WO2008067709A1 - Composés de cyclobutane substitués, procédés de préparation et leurs utilisations pharmaceutiques - Google Patents

Composés de cyclobutane substitués, procédés de préparation et leurs utilisations pharmaceutiques Download PDF

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WO2008067709A1
WO2008067709A1 PCT/CN2007/002768 CN2007002768W WO2008067709A1 WO 2008067709 A1 WO2008067709 A1 WO 2008067709A1 CN 2007002768 W CN2007002768 W CN 2007002768W WO 2008067709 A1 WO2008067709 A1 WO 2008067709A1
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group
substituted
halogen atom
decyloxy
groups
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PCT/CN2007/002768
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Chinese (zh)
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Mingwei Wang
Na Li
Qing Liu
Lilin Lin
Yueyun Zhang
Jiayu Liao
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Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
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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
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40—Thiophene-2-carboxylic acid
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D409/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • the present invention relates to a compound having a substituted cyclobutane structure, a preparation method thereof, and a glucagon-like peptide
  • Glucagon like peptide-1 receptor (GLP-1R) modulators prevent and/or treat metabolic disorders (including but not limited to diabetes, insulin resistance and obesity, etc.), cardiovascular disease, neurodegenerative Medical use of diseases such as Alzheimer's disease.
  • metabolic disorders including but not limited to diabetes, insulin resistance and obesity, etc.
  • cardiovascular disease including but not limited to diabetes, insulin resistance and obesity, etc.
  • neurodegenerative Medical use of diseases such as Alzheimer's disease.
  • Type 1 diabetes Disorders of glucose metabolism, especially diabetes, have become a major threat to human health and life in modern society. It is predicted that diabetes patients worldwide are increasing at a rate of 6% per year. By the end of 2006, there were 320 million patients (China's '60 million people, ranking second). Diabetes is a group of clinical syndromes caused by the interaction of genetic and environmental factors. It is mainly divided into type 1 and type 2. The basic pathophysiology of type 1 diabetes is absolute insulin secretion, and clinical treatment is mainly supplemented with insulin. It is also known as insulin-dependent diabetes. Type 2 diabetes accounts for more than 95% of the diseased population.
  • Insulin resistance is a key factor in the development and progression of type 2 diabetes.
  • Therapeutic drugs for type 2 diabetes include sulfonylureas, biguanides, other insulin sensitizers, and ancillary measures.
  • the potassium ion channel is closed, and the potassium ion efflux is blocked, which leads to depolarization of the cell membrane, causing the Ca 2+ channel to be released, resulting in extracellular calcium influx.
  • the increase in intracellular calcium concentration triggers the release of insulin.
  • the first generation such as toluene propyl propyl urea
  • the second generation including glibenclamide (glibenclamide), gliclazide (Damecon), glipizide (mepyrazin) ) and gliclazide (sugar leveling) and the like.
  • 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.), P 3-adrenergic receptor modulators, glucagon receptor antagonists, Fatty acid metabolism interfering drugs, ⁇ -glycosidase inhibitors (such as acarbose, voglibose, miglitol, etc.) and aldose reductase inhibitors.
  • Thiazolidinediones such as troglitazone, rosiglitazone, pioglitazone, etc.
  • P 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 In vitro, GLP-1 promotes differentiation of embryonic stem cells into islets A secretory cell-like cell (J Endocrinol. 2005, 186: 343-52). GLP-1 acts on the central body to promote cell survival and reduce apoptosis, reduce the neurotoxicity of amyloid peptides, inhibit the progression of neurodegenerative diseases, and promote learning and memory. Therefore, it has recently been proposed to use GLP-1 for Alzheimer's. Treatment of the disease (Ann NY Acad Sci, 2004, 1035: 290-315; Nat Med, 2003, 9: 1173-1179; Curr Alzheimer Res, 2005, 2: 377-385; J Pharmacol Exp Ther, 2002, 302: 881 - 888). In addition, GLP-1 also plays an important role in the cardiovascular system.
  • GLP-1R has the effect of lowering blood pressure and dilating blood vessels.
  • Acute injection of GLP-1 can improve left ventricular systolic function in cardiac hypertrophy experiments. It also reduces myocardial cell damage in the presence of myocardial ischemia and reperfusion (J. Hypertens, 2003, 21: 1125 - 1135; Am J Physiol Endocrinol Metab, 2004, 287: E1209 - E1215; Circulation, 2004, 110 : 955 - 961 ; Diabetes, 2005, 54 : 146 - 151). Due to the above-mentioned clear physiological effects, since the discovery of this target in the mid-1980s, the search for small molecule agonists of GLP-1R has been a research hotspot of many new drug development institutions in the world.
