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Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof

a technology of glucocorticoid mimetics and ligands, applied in the field of glucocorticoid mimetics or ligands, can solve the problems of increased transcription rate, severe and life-threatening, and number of adverse side effects

Inactive Publication Date: 2006-01-19
BOEHRINGER INGELHEIM PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0170] In another aspect of the invention, the compounds according to the invention are formulated into pharmaceutical compositions comprising an effective amount, preferably a pharmaceutically effective amount, of a compound according to the invention or a tautomer, prodrug, solvate, or salt thereof, and a pharmaceutically acceptable excipient or carrier.
[0171] The invention also provides a method of modulating the glucocorticoid receptor function in a patient, the method comprising administering to the patient an effective amount of a compound according to the invention or a tautomer, prodrug, solvate, or salt thereof.
[0172] The invention further provides a method of treating a disease-state or condition mediated by the glucocorticoid receptor function in a patient in need of such treatment, the method comprising administering to the patient an effective amount of a pharmaceutically acceptable compound according to the invention or a tautomer, prodrug, solvate, or salt thereof.
[0173] In addition, the invention also provides a method of treating a disease-state or condition selected from: type II diabetes, obesity, cardiovascular diseases, hypertension, arteriosclerosis, neurological diseases, adrenal and pituitary tumors, and glaucoma, in a patient in need of such treatment, the method comprising administering to the patient an effective amount of a pharmaceutically acceptable compound according to the invention or a tautomer, prodrug, solvate, or salt thereof.
[0174] The invention provides a method of treating a disease characterized by inflammatory, allergic, or proliferative processes, in a patient in need of such treatment, the method comprising administering to the patient an effective amount of a pharmaceutically acceptable compound according to the invention or a tautomer, prodrug, solvate, or sal

Problems solved by technology

Unfortunately, in addition to the desired therapeutic effects of glucocorticoids, their use is associated with a number of adverse side-effects, some of which can be severe and life-threatening.
The result is an increased transcription rate of these genes which is believed to result, ultimately, in the observed side effects.

Method used

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  • Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
  • Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
  • Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of 2-methylpropane-2-sulfinic acid [3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-trifluoromethylbut-(Z)-ylidene]-amide (Methods A and B)

[0284]

[0285] To a mixture of 8.5 g (49.9 mmol) of ethyl trifluoromethylpyruvate, 6.6 g (120 mmol) of manganese, and 0.65 g (4.8 mmol) of zinc chloride in 40 mL of THF warmed at reflux, was added 200 microL (2 mmol) of 1-bromo-2-methylpropene. After 30 min, 9.13 mL (90.5 mmol) of 1-bromo-2-methylpropene in 30 mL of THF was added dropwise over a 1 hour period. The mixture was refluxed for 1 hour after the addition, and was then cooled to 0° C. and diluted with 150 mL of saturated aqueous ammonium chloride and 100 mL of EtOAc. The organic phase was separated and the aqueous layer extracted with three 100 mL portions of EtOAc. The combined organic layers were washed with two 50 mL portions of saturated aqueous ammonium chloride, two 50 mL portions of brine, dried over magnesium sulfate (MgSO4), filtered, and concentrated in vacuo. The crude residu...

example 2

Synthesis of 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentanoic acid ethyl ester (Method C)

[0291]

[0292] To a room temperature solution of 45 mL (22.5 mmol) of a 0.5 M solution of 2-methyl-2-phenylpropylmagnesium chloride in diethyl ether was added 38 g (22.5 mmol) of ethyl trifluoropyruvate in 10 mL of anhydrous THF. The reaction became slightly warm to the touch and a white precipitate quickly developed. After 2 hours, the reaction was diluted with diethyl ether and quenched with 1 N aqueous HCl. The aqueous layer was separated and extracted with ether. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a brown oil. Chromatography on silica gel eluting with hexanes-EtOAc (98:2), afforded the title compound as a clear, colorless oil (4.6 g, 67%).

