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WO2005025554A2 - Inhibiteur de la dipeptidylpeptidase iv - Google Patents

Inhibiteur de la dipeptidylpeptidase iv Download PDF

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Publication number
WO2005025554A2
WO2005025554A2 PCT/JP2004/013480 JP2004013480W WO2005025554A2 WO 2005025554 A2 WO2005025554 A2 WO 2005025554A2 JP 2004013480 W JP2004013480 W JP 2004013480W WO 2005025554 A2 WO2005025554 A2 WO 2005025554A2
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Prior art keywords
alkyl
alkoxy
heterocyclyl
following
cycloalkyl
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WO2005025554A3 (fr
Inventor
Kazuhiro Tsutsumi
Hisashi Shinkai
Yuki Kitao
Masaki Yamashita
Satoru Kobayashi
Kenichi Matsui
Tomohiro Oda
Toshio Taniguchi
Kota Asahina
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Japan Tobacco Inc
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Japan Tobacco Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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

Definitions

  • the present invention relates to a compound useful as a dipeptidyl peptidase IV inhibitor and a dipeptidyl peptidase IV inhibitor.
  • Aminopeptidase in a wide sense, which liberates the N- terminal amino acid from proteins and peptides includes aminopeptidase (hereinafter to be abbreviated as "AP”) that liberates one residue, dipeptidyl peptidase (hereinafter to be abbreviated as "DPP”) that liberates two residues, and tripeptidyl peptidase (hereinafter to be abbreviated as "TPP”) that liberates three residues.
  • AP aminopeptidase
  • DPP dipeptidyl peptidase
  • TPP tripeptidyl peptidase
  • AP is classified into arginyl aminopeptidase, methionyl aminopeptidase, aspartyl aminopeptidase, alanyl aminopeptidase, glutamyl aminopeptidase, prolyl aminopeptidase, leucyl aminopeptidase and cystinyl aminopeptidase based on the substrate specificity. In general, the substrate specificities of these often overlap with each other.
  • DPP includes four kinds of enzymes of DPP-I , DPP-II, DPP-III and DPP-IV, based on the differences in the substrate specificity thereof, physicochemical properties and intracellular localization. Moreover, the presence of DPP-VI , DPP-VIII, DPP-IX and DPP-X has been recently reported in a literature.
  • TPP includes two kinds of enzymes of TPP-I and TPP-II, based on the differences in the substrate specificity, molecular weight and intracellular localization.
  • Dipeptidyl peptidase IV (EC3.4.14.5, hereinafter to be abbreviated as "DPP-IV”) is a glycoprotein on a cell surface, which has been found as a T cell activated antigen and which is a serine protease that cleaves the second peptide bond on C-terminal from N-terminal of protein and peptide having an X-Pro or X-Ala structure on the N-terminus .
  • DPP- ⁇ V is widely distributed in the kidney, liver, salivary glands, connective tissues and the like, and is also present in body fluids such as serum, urine, saliva and the like. In the immune system, moreover, it has been clarified that DPP-IV is the same molecule as a T cell activated antigen CD26.
  • GLP-1 glucagons-like peptide-1
  • GLP-1 is released from enteroendocrine L-cells in the distal small intestine and colon in response to oral ingestion of nutrients .
  • Active GLP-1 is rapidly converted to inactive GLP-1 by the action of DPP-IV that cleaves the N-terminal dipeptide (His- Ala) of active GLP-1.
  • this inactive GLP-1 acts as an antagonist and shows an antagonistic action against GLP-1 receptor, thus suppressing the function of GLP-1 (see, Journal of Clinical Endocrinology and Metabolism, 80(3) , 952-957 (1995) , American Journal of Physiology, 271, E458-E464 (1996) , European Journal of Pharmacology, 318, 429-435 (1996), Diabetes, 47(11) , 1663-1670 (1998)) .
