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WO2008067713A1 - Composés à structure de cyclopentane, leurs procédés de préparation et leurs utilisations médicales - Google Patents

Composés à structure de cyclopentane, leurs procédés de préparation et leurs utilisations médicales Download PDF

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WO2008067713A1
WO2008067713A1 PCT/CN2007/002982 CN2007002982W WO2008067713A1 WO 2008067713 A1 WO2008067713 A1 WO 2008067713A1 CN 2007002982 W CN2007002982 W CN 2007002982W WO 2008067713 A1 WO2008067713 A1 WO 2008067713A1
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group
substituted
alkoxy
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alkyl
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Mingwei Wang
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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
    • C07D333/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/08—Hydrogen atoms or radicals containing only hydrogen and carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C62/30—Unsaturated compounds
    • C07C62/38—Unsaturated compounds containing keto groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to a class of compounds having a substituted cyclopentane structure, a process for the preparation thereof, and a glucagon-like peptide-1 receptor (Glucagon like Peptide- 1 receptor, GLP-1R ) modulators in the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin resistance and obesity, etc.), cardiovascular diseases, neurodegenerative diseases (eg Alzheimer's disease) Medical use.
  • Glucagon like Peptide- 1 receptor, GLP-1R glucagon like Peptide- 1 receptor
  • GLP-1R glucagon like Peptide- 1 receptor
  • Diabetes is a group of clinical syndromes caused by the interaction of genetic and environmental factors. It is mainly divided into type 1 and type 2.
  • the basic pathophysiology of type 1 diabetes is absolute insulin secretion, and clinical treatment is mainly supplemented with insulin. It is also known as insulin-dependent diabetes.
  • Type 2 diabetes accounts for more than 95% of the diseased population.
  • Clinical studies have found that most patients with type 2 diabetes can synthesize normal or even excess insulin, but the sensitivity of target cells to insulin is reduced (also known as "insulin resistance"), resulting in Relatively insufficient insulin, also known as non-insulin dependent diabetes. Insulin resistance is a key factor in the development and progression of type 2 diabetes.
  • Therapeutic drugs for type 2 diabetes include sulfonylureas, biguanides, other insulin sensitizers, and ancillary measures.
  • sulfonylurea hypoglycemic agent binds to the receptor of the pancreatic ⁇ -cell membrane, the potassium channel is blocked, and the potassium ion efflux is blocked, which leads to depolarization of the cell membrane, promotes the opening of the Ca 2+ channel, and causes extracellular calcium influx, intracellular.
  • the calcium ion concentration is increased, the release of insulin is triggered.
  • the biguanide hypoglycemic agent can suppress appetite, increase the binding of insulin to the receptor, promote the anaerobic glycolysis of glucose, inhibit tissue respiration, and inhibit hepatic gluconeogenesis.
  • glibenclamide excellent Hypoglycemic
  • gliclazide damecon
  • glipizide mepyridone
  • gliclazide sucrose flat
  • the biguanide hypoglycemic agent can suppress appetite, increase the binding of insulin to the receptor, promote the anaerobic glycolysis of glucose, inhibit tissue respiration, and inhibit hepatic gluconeogenesis.
  • hypoglycemic agents mainly include Thiazolidinediones (such as troglitazone, rosiglitazone, pioglitazone, etc.), ⁇ 3-adrenergic receptor modulators, glucagon receptor antagonists, and fatty acids.
  • Metabolic interference drugs such as ⁇ -glucosidase inhibitors (such as acarbose, voglibose, miglitol, etc.) and aldose reductase inhibitors.
  • GLP-1 R belongs to type B G protein-coupled receptor (GPCR).
  • GLP-1 gutagon-like glucagon-like peptide-1 released by the enteroendocrine cells is activated by highly specific binding to GLP-IR. It stimulates insulin secretion, inhibits the production of glucagon, and lowers postprandial blood glucose and maintains it at a constant level. Under physiological conditions, the effect of GLP-1 on insulin secretion is dependent on blood glucose concentration, and hypoglycemia does not occur due to sustained secretion. GLP-1 also promotes the proliferation and differentiation of beta cells, as well as neuromodulation, delays gastric emptying, and reduces appetite.
  • GLP-1 In vitro, 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 nervous system to promote cell survival and reduce apoptosis, reduce the neurotoxicity of ⁇ -amyloid peptide, inhibit the progression of neurodegenerative diseases, and promote learning and memory. Therefore, GLP-1 has recently been proposed for Alzheimer's disease. Treatment ( Ann NY Acad Sci, 2004, 1035: 290-315; Nat Med, 2003, 9: 1173-1179; Curr Alzheimer Res, 2005, 2: 377-385; J Pharmacol Exp Ther, 2002, 302: 881- 888) contendIn addition, GLP-1 also plays an important role in the cardiovascular system.
  • GLP-1 has the effect of lowering blood pressure and dilating blood vessels.
  • Acute injection of GLP-1 can be used in cardiac hypertrophy. Improve the contractile function of the left ventricle during the test. 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).
  • GLP-1R small molecule agonists of GLP-1R
  • GLP-1 derivative developed by Danovo Nordisk, Denmark (trade name Liraglutide; entering Phase III clinical trials) and Amylin Pharmaceuticals and Eli Lilly and Company
  • GLP-1 analogue Exendin-4 trade name Exenatide; was approved for marketing in April last year and is expected to exceed $1 billion in sales this year).
  • An object of the present invention is to provide a compound represented by the following formula and a pharmaceutically acceptable salt thereof; another object of the present invention is to provide a process for producing a compound represented by the following formula; A further object is to provide a pharmaceutical composition comprising a compound represented by the following formula; A further object of the present invention is to provide a compound represented by the following formula as a glucagon-like peptide-1 receptor modulator for preventing and/or treating metabolic disorders including, but not limited to, diabetes, insulin resistance and obesity ), cardiovascular disease and neurodegenerative diseases (such as
  • the present invention provides a glucagon-like peptide-1 receptor modulator, which increases the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases ( Members of drugs such as Alzheimer's disease).
