇ C 6 alkyl groups including a halogen atom, an alkoxy group of C "0" or a hydroxy group ; (: 2 -( 6 alkenyl; containing halogen Any one, two or three substituted c 2 c (i alkenyl group; c 2 - c 6 alkynyl group of the atom, c, -c 6 alkoxy group or hydroxy group; containing a halogen atom, Ci Any one, two or three substituted C 2 -C 6 alkynyl groups of -Ce alkoxy or hydroxy; C 3 - C e cyclodecyl; containing a halogen atom including a halogen atom, d-Ce Any one, two or three substituted c 3 -c 6 cycloalkyl groups, such as aryl; benzyl; furyl;
  • a three-substituted aryl group containing a halogen atom, an alkyl group of ( ⁇ - ⁇ , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a thiol group, a methylthio group, a thio, including any one, two or three substituted pyridyl; include a halogen atom-containing, c 4 alkyl, nitro, carboxamide , Any aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two or three substituents furanyl; containing a halogen atom include, dc 4 Any one, two or three substituted pyrans of alkyl, nitro, carboxy, aldehyde, alkoxy, amine, amide, carboxamide, s
  • Each of which is independently a substituent of any of the following: H; an alkyl group of Cr C 6 ; an alkyl group containing any one, two or three substituents including a halogen atom, an alkoxy group of d- or a hydroxyl group; a C 2 -alkenyl group; any one, two or three substituted ( 2- ( 6 alkenyl; C 2 -C B 1 ⁇ 2 alkyne) containing a halogen atom, an alkoxy group of CrC 6 or a hydroxyl group; Any one, two or three substituted C 2 -C e alkynyl groups including a halogen atom, an alkoxy group of d-Ce or a hydroxyl group; a C 3 -C 6 cycloalkyl group; Any one, two or three substituted C 3 -C 6 cycloalkyl groups such as a halogen atom, a d-C 6 alkoxy group or a hydroxy
  • R, and R 2 are each independently:
  • R 12, R 13 are each independently any of the following substituent groups: H; C (group 6 of the embankment; contain any halogen atom include, CrC 6 alkoxy or hydroxy, including one, two or three substituents An alkyl group of (2); C 2 - ( 8 alkenyl; an optionally, two or three substituted C 2 - C e alkenyl group including a halogen atom, an alkoxy group of CrC 6 or a hydroxyl group ; C 2 -C fi alkynyl; any one, two or three substituted C 2 - (: 6 alkynyl group; C 3 - C containing a halogen atom, a decyloxy group of C s or a hydroxyl group; 6 cycloalkyl; includes any halogen atom-containing, CrC 6 alkoxy or hydroxy, including one, two or three substituents of C 3 - C e cycloalkyl; aryl; benzyl; fu
  • a substituted thienyl group contains include halogen atoms, - (4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio in Any one, two or three substituted pyrrolyl groups; dC 6 decanoyl group; any one, two or three substituted Ci-Ce containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group the embankment acyl; C 2 -C 6 alkenyl group; a halogen atom-containing include, - embankment any alkoxy or hydroxy (6, including one, two or three substituents of c 2 -c 6 alkenyl group; a C An alkynyl group of 2 - C 6 ; a acetylene group of any one, two or three substituted c 2 - c 6 containing a halogen
  • any one of the following substituents H; - ( 6 fluorenyl; any one, two or three substituted Cr ( 6 alkyl group) including a halogen atom, a Cr ⁇ decyloxy group or a hydroxyl group
  • C 2 - C 6 Alkynyl any one, two or three substituted C 2 -C 6 alkynyl group including a halogen atom, an alkoxy group of dC e or a hydroxyl group; a C 3 -C e cycloalkyl group
  • halogen atom Containing any one including a halogen atom, (-, fluorenyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, thiol group, methylthio group, ethylthio group) , two or three substituted pyranyl groups; containing a halogen atom, d-( ⁇ , alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, A Any one, two or three substituted thienyl groups including a thio group or an ethylthio group; containing a halogen atom, an alkyl group of 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group , carboxamide, sulfhydryl
  • R 3 and R 4 are -
  • R 7 and R 8 are each independently one of the following substituents: H; dC fluorenyl; any one, two or three substituted CrCe containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; An alkyl group; a C 2 -C e alkenyl group; any one, two or three substituted C 2 - ( ⁇ alkenyl groups) containing an alkoxy group or a hydroxyl group including a halogen atom, C, -C s ; (alkynyl group of 2 6 ; alkynyl group having any one, two or three substituted C 2 - C s including a halogen atom, an alkoxy group or a hydroxyl group; a C 3 -C 6 cycloalkyl group; ; include a halogen atom-containing, C, - C e of any embankment or a hydroxyl group, including one, two or three substituents
