WO1998024803A1 - Steroidester, verfahren zu ihrer herstellung und ihre pharmazeutische verwendung - Google Patents
Steroidester, verfahren zu ihrer herstellung und ihre pharmazeutische verwendung Download PDFInfo
- Publication number
- WO1998024803A1 WO1998024803A1 PCT/EP1997/006829 EP9706829W WO9824803A1 WO 1998024803 A1 WO1998024803 A1 WO 1998024803A1 EP 9706829 W EP9706829 W EP 9706829W WO 9824803 A1 WO9824803 A1 WO 9824803A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hydroxy
- dihydro
- naphtho
- oxo
- llα
- Prior art date
Links
- 0 CC(C)C(CC1)(CC2)CC12C(OC(CC1)(CC2)CC12C=C[C@@]1(CC2)O[C@]1(C[C@@]1c(cc3)c(C4)cc3-c3ccc(*)cc3)C2C(CC2)C1C4(CC1)C2=CC1=O)=O Chemical compound CC(C)C(CC1)(CC2)CC12C(OC(CC1)(CC2)CC12C=C[C@@]1(CC2)O[C@]1(C[C@@]1c(cc3)c(C4)cc3-c3ccc(*)cc3)C2C(CC2)C1C4(CC1)C2=CC1=O)=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
- C07J53/002—Carbocyclic rings fused
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention relates to steroid esters, processes for their preparation and their use as auxiliaries for pharmacological studies and as medicinal substances.
- the invention relates to steroid esters of the formula I.
- DE-A 44 34 488 describes that the solubility of such compounds can be considerably improved if a free hydroxyl group is esterified or provided with an amide group at a suitable point in the molecule.
- the alkanoyloxy group of the ester grouping in the general formula shows in the structurally closest cases, ie in the case of a 3-keto-4-en-11 ⁇ , 19- [4- (4-sub-phenyl) -o-phenylene] steroid with 17 ⁇ -alk-l-enyl side chain at least 6 carbon atoms.
- 3-keto-4-en-11ß, 19- [4- (4-sub-phenyl) -o-phenylene] steroids with a 17-alk-l-enyl side chain with terminal hydroxyl function are in the EP A 0 283 428; the hydroxy group can be esterified with an acyl group having up to 4 carbon atoms. Special esters are not described.
- the invention further relates to processes for the preparation of steroid esters of the formula I, in which compounds of the formula II which carry a free hydroxyl group and in which m, X and the dashed line between the carbon atoms 15 and 16 have the meanings given in formula I, with an acid anhydride of formula IIC or an acid chloride of formula IV, wherein n is 0 or 1, esterified.
- the esterification takes place according to the methods familiar to the person skilled in the art, for example according to the procedure described in Example 1.
- solubility is significantly improved compared to the unesterified compound.
- the hydrolysis stability of the esters under strongly basic conditions can be as
- the animals are housed in Makrolon cages in controlled, exposed rooms (10 hours
- Standard diet (pelleted altromin) fed and soaked with tap water ad libitum.
- test substances are suspended in a carrier liquid (85 mg myrj in 100 ml 0.9% w / v sodium chloride solution) and the daily dose (see table) is administered orally in a volume of 0.5 ml.
- a carrier liquid 85 mg myrj in 100 ml 0.9% w / v sodium chloride solution
- the daily dose is administered orally in a volume of 0.5 ml.
- the rats are mated in the Proestrus; the beginning of pregnancy is marked by
- Pregnancy (dl p.c.) - determined. The animals are randomized and the individual
- test substance is administered daily from the 5th to the 7th day of pregnancy. Vaginal smears are taken on day 9 and the animals are killed with CO 2 gas. Evaluation: * ⁇
- the effect of the treatment is examined by inspection of the uterus.
- the regression of implants and pathological, hemorrhagic or otherwise abnormal nidation sites are counted as abortions.
- Reference compound 2 is (Z) -6 '- (4-cyanophenyl) -9, ll ⁇ - dihydro-17 ⁇ - [3- (3,3-dimethyl-l-oxobutoxy) -l-propenyl] -17ß-hydroxy-4 'H-naphtho [3', 2,, l: 10.9, ll] estr-4-en-3-one (example 7 in DE-a 44 34 488) extending only through an additional methyl group in Alkanoyl group of the ester differs from the compound 1 of the present application, as well as the already mentioned reference compound 3.
