CN101863903B

CN101863903B - 1,4-dihydrobithiophene [3', 2': 5, 6] bithiapyran [4, 3-c] pyrazol-3-carboxylic acid derivative and application thereof

Info

Publication number: CN101863903B
Application number: CN201010194295.2A
Authority: CN
Inventors: 胡春; 孙蕊; 王欣; 宋菁; 黄二芳; 徐赫男; 刘晓平; 李大伟
Original assignee: Shenyang Pharmaceutical University
Current assignee: Shenyang Pharmaceutical University
Priority date: 2010-06-08
Filing date: 2010-06-08
Publication date: 2014-03-12
Anticipated expiration: 2030-06-08
Also published as: CN101863903A

Abstract

本发明属于医药技术领域，涉及1，4-二氢噻吩并[3’，2’：5，6]噻喃并[4，3-c]吡唑-3-羧酸衍生物及其作为雌激素受体调节剂的应用。1，4-二氢噻吩并[3’，2’：5，6]噻喃并[4，3-c]吡唑-3-羧酸衍生物和药学上可接受的盐，或其立体异构体和前药，及其药学上配伍可接受的载体或稀释剂作为雌激素受体调节剂。其结构通式如右所示：在结构式中，R₁可以独立的选自取代或未取代的胺基；和R₂可以独立的选自H或者乙酰基。用于治疗或预防与雌激素功能相关的各种疾病。如：与雌激素缺乏相关的疾病，激素敏感性癌症和增生，子宫内膜异位、子宫肌瘤和骨关节炎；其化合物或其组合物也可以单独或与孕激素或孕激素拮抗剂联用作为避孕药。

The invention belongs to the technical field of medicine, and relates to 1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carboxylic acid derivatives and their estradiol Use of hormone receptor modulators. 1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carboxylic acid derivatives and pharmaceutically acceptable salts thereof, or stereoisomers thereof Constructs and prodrugs, and pharmaceutically compatible carriers or diluents used as estrogen receptor modulators. Its general structural formula is shown on the right: In the structural formula, R ₁ can be independently selected from substituted or unsubstituted amine groups; and R ₂ can be independently selected from H or acetyl groups. For the treatment or prevention of various diseases related to estrogen function. Such as: diseases associated with estrogen deficiency, hormone-sensitive cancers and hyperplasia, endometriosis, uterine fibroids and osteoarthritis; its compounds or combinations thereof can also be used alone or in combination with progestins or progesterone antagonists Used as a contraceptive.

Description

Also also [4,3-c] pyrazoles-3-carboxylic acid derivative and the application thereof of [3 ', 2 ': 5,6] thiapyran of Isosorbide-5-Nitrae-dihydro-thiophene

Technical field

The present invention relates to also also [4,3-c] pyrazoles-3-carboxylic acid derivative or its pharmacy acceptable salt of [3 ', 2 ': 5,6] thiapyran of Isosorbide-5-Nitrae-dihydro-thiophene.The invention still further relates to the preparation method of described compound and the pharmaceutically acceptable composition that comprises them and the application in treatment disease thereof.

Background technology

Known oestrogenic hormon is Female Sexual Hormones.Yet, have recently many about oestrogenic hormon the tissue-specific report in organ, that described character is not considered to oestrogenic hormon-sensitivity traditionally or oestrogenic hormon-reaction.In climacteric, estrogenic secretion declines significantly.Estrogenic minimizing can be brought out short-term and the long-term symptom of vasomotorium, urogenital system, cardiovascular systems, Skeletal system and central nervous system disease: for example hot flush, urogenital atrophy, the dangerous increase of cardiovascular disorder, osteoporosis, cognitive decline and mental defect, comprise the increase of cognitive disorder and presenile dementia danger.

Hormone Replacement Therapy (HRT) is controversies in hormone replacement in the elderly (ERT) more precisely, generally designate with solving the medical problem relevant to menopause, also contribute to stop with preventative and therapeutic mode the generation of osteoporosis and primary cardiovascular complication (for example coronary artery disease) simultaneously.Therefore, HRT is considered to a kind of for extending postmenopausal women's mean lifetime and the pharmacotherapy of improving the quality of living.

ERT has been alleviated menopausal symptoms and apparatus urogenitalis symptom effectively, and having shown is having certain benefit aspect prevention and treatment postmenopausal women heart.Yet, also have the side effect relevant to the ERT that reduces patient compliance.The danger that uterus carcinoma and/or mammary cancer occur for venous thromboembolism, gallbladder disease, menstruation recovery, mastalgia and may increasing is the risk relevant to ERT.Carry out having in the women of ERT not completing described therapy up to 30%, and the termination rate of ERT is between 38% and 70%, wherein ending most important reason is to security concern and side effect.

Raloxifene is that on-steroidal benzothiophene kind is just sold on US and European market, for prevention and treatment osteoporosis.Show, raloxifene reduces bone loss, and prevents fracture, not negative stimulon Endometrium and mammary tissue, just raloxifene than ERT inferior a little aspect opposing bone loss.Raloxifene is unique, and has significant difference with ERT, because its stimulon Endometrium not, thereby has the potentiality of Breast Cancer Prevention.Also prove, the estrogen agonist effect that raloxifene is useful to cardiovascular danger sexual factor, say more accurately with total lipoprotein cholesterol level and low-density lipoprotein cholesterol level in the patient body of raloxifene treatment, to there is useful estrogen agonist effect by quick and continuous decrease.In addition, show, it is the plasma concentration of the independent risk factor of atherosclerosis and thrombotic disease that raloxifene reduces homocysteine.

Yet, it is reported, raloxifene accelerates the symptom relevant to menopause for example hot flush and vagina drying, and does not improve gerontal patient's cognitive function.It is reported, the patient of picked-up raloxifene compares with placebo or ERT user, hot flush incidence is higher, higher than placebo user's shank cramp, although it is higher than the incidence of raloxifene or placebo user's vaginal hemorrhage and breast discomfort to accept the women of ERT.

Moreover, raloxifene and any other current available selective estrogen receptor modulators all can not provide current available ERT benefit, for example control post-menopause syndrome and prevention presenile dementia, and do not cause the adverse side effects such as carcinoma of endometrium and mammary cancer and hemorrhage risk increase.Therefore, need a kind of like this compound: they are selective estrogen receptor modulatorss, and provide the institute of ERT benefit, the while is solution vasomotion, apparatus urogenitalis and cognitive disorder or the illness relevant to menopause related system estrogen decrease also.

Summary of the invention

The present invention relates to also also [4,3-c] pyrazoles-3-carboxylic acid derivative or its pharmacy acceptable salt or prodrug of [3 ', 2 ': 5,6] thiapyran of Isosorbide-5-Nitrae-dihydro-thiophene that general formula I represents, be used for treating and/or preventing the disease relevant to estrogen deficiency.

In formula, R ₁can independently be selected from OCH ₃or replacement or unsubstituted amido;

R ₂can independently be selected from H or ethanoyl.

Another object of the present invention is to provide a kind of medicinal compositions, the described compound of Formula I that said composition comprises significant quantity or its atoxic pharmacy acceptable salt and pharmaceutically compatibility acceptable carrier, or its steric isomer and prodrug, and pharmaceutically compatibility acceptable carrier or thinner.