  • the present invention relates to a compound represented by the following formula, or a pharmaceutically acceptable salt thereof, and all stereo and optical isomers thereof, or a prodrug having the same pharmacological action thereto, an ester thereof, a solvate thereof or a metal thereof Complex:
  • X, ⁇ , Z are each (CH 2 ) n , n is 0-2, oxygen, sulfur or nitrogen;
  • RR 2 , R 3 are each independently one of the following substituents: hydrogen; halogen; alkane; Cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; amide; carboxamide; fluorenyl; alkylthio; ether; thioether; substituted or unsubstituted aryl; 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;
  • R 4 , R 5 , R 6 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 above compound of the formula is characterized by:
  • X, ⁇ , Z are (CH 2 ) n , n is 0-2, oxygen, sulfur or nitrogen, and RR 2 and R 3 are each independently:
  • R 7 is any one of the following substituents: H; C, -C 6 alkyl; any one, two or three substituted d-containing halogen atom, dC 6 alkoxy group or hydroxyl group.
  • alkyl; C 2 -C 6 alkenyl group includes any pigment containing atoms, alkoxy or hydroxy CrC 6, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 Alkynyl group of -C 6 ; any one, two or three substituted C 2 -C 6 alkynyl groups including a facet atom, an alkoxy group of C6 or a hydroxyl group; a C 3 -C 6 cycloalkane Base; contains included!
  • a three-substituted pyranyl group containing an alkyl group including a hydrocarbon atom, CC 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group Any one, two or three substituted thienyl groups including an ethylthio group; an alkyl group including a halogen atom, c, -c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group Any one, two or three substituted pyrrolyl groups, a carboxamide group, a fluorenyl group, a sulfonium group, an ethylthio group; a C6 alkanoyl group; 3 ⁇ 4 atom, any c r c
  • R 8 is any one of the following substituents: H; -C 6 alkyl; any one, two or three substituted Cs including a halogen atom, C, -C 6 alkoxy group or a hydroxyl group
  • An alkyl group of R C 6 a C 2 -C 6 alkenyl group; containing an alkoxy group or a hydroxyl group including a [3 ⁇ 4 atom, a -C 6 atom
  • R 9 and R 10 are independently of any one of the following substituents: H; an alkyl group of dC 6 ; any one, two or three substituents including a prime atom, an alkoxy group of -C 6 or a hydroxyl group.
  • Ci-C 6 alkyl C 2 -C 6 alkenyl group; a, any two or three substituents include a halogen atom-containing, C r C 6 alkoxy or hydroxy, including a C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; a halogen atom includes any containing, -C 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkynyl group; a C 3 -C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, an alkoxy group of CC 6 or a hydroxyl group; an aryl group; a furanyl group; a pyranyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group; a pyridyl group; an an
  • One, two or three substituted pyranyl groups containing an atomic group, a d-alkyl group, a nitro group, a carboxyl group, Any one, two or three substituted thienyl groups including an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; containing a halogen atom, c, - c any alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, Yue thio, ethylthio 4 including one, two or three substituents of Pyrrolyl group;
  • An alkanoyl group of C,-C 6 an alkanoyl group of any one, two or three substituted C6 groups including a gas atom, an alkoxy group or a hydroxyl group; a C 2 -C 6 alkenoyl group; Any one, two or three substituted C 2 -C 6 alkenoyl groups such as an atom, an alkoxy group of d-Ce or a hydroxyl group; a C 2 -C 6 alkynyl group; Any one, two or three substituted C 2 -C 6 alkynyl groups including a C atom, an alkoxy group or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; containing a ?
  • RH is any one of the following substituents: H; C, -C 6 alkyl; any one, two or three substituted OC 6 alkyls including a halogen atom, an alkoxy group of d- or a hydroxyl group a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C 6 alkenyl groups including a prime atom, an alkoxy group of -C6 or a hydroxyl group; C 2 -C 6 alkynyl; contains included!
  • One, two or three substituted pyranyl groups Any atomic element, dC alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, Yue thio, ethylthio, including 4, two or three Substituted thienyl; containing an alkyl group including a halogen atom, c, -c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethyl sulfide Any one, two or three substituted pyrrolyl groups including a base;
  • alkanoyl group of C r C 6 an alkanoyl group having any one, two or three substituted c r c 6 including a sulfonate atom, a d-alkoxy group or a hydroxyl group; a c 2 -c 6 alkenoyl group; Contains included!
  • R 12 and R 13 are each independently a substituent of any of the following: H; d-alkyl; any one, two or three substituted groups including a gas atom, an alkoxy group of dC 6 or a hydroxyl group.
  • An alkyl group of C rC 6 ; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C 6 alkenyl groups including a halogen atom, an alkoxy group of -C6 or a hydroxyl group; ; C 2 -C 6 alkynyl group; a halogen atom include any containing, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkynyl group of; C 3 - C 6 cycloalkyl; include a halogen atom-containing, 0 (: any 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -
  • a three-substituted furyl group containing an alkyl group including a halogen atom, d-, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group Any one, two or three substituted pyranyl groups; containing a halogen atom, a thiol group of 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 thienyl groups including a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, c r c 4 , a nitro group
  • any C r C 6 alkoxy or hydroxy including one, two or three substituents of C 3 -C 6 cycloalkyl group; Yue group adamantane, substituted adamantane Yue group; aryl Acyl; benzoyl; furanoyl; pyranoyl; thiophene acyl; pyrrolidinyl; , ⁇ ), n is 0-2, O; S or NH; X 2 is (CH 2 ) n , n is 0-2, 0; S or NH.
  • R, R 2 and R 3 are each independently:
  • R 14 and R 15 are each independently a substituent of any of the following: H; an alkyl group of d-Ce; or any one, two or three containing a surface atom, an alkoxy group of -C 6 or a hydroxyl group.
  • a substituted C r C 6 alkyl group a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group 6 alkenyl group; a C 2 -C 6 alkynyl group; includes any containing [3 ⁇ 4 prime atoms, C6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkynyl group; a C 3 -C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; an aryl group; a furanyl group; a pyrenyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group; a pyri
  • R 4 , R 5 and R 6 are respectively: Wherein R 8 is any one of the following substituents: H; C, -C 6 alkyl; any one, two or three substituted C groups including a halogen atom, an alkoxy group of d- or a hydroxyl group alkyl; C 2 -C 6 alkenyl group; includes any containing [3 ⁇ 4 prime atoms, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group of a C 2 -C 6 alkynyl group; any one, two or three substituted C 2 -C 6 alkynyl groups including a aryl group or a hydroxy group; a C 3 -C 6 ring; alkyl;!
