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Fused tricyclic substituted amino six-membered ring derivative and application thereof in medicine

An amino six-membered ring type, fused ring technology, applied in the field of dipeptidyl peptidase IV inhibitors, can solve problems such as diabetes burden

Active Publication Date: 2015-11-25
SICHUAN HAISCO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Diabetes treatment places a heavy burden on families and society

Method used

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  • Fused tricyclic substituted amino six-membered ring derivative and application thereof in medicine
  • Fused tricyclic substituted amino six-membered ring derivative and application thereof in medicine
  • Fused tricyclic substituted amino six-membered ring derivative and application thereof in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0229] 2-(5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-3b,4,5,6 ,6a,7-hexahydro-2H-pyrrolo[3',4':3,4]cyclopento[1,2-c]pyrazol-2-yl)ethanol (Compound 1-1)

[0230] 2-(5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-3b,4,5,6,6a,7- hexahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazol-2-yl)ethanol

[0231]

[0232] 2-(5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-3b,4,5,6 ,6a,7-Hexahydro-1H-pyrrolo[3',4':3,4]cyclopento[1,2-c]pyrazol-1-yl)ethanol (Compound 1-2)

[0233] 2-(5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-3b,4,5,6,6a,7- hexahydro-1H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazol-1-yl)ethanol

[0234]

[0235]

[0236] The first step: tert-butyl 2-(2-ethoxy-2-carbonylethyl)-3b,4,6a,7-tetrahydro-2H-pyrrolo[3',4':3,4] ring Pento[1,2-c]pyrazole-5(6H)-carboxylate (1a-1)

[0237] tert-butyl2-(2-ethoxy-2-oxoethyl)-3b,4,6a,7-tetrahydro-2H-pyrrolo[3',4':3,4]cyclopenta

...

Embodiment 2

[0274] (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(3b,4,6a,7-tetrahydro-2H-pyrrolo[3',4':3,4] Cyclopenta[1,2-c]pyrazol-5(6H)-yl)tetrahydro-2H-pyran-3-amino (compound 2)

[0275] (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(3b,4,6a,7-tetrahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2 -c]pyrazol-5(6H)-yl)tetrahydro-2H-pyran-3-amine

[0276]

[0277] The first step: (3b,4,5,6,6a,7-hexahydro-2H-pyrrolo[3',4':3,4]cyclopento[1,2-c]pyrazolebenzenesulfonic acid salt (2a)

[0278] 3b,4,5,6,6a,7-hexahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazolebenzenesulfonate

[0279] At room temperature, intermediate 2 (0.250 g, 1.00 mmol) and benzenesulfonic acid (0.250 g, 1.50 mmol) were dissolved in methanol (6 mL) and reacted at 68° C. for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a white solid 2a (0.362 g, yield 100%).

[0280] MS m / z (ESI): 150.3 [M+1].

[0281]The second step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(3b,4,6a,7-tetrahydro-2H-pyrrolo[3...

Embodiment 3

[0290] Example 3 Two optical isomers of compound 2, namely compound 3-1 and compound 3-2

[0291] Using intermediate 2-1 as raw material, compound 3-1 was obtained with reference to the synthetic method of Example 2;

[0292] MSm / z(ESI): 361.3[M+1];

[0293] 1 HNMR (400MHz, CDCl 3 ):δ7.21(s,1H),δ7.14-6.99(m,3H),4.18-4.16(d,1H),4.14-4.09(m,1H),3.52-3.50(m,1H),3.43 -3.29(d,1H), 2.97-2.91(m,3H), 2.78-2.53(m,1H), 2.44-2.31(m,5H), 1.40-1.13(m,4H).

[0294] Using intermediate 2-2 as raw material, compound 3-2 was obtained with reference to the synthetic method of Example 2;

[0295] MSm / z(ESI): 361.3[M+1];

[0296] 1 HNMR (400MHz, CDCl 3 ):δ7.17(s,1H),7.10-6.95(m,3H),4.14-4.12(d,1H),4.10-4.02(m,1H),3.52-3.43(m,1H),3.43(m , 1H), 3.43-3.29(d, 1H), 2.97-2.91(m, 2H), 2.78-2.53(m, 1H), 2.71-2.36(m, 5H), 1.40-1.13(m, 4H).

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Abstract

The invention relates to a fused tricyclic substituted amino six-membered ring derivative and application thereof in medicine, particularly a fused tricyclic substituted amino six-membered ring derivative shown in a formula (I) or stereoisomers and pharmaceutically acceptable salts or pro-drugs of the derivative, a pharmaceutical composition comprising the derivative and use of the derivative in preparing a dipeptidyl peptidase IV (DPP-IV) inhibitor in medicine, wherein the substituents in the formula (I) are defined as in the description. The formula (I) is shown in the description.

Description

technical field [0001] The present invention relates to a kind of amino six-membered ring derivatives substituted by three-membered condensed ring and its application in medicine, in particular to three-membered condensed ring-substituted amino six-membered ring derivatives represented by general formula (I) Drugs or their pharmaceutically acceptable salts or stereoisomers thereof and pharmaceutical compositions containing the derivatives, and their use as therapeutic agents, in particular as dipeptidyl peptidase IV (DPP-IV) inhibitors. Background technique [0002] Diabetes is a major medical problem worldwide. According to the International Diabetes Federation (IDF), the number of diabetic patients worldwide reached 382 million in 2013, and the global medical expenditure reached 548 billion US dollars, accounting for 11% of the global medical expenditure. Global healthcare spending related to diabetes is projected to reach $627.3 billion by 2035. Insulin is the hormone ne...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/4162A61K31/519A61P3/10A61P27/02A61P25/00A61P13/12A61P5/50A61P3/06A61P3/04A61P9/10A61P9/12
CPCC07D487/04
Inventor 范江冯建川彭飞陈清平
Owner SICHUAN HAISCO PHARMA CO LTD
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