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WO2008067710A1 - Composés de cyclohexane substitués, procédés de préparation et utilisations médicales correspondants - Google Patents

Composés de cyclohexane substitués, procédés de préparation et utilisations médicales correspondants Download PDF

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WO2008067710A1
WO2008067710A1 PCT/CN2007/002769 CN2007002769W WO2008067710A1 WO 2008067710 A1 WO2008067710 A1 WO 2008067710A1 CN 2007002769 W CN2007002769 W CN 2007002769W WO 2008067710 A1 WO2008067710 A1 WO 2008067710A1
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group
substituted
halogen atom
alkoxy
amide
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Mingwei Wang
Qing Liu
Na Li
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Shanghai Institute of Materia Medica of CAS
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • 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
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    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • 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
    • C07C237/38—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 the nitrogen atom of the carboxamide group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/78—Benzoic acid esters
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing alicyclic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a compound having a substituted cyclohexanyl structure, a preparation method thereof and a modulator of Glucagon like peptide-1 receptor (GLP-1R) in prevention and/or treatment
  • GLP-1R Glucagon like peptide-1 receptor
  • Medical use of 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.
  • 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, Fatty acid metabolism interfering drugs, a-glycosidase inhibitors (such as acarbose, voglibose, miglitol, etc.) and aldose reductase inhibitors.
  • Thiazolidinediones such as troglitazone, rosiglitazone, pioglitazone, etc.
  • ⁇ 3-adrenergic receptor modulators such as glucagon receptor antagonists
  • Fatty acid metabolism interfering 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 promotes the differentiation of embryonic stem cells into cell-like cells with insulin secretion (J Endocrinol. 2005, 186: 343-52). GLP-1 acts on the central body to promote Cell survival reduces apoptosis, reduces neurotoxicity of amyloid peptides, inhibits the progression of neurodegenerative diseases, and promotes learning and memory, so GLP-1 has recently been proposed for the treatment of Alzheimer'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 (X Hypertens, 2003, 21: 1125 - 1135; Am J Physiol Endocrinol Metab, 2004, 287: E1209 - E1215; Circulation, 2004, 110: 955 - 961 ; Diabetes, 2005, 54 : 146 - 151). Due to the above-mentioned clear physiological effects, since the discovery of this target in the mid-1980s, the search for small molecule agonists of GLP-1R has been a research hotspot of many new drug development institutions in the world.
  • GLP-1 drugs such as the GLP-1 derivative developed by Danovo Nordisk, Denmark (trade name Liraglutide; entering Phase III clinical trials) and Amylin Pharmaceuticals and Eli Lilly and Company
  • GLP-1 analogue Exendin-4 trade name Exenatide; was approved for 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.
  • Another object of the present invention is to provide a process for producing a compound represented by any one of the following formulae I to VI;
  • a further object of the present invention is to provide a pharmaceutical composition containing a compound represented by any one of the following Formulae I to VI;
  • a further object of the present invention is to provide a compound represented by any one of the following Formulae I to VI as a glucagon-like peptide-1 receptor modulator for preventing and/or treating metabolic disorders (including but not limited to diabetes, Medical uses such as insulin resistance and obesity, cardiovascular disease and neurodegenerative diseases such as Alzheimer's disease.
  • metabolic disorders including but not limited to diabetes, Medical uses such as insulin resistance and obesity, cardiovascular disease 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 the drug such as Alzheimer's disease.
  • the present invention relates to a compound represented by any one of the following formulae I to VI, or a pharmaceutically acceptable salt thereof:
  • X, ⁇ , Z are (C) n and n is 0-2, oxygen, sulfur or nitrogen.
  • R t , R 2 , R 3 , R 4 are each independently one of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; oxiran; Amine group; amide group; carboxamide group; fluorenyl group; alkylthio group; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted a pyranyl group; a substituted or unsubstituted thienyl group; a substituted or unsubstituted pyrrolyl group.
  • R 5 , R 6 , R 7 are each independently any of the following substituents: gas; alkane; cycloalkane; anthracene; amine; amine alkyl; amide; carboxamide; alkylthio; Or an unsubstituted aryl group; a substituted or unsubstituted pyridyl group; a substituted or unsubstituted furyl group; a substituted or unsubstituted pyranyl group; a substituted or unsubstituted thienyl group; a substituted or unsubstituted pyrrolyl group.