  • 3 ⁇ 4 containing pigment comprising atoms, C r C 6 alkoxy or hydroxy, including any one, two or three substituents of C 3 -C 6 cycloalkyl; aryl; benzyl; furan group; tetrahydropyranyl; thienyl; pyrrolyl; pyridyl; containing pigment include 3 ⁇ 4 atoms, C r C alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide 4!
  • any group, a mercapto group, Yue thio, ethylthio, including one, two or three aryl group substituents; containing a halogen atom include, dC 4 alkyl, nitro, carboxamide , Any aldehyde, alkoxy, amine, amide, carboxamide, mercapto, Yue thio, ethylthio, including one, two, three or substituted pyridyl; comprising comprising!
  • R 9 is independently a substituent of any of the following: H; an alkyl group of dC 6 ; 3 ⁇ 4 any prime atoms, alkoxy or hydroxy CrC 6, including one, two or three substituents of C r C 6 alkyl; C 2 -C 6 alkenyl group; a halogen atom-containing include, dC 6 Any one, two or three substituted C 2 -C 6 alkenyl groups such as alkoxy or hydroxy; C 2 -C 6 alkynyl; containing a halogen atom, an alkoxy group or a hydroxyl group Any one, two or three substituted C 2 -C 6 alkynyl groups; a C 3 -C 6 cycloalkyl group; any one or two containing a halogen atom, an alkoxy group of d- or a hydroxyl group Or three substituted C 3 -C 6 cycloalkyl groups; aryl; benzyl
  • a three-substituted aryl 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, a fluorenyl group, a thiol group, an ethylthio group Any one, two or three substituted pyridyl groups; containing an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, Any one, two or three substitutions including sulfhydryl, thiol and ethylthio Furanyl; containing comprising [3 ⁇ 4 atom, -C 4 alkyl group, a nitro group, a carboxyl group,
  • R n is any one of the following substituents: H; an alkyl group of CrC 6 ; any one, two or three substituted d-containing an alkoxy group or a hydroxyl group including a halogen atom, C, -C 6 alkyl; C 2 -C 6 Hay-yl; a prime 13 ⁇ 4 contain any atoms including, dC alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 Hay-yl; and (2 - (: 6 alkynyl; Contains included!
  • C r C 6 alkanoyl; a 3 ⁇ 4 comprise any pigment containing atoms, alkoxy or hydroxy CrC 6, including one, two or three substituents of C r C 6 alkanoyl;! C 2 -C 6 of Any one, two or three substituted C 2 -C 6 alkenoyl groups including a 3 ⁇ 4 atom atom, a C 6 alkoxy group or a hydroxyl group; a C 2 -C 6 alkynyl group; Any one, two or three substituted c 2 -c 6 alkynyl groups including a halogen atom, an alkoxy group or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; Any one, two or three substituted c 3 -c 6 cycloalkanoyl groups of a 3 atomic atom, an alkoxy group of dC 6 or a hydroxyl group; adamantyl decanoyl group, Substitu
  • R l2 and R 13 are each independently a substituent of any of the following: H; d-alkyl; any one, two or three containing an alkoxy group including a prime atom, C, or C 6 or a hydroxyl group.
  • C r C 6 Any one, two or three substituted dC 6 alkanoyl groups such as an alkoxy group or a hydroxyl group; a c 2 -c 6 alkenoyl group; or an alkoxy group including a sulfonate atom, an alkoxy group or a hydroxyl group; Two or three substituted c 2 -c 6 enoyl groups; c 2 -c 6 alkynyl groups; any one, two or three substitutions including a halogen atom, an alkoxy group of d- or a hydroxyl group of
  • a C 2 -C 6 alkynyl group a C 3 -C 6 cycloalkanoyl group; any one, two or three substituted c 3 - including a ? 3 ⁇ 4 atom, an cc 6 alkoxy group or a hydroxyl group; c cycloalkanoyl 6; adamantane Yue group, a substituted adamantane Yue group; an aryl group; a benzyl group; furan Yue group; pyran Yue group; thiophene Yue group; pyrroyl; 1 ((: 13 ⁇ 4) [1 , n is 0-2, 0; S or NH; X 2 is (CH 2 ) n , n is 0-2, 0; S or NH.
  • RR 2 and R 3 are respectively independent:
  • R l6 is any of the following substituent groups: H; C r C 6 alkyl group; one, two or three substituents include a halogen atom contain any, d- alkoxy or hydroxy alkyl group, including the ; a C 2 -C 6 alkenyl; includes any pigment containing atoms, C r C 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkenyl; C 2 -C 6 alkynyl group; a halogen atom includes any containing, C, -C 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkynyl group; a C 3 -C 6 cycloalkyl Alkyl; contains included!
  • R 4 , R 5 and R 6 are respectively:
  • R 8 is any one of the following substituents: H; an alkyl group of d-Ce; any one, two or three substituted groups including a halogen atom, C, -C 6 alkoxy group or a hydroxyl group ( ⁇ - ( ⁇ alkyl; C 2 -C 6 alkenyl group; contain any include halogen atoms, alkoxy or hydroxy -C6 inner one, two or three substituents of a C 2 -C 6 alkenyl a C 2 -C 6 alkynyl group; any one, two or three substituted C 2 -C 6 alkynyl groups including a prime atom, an alkoxy group of -C6 or a hydroxyl group; C 3 -C 6 cycloalkyl; includes any containing [3 ⁇ 4 prime atoms, alkoxy or hydroxy dC 6, including one, two or three substituents of C 3 -C 6 cycloalkyl; aryl; a benz
  • R 9 and R l() are each independently a substituent of any of the following: H; an alkyl group of dC 6 ; 3 ⁇ 4 atom, any C r C 6 alkoxy or hydroxy, including one, two or three of the substituents -C 6 alkyl; C 2 -C 6 alkenyl group; a halogen atom-containing include, dC 6 any alkoxy or hydroxy, including one, two or three substituents Hay a C 2 -C 6 group; a C 2 -C 6 alkynyl group; containing pigment include 3 ⁇ 4 atoms, C r C 6 alkyl!
