Gonadotropin-releasing hormone receptor antagonists and methods relating thereto

a technology of gonadotropin and receptor antagonists, which is applied in the field of gonadotropin-releasing hormone receptor antagonists, can solve the problems of low bioavailability and adverse side effects of peptidic antagonists with low histamine release properties, and the clinical use of such antagonists, and achieve the effect of preventing or treating bone loss

Inactive Publication Date: 2006-01-26
NEUROCRINE BIOSCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

To date, some of the primary obstacles to the clinical use of such antagonists have been their relatively low bioavailability and adverse side effects caused by histamine release.
However, several peptidic antagonists with low histamine release properties have been reported, although they still must be delivered via sustained delivery routes (such as subcutaneous injection or intranasal spray) due to limited bioavailability.

Method used

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  • Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
  • Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
  • Gonadotropin-releasing hormone receptor antagonists and methods relating thereto

Examples

Experimental program
Comparison scheme
Effect test

example 1

SYNTHESIS OF 1-(2,6-DIFLUOROBENZYL)-2,6-DIMETHYL-3-BROMO-5-ETHOXYCARBONYL-4-PYRIDONE

[0119]

Step 1A Ethyl-3-(2.6-difluorobenzylamino)crotonate:

[0120] 2,6-Difluorobenzylamine (5.00 g, 35.0 mmol) was added to trimethyl orthoformate (88.0 mL) under N2. The resulting solution was stirred at room temperature for 20 minutes. Ethyl acetoacetate (4.5 mL, 35.0 mmol) was then added dropwise and the resulting mixture stirred for 24 hours (reaction progress monitored by LC / MS). The volatiles were removed under vacuum and the product solidified upon standing. Yield 7.88 g (30.9 mmol, 88%). 1H NMR (CDCl3, 300 MHz): 8.86 (br, 1H), 7.30-7.21 (m, 1H), 6.94-6.81 (m, 2H), 4.48 (s, 2H), 4.07 (q, J=6.9 Hz, 2H), 2.03 (s, 3H), 1.23 (t, J=6.9 Hz, 3H); LRMS m / z 256.1 (M++1).

Step 1B 1-(2.6-Difluorobenzyl)-2,6-dimethyl-3-ethoxycarbonyl-4-pyridone:

[0121] A mixture of ethyl-3-(2,6-difluorobenzylamino)crotonate (2.55 g, 10.0 mmol) and 2,2,6-trimethyl-1,3-dioxin-4-one (1.85 g, 13.0 mmol) in toluene (100 mL) was...

example 2

SYNTHESIS OF 1-(2,6-DIFLUOROBENZYL)-2,6-DIMETHYL-3-(2-FLUORO-3-METHOXYPHENYL)-5-[2-(2-PYRIDYL)ETHYLAMINOMETHYL]-4-PYRIDONE

[0123]

Step 2A 1-(2,6-Difluorobenzyl)-2.6-dimethyl-3-(2-fluoro-3-methoxyphenyl)-5-ethoxycarbonyl-4-pyridone

[0124] 1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-bromo-5-ethoxycarbonyl-4-pyridone (1.5 g, 3.7 mmol) was evacuated in a pressure vessel with 2-fluoro-3-methoxyphenyl boronic acid (764 mg, 4.5 mmol) and tetrakis(triphenylphosphine) palladium (0) (428 mg, 370 μmol). A mixture of benzene / ethanol / 1,2-dimethoxyethane (74 ml in a 10 / 1 / 11 ratio) and barium hydroxide (saturated aqueous, about 0.5 M) was then added under vacuum, the vessel sealed under N2, and the reaction stirred at 90° C. for twelve hours, protected from light. The organic layer was concentrated and purified using flash silica chromatography (EtOAc / hexanes-1 / 4 to MeOH / CH2Cl2-2 / 98), with the product eluting as the third spot. The product was dried as an amber oil (1.12 g, 2.5 mmol, 68%). 1H NMR (CDCl3,...