Another aspect of the present invention, provides the method for the treatment of the patient of the disease that has one or more Mediated by Estrogen Receptors, and described method comprises arbitrary above-claimed cpd or the medicinal compositions that gives affiliated patient treatment significant quantity.

Another aspect of the present invention, is to provide a kind of contraceptive device, and described method comprises the integrated processes that has a kind of formula of the patient treatment of needs significant quantity (I) compound and progestogen or progesterone antagonist.

Another aspect of the present invention, it is the purposes of arbitrary compound described herein in have the following disease of patient of needs and the medicine of contraception for the preparation for the treatment of: (a) hot flush, (b) vagina drying, (c) bone amount reduces, (d) osteoporosis, (e) hyperlipidemia, (f) cognitive function is lost, (g) sex change encephalopathy (HIE), (h) cardiovascular disorder, (i) cerebrovascular disease, (j) mammary cancer, (k) carcinoma of endometrium, (l) cervical cancer, (m) prostate cancer, (n) benign prostatic hyperplasia, (o) endometriosis, (p) hysteromyoma, (q) osteoarthritis.

Particular compound in general formula (I):

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-phenylpiperazine (compound number 1);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(4-p-methoxy-phenyl) piperazine (compound number 2);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(3-chloro-2-methyl phenyl) piperazine (compound number 3);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(the chloro-4-aminomethyl phenyl of 2-) piperazine (compound number 4);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(4-chloro-phenyl-) piperazine (compound number 5);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-[(4-chloro-phenyl-) phenyl] methyl) piperazine (compound number 6);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(the chloro-4-aminomethyl phenyl of 3-) piperazine (compound number 7);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(diphenyl-methyl) piperazine (compound number 8);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(4-aminomethyl phenyl) piperazine (compound number 9);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(3-chloro-phenyl-) piperazine (compound number 10);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(3-Trifluoromethoxyphen-l) piperazine (compound number 11);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(2-chloro-phenyl-) piperazine (compound number 12);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(the chloro-4-fluorophenyl of 3-) piperazine (compound number 13);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(2-aminomethyl phenyl) piperazine (compound number 14);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(4-ethoxyl phenenyl) piperazine (compound number 15);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-methylpiperazine (compound number 16);

N-[2-(diethylamino) ethyl]-Isosorbide-5-Nitrae-dihydro-thiophene [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazole-3-formamide (compound number 17) also also;

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(2,5-3,5-dimethylphenyl) piperazine (compound number 18);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(2,3-3,5-dimethylphenyl) piperazine (compound number 19);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(2,6-3,5-dimethylphenyl) piperazine (compound number 20);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(4-Trifluoromethoxyphen-l) piperazine (compound number 21);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(4-trifluoromethyl) piperazine (compound number 22);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(1-styroyl) piperazine (compound number 23);

The N-tertiary butyl-Isosorbide-5-Nitrae-dihydro-thiophene is [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazole-3-formamide (compound number 24) also also;

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-tertiary butyl piperazine (compound number 25);

N-(1-styroyl)-Isosorbide-5-Nitrae-dihydro-thiophene is [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazole-3-formamide (compound number 26) also also;

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(3-aminomethyl phenyl) piperazine (compound number 27);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(1-naphthyl) piperazine (compound number 28);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-cyclopropyl piperazine (compound number 29);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-phenmethyl piperazine (compound number 30);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(4-fluorophenyl) piperazine (compound number 31);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(3-fluorophenyl) piperazine (compound number 32);

N-[2-(4-morpholinyl) ethyl]-Isosorbide-5-Nitrae-dihydro-thiophene [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazole-3-formamide (compound number 33) also also;

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(2-fluorophenyl) piperazine (compound number 34);

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-n-hexyl piperazine (compound number 35);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-phenylpiperazine (compound number 36);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(4-p-methoxy-phenyl) piperazine (compound number 37);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(3-chloro-2-methyl phenyl) piperazine (compound number 38);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(the chloro-4-aminomethyl phenyl of 2-) piperazine (compound number 39);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(4-chloro-phenyl-) piperazine (compound number 40);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-((4-chloro-phenyl-) phenyl) methyl) piperazine (compound number 41);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(the chloro-4-aminomethyl phenyl of 3-) piperazine (compound number 42);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4--benzhydryl piperazidine (compound number 43);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(4-aminomethyl phenyl) piperazine (compound number 44);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(3-chloro-phenyl-) piperazine (compound number 45);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(3-Trifluoromethoxyphen-l) piperazine (compound number 46);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(2-chloro-phenyl-) piperazine (compound number 47);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(the chloro-4-fluorophenyl of 3-) piperazine (compound number 48);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(2-aminomethyl phenyl) piperazine (compound number 49);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(4-ethoxyl phenenyl) piperazine (compound number 50);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-methylpiperazine (compound number 51);

N-[2-(diethylamino) ethyl]-6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazole-3-formamide (compound number 52) also also;

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(2,5-3,5-dimethylphenyl) piperazine (compound number 53);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(2,3-3,5-dimethylphenyl) piperazine (compound number 54);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(2,6-3,5-dimethylphenyl) piperazine (compound number 55);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(4-Trifluoromethoxyphen-l) piperazine (compound number 56);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(4-trifluoromethyl) piperazine (compound number 57);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(1-styroyl) piperazine (compound number 58);

The N-tertiary butyl-6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene is [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazole-3-formamide (compound number 59) also also;

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-tertiary butyl piperazine (compound number 60);

N-(1-styroyl)-6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene is [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazole-3-formamide (compound number 61) also also;

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(3-aminomethyl phenyl) piperazine (compound number 62);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(1-naphthyl) piperazine (compound number 63);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-cyclopropyl piperazine (compound number 64);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-phenmethyl piperazine (compound number 65);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(4-fluorophenyl) piperazine (compound number 66);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(3-fluorophenyl) piperazine (compound number 67);

N-[2-(4-morpholinyl) ethyl]-6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazole-3-formamide (compound number 68) also also;

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(2-fluorophenyl) piperazine (compound number 69);

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-n-hexyl piperazine (compound number 70).

Definition

In entire description, following term has the implication of appointment.

The term using in content of the present invention " one ", " one " or " this " and similar type are especially in appended claims) should be interpreted as comprising odd number and plural number, unless be otherwise noted or obviously contradicted with context herein.

In appended claims and specification sheets of the present invention, unless context needs or expresses the reason of speech or necessary connotation, term " comprises " or its version " comprises " or " containing " is used as including property connotation, for showing, there is described feature, but be also not precluded within, in various embodiment of the present invention, exist or increase other features.

Term used herein " compound " refers to any compound that general formula described herein is contained.Compound described herein can contain one or more pairs of keys, thereby may have steric isomer.Therefore, the possible steric isomer of compound shown in chemical structure described herein has contained, comprises stereoisomerism purified form (for example, rotamerism is pure) and three-dimensional heterogeneous mixture.Compound also can multiple tautomeric form exist, and comprises enol form, keto-acid and composition thereof.Therefore, herein shown in chemical structure contained shown in all possible tautomeric form of mixture.Compound also can have one or more asymmetric centers or plane.The compounds of this invention that contains Asymmetrical substitute atom can optically active or racemic form separation.How to prepare as everyone knows optical activity form, for example isomorphism resolution of racemic form (racemic compound), by asymmetric synthesis, or passes through from optics initial substance synthetic.The separation of racemic compound can complete by ordinary method, for example crystallization under the existence of resolving agent, or for example adopt the chromatography of hand-type HPLC post.Compound can non-solvent compound and solvate form thereof exist, comprise hydrated form.Compound generally can hydration or solvation.Some compound can multiple crystallization or amorphous form existence.Conventionally, in the application that all physical form are considered herein, be equivalent, be included in scope of the present invention.When real part of compounds structure, hyphen ("-") represents the tie point of described structure division and molecule rest part.