[0293] This intermediate may then be used as described in Example 1 and Scheme I of the General Synthetic Methods section to produce compounds of the invention.

example 3

Synthesis of 1,1,1-trifluoro-4-(4-fluorophenyl)-4-methylpentan-2-one (Method D)

[0294]

[0295] To a mixture of 15.8 g of N,O-dimethylhydroxylamine hydrochloride and 21.7 mL of trifluoroacetic anhydride in 400 mL of CH2Cl2 was added 37 mL of pyridine dropwise at 0° C. The resulting mixture was allowed to stir at 0° C. for 30 min and then quenched with water. The organic layer was washed with water, 1 N HCl, water, and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residual colorless oil was placed under vacuum for 5 min, providing 2,2,2-trifluoro-N-methoxy-N-methylacetamide which was used for the next reaction without further purification.

[0296] A mixture of 3 g of the above 2,2,2-trifluoro-N-methoxy-N-methylacetamide in 30 mL of anhydrous ether was cooled to 0° C. and treated with 42 mL of 0.5 M solution of 2-methylpropenylmagnesium bromide in THF. The reaction mixture was stirred at 0° C. for 30 min and then allowed to warm to room temperature. The res...

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Abstract

A compound of Formula (IA) or Formula (IB) wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined herein, or a tautomer, prodrug, solvate, or salt thereof; pharmaceutical compositions containing such compounds, and methods of modulating the glucocorticoid receptor function and methods of treating disease-states or conditions mediated by the glucocorticoid receptor function or characterized by inflammatory, allergic, or proliferative processes in a patient using these compounds.

Description

[0001] This application is a divisional of U.S. application Ser. No. 10 / 446,355 filed May 28, 2003, which claims the benefit of U.S. Provisional Application No. 60 / 386,334, filed on Jun. 6, 2002, which applications are herein incorporated by reference in their entirety.FIELD OF THE INVENTION [0002] The present invention relates to glucocorticoid mimetics or ligands, methods of making such compounds, their use in pharmaceutical compositions, and their use in modulating the glucocorticoid receptor function, treating disease-states or conditions mediated by the glucocorticoid receptor function in a patient in need of such treatment, and other uses. BACKGROUND OF THE INVENTION [0003] Glucocorticoids, a class of corticosteroids, are endogenous hormones with profound effects on the immune system and multiple organ systems. They suppress a variety of immune and inflammatory functions by inhibition of inflammatory cytokines such as IL-1, IL-2, IL-6, and TNF, inhibition of arachidonic acid m...

Claims

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Application Information

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IPC IPC(8): A61K31/47A61K31/506A61K31/4965A61K31/428A61K31/422A61K31/137A61K31/4045A61K31/4184A61K31/437A61K31/44A61K31/4402A61K31/443A61K31/4439A61P1/00A61P1/16A61P3/04A61P3/10A61P5/00A61P7/00A61P9/00A61P9/04A61P9/08A61P9/10A61P9/12A61P11/00A61P13/00A61P13/12A61P17/00A61P17/02A61P19/02A61P19/08A61P25/00A61P25/04A61P25/28A61P27/02A61P27/06A61P27/16A61P29/00A61P35/00A61P37/02A61P37/08A61P43/00C07D209/14C07D213/38C07D213/61C07D215/12C07D215/14C07D215/18C07D235/10C07D235/14C07D401/06C07D405/06C07D471/04
CPCC07D209/14C07D213/38C07D213/61C07D215/12C07D471/04C07D215/18C07D235/14C07D401/06C07D405/06C07D215/14A61P1/00A61P1/16A61P3/04A61P3/10A61P5/00A61P7/00A61P9/00A61P9/04A61P9/08A61P9/10A61P9/12A61P11/00A61P13/00A61P13/12A61P17/00A61P17/02A61P19/02A61P19/08A61P25/00A61P25/04A61P25/28A61P27/02A61P27/06A61P27/16A61P29/00A61P35/00A61P37/02A61P37/08A61P43/00
Inventor KIRRANE, THOMAS MARTIN JR.KUZMICH, DANIELPROUDFOOT, JOHN ROBERTRAZAVI, HOSSEINTHOMSON, DAVID
Owner BOEHRINGER INGELHEIM PHARMA INC
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