  • GLP-1 innovative drugs such as the GLP-1 derivative developed by Danovo Nordisk in Denmark (trade name Liraglutide; entering Phase III clinical trials) and Amylin Pharmaceuticals and Lilly in the United States.
  • the company's joint development of the GLP-1 analogue Exendin-4 (trade name Exenatide; has been approved for listing in April last year, this year's sales are expected to exceed $1 billion).
  • GLP-1 and its peptide analogs there have been no reports of successful development of non-peptide small molecule GLP-1R agonists. Due to the inconvenient oral administration of peptide drugs, the search for non-peptide GLP-1R regulators and the development of new anti-diabetic drugs with independent intellectual property rights are the common concerns of many new drug research institutions.
  • a still further object of the invention is to provide a pharmaceutical composition comprising a compound represented by the following formula I or ⁇ ;
  • a further object of the present invention is to provide a compound represented by the following formula I or ⁇ as a glucagon-like peptide- 1 Receptor modulators for medical use in the prevention and/or treatment of metabolic disorders, including but not limited to diabetes, insulin resistance and obesity, cardiovascular diseases and neurodegenerative diseases such as Alzheimer's disease.
  • the present invention provides a glucagon-like peptide-1 receptor modulator, which increases the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases ( Members of drugs such as Alzheimer's disease.
  • the present invention relates to a compound represented by the following formula I or II, or a pharmaceutically acceptable salt thereof: And all of its stereo and optical isomers, or prodrugs having the same pharmacological effects, esters thereof, solvates thereof or metal complexes thereof.
  • X and Y are respectively (CH Stud, n is 0-2; 0; S or NH.
  • R 2 is each independently a substituent of any of the following: hydrogen; halogen; alkane; cycloalkyl hydrocarbon; hydroxyl group; nitro group; carboxyl group; aldehyde group; alkoxy group; amine group; amine group; amide group; Amido; thiol; sulfhydryl; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Substituted thienyl; substituted or unsubstituted pyrrolyl;
  • R 3 , ! ⁇ independently of any of the following substituents: hydrogen; anthracene; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; thiol; substituted or unsubstituted aryl; Substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • the compounds of the above formulae I and II are characterized in that: X, Y are respectively (CH 2 ) n, n is 0-2; 0; S or NH, Rmony R 2 are each independently:
  • R 5 is any of the following substituents: H; - fluorenyl; - any one, two or three substituted C-containing groups including a halogen atom, a decyloxy group of d-C 6 or a hydroxyl group, - a fluorenyl group of C 6 ; a C 2 - (: 6 alkenyl group; any one, two or three substituted C 2 -C 6 alkenyl groups including a halogen atom, an alkoxy group of d- or a hydroxyl group C 2 - (: 6 alkynyl; any one, two or three substituted C 2 -C 6 alkynyl group including a halogen atom, C "C 6 decyloxy group or hydroxyl group”; C 3 - a C 6 cycloalkyl group; any one, two or three substituted (: 3 - C 6 cycloalkyl) groups containing a halogen atom, C, -C
  • R 6 is any one of the following substituents: H; a fluorenyl group of d-C e ; containing any one, two or three including a halogen atom, an alkoxy group or a hydroxyl group of (:, - (: 6 ) Substituted (VC 6 alkyl; C 2 - (: 6 alkenyl; containing any one, two or three substituted (including a halogen atom, C, -C 6 decyloxy or hydroxy group): 2 -(: 6 alkenyl; (: 2 -( 6 alkynyl; containing any one, two or three substituted ⁇ -C 6 including a halogen atom, (alkoxy group of Ce or a hydroxyl group) alkynyl; C 3 -C 6 cycloalkyl group embankment; contain any halogen atoms include, d-Ce alkoxy or hydroxy the embankment, including one
  • R 7 and R s are each independently a substituent of any of the following: H; ( ⁇ -(: 6 fluorenyl; any one, two or three containing a halogen atom, an alkoxy group of CG or a hydroxyl group) Substituted ( ⁇ -(: 6 fluorenyl; (: 2 -(: 6 alkenyl; any one, two or three substituted C containing a halogen atom, a fluorenyloxy group or a hydroxy group) 2 -alkenyl; C 2 -C 6 alkynyl; any one, two or three substituted C 2 -C 6 alkynyl group containing a halogen atom, a decyloxy group or a hydroxyl group of d-Ce ; C 3 -C 6 cycloalkyl group embankment; includes any halogen atom-containing, dC e the embankment or a hydroxyl group, including one, two or three