Term " prodrug " refers to the compound that activity in vivo strengthens.The compounds of this invention also can exist with prodrug forms, as the hydrolysis of < < medicine and prodrug metabolic process: chemistry, biological chemistry and zymetology > > (Hydrolysis in Drugand Prodrug Metabolism:Chemistry, and Enzymology) (Testa, Bernard and Mayer, Joachim.Wiley-VHCA, Zurich, Switzerland, 2003) described in.The prodrug of compound described herein is the structural modification form that chemical reaction forms the compound of the compounds of this invention that easily occurs under physiological conditions.In addition, prodrug can be converted into the compounds of this invention by chemistry or biochemical method in live body environment.For example, if be placed in the transdermal patch bank of suitable enzyme or chemical reagent, prodrug can be converted into compound.In some situation, prodrug is usually useful, because they are than the compounds of this invention or the easier administration of parent drug.For example, prodrug can be bioavailable by oral administration, and parent compound is not all right.The solubleness of prodrug in pharmaceutical composition is also high than parent.Many prodrug derivants are known in the art, for example, depend on the hydrolytic cleavage of prodrug or the prodrug derivant of oxidized activating.The non-limitative example of prodrug can be with ester-formin (" prodrug "), to give to form by hydrolysis metabolism the compound of carboxylic acid (active individual).Other example comprises the peptide radical derivative of compound.

The compounds of this invention can pharmacy acceptable salt form exist.The present invention includes the above-claimed cpd of salt form, especially acid salt.Suitable salt comprises and salt organic and that mineral acid forms.These acid salt are normally pharmaceutically acceptable.Yet non-pharmacy acceptable salt can be used for the preparation and purification of described compound.Also can form base addition salt, be also pharmaceutically acceptable.For the preparation of salt and the discussion more comprehensively of selection aspect referring to < < drug salts: character, selection and purposes > > (PhamaceuticalSalts:Properties, Selection, and use) (Stahl, P.Heinrch.Wiley-VHCA, Zurich, Switzerland, 2002).

Term used herein " pharmacy acceptable salt " or " acceptable salt in treatment " represent to define the water-soluble or oil soluble of the compounds of this invention herein or water dispersibles or oil dispersibles and treat acceptable salt or zwitterionic form.This salt can be prepared during the final separation of this compound and purifying, or by the suitable combination thing of free alkali form and suitable acid-respons, prepares independently.Representational acid salt comprises: acetate, adipate, alginate, 1-ascorbate salt, aspartate, benzoate, this sulfonate, hydrosulfate, butyrates, camphorate, camsilate, Citrate trianion, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycollate, Hemisulphate, enanthate, hexanoate, hippurate, hydrochloride, hydrobromate, hydriodate, 2-isethionate (isethionate), lactic acid salt, maleate, malonate, DL-mandelate, 1，3，5-trimethyl-benzene sulfonate, mesylate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate (pamoate), pectate (pectinate), persulphate, 3-phenylpropionic acid salt, phosphoric acid salt, picrate, Pivalate, propionic salt, pyroglutamate, succinate, sulfonate, tartrate, L-TARTARIC ACID salt, trichloroacetate, trifluoroacetate, phosphonate, glutaminate, supercarbonate, tosilate and undecylate.And the basic group in the compounds of this invention can be quaternized with following group: the muriate of methyl, ethyl, propyl group, butyl, bromide and iodide; Methyl-sulfate, ethyl sulfate, dibutyl sulfate and sulfuric acid diamyl ester; Muriate, bromide and the iodide of decyl, lauryl, tetradecyl and sterol base; The bromide of benzyl and styroyl.The sour example that can be used for the upper acceptable addition salt of formation treatment comprises mineral acid, for example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid; Organic acid, as oxalic acid, toxilic acid, succsinic acid and citric acid.Salt also can form by this compound and basic metal or alkaline-earth metal ions coordination.Therefore, the present invention takes the sodium salt of compound, sylvite, magnesium salts and calcium salt etc. into account.

In one embodiment, " treatment " any disease or illness refer to and alleviate disease or illness (stoping or reduce the development of disease or its at least one clinical symptom).In another embodiment, " treatment " refer to and improve the body parameter that at least one patient may impalpable.In another embodiment, " treatment " refers to aspect physics (for example stable can distinguish symptom), for example, in physiology aspect (, stablizing body parameter) or two aspects disease or illness always.At another embodiment, " treatment " refers to the generation that postpones disease or illness.As used herein, the symptom of alleviating concrete illness by giving specific compound or pharmaceutical composition refers to and gives the credit to composition or give composition relevant permanent or temporary, lasting or of short duration alleviating arbitrarily.

" treatment significant quantity " refers to after the object administration of needs, produces the compound amount of result for the treatment of (for example treat, control, alleviate, prevent, postpone the generation of disease, illness or its situation or symptom or reduce the possible of its generation) in treatment target.Result for the treatment of can be objective (can measure by some test or marker) or subjective (being that object provides indication or photosensitive effect)." treatment significant quantity " will be with compound.Factors such as the age of mode of administration, disease and seriousness thereof and object to be treated, body weight and changing.

Pharmaceutical composition

According to another embodiment, the invention provides the compound or its pharmacy acceptable salt that comprise general formula (I), and the pharmaceutical composition of pharmaceutically acceptable thinner as described herein, carrier or vehicle.

Although can be alone or in combination, directly rather than by preparation way, give the compound of the general formula (I) of pharmacy effective dose, common way is the compound of the pharmaceutical dosage form form that comprises pharmaceutically acceptable vehicle and activeconstituents.The compound of general formula (I) can be containing oral administration, parenteral in the measure unit preparation of the pharmaceutically acceptable carrier of conventional nontoxicity, auxiliary reagent and vehicle or give by suction.Especially preferred be tablet, capsule, elixir, syrup, lozenge, oral containing forms such as ingots.Term parenteral used herein comprises injection or the infusion modes such as subcutaneous injection, intradermal, blood vessel interior (such as intravenously), muscle, backbone intrathecal injection.In addition, also provide the pharmaceutical preparation that comprises general formula (I) and pharmaceutically acceptable carrier.The compound of one or more general formulas (I) can coexist with the pharmaceutically acceptable carrier of one or more nontoxicitys and/or thinner and/or auxiliary reagent, while needing, also can comprise other activeconstituents.Pharmaceutical composition containing the compound of general formula (I) can be suitable oral dosage form, for example tablet, containing ingot, lozenge, water-based or oil-based suspension, dispersible powder or particle, emulsion, hard capsule or soft capsule or syrup or elixir.