example 3

SYNTHESIS OF 1-(2,6-DIFLUOROBENZYL)-2,6-DIMETHYL-3-(2-FLUORO-3-METHOXYPHENYL)-5-[2-(2-PYRIDYL)ETHYLAMINOMETHYL]-4-PYRIDONE

[0129]

Step 3A 1-(2.6-Difluorobenzyl)-2.6-dimethyl-3-(2-fluoro-3-methoxyphenyl)-5-[N-{2-(2-pyridyl)ethyl}-N-methylaminomethyl]-4-pyridone

[0130] Sodium triacetoxyborohydride (30 mg, 142 μmol) was added to a stirring solution of 1-(2,6-difluorobenzyl)-2,6-dimethyl-3-(2-fluoro-3-methoxybenzyl)-5-formyl-4-pyridone (20 mg, 50 μmol) and 2-(2-methylaminoethyl)pyridine (0.14 mL, 985 μmol) in dichloromethane (1 mL). The solution stirred overnight at r.t., MeOH (0.5 mL) was added and the solution concentrated, taken up in acetonitrile, filtered and purified using a Gilson Prep-HPLC system to give the product as a TFA salt in 34% yield.

[0131] The following compounds are synthesized according to above procedure.

TABLE 3No.R6R1R2N—MS (MH+)3-12-F-3-MeOPh2-PyCH2CH2NMe5223-22-F-3-MeOPhPhCH2NMe5073-32-F-3-MeOPh2-PyCH2NMe5083-42-F-3-MeOPh2-PyCH2NEt5223-52-F-3-MeOPh(2-PyCH2)2N58...

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Abstract

GnPRH receptor antagonists are disclosed which have utility in the treatment of a variety of sex-hormone related conditions in both men and women. The compounds of this invention have the structure: wherein A, R1, R2, R3a, R3b, R4, R5, R6 R7 and n are as defined herein, including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for antagonizing gonadotropin-releasing hormone in a subject in need thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATION [0001] This application is a divisional of U.S. application Ser. No. 10 / 211,978, filed Aug. 2, 2002, now allowed, which claims the benefit of U.S. Provisional Patent Application No. 60 / 309,937, filed Aug. 2, 2001, both of which applications are incorporated herein by reference in their entireties.STATEMENT OF GOVERNMENT INTEREST [0002] Partial funding of the work described herein was provided by the U.S. Government under Grant No. R43-HD38625 provided by the National Institute of Health. The U.S. Government may have certain rights in this invention.BACKGROUND OF THE INVENTION [0003] 1. Field of the Invention [0004] This invention relates generally to gonadotropin-releasing hormone (GnRH) receptor antagonists, and to methods of treating disorders by administration of such antagonists to a warm-blooded animal in need thereof. [0005] 2. Description of the Related Art [0006] Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-r...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/44A61K31/439A61K31/4418A61K31/443A61K31/4436A61K31/4439A61K31/444A61K31/455A61K31/4709A61K31/4725A61K31/496A61K31/506A61K31/52A61K31/5377A61P1/00A61P5/00A61P5/04A61P13/08A61P15/00A61P17/00A61P25/20A61P35/00A61P37/02A61P43/00C07D211/86C07D213/68C07D213/69C07D213/74C07D213/80C07D401/06C07D401/12C07D405/12C07D409/04C07D409/14C07D413/06C07D413/14C07D453/02C07D453/06C07D473/24
CPCC07D211/86C07D213/68C07D213/69C07D401/06C07D401/12C07D473/24C07D409/04C07D409/14C07D453/02C07D453/06C07D405/12A61P1/00A61P5/00A61P5/04A61P13/08A61P15/00A61P17/00A61P25/20A61P35/00A61P37/02A61P43/00
Inventor TUCCI, FABIOCONNORS, PATRICK J.ZHU, YUN-FEICHEN, CHEN
Owner NEUROCRINE BIOSCI INC
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