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Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes

An alkyl, hydroxyl technology, applied in the field of hexahydrodiazepine _ ketone compounds, can solve problems such as DP-IV inhibitors that have not been extensively studied

Inactive Publication Date: 2005-12-07
SCHERING AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

DP-IV inhibitors have not been studied extensively, especially for uses other than diabetes

Method used

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  • Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
  • Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
  • Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0358]

[0359] (3R)-4-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butyryl]-hexahydro-3-methyl-2H-1,4-diazepine _-2-keto hydrochloride

[0360] Step A: N-(tert-butoxycarbonyl)-N-(2-cyanoethyl)-D-alanine methyl ester

[0361] To a stirred suspension of D-alanine methyl ester hydrochloride (2.0 g) and 5N aqueous sodium hydroxide solution (2.9 mL) in water (15 mL) was added acrylonitrile (1.1 mL) at 0°C. The resulting mixture was stirred at 70°C for 3.5 hours and cooled to room temperature. Di-tert-butyl dicarbonate (30 mL) was added and the reaction mixture was stirred for 2 days. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated. Purification of the residue by flash column chromatography (silica gel, ethyl acetate / hexane 2:3) afforded N-(tert-butoxycarbonyl)-N-(2-cyanoethyl)-D-propanamine acid methyl ester.

[03...

Embodiment 2

[0374]

[0375] 4-[(3R)-3-amino-4-(2,5-difluorophenyl)butyryl]hexahydro-1-methyl-2H-1,4-diazepin-2-one hydrochloride Salt

[0376] Step A: N-(3-aminopropyl)-N-(tert-butoxycarbonyl)glycine methyl ester

[0377] The title compound was prepared from glycine methyl ester hydrochloride as described in Example 1, Steps A-B.

[0378] LC / MS 241.0 (M+1).

[0379] Step B: tert-butyl hexahydro-3-oxo-1H-1,4-diaza-1-carboxylate

[0380] To a solution of N-(3-aminopropyl)-N-(tert-butoxycarbonyl)glycine methyl ester (10.2 g) in tetrahydrofuran (THF) / methanol (2 / 1, 300 mL) was added 1M lithium hydroxide aqueous solution (60 mL). The resulting mixture was stirred overnight at room temperature. Another 20 mL of 1M aqueous lithium hydroxide was added, and the mixture was stirred for 6 hours. The solvent was removed under reduced pressure, the residue was dissolved in 50 mL methanol and 200 mL toluene, and concentrated in vacuo. To the residue in dichloromethane (300 mL) were added 1-et...

Embodiment 3

[0391]

[0392] (3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-benzylhexahydro-1-methyl-2H-1,4 -Diazapin_-2-one hydrochloride

[0393] Step A: tert-butyl 2-benzylhexahydro-4-methyl-3-oxo-1H-1,4-diazepine-1-carboxylate

[0394] At -78°C, to tert-butyl hexahydro-4-methyl-3-oxo-1H-1,4-diazepine-1-carboxylate (180 mg) prepared as described in Example 2 Step C To a stirred solution in THF (8 mL) was added a solution of lithium diisopropylamide (LDA) (1.5 M in hexane, 0.53 mL). After stirring the mixture for 40 minutes, benzyl bromide (0.28 mL) was added. The resulting mixture was stirred for a further 6 hours at -78°C. The reaction mixture was then diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated. Purification of the residue by chromatography (silica gel, 2% methanol / dichlor...

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PUM

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Abstract

The present invention is directed to compounds which are inhibitors of the dipeptidyl peptidase-IV enzyme ('DP-IV inhibitors') 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

Background of the invention [0001] Diabetes mellitus is a multifactorial disease process characterized by elevated plasma glucose levels or hyperglycemia following glucose administration in the fasted state or during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with premature disease development and increased mortality. Recurrent abnormal glucose homeostasis is directly or indirectly related to lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disorders. Patients with type 2 diabetes are therefore at a particularly high risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutic control of glucose homeostasis, lipid metabolism, and hypertension is extremely important in the clinical management and treatment of diabetes. [0002] There are two common forms o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61KA61K31/55A61K31/551A61P3/10C07D243/08C07D307/94C07D401/06C07D403/06C07D405/12C07D405/14C07D491/107C07K5/06
CPCC07D243/08C07D401/06C07D403/06C07K5/06191A61P1/04A61P13/12A61P25/28A61P27/02A61P3/04A61P3/06A61P43/00A61P9/00A61P9/10A61P3/10C07D307/94C07D405/12C07D405/14C07D491/107A61K31/55A61K31/551
Inventor T·比夫图梁贵柏钱晓霞A·E·韦伯冯丹青
Owner SCHERING AG
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