  • the above formula compound is characterized by -
  • X, Y, ⁇ are (CH 2 ) n , n is 0-2, oxygen, sulfur or nitrogen, Rpremise R 2 , R 3 are each independently: Wherein any of the following substituents is H; d- (alkyl group; an alkyl group containing any one, two or three substituted d- groups including a halogen atom, d-(alkoxy group or hydroxyl group) a C 2 -alkenyl group; any one, two or three substituted C 2 _C e 1 ⁇ 2 alkenyl groups including a halogen atom, a decyloxy group or a hydroxyl group; a C 2 -C 6 alkynyl group; Any one, two or three substituted C 2 -C 6 alkynyl group including a halogen atom, C "C 6 alkoxy group or a hydroxyl group; a C 3 _C e cycloalkyl group; Any one, two or three substituted C 3 -
  • R 6 , R 7 are: Wherein is any one of the following substituents: H ; a group of d-C 6 ; an alkyl group containing any one, two or three substituted dC 6 including a halogen atom, an alkoxy group or a hydroxyl group.
  • a substituted pyranyl group containing a halogen atom, d- (: 4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, thiol group, methylthio group, B Any one, two or three substituted thienyl groups including a thio group; 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 Any one, two or three substituted pyrrolyl groups, fluorenyl, methylthio, ethylthio; (c r , decanoyl; containing a halogen atom, (alkoxy group of Cs or hydroxyl group) Any one, two or three substituted c, - c e de
  • R w , Ru are each independently a substituent of any of the following: H ; alkyl of dC 6 ; any one, two or three substituted Cs including a halogen atom, an alkoxy group of d- or a hydroxyl group "C 6 thiol; C 2 - ( 6 alkenyl; any one, two or three substituted C 2 - (: 6 alkenyl group) including a halogen atom, an alkoxy group or a hydroxyl group; C 2 - (: 6 alkynyl; any one, two or three substituted C 2 - ( 6 alkynyl group; C 3 - C 6 containing an alkoxy group including a halogen atom, dC e or a hydroxyl group; Any one, two or three substituted C 3 -C 6 cyclodecyl groups including a halogen atom, an alkoxy group
  • R 12 is any one of the following substituents: H; C" (alkyl group of 6 ; any one, two or three substituted alkyl groups including a halogen atom, a c alkoxy group or a hydroxyl group) C 2 - (: 6 alkenyl; any one, two or three substituted c 2 -c alkenyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; c 2 - c 6 An alkynyl group; any one, two or three substituted c 2 -c 6 alkynyl groups including a halogen atom, an alkoxy group of dC e or a hydroxyl group; a c 3 - c 6 cyclodecyl group; Any one, two or three substituted c 3 - c 6 cycloalkyl groups of a halogen atom, c "
  • R 6 and R 7 are: Wherein R 13 and R w are each independently a substituent of any one of the following: H; ( ⁇ -(: 6 fen); any one or two containing an alkoxy group including a halogen atom, d-Cs or a hydroxyl group; Or a three-substituted C "C 6 alkyl group; a C 2 - C 6 alkenyl group; any one, two or three substituted groups including a halogen atom, a dC 6 decyloxy group or a hydroxyl group ( 2 - ( 6 alkenyl; C 2 - ( 6 alkynyl; any one, two or three substituted C 2 - C 6 containing a halogen atom, C "C 6 of a hospitaloxy group or a hydroxyl group"Alkynyl; C 3 -C 6 cycloalkyl; any one, two or three substituted C 3 -C 6 cyclodecyl groups containing
  • R 15 and R 16 each independently are any one of the following substituents: H; d- ( 6 alkyl; any one or two containing a halogen atom, C "C 6 alkoxy group or a hydroxyl group” or a three-substituted alkyl group of d-Ce; a C 2 -C 6 alkenyl group; Any one, two or three substituted ( 2- ( 6 alkenyl; C 2 -C e alkynyl) containing a halogen atom, a decyloxy group or a hydroxyl group of d-Ce; containing a halogen atom, CrC Any one, two or three substituted c 2 - c 6 block groups of 6 alkoxy groups or hydroxyl groups; c 3 -c 6 cycloalkyl groups; containing alkane including a prime atom, c "c 6 Any one, two or three substituted
