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Compound serving as dipeptidyl enzyme inhibitor and composition thereof and applications of compound and composition

A compound, alkyl technology, applied in the field of disease compounds, type II diabetes, prevention or treatment of diseases related to dipeptidyl peptidase-IV enzyme, can solve the problem that DPP-IV inhibitors are not widely studied

Inactive Publication Date: 2013-05-08
CGENETECH (SUZHOU CHINA) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, to date, DPP-IV inhibitors have not been extensively studied, especially for uses other than diabetes

Method used

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  • Compound serving as dipeptidyl enzyme inhibitor and composition thereof and applications of compound and composition
  • Compound serving as dipeptidyl enzyme inhibitor and composition thereof and applications of compound and composition
  • Compound serving as dipeptidyl enzyme inhibitor and composition thereof and applications of compound and composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1 and 2

[0167] Synthetic Route 1 of Diastereomers 1 and 2

[0168]

[0169] Step 1: Synthesis of 3-methylpyrazine-2-carbonitrile (1A)

[0170] Dissolve 173 grams (1 mole) of 2-bromo-3-methylpyrazine in 2 liters of DMF, then add 121.2 grams (1.2 moles) of triethylamine, 97.5 grams (1.2 moles) of zinc cyanide, and tetrakistriphenyl 17.3 grams of phosphopalladium (catalytic amount), the resulting solution was heated to 100°C under nitrogen protection, reacted for 24 hours, cooled, poured into 2 liters of ice water, extracted three times with 500 milliliters of ethyl acetate, combined the organic phases, washed with water, Washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 159 g of product with a yield of 75%.

[0171] Step 2: Synthesis of (3-methylpyrazin-2-yl)methylammonia (1B)

[0172] 59.56 grams (0.5 moles) of compound 1A were dissolved in 1 liter of methanol, 6 grams of 10% palladium carbon was added, and the resulting solu...

Embodiment 3 and 4

[0185] Diastereomers 3 and 4

[0186] Synthesis path 2

[0187]

[0188] Step 1: Synthesis of tert-butyl 8-methyl-3-trifluoromethyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (3A)

[0189] Dissolve 20.5 g (0.1 mol) of compound 1E in 200 ml of dichloromethane, add 12.12 g (0.12 mol) of triethylamine, and add (Boc) under ice water cooling 2 O25.96 g (0.12 mol), reacted at room temperature for 2 hours, poured into 1 liter of ice water, washed the organic phase with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 27.5 g of the product, with a yield of 90%.

[0190] Step 2: Synthesis of tert-butyl 1-bromo-8-methyl-3-trifluoromethyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (3B)

[0191] 15.3 g (0.05 mol) of compound 3A was dissolved in 200 ml of dichloromethane, 8.9 g (0.05 mol) of NBS was added, reacted at room temperature for 24 hours, poured into 500 ml of ice water, and the organic phas...

Embodiment 5 and 6

[0202] Diastereomers 5 and 6

[0203] Synthesis path 3

[0204]

[0205] Step 1: Synthesis of 7-[(R)-3-(tert-butoxycarboxamido)-4-(2,4,5-trifluorophenyl)butyryl)]-8-methyl-3-tri Fluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid (5A)

[0206] 2.89 g (0.005 mol) of compound 3E was dissolved in 20 ml of methanol and 10 ml of water, added 0.24 g (0.01 mol) of lithium hydroxide, reacted at room temperature for 24 hours, added 1N hydrochloric acid to adjust the pH to 7, extracted three times with 20 ml of ethyl acetate , the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product.

[0207] Step 2: Synthesis of 7-[(R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl)]-8-methyl-3-trifluoromethyl-5,6, 7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid (5 and 6)

[0208] According to the method of Step 8 in Examples 1 and 2, 5A was deprotected to...

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Abstract

The invention provides a compound serving as a dipeptidyl enzyme inhibitor and a composition thereof and applications of the compound and the composition, wherein the compound is shown as the general formula (I). The invention also provides a diastereoisomer of the compounds or pharmaceutically acceptable salt or prodrug or tautomer and application thereof. The invention provides multiple compounds and a composition for treating the diseases related to dipeptidyl enzyme and particularly for treating non-insulin dependent diabetes mellitus; and the compounds also can be used for treating the diseases such as hyperglycemia, obesity, osteoporosis and growth hormone defect. The compounds and composition thereof provided by the invention realize a relatively good curative effect on multiple diseases and have important application value.

Description

technical field [0001] The present invention relates to the field of medicine, more particularly to compounds used as dipeptidyl peptidase-IV enzyme (DPP-IV) inhibitors for the treatment or prevention of diseases associated with dipeptidyl peptidase-IV enzymes, such as diabetes, in particular It is type II diabetes. The present invention also relates to compositions of such compounds, and their use in the prevention or treatment of diseases associated with dipeptidyl peptidase-IV enzymes. Background technique [0002] Diabetes is a disease in which glucose in the blood tends to accumulate too much. It is caused by various pathogenic factors such as genetic factors and immune dysfunction. It is manifested in the fasting state or oral glucose tolerance test. Elevated plasma glucose levels or hyperglycemia. [0003] Diabetes is roughly divided into type I diabetes and type II diabetes. Type 1 diabetes is an autoimmune disease, also known as insulin-dependent diabetes mellitu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/4985A61K31/5377A61P3/10A61P3/04A61P5/48A61P3/06A61P3/00A61P9/10A61P5/00A61P37/02A61P31/18A61P1/00A61P35/04A61P13/08A61P29/00A61P1/02A61P9/12A61P19/10A61P15/08A61P3/08A61P9/00A61P1/04A61P1/18A61P25/28A61P13/12A61P25/00A61K45/00A61K45/06
Inventor 余强王彤
Owner CGENETECH (SUZHOU CHINA) CO LTD
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