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5-(1',1'-cycloalkyl/alkenyl)methylidene 1,2-dihydro-5H-chromeno-[3,4-f]-quinolines as selective progesterone receptor modulator compounds

a technology of progesterone receptor and methylidene, which is applied in the field of nonsteroidal 5(1′, 1′cycloalkyl/alkenyl)methylidene 1, 2dihydro5hchromeno3, 4fquinolines, 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: 2006-10-05
LIGAND PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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-(1',1'-cycloalkyl/alkenyl)methylidene 1,2-dihydro-5H-chromeno-[3,4-f]-quinolines as selective progesterone receptor modulator compounds
  • 5-(1',1'-cycloalkyl/alkenyl)methylidene 1,2-dihydro-5H-chromeno-[3,4-f]-quinolines as selective progesterone receptor modulator compounds
  • 5-(1',1'-cycloalkyl/alkenyl)methylidene 1,2-dihydro-5H-chromeno-[3,4-f]-quinolines as selective progesterone receptor modulator compounds

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of 9-Fluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 10, Structure 4 of Scheme I, where R4=methyl, R7=R8=R10=R11=H, R9=F, Y=Z=S)

[0081] To a solution of 1,3-dithiane (0.24 g, 2.0 mmol) in THF (10 mL) at −70° C. was added n-BuLi (1.6 M in hexane, 1.3 mL) and the resulting mixture was stirred at −10° C. for 2 h. To the reaction mixture at −70° C. was added 9-fluoro-1,2-dihydro-2,2,4-trimethyl-5-coumarino[3,4-f]quinoline (Compound 11, Structure 1 of Scheme I, where R4=methyl, R7=R8=H, R9=F) (0.12 g, 0.40 mmol) in THF (1 mL). The dark red solution was slowly warmed to −30° C. till the red color faded away and was quenched immediately with water. Extraction with EtOAc and chromatography afforded 9-fluoro-5-(1,3-dithia-2-cyclohexyl)-5-hydroxy-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 12, Structure 3 of Scheme I, where R4=methyl, R7=R8=R10=R11=H, R9=F, Y=Z=S), which was then treated in CH2Cl2 (10 ...

example 2

Preparation of 8-methoxy-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 13, Structure 4 of Scheme I, where R4=methyl, R7=R9=R10=R11=H, R8=methoxy, Y=Z=S)

[0082] This compound was prepared in a similar fashion as that described in Example 1 from 1,3-dithiane and 8-methoxy-1,2-dihydro-2,2,4-trimethyl-5-coumarino[3,4-f]quinoline (Compound 14, Structure 1 of Scheme I, where R4=methyl, R7=R9=H, R8=methoxy) as a yellow solid: 1H-NMR (400 MHz, CDCl3) 7.39 (d, J=8.2, 1H), 7.20 (d, J=2.9, 11H), 7.07 (d, J=8.9, 1H), 6.73 (dd, J=8.9, 2.9, 1H), 6.63 (d, J=8.2, 1H), 5.47 (s, 1H), 4.1 (bs, 1H), 3.82 (s, 3H), 3.04-2.98 (m, 1H), 2.89-2.78 (m, 2H), 2.68-2.64 (m, 1H), 2.16-2.03 (m, 2H), 1.99 (s, 3H), 1.41 (s, 3H), 1.25 (s, 3H).

example 3

Preparation of 7,9-difluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 15, Structure 4 of Scheme I, where R4=methyl, R8=R10=R11=H, R7=R9=fluorine, Y=Z=S)

[0083] This compound was prepared in a similar fashion as that described in Example 1 from 1,3-dithiane and 7,9-difluoro-1,2-dihydro-2,2,4-trimethyl-5-coumarino[3,4-f]quinoline (Compound 16, Structure 1 of Scheme I, where R4=methyl, R7=R9=fluorine, R8=H) as a yellow solid: 1H-NMR (500 MHz, CDCl3) 7.31 (d, J=8.2, 1H), 7.14-7.11 (m, 1H), 6.72 (ddd, J=10.1, 8.2, 2.7, 1H), 6.62 (d, J=8.2, 1H), 5.48 (s, 1H), 4.18 (bs, 1H), 3.07-3.01 (m, 1H), 2.92-2.82 (m, 2H), 2.72-2.67 (m, 1H), 2.18-2.07 (m, 2H), 1.99 (d, J=1.2, 3H), 1.41 (s, 3H), 1.28 (s, 3H).

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Abstract

The present invention is directed to compounds, pharmaceutical compositions and methods for modulating processes mediated by Progesterone Receptor. Also provided are methods of making such compounds and pharmaceutical compositions.

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 / 684,227, 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 / 418,140, filed Oct. 11, 2002. The entire disclosure of each of these applications is incorporated herein by reference.FIELD OF THE INVENTION [0002] This invention relates to nonsteroidal 5-(1′,1′-cycloalkyl / alkenyl)-methylidene 1,2-dihydro-5H-chromeno[3,4-f]quinolines 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 undes...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4741A61P19/00A61P35/00C07D491/04G01N33/74
CPCG01N33/743C07D491/04A61P13/08A61P15/00A61P15/08A61P19/00A61P19/10A61P35/00A61P43/00A61P5/30A61P5/34
Inventor ZHI, LINVAN OEVEREN, CORNELIS ARJAN
Owner LIGAND PHARMA INC
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