WO2005105823A1 - Derives steroidiens - Google Patents

Derives steroidiens Download PDF

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Publication number
WO2005105823A1
WO2005105823A1 PCT/CN2005/000287 CN2005000287W WO2005105823A1 WO 2005105823 A1 WO2005105823 A1 WO 2005105823A1 CN 2005000287 W CN2005000287 W CN 2005000287W WO 2005105823 A1 WO2005105823 A1 WO 2005105823A1
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WO
WIPO (PCT)
Prior art keywords
reaction
estrogen
compound
fulvestrant
carbon atoms
Prior art date
Application number
PCT/CN2005/000287
Other languages
English (en)
Chinese (zh)
Inventor
Huijuan Zhong
Aifeng Lv
Original Assignee
Jiangsu Hansen Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jiangsu Hansen Pharmaceutical Co., Ltd. filed Critical Jiangsu Hansen Pharmaceutical Co., Ltd.
Publication of WO2005105823A1 publication Critical patent/WO2005105823A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens

Definitions

  • the invention relates to a body derivative, and the obtained product can be used as a medicine to treat female breast cancer. Background technique
  • Breast cancer is one of the major diseases affecting women's health worldwide. Once breast cancer is formed, it is a systemic disease. Cancer cells continuously fall off from the primary tumor and enter the blood and lymph fluid circulation. Even in the early stage, there may be micrometastases in the body. Breast cancer patients have a survival rate of 64% and 46% by 5 and 10 years even after surgical resection.
  • the reported drugs for breast cancer treatment are mainly concentrated in three aspects: chemical treatment drugs, endocrine treatment drugs, and body immune drugs.
  • endocrine therapy drugs play an important role in breast cancer drug treatment through anti-estrogen and other effects, and it has been reported to reduce annual mortality by 25%.
  • adjuvant treatment with drugs reduces postoperative mortality.
  • high mortality rates still indicate an increased need for treatment and prevention of breast cancer.
  • European patent EP 0138504 A discloses a series of steroidal compounds, in which the compound fulvestrant (fluvestrant, 7 ⁇ -[9- (4, 4, 5, 5, 5-pentafluoropentylsulfonyl) nonyl] female Steroid-1, 3, 5 (10) triene-3-, 17 ⁇ -diol) as anti-estrogen drugs have very good therapeutic effects on breast cancer.
  • Fulvestrant has estrogen antagonist activity, and its affinity for estrogen receptors is similar to that of estradiol. It completely blocks the growth-stimulating effect of estradiol on human breast cancer cells in vitro.
  • fulvestrant's anti-estrogen efficacy is stronger than many existing anti-estrogen drugs.
  • fulvestrant and estrogen receptors have 100 times the affinity of tamoxifen.
  • fulvestrant has far fewer side effects than similar drugs. It does not cause similar estrogen-like effects on uterine tissues and osteoporosis of other similar anti-estrogen drugs.
  • the estrogen effects on uterine tissues are dangerous for women in treatment, and it easily causes endometrial cancer happened.
  • Fulvestrant with good efficacy and less side effects means a major breakthrough in breast cancer treatment.
  • CN 1431905 A discloses the application of the drug in treating breast cancer patients who have failed drugs such as aromatase inhibitors
  • CN 1394141 A, US 5183814 A, etc. disclose formulations that improve the use of the drug .
  • US 5204337 A provides a compound with a structure similar to fulvestrant. This compound introduces a new group into the side chain at position 9 and halogen modification at position 16. However, it has not been found that the compound of this structure has the same activity as fulvestrant and its side effects are significantly less than fulvestrant. Therefore, how to reduce the side effects of fulvestrant on the human body without affecting the treatment effect is still a matter of concern at present.
  • the present invention provides a novel compound and a medicament having the same therapeutic effect as fulvestrant and lower side effects by modifying and screening the compound structure. Summary of the invention
  • the present invention provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof,
  • R1 is a straight or branched alkyl group of 1 to 6 carbon atoms, or a straight or branched fluorenyl group of 1 to 6 carbon atoms substituted by a halogen atom; the halogen atom is a fluorine atom, a chlorine atom, a bromine atom And iodine atom, preferably R1 is a straight or branched fluorenyl group of 1-4 carbon atoms, or a straight or branched alkyl group of 1-4 carbon atoms substituted by a halogen atom, R1 is preferably ethyl, Propyl and fluoroethyl, particularly preferably R1 is ethyl.
  • the compounds provided by the present invention have the same or similar therapeutic effects as fulvestrant, but the toxic and side effects are less than fulvestrant. Therefore, the compounds provided by the present invention can provide those which cannot be treated with fulvestrant due to side effects. Important help for patients.
  • the compound of the present application Since the compound of the present application has the same therapeutic effect as fulvestrant, it also has a high affinity for the estrogen receptor, and exhibits pure estrogen antagonist activity without estrogen-like activity. Therefore, the compound of the present application can block the stimulation effect of estrogen-estradiol on estrogen receptor in vivo by high affinity with estrogen receptor, and is used for treating diseases caused by estrogen abnormality, especially breast cancer. treatment. It can be seen from pharmacological experiments that the compounds of the present application can completely replace fulvestrant in the treatment of anti-breast cancer, and can simultaneously reduce the side effects of fulvestrant, providing a new way for the treatment of breast cancer.
