6H-[1]benzopyrano[4,3-b]quinolines and their use as estrogenic agents

A halogen and phenyl technology, applied in the field of 6H-[1]benzopyrano[4

Inactive Publication Date: 2007-10-10
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The exact reason why the same compound can have cell-specific effects has not been elucidated, bu

Method used

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  • 6H-[1]benzopyrano[4,3-b]quinolines and their use as estrogenic agents
  • 6H-[1]benzopyrano[4,3-b]quinolines and their use as estrogenic agents
  • 6H-[1]benzopyrano[4,3-b]quinolines and their use as estrogenic agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] 3-(3-Methoxy-phenoxy)-propionic acid (1)

[0105] Method A: To a mixture of 3-bromopropionic acid (14.70 g, 118 mmol) in water (100 mL) was slowly added NaHCO 3 (8.40 g, 100 mmol), and the resulting mixture was stirred for 5 minutes. To this solution was added 70-mL 3-methoxyphenol (14.70 g, 96 mmol) in NaOH (4.67 g, 119 mmol) in water, and the resulting mixture was heated at 100 °C for 3 hours. After cooling to room temperature, the reaction mixture was acidified with 1N HCl and washed with Et 2 O extraction. with NaHCO 3 (3x) aqueous wash with Et 2 Layer O. The aqueous layer was again acidified with 1N HCl and washed with Et 2 O extraction. Wash Et with water, brine 2 O layer, dry (Na 2 SO 4 ), filtered and concentrated to obtain a brown solid crude product, which was recrystallized (Et 2 0 / -20 °C), the pure product was obtained as a yellow solid. Yield: 17.0 g (23%). 1 H-NMR (300MHz, CDCl 3 ): δ2.85(t, J=6.3Hz, 2H), 3.79(s, 3H), 4.24(t, J=6.3Hz, 2H), 6....

Embodiment 2

[0107] 7-Methoxy-chroman-4-one (2)

[0108] Method B: To a reactor containing 3-(3-methoxy-phenoxy)-propionic acid (1) (7.00 g, 35.6 mmol) was slowly added trifluoromethanesulfonic acid (15 mL) at 0°C. The reaction mixture was stirred for 3 hours while allowing to warm to room temperature. After cooling to 0°C, the reaction mixture was quenched with crushed ice, then washed with Et 2 O (2 x 300 mL) was extracted. Water (2x), NaHCO 3 The organic layer was washed with aqueous solution, water, brine, and then dried (Na 2 SO 4 ), filtered and concentrated to give a crude oil which was purified by silica gel chromatography to give the pure product as a yellow solid. Yield: 4.26g (67%). 1 H-NMR (300MHz, CDCl 3 ): δ2.76(t, J=6.3Hz, 2H), 3.84(s, 3H), 4.52(t, J=6.3Hz, 2H), 6.41(d, J=2.3Hz, 1H), 6.58(dd , J=8.8, 2.3Hz, 1H), 7.84 (d, J=8.8Hz, 1H); MS (ESI) m / z 179 ([M+H] + ).

Embodiment 3

[0110] 3,9-Dimethoxy-6H-chromeno(CHROMENO)[4,3-b]quinolin-7-ol (3)

[0111] Method C: Mix 2-amino-5-methoxybenzoic acid (1.839g, 11.00mmol) and 7-methoxy-chroman-4-one (2) (1.960g, 11.00mmol) at Ph 2 The mixture in O (10 mL) was heated at 170 °C for 1 h and at 200 °C for 7 h. After cooling to room temperature, hexane was added. The yellow precipitate formed was collected by filtration and washed with hexane and Et 2 O was washed thoroughly and dried under vacuum. Yield: 2.171 g (64%). mp 298℃(dec.); 1 H-NMR (300MHz, DMSO-d6) δ3.82(s, 3H), 3.84(s, 3H), 5.17(s, 2H), 6.64(d, J=2.4Hz, 1H), 6.79(dd, J =8.7, 2.4Hz, 1H), 7.31(dd, J=9.0, 2.9Hz, 1H), 7.50(d, J=2.8Hz, 1H), 7.74(d, J=9.0Hz, 1H), 7.99(d , J=8.7Hz, 1H), 11.56(s, 1H); MS (ESI) m / z 308 ([M-H] - ), 310 ([M+H] + ); HRMS (ESI + ) Calculated value C 18 h 15 NO 4 310.1074 ([M+H] + ), the measured value is 310.1068.

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Abstract

This invention provides 6H-[1]benzopyrano[4,3-b]quinoline compounds having the formula I: The invention further provides compositions including the compounds, methods for the use of the compounds, and the methods of preparation of the compounds.

Description

field of invention [0001] The present invention relates to 6H-[1]benzopyrano[4,3-b]quinoline compounds, their use as estrogen drugs and their preparation. Background of the invention [0002] The pleiotropic effects of estrogens in mammalian tissues are well documented, and estrogens are now understood to affect many organ systems (see Mendelsohn and Karas, New England Journal of Medicine 340:1801-1811 (1999), Epperson, et al., Psychosomatic Medicine 61: 676-697 (1999), Crandall, Journal of Womens Health & Gender Based Medicine 8: 1155-1166 (1999), Monk and Brodaty, Dementia & Geriatric Cognitive Disorders 11: 1-10 (2000), Hurn and Macrae, Journal of Cerebral Blood Flow & Metabolism 20: 631-652 (2000), Calvin, Maturitas 34: 195-210 (2000), Finking, et al., Zeitschrift fur Kardiologie 89: 442-453 (2000), Brincat, Maturitas 35: 107-117 (2000), Al-Azzawi, Postgraduate Medical Journal 77: 292-304 (2001)). Estrogens can act on tissues in several ways, the most characterized mec...

Claims

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Application Information

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IPC IPC(8): C07D491/06A61P35/00A61K31/47
CPCC07D491/04C07F7/0812A61P1/00A61P1/04A61P1/16A61P11/00A61P11/06A61P13/00A61P13/02A61P13/12A61P15/00A61P15/02A61P17/00A61P17/04A61P17/06A61P17/14A61P19/00A61P19/02A61P19/10A61P21/00A61P25/00A61P25/20A61P25/22A61P25/28A61P27/02A61P29/00A61P31/06A61P35/00A61P35/02A61P3/06A61P37/02A61P43/00A61P7/00A61P9/00A61P9/10A61P3/10A61K31/47
Inventor A·-T·伍
Owner WYETH LLC
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