  • R 7 are: Wherein is any one of the following substituents: H; a fluorenyl group of Cr C 6 ; any one, two or three substituted d-C B 1 ⁇ 2 containing a halogen atom, a decyloxy group or a hydroxyl group of d- ⁇ embankment group; C 2 - C e alkylene group; containing optionally include halogen, C "C 6 alkoxy or hydroxy embankment inner one, two or three substituents of C 2 - C 6 alkenyl; C 2 - (: 6 alkynyl group; contain any alkoxy or hydroxy include halogen atoms, the inner one, two or three substituents of C 2 -C e alkynyl group; C 3 - C 6 cycloalkyl group of embankment ; contain any halogen atoms include, d-Ce alkoxy or hydroxy the embankment, including one, two or three substituents of (3 -
  • two or three substituted furanyl groups containing a halogen atom, a halogen 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 methylthio group, Any one, two or three substituted pyranyl groups including an ethylthio group; an alkyl group including a halogen atom, CrG, a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carbon amide any group, a mercapto group, methylthio, ethylthio, including one, two or three substituents thienyl; comprising pigment containing atoms, C "(alkyl, nitro, carboxyl, aldehyde, alkoxy 4 Base, amine group,
  • R 5 , , R 7 are: Wherein, each independently is any one of the following substituents: H; a fluorenyl group of d-C 6 ; any one, two or three substituted groups including a halogen atom, a decyloxy group of dC 6 or a hydroxyl group - an alkyl group of C 6 ; an alkenyl group of C 2 - G; an alkenyl group containing any one, two or three substituted C 2 - C 6 groups including a halogen atom, a decyloxy group of -Ce or a hydroxyl group; C 2 - (6 alkynyl; comprising any one, two or three substituents of C 2 include a halogen atom, an alkoxy group or a hydroxyl dC including the e - (6 alkynyl; C 3 -C 6 of cycloalkyl; comprising any one, two or three of the substituents include C 3 prime atoms
  • R 12 is any one of the following substituents: H; d-(alkyl; any one, two or three substituted Cr C including a halogen atom, d- (a alkoxy group or a hydroxyl group) e alkyl; ⁇ - ⁇ alkenyl; include halogen atom-containing, ( ⁇ - alkoxy or hydroxy arbitrary (6, including one, two or three substituents of C 2 - (6 alkenyl; C 2 - (alkynyl; any one, two or three substituted C 2 -C 3 alkynyl groups including a halogen atom, an alkoxy group of d-C 6 or a hydroxyl group; C 3 - C e cyclic alkyl with; containing optionally include halogen atoms, C "C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 - C 6 cycloalkyl group emb
  • R 5 , R 6 , R 7 are: Wherein R 13 and R 14 are each independently a substituent of any of the following: H; an alkyl group of d-C 6 ; any one, two or three containing a halogen atom, a hydroxyl group of d- or a hydroxyl group.
  • 3 ⁇ 4 comprise any pigment containing atoms, a hydroxyl group or a -Ce the embankment, including one, two or three substituents of C 2 -C 6 Alkynyl; C 3 -C 6 cycloalkanoyl; any one, two or three substituted C 3 - ( 6 ring) containing an alkoxy group including a halogen atom, C, -C 6 or a hydroxyl group Alkanoyl; adamantyl formyl, substituted adamantyl formyl; aroyl; benzoyl; furoyl; pyranoyl; thiophene; pyrrole benzoyl; ) ⁇ (C) n , n is 0-2 , 0; S or NH; (C3 ⁇ 4) possibly, n is 0-2, 0; S or NH.
