15beta-substituted steroids having selective estrogenic activity

A technology of steroid and hormone therapy, applied in the direction of organic active ingredients, medical preparations containing active ingredients, organic chemistry, etc., can solve problems such as increasing the risk of breast cancer

Inactive Publication Date: 2012-08-22
VRIJE UNIV MEDISCH CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Unfortunately, the addition of progestin compounds to this therapy increased the risk of breast cancer, as shown in a recent Women's Health Initiative (WHI) study (see Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogenplus progestin in healthy postmenopausal women: principal results from The Women's Health Initi a t i ve r andomi zedcontrolled trial. JAMA 2002; 288: 321-333) confirmed

Method used

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  • 15beta-substituted steroids having selective estrogenic activity
  • 15beta-substituted steroids having selective estrogenic activity
  • 15beta-substituted steroids having selective estrogenic activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Preparation of 7α-ethyl-15β-methyl-19-nor-17α-pregna-1,3,5(10)-triene-20-yne-3,17β-diol (8) (see Scheme II ).

[0062] Preparation of 7α-ethyl-3-methoxy-estr-1,3,5(10),15-tetraen-17-one (3).

[0063] From 17β-17-(acetyloxy)-estra-4,6-dien-3-one and ethyl bromide in a manner similar to that described in EP 0869132A1 (see Example I and Scheme I, compounds 1-5) Preparation of 7α-ethyl-3-methoxyestrone 1 from base magnesium.

[0064] To a solution of LDA [prepared by adding a 1.6 M solution of n-butyllithium in heptane (4.7 ml) to diisopropylamine (2.1 ml) in THF (15 ml) at -50 °C] dropwise A solution of 7a-ethyl-3-methoxyestrone 1 (1 g) in THF (3 ml) was added. The mixture was stirred at -60°C for half an hour and then treated with trimethylsilyl chloride (2ml). The reaction mixture was warmed to 0 °C within half an hour, then poured into 10% NH 4 Cl aqueous solution (100ml), extracted with ethyl acetate. Washed, dried (Na 2 SO 4 ), followed by concentration to pro...

Embodiment 2

[0075] Preparation of 3-pivaloyloxy-7α-ethyl-15β-methyl-19-nor-17α-pregna-1,3,5(10)-triene-20-yne 17β-ol (9a)

[0076] Compound 8 (300mg) was dissolved in pyridine (10ml). Pivaloyl chloride (1.5 equiv) was added dropwise. After 2 hours, the reaction mixture was quenched with water. The reaction mixture was concentrated, redissolved in ethyl acetate, and extracted with aqueous sodium bicarbonate and water. dry (Na 2 SO 4 ) and concentrate the organic layer. Purification of the residue by chromatography on silica gel (heptane-ethyl acetate (1:0 -> 4:1) yielded pure 9a (347 mg). NMR (CDCl 3 ) δ 1.35 (s, 9H, pivaloyl), 1.08 (d, 3H, 15β-Me), 1.02 (s, 3H, 18-Me), 0.94 (t, 3H, 7-ethyl).

[0077] Compound 9b (289 mg; NMR (CDCl 3 ) δ3.0 and 3.08 (2xs, 6H, NMe 2 ) 1.08 (d, 3H, 15β-Me), 1.02 (s, 3H, 18-Me), 0.93 (t, 3H, 7-ethyl)) and 9c (283 mg; NMR (CDCl 3 )δ4.32(q, 2H, OCH 2 CH 3 ), 1.38 (d, 3H, OCH 2 CH 3 ), 1.08 (d, 3H, 15β-Me), 1.02 (s, 3H, 18-Me), 0.93 (t, 3H, 7-ethyl)...

Embodiment 3

[0079] The agonistic activity of the compounds on the estrogen receptor was determined in an in vitro bioassay using recombinant Chinese hamster ovary (CHO) cells prepared with human estrogen receptor α-(hERα-) or β-(hERβ-) , rat oxytocin-promoting factor (RO) and luciferase reporter gene (LUC) stably co-transfected cells. The potency of the test compound to stimulate luciferase through estrogen receptor hERα- or hERβ-mediated transactivation, i.e. estrogen agonistic transactivation is expressed as EC relative to the standard estrogen 17β-estradiol 50 Percentage (%) of (potency of test compound=(EC of 17β-estradiol 50 / EC of test compound 50 )×100%). Efficacy, i.e. the amount of maximal activation of the receptor induced by the compound, is expressed as a percentage (%) relative to the maximal activation induced by the standard estrogen 17β-estradiol (efficacy of test compound = (test Maximum activation of compound / maximum activation of 17β-estradiol)×100%). A more thorou...

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Abstract

The invention provides 15beta-substituted steroidal compounds having selective estrogen receptor activity according to Formula (I) wherein, R<1 >is H, C1-5 alkyl, C1-12 acyl, di-(C1-5 alkyl)aminocarbonyl, (C1-5alkyl)oxycarbonyl or sulfamoyl, R<2> is H, C1-3alkyl, C2-3alkenyl or C2-3alkynyl, each of which may be optionally substituted with a halogen, R<3> is C1-2alkyl, ethenyl or ethynyl, each of which may be optionally substituted with a halogen, and R<4> is H or C1-12 acyl.

Description

field of invention [0001] The present invention relates to 15β-substituted steroid compounds having selective estrogenic activity, pharmaceutical compositions comprising said compounds, said compounds for use in therapy, and to the preparation of said compounds for use in the treatment of estrogen receptor-associated diseases Or prevention or use of a medicament for the regulation or treatment or prevention of other estrogen receptor-associated physiological conditions. Background of the invention [0002] Compounds with an affinity for the estrogen receptor have been used extensively for the treatment of many medical conditions over the years. The therapeutic utility of ligands for the estrogen receptor is important because of the widespread tissue distribution of the estrogen receptor. In particular, its use has been related to contraception and the prevention or treatment of: [0003] Discomforts of menopause: hot flashes, night sweats, and mood swings; [0004] Bone l...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J1/00A61P5/00A61K31/56
Inventor H・J・J・鲁泽A・G・H・埃德温F・A・迪吉克斯
Owner VRIJE UNIV MEDISCH CENT
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