  • R 3 is any one of the following substituents: H; c, a fluorenyl group; any one, two or three substituted (including 6 fluorenyl groups including a halogen atom, (a alkoxy group or a hydroxyl group)
  • An alkenyl group of c 2 - c e any one, two or three substituted C 2 -C 6 alkenyl groups including a halogen atom, a decyloxy group of dC 6 or a hydroxyl group
  • One, two or three substituents pyrrolyl; of Cr alkanoyl; contains include halogen atoms, - alkoxy or hydroxy arbitrary, including one, two or three C embankment substituted acyl group "of the C 6; a C 2 -C 6 alkenoyl group; any one, two or three substituted C 2 -C 6 alkenoyl groups including a halogen atom, an alkoxy group of d-Ce or a hydroxyl group; C 2 - C e Alkynyl group; any one, two or three substituted C 2 -C 6 alky
  • R tl are each independently a substituent of any of the following: H; an alkyl group of d-C 6 ; any one, two or three substituted dCs including a halogen atom, an alkoxy group of CrC 6 or a hydroxyl group; Alkenyl group; C 2 -C e alkenyl group; any one, two or three substituted C 2 -C 6 alkenyl group including a halogen atom, a decyloxy group or a hydroxyl group of Cr; C 2 - an alkynyl group; any one, two or three substituted C 2 - ( 6 alkynyl groups; C 3 - C 6 containing an alkoxy group including a halogen atom, C, -C 6 or a hydroxyl group; a cycloalkyl group; any one, two or three substituted C 3 - C s cycloalkyl groups including a halogen atom, an alkoxy group of
  • R 2 is each independently:
  • RM is any one of the following substituents: H; an alkyl group of CrCe; any one, two or three substituted ( 6 alkyl groups) including a halogen atom, a decyloxy group of d-C 6 or a hydroxyl group C 2 - ( 6 alkenyl; any one, two or three substituted C 2 - ( 6 alkenyl; C 2 - (; 6 ) containing a halogen atom, an alkoxy group or a hydroxyl group; An alkynyl group; any one, two or three substituted C 2 -C B alkynyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; a C 3 -C 6 cycloalkyl group; Any one, two or three substituted C 3 -C 6 cyclodecyl groups such as a halogen atom, an alkoxy group of a CrC 6 or a hydroxyl group;
  • H is any one of the following substituents: H; ("( 6 fluorenyl; any one, two or three substituted d- including a lii atom, C" (a alkoxy group or a hydroxyl group)
  • two or three substituted pyranyl groups containing a halogen atom, a fluorenyl group of d-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 group Any one, two or three substituted thienyl groups including a thio group or an ethylthio group; containing a halogen atom, a mercapto group of ( 4 ), a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, Amido, carboxamide, sulfhydryl, methylthio, B Group, including any one, two or three substituents pyrrolyl; c, - C B of alkanoyl; contain any halogen atoms include, dC 6 alkoxy,
  • R 7 each independently is any one of the following substituents: H; d- ( 6 alkyl; any one, two or three substituted including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group) a fluorenyl group; a C 2 -CJ alkenyl group; any one, two or three substituted C 2 - ( 6 alkenyl groups; C 2 containing an alkoxy group including a halogen atom, d-Ce or a hydroxyl group; Alkynyl group of -C 6 ; alkynyl group of any one, two or three substituted C 2 - C s including a halogen 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 e cyclodecyl groups including a halogen atom, an alkoxy group of d-C
  • R 3 is any one of the following substituents: H; C" thiol group of C e ; any one, two or three substituted groups including a halogen atom, a d-C alkoxy group or a hydroxyl group - ( 6 ⁇ group; c 2 - alkenyl; optionally include a halogen atom-containing, CrC 6 alkoxy or hydroxy, including one, two or three substituents of C 2 - (alkenyl; C 2 - (6 alkynyl Any one, two or three substituted C 2 -C B alkynyl group including a halogen atom, an alkoxy group or a hydroxyl group of CrCe; a cycloalkyl group of c 3 - C s ; containing a halogen atom any alkoxy or hydroxy dC e inner one, two or three substituents of ⁇ - c 6 cycloalkyl; and aryl
  • each of Ru and Ru is independently any one of the following substituents: H; dC fluorenyl; any one, two or three substituted dGs including a halogen atom, an alkoxy group of d-Ce or a hydroxyl group; An alkyl group; a C 2 -C cramp alkenyl group; any one, two or three substituted C 2 - C (; alkenyl group; C containing an alkoxy group including a halogen atom, d-Ce or a hydroxyl group; 2 - (6 alkynyl; contain optional atoms including vegetarian, C "C 6 alkoxy or hydroxy embankment inner one, two or three substituents of C 2 - C 6 alkynyl group; C 3 - C 6 a cycloalkyl group; any one, two or three substituted C 3 -C e cycloalkyl groups including a halogen atom, an alkoxy group of d-C 6 or