  • R 9 is any one of the following substituents: H; (:, -(: 6 fluorenyl; any one, two or three substitutions including a halogen atom, d-(alkoxy group or hydroxy group) a fluorenyl group of d-Cs; (: 2 -( 6 alkenyl; any one, two or three substituted C 2 - C 6 containing a halogen atom, a decyloxy group of dC 6 or a hydroxyl group) Alkenyl; C 2 -C 6 alkynyl; any one, two or three substituted C 2 -C fi alkynyl group containing a halogen atom, C,-C 6 decyloxy or hydroxy group; a C 3 -C fi cyclodecyl group; any one, two or three substituted C 3 -C 6 cyclodecyl groups containing a halogen atom, a C,
  • Ru each independently is any one of the following substituents: H; Ct- (: 6 alkyl; any one, two or three substituted d including a halogen atom, d- alkoxy group or a hydroxyl group - fluorenyl; (: 2 - (: 6 alkenyl; any one, two or three substituted C 2 - containing: a halogen atom, C, -C e methoxy or hydroxy group (: 6 alkenyl; ( 2- ( 6 alkynyl; any one, two or three substituted C 2 - ( ⁇ alkynyl group) including a halogen atom, a decyloxy group of CrC 6 or a hydroxyl group; C a cycloalkyl group of 3 -C e ; any one, two or three substituted C:,-C 6 cyclodecyl groups including a halogen atom, a C, or a C
  • R 13 are each independently a substituent of any of the following: H; C "indenyl group of C 6 ; any one or two of a fluorenyl group or a hydroxy group including a halogen atom, C, -C fi or Three substituted (:, -(: 6 alkyl); alkenyl; any one, two or three substituted ( 2 -(:) containing a halogen atom, a decyloxy group or a hydroxyl group of d-: 6 alkenyl; C 2 - (: 6 alkynyl group; a halogen atom includes contain any, or a hydroxyl group dC embankment 6 of the inner one, two or three substituents of C 2 - (alkynyl; C a cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, a dec
  • R 6 is any one of the following substituents: H; (: 6 fluorenyl; or any one, two or three substituted dC 6 including a halogen atom, ( 6 alkoxy group or hydroxyl group) Alkyl; (: 2 -(: 6 alkenyl; any one, two or three substituted (including 2 -( 6 alkenyl; C) containing a halogen atom, a fluorenyloxy group or a hydroxy group 2 - (: 6 alkynyl; any one, two or three substituted C 2 -C 6 alkynyl groups containing a halogen atom, a C, a C 6 decyloxy group or a hydroxyl group; C 3 - a cyclic fluorenyl group of C 6 ; a C 2 -C B cyclodecyl group containing a halogen atom, a decyloxy group or a hydroxyl group of a Ct-C
  • R 7 and R 8 are each independently a substituent of any of the following: H; C "indenyl group of C e ; any one or two of a decyloxy group or a hydroxyl group including a halogen atom, C, -C 6 Or a three-substituted alkyl group; a C 2 - (: 6 alkenyl group; any one, two or three substituted groups including a halogen atom, an alkoxy group of d- or a hydroxyl group ( 2- ( 6 ) alkenyl group; (: 2 - (: 6 alkynyl group; a halogen atom include containing, C, - one, two or three of any alkoxy or hydroxy-substituted C 6 of the inner (: 2 - (: 6 Alkynyl; C 3 -C e cycloalkyl; any one, two or three substituted C 3 -C 6 cyclodecyl groups containing a
  • R 9 is any one of the following substituents: H; C, -C 6 fluorenyl; any one, two or three substituted d including a halogen atom, ( 6 decyloxy or hydroxy group) - an alkyl group of c 6 ; an alkenyl group of c 2 -c 6 ; any one, two or three substituted C 2 - (: 6 ) including a halogen atom, an alkoxy group of d-Ce or a hydroxyl group Alkenyl; C 2 -alkynyl; any one, two or three substituted c 2 -c 6 alkynyl group containing a halogen atom, c,-c 6 alkoxy group or hydroxyl group; C 3 a cycloalkyl group of _C 6 ; a mono-, two- or three-substituted c 3 -c 6 cyclodecyl group containing a halogen atom, a de
  • R 3 and R 4 are:
  • R,. , Ru 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 C _C 6 methoxy group or a hydroxyl group
  • Three substituted c 2 - (: 6 alkynyl; c 3 - c 6 cycloalkyl; any one, two or three containing an alkoxy group including a halogen atom, c, -c 6 or a
  • a thiophenyl group containing a halogen atom, a C "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 thiol group, a methylthio group, an ethylthio group, etc.
