Novel heteroatom containing tetracyclic derivatives as selective estrogen receptor modulators

A compound, piperidine technology, applied in the field of tetracyclic derivatives, can solve the problems of high incidence and aggravation of leg cramps, and failure to improve the cognitive function of elderly patients

Inactive Publication Date: 2006-03-08
ORTHO MCNEIL PHARM INC
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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 menopausal-related symptoms, such as hot flashes and vaginal dryness, and to fail to improve cognitive function in older patients
Although a higher incidence of vaginal bleeding and breast discomfort was reported in women taking ERT compared with women taking raloxifene or placebo, patients taking raloxifene compared with placebo or ERT , a higher incidence of hot flashes, and a higher incidence of leg cramps compared with placebo patients
[0014] So far, neither raloxifene nor any other existing SERM compound has the ability to provide all the benefits of existing ERTs (such as control of postmenopausal syndrome and prevention of AD) without causing diseases such as endometrial cancer, breast cancer, etc. and side effects such as bleeding

Method used

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  • Novel heteroatom containing tetracyclic derivatives as selective estrogen receptor modulators
  • Novel heteroatom containing tetracyclic derivatives as selective estrogen receptor modulators
  • Novel heteroatom containing tetracyclic derivatives as selective estrogen receptor modulators

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Experimental program
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preparation example Construction

[0550] The present invention also relates to the method for preparing the compound of formula (DX) described in detail in Scheme 16.

[0551]

[0552] Process 16

[0553] Accordingly, the appropriately substituted compound of formula (VIII) is a known compound or a compound prepared by a known method, wherein R A , R B , N, R 3 , M, R 4 And Z are the previous definitions, X is O or S, Pg 10 It is a suitable protecting group such as alkyl (e.g. methyl), benzyl, benzoyl, SEM, MOM, BOM, pivaloyl, etc. (see e.g. Protective Groups in Organic Chemistry , Editor-in-Chief J.F.W.McOmie, Plenum Press, 1973; T.W.Greene & P.G.M.Wuts, Protective Groups in Organic Synthesis , JohnWiley & Sons, 1991), react it with a base (such as LiHMDS, LDA, KHMDS, NaHMDS, etc.); preferably the reaction temperature is less than or equal to about room temperature, more preferably about 30°C to about -100°C, more preferably about -10 ℃ to about -30℃; solvent with aprotic organic solvents s...

Embodiment 1

[0582] Acetic acid 3-(2,4-dimethoxyphenyl)-7-hydroxy-4-methyl-2-oxo-2H-chromene-7-yl ester

[0583]

[0584] Combine 2,4-dihydroxyacetophenone (2.233g, 14.67mmol, 1eq), 2,4-dimethoxyphenylacetic acid (2.88g, 14.67mmol, 1eq), acetic anhydride (7.5mL, 78mmol, 5eq) A mixture of) and triethylamine (1.49 mL, 2.05 mmol, 1 eq) was stirred, and heated to reflux for 48 h under a nitrogen atmosphere. After cooling to room temperature, the black slurry reaction mixture was poured into ice water (~450 mL). To the mixture was slowly added solid sodium bicarbonate to neutralize the suspension of viscous semi-solid product. The mixture was then allowed to solidify overnight. The black solid was separated by filtration, washed with water, sucked dry, and recrystallized from acetic acid to obtain the title compound as a milky white crystalline solid. The second batch of product (0.95 g, 18.3%) was isolated from the mother liquor.

[0585] mp: 146-148°C

[0586] MS(CI)m / z355(M+H) +

[0587] 1 H...

Embodiment 2

[0591] Acetic acid 3-(2,4-dimethoxyphenyl)-8-hydroxy-4-methyl-2-oxo-2H-chromene-7-yl ester

[0592]

[0593] The title compound was prepared according to the method described in Example 1, in which 2,3-dihydroxyacetophenone was substituted for 2,4-dihydroxyacetophenone.

[0594] mp140-141℃

[0595] MS(CI)m / z 355, (M+H) + , 377(M+Na) +

[0596] 1 H NMR(300MHz, CDCl 3 ): δ 7.55 (1H, d, d, J = 4.2, 5.32 Hz), 7.29 (1H, d, J = 1.29 Hz), 7.27 (1H, d, J = 4.37 Hz), 7.08 (1H, d, J=8.13 Hz), 6.57-6.55 (2H, m), 3.86 (3H, s), 3.76 (3H, s), 2.43 (3H, s), 2.24 (3H, s).

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PUM

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Abstract

The present invention is directed to novel heteroatom containing tetracyclic derivatives, pharmaceuticalcompositions contianing them, their use in the treatment and / or prevention of disorders mediated by oneor more estrogen receptors and processes for their preparation. The compounds of the invention areuseful in the treatment and / or prevention of disorders associated with the depletion of estrogen such ashot flashes, vaginal dryness, osteopenia and osteoporosis; hormone sensitive cancers and hyperplasia of the breast, endometrium, cervix and prostate; endometriosis, uterine fibroids, osteoarthritis and as contraceptive agents, alone or in combination with a progestogen or progestogen antagonist.

Description

Invention field [0001] The present invention relates to new heteroatom-containing tetracyclic derivatives, pharmaceutical compositions containing these compounds, their use in the treatment of one or more estrogen receptor-mediated diseases and their preparation methods. Thus, the compounds of the present invention can be used to treat and / or prevent estrogen deficiency related diseases (including but not limited to hot flashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia, impaired cognitive function, Degenerative encephalopathy, cardiovascular and cerebrovascular diseases); used to treat hormone-sensitive cancer and hyperplasia of tissues (including female breast, endometrial and cervix, and male prostate); used to treat and prevent endometriosis, Uterine fibroids and osteoarthritis; and can be used as contraceptives alone or in combination with progesterone or progesterone antagonists. Background of the invention [0002] Estrogens are a group of female hormones t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/04A61K31/35A61P19/10C22B3/06C22B3/10C22B11/00
CPCC07D493/04A61P13/08A61P15/00A61P15/16A61P15/18A61P19/02A61P19/10A61P25/00A61P25/28A61P35/00A61P3/06A61P43/00A61P5/30A61P9/00
Inventor R·M·卡诺吉亚N·F·贾因R·吴Z·隋J·徐
Owner ORTHO MCNEIL PHARM INC
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