  • another aspect of the present invention provides a pharmaceutical composition containing the above compound and a pharmaceutically acceptable carrier, and the use of the compound to prepare a medicament, which medicament treats a disease caused by an estrogen abnormality, preferably breast cancer.
  • the compound (I II) refers to an organic reagent, and particularly to a Grignard reagent.
  • z refers to a leaving group, and the usual leaving group refers to a halogen atom, mesylate and p-toluenesulfonate.
  • the leaving group Z refers to a metal halide, and the molecular formula is R2 -M, where M is a metal ion and R2 is a halogen atom.
  • M refers to metals such as magnesium, zinc, aluminum, and titanium, and magnesium is preferred; R2 refers to chlorine, bromine, and iodine, and bromine is preferred.
  • a cuprous salt is used as a catalyst, such as cuprous halide and cuprous cyanide.
  • the present invention is preferably cuprous chloride.
  • the solvent used in the reaction is ether, preferably tetrahydrofuran.
  • the reaction temperature is from -50-0 °. C, preferably -40--30 ° C.
  • This step is performed in an acidic environment.
  • the acids used are inorganic or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, and trifluoroacetic acid, and acetic acid and hydrochloric acid are preferred.
  • the solvents used in the reaction are polar solvents such as water, methanol, and ethanol. Water is preferred; in addition, in order to increase the solubility of the raw materials, a suitable solvent such as tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, etc. is selected, and tetrahydrofuran is preferred; the temperature of the reaction is controlled at 20-80 ° C, preferably 40-50 ° C.
  • a copper salt such as copper bromide is added to a solvent formed by the intermediate (4) and an organic solvent such as acetonitrile.
  • an alkali metal halide such as lithium bromide is added to the reaction to promote the solubility of copper bromide and reduce the amount of solvent; the reaction temperature is controlled at 40-80
  • V is preferably about 60 ° C.
  • Intermediate (6) is obtained by nucleophilic substitution reaction between intermediate (5) and thiolate.
  • the thiolate is obtained by the reaction of a thiol and a strong base.
  • the strong base used is sodium, sodium hydrogen (60% -80%), sodium amide, potassium, sodium methoxide, potassium t-butoxide, sodium ethoxide, etc., sodium is preferred Hydrogen (60% -80%);
  • the solvents used in the reaction are tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, etc., preferably tetrahydrofuran;
  • the reaction temperature is controlled at -10-20 ° C, preferably-5- 0 ° C;
  • nucleophilic substitution reaction temperature is controlled at 0- 50 ° C, preferably 0-20 ° C;
  • the reaction time is controlled at 1 to 4 hours, preferably 1.5 hours.
  • the oxidation reaction uses the conventional method for oxidizing sulfide to sulfoxide:
  • the selected oxidants are hydrogen peroxide, peracid (such as m-chloroperoxybenzoic acid, peroxyacetic acid), sodium periodate, etc., preferably hydrogen peroxide.
  • sodium periodate in order to avoid excessive oxidation, a suitable amount of oxidant should be selected, preferably 1-2 times the amount of oxidant; the reaction temperature is controlled at 0-50 ° C, preferably 20-25 ° C. detailed description
  • intermediate (2) (25g), glacial acetic acid (150ml), water (75ml) and tetrahydrofuran (130ml) into a 1L reaction flask, stir and heat to 50 ° C for 3 hours, and concentrate under reduced pressure to near Dry, add ethyl acetate (500 ml) and water (200 ml) to the residue, separate the layers, and extract the aqueous layer back with ethyl acetate (200 ml * 2). Combine the organic layers and use a saturated sodium bicarbonate solution in this order. (150 ml * 2), water (200 ml) and brine (200 ml * 2), washed, dried, filtered and concentrated to dryness to obtain intermediate (3): 18 g (light yellow oil).
  • Example 1 5 S. C 5 3 22 62 ⁇ 11 98 + 1.7 soil 79.
  • RTV relative tumor volume (V n / V fl )
  • T / C Antitumor activity evaluation index (test group RTV / control group RTV)
  • Fulvestrant can significantly inhibit the growth of estrogen-dependent human breast cancer MCF-7 nude mice .
  • the compounds of the present invention also have good inhibitory effects on tumors. In terms of toxicity, the compounds of the present invention are relatively less toxic.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention concerne des composés représentés par la formule générale (I) et leurs sels. Dans cette formule générale, R1 désigne un alkyle à chaîne droite ou ramifiée comprenant 1-4 atomes de carbone ou un alkyle à chaîne droite ou ramifiée à substitution halogène, l'halogène utilisé étant du fluor, du chlore, du brome ou de l'iode. Ces composés permettent de traiter le cancer du sein.
PCT/CN2005/000287 2004-04-28 2005-03-09 Derives steroidiens WO2005105823A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200410037524.4 2004-04-28
CNB2004100375244A CN100395259C (zh) 2004-04-28 2004-04-28 甾体类衍生物