  • R 2 is each independently:
  • R 14 is any one of the following substituents: H; (: "(: 6 alkyl; containing any one, two or three including a halogen atom, (": 6 alkoxy or hydroxy group Substituted ( ⁇ -(: 6 fluorenyl; (: 2 - (: 6 alkenyl; containing any one, two including a halogen atom, (:, - (: 6 alkoxy or hydroxy) Or three substituted (: 2 -(: 6 alkenyl; C 2 - ⁇ alkynyl; any one, two or three substituted C 2 containing a halogen atom, an alkoxy group or a hydroxyl group) -C 6 alkynyl; C 3 -C 6 cycloalkyl; any one, two or three substituted ( 3 - C 6 ring) containing a halogen atom, d-alkoxy or hydroxy group Alkyl; aryl; benzyl; furyl; pyranyl
  • Substituted pyridyl containing a halogen atom, d-(alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio Arbitrarily One, two or three substituted furanyl groups; containing a halogen atom, an alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group Any one, two or three substituted pyranyl groups including an ethylthio group; containing a halogen atom, ( ⁇ -(: 4 fluorenyl group, nitro group, carboxyl group, aldehyde group, decyloxy group, amine group) Any one, two or three substituted thienyl
  • R 6 is any one of the following substituents: H; C, - (: 6 fluorenyl; any one, two or three substituted including a halogen atom, a decyloxy group or a hydroxyl group of d- embankment group; C 2 -C 6 alkenyl group; a halogen atom include containing, C, - any C 6 alkoxy or hydroxy embankment inner one, two or three substituents of C 2 - C 6 alkenyl group; C 2 - (: 6 alkynyl; any one, two or three substituted C 2 -C 6 alkynyl group including a halogen atom, a decyloxy group or a hydroxyl group; a C 3 - C e ring a fluorenyl group containing any one, two or three substituted c 3 -c e including a halogen atom, a decyloxy group or a hydroxyl group of a Ct
  • One, two or three substituted pyranyl groups containing a halogen group including a halogen atom, c, - ⁇ , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, Any one, two or three substituted thienyl groups including a methylthio group, an ethylthio group; an alkyl group including a halogen atom, c, -c 4 , a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group Base, amide group, carboxamide group, sulfhydryl group, methylthio group, ethylthio group Any one, two or three substituents pyrrolyl; - (alkanoyl; containing optionally include a halogen atom, a hydroxy
  • R 3 and R 4 are:
  • R 7 and R are each independently a substituent of any of the following: H; d-alkyl; any one, two or three substituted groups including a halogen atom, a decyloxy group of dC 6 or a hydroxyl group.
  • R 3 and R 4 are:
  • R 9 is any one of the following substituents: H; an fluorenyl group; any one, two or three substituted groups including a halogen atom, a -C methoxy group or a hydroxyl group (;-(: 6 ⁇ ) Any one, two or three substituted C 2 - (: 6 alkenyl; C 2 -C alkynyl group containing a halogen atom, a decyloxy group of dC 6 or a hydroxyl group; Any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group of C Ce 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 of d- alkoxy or hydroxy; aryl; benzyl; furyl; pyranyl; thienyl; a
  • halogen atom Containing any one including a halogen atom, -(: 4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, thiol group, methylthio group, ethylthio group) , two or three substituted pyranyl groups; containing a halogen atom, -(: 4 alkyl group, nitro group, carboxyl group, aldehyde group, decyloxy group, amine group, amide group, carboxamide group, fluorenyl group, A Any one, two or three substituted thienyl groups including a thio group or an ethylthio group; containing an alkyl group including a halogen atom, d-c 4 , a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, Amid
  • a decanoyl group of C, -C 6 an alkanoyl group of any one, two or three substituted dcs including a halogen atom, an alkoxy group of CrCe or a hydroxyl group; an alkenoyl group of c 2 -c 6 ; a halogen atom, d- (: any embankment 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 halogen atom-containing include, Any one, two or three substituted c 2 -c 6 alkynyl groups of c, - ⁇ alkoxy or hydroxy; c 3 -c 6 cycloalkanoyl; containing an alkane including a halogen atom, C Any one, two or three substituted C 3 - (; 6 cyclodecanoyl; adamantyl, substituted
