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Novel 2H-chromene derivatives as selective estrogen receptormodulators

A chromene and selected technology, applied in the field of selective estrogen receptor modulators, can solve the problems of not improving the cognitive function of elderly patients

Inactive Publication Date: 2008-01-09
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] However, raloxifene has been reported to worsen symptoms associated with menopause, such as hot flashes and vaginal dryness, and not to improve cognitive function in older patients

Method used

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  • Novel 2H-chromene derivatives as selective estrogen receptormodulators
  • Novel 2H-chromene derivatives as selective estrogen receptormodulators
  • Novel 2H-chromene derivatives as selective estrogen receptormodulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0168] 4-Methyl-2-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-2H-chromene-7-ol (Compound ID#4)

[0169]

[0170] Step A: Preparation of 4-methyl-7-(2-trimethylsilyl-ethoxymethoxy)-2H-chromen-2-ol

[0171] To a solution of 4-methyl-7-(2-trimethylsilyl-ethoxymethoxy)-chromen-2-one (1.53g, 5mmol) in toluene (50mL) at -78°C A 1.5M solution of DIBAL-H in toluene (3.34 mL, 5 mmol) was added slowly. After stirring at -78 °C for 30 min, the reaction mixture was quenched with methanol (1 mL). The reaction mixture was then diluted with ethyl acetate (500 mL) and washed with saturated aqueous potassium sodium tartrate (4 x 200 mL). The organic layer was dried over sodium sulfate and concentrated to give the crude product as a colorless oil. The crude product was used in the next step without further purification.

[0172] Step B: Preparation of 4-Methyl-2-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-2H-chromen-7-ol

[0173]To a solution of 1-[2-(4-iodo-phenoxy)-ethyl]-piperidine (15 mmol) (...

Embodiment 2

[0177] 4-Methyl-2-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(2-trimethylsilyl-ethoxy Methyl)-2H-chromen-7-ol (Compound ID#2)

[0178]

[0179] Step A: Preparation of 4-methyl-7-(2-trimethylsilyl-ethoxymethoxy)-3-(2-trimethylsilyl-ethoxymethyl)-chromene-2 -ketone

[0180] To a solution of 4-methyl-7-(2-trimethylsilyl-ethoxymethoxy)-chromen-2-one (306 mg, 1 mmol) in THF (10 mL) at -10°C was added LiHMDS (1.5 mL, 1.0 M in THF). The resulting yellowish solution was stirred for 30 min, then SEMCl (0.21 mL, 1.2 mmol) was added. After 2 hours, the reaction was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Flash column to get 4-methyl-7-(2-trimethylsilyl-ethoxymethoxy)-3-(2-trimethylsilyl-ethoxymethyl)-chromene-2- Ketones are colorless oily substances.

[0181] 1 HNMR (CDCl 3 , 400MHz) δ (ppm) 7.8 (d, J = 8.4Hz, 1H), 7.2 (d, J = 8.4Hz, 2H), 5.51 (s, 2H), 4.77 (s, 2H), 4.01 (t, J ...

Embodiment 3

[0198] S * -4-Methyl-2-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(2-trimethylsilylethoxymethyl)-2H-color En-7-ol and

[0199] R * -4-Methyl-2-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(2-trimethylsilylethylhydrogenmethyl)-2H-color En-7-ol (Compound ID#3 and Compound ID#11)

[0200]

[0201]The racemic compound 4-methyl-2-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(2-trimethylsilylethoxymethyl) -2H-chromen-7-ol (2.5 g) was loaded onto a ChiralPak AD chiral HPLC column (5 cm I.D. x 50 cm L), and eluted with 20% MeOH / IPA at a flow rate of 90 mL / min. Under vacuum, the two peaks were separated to give the following product:

[0202] Peak 1: S * -4-Methyl-2-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(2-trimethylsilylethoxymethyl)-2H-color en-7-ol

[0203] 1 HNMR (CDCl 3 , 400MHz) δ (ppm) 7.2 (d, J = 8.4Hz, 2H), 7.05 (d, J = 8.4Hz, 1H), 6.65 (d, J = 6.8Hz, 2H), 6.35 (dd, 1 J=8.4Hz, 2 J=2Hz, 1H), 6.20(d, J=2Hz, 1H), 5.75(s, 1H), 4.2(d, J=10Hz, 1H), 4.0(t, J=6Hz, 2H), 3.7(d , J=10Hz,...

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Abstract

The present invention is directed to novel 2H-chromene derivatives, pharmaceutical compositions containing them, their use in the treatment of disorders mediated by one or more estrogen receptors and processes for their preparation.

Description

field of invention [0001] The present invention relates to novel 2H-chromene derivatives; pharmaceutical compositions comprising them and their use in the treatment or prevention of estrogen receptor mediated diseases and conditions such as: hot flashes, vaginal dryness, osteopenia , osteoporosis, hyperlipidemia, cognitive impairment, degenerative brain disease, cardiovascular disease, cerebrovascular disease; hormone-sensitive cancer and hyperplasia (in women including breast, endometrium, and cervix; male prostate in tissues including), endometriosis, uterine fibroids, osteoarthritis; and use as a contraceptive, alone or in combination with progestins or progesterone antagonists. The compounds of the present invention are selective estrogen receptor modulators. Background of the invention [0002] Estrogens are a class of female hormones necessary for the reproductive process and for the development of the uterus, breasts, and other bodily changes associated with puberty....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/60A61K31/352C07D311/78A61K31/35C07D311/80A61P5/28C07D493/04
CPCC07D311/18C07D493/04C07D311/78C07D311/60C07F7/1856C07F7/1804A61P15/02A61P15/08A61P15/18A61P19/02A61P19/10A61P25/28A61P35/00A61P3/06A61P43/00A61P5/00A61P5/28A61P9/00A61P9/10
Inventor N·F·贾因J·徐Z·隋
Owner JANSSEN PHARMA NV