  • Two or three substituted pyranyl groups containing a halogen atom, d-( ⁇ , alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio Any one, two or three substituted thienyl groups, including a halogen atom; (-(: 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, Any one, two or three substituted pyrrolyl groups such as an amide group, a carboxamide group, a fluorenyl group, a methylthio group or an ethylthio group; a decanoyl group of dC 6 ; an alkoxy group containing a halogen atom, C "C 6 " Any one, two or three substitutions, including a hydroxy group Cr C e alkanoyl; C 2 -C 6 alkenyl group; a halogen
  • R and R 2 are each independently:
  • R 15 and R 16 are each independently a substituent of any of the following: H; an alkyl group of dC 6 ; any one, two or three substituted groups including a halogen atom, an alkoxy group of d- or a hydroxyl group; An alkyl group of c!-; an alkenyl group of c 2 -c 6 ; an alkenyl group containing any one, two or three substituted c 2 -c 6 groups including a halogen atom, an alkoxy group of c 6 or a hydroxyl group; C 2 - (alkynyl group of 6 ; alkynyl group containing any one, two or three substituted C 2 - C s including a halogen atom, (alkoxy group of Ce or a hydroxyl group); C 3 -C 6 cycloalkyl; contain any halogen atoms include, d-Ce alkoxy or hydroxy the embankment, including one, two or three substituent
  • a three-substituted furyl group containing an alkyl group including a halogen atom, Cr 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 methylthio group, an ethyl sulfide Arbitrarily One, two or three substituted pyranyl groups; containing a halogen atom, d-( ⁇ , alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, Any one, two or three substituted thienyl groups including a methylthio group and an ethylthio group; containing an alkyl group including a halogen atom, d-c, a nitro group, a carboxyl group, an acid group, an alkoxy group, an
  • alkanoyl alkanoyl group containing any one, two or three substituted C e including a halogen atom, an alkoxy group or a hydroxyl group of CrCe; a C 2 - C 6 alkenoyl group; containing a 13 ⁇ 4 atom any alkoxy or hydroxy c 'c E inner one, two or three substituents of c 2 - C 6 alkenyl group of; C 2 - C s alkynyl group; contains include halogen atoms, the oxygen embankment Any one, two or three substituted c 2 -c 6 alkynyl groups, or a hydroxyl group; c 3 -c s cycloalkanoyl group; containing a halogen atom, d- alkoxy group or hydroxyl group Any one, two or three substituted c 3 - ⁇ cyclodecanoyl; adamantyl formyl, substituted adamantyl formyl;
  • any one of the following substituent groups H; alkyl C "6, C; include a halogen atom-containing, any alkoxy or hydroxy (6, including one, two or three substituents of C 6 D- Alkyl; C 2 _C S alkenyl; any one, two or three substituted C 2 - ( 6 alkenyl; C 2 - containing a halogen atom, an alkoxy group of d-Ce or a hydroxyl group; (6 alkynyl group; a halogen atom includes any containing, G-Ce alkoxy or hydroxy group including one, two or three substituents of C 2 -C e alkynyl group; C 3 - C 6 cycloalkyl firing of Any one, two or three substituted ( 3 -C e cycloalkyl groups; aryl; benzyl; furyl; pyran) containing a halogen atom, an alkoxy group of d-Ce or a
  • R 7 is each independently a substituent of any of the following: H; a fluorenyl group of C 6 ; any one, two or three substituted C's including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group.
  • H is any one of the following substituents: H; d- (: 6 alkyl; any one, two or three substituted d-containing a halogen atom or a hydroxyl group including a halogen atom, d-C e ( 6 : an alkyl group; a C 2 -C 6 alkenyl group; any one, two or three substituted ( 2- ( 6- ) alkenyl group including a halogen atom, a decyloxy group or a hydroxyl group of dC e
  • R u are each independently any of the following substituent groups: H; CrC 6 alkyl; one, two or three substituents include a halogen atom-containing arbitrary, C, -C 3 alkoxy or hydroxy embankment inner of D- ⁇ alkyl; C 2 -C e alkenyl; any one, two or three substituted ( 2- ( 6 olefin) containing a halogen atom, a decyloxy group or a hydroxyl group of d-Cs a C 2 - (alkynyl group; any one or two containing an alkoxy group including a halogen atom, C, or C 6 or a hydroxyl group; 2007/002959 three substituted c 2 -C e alkynyl groups; C 3 -C 6 cycloalkyl groups; containing any one or two including a halogen atom, an alkoxy group of d-c 6 or a hydroxyl group or Three substituted
  • 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 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 neurodegenerative diseases (eg Alzheimer's) Ill).
