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Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes

An alkyl and hydroxyl technology, applied in the field of type 2 diabetes, can solve problems such as extensive research on DPP-4 inhibitors

Inactive Publication Date: 2009-04-15
SCHERING AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

To date, DPP-4 inhibitors have not been extensively studied, especially for applications other than diabetes

Method used

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  • Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
  • Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
  • Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0277]

[0278] (2R, 3S, 5R)-5-(1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-2-(2,4,5 -Trifluorophenyl)tetrahydro-2H-pyran-3-amine dihydrochloride

[0279] Step A: [(2R,3S,5R)-5-(1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-2-(2 , 4,5-trifluorophenyl)tetrahydro-2H-pyran-3-ylcarbamate tert-butyl ester

[0280] To a stirred solution of Intermediate 1 (50 mg, 0.145 mmol) and Intermediate 4 (29 mg, 0.235 mmol) in methanol (1.0 mL) was added decaborane (6 mg, 0.048 mmol), and the mixture was stirred for 15 hours and under reduced pressure. Evaporate under pressure. The product (diastereomer with poor TLC mobility) was purified by preparative thin layer chromatography using 5% methanol in dichloromethane to give [(2R,3S,5S)-5-(1 -Methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyridine tert-butyl pyran-3-ylcarbamate. LC-MS 453.17(M+1).

[0281] Step B: (2R,3S,5R)-5-(1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-2-...

Embodiment 2

[0284]

[0285] (2R, 3S, 5R)-5-(1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-2-(2,4,5 -Trifluorophenyl)tetrahydro-2H-pyran-3-amine dihydrochloride

[0286] This compound was prepared in a similar manner to Example 1 Step B, but using the diastereomer [(2R, 3S, 5R)-5-(1 -Methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyridine tert-butyl pyran-3-ylcarbamate. 1 H NMR (500MHz, CD 3 OD): δ8.14-8.05(m, 1H); 7.41(s, 1H); 7.31-7.24(m, 1H); 4.96-4.82(m, 4H); 4.52(d, 1H, J=16Hz); 4.20(s, 1H); 4.14-4.04(m, 2H); 3.90(s, 3H); 3.33-3.28(m, 1H); 2.83(d, 1H, J=16Hz); 2.41(t, 1H, J =16Hz); LC-MS 353.17(M+1).

Embodiment 3

[0288]

[0289] (2R,3S,5R)-2-(2,5-difluorophenyl)tetrahydro)-5-(4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)- base) tetrahydro-2H-pyran-3-amine dihydrochloride

[0290] Step A: [(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H) -yl)-)tert-butyl tetrahydro-2H-pyran-3-ylcarbamate

[0291] A solution of Intermediate 2 (6.03 g, 18.4 mmol) and Intermediate 3 (2.61 g, 23.94 mmol) in methanol (135 mL) was stirred for 30 minutes and then treated with decaborane (674 mg, 5.53 mmol). The mixture was stirred overnight and evaporated under reduced pressure. The resulting residue is in (Silicon dioxide, with ethyl acetate (6L), 10% ammonia ethyl acetate solution (2L) containing 5-6% ethanol, 10% ammonia ethyl acetate solution (3L) containing 8-12% ethanol Purification on (sequential elution) gave the title compound as the less mobile diastereomer (silica, TLC in 6% methanol in dichloromethane containing 10% ammonia). 1 H NMR (500MHz, CD 3 OD): δ1.18-1.24(m, 9H...

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Abstract

The present invention is directed to novel substituted aminotetrahydropyrans of structural formula (I) which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

Description

field of invention [0001] The present invention relates to novel substituted amino tetramers that are dipeptidyl peptidase-IV enzyme inhibitors ("DPP-4 inhibitors") and can be used in the treatment or prevention of diseases in which dipeptidyl peptidase-IV enzyme is involved. Hydropyrans, such diseases as diabetes, and especially type 2 diabetes. The present invention also relates to pharmaceutical compositions containing these compounds, and the use of these compounds and compositions in the prevention or treatment of diseases involving dipeptidyl peptidase-IV enzymes. Background of the invention [0002] Diabetes mellitus refers to a disease process caused by multiple etiological factors and characterized by elevated plasma glucose levels, or hyperglycemia, in the fasted state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often, abnorma...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/351
Inventor T·比夫图A·E·韦伯
Owner SCHERING AG
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