  • R 2 , R 3 are each independently : Wherein Rn is any one of the following substituents: 3 ⁇ 4; C"(fluorenyl); any one, two or three substituted (C 6 fluorenyl group containing a halogen atom, a fluorenyloxy group or a hydroxyl group) ; C 2 - C 6 alkenyl group; a halogen atom-containing include any, (the embankment of Ce alkoxy or hydroxy, including one, two or three substituents of C 2 _C 6 alkenyl; C 2 - (alkynyl Any one, two or three substituted C 2 -C 6 alkynyl group including a halogen atom, a Cr alkoxy group or a hydroxyl group; a C 3 - C 6 cycloalkyl group; containing a halogen atom, Any one, two or three substituted C 3 -C 6 cycloalkyl groups such as alkoxy or hydroxy groups
  • n is 0-2, 0; S or Lan time;
  • R 5 , R 6 and R 7 are: Wherein is any one of the following substituents: H; d-C e fluorenyl; any one, two or three substituted C" (including 6 ) containing a halogen atom, a decyloxy group or a hydroxyl group of d-Ce Alkyl; C 2 -C 6 alkenyl; containing halogen Atom, an optionally c "c embankment 6 alkoxy or hydroxy, including one, two or three substituents of C 2 - (: 6 alkenyl; C 2 - (6 alkynyl; include a halogen atom-containing, CrC Any one, two or three substituted C 2 -C 6 alkynyl groups including an alkoxy group or a hydroxyl group of e ; a C 3 -C 6 cyclodecyl group; a fluorene containing a halogen atom, C "C e " any of a group or a
  • R 5 , R 6 , R 7 are:
  • each of Ru independently is any one of the following substituents: H; C" (alkyl group of 6 ; any one, two or three substituted groups including a halogen atom, a decyloxy group of dC 6 or a hydroxyl group) C 6 alkyl; C 2 - (: 6 alkenyl; any one, two or three substituted ( 2- ( 6 olefin) containing a halogen atom, d- alkoxy group or a hydroxyl group) group; (2 alkynyl group; comprises contain any halogen atom, C "C e alkoxy or hydroxy group including one, two or three substituents of C 2 - C 6 alkynyl group; C 3 -C e a cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a sulfhydryl group or a hydroxy group including a aryl group; d-Ce;
  • R 12 is any of the following substituents: H ; a fluorenyl group of CrC e ; an alkoxy group containing a halogen atom, -Cs Any one, two or three substituted d-(: 6 fluorenyl groups; C 2 - ( 6 alkenyl group; containing a halogen atom, an alkoxy group or a hydroxyl group, etc.)
  • One, two or three substituted C 2 - (: 6 alkenyl; C 2 - ( 6 alkynyl; containing any one or two including a halogen atom, an alkoxy group or a hydroxyl group three substituted C 2 -C 6 alkynyl group of; C 3 - C e cycloalkyl; contain any halogen atoms include, CrC e alkoxy or hydroxy group including one, two or three substituents of ( 3 -C
  • R 5 , R 6 , R 7 are: .
  • R 13 and R 14 are each independently a substituent of any of the following: H; a fluorenyl group of d-C 6 ; any one, two or three groups including a halogen atom, a decyloxy group of dC 6 or a hydroxyl group; Substituted d-(alkyl; C 2 - 0>alkenyl; any one, two or three substituted C 2 - including a halogen atom, C, -C 6 alkoxy group or hydroxyl group (6 alkenyl; C 2 -C 6 alkynyl group; a halogen atom-containing optionally include, dC 6 alkoxy or hydroxy, including one, two or three substituents of C 2 - C s alkynyl; a C 3 -C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, a decyloxy
  • R 18 and R w are each independently a substituent of any of the following: H; an alkyl group of d-C 6 ; any one, two or three substitutions including a halogen atom, an alkoxy group of dc or a hydroxyl group; D-( 6 alkyl; C 2 -C fi alkenyl; any one, two or three substituted C 2 - C 6 dry groups containing a halogen atom, an alkoxy group or a hydroxyl group C 2 - ( 6 alkynyl; any one, two or three substituted C 2 _C e alkynyl group including a halogen atom, a decyloxy group or a hydroxyl group of d C 6 ; C 3 - C e a cycloalkyl group; any one, two or three substituted C 3 -C 6 cyclodecyl groups including a halogen atom, an alkyl group of d-C 6 ; any one, two
  • a substituted fluorenyl group containing a halogen atom, d-(indenyl group, nitro group, carboxyl group, aldehyde group, decyloxy group, amine group, amide group, carboxamide group, fluorenyl group, methylthio group, ethylthio group Any one, two or three substituted pyranyl groups; containing a halogen atom, a fluorenyl group of a Cr C 4 group, a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group Any one, two or three substituted thienyl groups including a fluorenyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, C t - C 4 , a nitro group, a carboxyl group, an alde
  • R 5 , R 6 and R 7 are: Wherein R 9 is any one of the following substituents: H; an alkyl group of Cr ( ⁇ ; an arbitrary one, two or three substituted Cs including a halogen atom, a C: ( 6 alkoxy group or a hydroxyl group) An alkyl group of t -C 6 ; 0 2 -(: 6 alkenyl; any one, two or three substituted C 2 - (alkenes) including a halogen atom, a decyloxy group or a hydroxyl group of d- groups; C 2 - (6 alkynyl; contain any include halogen atoms, hydroxyl group, or embankment Cr C 6 inner one, two or three substituents of C 2 -C e alkynyl group; C 3 - a C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cyclodecyl groups including a halogen atom
  • R 7 is -
  • R w each independently is any one of the following substituents: H ; a fluorenyl group of dC 6 ; any one, two or three substituted groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group Alkyl; C 2 - (: 6 alkenyl; any one, two or three substituted C 2 - (alkenyl; C 2 - containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group) (6 alkynyl group; includes any containing halogen atoms, C "C 6 alkoxy or hydroxy, including one, two, or Three substituted C 2 - (6 alkynyl group; c 3 - c fi embankment cycloalkyl group; one, two or three substituents include a halogen atom contain any, c "c embankment 6 alkoxy or hydroxy, including the c 3 - c e cycl
  • Substituted furanyl containing any of a halogen atom, a dc 4 graft, 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, and the like.