  • 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 which 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.
  • a compound having a substituted four-membered ring structure represented by II, or a pharmaceutically acceptable salt, ester, solvate, metal complex thereof or prodrug having the same pharmacological action The compounds include all stereo and optical isomers thereof.
  • X and Y are respectively (CH 2 ) march, n is 0-2; 0; S or NH.
  • R 2 is each independently one of the following substituents: hydrogen; halogen; alkyl; cycloalkyl; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine sulfhydryl; Carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Unsubstituted thienyl; or substituted or unsubstituted pyrrolyl.
  • Each of which is independently a substituent of any of the following: hydrogen; alkyl; cycloalkyl; 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 or II -
  • X and Y are respectively (CH 2 ) march, n is 0-2; 0; S or NH.
  • R 2 is each independently one of the following substituents: hydrogen; halogen; alkyl; cycloalkyl; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine sulfhydryl; ; carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Or an unsubstituted thiophenyl group; or a substituted or unsubstituted pyrrolyl group.
  • R 3 each independently of any of the following substituents: hydrogen; alkyl; cycloalkyl; 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 sputum not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and 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 disorders including sputum not limited to diabetes, insulin resistance and obesity
  • cardiovascular diseases such as Alzheimer's disease.
  • neurodegenerative diseases such as Alzheimer's disease.
  • 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 insulin secretion and/or dysfunction.
  • the metabolic disorders in the body are not well controlled, leading to chronic complications of tissues such as the eyes, kidneys, nerves, blood vessels and heart, resulting in blindness, gangrene in the lower limbs, Uremic, stroke or myocardial infarction, even life-threatening.
  • insulin resistance refers to a decrease in the sensitivity of tissues surrounding the body 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 male 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.
  • AD Alzheimer's Disease
  • AD Alzheimer's dementia
  • 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.
  • 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 substance, such as enzymatic activity and biological activity.
  • Methods for producing 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 into 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 to transport precursors of properties, to mask their side effects or toxicity, to improve the taste of the drug, or to alter other properties.
  • substantially is the same or uniform or similar, and the understanding of the related art by those skilled in the art can vary from context to context and is generally at least 70%, preferably at least 80%, more preferably at least 90%. , optimally at least 95% identical.
  • composition refers to any mixture. It may be a solution, suspension, liquid, powder, ointment, aqueous, non-aqueous or any combination thereof.
  • object as used herein includes humans and animals, for example, dogs, cats, cows, pigs, rodents, and the like.
  • metabolic disorders including but not limited to diabetes, insulin resistance and obesity
  • cardiovascular disease including but not limited to diabetes, insulin resistance and obesity
  • neurodegenerative diseases such as Alzheimer's disease
  • B-glucagon-like peptide-1 receptor modulator The present invention provides a modulator of glucagon-like peptide-1 receptor function, which increases prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and Neurodegenerative diseases (such as
  • the present invention relates to a compound having a substituted four-membered ring structure represented by the following formula I or II, or a pharmaceutically acceptable salt, ester, solvate, metal complex thereof or prodrug having the same pharmacological action -
  • the compounds include all stereo and optical isomers thereof.
  • X and Y are respectively (CH 2 ) march, n is 0-2; 0; S or NH.
  • R 2 is each independently one of the following substituents: hydrogen; halogen; alkyl; cycloalkyl; hydroxy; nitro; carboxy; aldehyde; oxiran; amine; amine alkyl; Carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Unsubstituted thienyl; or substituted or unsubstituted pyrrolyl.
  • R 4 are each independently one of the following substituents: hydrogen; alkyl; cycloalkyl; 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 present invention may be a specific stereoisomer, such as the R- or S-configuration, or a mixture thereof, for example, a racemic mixture.
  • the 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 different amounts of bound water molecules.
  • the compounds of the invention may be prepared or synthesized according to any suitable method.
  • the compound is prepared by the synthetic method cited in Section F below.
  • 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.
  • suitable acid for example, 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 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 willingness 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 four-membered ring structure represented by the following formula I or II, or a pharmaceutically acceptable salt, ester, solvate, metal complex thereof or the same pharmacological agent
  • a compound having a substituted four-membered ring structure represented by the following formula I or II or a pharmaceutically acceptable salt, ester, solvate, metal complex thereof or the same pharmacological agent
  • the compounds include all stereo and optical isomers thereof.
  • X and Y are respectively (CH 2 ) march, n is 0-2; 0; S or NH.
  • R 2 is each independently one of the following substituents: hydrogen; halogen; alkyl; cycloalkyl; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; Carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Unsubstituted thienyl; or substituted or unsubstituted pyrrolyl.
  • Each of which is independently a substituent of any of the following: hydrogen; alkyl; cycloalkyl; 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.