The composition of oral application can be prepared according to any pharmaceutical composition preparation method known in the art, these compositions can comprise one or more reagent that is selected from lower group: sweeting agent, correctives, tinting material and sanitas, and so that pharmaceutically good to eat preparation to be provided.Tablet contains activeconstituents and is applicable to the pharmaceutically acceptable vehicle of nontoxicity prepared by tablet.These vehicle can be inert diluents, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating agent or disintegrating agent, for example W-Gum or Lalgine; Tackiness agent, for example starch, gelatin or gum arabic; Lubricant, for example Magnesium Stearate, stearic acid or talcum powder.Tablet is dressing not, or passes through known technology dressing with delay disintegration and absorption in gi tract, thereby provides continuous action within the longer time period.For example, can adopt time lag material as glyceryl monostearate or distearin.

The preparation orally using can be also hard gelatin capsule, wherein, activeconstituents mixes with inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin: or soft gelatin capsule, wherein, activeconstituents for example, mixes in water or oily medium (peanut oil, Liquid Paraffin or sweet oil).

The vehicle that aqueous suspension comprises activeconstituents and is used in preparation aqueous suspension.These vehicle can be suspending agents, for example Xylo-Mucine, methylcellulose gum, Vltra tears, sodium alginate, polyvinylpyrrolidone, tragakanta and gum arabic; Dispersion agent or wetting agent, for example condensation product (as polyethylene sorbitan monooleate) of the derivative part ester of the condensation product (as polyoxyethylene 80 sorbitan monooleate) of the derivative part ester of the condensation product (as polyoxyethylene stearic acid ester) of the phosphatide of natural origin (for example Yelkin TTS) or alkene oxide and lipid acid or the condensation product of oxyethane and long chain aliphatic alcohol (as 17 oxyethyl group hexadecanols) or oxyethane and lipid acid and hexitol or oxyethane and lipid acid and hexitol acid anhydrides.Aqueous suspension also can comprise one or more tinting materials; One or more perfume compound (flavoring agent); And one or more sweeting agents are as sucrose or asccharin.

Oiliness suspensoid can for example, for example, be prepared by activeconstituents being suspended in vegetables oil (, peanut oil, sweet oil, sesame oil or Oleum Cocois) or mineral oil (Liquid Paraffin).Oiliness suspensoid can comprise thickening material, for example beeswax, solid paraffin or hexadecanol.Sweeting agent as mentioned above.As add perfume compound to form good to eat oral preparations.These compositions can be anticorrosion by adding antioxidant and xitix.

Being applicable to add water forms the dispersible powder of aqueous suspension or particle activeconstituents and dispersion agent or wetting agent, suspending agent, one or more sanitass is provided.The example of suitable dispersion agent or wetting agent and suspending agent as mentioned above.Also can there is other vehicle, for example sweeting agent, perfume compound and tinting material.

Pharmaceutical composition of the present invention can also be the form of oil-in-water emulsion.Oil phase can be vegetables oil (for example sweet oil or Semen Maydis oil), or mineral oil (for example whiteruss) or their mixture.Suitable emulsifying agent can be the natural gum (for example gum arabic or tragakanta) of natural origin, the phosphatide of natural origin (for example soybean phospholipid, Yelkin TTS), lipid acid and hexitol, the ester that acid anhydrides is derivative or part ester (for example sorbitan monooleate), the condensation product of described part ester and oxyethane (for example polyoxyethylene sorbitan monooleate direactive glyceride).These emulsions also can comprise sweeting agent and perfume compound.

Available sweeting agent (for example glycerine, propylene glycol, Sorbitol Powder and sucrose) configures syrup and elixir.These preparations also can comprise demulcent, sanitas, correctives and tinting material.Pharmaceutical composition can sterile water for injection or the form of oil suspensoid.Described suspensoid can adopt above-mentioned suitable dispersion agent or wetting agent and suspending agent to prepare according to methods known in the art.This aseptic injection can be also solvent or the suspensoid for aseptic injection of for example, in the acceptable thinner of nontoxicity parenteral or solvent (1,3-bis-butanols) preparation with preparation.The acceptable vehicle or the solvent that adopt comprise water, Ringer's solution and isotonic sodium chlorrde solution.In addition, aseptic fixed oil is also conventional solvent or suspension medium.For this purpose, the nonvolatile oil of any gentleness be can adopt, synthetic direactive glyceride and double glyceride comprised.In addition, lipid acid also can be used for preparing injection as oleic acid.

The compound of general formula (I) can also suppository form give, for example, for rectal administration.These compositions can be prepared in the following manner: medicine is mixed with suitable non-irritating excipient, and described vehicle is solid-state but liquid under rectal temperature at normal temperatures, thereby in rectum, dissolves to discharge medicine.These materials are cocoa beans ester and polyoxyethylene glycol.

The compound of general formula (I) can give by parenteral in sterile media.According to vehicle used and working concentration, medicine can suspendible or is dissolved in vehicle.Valuably, auxiliary reagent also may be dissolved in vehicle as local anesthetic, sanitas and buffer reagent.

Age, body weight and symptom by dosage form, administering mode, application target and patient to be treated decide suitable dose, and dosage is not constant.

The preparation method of the compounds of this invention is provided in yet another embodiment of the present invention.In the synthetic method of representational the compounds of this invention non-restrictive version below, mention.Initial substance can business be buied, or prepares by literature method as well known to those skilled in the art.The substituent character that final compound is required is depended in the selection that should be understood that concrete synthetic method.The order of synthesis step can change, can working conditions and the known variables of preparation process prepare these compounds.

Term used herein " sex change encephalopathy (HIE) " should comprise cognitive disorder, dementia and the presenile dementia of unknown cause.

Term used herein " cardiovascular disorder " should comprise blood lipid level rising, coronary atherosclerosis and coronary heart disease.

Term used herein " cerebrovascular disease " should comprise the abnormal and local ischemic brain injury of LCBF.

Term used herein " progesterone antagonist " should comprise mifepristone (RU-486), J-867 (Jenapharm/[AP Pharmaceuticals), J-956 (Jenapharm/TAP Pharmaceuticals), ORG-31710 (Organon), ORG-32638 (Organon), ORG-31806 (Organon), onapristone (ZK98299) and PRA248 (Wyeth).

Term used herein " conjoint therapy " refers to by giving one or more formulas I compound and progestogen or progesterone antagonist treats the patient who needs, wherein said formula I compound and progestogen and progesterone antagonist by applicable mode simultaneously, sequential, independently give or give in a kind of pharmaceutical preparation.At described formula I compound and progestogen and progesterone antagonist, with different formulations, give in situation, the administration number of times of every kind of compound every day can be identical or different.Described formula I compound and progestogen or progesterone antagonist can be by identical or different route of administration administrations.That the example of suitable medication includes but not limited to is oral, intravenously (iv), intramuscular (im), subcutaneous (sc), transdermal or rectum.Compound directly can be administered to neural system, include but not limited to that brain is interior, indoor, route of administration in Intraventricular, sheath, in brain pond, in backbone and/or around backbone, in the encephalic by with or without pumping unit or backbone, syringe needle and/or conduit carry out administration.Can be according to simultaneously or alternate scheme, simultaneously or at different time, during the course for the treatment of, in different or same formulation, give described formula I compound and progestogen or progesterone antagonist.

Therefore, the compound of general formula of the present invention (I) can be prepared by following scheme.

In an embodiment of the invention, the compound of general formula (I) is prepared by scheme 1.