  • Any one, two or three substituted C 2 -C 6 alkynyl groups such as an oxy group or a hydroxyl group; a C 3 -C 6 cycloalkyl group; an alkoxy group or a hydroxyl group containing a halogen atom, d- Any one, two or three substituted C 3 -C 6 cycloalkyl groups; aryl; benzyl; furyl; pyranyl; thiahaki; pyrrolyl; pyridyl; Any one or two of an atom, a C, a C 4 alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, and an ethylthio group.
  • three or substituted aryl include halogen atoms contained, the CC alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide group 4, Any group, Yue thio, ethylthio, including one, two, three or substituted pyridyl; include halogen-containing Any one, two or three of an atom, an alkyl group of a d-C4, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, or an ethylthio group.
  • Substituted furanyl containing an alkyl group including a halogen atom, c, -c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethyl sulfide Any one, two or three substituted pyranyl groups, including a 3 ⁇ 4 atom, dC 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carbon Any one, two or three substituted thienyl groups including an amide group, a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, d-, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group Any one,
  • dC any alkoxy or hydroxy including 6, two or three Substituted dC 6 alkanoyl; C 2 -C 6 alkenyl group; a comprises containing atom, ( ⁇ - one, two or three substituents at any of alkoxy or hydroxy (6, including a C 2 -C 6 alkenoyl; 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 6 alkynyl group; a C a cycloalkanoyl group of r C 6 ; any one, two or three substituted C 3 -C 6 cycloalkanoyl groups including a 3 ⁇ 4 atomic atom, an alkoxy group of d- or a hydroxyl group; adamantyl decanoyl group , substituted adamantyl decanoyl; aroy
  • RH is any one of the following substituents: H; alkyl group of C R C 6 ; any one, two or three substituted groups including a halogen atom, an alkoxy group of d- or a hydroxyl group -C6 alkyl; C 2 -C 6 alkenyl; contains included! 3 ⁇ 4 atom, any CC 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; a comprises containing 3 ⁇ 4 atom,!
  • Any one, two or three substituted C 2 -C 6 alkynyl groups such as a alkoxy group or a hydroxyl group; a C 3 -C 6 cycloalkyl group; an alkoxy group containing a halogen atom, -C6
  • 3 ⁇ 4 containing pigment comprising atoms, C r C 4 alkyl, nitro Any one, two or three substituted furanyl groups, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; Any one, two or three of an atom, an alkyl group of a d-C4, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, or an ethylthio group.
  • a substituted pyranyl group containing an alkyl group including a halogen atom, C rC 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethyl thio group Any one, two or three substituted thienyl groups; containing an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, a keto group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group Any one, two or three substituted pyrrolyl groups such as thiol or ethylthio; d-C 6 alkanoyl; Any one, two or three substituted C aC 6 alkanoyl groups of a 3 atomic
  • R 12, R l3 are each independently any one of the following substituent groups: H; -C 6 alkyl group; a halogen atom include any one containing, C r C 6 alkoxy or hydroxy, including, two or three a substituted C, -C 6 alkyl; C 2 -C 6 alkenyl group; a halogen atom include any containing, R & lt alkoxy or hydroxy C 6 C inner one, two or three substituents of C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; any one, two or three substituted C 2 -C 6 alkyne containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group group; C 3 -C 6 cycloalkyl; contain any halogen atom includes, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl; Aryl;
  • R, R 2 and R 3 are respectively independent:
  • R 17 and R l8 are each independently a substituent of any of the following: H; an alkyl group of C r C 6 ; any one or two containing an alkoxy group including a halogen atom, C, or C 6 or a hydroxyl group; three or substituted dC ⁇ alkyl; C 2 -C 6 alkenyl group; a!
  • 3 ⁇ 4 containing pigment comprising atoms, C r C 6 alkoxy or hydroxy inner any one, two or three substituents of C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; any one, two or three substituted C 2 -C 6 containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group Alkynyl; C 3 -C 6 cycloalkyl; Any one, two or three substituted c 3 -c 6 cycloalkyl groups such as a halogen atom, a d-alkoxy group or a hydroxyl group; an aryl group; a benzyl group; a furyl group; a pyranyl group; a pyrrolyl group; a pyridyl group; a pyridyl group; an alkyl group including a C 4 atom, a nitro group, a carboxy group, an aldehyde
  • R 8 is any one of the following substituents: H; an alkyl group of dC 6 ; any one, two or three substituted CrC 6 containing an alkoxy group including a halogen atom, C, -C 6 or a hydroxyl group ; An alkyl group; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C 6 alkenyl groups including a facet atom, an alkoxy group of dC 6 or a hydroxyl group; a 2- C6 alkynyl group; any one, two or three substituted C 2 -C 6 alkynyl groups including a pertinar atom, an alkoxy group of CC 6 or a hydroxyl group; a C 3 -C 6 ring Any one, two or three substituted C 3 -C 6 cycloalkyl groups including a prime atom, an alkoxy group of dC 6 or a hydroxyl group; an aryl group
  • Any one, two or three substituted furan groups including an alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group. Containing a 3 ⁇ 4 atom, an alkyl group of -C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethyl thio group, etc.
  • X 2 is (CH 2 ) n , n is 0-2, O; S or NH; or R 4 , R 5 , R 6 are:
  • R 9, R l () each independently is any of the following substituents: H; C r C 6 alkyl; containing any one include halogen atoms, alkoxy or hydroxy, including the C6, two or three a substituted C r C 6 alkyl group; a C 2 -C 6 fluorenyl group; any one, two or three substituted C 2 groups including a ?
  • two or three substituted aryl groups containing alkane, d-C4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, sulfonium Any one, two or three substituted pyridyl groups including a thiol group; an alkyl group including a halogen atom, - a nitro group, a carboxy group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carbon group Any one, two or three substituted furanyl groups including an amide group, a fluorenyl group, a thiol group, an ethylthio group; an alkyl group, a nitro group, a carboxyl group, an aldehyde group, including a ?-?
