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Thio-oxindole derivatives

a technology of thio-oxindole and derivatives, applied in the field of compounds, can solve problems such as increasing the risk of uterine cancer

Inactive Publication Date: 2005-08-04
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

ER agonists are used to treat the symptoms of menopause, but have been associated with a proliferative effect on the uterus which can lead to an increased risk of uterine cancers.

Method used

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  • Thio-oxindole derivatives
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Examples

Experimental program
Comparison scheme
Effect test

example 1

5′-(3-chlorophenyl)spiro[cyclohexane-1,3′-[3H]indole]-2′(1′H)-thione

Spiro[cyclohexane-1,3′-[3H]indol]-2′-(1′H)one

[0198] A solution of oxindole (25 g, 0.19 mol) in anhydrous tetrahydrofuran (800 cm3) was cooled to −20° C., then n-butyllithium (2.5M in hexanes, 152 cm3, 0.38 mol) was added slowly followed by N,N,N′,N′-tetramethylethylenediamine (51 cm3, 0.38 mol). After 15 min. 1,5-diiodopentane (174 g, 0.54 mol) was added slowly and the mixture was allowed to warm to room temperature. After stirring for 16 h. saturated aqueous ammonium chloride solution (1 L) and EtOAc (1 L) were added. After 15 min., the layers were separated and the aqueous phase was extracted with EtOAc (×2). The combined organic layers were extracted with hydrochloric acid (1N), then washed with brine (500 cm3), dried (MgSO4), and concentrated to obtain an oil. The oil was triturated with hexane (200 cm3) and benzene (20 cm3). The precipitate was collected and dried in vacuo to obtain the subtitled compound (26...

example 2

3-(1′,2′-dihydro-2′-thioxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzonitrile

[0202] To a solution of 5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (1.00 g, 3.57 mmol) in dimethoxyethane (20 cm3) was added tetrakis(triphenylphosphine)palladium (0.20 g, 0.17 mmol). After 15 min. 3-formylphenylboronic acid (1.00 g, 6.93 g) was added followed by potassium carbonate (2.90 g, 21 mmol) in water (10 cm3). After 20 h at reflux, the mixture was cooled poured into water and extracted with EtOAc (×3). The combined organic extract was washed with saturated brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, EtOAc:hexane, gradient elution) to afford the title compound (0.66 g, 2.15 mmol, 60%) as a white solid, 1H NMR (CDCl3) δ 1.65-1.85 (m, 6H), 1.86-2.08 (m, 4H), 7.22 (d, 1H, J=8 Hz), 7.48 (dd, 1H, J=8, 2 Hz), 7.61 (t, 1H, J=8 Hz), 7.66 (d, 1H, J=2 Hz), 7.81-7.88 (m, 2H), 8.06 (t, 1H, J=2 Hz), 8.30 (s, 1H, br); MS ((+)ESI) m / z 306 (M+H)+.

3-(1′...

example 3

4-(1′,2′-dihydro-2′-thioxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-2-thiophenecarbonitrile

3-(Trimethylstannyl)-2-thiophenecarbonitrile

[0206] A solution of 3-bromo-2-thiophenecarbonitrile (0.8 g, 4.3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.25 g, 0.2 mmol) and hexamethylditin (1.4 g, 4.3 mmol) in dimethoxyethane (5 cm3) was heated under reflux for 14 h then cooled to RT. The reaction mixture was absorbed onto florisil and purified by column chromatography (SiO2, methylene chloride: hexane 1:9) to afford the subtitled compound (1.04 g, 3.8 mmol, 90%) as a clear viscous oil: 1H NMR (CDCl3) δ 0.35 (s, 9H), 7.56 (d, J=0.9 Hz, 1H), 7.66 (d, J=0.9 Hz, 1H).

4-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-thiophenecarbonitrile

[0207] A solution of the 5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (0.53 g, 1.9 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.1 g, 0.14 mmol) and triphenylarsine (0.14 g, 0.47 mmol) in dimethoxyethane (8 cm3) was stirred und...

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Abstract

This invention relates to methods of co-administering compounds of formula 1 which are agonists of the progesterone receptor which have the general structure: wherein: R1, R2, R3, R4, R5 and Q1 are as defined herein, or a pharmaceutically acceptable salt thereof, with estrogen, an estrone, or an estrogen receptor agonist for contraception, hormone replacement therapy, or treating progesterone-related carcinomas and adenocarcinomas.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a divisional of U.S. patent application Ser. No. 10 / 117,156, filed Apr. 5, 2002, which is a continuation of U.S. patent application Ser. No. 10 / 022,467, filed Oct. 30, 2001, which is a divisional of U.S. patent application Ser. No. 09 / 552,033, filed Apr. 19, 2000, now U.S. Pat. No. 6,355,648, issued Mar. 12, 2002, which claims the benefit of the priority of U.S. Provisional Patent Application No. 60 / 172,259, filed May 4, 1999, now abandoned.BACKGROUND OF THE INVENTION [0002] This invention relates to compounds which are agonists of the progesterone receptor, their preparation and utility. [0003] Intracellular receptors (IR) form a class of structurally related gene regulators known as “ligand dependent transcription factors” (R. M. Evans, Science, 240, 889, 1988). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocortic...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/404A61P1/00C07D409/10A61P5/34A61P5/36A61P7/00A61P7/04A61P13/08A61P15/00A61P35/00A61P43/00C07D209/08C07D209/30C07D209/40C07D209/96
CPCC07D209/08C07D209/40C07D209/30A61P1/00A61P13/08A61P15/00A61P35/00A61P43/00A61P5/34A61P5/36A61P7/00A61P7/04
Inventor FENSOME, ANDREWZHANG, PUWENKOKO, MARCI C.ZHI, LINJONES, TODD K.WROBEL, JAY E.TEGLEY, CHRISTOPHER M.EDWARDS, JAMES P.MELENSKI, EDWARD G.
Owner WYETH LLC
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