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CRF receptor antagonists and methods relating thereto

A technology for stereoisomers and compounds, which is used in medical preparations containing active ingredients, organic chemistry, pharmaceutical formulations, etc.

Inactive Publication Date: 2001-12-26
NEUROCRINE BIOSCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Although great progress has been made in the modulation of CRF by administering CRF receptor antagonists, there is still a need for effective small molecule CRF receptor antagonists

Method used

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  • CRF receptor antagonists and methods relating thereto

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0125] Synthesis of Representative Compounds of Structural Formula (I-1)

[0126] Structural formula (I-1a) Compound (2)

[0127] 2,4-Dichloro-6-methyl-3-ethylpyridine (1) (5.0g 21.36mmol), 4-heptylamine (21.36mmol) and triethylamine (2.97ml, 21.36mmol) in ethanol The solution was heated to reflux overnight. Ethanol was distilled off and the residue was dissolved in ethyl acetate, washed with saturated bicarbonate solution and brine. The organic layer was dried over sodium carbonate and concentrated in vacuo. Compound (2) was separated from (1) and (3) by silica gel column eluting with ethyl acetate-hexane. Compound (4)

[0128] A solution of compound (2) (20.0 mmol) and hydrazine (25.0 mmol) in ethanol was refluxed overnight. Ethanol was distilled off and the residue was dissolved in ethyl acetate, washed with water, dried over sodium sulfate and concentrated in vacuo to give compound (4), which was used directly in subsequent steps without ...

Embodiment 2

[0140] Synthesis of Representative Compounds of Structural Formula (I-2)

[0141] Structural formula (I-2a) α-phthalimide-2,4-trichloroacetophenone (1)

[0142] α-2,4-Trichloroacetophenone (15 g, 67 mmol) was added to potassium phthalimide (16 g, 86 mmol) in N, N-dimethylformamide ( 70ml) suspension. After 5 minutes, the resulting solution was allowed to warm to room temperature and then heated at 50°C for 0.5 hours. After heating, the solution was concentrated by pump and the resulting solid was partitioned between ethyl acetate / sodium bicarbonate solution and the resulting organic layers were combined. The organic layer was dried and all solvent was evaporated to obtain a solid. The solid was recrystallized from dichloromethane and diethyl ether to obtain compound (1), 9.6 g. Compound (2)

[0143] A solution of α-phthalimide-2,4-trichloroacetophenone (1) (9.6 g) in dimethylformamide dimethyl acetal (30 ml) was refluxed for 1 hour. After reflu...

Embodiment 3

[0171] Synthesis of Representative Compounds of Structural Formula (I-3) N-oxides (4)

[0172] Compound (3) (7.31 g, 50 mmol), mCPBA (9.49 g, 55 mmol) prepared by the method disclosed by Clayton and Kenyon ("Chemical Society Journal" (J.Chem.Soc.), 2952-57, 1950) were prepared in The mixture in dichloromethane (200 mL) was stirred at room temperature for 2 hours. The reaction mixture was partitioned between dichloromethane and water. The dichloromethane was dried over sodium sulfate, filtered and concentrated to give the desired product N-oxide (4). Compound (5)

[0173] A mixture of N-oxide (4) (4.87 g, 30 mmol) and phosphorus oxychloride (15 mL) was refluxed for 3 h, cooled, poured onto crushed ice, and neutralized with 1N NaOH. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give compound (5). Compound (6)

[0174] To a mixture of compound (5) (3.61 g, 20 mmol) in ...

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Abstract

CRF receptor antagonists are disclosed which have utility in the treatment of a variety of disorders, including the treatment of disorders manifesting hypersecretion of CRF in a warm-blooded animals, such as stroke. The CRF receptor antagonists of this invention have the following structure:including stereoisomers and pharmaceutically acceptable salts thereof, wherein n, m, A, B, C, R, R1, R2 and Ar are as defined herein. Compositions containing a CRF receptor antagonist in combination with a pharmaceutically acceptable carrier are also disclosed, as well as methods for use of the same

Description

technical field [0001] The present invention relates generally to CRF receptor antagonists and methods of treating disease by administering said antagonists to a warm-blooded animal in need thereof. Background of the invention [0002] The first corticotropin-releasing factor (CRF) was isolated from the sheep hypothalamus and confirmed to be a 41 amino acid peptide (Vale et al., Science 213:1394-1397, 1981). Subsequently, the sequences of human and rat CRFs were isolated and confirmed to be identical, but they differed from the sheep CRF in 7 out of 41 amino acid residues (Rivier et al., Proc. USA) 80: 4851, 1983; Shibahara et al., EMBO J. 2: 775, 1983). [0003] CRF has been found to cause significant changes in the function of the endocrine, nervous and immune systems. CRF is believed to be the basal release and response of adrenocorticotropic hormone ("ACTH"), beta-endorphin, and other opiate-melanotrophin-procorticotropin ("POMC")-derived peptides from the anterior pit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4985A61K31/551A61P5/02A61P25/00A61P25/08A61P25/18A61P25/24C07D471/16C07D487/16
CPCC07D471/16C07D487/16A61P25/00A61P25/08A61P25/18A61P25/24A61P5/02
Inventor M·哈达彻J·耐尔森B·P·迪克郭志强黄青J·R·穆卡赛
Owner NEUROCRINE BIOSCI INC
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