11-beta-hydroxysteroid dehydrogenase 1 inhibitors useful for the treatment of diabetes, obesity and dyslipidemia

A solvate, alkyl technology, applied in the field of enzyme inhibitor of type I 11-β-hydroxysterol dehydrogenase, can solve problems such as lactic acidosis, nausea and diarrhea

Inactive Publication Date: 2005-08-24
SCHERING AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, many biguanides, such as glucocorticoids and metformin, cause lactic acidosis, nausea, and diarrhea

Method used

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  • 11-beta-hydroxysteroid dehydrogenase 1 inhibitors useful for the treatment of diabetes, obesity and dyslipidemia
  • 11-beta-hydroxysteroid dehydrogenase 1 inhibitors useful for the treatment of diabetes, obesity and dyslipidemia
  • 11-beta-hydroxysteroid dehydrogenase 1 inhibitors useful for the treatment of diabetes, obesity and dyslipidemia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0180] general process

[0181]

[0182] substance

quantity

concentration

Mmol

S.M. in DMF

714μl

0.14M in DMF

0.1

TFFH in DMF

200μl

0.5M in DMF

0.1

Triethylamine in DMF

400μL

0.5M in DMF

0.2

Hydrazine in DMF

240μl

0.5M in DMF

0.12

Imino ether A in DMF

600μL

0.25M in DMF

0.15

[0183] The synthesis of the following one-dimensional, single pure compound library was completed in Myriad Core System. All reaction vessels were dried at 120° C. for 12 hours under nitrogen flow before use. Solvents were dried over molecular sieves for at least 12 hours before use. Reagents and subgroups (carboxylic acids and 8-methoxy-2,3,4,5,6,7-azocine (iminoether A)) were dissolved in a suitable solvent immediately before use.

[0184] Synthesis The carboxylic acids shown in the table below were added as starting materials to a dry 10 mL sintered Myria...

Embodiment 2

[0217] Method 2A

[0218] general process

[0219]

[0220] Preparation of 3-(1,1-diphenylpropyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine ( 2-1)

[0221]

[0222] 2,2-Diphenylbutyric acid (39.6mg, 0.166mmol) was dissolved in DMF (0.33ml). Fluoro-N,N,N',N'-tetramethylformamide hexafluorophosphate (TFFH, 43.6 mg) and anhydrous triethylamine (46.4 μl) were added, and the solution was cooled to 0°C. After 10 minutes, hydrazine monohydrate (6.5 μl) was added. After stirring at room temperature for 30 minutes, HPLC / MS showed complete conversion to 2,2-diphenylbutanylhydrazide. 8-Methoxy-2,3,4,5,6,7-hexahydroazocine (38ml, 0.249mmol) was added, and the solution was stirred overnight at 120°C. After warming to room temperature, the product was purified by preparative HPLC and isolated as the trifluoroacetate salt. The salt was added to saturated sodium bicarbonate solution and extracted with ethyl acetate to give the free base. The extract was dried over magne...

Embodiment 3

[0302] Method 3A

[0303] Preparation of 1-(4-chlorophenyl)cyclobutanehydrazide

[0304]

[0305] 1-(4-Chlorophenyl)cyclobutanecarboxylic acid (10.0g) was dissolved in dichloromethane (150ml) and cooled to -10°C in an ice / brine bath. Pyridine (3.84ml) was added followed by cyanuric fluoride (8.9ml in 25ml dichloromethane). After stirring at room temperature for 1 hour, TLC indicated that the reaction was complete. The solution was added to a separatory funnel filled with ice (150 mL). After vigorous shaking, the organic layer was removed, dried over magnesium sulfate, filtered, and concentrated to give carbonyl fluoride.

[0306] Hydrazine (2.02 mL) was dissolved in acetonitrile (100 mL) and cooled to 0°C. Triethylamine (12.8ml) was added followed by 1-(4-chlorophenyl)cyclobutaneoyl fluoride (10g) in acetonitrile (25ml). After stirring at room temperature for 1 hour, the acetonitrile was removed by evaporation. The product was obtained after chromatography on silica g...

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PUM

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Abstract

Compounds having Formula (I), including pharmaceutically acceptable salts, hydrates and solvates thereof: are selective inhibitors of the 11beta-HSD1 enzyme. The compounds are useful for the treatment of diabetes, such as noninsulin-dependent diabetes (NIDDM), hyperglycemia, obesity, insulin resistance, dylsipidernia, hyperlipidemia, hypertension, Syndrome X, and other symptoms associated with NIDDM.

Description

technical field [0001] The present invention relates to enzyme inhibitors of type I 11-beta-hydroxysterol dehydrogenase (11beta-HSD-1 or HSD-1), methods of treatment using such compounds. The compounds are useful in the treatment of diabetes, such as non-insulin dependent type 2 diabetes mellitus (NIDDM), insulin resistance, obesity, lipid disorders and other diseases and conditions. Background technique [0002] Diabetes mellitus is multifactorial, the simplest feature being elevated plasma glucose concentrations in the fasted state (hyperglycemia). There are two generally recognized forms of diabetes: type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), in which the patient produces little or no hormone insulin, which regulates glucose utilization; and type 2 diabetes, or non-insulin-dependent diabetes mellitus (NIDDM). ), in which the patient produces insulin and even exhibits hyperinsulinemia (plasma insulin concentration is the same or even higher than that ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/00A61KA61K31/4196A61K31/433A61PA61P1/18A61P3/04A61P3/06A61P3/08A61P3/10A61P5/48A61P5/50A61P9/10A61P9/12A61P9/14A61P13/12A61P25/00A61P25/08A61P27/02A61P43/00C07DC07D249/08C07D403/04C07D405/04C07D417/04C07D487/04
CPCC07D249/08A61P1/18A61P13/12A61P25/00A61P25/08A61P27/02A61P3/04A61P3/06A61P3/08A61P43/00A61P5/48A61P5/50A61P9/10A61P9/12A61P9/14A61P3/10C07D487/04
Inventor S·H·奥尔森J·M·巴尔科维克朱渝萍
Owner SCHERING AG
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