  • substituents pyranyl include halogen atom-containing, ( ⁇ - (alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto 4 Any one, two or three substituted thienyl groups including a methylthio group and an ethylthio group; containing a halogen atom, c "c 4 sulfhydryl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group Base, amide group, carboxamide group, sulfhydryl group, methylthio group, ethyl sulphide Including any one, two or three substituents pyrrolyl; d_c 6 alkanoyl; includes any halogen atom-containing, c "c embankment 6 alkoxy or hydroxy, including one, two or three substituents of c"C
  • ⁇ is any of the following substituents: H; C "C fl alkyl; any one, two or three substituted Cs including a halogen atom, (; - (; 6 alkoxy or hydroxy group) "C 6 alkyl with; C 2 - C 6 alkenyl group; a halogen atom-containing include, CrC 6 alkoxy or hydroxy embankment, including any one, two or three substituents of C 2 -C 6 alkenyl group; An alkynyl group of C 2 - C B ; an alkynyl group containing any one, two or three substituted C 2 _C B groups including a halogen atom, an alkoxy group or a hydroxyl group of -Ce; a ring of C 3 - C 6 alkyl; include halogen atom-containing, C "C 6 alkoxy or hydroxy embankment, including any one, two or three substituents: H; C "C fl alkyl; any one
  • R 13 and R 14 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, a decyloxy group of CrC 6 or a hydroxyl group; (; 6 alkyl; C 2 -C 6 alkenyl group; includes any containing halogen atoms, C alkoxy or hydroxy group including one, two or three substituents of C 2 - C 6 alkenyl group; C 2 -C e alkynyl; any one, two or three substituted C 2 -C 6 alkynyl group including a halogen atom, an alkoxy group of C "C e or a hydroxyl group; C 3 - C e a cycloalkyl group; any one, two or three substituted C 3 -C 6 cyclodecyl groups
  • such a compound or a physiologically 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 neurodegenerative diseases ('such as Alzheimer' s disease) and so on.
  • the invention relates to a method 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 willingness to receive treatment or prevention a compound having a fair amount of a glucagon-like peptide-1 receptor or a pharmaceutically acceptable salt thereof for preventing or Treat the above diseases or symptoms.
  • the above metabolic disorders including but not limited to diabetes, insulin resistance and obesity
  • cardiovascular diseases and neurodegenerative diseases such as Alzheimer's disease
  • X, ⁇ , Z are (CH 2 ) n , and n is 0 - 2, oxygen, sulfur or nitrogen.
  • R 2 , R 3 are each independently one of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine sulfhydryl; Carboxamide; mercapto; sulfonyl; ether; thioether; 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 , R 6 , R 7 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; 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 -
  • X, ⁇ , Z are ((3 ⁇ 4) thread, n is 0-2, oxygen, sulfur or nitrogen.
  • RR 2 , R 3 , R 4 are each independently one of the following substituents: hydrogen; halogen; alkane; cycloalkyl; light base; nitro; carboxy; aldehyde; methoxy; amine; Amide; carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; Substituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • Ra, R 7 are each independently any one of the following substituents: hydrogen; anthracene; a cyclic alkane; an alkoxy group; an amine group; an amine group; an amide group; a carboxamide group; an alkylthio group; Substituted 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-described combination preparation for the prevention and/or treatment of a disorder (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer' s disease), etc., to achieve selective stimulation of the glucagon-like peptide-1 receptor, improve the patient's symptoms and quality of life.
  • a disorder including but not limited to diabetes, insulin resistance and obesity
  • cardiovascular diseases and neurodegenerative 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. With “onset The rate is high, the mortality rate is high, the disability rate is high, the recurrence rate is high, and the “complication is more”.