  • DPP-IV Suppression of degradation of GLP-1 by inhibiting DPP-IV is considered to be the most preferable method as a means to enhance GLP-1 action. That is, reports have documented that a DPP-IV inhibitor can enhance glucose-dependent insulin secretion and improve glucose tolerance in non-insulin-dependent diabetes mellitus (NIDDM) and in various diabetic animal models , and it can be a superior pharmaceutical agent that improve postprandial hyperglycemia, which is unaccompanied by side effects such as persistent hypoglycemia and the like.
  • NIDDM non-insulin-dependent diabetes mellitus
  • DPP-IV inhibitor As a DPP-IV inhibitor, the following compounds are known.
  • T is described as an intermediate for the production of a protease inhibitor in WO98/45330, JP-A-2002-504094 , USP6291687, US2001/044547A, USP6489364 and EP1005493A. Furthermore ,
  • (U) (V) is described as an intermediate for the production of a matrix metalloproteinase inhibitor in WO96/06074, JP-A-10-504821 , USP5763621, EP777646A and EP777646B. Moreover, is described as an intermediate for the production of a cathepsins inhibitor in WO03/029200.
  • the present invention aims at providing a superior DPP-IV inhibitor.
  • the present invention aims at providing a compound showing a DPP-IV inhibitory activity and effective for the treatment of diabetes, especially type II diabetes, as well as hyperglycemia , hypoglycemia, Syndrome X, diabetic complications, hyperinsulinemia , obesity, atherosclerosis and related diseases thereof, anxiety, eating disorders, neurodegenerative diseases, as well as various immunomodulatory diseases including psoriasis , multiple sclerosis, rheumatoid arthritis, and chronic inflammatory bowel disease, for organ transplantation, and the like.
  • compound [I] a compound represented by the following formula [I] (hereinafter sometimes to be referred to as "compound [I]”) has a superior DPP-IV inhibitory activity, which resulted in the completion of the present invention. While many of the conventionally known DPP-IV inhibitors have proline as a basic structure, the present invention is a DPP-IV inhibitor having a completely new structure wherein a 5-membered ring of proline is cleaved.
  • the present invention provides the following (1) to (29) .
  • a DPP-IV inhibitor comprising a compound represented by the formula [I]
  • R 1 is selected from the following [A]-[E]:
  • (Ba2) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following ⁇ Baal>- ⁇ Baal7>) , ... ⁇ Baal> halogen atom, ••• ⁇ Baa2> C ⁇ - 6 alkyl, ••• ⁇ Baa3> halo-C_- 6 alkyl, ••• ⁇ Baa4> C 3 - 12 cycloalkyl, ⁇ • ⁇ Baa5> aralkyl, ••• ⁇ Baa6> heterocyclyl-C ⁇ _ 6 alkyl, ⁇ • ⁇ Baa7> hydroxyl , ••• ⁇ Baa8> C1-6 alkoxy, ••• ⁇ Baa9> C ⁇ _ 6 alkylthio, ••• ⁇ Baal0> aryloxy, ⁇ Baall> aralkyloxy,
  • [C] C 3 - ⁇ 2 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ C1>- ⁇ C17>) , ⁇ ⁇ C1> halogen atom, • ⁇ C2> C ⁇ - 6 alkyl, • ⁇ C3> halo-C ⁇ - 6 alkyl ,
  • R 12 and R 13 are each independently selected from the following (E1)-(E3), j and k are each independently an integer of
  • X 12 is selected from the following (Ebl) - (Eb24) ) , "(Eal) aryl and
  • R 2 is selected from the following [F]-[H]:
  • Ci- 6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ G1>- ⁇ G18>) ,
  • R 3 is selected from the following [I] and [J]
  • R 4 is selected from the following [K]-[S]:
  • R 41 is selected from the following (Lal)-(La8), and
  • Y 41 is selected from the following (Lbl) and (Lb2) ) ,
  • R 413 is Ci-6 alkyl , C 3 - ⁇ 2 cycloalkyl or aryl ,
  • R 414 R 415 and R 416 are the same or different and each is hydrogen atom, Ci-6 alkyl, C 3 - 12 cycloalkyl or aryl,
  • R is hydrogen atom or C ⁇ - 6 alkyl , or R 417 in combination with R 413 form C ⁇ _ 4 alkylene) ;
  • cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and heterocyclylalkyl are optionally substituted by 1 to 3 substituents selected from the following ⁇ Labl>- ⁇ Lab33>) , ••• ⁇ Labl> halogen atom,
  • Ci_ 6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from hydroxyl, Ci-_ alkoxy, -S0 2 -C ⁇ -6 alkyl, -S0 2 -aryl, -NHS0 2 -C ⁇ - 6 alkyl and -NHS0 2 -halo-Ci- 6 alkyl) ,
  • X 41 is (CHR 418 ) C - • X 41a -(CHR 419 ) d - X 41a is selected from the following (Lbal) - (Lba23) , R 418 and R 419 are the same or different and each is hydrogen atom or C ⁇ - 6 alkyl, c is an integer of 0 to 2, and d is an integer of 0 to 4) ,
  • R 41 is as defined above, and Y 42 is selected from the following (Mai) - (Mal2) ) , (Mai) single bond,
  • X 2a is selected from the following (Maal) (Maa23)
  • R 420 and R 421 are the same or different and each is hydrogen atom or C ⁇ - 6 alkyl
  • e and f are each independently an integer of 0 to 2
  • Z 41 and Z 42 are the same or different and each is selected from the following (Mabl).- (Mab6)
  • Z 43 is selected.
  • (Mab3) C 2 _ 6 alkynylene (said alkylene, alkenylene and alkynylene are optionally substituted by 1 to 3 substituents selected from the following ⁇ Mabal>- ⁇ Mabal3>) , •" ⁇ ⁇ Mabal> halogen atom, ⁇ Maba2> C 3 - 12 cycloalkyl,
  • (Mabba4) , and X 4c is selected from the following (Mabbbl) - (Mabbb9) ) (Mabbal) hydrogen atom, (Mabba2) C ⁇ _ 6 alkyl , (Mabba3) aryl and (Mabba4) aralkyl (alkyl, aryl and aralkyl are optionally substituted by 1 to 3 substituents selected from the following ⁇ Mabbaal>- ⁇ Mabbaa4>)
  • (Mac2) C2-6 alkenetriyl (said alkanetriyl and alkenetriyl are optionally substituted by 1 to 3 substituents selected from the following ⁇ Macal>- ⁇ Macal3>) "•• ⁇ Macal> halogen atom, ⁇ Maca2> C 3 - ⁇ 2 cycloalkyl ,
  • heterocyclyl-C ⁇ - 6 alkyl (said aryl, aralkyl, heterocyclyl and heterocyclyl-C ⁇ -6 alkyl are optionally substituted by 1 to 3 substituents selected from the following ⁇ N1>- ⁇ N19>) ,
  • R 42 and R 43 are each independently selected from the following (SI) -(S3) , and m and n are each independently an integer of 0 to
  • Ci-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ U1>- ⁇ U14>) ,
  • (Ua2) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following ⁇ Uaal>- ⁇ Uaal7>) " ⁇ Uaal> halogen atom, "• ⁇ Uaa2> Ci- 6 alkyl, ' ••• ⁇ Uaa3> halo-Ci- 6 alkyl,
  • [V] C 3 -i 2 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ V1>- ⁇ V17>) , • ⁇ V1> halogen atom, • ⁇ V2> Ci- 6 alkyl, • ⁇ V3> halo-C . - . alkyl, • ⁇ V4> aralkyl,
  • heterocyclyl-C ⁇ - 6 alkyl saturated heterocycle, aryl, heterocyclyl, aralkyl and heterocyclyl-C ⁇ _ 6 alkyl are optionally substituted by 1 to 3 substituents selected from the following '
  • R 1 is selected from the following [A]-[E]:
  • Ci- 6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ B1>- ⁇ B14>) ,
  • R 12 , R 13 ,j and k are as defined in the above-mentioned (1) , which is formed by R 1 and R 4' in combination;