  • the invention may be used alone or in combination with other diabetes therapeutics, including insulin sensitizers that are already on the market or to be marketed. compound of.
  • 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.
  • Administration of the compounds of the invention alone or in combination with other suitable diabetes therapeutics including insulin sensitizers can be by any suitable method. For example, 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 prognosis 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 associated disease or condition and its prognosis.
  • Diagnosis and prognosis can be based on detecting and/or identifying any or all of the in vivo material, 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 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 one or more therapeutic agents for metabolic disorders include insulin sensitizers.
  • such a combination comprises a compound of the present invention or a pharmaceutically acceptable salt thereof and a therapeutic agent for one or more metabolic disorders including an insulin sensitizer, which is represented by the following formula I or II:
  • X and Y are respectively (CH, n is 0-2; 0; S or NH.
  • each independently is any one of the following substituents: hydrogen; halogen; alkyl; cycloalkyl; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; Amido; thiol; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Substituted thienyl; or substituted or unsubstituted pyrrolyl.
  • R 3 each independently of any of the following substituents: hydrogen; alkyl; cycloalkyl; alkoxy; amine; amine alkyl; amide; carboxamide; thiol; 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 method of treating or preventing a disease or condition caused or accompanied by insulin secretion and/or dysfunction is provided, the method comprising administering an effective amount to a subject in need and willing to receive treatment or prevention The above combined preparation, or a pharmaceutically acceptable salt thereof, thereby treating or preventing the above 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.
  • kits 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 added 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 a powder form with a suitable vehicle, sterile non-pyrogenic water or other solvent before use.
  • the topical preparation of the present invention may be a foam, a gel, an ointment, an ointment, a transdermal patch, or a paste.
  • compositions and methods for administration that may be used in the present invention include, but are not limited to, U.S. Patents 5,736,154, 6,197, 801 Bl, 5,741,511, 5, 886, 039 5, 941, 868, 6, 258, 374B1 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.
  • the dose and frequency of administration will vary with age, weight, health status, and individual patient response.
  • Dosage forms include tablets, lozenges, lenticular capsules, dispersing agents, suspending agents, solutions, capsules, films and the like.
  • the compound of the present invention may be in accordance with a general pharmaceutical mixing technique with a pharmaceutical carrier or excipient such as ⁇ -cyclodextrin and 2-hydroxypropyl- ⁇ -cyclodextrin. Finely mixed.
  • a pharmaceutical carrier or excipient such as ⁇ -cyclodextrin and 2-hydroxypropyl- ⁇ -cyclodextrin. Finely 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 preferably a sterile solution
  • Typical pharmaceutically acceptable solutions are physiological saline and dextrose solutions.
  • the kit of the present invention further comprises a needle or syringe and/or a packaged alcohol pad for injection of the composition, preferably in a sterile form. Instructions for use by a doctor or patient may optionally be included.
  • the compound represented by the formula I or II of the present invention is produced by the method described below, wherein the starting materials are synthesized by the synthesis method described in the Chinese Patent Application (Application No.: 200310109331. 0).
  • the preparation method of the compound represented by the formula I or II of the present invention is as follows:
  • the compound 1 and the compound 2 are dissolved in a suitable amount of a mixed solvent of dichloromethane, water, dichloroethane, DMSO, dioxane or the above solvent, optionally with a catalytic amount of benzophenone, and the reaction temperature is controlled at 0. Between C and 60 ° C, placed in a 150W high-pressure mercury lamp or natural light for 1 day to 2 months, during the period by HPLC detection of the reaction, lyophilization to remove the solvent, the residue was separated by reverse-phase silica gel column chromatography to obtain the present invention Compound.
  • a mixed solvent of dichloromethane water, dichloroethane, DMSO, dioxane or the above solvent
  • a catalytic amount of benzophenone optionally with a catalytic amount of benzophenone
  • Figure 1 illustrates in vitro pharmacodynamic test results of compounds S4P and Boc5 a.
  • HEK293/GLP1R+Luc was induced with different concentrations of GLP-1, S4P and Boc5, respectively, and compounds were evaluated by detecting the expression of CRE-driven luciferase reporter gene.
  • Boc5 of compound S4P and GLP- 1R agonistic activity is dose-dependent average, and both the EC 5.
  • the values are similar (S4P is 1. 2 ⁇ ⁇ , Boc5 is 3.1 ⁇ ⁇ ), but the reaction intensity of S4P at 10 ⁇ is 37.3% of GLP-1 ( ⁇ ), and Boc5 is GLP-1R Full agonist.