  • R 15 , R ie are each independently a substituent of any of the following: H; an fluorenyl group; any one, two or three substituted Cs including a halogen atom, a decyloxy group or a hydroxyl group of d-, An alkyl group of C 6 ; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 - ( 6 alkenyl groups) containing a halogen atom, an alkoxy group of CrCe or a hydroxyl group; a C 2 -C 6 alkynyl group; any one, two or three substituted groups including a halogen atom, C "C 6 alkoxy group or a hydroxyl group (: 2 - (: 6 alkynyl group; C 3) a cycloalkyl group of C fi ; a C 2 -C 6 cyclodecyl group containing a halogen
  • a fluorenyl group including a halogen atom, C-C 4 , a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, a Any one, two or three substituted furanyl groups including a thio group; a fluorenyl group including a halogen atom, C-C 4 , a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carbon group amide groups, mercapto, methylthio, ethylthio, including one, two or three of the substituents pyranyl; containing a halogen atom include, _ (4 embankment group, a nitro group, a carboxyl group, an aldehyde group,
  • R6 is any of the following substituent groups: H; d- (group 6 of the embankment; includes any containing a halogen atom, C "C 6 alkoxy or hydroxy embankment inner one, two or three substituents of C, - (: 6 alkyl; C 2 - C fi alkenyl group; or a hydroxyl group optionally having embankment include a halogen atom, the inner one, two or three substituents of C 2 - C fi alkenyl; C a 2- C6 alkynyl group; any one, two or three substituted c 2 -c 6 alkynyl groups including a halogen atom, a decyloxy group or a hydroxyl group; a C 3 -C e cyclodecyl group; Any one, two or three substituted ( 3 -(: 6 cyclodecyl; aryl; benzyl; furyl; pyranyl; thiophene) containing
  • a halogen atom (:, -(: 4 alkyl group, nitro group, carboxyl group, aldehyde group, decyloxy group, amine group, amide group, carboxamide group, thiol group, methylthio group, ethylthio group, etc.) Any one, two or three substituted pyranyl groups; containing an alkyl group including a halogen atom, C, -C 4 , 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 mercapto group, a methylthio group, an ethylthio group; a mercapto group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an aldehyde group, an alkyl group,
  • R 7 and R 8 are each independently a substituent of any of the following: H; a fluorenyl group of d-Ce; any one, two or three substituents including a halogen atom, a hydroxyl group of CC e or a hydroxyl group; a d-C 6 fluorenyl group; a C 2 -C 6 alkenyl group; any one, two or three substituted (including 2 -(:) containing a halogen atom, a decyloxy group of dC 6 or a hydroxyl group; 6 alkenyl; C 2 -C 6 alkynyl group; a halogen atom-containing optionally include, d- or hydroxyl group of the embankment, including one, two or three substituents of C 2 -C 6 alkynyl group; a C a 3- C 6 cycloalkyl group; a C 2 -C fi cyclodecyl group containing an alk
  • R 9 is any one of the following substituents: H; C, -C fi fluorenyl; any one, two or three substituted C's including a halogen atom, a -oxy group or a hydroxyl group C 6 fluorenyl; C 2 -alkenyl; containing any one, two or three substituted C 2 - (: 6 olefins including a halogen atom, (": 6 decyloxy or hydroxy group a C 2 -C 6 alkynyl group; any one, two or three substituted C 2 -C e alkynyl groups including a halogen atom, an alkoxy group of d- or a hydroxyl group; C 3 -C embankment 6 cycloalkyl group; a halogen atom-containing optionally include, d- alkoxy or hydroxy group including one, two or three substituents of (: 3 - C 6 cycloalkyl; aryl; benzy
  • R 3 , ⁇ are - K x i Ri respectively .
  • R in, Ru are each independently any of the following substituent groups: H; C, - alkyl; containing optionally include halogen atoms, C "C 6 alkoxy or hydroxy, including one, two or three Substituted d-alkyl; C 2 -( ⁇ alkenyl; any one, two or three substituted C 2 - C s containing a halogen atom, a decyloxy group or a hydroxyl group of d- Alkenyl; C 2 -C 6 alkynyl group; a halogen atom include containing, C, - ⁇ alkoxy or hydroxy embankment any inner one, two or three substituents of c 2 - C 6 alkynyl group; a C a cycloalkyl group of 3 - C 6 ; any one, two or three substituted c 3 -c 6 cycloalkyl groups including a halogen atom, an alkoxy group of C- or a
  • the compound or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, either alone or in combination with a pharmaceutically acceptable carrier or excipient.
  • the invention also provides a medicament comprising the above compound for preventing and/or treating metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (eg Alzheimer's) Ill).
  • the invention relates to methods of preventing and/or treating metabolic disorders, including but not limited to diabetes, insulin resistance and obesity, cardiovascular diseases and neurodegenerative diseases such as Alzheimer's disease.