  • Any one, two or three substituted pyranyl groups including an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a sulfonium group, an ethylthio group; containing a ?
  • 3 ⁇ 4 atom, dC 4 Any one, two or three substituted thienyl groups of an alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; Containing a halogen atom, d-alkyl group, nitro group, carboxyl group Any aldehyde, alkoxy, amine, amide, carboxamide, mercapto, Yue thio, ethylthio, including one, two or three substituents pyrrolyl; C r C 6 alkoxy group; and includes any pigment containing 3 ⁇ 4 atoms, C r C 6 alkoxy or hydroxy, including one, two or three substituents of d- alkanoyl;!
  • C 2 -C 6 alkenyl group; a halogen atom-containing include, Any one, two or three substituted C 2 -C 6 enoyl groups such as alkoxy or hydroxy group of dC 6 ; C 2 -C 6 alkynyl group; alkoxy group containing a halogen atom, d- Or one, two or three substituted C 2 -C 6 alkynyl groups, or a C 3 -C 6 cycloalkanoyl group; 3 ⁇ 4 atom, any C r C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl group; Yue group adamantane, substituted adamantane Yue group; aroyl Benzyl; furanoyl; pyranoyl; thiophene acyl; pyrrolyl hydrazide; 1 is (( 13 ⁇ 4) 11 , n is 0-2, O;
  • Substituted aryl containing an alkyl group including a ? atom, d-, nitro, carboxy, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, sulfonyl, ethylthio including any one, two or three substituents pyridyl;!
  • 3 ⁇ 4 containing pigment comprising atoms, C r C 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carbon Any one, two or three substituted furanyl groups including an amide group, a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a ?3 ⁇ 4 atom, a d-C4 group, a nitro group, a carboxyl group, an aldehyde group, Any one, two or three substituted pyranyl groups including an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, CC 4 , nitro, carboxyl, aldehyde, alkoxy, amine, amide, carbonyl Group, any mercapto, Yue
  • any one, two or three of a 3 ⁇ 4 atomic atom, a C 6 alkoxy group or a hydroxyl group Substituted c 2 -c 6 enoyl; c 2 -c 6 alkynyl; any one, two or three substituted c containing an alkoxy group including a halogen atom, c, -c 6 or a hydroxyl group 2 - C6 alkynyl; C 3 -C 6 cycloalkanoyl; contains included!
  • R l2 and R l3 are each independently a substituent of any of the following: H; an alkyl group of C6; any one, two or three substituted Cs including a pertiny atom, alkoxy group of d- or a hydroxyl group.
  • -C 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 of ; C 2 -C 6 alkynyl group; a halogen atom includes any containing, C, -C 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkynyl group; C 3 a C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, a C 6 alkoxy group or a hydroxyl group; an aryl group; a benzyl group ; furanyl; pyranyl; thienyl; pyrrolyl; pyridyl; Any one of a C, a C, a C 4 alkyl group, a nitro group
  • Two or three substituted aryl groups contain included! Any one or two of a 3 atomic atom, a d-alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group, or a three-substituted pyridyl group; containing an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, a keto group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a sulfonium group, an ethane group Any one, two or three substitutions a furanyl group; containing a 3 ⁇ 4 atom, ( ⁇ -(: 4 alkyl, nitro, carboxyl
  • n is 0-2, O; S or NH;
  • X 2 is (CH 2 ) n , n is 0-2, 0; S or NH.
  • the compound or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition, either alone or with pharmacology
  • An acceptable carrier or excipient is provided in combination.
  • 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), heart Vascular disease and neurodegenerative diseases (such as Alzheimer's disease), etc. It relates to the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (eg Alzheimer's disease) and other methods.
  • the method comprises administering to a subject in need or willing to receive treatment or prevention an effective amount of a compound that selectively modulates the glucagon-like peptide-1 receptor or a pharmaceutically acceptable salt thereof for preventing or treating the above Disease or symptom.
  • a compound that selectively modulates the glucagon-like peptide-1 receptor or a pharmaceutically acceptable salt thereof for preventing or treating the above Disease or symptom.
  • the above metabolic disorders including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease), etc.
  • X, ⁇ , Z are (CH 2 ) n , n is 0-2, oxygen, sulfur or nitrogen;
  • R, R 2 , R 3 are each independently one of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; Carboxamide; mercapto; alkylthio; 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 4 , R 5 , each independently of any of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl
  • the present invention relates to a combination preparation
  • 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.
  • the compound has the structure of the following general formula, and all of its stereo and optical isomers, or prodrugs having the same pharmacological action, esters thereof, solvates thereof or metal complexes thereof:
  • R, R 2 , R 3 are each independently one of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; Carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; Unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl;
  • R 4 , R 5 , R 6 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 provides a kit comprising the above combined preparation.
  • the present invention still further provides the use of the above combined preparation for the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin 4 and obesity), cardiovascular diseases and neurodegenerative diseases (eg Alzheimer's disease, etc., achieves the efficacy of selectively stimulating the glucagon-like peptide-1 receptor, improving the symptoms and quality of life of the patient.
  • metabolic disorders including but not limited to diabetes, insulin 4 and obesity
  • cardiovascular diseases and neurodegenerative diseases eg Alzheimer's disease, etc., achieves the efficacy of selectively stimulating the glucagon-like peptide-1 receptor, improving the symptoms and quality of life of the patient.
  • diabetes refers to a multi-pathogenic metabolic disease characterized by chronic hyperglycemia accompanied by disorders of sugar, fat and protein metabolism caused by defects in insulin secretion and/or function. As the time of diabetes is prolonged, 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 the surrounding tissues to insulin, and target tissues such as muscles and fats are resistant to insulin-induced glucose uptake.
  • Insulin resistance is prevalent in type 2 diabetes, accounting for more than 90%, and is one of the main factors in the development of type 2 diabetes.
  • “obesity” refers to the phenomenon that the amount of body fat is too much, that a man weighs more than 25% of the ideal body weight or that the woman weighs more than 30% of the ideal body weight. Genetic factors, hypothalamic disease, endocrine disorders, overdose And too few activities are the cause of obesity.