  • Exendin (9-39) was used to verify the receptor specificity of the compound for GLP-1R agonistic activity. When added to 0.05 nM GLP-1, 10 4M S4P and Boc5, Exendin (9-39) dose-dependently inhibited the expression of the reporter gene induced by it, IC 5 . The values were 68.22, 14.69 and 33.38 nM, respectively, indicating that the biological activities of S4P and Boc5 and GLP-1 are mediated by GLP-1R. c. Using the 125 1 labeled GLP-1 as a ligand, the affinity of the compound for the receptor is tested by a competitive binding assay.
  • Intraperitoneal injection of Boc5 to suppress appetite ED 6 rendervalue is 1.57 ⁇ 0. 09 mg ⁇ 80 mg / kg.
  • Boc5 intraperitoneal injection of appetite inhibition can be induced by prophylactic intraperitoneal injection of exendin (9-39 Antagonism d.
  • Boc5 oral administration ED 5 for feeding inhibition The value is 0. 53 soil 0. 08 mg.
  • the appetite suppressing effect of oral administration of Boc5 can be antagonized by prophylactic intraperitoneal injection of exendin (9-39).
  • Figure 3 shows the pharmacokinetic parameters of Boc5 in normal C57BL/6 mice. Normal C57BL/6 mice were injected intraperitoneally with Boc5 2mg/20g body weight (3 per time point). The pharmacokinetic parameters were determined by HPLC. analysis. The final elimination half-life is 7.5 ⁇ 1. 2 hours.
  • FIG. 4 illustrates the long-term pharmacodynamic study of compounds S4P and Boc5 a.
  • Each group of mice was randomly divided into blank control group, S4P treatment group and wild type control group according to HbAlc level. The results showed that HbAlc was significantly down-regulated after S4P administration; b.
  • Each group of mice were randomly divided into a free feeding control group, a feeding restriction control group, a Boc5 1 mg group, a Boc5 2 mg group, and a wild type control group according to HbAlc levels.
  • HbAlc was gradually decreased in the intraperitoneal injection of Boc5 1 mg or 2 mg diabetic mice, which reached normal levels at 4-6 weeks of treatment, and was not significantly different from wild-type mice, but significantly lower than the free-feeding control group and the feeding restriction control.
  • Group; c. The fasting blood glucose changes in mice were unstable, but the response trend of each group was related to HbAlc;
  • d. The food intake of the mice in the free feeding control group increased by 23%, and the average body weight increased by 12 g;
  • the body weight changes of Boc5 1 mg and 2 mg treatment groups were not significantly different from wild-type mice, and the weight gain was significantly lower than that of the free-feeding control group.
  • mice were randomly selected for abdominal cavity.
  • the injection glucose tolerance test (IPGTT) showed that the area under the curve (AUC) of the B 0 c5 2 mg treatment group was significantly lower than that of the free feeding control group and the feeding restriction control group ( ). 0006 and). 0006), and the wild There was no significant difference between the mice, suggesting that the glucose tolerance of the Boc5 2 mg treatment group has returned to normal; f.
  • the fasting insulin level of the free feeding control group and the feeding restriction control group is significantly higher than that of the wild type mice. Tip a decrease in insulin sensitivity, and limit food intake compared to the control group, Boc5 1 mg and 2 mg treatment group had some degree of downward trend.
  • HP1100 HPLC system with binary gradient pump, online vacuum degasser, autosampler, column oven and photodiode array detector The column was ZORBAX SB-C18 ( 2. 1 x 150 mm, 3. 5 ⁇ ), the mobile phase was acetonitrile/water 65:35, the flow rate was 0. 2 ml/min, and the detection wavelength was 254 nm.
  • the enthalpy 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 0D or DMSO-cU; ESI-MS was measured by AB Mariner mass spectrometer EI was measured by a Finnigan MAT95 mass spectrometer.
  • the materials used in the synthesis were all commercially available except for the specific source. The following specific examples are intended to further illustrate the invention but are not intended to limit the invention.
  • the compound Wang516 (1 g) was dissolved in an appropriate amount of DMSO, placed under a 150 W high-pressure mercury lamp for 3 days, and 1 ml of water was added thereto for further 7-10 days, during which time the reaction was followed by HPLC. After completion of the reaction, the solvent was removed by cold drying, and the residue was separated by column chromatography. The pale yellow powdery solid compound S4P was obtained.
  • 13 CN R (75MHz, DMS0-d 6 ) 174.7, 172.8, 166.8, 159.4, 150.1, 142.1, 137.7, 135.2, 133.6, 131.6, 129.1, 128.7, 128.1, 122.5, 122.1, 118.1, 112.5, 63.2, 54.9, 48.4 , 45.3, 30.0, 25.7.
  • the compound Wan g 520 (10 g) was dissolved in an appropriate amount of DMS0, placed under a 150 W high pressure mercury lamp for 3 days, and 1 ml of water was added thereto, and the irradiation was continued for 25-30 days, during which time the reaction was followed by HPLC. After completion of the reaction, the solvent was removed by cold drying, and the residue was separated by column chromatography. The pale yellow powdery solid compound Boc5 was obtained.
