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CRF receptor antagonists and methods relating thereto

A stereoisomer, CH2OCH3 technology, applied in anti-inflammatory agents, medical preparations containing active ingredients, organic chemistry, etc.

Inactive Publication Date: 2004-12-08
NEUROCRINE BIOSCIENCES 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
  • CRF receptor antagonists and methods relating thereto
  • CRF receptor antagonists and methods relating thereto

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] Synthesis of Representative Compounds of Structural Formula (IA)

[0100]

[0101]

[0102] Compound (4 )

[0103] 4,6-Dichloro-2-methyl-5-nitropyrimidine (3; J.Chem.Soc. 1954, 3836) (2.23 g, 11 mmol) in ethanol (30 mL) A solution of Ethanol was treated with a solution of 1-ethylpropylamine (870 mg, 10 mmol) in ethanol (8 mL) at -30°C and the reaction mixture was stirred at -30°C for 1 hour before warming to room temperature. The volatiles were evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was dried (sodium sulfate), evaporated and purified by flash chromatography (silica gel) to give compound (4).

[0104] Compound (5 )

[0105] A solution of compound (4) (2.07 g, 8 mmol) in acetonitrile (15 mL) was treated with 2,4,6-trimethylaniline (1.35 g, 10 mmol) at room temperature, followed by addition of triethylamine (1.52 g, 15 mmol) . The reaction mixture was stirred at room temperature for 2 hours. T...

Embodiment 2

[0115] Synthesis of Compounds of Structural Formula (IB)

[0116] Compounds of formula (IB) can be prepared by the same synthetic route as disclosed in Example 1 above, but substituting the corresponding pyridine compound (1) for pyrimidine. For example, representative compounds of the invention can be prepared by the following reaction schemes:

[0117]

[0118]

Embodiment 3

[0120] Synthesis of Representative Compounds

[0121] Other representative compounds of the invention were prepared by the general reaction schemes disclosed above and / or the methods of Examples 1 and 2, and are shown in the table below.

[0122] surface

[0123] representative compound

[0124]

[0125] Cpd

R

X

R 1

Ar

(I-1)

H

N

-CH(CH 2 CH 2 CH 3 ) 2

2,4,6-Trimethylphenyl

(I-2)

H

CH

-CH(CH 2 CH 2 CH 3 ) 2

2-Chloro-4-methylphenyl

(I-3)

H

CH

-CH(CH 2 CH 2 CH 3 ) 2

2-Bromo-4-isopropylphenyl

[0126]

[0127] Cpd

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PUM

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Abstract

Compounds 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, including stroke. The compounds of this invention have the following structures: wherein n, m, R, R1, R2, X and Ar are as defined herein, including stereoisomes and pharmaceutically acceptable salts thereof.

Description

technical field [0001] The present invention relates 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 pituitary gla...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/4985A61P1/00A61P1/14A61P3/04A61P9/10A61P9/12A61P25/00A61P25/08A61P25/22A61P25/24A61P25/30A61P29/00A61P37/02A61P43/00C07D471/16C07D487/16
CPCC07D487/16C07D471/16A61P1/00A61P1/14A61P25/00A61P25/08A61P25/22A61P25/24A61P25/30A61P29/00A61P3/04A61P37/02A61P43/00A61P9/10A61P9/12
Inventor M·哈达彻郭志强J·R·穆卡赛
Owner NEUROCRINE BIOSCIENCES INC
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