  • R 2 ' is selected from the following [F]-[H], [F] hydrogen atom, [G] C ⁇ _ 6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ G1>- ⁇ G18>) , • ⁇ G1> halogen atom, • ⁇ G2> C3-12 cycloalkyl, • ⁇ G3> hydroxyl,
  • R 3' is the following [J]
  • R 4 ' is selected from the following [K]-[M], [P] , [R] and [S] ,
  • Ci- 6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ L1>- ⁇ L14>)
  • R 41' is selected from the following (Lai) , (La2) , (La5) and (La7) , and Y 41 is as defined in the above-mentioned (1) ) , (Lai) hydrogen atom,
  • (La2) C ⁇ _ 6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ Laal>- ⁇ Laa24>) ,
  • Ci- 6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from hydroxyl, C.-e alkoxy, -S0 2 -C ⁇ _ 6 alkyl, -S0 2 -aryl, -NHS0 2 -C ⁇ - 6 alkyl and -NHS0 2 -halo-C__6 alkyl) ,
  • R 413 , R 414 , R 415 , R 41 ⁇ and R 417 are as defined in the above-mentioned
  • [M] C 3 _ ⁇ 2 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ M1>- ⁇ M18>) , ⁇ M1> halogen atom, ⁇ M2> Ci-6 alkyl, ⁇ M3> halo-C ⁇ -6 alkyl, ⁇ M4> aralkyl,
  • R 42 and R 43 are each as defined in the above-mentioned (1) , m and n are each independently an integer of 0 to 3) formed by R 4' and R 5 ' in combination,
  • R 5' is selected from the following [T]-[W] and [BB] , [T] hydrogen atom,
  • C ⁇ _ 6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ U1>— ⁇ U14>) , • ⁇ U1> halogen atom, , - ⁇ U2> C3-12 cycloalkyl, • ⁇ U3> hydroxyl, • ⁇ U4> Ci-6 alkoxy, • ⁇ U5> Ci- 6 alkylthio, - ⁇ U6> aryloxy, • ⁇ U7> aralkyloxy, • ⁇ U8> heterocyclyloxy, • ⁇ U9> heterocyclyl-C ⁇ _6 alkoxy, • ⁇ U10> nitro, - ⁇ U11> amino, • ⁇ U12> cyano, • ⁇ U13> carboxyl and • ⁇ U14> -X 44 -R 45 (R 45 and X 44 are as defined in the above-mentioned
  • Ci- 6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ Laal>- ⁇ Laa24>) , ⁇ Laal> halogen atom, ⁇ Laa2> C3-12 cycloalkyl, ⁇ Laa3> hydroxyl, ⁇ Laa4> aralkyloxy, ⁇ Laa5> heterocyclyloxy, ⁇ Laa6> heterocyclyl-C ⁇ _ 6 alkoxy, ⁇ Laa7> nitro, ⁇ Laa8> cyano, ⁇ Laa9> carboxyl,
  • R is Ci- 6 alkyl , C 3 _ ⁇ 2 cycloalkyl or aryl ,
  • R 414 , R 415 and R 416 are the same or different and each is hydrogen atom, Ci-6 alkyl , C 3 __ 2 cycloalkyl or aryl ,
  • R' 417 is hydrogen atom or G1- 6 alkyl) ;
  • Ci- 6 alkyl (alkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ Lbaaal>- ⁇ Lbaaal3>) , ⁇ " ⁇ Lbaaal> halogen atom,
  • C ⁇ _6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ B1>- ⁇ B4>, ⁇ B10>- ⁇ B12> and ⁇ B14>) , « ⁇ B1> halogen atom,
  • C3_i 2 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ C1>, ⁇ C2>, ⁇ C6>,
  • Ci- 6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from ⁇ G1>- ⁇ G4>, ⁇ G10>- ⁇ G13> and ⁇ G16>- ⁇ G18>) , ⁇ G1> halogen atom, • ⁇ G2> C 3 -1 2 cycloalkyl, • ⁇ G3> hydroxyl, • ⁇ G4> Ci-e alkoxy, • ⁇ G10> nitro,
  • [L] C ⁇ - 6 alkyl (said alkyl is optionally substituted by 1 to * 3 substituents selected from the following ⁇ L1>- ⁇ L4> and ⁇ L10>-
  • [P] 3 to 7-membered saturated heterocycle (said saturated heterocycle is optionally substituted by 1 to 3 substituents selected from the following ⁇ N1>, ⁇ N2>, ⁇ N7>, ⁇ N8>, ⁇ N14>- ⁇ N16> and ⁇ N18>) ,
  • R 42 and R 43 are each as defined in the above-mentioned (1) and m and n are each independently an integer of 0 to 3) formed by R 4 ' and R 5 ' in combination; and R5' is
  • Ci-e alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ U1>- ⁇ U4> and ⁇ U10>-