  • “Alzheimer's Disease (Al, Alzheimer's disease, also known as Alzheimer's dementia) is a neurological system of degenerative diseases, clinical It manifests as a chronic impairment of intelligence and a chronic loss of memory.
  • 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 as used herein refers to an amount sufficient to ameliorate or to some extent alleviate the symptoms associated with the disease. This dose can be single Dosing can also be administered according to the treatment regimen. This dose cures the disease, but is typically administered to improve the condition. Repeated administration to improve symptoms may be desirable.
  • pharmaceutically acceptable salts, esters or other derivatives include any salt, ester or derivative which is readily prepared by those skilled in the art by known methods.
  • the compounds thus derived and produced can be administered to animals and humans without toxic effects.
  • the compound is either pharmaceutically active or a prodrug.
  • treatment means that the disease and symptoms are improved in any way, or other beneficial changes. Treatment also includes the use of the compounds of the invention in medicine.
  • administration of a particular pharmaceutical composition to "improve” the symptoms of a particular disease means any reduction, whether permanent, temporary, prolonged, transient, can be attributed to or associated with the pharmaceutical composition.
  • substantially pure means sufficient homogeny to detect impurities by standard analytical methods used by those skilled in the art for evaluating purity, such as thin layer chromatography (TLC), gel electrophoresis. And high performance liquid chromatography (HPLC).
  • prodrug refers to a compound that is administered in vivo and which can be metabolized or converted to a biologically, pharmaceutically or therapeutically active form. To produce a prodrug, the pharmaceutically active compound will be modified to reproduce the active compound by metabolic processes.
  • Prodrugs can be designed to alter their metabolic stability, or transport properties Precursors to mask their side effects or toxicity, improve the taste of the drug, or alter other characteristics. By virtue of knowledge of pharmacokinetics and metabolism of the drug in the body, once the pharmaceutically active compound is known, one skilled in the art can design a prodrug of the compound. [See
  • composition refers to any mixture. It can be a solution, suspension, liquid, powder, ointment, aqueous, non-aqueous or any combination thereof.
  • union refers to any association between two or more.
  • subject 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. Any of the protective groups used herein, abbreviations for amino acids and other compounds, are consistent with their common, recognized abbreviations or the biochemical nomenclature issued by the IUPAC-IUB committee, unless specifically stated.
  • the present invention provides a modulator of glucagon-like peptide-1 receptor function, which increases the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, Members of the drug such as insulin resistance and obesity;), cardiovascular disease and neurodegenerative diseases such as Alzheimer's disease.
  • the present invention relates to a compound represented by the following formula, or a pharmaceutically acceptable salt thereof, and All stereo and optical isomers, or prodrugs, esters, solvates or metal complexes thereof having the same pharmacological effects:
  • X, ⁇ , Z are (CH 2 ) n , n is 0-2, oxygen, sulfur or nitrogen;
  • R, R 2 , R 3 are each independently one of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; Carboxamide; mercapto; alkylthio; 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 4 , R 5 , R 6 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 compounds of the invention may be a specific stereoisomer, such as the R- or S-configuration, or mixtures thereof, for example, a racemic mixture.
  • the compounds considered here include all A pharmaceutically active compound species, or a solution or mixture 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.
  • This compound was prepared by the synthesis described in Section F below. Further preferably, the compound or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, either alone or in combination with a pharmaceutically acceptable carrier or excipient.
  • the compounds of the invention may be prepared in the form of any suitable acid in the form of their pharmaceutically acceptable salts.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, acid, phosphoric acid, etc.
  • organic acids such as citric acid, acetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, etc.
  • An alkylsulfonic acid such as mercaptosulfonic acid, ethylsulfonic acid or the like
  • an arylsulfonic acid such as benzenesulfonic acid, p-toluenesulfonic acid or the like can be used.
  • the present invention relates to the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin 4 and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease).
  • the method comprises administering to a subject in need or willing to receive treatment or prevention an effective amount of a compound that selectively agonizes the glucagon-like peptide-1 receptor or a pharmaceutically acceptable salt thereof for treating or preventing the above-mentioned diseases. Or symptoms.
  • the above metabolic disorder is caused by administering an effective amount of a compound represented by the following formula or a pharmaceutically acceptable salt thereof, and all of the stereo and optical isomers thereof, or a prodrug having the same pharmacological action thereto , its ester, its solvate or its metal complex
  • a compound represented by the following formula or a pharmaceutically acceptable salt thereof and all of the stereo and optical isomers thereof, or a prodrug having the same pharmacological action thereto , its ester, its solvate or its metal complex
  • R, R 2 , R 3 are each independently one of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; Carboxamide; mercapto; alkylthio; 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 4 , R 5 , R 6 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. Any subject can be controlled by this method, preferably a mammal, more preferably a human.
  • the method can be used to prevent 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.
  • the above-mentioned diabetes therapeutic agents including insulin sensitizers
  • Suitable diabetes treatments include the use of insulin sensitizers in combination.
  • it can be administered by intracavitary injection, subcutaneous injection, intravenous injection, intramuscular injection, intradermal injection, orally or topically with the compound of the present invention, or with a pharmaceutically acceptable salt thereof.
  • the method further comprises performing a diagnosis and prognostic assessment of the disease or condition of the subject to whom it is administered. Any suitable method can be used to diagnose and assess the 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 the like.
  • international patent WO can be used The diagnostic or prognostic method disclosed in U.S. Patent No. 5,571,674.
  • D. Combination of Formulations, Kits and Combinations On the other hand, 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 all stereo and optical isomers thereof, or a prodrug having the same pharmacological action thereto, an ester thereof, a solvate thereof or
  • the metal complex and one or more therapeutic agents for metabolic disorders include insulin sensitizers, which are represented by the general formula: wherein X, Y, Z are (CH 2 ) n and n is 0-2, respectively. Oxygen, stone or nitrogen;
  • R, R 2 , R 3 are each independently one of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; Carboxamide; mercapto; alkylthio; 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 4 , R 5 , R 6 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.