Publications (1)

Publication Number Publication Date
WO2005105823A1 true WO2005105823A1 (fr) 2005-11-10

Family

ID=35241620

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2005/000287 WO2005105823A1 (fr) 2004-04-28 2005-03-09 Derives steroidiens

Country Status (2)

Country Link
CN (1) CN100395259C (fr)
WO (1) WO2005105823A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20150143842A (ko) * 2013-04-18 2015-12-23 시안 리방 파마슈티컬 테크놀로지 컴퍼니 리미티드 항암 활성을 갖는 7-α-[9-(4,4,5,5,5-펜타플루오로펜틸설피닐)노닐]-에스트라-1,3,5(10)-트리엔-3,17β-디올의 에스테르 유도체 및 그의 제조 방법
US20160038439A1 (en) * 2013-04-18 2016-02-11 Xi'anlibang Pharmaceutical Technology Co., Ltd. Use of 7-a-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-estra-1,3,5(10)- triene-3,17B-diol and derivatives thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111116428B (zh) * 2018-11-01 2023-09-15 江苏豪森药业集团有限公司 制备氟维司群的方法和中间体
CN111662356A (zh) * 2019-03-06 2020-09-15 正大天晴药业集团股份有限公司 一种氟维司群的杂质控制方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0138504A2 (fr) * 1983-10-12 1985-04-24 Imperial Chemical Industries Plc Derivés de stéroides
US5204337A (en) * 1988-10-31 1993-04-20 Endorecherche Inc. Estrogen nucleus derivatives for use in inhibition of sex steroid activity

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0138504A2 (fr) * 1983-10-12 1985-04-24 Imperial Chemical Industries Plc Derivés de stéroides
US5204337A (en) * 1988-10-31 1993-04-20 Endorecherche Inc. Estrogen nucleus derivatives for use in inhibition of sex steroid activity

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20150143842A (ko) * 2013-04-18 2015-12-23 시안 리방 파마슈티컬 테크놀로지 컴퍼니 리미티드 항암 활성을 갖는 7-α-[9-(4,4,5,5,5-펜타플루오로펜틸설피닐)노닐]-에스트라-1,3,5(10)-트리엔-3,17β-디올의 에스테르 유도체 및 그의 제조 방법
US20160038439A1 (en) * 2013-04-18 2016-02-11 Xi'anlibang Pharmaceutical Technology Co., Ltd. Use of 7-a-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-estra-1,3,5(10)- triene-3,17B-diol and derivatives thereof
JP2016517849A (ja) * 2013-04-18 2016-06-20 シーアン リーバン ファーマシューティカル テクノロジー シーオー．， エルティーディー．Ｘｉ’Ａｎ Ｌｉｂａｎｇ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｔｅｃｈｎｏｌｏｇｙ Ｃｏ．， Ｌｔｄ． 抗腫瘍活性を有する７−α−［９−（４，４，５，５，５−ペンタフルオロペンチルスルフィニル）ノニル］−エストラ−１，３，５（１０）−トリエン−３，１７β−ジオールのエステル誘導体及びその調製方法
EP2987799A4 (fr) * 2013-04-18 2016-10-05 Xi An Libang Pharmaceutical Technology Co Ltd Dérivé ester du 7-alpha-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl] stra-1,3,5(10)-triène-3,17-bêta-diol possédant une activité antitumorale et procédé de préparation correspondant
JP2016539077A (ja) * 2013-04-18 2016-12-15 シーアン リーバン ファーマシューティカル テクノロジー シーオー．， エルティーディー．Ｘｉ’Ａｎ Ｌｉｂａｎｇ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｔｅｃｈｎｏｌｏｇｙ Ｃｏ．， Ｌｔｄ． ７−α−［９−（４，４，５，５，５−ペンタフルオロ−ペンチル−スルフィニル）ノニル］−エストラ−１，３，５（１０）−トリエン−３，１７β−ジオール及びその誘導体の使用
AU2013386732B2 (en) * 2013-04-18 2018-10-18 Xi'an Libang Pharmaceutical Technology Co., Ltd. Ester derivative of 7-alpha-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(10)-triene-3,17beta-diol having antitumour activity and preparation method thereof
AU2013386726B2 (en) * 2013-04-18 2019-08-01 Xi'an Libang Pharmaceutical Technology Co., Ltd. Use of 7-alpha-[9-(4,4,5,5,5 - pentafluoro-pentyl-sulfinyl)nonyl]-estra-1,3,5(10)-triene-3,17beta-diol and derivatives thereof
KR102046415B1 (ko) * 2013-04-18 2019-12-02 시안 리방 파마슈티컬 테크놀로지 컴퍼니 리미티드 항암 활성을 갖는 7-α-[9-(4,4,5,5,5-펜타플루오로펜틸설피닐)노닐]-에스트라-1,3,5(10)-트리엔-3,17β-디올의 에스테르 유도체 및 그의 제조 방법

Also Published As

Publication number Publication date
CN1690073A (zh) 2005-11-02
CN100395259C (zh) 2008-06-18

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