  • R 4a is selected from the following [MabbO] , [Mabbl] and [Mabbl ⁇ ] , [MabbO] hydrogen atom, [Mabbl] halogen atom and
  • R 41a and R 41d are the same or different and each is hydrogen atom or C -6 alkyl) ;
  • R 4b is selected from the following [Lai] , [La2] , [La5] and [La6] ,
  • alkyl, aryl and aralkyl are optionally substituted by 1 to 3 substituents selected from the following ⁇ Labl>, ⁇ Lab2>, ⁇ Lab7>,
  • Ci-e alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from C ⁇ _ 6 alkoxy, -S0 2 -C ⁇ - 6 alkyl, -S0 2 -aryl, - NHS0 2 -C ⁇ - 6 alkyl and -NHS0 2 -halo-C ⁇ _ 6 alkyl) ,
  • R 41f , R 1g are the same or different and each is hydrogen atom or Ci-e alkyl and R 41h is C ⁇ _ 6 alkyl) ;
  • X 4b is selected from the following [Maal]- [Maa ⁇ ] , [Maa9] , [Maal2]-
  • R 41b and R 41e are the same or different and each is hydrogen atom or Ci-e alkyl, or show -(CH 2 ) 2 -, -(CH 2 ) 3 -, - (CH 2 ) 4 - or -(CH 2 ) 5 - together with R 4b ) ;
  • R 4d is hydrogen atom or C ⁇ - 6 alkyl
  • a is an integer of 1 to 4
  • b is an integer of 0 to 4
  • c is an integer of 0 to 2
  • d is an integer of 0 to 4 , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • each symbol is as defined in the above-mentioned (5) , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • each symbol is as defined in the above-mentioned (5) , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • a DPP-IV inhibitor which comprises a compound of any of the above-mentioned (2) to (15) , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • the different therapeutic drug for diabetes, the therapeutic drug for diabetic complication, the therapeutic drug for hyperlipidemia or the anti-obesity drug is selected from insulin preparations (injection) , low-molecular insulin preparations (oral agent) , sulfonylurea receptor agonists (SU drugs), short acting insulin secretagogues , ⁇ -glucosidase inhibitors, insulin sensitizers, PPAR ⁇ receptor agonists, PPAR ⁇ receptor agonists/antagonists, PPAR ⁇ receptor agonists, tGLP-1 receptor agonists, glucagon receptor antagonists, glucocorticoid receptor antagonists, biguanides, SGLUT inhibitors, fructose-1 ,6- bisphosphatases (FBPase) inhibitors, glycogen synthase kinase 3 (GSK-3) inhibitors, phosphoenolpyruvate carboxykinas
  • a method for treating diabetes which comprises administering an effective amount of the compound of any of the above-mentioned (2) to (15) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, to a mammal.
  • a method for inhibiting DPP-IV comprising using the compound of the above-mentioned (2) to (15) , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • the different therapeutic drug for diabetes , the therapeutic drug for diabetic complication, the therapeutic drug for hyperlipidemia or the anti- obesity drug is selected from insulin preparations (injection) , low-molecular insulin preparations (oral agent) , sulfonylurea receptor agonists (SU drugs), short acting insulin secretagogues , ⁇ -glucosidase inhibitors , insulin sensitizers , PPAR receptor agonists, PPAR ⁇ receptor agonists/antagonists, PPAR ⁇ receptor agonists, tGLP-1 receptor agonists, glucagon receptor antagonists, glucocorticoid receptor antagonists , biguanides , SGLUT inhibitors , fructose-1 , 6-bisphosphatases (FBPase) inhibitors, glycogen synthase kinase 3 (GSK-3) inhibitors ,,.