  • the method comprises administering to a subject in need or willing to receive treatment or prevention an effective amount of a compound which selectively modulates the glucagon-like peptide-1 receptor or a pharmaceutically acceptable salt thereof for preventing or treating the above Disease or symptom.
  • the above metabolic disorders including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease), etc., by administering an effective amount of the following Formula I or a compound represented by II or a pharmaceutically acceptable salt thereof for prevention or treatment:
  • X and Y are respectively (CH, n is 0-2; 0; S or .NH.
  • R, R 2 are each independently one of the following substituents: hydrogen; halogen; anthracene; cyclohexane; hydroxy; nitro; carboxyl; aldehyde; alkoxy; amine; amidoxime; 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 3 , R 4 are each independently any one of the following substituents: hydrogen; anthracene; cyclononene; anthracene; amine; amidoxime; 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.
  • the present invention relates to a combination preparation comprising a compound having a selective modulation of a glucagon-like peptide-1 receptor, particularly a function of activating the receptor, or a pharmaceutically acceptable salt thereof Or alone or in combination with a pharmaceutically acceptable carrier or excipient.
  • This compound has the structure of the following formula I or II:
  • X and Y are respectively (CH, n is 0-2; 0; S or NH.
  • R 2 is each independently any one of the following substituents: hydrogen; halogen; anthracene; a cyclic hydrocarbon; a hydroxyl group; a nitro group; a carboxyl group; an aldehyde group; an anthracene group; an amine group; an amine group; an amide group; Carboxamide; fluorenyl; sulfhydryl; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • R 3 each independently of any of the following substituents: hydrogen; anthracene; cyclononene; alkoxy; amine; alkane Amide; carboxamide; alkylthio; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted a thienyl group; a substituted or unsubstituted pyrrolyl group.
  • the present invention provides a kit comprising the above combined preparation.
  • the present invention further provides the use of the above combined preparations for 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, etc., to achieve selective stimulation of the glucagon-like peptide-1 receptor, improve the patient's symptoms and quality of life.
  • metabolic disorders including, but not limited to, diabetes, insulin resistance and obesity, cardiovascular diseases and neurodegenerative diseases (eg Alzheimer's). Disease, etc., to achieve selective stimulation of the glucagon-like peptide-1 receptor, improve the patient's symptoms and quality of life.
  • metabolic disorder refers to a related symptom and/or disease caused by metabolic disorders such as sugar, fat or protein caused by various causes.
  • diabetes refers to a multi-pathogenic metabolic disease characterized by chronic hyperglycemia accompanied by disorders of sugar, fat and protein metabolism caused by 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.
  • Alzheimer's disease As used herein, Alzheimer's disease (Alzheimer's disease, also known as Alzheimer's dementia) is a progressive degenerative disease of the nervous system, clinically characterized by chronic impairment of intelligence and memory. Chronic loss.
  • 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 used to treat a particular disease means sufficient improvement or to some extent Reduce the amount of symptoms associated with this 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 one 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 are the same or are either hooked or similar, and the understanding of the relevant art may vary in the context, and is generally at least 70%, preferably at least 80%, more preferably at least 90%, The optimal is at least 95% identical.
  • composition refers to any mixture. It may be a solution, suspension, liquid, powder, ointment, aqueous, non-aqueous or any combination thereof.
  • object as used herein includes humans and animals, for example, dogs, cats, cows, pigs, rodents, and the like.
  • metabolic disorders including but not limited to diabetes, insulin resistance and obesity
  • cardiovascular disease including but not limited to diabetes, insulin resistance and obesity
  • neurodegenerative diseases such as Alzheimer's disease
  • 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.
  • metabolic disorders including but not limited to diabetes, insulin resistance and obesity
  • cardiovascular diseases including but not limited to diabetes, insulin resistance and obesity
  • neurodegenerative diseases including neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders (such aspirin, diabetes, diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases.
  • Sexual diseases such as
  • the present invention relates to a compound represented by the following formula I or II, or a pharmaceutically acceptable salt thereof:
  • X and Y are respectively (CH, n is 0-2; 0; S or NH.
  • R t , R 2 are each independently any one of the following substituents: hydrogen; halogen; anthracene; cyclohexane; hydroxy; nitro; carboxy; aldehyde; methoxy; amine; 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 3 , R 4 are each independently any one of the following substituents: hydrogen; anthracene hydrocarbon; a cyclic anthracene: anthracenyloxy; an amine group; an amine group; an amide group; a carboxamide group; a thiol group; Substituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • the compound of the present invention may be a specific stereoisomer, such as the R- or S-configuration, or a mixture thereof, for example, a racemic mixture.