  • an "effective amount" of a compound for treating a particular condition 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 using 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 relevant art by those skilled in the art may vary in the context and is generally at least 70%, preferably at least 80°/. , 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. Experienced practitioners should understand that the subject is suitable and willing to treat and prevent diabetes and its complications.
  • 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, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases.
  • a member of a drug such as a sexually transmitted disease (such as Alzheimer's disease).
  • the present invention relates to a compound represented by any one of the following formulae I to VI, or a pharmaceutically acceptable salt thereof:
  • X, ⁇ , Z are (C3 ⁇ 4) n , n is 0-2, oxygen, sulfur or nitrogen.
  • R 1 R 2 each independently is any one of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; aminyl; Carboxamide; mercapto; sulfonyl; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • R 5, 3 ⁇ 4, R 7 are each independently any of the following substituents: hydrogen; hydrocarbon embankment; cyclic hydrocarbon embankment; alkoxy; amino; alkyl with an amine; amide group; carboxamide group; burning thio; substituted Or an unsubstituted aryl group; a substituted or unsubstituted pyridyl group; a substituted or unsubstituted furyl group; a substituted or unsubstituted pyranyl group; a substituted or unsubstituted thienyl group; a substituted or unsubstituted pyrrolyl group.
  • 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.
  • 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.
  • 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 disease is treated or prevented by administering an effective amount of a compound represented by any one of the following formulas I to VI or a pharmaceutically acceptable salt thereof:
  • X, Y, and ⁇ are (CH, ⁇ is 0-2, oxygen, sulfur or nitrogen, respectively).
  • RR 2 , R 3 are each independently one of the following substituents: hydrogen; halogen; alkane; cycloalkane; light base; nitro; carboxyl; aldehyde; alkoxy; amine; Amido; carboxamide; sulfhydryl; sulfhydryl; ether; a thioether; a substituted or unsubstituted aryl group; a substituted or unsubstituted pyridyl group; a substituted or unsubstituted furyl group; a substituted or unsubstituted pyranyl group; a substituted or unsubstituted thienyl group; a substituted or unsubstituted pyrrole group; base.
  • R 7 are each independently a substituent of any of the following: hydrogen; anthracene; a cycloalkyl; an oxirane; an amine; an amine alkyl; an amide; a carboxamide; an alkylthio; a 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, insulin resistance and obesity
  • it can be used alone or in combination with other diabetes treatments including insulin sensitizers that are marketed or will be marketed.
  • insulin sensitizers that are marketed or will be marketed.
  • Inventive compound 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
  • diabetes therapeutics including insulin sensitizers
  • it can be administered alone or in combination with other suitable diabetes therapeutics, including insulin sensitizers, by any suitable method.
  • 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 substances, such as glycated hemoglobin, enzymes, anti-pro-, 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 invention also relates to a combination formulation comprising a compound that selectively modulates glucagon-like peptide-1 receptor function, or a pharmaceutically acceptable salt thereof, and one or more Therapeutic drugs for metabolic disorders include insulin sensitizers.
  • such a combination comprises a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more therapeutic agents for metabolic disorders including an insulin sensitizer, which is represented by any one of the following formulas I to VI -
  • X, ⁇ , Z are (CH 2 ) coherent, n is 0-2, oxygen, sulfur or nitrogen.
  • R l 7 R 2 , R 3 , R 4 are each independently one of the following substituents: hydrogen; dentate; alkane; cycloalkane light; hydroxy; nitro; carboxy; acid group; alkoxy group; Amine alkyl; amide group; carboxamide; fluorenyl; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; Or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • R 5 , Re, R 7 are each independently any of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; Substituted 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 including insulin sensitizers, can be used in the combination formulations of the invention.
  • one or more of the above-mentioned 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 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 of the above, and treatment with the combination Or instructions for the prevention of 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, intradermal Injection, oral or topical.
  • 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 medicament 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, troches, soy 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, can be used depending on the needs of the administration.
  • 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.
  • the preferred pharmaceutical form is in combination with sterile saline, dextrose solution, buffer solution, or other pharmaceutically acceptable sterile liquid.
  • the composition may be frozen 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.
  • Typical pharmaceutically acceptable solutions are physiological saline and dextrose solutions.
  • the kit of the invention further comprises a composition for injection, preferably in sterile form A needle or syringe and/or a packed alcohol pad. Instructions for use by a doctor or patient may optionally be included.