  • insulin preparations injection
  • oral agent low-molecular insulin preparations
  • SU drugs sulfonylurea
  • PPCK protein tyrosine phosphatase IB
  • SH2 domain-containing inositol phosphatase (SHIP2) inhibitors SH2 domain-containing inositol phosphatase (SHIP2) inhibitors
  • AMPK AMP-activated protein kinase
  • GP glycogen phosphorylase
  • GP glycogen phosphorylase
  • PDHK microsomal triglyceride transfer protein
  • MTP diacylglycerol acyltransferase
  • CETP cholesteryl ester transfer protein
  • HMG-CoA reductase inhibitors ⁇ 3 adrenaline receptor agonists
  • Apo-Al apolipoprotein-Al
  • lipoprotein lipoprotein
  • the present invention includes the following embodiments .
  • a DPP-IV inhibitor comprising a compound of the formula [I] , wherein
  • R 4 is selected from the following [K]-[S], or a salt thereof.
  • R 41 is selected from the following (La2) and (La4)-
  • (La7) , and Y 41 is selected from the following (Lbl) and (Lb2) ) , •• (La2) Ci- 6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ Laal>- ⁇ Laal0>, ⁇ Laal6> and ⁇ Laal9>) ,
  • heterocyclyl (said aryl, aralkyl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following ⁇ Labl>- ⁇ Labl5>, ⁇ Labl9> and ⁇ Lab28>) ,
  • (Lb2) X 41 (X q ⁇ is selected from the following (Lbal) - (Lba23) ) , ⁇ (Lbal) -0-, -OCH 2 -, -OCH 2 CH 2 -, -CH2O-, -CH 2 CH 2 0-, (Lba2) -S-, -SCF ⁇ 2 -, -SCH 2 CH 2 -, -CH 2 S-, -CH 2 CH 2 S-,
  • (Lbaa2) C ⁇ - 6 alkyl (said alkyl is optionally substituted by 1 to substituents selected from the following ⁇ Lbaaal>- ⁇ Lbaaal3>) , • ⁇ Lbaaal> halogen atom, • ⁇ Lbaaa2> C 3 - 12 cycloalkyl, ⁇ Lbaaa3> hydroxyl, " ⁇ Lbaaa4> C ⁇ - 6 alkoxy, • ⁇ Lbaaa5> Ci-e alkylthio, • ⁇ Lbaa6> aryloxy, •• ⁇ Lbaaa7> aralkyloxy, • ⁇ Lbaaa8> heterocyclyloxy, • ⁇ Lbaaa9> heterocyclyl-C ⁇ _6 alkoxy r •" ⁇ LbaaalO> nitro,
  • X 41 is as defined above, X 42 and X 43 are the same as X 41 , Z 41 and Z 42 are the same or different and each is selected from the following (Mabl) , (Mab3)-(Mab6) and Z 43 is selected from the following (Macl) ,
  • ⁇ "(Mac5) trivalent heterocycle (asid cycloalkanetriyl, arenetriyl and heterocycle are optionally substituted by 1 to 3 substituents selected from the following ⁇ Macbl>- ⁇ Macbl7>) , •• •• ⁇ Macbl> halogen atom, ⁇ Macb2> Ci-e alkyl , ⁇ Macb3> halo-Ci-e alkyl,

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Abstract

Selon l'invention, un composé de formule [I], dans laquelle chaque symbole est tel que défini dans la spécification, ou un stéréoisomère associé, un sel acceptable pharmaceutiquement ou un solvate associé présentent une activité inhibitrice de la dipeptidylpeptidase IV et constituent de nouveaux composés efficaces dans le traitement de diabètes de type II, de l'obésité et similaire.
