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Amino six-membered ring derivative and application thereof in medicines

A technology of amino six-membered rings and derivatives, which can be used in pharmaceutical formulations, medical preparations containing active ingredients, drug combinations, etc., and can solve problems such as the burden of diabetes

Inactive Publication Date: 2015-11-11
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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  • Amino six-membered ring derivative and application thereof in medicines
  • Amino six-membered ring derivative and application thereof in medicines
  • Amino six-membered ring derivative and application thereof in medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0333] (S)-Ethyl 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)-1-( Methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate (Compound 1)

[0334] (S)-ethyl5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4, 5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate

[0335]

[0336]

[0337] The first step: (S)-ethyl 1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate (1a)

[0338] (S)-ethyl1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate

[0339] Dissolve Intermediate 2 (0.3g, 0.84mmol) in dichloromethane (1mL) at room temperature, cool down to 0°C, add trifluoroacetic acid (3mL), stir and react at 0°C for 2 hours, then concentrate the reaction solution under reduced pressure . Purified by column chromatography [(dichloromethane / methanol (v / v)=40:1-20:1), adding a small amount of ammonia water] to obtain off-white solid 1a (0.22 g, yield 100%).

...

Embodiment 2

[0351] (S)-5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)-1-(methyl Sulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)methanol (Compound 2)

[0352] ((S)-5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4 ,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)methanol

[0353]

[0354] The first step: (S)-tert-butyl 4-(hydroxymethyl)1-(methylsulfonyl)pyrrolo[3,4-c]pyrazole-4,5-(1H,4H,6H)- Carboxylate (2a)

[0355] (S)-tert-butyl4-(hydroxymethyl)-1-(methylsulfonyl)pyrrolo[3,4-c]pyrazole-5(1H,4H,6H)-carboxylate

[0356] Intermediate 2 (1.4g, 3.9mmol) was dissolved in tetrahydrofuran (15mL) at room temperature, cooled to 0°C, lithium borohydride (0.206g, 9.48mmol) was added, and allowed to rise to room temperature for 5 hours. The reaction solution was cooled to 0°C, saturated ammonium chloride solution (20 mL) was added, extracted with ethyl acetate (30 mL×3), the organic phases were combined, and washed with satu...

Embodiment 3

[0372] (R)-Methyl 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-(methyl Sulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate (Compound 3)

[0373] (R)-methyl5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5 ,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate

[0374]

[0375] The first step: (R)-methyl 1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate (3a)

[0376] (R)-methyl1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate

[0377] Intermediate 3 (1 g, 2.90 mmol) was dissolved in dichloromethane (15 mL) at room temperature, cooled to 0 °C, trifluoroacetic acid (5 mL) was added, and reacted at 0 °C for 7.5 hours. Concentrate the reaction solution under reduced pressure, add dichloromethane (20mL), methanol (1mL) and 5 drops of ammonia water to mix the sample, and purify by column chromatography [(dichloromethane / methanol (v / v)=40:1-20:1 ), add...

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Abstract

The invention relates to an amino six-membered ring derivative and an application thereof in medicines, and in particular, the invention relates to an amino six-membered ring derivative represented as the general formula (I), or a stereisomer thereof, a pharmaceutically-acceptable salt thereof, a pre-drug thereof, a drug composition comprising the derivative, and the application in a medicine of preparing a dipeptidyl peptidase IV (DPP-IV) inhibitor, wherein the substituent groups in the general formula (I) are defined as same as that in the specification.

Description

technical field [0001] The present invention relates to an amino six-membered ring derivative and its application, in particular to an amino six-membered ring derivative represented by general formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof and a derivative containing the derivative A pharmaceutical composition of the drug or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and its use as a therapeutic agent, especially as a dipeptidyl peptidase IV (DPP-IV) inhibitor. Background technique [0002] Diabetes is a major medical problem worldwide. According to the statistics of the International Diabetes Federation (IDF), the number of diabetic patients in the world 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 costs related to diabetes are projected to reach $627.3 billion by 2035. Insulin is a hormon...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/4162A61K45/06A61P3/10A61P9/10A61P27/02A61P25/00A61P13/12A61P5/50A61P3/06A61P3/04A61P9/12
CPCC07D487/04
Inventor 范江陈清平江伟郑苏欣叶飞
Owner SICHUAN HAISCO PHARMA CO LTD
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