  • the ketone (0. 67 eq) of COOH was dissolved in an appropriate amount of diethyl ether and water, and cooled in an ice salt bath.
  • Sodium cyanide (1. 67 eq) was added and stirred vigorously. When most of the sodium cyanide is dissolved and the temperature of the reaction solution falls below 5 °C, an appropriate amount of concentrated hydrochloric acid is slowly added dropwise to maintain the reaction temperature between 5 ° C and 10 ° C. After the completion of the dropwise addition, the ice bath was removed while vigorously stirring for 2 hours. After standing, the ether layer was separated, and the aqueous layer was poured into a reaction flask, and water was added to dissolve the salt.
  • the aqueous layer was extracted with diethyl ether. EtOAc was evaporated. The residue was poured into concentrated hydrochloric acid and saturated with hydrogen chloride gas and stood overnight. Then, take part of the hydrogen chloride gas with air, and then slowly add 50% sodium hydroxide solution to adjust to alkaline. The mixture was cooled in an ice-bath, and stirred with mechanical stirring, sodium hydroxide solid (0. 6 eq.), and steam distilled until no excess of ammonia and ketone. Dilute with water and extract with ether (discard). The aqueous layer was acidified with concentrated hydrochloric acid, cooled, and filtered to give an hydroxy acid.
  • A-hydroxy acid (0, 69 eq) was added to the acid chloride (0.66 eq), and the reaction was heated in a water bath. The crystallized was cooled to obtain a product. Under nitrogen, take LDA (1.2mra 0 l) in an appropriate amount of tetrahydrofuran, cool to 50 ⁇ , slowly add carboxylic acid (0.5 mmol), continue to stir for 30 minutes, continue at 50 °C Stir for 2 hours. Cool to a 10 (TC, drop nitro-substituted olefin (1.5 awake 0 1) with a liquid nitrogen/methanol bath, react for 5 hours, and slowly raise the temperature of the reaction solution to 0-10 ° C. Add the appropriate amount. 17% dilute hydrochloric acid, stirring in an ice bath overnight. Add water, dichloromethane extract, wash with water and saturated brine, and dry.
  • FIG. 1 Reporter gene method to detect the agonistic effects of compounds on GLP-1R.
  • the GLP-1 concentration gradient is 10, 1, 0.1.
  • FIG. 1 Reporter gene assay for the antagonism of exendin 9-39 on GLP-1.
  • concentration of GLP-1 was chosen to be 0.05 nM, and the concentration gradient of exendi- 39 was 10000, 1000, 100, 10, 1, 0. 1, 0 nM, and the activity of exendir 39 was set to 100%.
  • exendin ⁇ reported dose-dependently induced by inhibition of gene expression of GLP- 1, which IC 5. The value was 68. 22 nM, indicating that its biological activity is mediated by GLP-1R.
  • FIG. 4 Receptor competitive binding assay method to detect the affinity of GLP-1 for receptors.
  • the GLP-1 concentration gradient is 1000, 200, 40, 8, 1. 6, 0. 32, 0. 064, 0 nM.
  • GLP-1 can specifically bind to GLP-1R in a competitive manner with 125 1 standard GLP-1, and its IC 50 value is 0. 66 nMo
  • HP1100 HPLC system with binary gradient pump, online vacuum degasser, autosampler, column oven and photodiode array detector The column was ZORBAX SB-C18 (2.11 x 150 mm, 3. 5 ⁇ ), the mobile phase was acetonitrile/water, the flow rate was 0.2 ml/min, and the detection wavelength was 254 nm.
  • the melting point was measured by an IA6304 melting point apparatus; NMR was measured by Varian Mercury-300 and Varian Mercury Plus 400 nuclear magnetic resonance spectrometer (solvent CDC1 3 , CD 3 0D or DMS0-d 6 ); ESI-MS by AB Mariner mass spectrometer The EI was measured by a Finnigan MAT95 mass spectrometer.
  • the materials used in the synthesis are commercially available products unless otherwise specified.
  • the temperature should be between 5 ° C and 10 °.
  • the ice bath was removed while vigorously stirring for 2 hours.
  • the ethyl ether layer was separated, and the aqueous layer was poured into a reaction flask, and water was added to dissolve the salt.
  • the aqueous layer was extracted with diethyl ether.