PCT/JP2004/013480 2003-09-09 2004-09-09 Inhibiteur de la dipeptidylpeptidase iv Ceased WO2005025554A2 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP2003-317407 2003-09-09
JP2003317407 2003-09-09
JP2003-395879 2003-11-26
JP2003395879 2003-11-26
JP2004114685 2004-04-08
JP2004-114685 2004-04-08

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WO2005025554A2 true WO2005025554A2 (fr) 2005-03-24
WO2005025554A3 WO2005025554A3 (fr) 2005-07-28

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PE (1) PE20050948A1 (fr)
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Cited By (55)

* Cited by examiner, † Cited by third party
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WO2007072083A1 (fr) 2005-12-23 2007-06-28 Prosidion Limited Traitement du diabete de type 2 par combinaison d'un inhibiteur de dpiv a de la metformine ou de la thiazolidinedione
WO2007120702A2 (fr) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Agonistes du récepteur de gpr119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose et autres états se caractérisant par une masse osseuse faible, et thérapie de combinaison associée
WO2007027225A3 (fr) * 2005-04-27 2007-11-22 Arena Pharm Inc Polytherapie pour le traitement, d'une part, de l'obesite et de diabetes et des troubles associes et, d'autre part, de troubles ameliores par l'augmentation d'un niveau glp-1 sanguin
WO2008020037A1 (fr) * 2006-08-16 2008-02-21 Action Medicines, S.L. Utilisation de dérivés de 2,5-dihydroxybenzène pour le traitement de l'obésité, de l'hirsutisme, de l'hypertricose et des verrues virales
WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
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US7728146B2 (en) 2006-04-12 2010-06-01 Probiodrug Ag Enzyme inhibitors
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WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
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WO2011127051A1 (fr) 2010-04-06 2011-10-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur de gpr119 et traitement de troubles associés
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US20130053364A1 (en) * 2009-10-09 2013-02-28 Hazel J. Dyke Sulphone Compounds and Methods of Making and Using Same
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WO2017176461A1 (fr) * 2016-04-04 2017-10-12 Research Triangle Institute Agonistes du récepteur du neuropeptide s (npsr)
JP2017538678A (ja) * 2014-11-05 2017-12-28 フレクサス・バイオサイエンシーズ・インコーポレイテッドＦｌｅｘｕｓ Ｂｉｏｓｃｉｅｎｃｅｓ， Ｉｎｃ． 免疫調節剤
US9868717B2 (en) 2012-11-05 2018-01-16 Zafgen, Inc. Tricyclic sulphonamide compounds and methods of making and using same
US10005733B2 (en) 2014-12-17 2018-06-26 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamide and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)-benzenesulfonamide compounds and their therapeutic use
US10106546B2 (en) 2014-11-05 2018-10-23 Flexus Biosciences, Inc. Immunoregulatory agents
US10174009B2 (en) 2012-11-05 2019-01-08 Zafgen, Inc. Tricyclic sulphonamide compounds and methods of making and using same
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US10654800B1 (en) * 2019-11-21 2020-05-19 King Abdulaziz Univeristy Antidiabetic compounds
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US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
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WO2025131062A1 (fr) * 2023-12-21 2025-06-26 江苏恒瑞医药股份有限公司 Composé oléfinique, son procédé de préparation et son utilisation en médecine

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Family Cites Families (5)

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Publication number Priority date Publication date Assignee Title
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SE9701245D0 (sv) * 1997-04-04 1997-04-04 Bjoern Classon Antivirals
CO5150173A1 (es) * 1998-12-10 2002-04-29 Novartis Ag Compuestos n-(glicilo sustituido)-2-cianopirrolidinas inhibidores de peptidasa de dipeptidilo-iv (dpp-iv) los cuales son efectivos en el tratamiento de condiciones mediadas por la inhibicion de dpp-iv
JP2005504827A (ja) * 2001-10-02 2005-02-17 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド システインプロテアーゼの可逆性インヒビターとして有用な化合物
WO2003045977A2 (fr) * 2001-11-26 2003-06-05 Trustees Of Tufts College Inhibiteurs peptidomimetiques d'enzymes de clivage post-proline

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