  • the compounds contemplated herein include all classes of pharmaceutically active compounds, or solutions or mixtures thereof. Also included are hydration types thereof, such as aqueous solutions, hydrolysates or ionized products of these compounds; and these compounds may contain different amounts of bound water molecules.
  • the compounds of the invention may be prepared or synthesized according to any suitable method.
  • the compound is prepared by the synthetic method cited in Section F below.
  • the compound or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, either alone or in combination with a pharmaceutically acceptable carrier or excipient.
  • the compounds of the invention may be prepared in the form of their pharmaceutically acceptable salts with any suitable acid.
  • suitable acid for example, inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; organic acids such as formic acid, acetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, etc.; Sulfonic acid such as methanesulfonic acid, ethylsulfonic acid, etc.; arylsulfonate An 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 the following formula I or II or a pharmaceutically acceptable salt thereof:
  • X and Y are respectively (CH 2 ) march, n is 0-2; 0; S or NH.
  • R, R 2 are each independently one of the following substituents: hydrogen; halogen; anthracene; cyclohexane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amidoxime; 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 3 each independently of any of the following substituents: hydrogen; alkane; cycloalkylene; alkoxy; amine; amine alkyl; amide; carboxamide; thiol; substituted or unsubstituted aryl Substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • Any subject can be controlled by this method, preferably a mammal, more preferably a human.
  • the method can be used to control metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease).
  • a preferred disease or condition is any disease or condition caused or accompanied by insulin secretion and/or dysfunction.
  • the invention may be used alone or in combination with other diabetes therapeutics, including insulin sensitizers that are already on the market or to be marketed. compound of.
  • Any suitable metabolic disorder (including but not limited to diabetes, insulin resistance, and obesity) therapeutic agents can be used in combination with the compounds of the present invention.
  • typical insulin sensitizers include rosiglitazone and pioglitazone.
  • the above insulin sensitizer is not administered when the compound of the invention is used. More preferred 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 treatment drugs (including insulin sensitizers) which have been marketed or will be marketed to cause drug resistance or side effects.
  • diabetes treatment drugs including insulin sensitizers
  • Administration of the compounds of the invention alone or in combination with other suitable diabetes therapeutics including insulin sensitizers can be by any suitable method.
  • it can be administered by intracavitary injection, subcutaneous injection, intravenous injection, intramuscular injection, intradermal injection, orally or topically, with a compound of the present invention, or with a pharmaceutically acceptable salt thereof.
  • the method further comprises performing a diagnosis and prognosis assessment of the disease or condition of the subject to whom it is administered.
  • Any suitable method can be used to diagnose and assess the associated disease or condition and its prognosis.
  • Diagnosis and prognosis can be based on detecting and/or identifying any or all of the in vivo material, such as glycated hemoglobin, enzymes, antigens, antibodies, nucleic acids or other pathological and clinical markers, and related symptoms.
  • a diagnostic or prognostic method disclosed in International Patent No. WO 01/44815 and U.S. Patent No. 5,571,674 can be used.
  • the 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 a therapeutic agent for one or more metabolic disorders including an insulin sensitizer, which is represented by the following formula I or ⁇ :
  • X and Y are each (CH 2 ) n and n is 0-2; 0; S or NH.
  • RR 2 is each independently one of the following substituents: hydrogen; halogen; anthracene; cycloalkyl; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; Amido; thiol; sulfhydryl; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Substituted thienyl; substituted or unsubstituted pyrrolyl.
  • R 3 , R 4 are each independently any of the following substituents: hydrogen; anthracene; cyclononene; anthracene; amine; amine sulfhydryl; amide; carbonamide; thiol; 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 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 comprising administering an effective amount to a subject in need and willing to receive treatment or prevention The above combined preparation, or a pharmaceutically acceptable salt thereof, thereby treating or preventing the above diseases or symptoms.
  • kits comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, and the use of the above compound or a pharmaceutically acceptable salt thereof for controlling secretion and/or secretion by insulin Instructions for the use of a disease or condition caused by or associated with a dysfunction.
  • kits comprising the combination described above and instructions for using the combination to treat or prevent a disease or condition caused or accompanied by insulin secretion and/or dysfunction.
  • the compounds of the invention are formulated for any suitable route of administration, for example, intraluminal, subcutaneous, intravenous, intramuscular, 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, lozenges, lenticular capsules, dispersing agents, suspending agents, solutions, capsules, films and the like.