Scheme 1

As shown in scheme 1, under triethylamine exists, Compound I is reacted with vinylformic acid, generates Compound I I.Compound I I further reacts with oxalyl chloride and generate compound III under stannic chloride catalysis.There is condensation reaction in III and dimethyl oxalate, generate compound IV under the catalysis of sodium alkoxide.Acetic acid is solvent, compound IV and hydrazine hydrate reacting generating compound V.V, through hydrolysis, generates compound VI.VI reacts generation general formula VII compound with suitable amine again.

General formula VII compound and acetic anhydride generate acetylized compound VIII.

The compounds of this invention can be used for treating and/or preventing the disease relevant to estrogen deficiency (including but not limited to hot flush, vagina drying, the minimizing of bone amount, osteoporosis, hyperlipidemia, cognitive function forfeiture, sex change encephalopathy (HIE), cardiovascular disorder, cerebrovascular disease); Can be used for treating hormone-sensitive cancer and hyperplasia (in the tissue of prostate gland that comprises women's mammary gland, uterine endometrium and uterine cervix and the male sex); Can be used for treatment and prevention endometriosis, hysteromyoma and osteoarthritis; And can be separately or with progestogen or progesterone antagonist coupling as contraceptive bian.

The concrete dosage of the compounds of this invention and concrete formulation should determine according to particular case.Precise dosage and route of administration are preferably determined by attending doctor.The typical per daily dose of the compounds of this invention should comprise the non-toxic dosage of 0.001mg-800mg/ days.Preferably per daily dose is about 0.001mg-60mg/ days conventionally.This dosage is single administration or be divided into separately administration of twice or three times as required.

Embodiment:

Describe in the following embodiments the present invention in detail, these embodiment are only exemplary, thereby should not be construed as scope of the present invention.The present invention is only subject to the restriction of appended claims.

Preparation Example

Embodiment 1:

1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-phenylpiperazine (compound number 1) (compound number 1)

The preparation of steps A: 3-(thiophene-2-sulfenyl) propionic acid (II)

In 100mL round-bottomed flask, add 4.64g 2-mercapto-thiophene (I), 40mL tetrahydrofuran (THF), the lower 11mL of dropping of stirring triethylamine, reaction solution is orange muddiness.Continue to add 3.3mL vinylformic acid, reaction solution becomes clarification from orange muddiness.Reflux 12h, reaction solution is from the orange yellow that becomes, then from yellow, become blackish green.React complete, boil off tetrahydrofuran (THF).Cooling, add ethyl acetate, water (2: 1) 40mL, 18% hydrochloric acid is adjusted to pH=2, gets organic layer, and water layer is extracted with ethyl acetate (50mL * 3).Merge organic layer.With anhydrous magnesium sulfate drying 2 hours.Suction filtration, gets filtrate and boils off solvent.Cooling, separate out brown solid.Add 100mL acetone recrystallization, obtain white needles solid chemical compound (II), 5.10 grams of output, yield 67.1%.

Step B: the preparation of thieno-[2,3-b] thiapyran-4-ketone (III)

In 100mL round-bottomed flask, add 3.76g 3-(thiophene-2-sulfenyl) propionic acid (II), 20mL methylene dichloride, 5 DMF; under nitrogen protection; dichloromethane solution (oxalyl chloride 2.2mL, the methylene dichloride 16mL) reaction solution that drips oxalyl chloride is yellow clarification.Stirring at room 1h.Reaction solution is bathed and is cooled to-10 ℃ with cryosel, drip dichloromethane solution (tin tetrachloride 1.15mL, the methylene dichloride 10mL) solution of tin tetrachloride.After dripping off, stir 0.5h at 0 ℃, it is yellow muddy that reaction solution is.Add after 20mL water, reaction solution is yellow clarification.Separatory, gets organic phase.After placing, solution becomes pink from yellow.Twice of dichloromethane extraction (20mL * 2) for water.Merge organic phase.Organic phase is used saturated solution of sodium carbonate (20mL * 2), water (20mL * 2), sodium chloride saturated solution (20mL * 1) washing successively.Anhydrous magnesium sulfate drying two hours.Liquid pinkiness.Suction filtration, boils off solvent, cooling crude product, the crude product yield > 99% of obtaining.Acetone recrystallization, obtains white needles solid (III), output 2.19g, productive rate 64.41%.

The preparation of step C:4-oxo thieno-[2,3-b] thiapyran-3-carboxylate methyl ester (IV)

The preparation of sodium methylate: 0.7g sodium is cut into sodium bits, adds 20mL anhydrous methanol, be back to sodium solids disappeared, revolve and boil off methyl alcohol, obtain white solid.To the toluene solution that adds 2.36g dimethyl oxalate, 20mL toluene, thieno-[2,3-b] thiapyran-4-ketone (III) 1.70g in reaction flask.Reaction solution is orange.Stirring at room 24h, reaction solution becomes yellow muddy.By in reaction solution impouring 100mL frozen water, separatory water intaking layer.By organic phase in 20mL anhydrous diethyl ether washing water layer, with 18% dilute hydrochloric acid acidifying water layer, obtain yellow solid.Suction filtration obtains crude product.Acetone recrystallization obtains 1.0 grams of yellow needle-like crystals (IV).Yield 43.86%.

Step D:1, the also also preparation of [4,3-c] pyrazoles-3-carboxylate methyl ester (V) of [3 ', 2 ': 5,6] thiapyran of 4-dihydro-thiophene

In 100mL round-bottomed flask, add 0.5g 4-oxo thieno-[2,3-b] thiapyran-3-carboxylate methyl ester (IV), add 10mL Glacial acetic acid, under stirring, add 2mL hydrazine hydrate, reflux 10h, pours reaction flask in 200mL frozen water into and stirs, occur white solid, suction filtration obtains crude product.Add acetone recrystallization, obtain white solid (V) 0.64g.Yield is 63.2%.

The preparation of step e: 1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-phenylpiperazine (compound number 1)

In 100mL round-bottomed flask, add also [3 ', 2 ': 5,6] thiapyran also [4 of 0.5g Isosorbide-5-Nitrae-dihydro-thiophene, 3-c] pyrazoles-3-carboxylate methyl ester (V), add 10mL methyl alcohol, under stirring, add 0.32g 1-php,, there is white solid in reflux 12h, suction filtration obtains crude product.With acetone recrystallization, obtain white solid (VI) 0.50g.Yield is 67.0%.

Embodiment 2:

1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-phenylpiperazine (compound number 36)

The preparation of step F: 1-(6-ethanoyl-Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-phenylpiperazine (compound number 36).

In the dichloromethane solution that contains 0.50g 1-(Isosorbide-5-Nitrae-dihydro-thiophene also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-phenylpiperazine (compound number 1), add 0.14g acetic anhydride., there is yellow mercury oxide in stirring at room 12h, suction filtration obtains crude product.With acetone recrystallization, obtain yellow solid (compound 36) 0.34g. yield 61.5%

Adopt embodiment 1 to prepare 1-35 compound, adopt embodiment 2 to prepare 36-70 compound.Following table (table 1) has shown the characterization data of the compounds of this invention.

Table 1

Pharmacology embodiment

Embodiment 3:

The quick plate of estrogen receptor alpha is measured

The combination of this mensuration detection of radioactive labels oestrogenic hormon and estrogen receptor.This mensuration is carried out on BioMek2000 (Beckman).Plate is at the upper reading of scintillometer (Packard Topcount), and counting reduces explanation compound and described receptors bind.Described mensuration is according to Allan etc., Anal.Biochem (1999), and the method that 275 (2), 243-247 introduces is carried out.