  • GLP-1R is a G protein-coupled receptor.
  • the Get 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).
  • HEK 293 human embryonic kidney cell strain stably transfected with a GLP-1R receptor gene expression vector and a luciferase reporter gene expression vector regulated by a cAMP response element was used to detect its response to a test compound (Cell). Biology, 1992, Vol. 89:8641-8645; Proc. Natl. Acad. Sci. USA 1987, Vol. 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.
  • DMEM medium (GIBC0 company) Steady-GloTM Luciferase Assay System (Promega)
  • HEK293/GLP1R+Luc cells were inserted into 96-well culture plates at 20,000/100 ⁇ /well, and cultured overnight at 37 ° C in DMEM medium containing 10% fetal bovine serum and 500 ⁇ M/ml G418.
  • the GLP-1 standard and the test compounds S4P and Boc5 were each diluted to a certain concentration gradient, and then added to the above 96-well microplate in ⁇ /well.
  • cultured for 6 hours under 5% CO 2 conditions. Luciferase activity was measured by the Steady-GloTM Luciferase Assay System Kit and the Victor2 reader was used for reading.
  • HEK293/GLP1R+Luc cells were inserted into 96-well culture plates at 20,000/100 ⁇ /well, and cultured overnight at 37 ° C in DMEM medium containing 10% fetal bovine serum and 500 g/ml G418. Dilute Exendin (9-39) to a certain concentration gradient, then add 1 ⁇ /well to the above 96-well microplate, incubate at 37 ° C, 5% CO 2 for 10 minutes, then add 10 ⁇ M S4P, Boc5 and 0. 05 nMGLP-1, at 37. C, cultured for 6 hours under 5% CO 2 conditions. Luciferase activity was measured by the Steady-GloTM Luciferase Assay Kit, and the Victor2 reader was used for reading.
  • HEK 293/GLP1R+Luc cells in 10 5 logarithmic growth phase were incubated with 125 1 GLP-1 positive peptide (final concentration 40 ⁇ ) for 4 hours at 200 ° C in 200 ⁇ l assay buffer.
  • the cells were washed three times with a washing solution using a cell harvester. Scintillation fluid was added and each well reading was read on a Microbata counter.
  • Boc5 compound S4P and capable of specifically 12,511 standard competitive binding with GLP- (Table 3, FIG LC. At a concentration of 30 ⁇ M, 34? Inhibition rate of 8005 and 80.6%, respectively 63. The IC 5 value of the two is 286. 6 nM 1. 5 ⁇ M. Under the same experimental conditions, the IC 5 of the GLP-1 has a value of 0.66 nM.
  • GLP-1 analogues produces inhibition of food intake, delayed gastric emptying, stimulation of insulin secretion, inhibition of glucagon secretion, and repair of insulin first phase secretion (Regul Pept, 2004, Vol. 117 : 77 88 ).
  • Boc5 solution was intraperitoneally injected overnight after fasting to observe the inhibitory effect of acute administration of the compound on appetite.
  • mice female, 6 weeks old, 18-20 g, purchased from Shanghai Slack Laboratory Animal Co., Ltd.
  • Test compound Boc5 with different dose gradients were dissolved in 1% DMS0 and 20% PEG400 saline (abdominal Cavity injection test) or 2% DMS0 and 20% PEG400 saline (oral administration test)
  • mice After overnight fasting, the mice were housed in single cages and then divided into blank control group, exendin- 4 1 g group, Boc5 0. 1 mg group, Boc5 0. 3 rag group, Boc5 1 mg group and Boc5 2 mg group.
  • the mode of administration is intraperitoneal injection. Each group of mice was fed ad libitum, and the remaining feed was observed at intervals of 15-30 minutes before and after administration, and the observation data for 12 hours was used to calculate the cumulative food intake.
  • a blank control group, Boc5 0.3 mg group, Boc5 1 rag group, Boc5 3 mg group, and Boc5 10 mg group were set, the intragastric volume was 1 ml, and the observation period was 6 hours.
  • GLP-1R agonists can reduce body weight in obese animal models, reducing HbAlc and blood lipids, restoring beta cell function, increasing insulin sensitivity, and inducing beta cell proliferation and differentiation in an animal model of type 2 diabetes (Regul P. T, 2004, Vol. 117: 77-88).
  • type 2 diabetes model 578176]-111+/+ 1 ⁇ ) * ( /3 ⁇ 43 ⁇ 4) mice a pharmacodynamic study of intraperitoneal injections of Boc5 and S4P was performed.
  • CS BL/ej-m+Z+ Lepr 1 * Mice Male and female, 8 weeks old, purchased from the Model Animal Research Center of Nanjing University (identified by the center to meet the characteristics of type 2 diabetes).