  • the compound of the present invention may be in accordance with a general pharmaceutical mixing technique with a pharmaceutical carrier or excipient such as ⁇ -cyclodextrin and 2-hydroxypropyl- ⁇ -cyclodextrin. Finely mixed.
  • a pharmaceutical carrier or excipient such as ⁇ -cyclodextrin and 2-hydroxypropyl- ⁇ -cyclodextrin. Finely mixed.
  • a special carrier a local or parenteral route, may be employed.
  • parenteral dosage forms such as compositions for intravenous injection or infusion
  • similar pharmaceutical vehicles can be employed, water, glycols, oils, buffers, sugars, preservatives, liposomes, etc., which are well known to those skilled in the art. .
  • parenteral compositions examples include, but are not limited to, 5% W/V Dextrose, saline or other solution.
  • 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 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.
  • Typical pharmaceutically acceptable solutions are physiological saline and dextrose solutions.
  • the kit of the present invention further comprises a needle or syringe and/or a packaged alcohol pad for injection of the composition, preferably in a sterile form. Instructions for use by a doctor or patient may optionally be included.
  • the raw materials (0601 - 0610) used in the present invention were synthesized in accordance with the synthesis method described in the Chinese patent (Application No.: 200310109331. 0).
  • the invention is implemented by the following steps:
  • HP1100 HPLC system with binary gradient pump, online vacuum degasser, autosampler, column oven and photodiode array detector.
  • the column is ZORBAX SB-C18 (2.11 x 150 mm, 3. 5 ⁇ )
  • the mobile phase is acetonitrile/water 65: 35
  • the flow rate is 0. 2 ml/min
  • the detection wavelength is 254.
  • the melting point is IA6304 type melting point.
  • NMR was measured by Varian Mercury-300 and Varian Mercury Plus 400 NMR (solvent: CDCl :i , CD 3 0D or DMSO-de);
  • ESI-MS was measured by AB Mariner mass spectrometer, EI by Measured by a Finnigan MAT95 mass spectrometer.
  • the materials used in the synthesis are commercially available products unless otherwise specified. The following specific examples are intended to further illustrate the invention but are not intended to limit the invention.
  • Example 13 Preparation of compound GLP-D-3 NMR calibration: ⁇ H 2. 50 ppm (DMSO-d 6 ).
  • Example 15 Preparation of compound GLP-D-5 NMR calibration: ⁇ H 2. 50 ppm (DMS0-d e ).
  • Example 17 Preparation of compound GLP-D-7 NMR calibration: ⁇ H 2. 50 ppm (DMSO-d 6 ).
  • Example 20 Preparation of compound GLP-D-10 NMR calibration: ⁇ H 2. 50 ppm (DMSO-d 6 ).
  • Example 24 Preparation of compound GLP-D-14 NMR calibration: ⁇ H 2. 50 ppra (DMS0-d 6 ).
  • Example 26 Preparation of Compound GLP-D- R 16 bandit calibration: ⁇ H 2. 50 ppm (DMSO- d 6).
  • GLP-1R is a G protein-coupled receptor.
  • GLP-1R binds to an agonist, the G a 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 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)
  • Forma Carbon Dioxide Incubator Forma
  • Victor 2 plate reader Wood 2 plate reader
  • Test compound GLP-A-1, GLP-B-3, GLP-B-6, GLP-B-7
  • 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 and the test compounds GLP-A-1, GLP-B-3, GLP-B-6, and GLP-B-7 were each diluted to a certain concentration gradient, and then added to the above 96 wells at 1 ⁇ M/well. In microplates. Incubate for 6 hours at 37° (:, 5% CO 2 ). Luciferase activity was measured by the Steady-G1 0 TM Luciferase Assay System Kit, and the Victor 2 reader was used for reading.

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Abstract

L'invention concerne des composés de cyclobutane substitués représentés par la formule I ou II. L'invention concerne également le procédé de préparation de ces composés et leurs utilisations comme régulateurs de récepteurs de peptide 1 (GLP-1R) de type glucagon pour prévenir et/ou traiter des troubles métaboliques, dont le diabète, l'insulinorésistance et l'obésité, etc..., les maladies cardiovasculaires et neurodégénératives telles que la maladie d'Alzheimer, etc.
PCT/CN2007/002768 2006-12-05 2007-09-19 Composés de cyclobutane substitués, procédés de préparation et leurs utilisations pharmaceutiques WO2008067709A1 (fr)

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WO2017112889A1 (fr) 2015-12-23 2017-06-29 The Johns Hopkins University Agoniste de glp-1r à action prolongée pour la thérapie de troubles neurologiques et neurodégénératifs

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