First day, in each hole with the crosslinked 96 hole FlashPlate Plus plates of goat anti-mouse antibody (NEN Life Sciences), add 100 μ L to contain 5mM dithiothreitol (DTT) (DTT, Panvera), 0.5 μ g mouse irritation element acceptor monoclonal antibody (SRA-1010, Stressgen) and the oestrogenic hormon of 50ng Purification of Human estrogen receptor alpha (Panvera) screening damping fluid (ESB, Panvera).Seal this plate and in 4 ℃ of incubated overnight.

Second day, at room temperature wash three times with 200 μ L PBS pH7.2 in each hole, and then to adding 98 μ L radio-labeling oestrogenic hormon in each hole, (0.5nM, is equivalent to 6nCi for every crowd of 120Ci/mmol, Amersham), with ESB and 5mM dithiothreitol (DTT) (DTT) dilution.Then in each hole, add the test compound of 30% (v/v) methyl-sulphoxide/50mM HEPES pH7.5 dilution for 2.5 μ L.By suction, beat each hole is mixed three times, seal this plate and be at room temperature incubated 1 hour.Then in Topcount scintillometer (Packard), each hole is counted 1 minute.

Embodiment 4:

Erss fluorescence polarization determination

This mensuration detects the combination of oestrogenic hormon fluorescence analogue (Fluormone ES2, Panvera) and estrogen receptor.Plate can be set as the upper reading of the luminescent counter of polarization mode (Packard TopCount).With respect to solvent contrast, fluorescence reduces explanation compound and described receptors bind.

It is essential, in whole process, avoid bubble to introduce in the reaction in each hole of 96 orifice plates.(the bubble destruction optical throughput of reaction surface, thereby polarisation-affecting reading).Yet fully mixing is also vital after reactive component is joined to each hole.

At the 2X standard mixture of formation determination damping fluid (Panvera), 10nM DTT and 40nM ES2 on ice.At the also 2X reaction mixture of formation determination damping fluid (Panvera) and 20nM hER-β (Panvera) and 40nM ES2 on ice.

The diluent of preparing test compound with 30% (v/v) methyl-sulphoxide/50mM HEPES pH 7.5.Now, described diluent is the required final concentration of 40X.

Then in each hole, add 50 μ L standard mixtures.In porose to institute, add 48 μ L reaction mixtures.To adding diluted chemical compound liquid described in 2.5 μ L in appropriate well.Volumetric pipette mixes described reaction mixture by hand, and a rolls of aluminum foil adhesive faces is covered on this plate, then this plate is at room temperature incubated to 1 hour.

Then on LjL Analyst, read the reading in this each hole of plate under excitation wavelength 265nm and emission wavelength 538nm.

According to the method described above, test the combination of representative compound of the present invention and estrogen receptor alpha and erss, the results are shown in table 2:

Table 2

Numbering estrogen receptor alpha (μ M) erss (μ M)

1 0.382 0.004

2 0.018 0.272

3 3.275 2.167

4 1.002 3.898

5 0.001 0.248

6 0.173 0.073

7 0.004 0.002

8 1.820 3.892

9 0.054 0.083

10 0.873 1.865

11 2.876 0.008

12 0.018 0.654

13 ＞10K ＞10K

14 0.672 0.875

15 3.872 6.984

16 0.053 5.345

17 0.843 4.285

18 0.005 0.034

19 1.098 0.002

20 1.084 2.762

21 4.382 0.098

22 3.892 3.603

23 0.003 0.006

24 5.892 2.904

25 3.224 2.531

26 0.432 0.034

27 0.004 0.347

28 5.893 2.891

29 ＞10K 2.467

30 2.473 0.054

31 3.871 0.006

32 0.681 4.871

33 3.822 0.004

34 0.012 0.064

35 2.366 1.899

36 ＞10K ＞10K

37 3.225 6.351

38 0.003 0.005

39 0.002 0.004

40 0.001 0.007

41 0.115 0.223

42 0.006 0.007

43 0.014 0.016

44 0.146 0.144

45 0.324 0.254

46 0.244 0.325

47 1.392 5.981

48 5.342 6.932

49 0.002 0.005

50 0.004 0.005

51 0.024 0.045

52 0.052 0.068

53 0.033 0.081

54 3.942 6.932

55 1.452 3.759

56 2.485 3.975

57 0.002 0.005

58 1.004 1.034

59 5.342 4.932

60 0.004 0.006

61 2.432 4.953

62 5.982 ＞10K

63 0.508 0.604

64 1.006 0.006

65 0.673 0.846

66 3.868 6.734

67 9.547 3.244

68 0.456 5.876

69 0.006 0.554

70 0.474 0.470

Embodiment 5:

MCF-7 cell proliferating determining

According to Welshons etc. (Breast Cancet Res.Treat., 1987,10 (2), the method for 169-75) introducing, carries out this mensuration.

MCF-7 cell is maintained to RPMI 1640 without in phenol red medium (Gibco), and described substratum contains 10%FBS (Hyclone), supplements Sigma I8405 and non-essential amino acid (Sigma).First described cell uses 4-hydroxyl tamoxifen (10 ^-8m) process, then allow it standing 24 hours in 37 ℃.Carrying out after this insulation with tamoxifen, described cell is processed with the compound of different concns.

To the testing compound that adds the agonist pattern of different concns in described substratum.The pending compound of preparing equally antagonist pattern also adds 10nM 17 beta estradiols in described substratum.Described cell is incubated to 24 hours in 37 ℃.After insulation, in described substratum, add 0.1 μ Ci ¹⁴c-thymidine (56mCi/mmol, Amersham), is incubated 24 hours in 37 ℃ again by described cell.Then described cell uses (Gibco) washed twice of HankShi buffer salt solution (HBSS), then with scintillometer, counts.With respect to solvent compared with control cells, with the cell 14C-thymidine increase of described compound treatment, be reported as cell proliferation increase percentage.

Measure according to the method described above representative compound of the present invention, the results are shown in table 3:

Table 3

Numbering agonist (nM) antagonist (nM)

1 2400 ＞10K

2 ＞10K ＞10K

3 ＞10K ＞10K

4 87 ＞10K

5 ＞10K 6.98

6 ＞10K 543

7 432 649

8 ＞10K 540

9 ＞10K 3690

10 ＞10K 493

11 ＞10K 573

12 ＞10K 9900

13 ＞10K 5710

14 ＞10K 565

15 ＞10K 2900

16 ＞10K 4900

17 457 4720

18 ＞10K ＞10K

19 ＞1oK ＞10K

20 ＞10K 440

21 ＞10K 43

22 ＞10K 780

23 ＞10K 3200

24 ＞10K 879

25 58 500

26 402 5930

27 ＞10K 45

28 ＞10K 230

29 ＞10K 450

30 ＞10K 1200

31 ＞10K 110

32 ＞10K 290

33 ＞10K 5400

34 ＞10K 754

35 ＞10K ＞10K

36 302 ＞10K

37 ＞10K 580

38 ＞10K 120

39 65.3 4500

40 800 440

41 ＞10K 32

42 ＞10K 569

43 ＞10K 409

44 ＞10K 551

45 ＞10K 32

46 ＞10K 904

47 ＞10K ＞10K

48 ＞10K 3900

49 ＞10K 210

50 ＞10K 680

51 ＞10K 76

52 ＞10K 305

53 ＞10K 710

54 ＞10K 44

55 ＞10K 715

56 ＞10K 79

57 ＞10K ＞10K

58 ＞10K ＞10K

59 ＞10K ＞10K

60 ＞10K 39

61 ＞10K 452

62 ＞10K 2400

63 ＞10K 450

64 ＞10K ＞10K

65 ＞10K ＞10K

66 NA 490

67 ＞10K 561

68 ＞10K 1600

69 ＞10K ＞10K

70 ＞10K ＞10K

NA is illustrated in and activity under experimental concentration, do not detected.