  • 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.
  • a kit comprising the combination described above and instructions for using the combination to treat or prevent a disease or condition caused or accompanied by insulin secretion and/or dysfunction.
  • the compounds of the invention are formulated for any suitable route of administration, such as intraluminal, subcutaneous, Intravenous injection, intra-monthly injection, intradermal injection, oral or topical medication.
  • the method can be administered by injection, in a single dose, in an ampoule, or in a multi-dose container with an additional buffer.
  • the formulations may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles.
  • the formulations may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in the form of a powder in the form of a suitable carrier, sterile non-pyrogenic water or other solvent.
  • the topical medicament of the present invention may be a foam, a gel, an ointment, an ointment, a transdermal patch, or a paste.
  • Pharmaceutical compositions and methods for administration which may be used in the present invention include, but are not limited to, those set forth in U.S. Patent Nos. 5,736,154, 6,197,801 B1, 5,741,511, 5,886,039, 5,941,868, 6,258,374, and 5,686,102.
  • the size of the dose to be treated or prevented will vary depending on the severity of the condition and the route of administration.
  • Dosage forms include tablets, troches, soy gums, dispersing agents, suspending agents, solutions, capsules, films and the like.
  • the 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-hydroxy-propyl- ⁇ -cyclodextrin. Finely mixed.
  • a pharmaceutical carrier or excipient such as ⁇ -cyclodextrin and 2-hydroxy-propyl- ⁇ -cyclodextrin. Finely mixed.
  • a special carrier, a local or parenteral route, can be used depending on the needs of the administration.
  • Preparation of parenteral dosage forms, such as compositions for intravenous injection or infusion may employ similar pharmaceutical vehicles, water known to those skilled in the art, Ethylene glycol, oil, buffer, sugar, preservatives, liposomes, etc.
  • parenteral compositions include, but are not limited to, 5% w/v dextrose, physiological saline or other solutions.
  • the total dose of the compound of the present invention, alone or in combination with other preparations, can be administered in vial vials in a volume of from about 1 ml to about 2000 ml.
  • the amount of diluent will vary depending on the total dose administered.
  • the invention also provides a kit for achieving a therapeutic regimen.
  • the kit comprises an effective amount of a compound of the invention in a pharmaceutically acceptable form, alone or in combination with other agents, in one or more containers.
  • a preferred pharmaceutical form is in combination with sterile saline, dextrose solution, buffered solution, or other pharmaceutically acceptable sterile liquid.
  • the composition may be lyophilized or dried; in this case, the kit optionally further comprises a pharmaceutically acceptable solution, preferably a sterile solution, in a container to reconstitute the complex A solution for injection purposes is formed.
  • a pharmaceutically acceptable solution are physiological saline and dextrose solutions.
  • the kit of the invention further comprises a needle or syringe and/or a packaged alcohol pad for injection of the composition, preferably in sterile form. Instructions for use by a doctor or patient may optionally be included.
  • the COOH ketone (0.67 eq) was dissolved in an appropriate amount of diethyl ether and water, and cooled in a water-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 addition was completed, 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.
  • Reporter gene method detects the agonistic effects of compounds on GLP-1R.
  • the GLP-1 concentration gradient was 10, 1 , 0.1, 0.01, 0.001, 0.0001 nM, and the luciferase activity induced by ⁇ was 100%, and the EC 50 value of GLP-1 was 0.07 nM.
  • Figure 2. Reporter gene method to detect the antagonism of exendin ⁇ 39 on GLP-1.
  • the concentration of GLP-1 was 0.05 nM, the concentration gradient of exendin 9-39 was 10000, 1000, 100, 10, 1 , 0.1 , 0 nM, and the activity of ⁇ exendin 9-39 was set to 100%.
  • Reporter gene expression induced by GLP-1 was inhibited with an IC 50 value of 68.22 nM, indicating that its biological activity is mediated by GLP-1R.
  • Figure 3 Intracellular cAMP concentration detects the effect of GLP-1 on GLP-1R signaling.
  • the GLP-1 concentration gradient is 10, 1 , 0.1, 0.01, 0.001, 0.0001, 0 nM to 10 nM Induced cAMP activity was 100%, measured GLP-1 EC 50 value of 0.079 nM, suggesting that intracellular cAMP induced as GLP-1R agonist, a dose dependent manner.
  • Figure 4. Receptor competitive binding assay method to detect the affinity of GLP-1 for receptors.
  • the GLP-1 concentration gradient was 1000, 200, 40, 8, 1.6, 0.32, 0.064, 0 nM.
  • GLP-1 specifically binds GLP-1R to the 125 1 standard GLP-1 with an IC 5Q value of 0.66 nM.
  • 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, the flow rate was 0.2 ml/min, and the detection wavelength was 254 nm.
  • the melting point was determined by an IA6304 melting point apparatus; NMR was measured by Varian Mercury-300 and Varian Mercury Plus 400 nuclear magnetic resonance spectrometer (solvent was CDC1 3 , CD 3 OD or DMSO-d 6 ); ESI-MS was passed by AB Mariner type The instrument was measured by EI by a Finnigan MAT95 mass spectrometer. The materials used in the synthesis are commercially available products unless otherwise specified.
  • 3-Phenyl 1,2-cyclopentanedione (0.67 eq) was dissolved in an appropriate amount of diethyl ether and water and cooled in an ice 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 addition is complete, remove the water bath while stirring vigorously for 2 small Time. 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. The residue was poured into concentrated hydrochloric acid and saturated with hydrogen chloride gas and stood overnight. Then, some of the hydrogen chloride gas is taken away by air, and then slowly added with 50% sodium hydroxide solution to adjust to alkaline. Cool in an ice bath, mechanically stir, add sodium hydroxide solid (0.6 eq), and steam to distill until free 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 3-phenyl-1,2-dihydroxy-1,2-cyclopentadicarbonitrile.
  • GLP-1R is a G protein-coupled receptor.
  • GLP-1R binds to an agonist, the Ga subunit of the G protein is activated to stimulate adenylate cyclase, resulting in an increase in intracellular cAMP levels. Since the cAMP response element exists in the promoter region of the pre-insulin gene, cAMP binds to the response element to initiate transcription of the pre-insulin gene, thereby stimulating insulin expression and secretion (Diabetes, 2000, Vol.
