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Crf receptor antagonists and methods relating thereto

A technology of solvates and stereoisomers, applied in the field of disease treatment, can solve problems such as lack of stability, weakened pharmacological response of CRF, limited oral activity, etc.

Inactive Publication Date: 2007-03-28
SMITHKLINE BEECHAM (CORK) LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this class of peptides demonstrates that CRF receptor antagonists can indeed attenuate the pharmacological response to CRF, peptide CRF receptor antagonists still suffer from the general disadvantages of peptide therapeutics, including lack of stability and limited oral activity.

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

[0131] 7-(2-methoxy-phenyl)-3-(2-methoxy-4-pyrazol-1-yl-phenyl)-2,5-dimethyl-

[0132] Pyrazolo[1,5-A]pyrimidine

[0133]

[0134] Step 1A:

[0135]To a cooled suspension of methyl 4-amino-2-methoxybenzoate (6.82 g, 37.7 mmol) in 6N HCl (aq) was added dropwise a solution of sodium nitrite (2.60 g, 37.7 mmol). After stirring at 0°C for 20 minutes, tin dichloride dihydrate (24.7 g, 109.3 mmol) was added in portions. The resulting suspension was stirred at 0°C for 1.5 hours, then filtered. The collected solid was suspended in EtOH, malondialdehyde bis(dimethylacetal) (7.5 mL, 45.7 mmol) was added thereto, and the above reaction mixture was refluxed overnight. After removal of EtOH by evaporation, the residue was extracted between EtOAc and water, the organic phase was dried and evaporated to dryness. The residue was passed through a silica gel plug (25% EtOAc / hexanes) to give the compound as a mixture of methyl and ethyl benzoate 1b (7.43g).

[013...

Embodiment 1A

[0148] Alternative synthesis of intermediate 1f

[0149]

[0150] Step 1A-A:

[0151] Into a three-necked flask equipped with a mechanical stirrer was added 250 g (1.12 mol) of methyl 2-methoxy-4-acetamidobenzoate, and 1 L of methanol was added. After starting to stir, 94 mL (3.36 mmol, 3 eq) of concentrated sulfuric acid was slowly added to allow slight reflux. The mixture was stirred for 24 hours. The mixture was concentrated in vacuo to give a thick syrup. The slurry was filtered using a Buchner funnel, washing with 300 mL of cold methanol. The filter cake was collected and dried under vacuum at 45°C for 24 hours to obtain 302 g of hemisulfate 1a , yield 96%.

[0152] Step 1A-B:

[0153] Charge 200 g (716 mmol) of methyl 4-amino-2-methoxybenzoate into a 2 L three-necked Morton flask equipped with a mechanical stirrer and a thermocouple 1a . The solid was slurried with 700 mL of 6N hydrochloric acid, then frozen in an ice bath. To the mixture was added drop...

Embodiment 2

[0168] 7-isopropyl-3-(2-methoxy-4-pyrazol-1-yl-phenyl)-2,5-dimethyl-pyrazolo[1,5-A]pyrimidine

[0169]

[0170] Step 2A:

[0171] At room temperature, to the compound 1f (1.41g, 4.0mmol) and Fe(acac) 3 (424 mg, 1.2 mmol) in THF / NMP (v / v=8:1) was slowly added iPrMgCl (2.0 M in THF, 4.0 mL). After the reaction mixture was stirred for 1.5 hours, it was quenched with 1N HCl(aq). After extraction with EtOAc, the crude product was purified by column chromatography (25% EtOAc / hexane) to obtain compound 2-1 (628 mg).

[0172] According to the alkyl functional group in the alkylmagnesium halide, the compounds listed in the table below are synthesized:

[0173]

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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 (I), including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, Y, Ar, and Het 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

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application Serial No. 60 / 532,031, filed December 12, 2003, which is hereby incorporated by reference in its entirety. field of invention [0003] In general, the present invention relates to CRF receptor antagonists and methods of treating disease by administering such antagonists to a mammal in need thereof. Background of the invention [0004] The first corticotropin releasing factor (CRF) was isolated from the sheep hypothalamus and identified as a 41-amino acid peptide (Vale et al., Science 213:1394-1397, 1981). Human and rat CRF sequences have since been isolated and determined to be identical but differ from the sheep CRF in 7 of its 41 amino acid residues (Rivier et al., Proc. Natl. Acad. Sci. USA 80: 4851, 1983; Shibahara et al., EMBO J. 2:775, 1983). [0005] CRF has been found to cause important changes in the function of the endocrine, nervous and immune ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/495
CPCC07D487/04A61P1/00A61P1/04A61P25/00A61P25/08A61P25/18A61P25/22A61P25/24A61P3/04A61P7/02A61K31/495
Inventor 罗志勇德博拉·斯利约翰·E·特卢约翰·威廉斯张小虎
Owner SMITHKLINE BEECHAM (CORK) LTD
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