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5-Cycloalkenyl 5H-chromeno[3,4-f]quinoline derivatives as selective progesterone receptor modulator compounds

a technology of progesterone receptor and derivative, which is applied in the direction of heterocyclic compound active ingredients, drug compositions, biocides, etc., can solve the problems of homeostatic imbalance in patients, and achieve the effects of reducing individual fertility, modulating fertility, and increasing individual fertility

Inactive Publication Date: 2006-08-31
LIGAND PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about compounds that can interact with progesterone receptors, which are important for regulating various processes in the body. The invention provides nonsteroidal compounds that can act as agonists, partial agonists, or antagonists for progesterone receptors. The compounds have specific structures and can be used to treat medical conditions that are influenced by progesterone receptors. The invention also includes methods for making these compounds and pharmaceutical compositions containing them.

Problems solved by technology

The effectiveness of known steroidal PR modulators is often tempered by their undesired side-effect profile, particularly during long-term administration.
Similarly, the progesterone antagonist, mifepristone (RU486), if administered for chronic indications, such as uterine fibroids, endometriosis and certain hormone-dependent cancers, could lead to homeostatic imbalances in a patient due to its inherent cross-reactivity as a glucocorticoid receptor (GR) antagonist.

Method used

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  • 5-Cycloalkenyl 5H-chromeno[3,4-f]quinoline derivatives as selective progesterone receptor modulator compounds
  • 5-Cycloalkenyl 5H-chromeno[3,4-f]quinoline derivatives as selective progesterone receptor modulator compounds
  • 5-Cycloalkenyl 5H-chromeno[3,4-f]quinoline derivatives as selective progesterone receptor modulator compounds

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0157] Preparation of (±)-(5l,l′l)-5-(3-methyl-2-cyclohexenyl)-9-fluoro-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline and (±)-(5l,l′u)-5-(3-methyl-2-cyclohexenyl)-9-fluoro-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compounds 24 and 25, Structure 3 of Scheme I, where R8═R9═R13═R15═R18═R19═R20═R21═H, R10═F, R6═R17=methyl, R14 / R16=a bond, n=1)

[0158] These compounds were prepared according the following general procedure:

[0159] A mixture of a 5-methoxy-5H-chromeno[3,4-f]quinoline, such as 9-fluoro-2,2,4-trimethyl-5-methoxy-1,2-dihydro-5H-chromeno[3,4-f]quinoline (compound 26, Structure 2 of Scheme I, where R8═R9═H, R10═F, R6=methyl), and a cyclic allylsilane derivative, such as 3-(dimethylphenylsilyl)-3-methyl-1-cyclohexene (Structure 6 of Scheme I, where R17=methyl, R15═R18═R19═R20═R21═H, n=1) (1.0-1.5 equiv.), in dry CH2Cl2 was cooled to −25° C., after which a Lewis acid such as BF3Et2O (excess) was added dropwise. The resulting mixture was stirred at −25° C....

example 2

[0162] Preparation of (+)-(5l,l′l)-5-(3-methyl-2-cyclohexenyl)-9-fluoro-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline and (−)-(5l,l′l)-5-(3-methyl-2-cyclohexenyl)-9-fluoro-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compounds 27 and 28, Structure 3 of Scheme I, where R8═R9═R13═R15═R18═R19═R20═R21═H, R10═F, R6═R17=methyl, R14 / R16=a bond, n=1)

[0163] These compounds were obtained through chiral HPLC separation of compound 24 using a Chiral AD Semiprep Column, 250×20 mm ID, 90% Hexanes / EtOH. Data for compound 27, [α]22D=+332.3 and compound 28, [α]22D=−317.1 (EtOH).

example 3

[0164] Preparation of (±)-(5l,l′l)-5-(3-methyl-2-cyclohexenyl)-9-hydroxy-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline and (±)-(5l,l′u)-5-(3-methyl-2-cyclohexenyl)-9-hydroxy-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compounds 29 and 30, Structure 3 of Scheme I, where R8═R9═R13═R15═R18═R19═R20═R21═H, R10=hydroxy, R6═R17=methyl, R14 / R16=a bond, n=1)

[0165] These compounds were prepared in a similar fashion as that described in Example 1 general procedure from 3-(dimethylphenylsilyl)-3-methyl-1-cyclohexene (Structure 6 of Scheme I, where R17=methyl, R15═R18═R19═R20═R21═H, n=1) and 9-hydroxy-2,2,4-trimethyl-5-methoxy-1,2-dihydro-5H-chromeno[3,4-j]quinoline (Compound 31, Structure 2 of Scheme I, where R8═R9═H, R10=hydroxy, R6=methyl).

[0166] Compound 29 was isolated as the major isomer: 1H NMR (500 MHz, CDCl3) 7.38 (d, J=8.2, 1H), 7.10 (d, J=2.4, 1H), 6.86 (d, J=8.5, 1H), 6.82 (dt, J=8.6, 3.1, 1H), 6.62 (dd, J=8.5, 2.7, 1H), 6.60 (d, J=8.2, 1H), 5.67 (s, 1H), 5.5...

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Abstract

The present invention relates to methods for modulating processes mediated by progesterone receptor using nonsteroidal compounds and compositions which may be high affinity, high specificity agonists, partial agonists (i.e., partial activators and / or tissue-specific activators) and / or antagonists for progesterone receptors.

Description

RELATED APPLICATIONS [0001] This application is a continuation of and claims priority under 35 U.S.C. §120 to copending allowed U.S. patent application Ser. No.10 / 684,229, filed Oct. 10, 2003 to Zhi et al., which claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 60 / 417,975, filed Oct. 11, 2002. The disclosure of each of these applications is incorporated by reference herein in its entirety.FIELD OF THE INVENTION [0002] This invention relates to nonsteroidal 5-cycloalkenyl 5H-chromeno[3,4-j]-quinoline derivatives that may be modulators (i.e., agonists, partial agonists and antagonists) of progesterone receptors and to methods for the making and use of such compounds. BACKGROUND OF THE INVENTION [0003] Progesterone receptor (PR) modulators have been widely used in regulation of female reproduction systems and in treatment of female hormone dependent diseases. The effectiveness of known steroidal PR modulators is often tempered by their undesired side-effect p...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4741C07D491/04
CPCC07D491/04A61P15/00A61P15/08A61P15/12A61P15/18A61P19/10A61P35/00A61P43/00A61P5/24
Inventor ZHI, LINVAN OEVEREN, CORNELIS ARJANPEDRAM, BIJANKARANEWSKY, DONALD S.
Owner LIGAND PHARMA INC
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