  • the human embryonic kidney cell smear (HEK 293) stably transfected with the GLP-1R receptor gene expression vector and the luciferase reporter gene expression vector regulated by the cAMP response element was used to detect the response to the test compound.
  • 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 screening for a compound, It is considered to have GLP-1R agonistic activity.
  • DMEM medium (GIBCO)
  • Forma CO2 incubator Forma
  • HE 293/GLP1R+Luc cells were incubated at 20,000/100 ⁇ /well into 96-well plates at 37 with DMEM medium containing 10% fetal bovine serum and 500 g/ml G418. C cultured Night.
  • the GLP-1 standard was diluted to a concentration gradient and then added to the above 96-well microplate in ⁇ /well. Incubation was carried out 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.
  • Exendin 9- 3 9 antagonism test to confirm the active compound has a receptor-specific activation of the reporter gene, we used the specificity of GLP-1R antagonist, exendin 9-3 9 (Eur. J. Pharmacol . 1994, 269 : 183-191; Metabolism 2004, 53:252-259. ) to verify whether it antagonizes the agonistic activity of the above representative compounds on GLP-1R.
  • DMEM medium (GIBCO)
  • HEK293/GLP1R+Luc cells were incubated at 20,000/100 ⁇ /well into 96-well culture plates at 37 in DMEM medium containing 10% fetal bovine serum and 500 g/ml G418. C was cultured overnight. Dilute Exendin 9 _ 39 to a concentration gradient and add 1 ⁇ /well to the above 96-well microplate at 37 ⁇ . Incubate for 10 minutes at C, 5% C0 2 , then add 0.05 nMGLP-1 at 37. C, cultured for 6 hours under 5% C0 2 conditions. Luciferase activity was measured by the Steady-GloTM Luciferase Assay System Kit and the Victor 2 reader was used for reading.
  • Exendin W9 dose-dependently inhibited reporter gene expression induced by GLP-1 (Table 2, Figure 2), IC 5 . The value was 68.22 nM, indicating that its biological activity is mediated by GLP-1R. Table 2. Antagonism of Exendin 9-39 on GLP-1 (% response, 100% response to 0.05 nM GLP-1)
  • 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 the intracellular cAMP concentration, functional verification is performed directly using the cAMP test kit.
  • Test materials and instrument cell lines HEK 293/GLP-lR+Luc cell line stably expressed by GLP-1R and luciferase (self-built by National New Drug Screening Center) cAMP ⁇ 'j kit (Applied Biosystems) Forma carbon dioxide Incubator (Forma) Victor 2 plate reader (Wallac) cAMP standard (provided with the kit, Applied Biosystems) 3.2 test method
  • HEK 293 cells were inserted into a 96-well culture plate at 20,000 / lOOul / well, cultured overnight at 37 ° C, GLP-1 was diluted with disulfoxide, and added to the above 96-well microplate in lul / well. Incubate for 15 min at 37 ° C, 5% CO 2 . Intracellular cAMP levels were measured by cAMP-Screen DirectTM Systerm kit instructions.
  • GLP-1 dose-dependently induced cAMP in cells (Table 3, FIG. 3), which EC 5.
  • the value of 0.079 nM suggests that it acts as a GLP-1R agonist and plays a role in GLP-1R signaling.
  • Table 3 Induction of intracellular cAMP by GLP-1 (% response, 100% response to 10 nM GLP-1)
  • Receptor binding activity test In order to determine the binding ability of the active compound to the receptor, a large amount of cells expressing GLP-1R were prepared, and 125 1 labeled GLP-1 was used as a ligand, and the compound to be detected was simultaneously added. Isotope labeling on cell membranes when the test compound is competitively bound to
  • HEK 293/GLP1R+Luc cell line self-built by National New Drug Screening Center
  • Labeling compound 125 1 labeled GLP-1 (Amersham Biosciences)
  • GLP-1 specifically binds receptors to the 125 1 standard GLP-1 (Table 4, Figure 4) with an IC 5Q value of 0.66 nM. Table 4. Binding viability test of GLP-1 to GLP-1 R

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Abstract

L'invention concerne des composés à structure de cyclopentane substitué représentés par des formules I-IV, leurs procédés de préparation, et leur utilisation en tant que régulateur de récepteur peptide-1 de type glucagon dans la prévention et/ou le traitement de troubles métaboliques (notamment, entre autres le diabète, la résistance à l'insuline et l'obésité), de maladies cardiovasculaires, de maladies neurodégénératives (telles que la maladie d'Alzheimer) et analogue.
PCT/CN2007/002982 2006-12-05 2007-10-18 Composés à structure de cyclopentane, leurs procédés de préparation et leurs utilisations médicales Ceased WO2008067713A1 (fr)

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US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5

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CN102649947A (zh) * 2012-04-20 2012-08-29 无锡和邦生物科技有限公司 一种用于测定glp-1及其功能类似物生物活性的细胞株及其应用

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WO2004066929A2 (fr) * 2003-01-24 2004-08-12 Bristol-Myers Squibb Company Cycloalkyle contenant des ligands anilide pour le recepteur des hormones thyroidiennes
CN1626521A (zh) * 2003-12-12 2005-06-15 中国科学院上海药物研究所 一类胰高血糖样肽－1 受体激动剂及其制备方法和用途
CN1884278A (zh) * 2005-06-24 2006-12-27 中国科学院上海药物研究所 一类胰高血糖样肽－1受体调节剂、制备方法和用途

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WO2004066929A2 (fr) * 2003-01-24 2004-08-12 Bristol-Myers Squibb Company Cycloalkyle contenant des ligands anilide pour le recepteur des hormones thyroidiennes
CN1626521A (zh) * 2003-12-12 2005-06-15 中国科学院上海药物研究所 一类胰高血糖样肽－1 受体激动剂及其制备方法和用途
CN1884278A (zh) * 2005-06-24 2006-12-27 中国科学院上海药物研究所 一类胰高血糖样肽－1受体调节剂、制备方法和用途

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5

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