  • the residue was poured into concentrated hydrochloric acid and saturated with hydrogen chloride gas and stood overnight. Then use the air to remove some of the hydrogen chloride gas, and then slowly add 50% sodium hydroxide solution to adjust to alkaline. Cool in an ice bath, mechanically stir, add sodium hydroxide solid (0.6 eq), steam distilled until free of ammonia and ketone. Dilute with water and extract with ether (discard).
  • GLP-1R is a G protein-coupled receptor.
  • GLP-1R binds to an agonist, the G ⁇ subunit of the G protein is activated. Stimulation of adenylate cyclase leads to an increase in 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)
  • 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 calf serum and 500 ⁇ ⁇ / ⁇ 1 G418.
  • the GLP-1 standard was diluted to a concentration gradient and then added to the above 96-well microplate at 1 ⁇ /well. Incubate for 6 hours at 37 ° C under 5% CO 2 . Luciferase activity was measured by the Steady-GloTM Luciferase Assay System Kit, and the Victor 2 reader was used for reading.
  • DMEM medium (GIBC0 company)
  • 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 calf serum and 500 ⁇ ⁇ / ⁇ 1 G418.
  • the Exendir 39 was diluted to a certain concentration gradient, and then added to the above 96-well microplate at 1 ⁇ M/well, incubated at 37 ° C, 5% CO 2 for 10 minutes, and then added 0. 05 nMGLP-1 Incubate for 6 hours at 37 ° C under 5% CO 2 .
  • Luciferase activity was measured by the Steady-GloTM Luciferase Assay System Kit, and the Victor 2 reader was used for reading.
  • the reporter gene detection method is a method for indirectly determining the level of intracellular CAMP concentration. To confirm that the active compound does increase intracellular cAMP concentration, functional verification is performed directly using the cAMP assay kit.
  • HEK 293 cells were incubated at 20,000 cells/lOOul/well in 96-well culture plates, cultured overnight at 37 ° C, GLP-1 was serially diluted with dimethyl sulfoxide, and added to the above 96-well microplates at 1 ⁇ l/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 induced cAMP in cells (Table 3, FIG. 3), which EC 5.
  • the value was 0. 079 nM, suggesting that it acts as a GLP-1R agonist and plays a role in GLP-1R signaling.
  • HEK 293/GLP1R+Luc cell line self-built by National New Drug Screening Center
  • Labeled compound 125 1 labeled GLP-1 (Amersham Biosciences)
  • HEK 293/GLP1R+Luc cells in 10 5 logarithmic growth phase were incubated with 125 1 GLP-1 positive peptide (final concentration 40 M) for 4 hours at 25 ° C in 200 ⁇ l test 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.
  • GLP-1 specifically binds to receptors that compete with 125 1 GLP-1 (Table 4, Figure 4), its IC S .
  • the value is 0. 66 nM.

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Abstract

L'invention concerne des composés de cyclohexane substitués représentés par n'importe quelle formule comprise entre I et VI. L'invention concerne également le procédé de préparation de ces composés et leurs utilisations comme régulateurs du récepteur de peptide 1 de type glucagon dans la prévention et/ou le traitement de troubles métaboliques, dont le diabète, la résistance à l'insuline et l'obésité, etc, les maladies cardiovasculaires et les maladies neurodégénératives telles que la maladie d'Alzheimer.
PCT/CN2007/002769 2006-12-05 2007-09-19 Composés de cyclohexane substitués, procédés de préparation et utilisations médicales correspondants Ceased WO2008067710A1 (fr)

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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
WO2006136101A1 (fr) * 2005-06-24 2006-12-28 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Regulateurs de recepteurs de peptide-1 de type glucagon, procedes de preparation et d'utilisation de ceux-ci

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* 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
WO2006136101A1 (fr) * 2005-06-24 2006-12-28 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Regulateurs de recepteurs de peptide-1 de type glucagon, procedes de preparation et d'utilisation de ceux-ci

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE CA [online] CHANG D.Y. ET AL.: "Reactions of halogen compounds with disodium enolate of succinosuccinic ester. I. The reaction with iodoacetic ester", Database accession no. (50:40178) *
DATABASE CA [online] YONGJUN CHU ET AL.: "Synthesis and DNA binding studies of bis-intercalators with a novel spiro-cyclic linker", Database accession no. (145:118930) *
JOURNAL OF THE CHINESE CHEMICAL SOCIETY (TAIPEI, TAIWAN), vol. 2, 1955, pages 71 - 86 *
TETRAHEDRON, vol. 62, no. 23, 2006, pages 5536 - 5548 *

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