  • Test compound Boc5 or S4P with different dose gradients dissolved in 1% DMS0 and 20% PEG400 saline
  • mice Each group of mice was randomly divided into 4 groups (14-15/group) according to HbAlc levels, and the mode of administration was intraperitoneal injection.
  • the Boc5 1 mg group, and the Boc5 2 mg group a feeding restriction control group was set, and the daily food intake of the group was equal to the Boc5 2 mg group of the previous day to detect changes in blood glucose characteristics caused by feeding inhibition.
  • a group of wild-type non-diabetic C57BL/6 mice were set up to observe the normal range of values of each indicator. Observed indicators are as follows: HbAlc once a week, fasting blood glucose twice a week, body weight and food intake observed once a day.
  • mice in each group After 6 weeks of treatment, half of each group (7 - 8) were fasted overnight, fasting insulin levels were measured, and 2 g kg-1 D-glucose was injected intraperitoneally. The animals were sacrificed and blood samples were taken for total cholesterol and triglycerides. , high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, alanine aminotransferase, and aspartate aminotransferase. The remaining mice in each group after stopping the drug continued to observe for 6 weeks.
  • HbAlc was significantly down-regulated (Fig. 4a), so HbAlc was used as the main evaluation index for Boc5-related studies.
  • the db/db mice were randomly grouped according to the HbAlc value. Prior to dosing, HbAlc was significantly higher in each group of db/db mice than in wild-type mice, which maintained a lower level of HbAlc throughout the course of the experiment.
  • the experimental results showed that the HbAlc of the db/db mice in the free feeding control group and the feeding restriction group continued to be higher.
  • HbAlc in the intraperitoneal injection of Boc5 1 mg or 2 mg in diabetic mice gradually decreased, reaching normal levels at 4-6 weeks of treatment, with no significant difference from wild-type mice, but significantly lower than the free-feeding control.
  • Group and feeding restriction control group db/db mice (0. 0001; Tukey-Kramer test).
  • HbAlc in both treatment groups remained at normal levels (Fig. 4b).
  • mice showed little change in body weight, compared with 23% for food intake and 12 g for the free-feeding control group (Fig. 4d); There was no significant difference in body weight between the control group, Boc5 1 rag and 2 mg treatment groups. The weight gain was significantly lower than the free feeding control group R0. 0001).
  • each group of mice was randomly selected for intraperitoneal injection of glucose tolerance test (IPGTT).
  • the remaining mice in each group also underwent IPGTT test 15 weeks after discontinuation of the drug.
  • the blood glucose response of the mice was measured as the area under the curve (AUC) within 120 minutes after the glucose load of 2 g/kg (Fig. 4e).
  • AUC area under the curve
  • the AUC of the Boc5 2 mg-treated group was significantly lower than that of the free-feeding control group and the food-feeding control group (X 0006 and ). 0006), but there was no significant difference compared with the wild type mice ( ). 64). Therefore, the glucose tolerance of the Boc5 2 mg treatment group has returned to normal.
  • the glucose tolerance of the Boc5 1 mg treatment group was partially improved. After 15 weeks of drug withdrawal, the glucose tolerance of the mice in the treatment group rebounded, and there was no significant difference in the glucose tolerance status of each group of diabetic mice (AO. 05), which was significantly higher than that of the wild type mice (free feeding control group 0026). , feeding restriction control group 0153, Boc5 2 mg / ). 0072, Boc5 1 mg ). 0052).
  • triglycerides in the Boc5-treated group showed a downward trend, while total cholesterol decreased significantly ( ⁇ 0.0054 compared with the food-inhibited control group, 0002 compared with the free-feeding control group), due to low-density lipoprotein A slight decrease in cholesterol (3.0045) and a significant decrease in high-density lipoprotein cholesterol ( ).0005).

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Abstract

L'invention concerne des composés à structure de cycle à 4 éléments substitués représentés par la formule générale I ou la formule générale II, ou des sels, des esters, des solvates, des complexes métalliques de ceux-ci acceptables sur le plan pharmaceutique, ou des promédicaments possédant la même action pharmacologique. Elle concerne également leur utilisation en tant que type de régulateurs d'accepteurs de glucagons-1 dans la prévention et/ou le traitement de troubles métaboliques (notamment, mais sans s'y limiter, le diabète, la résistance à l'insuline et l'adipose), de l'angiocardiopathie, de maladies neurodégénératives (telles que la maladie d'Alzheimer).
PCT/CN2007/002959 2006-12-05 2007-10-16 Composés à structure du cycle à 4 éléments substitués et leurs utilisations en tant que médicament Ceased WO2008067711A1 (fr)

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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

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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

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