Embodiment 6

The alkaline phosphatase assay of people's uterine endometrium Ishikawa cell

According to Albert etc., Cancer Res, (9910), the method that 50 (11), 330-6-10 introduces is carried out this mensuration.

The DMEM/F12 (1: 1) that Ishikawa cell is maintained to supplementary 10% calf serum (Hyclone) is without in phenol red medium (Gibco).Test first 24 hours, by substratum be replaced by containing 2% calf serum without phenol red DMEM/F12 (1: 1).

To the testing compound that adds the agonist pattern of different concns in described substratum.The pending compound of preparing equally antagonist pattern also adds 10nM 17 beta estradiols in described substratum.Described cell is incubated to 3 days in 37 ℃.At the 3rd day, remove substratum, to each Kong Zhongxian, add the 1X dilution buffer liquid (Clontech) of 1 times of volume, add the mensuration damping fluid (Clontech) of 1 times of volume.Then described cell is at room temperature incubated to 5 minutes.(final concentration of CSPD is 1.25mM for the chemical luminous substrate of 1 times of volume (CSPD), the chemiluminescence intensifier of 19 times of volumes to add the chemoluminescence damping fluid of the fresh preparation of 1 times of volume; SigmaChemical Co.) described cell is at room temperature incubated to 10 minutes, then on luminometer, carries out quantitatively.With respect to solvent contrast, with chemoluminescence, increase the enhancing of calculating alkaline phosphatase activities.

According to the method described above, test representative compound of the present invention, the results are shown in table 4

Table 4

Numbering agonist (nM) antagonist (nM)

1 ＞10K ＞10K

2 230 ＞10K

3 ＞10K ＞10K

4 ＞10K ＞10K

5 95 23

6 ＞10K 340

7 ＞10K 30

8 ＞10K 50

9 400 320

10 790 ＞10K

11 ＞10K ＞10K

12 ＞10K ＞10K

13 ＞10K 43

14 ＞10K ＞10K

15 300 ＞10K

16 ＞10K ＞10K

17 ＞10K 54

18 ＞10K 3490

19 540 3200

20 ＞10K 43

21 ＞10K 67

22 110 53

23 ＞10K 98

24 ＞10K ＞10K

25 ＞10K ＞10K

26 ＞10K ＞10K

27 ＞10K 590

28 ＞10K ＞10K

29 ＞10K ＞10K

30 ＞10K ＞10K

31 ＞10K 86

32 ＞10K ＞10K

33 ＞10K ＞10K

34 ＞10K ＞10K

35 ＞10K ＞10K

36 ＞10K 440

37 ＞10K ＞10K

38 ＞10K ＞10K

39 ＞10K 990

40 ＞10K ＞10K

41 ＞10K 39

42 ＞10K ＞10K

43 ＞10K ＞10K

44 ＞10K 58

45 ＞10K ＞10K

46 ＞10K ＞10K

47 ＞10K 45

48 ＞10K ＞10K

49 ＞10K ＞10K

50 ＞10K 590

51 ＞10K 300

52 ＞10K ＞10K

53 ＞10K ＞10K

54 ＞10K ＞10K

55 ＞10K ＞10K

56 ＞10K ＞10K

57 ＞10K 46

58 ＞10K ＞10K

59 ＞10K ＞10K

60 ＞10K 5300

61 ＞10K ＞10K

62 ＞10K ＞10K

63 ＞10K 820

64 ＞10K ＞10K

65 ＞10K ＞10K

66 ＞10K ＞10K

67 ＞10K 4390

68 ＞10K ＞10K

69 ＞10K ＞10K

70 ＞10K ＞10K

Embodiment 7: the effect to IL-6 in HOB cell and GM-CSF production

In 96 hole wares, make it at conventional H OB substratum (HamShi F12 on human body osteoclast HOB bed board, be supplemented with 28mM HEPES, Ph7.4,10%FCS, 1.1mMCaCl2,2mM glutamine and 1% microbiotic-anti-mycotic agent) in density be 7 * 103 cells/well.Next day, cell is processed 30 minutes by compound or vehicle treated (0.2%DMSO), adds subsequently IL-1 β (1ng/mL) and TNF-α (10ng/mL).Cultivate and continue 18 to 24 hours.Utilize IL-6 and GM-CSF level in commercially available ELISA kit measurement substratum.The compounds of this invention demonstrates the restraining effect to IL-6 and GM-CSF.

Measure according to the method described above part representative compound of the present invention, the results are shown in table 5 (n=2):

Table 5

Embodiment 8: the effect to IL-6 in HOB cell and GM-CSF production

In 96 hole wares, make it at conventional H OB substratum (HamShi F12 on human body osteoclast HOB bed board, be supplemented with 28mM HEPES, Ph7.4,10%FCS, 1.1mM CaCl2,2mM glutamine and 1% microbiotic-anti-mycotic agent) in density be 7 * 103 cells/well.Next day, cell is processed 30 minutes by compound or vehicle treated (0.2%DMSO), adds subsequently IL-1 β (1ng/mL) and TNF-α (10ng/mL).Cultivate and continue 18 to 24 hours.Utilize IL-6 and GM-CSF level in commercially available ELISA kit measurement substratum.The compounds of this invention demonstrates the restraining effect to IL-6 and GM-CSF

Measure according to the method described above part representative compound of the present invention, the results are shown in table 6 (n=2):

Table 6

Embodiment 9: the effect to Proliferation of ovarian cancer cell SKOV 3

Logarithmic phase cell, with after trysinization, adds people's 96 well culture plates with 6 * 103/porocyte number, puts in 37 ℃, 5%CO2 incubator and cultivates, and within the 2nd day, treats 4 ℃ of thermostat container 1h of the adherent rearmounted people of most cells, to facilitate cell synchronization growth.Suck supernatant liquor, add people containing 10% newborn calf serum (FCS) RPMI1640 nutrient solution, 200 μ L/ holes, divide into groups by experimental design.The compound injection liquid of stroke-physiological saline solution preparation is added in 96 Zhong，Mei holes, hole and adds 200 μ L, make the drug level in every hole be respectively 1mg/mL, 2mg/mL and 5mg/mI, with the negative control group of 0mg/mL.Continue after cultivation 24,48,72h, each hole adds respectively people's 20 μ LMTT solution (concentration is 5mg/mL), light shaking culture plate, put back to and in incubator, hatch again 4h, then exhaust supernatant liquor, in each hole, add methyl-sulphoxide 200 μ L, put and on oscillator, shake 5-10min, with enzyme mark photometer, measure the light absorption value (A=580) that every hole medium wavelength is 580nm, A=580 value is directly proportional to viable cell quantity.

