Estratriene derivatives comprising heterocyclic bioisosteres for the phenolic a-ring

An alkenyl and compound technology, applied in the field of estriene derivatives of heterocyclic bioisosteres containing phenol A ring, can solve the problems of increased risk of venous thromboembolism and the like, and achieve the effect of reducing hepatic estrogen activity

Inactive Publication Date: 2011-06-22
BAYER SCHERING PHARMA OY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, administration of ethinyl estradiol is associated with increased risk of venous thromboembolism and high inter- and intra-individual variability in bioavailability

Method used

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  • Estratriene derivatives comprising heterocyclic bioisosteres for the phenolic a-ring
  • Estratriene derivatives comprising heterocyclic bioisosteres for the phenolic a-ring
  • Estratriene derivatives comprising heterocyclic bioisosteres for the phenolic a-ring

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0184] 2'H-pyrazolo[3',4':3,4]estra-1,3,5(10)-trien-17β-ol

[0185] a) 17β-hydroxy-4(Z)-hydroxymethylene-5α-estr-1-en-3-one

[0186]

[0187] A solution of 500 mg of 17β-hydroxy-5α-estr-1-en-3-one in 10 ml of pyridine and 15 ml of ethyl formate was cooled to -10°C. Sodium methoxide solution (15ml, 1M) was added portionwise. The mixture was allowed to warm to room temperature over two hours. The reaction mixture was poured into ice water and neutralized with hydrochloric acid, extracted with ethyl acetate, dried over sodium sulfate and concentrated under vacuum to give 540 mg of a yellow oil. This material was used in the next step without further purification and characterization.

[0188] b) 2'H-pyrazolo[5',4':3,4]-5α-est-1-en-17β-ol

[0189]

[0190] To a solution of 520 mg crude 17β-hydroxy-4(Z)-hydroxymethylene-5α-estr-1-en-3-one in 6 ml ethanol was added a solution of hydrazine in THF (1.9 ml, 1M). The mixture was stirred at room temperature for 3 hours. The m...

Embodiment 2

[0199] 2'H-pyrazolo[3',4':3,4]estra-1,3,5(10)-trien-17-one

[0200]

[0201] To 521mg 2'H-pyrazolo[3',4':3,4]estra-1,3,5(10)-triene-17β-alcohol (Example 1) in 19ml dichloromethane and 0.7ml To the suspension in pyridine was added 746 mg of Dess-Martin oxidizer. The reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under vacuum. The crude product was triturated with dichloromethane and hexanes to give 325 mg of 2'H-pyrazolo[3',4':3,4]estra-1,3,5(10)-triene-17 as a white solid -ketone.

[0202] MS(CI+): m / z=295(M+H) + ;

[0203] 1 H-NMR (400MHz, CDCl3): δ=8.05 (s, 1H); 7.39 (d, 1H); 7.32 (d, 1H); 3.22 (m, 2H); 2.50 (m, 3H); m, 4H); 1.45-1.80(m, 5H); 0.94(s, 3H); 0.88(t, 1H)

Embodiment 3

[0205] 17α-Methyl-2'H-pyrazolo[3',4':3,4]estra-1,3,5(10)-trien-17β-ol

[0206]

[0207] To a suspension of 80mg 2'H-pyrazolo[3',4':3,4]estra-1,3,5(10)-triene-17-one in 10ml THF was added 2.7ml THF Methylmagnesium bromide (3M). The reaction mixture was stirred for 20 hours. Water was then added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under vacuum. The crude product was chromatographed on silica gel 60 with hexane / ethyl acetate to give 53 mg of 17α-methyl-2'H-pyrazolo[3',4':3,4]estr-1 as a white solid, 3,5(10)-Trien-17β-ol.

[0208] MS(CI+): m / z=311(M+H) + ;

[0209] 1 H-NMR (400MHz, CDCl3): δ=8.03(s, 1H); 7.39(d, 1H); 7.30(d, 1H); 3.16(m, 2H); 2.40(m, 2H); 1H); 2.01(m, 2H); 1.20-1.80(m, 8H); 1.30(s, 3H); 0.92(s, 3H)

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Abstract

The present invention is directed to novel pyrazolo-estrien and triazolo-estrien-derivatives, pharmaceutical compositions containing them and their use in the treatment or prevention of disorders and diseases mediated by an estrogen receptor such as hot flashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia, loss of cognitive function, degenerative brain diseases, cardiovascular diseases, cerebrovascular diseases, hormone sensitive cancers and hyperplasia (in tissues including breast, endometrium, and cervix in women and prostate in men), endometriosis, uterine fibroids, osteoarthritis; and as contraceptive agents either alone or in combination with a progestogen or progestogen antagonist. The compounds of the invention are selective estrogen receptor modulators.

Description

technical field [0001] The present invention relates to novel pyrazoloestriene derivatives and triazoloestriene derivatives, pharmaceutical compositions containing them and their use in the treatment or prevention of the following disorders and diseases mediated by estrogen receptors Uses: such as hot flashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia, loss of cognitive function, degenerative encephalopathy, cardiovascular disease, cerebrovascular disease, hormone-sensitive cancers, and hyperplasia (including female breast, Endometrium and cervix and in tissues including the prostate gland in men), endometriosis, uterine fibroids, osteoarthritis; and use as a contraceptive alone or in combination with a progestin or progesterone antagonist . The compounds of the present invention are selective estrogen receptor modulators. Background technique [0002] Estrogens are a class of female hormones necessary for the reproductive process, uterine and breast develo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J71/00A61K31/58A61P5/30
CPCC07J71/0047A61P13/08A61P15/02A61P15/08A61P15/12A61P15/18A61P19/02A61P19/08A61P19/10A61P25/00A61P25/28A61P35/00A61P3/06A61P43/00A61P5/30A61P9/00A61P9/10C07J71/00A61K31/58
Inventor T·布卢默D·黑尔德曼N·施梅斯C·奥托T·温特曼特尔J·库恩克
Owner BAYER SCHERING PHARMA OY
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