Measure according to the method described above part representative compound of the present invention, the results are shown in table 7 (n=3):

Table 7

Embodiment 10: the effect to osteosarcoma U 2OS-EGFP-4A 12G propagation

Logarithmic phase cell is with after trysinization, trypan blue counting, be mixed with the cell suspension that cell density is 1 * 104/mL, be inoculated in 96 orifice plates, every hole 200 μ L, approximately 2 * 103, every hole cell, preculture 24h, adds the compound injection liquid of stroke-physiological saline solution preparation in 96 Zhong，Mei holes, hole and adds 200 μ L, make the drug level in every hole be respectively 1mg/mL, 2mg/mL and 5mg/mI, with the negative control group of 0mg/mL.After cultivating respectively 0h, 12h, 24h and 48h, every hole adds MTT solution (5mg/mL) 20 μ L, continues to hatch 4h, stops cultivating.Careful suction abandoned the supernatant liquor in culture hole, and every hole adds the dimethyl sulfoxide (DMSO) (DMSO) of 150 μ L, concussion 10min, make the cured abundant dissolving of first, select 490nm wavelength, on enzyme-linked immunosorbent assay instrument, measure each hole absorbance value (A value), duplicate detection 5 times.

Measure according to the method described above part representative compound of the present invention, the results are shown in table 8:

Table 8

FORMULATION EXAMPLE

Following FORMULATION EXAMPLE only illustrates protection scope of the present invention, but forms and limit never in any form.

Embodiment 11: gelatine capsule

The preparation of hard gelatin capsule adopts:

Can improve above-mentioned preparation according to provided reasonable change.

Embodiment 12: tablet

The preparation of tablet adopts

Said components is mixed and be pressed into tablet.

Embodiment 13: tablet

The tablet that contains 2.5-1000mg active ingredient in every is prepared as follows:

Make activeconstituents, starch and Mierocrystalline cellulose by No. 45 mesh sieves of the U.S. and thoroughly mix.Polyvinylpyrrolidonesolution solution is mixed with gained powder, with by No. 14 mesh sieves of the U.S..By the particle generating No. 18 mesh sieves of the dry Bing Jing U.S. at 50-60 ℃.The Xylo-Mucine, Magnesium Stearate and the talcum powder that pass through in advance No. 60 mesh sieves of the U.S. are joined in above-mentioned particle, mix subsequently, on tabletting machine, compacting obtains tablet.

Embodiment 14: suspension

The suspension that every 5ml contains 0.1-1000ma medicine is prepared as follows:

Make medicine through No. 45 mesh sieves of the U.S. and be mixed to form level and smooth paste with Xylo-Mucine and syrup.Benzoic acid solution, correctives and tinting material are also under agitation added to aforesaid paste with some water dilutions.Add subsequently enough water to reach required volume.

Embodiment 15: combined tablet-preparation

For above-mentioned explanation, those skilled in the art can easily understand essential feature of the present invention, do not deviate from the spirit and scope of the present invention, and the present invention can carry out various changes and improvements to adapt to different application and condition.

Claims

1. 1,4-Dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carboxylic acid derivatives selected from:

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-phenylpiperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(4-methoxybenzene base) piperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(3-chloro-2- Methylphenyl)piperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(2-chloro-4- Methylphenyl)piperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(4-chlorophenyl) Piperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-[(4-chlorophenyl ) phenyl] methyl) piperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(3-chloro-4- Methylphenyl)piperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(benzhydryl)piper Zinc;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(4-methylphenyl )Piperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(3-chlorophenyl) Piperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(3-trifluoromethoxy phenyl)piperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(2-chlorophenyl) Piperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(3-chloro-4- Fluorophenyl)piperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-formyl)-4-(2-methylphenyl )Piperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(4-ethoxybenzene base) piperazine;

1-(1,4-Dihydrothieno[3’,2’:5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-methylpiperazine;

N-[2-(Diethylamino)ethyl]-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carba amides;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(2,5-dimethyl phenyl)piperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(2,3-dimethyl phenyl)piperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(2,6-dimethyl phenyl)piperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(4-trifluoromethoxy phenyl)piperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(4-trifluoromethyl Phenyl)piperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(1-phenylethyl) Piperazine;

N-tert-butyl-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carboxamide;

1-(1,4-Dihydrothieno[3’,2’:5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-tert-butylpiperazine;

N-(1-phenethyl)-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carboxamide;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(3-methylphenyl )Piperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(1-naphthyl)piper Zinc;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-cyclopropylpiperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-benzylpiperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(4-fluorophenyl) Piperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(3-fluorophenyl) Piperazine;

N-[2-(4-morpholinyl)ethyl]-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3- Formamide;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(2-fluorophenyl) Piperazine;

1-(1,4-Dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-n-hexylpiperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-phenyl Piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(4 -methoxyphenyl)piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(3 -Chloro-2-methylphenyl)piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(2 -Chloro-4-methylphenyl)piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(4 -chlorophenyl)piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-formyl)-4-(( 4-chlorophenyl)phenyl)methyl)piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(3 -Chloro-4-methylphenyl)piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-diphenyl Methylpiperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(4 -methylphenyl)piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(3 -chlorophenyl)piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(3 -trifluoromethoxyphenyl)piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(2 -chlorophenyl)piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(3 -Chloro-4-fluorophenyl)piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(2 -methylphenyl)piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(4 -ethoxyphenyl)piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-methyl Piperazine;

N-[2-(Diethylamino)ethyl]-6-acetyl-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyridine Azole-3-carboxamide;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(2 ,5-Dimethylphenyl)piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(2 ,3-Dimethylphenyl)piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(2 ,6-Dimethylphenyl)piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(4 -trifluoromethoxyphenyl)piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(4 -trifluoromethylphenyl)piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(1 - phenethyl)piperazine;

N-tert-butyl-6-acetyl-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carboxamide;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-tert-butyl Basepiperazine;

N-(1-phenethyl)-6-acetyl-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carba amides;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(3 -methylphenyl)piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(1 -naphthyl)piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-cyclopropane Basepiperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-benzo Basepiperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(4 -fluorophenyl)piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(3 -fluorophenyl)piperazine;

N-[2-(4-morpholinyl)ethyl]-6-acetyl-1,4-dihydrothieno[3',2':5,6]thiopyrano[4,3-c] Pyrazole-3-carboxamide;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(2 -fluorophenyl)piperazine;

1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-n-hexyl Piperazine.

2. A pharmaceutical composition, it comprises the compound described in claim 1 of treatment effective amount and pharmaceutically acceptable carrier, diluent or excipient.

3. the application of the compound described in any one of claim 1-2 or the composition described in claim 2 in the medicine of the preparation treatment by estrogen receptor-mediated disease.

4. application according to claim 3, is characterized in that, gives the compound described in claim 1 or the composition described in claim 2 of effective amount.

5. application according to claim 3, is characterized in that, described disease mediated by estrogen receptor comprises hot flashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia, cognitive function Loss, degenerative encephalopathy, cardiovascular disease, cerebrovascular disease, breast tissue cancer, breast tissue hyperplasia, endometrial cancer, endometrial hyperplasia, cervical cancer, cervical hyperplasia, prostate cancer, prostatic hyperplasia, endometriosis bit, uterine fibroids and contraception.

6. application according to claim 4, it is characterized in that, combine with the compound described in claim 1 or the composition described in claim 2 and a kind of progesterone or a kind of progesterone antagonist of therapeutically effective amount Prepare birth control pills.