- NMU N-methyl-N-nitrosourea
- NMU-induced mammary tumor in the rat is largely dependent on estrogens and gestagens and less on prolactin. Estrogen and progesterone antagonists lead to an inhibition of tumor growth.
- mice Female rats (Sprague-Dawley), 55 ( ⁇ 3) days old; at least 9 animals per group.
- Test substance p.o.
- Vehicle volume p.o. 0.1 ml / 100g / d (0.9% NaCl / 0.085% Myrj-53).
- NMU iv 50 mg / kg / d; 1.5 ml / 200 g (0.9% NaCl / 0.085% Myrj-53).
- the animals receive a single 50 mg / kg NMU. The animals are then examined palpatory once a week for tumor development. Approximately One to more tumors per animal develop 6 to 8 weeks after NMU treatment. With a minimum size of 150 mm ⁇ / tumor / animal, the treatment (6 times a week) begins with the test substance, the determination of body weight and the tumor size (with the help of a caliper; 1 time per week).
- the breast cancer cell line ZR-75 is an estrogen- and progesterone-receptor-positive human line, which can be transplanted serially in the thymus-plastic nude mouse. She responds to the standard therapy of breast cancer in the clinic - tamoxifen - with an inhibition of growth.
- a sub-line used here developed tamoxifen resistance after a long therapy period.
- test substances are dissolved in benzyl benzoate and castor oil (1 + 4) and the single dose is applied in a volume of 0.1 ml sc. Therapy begins about 7 weeks after implantation (therapy of established tumors). The treatment time is max. 10 weeks. _ Test approach: * -
- the tumor fragments from several donor animals are s.c. on both sides in the
- mice are randomized 7 weeks after implantation of the tumors and the
- Tumor growth is determined by determining the area of the tumor using a caliper. The tumor area is calculated from the product of the longest and the perpendicular diameter of the tumor. At the end of the experiment, the animals are killed, the tumors prepared and weighed.
- the inhibition of the growth course of the tumors is shown graphically in the following figure for the compound from Example 1 in comparison to the untreated control group.
- the new compounds of the general formula I are therefore valuable pharmaceutical active ingredients. They have a strong affinity for the gestagen receptor and have strong anti-gestagen properties. This important biological activity can be used for medical purposes.
- the compounds according to the invention are very suitable for the treatment of hormone-dependent carcinomas.
- the compounds of the general formula I which are antigestagen active according to the invention can also be used with antiestrogenic compounds for the production of pharmaceutical preparations for the treatment of hormone-dependent tumors (EP-A 0 310 542), for induction of birth, for termination of pregnancy and for the treatment of gynecological disorders (EP-A 0 310 541 ) and for female contraception (WO 96/19997).
- the invention thus also relates to pharmaceuticals based on the pharmaceutically acceptable, i.e. in the doses used, non-toxic compounds of the general formula I, if appropriate in conjunction with an antiestrogen, together with the customary auxiliaries and carriers.
- the present invention also relates to the use of the compounds of the general formula I, optionally together with an antiestrogen, for the production of medicaments.
- the compounds according to the invention can be processed into pharmaceutical preparations for enteral, percutaneous, parenteral or local application according to known galenical methods. They can be in the form of tablets, coated tablets, gel capsules, granules, suppositories, implants, injectable sterile aqueous or oily solutions, suspensions or emulsions, ointments, creams and gels or by intravaginal (eg vaginal rings) or intrauterine systems (pessaries, spirals).
- intravaginal eg vaginal rings
- intrauterine systems pessaries, spirals.
- the active ingredient (s) can be combined with the auxiliary substances commonly used in galenics, e.g. Gum arabic, talc, starch, mannitol, methyl cellulose, lactose, surfactants such as tweens or myrj, magnesium stearate, aqueous or non-aqueous vehicles, paraffin derivatives, wetting, dispersing, emulsifying, preserving agents and flavoring agents for flavor correction (e.g. essential oils).
- auxiliary substances commonly used in galenics e.g. Gum arabic, talc, starch, mannitol, methyl cellulose, lactose, surfactants such as tweens or myrj, magnesium stearate, aqueous or non-aqueous vehicles, paraffin derivatives, wetting, dispersing, emulsifying, preserving agents and flavoring agents for flavor correction (e.g. essential oils).
- One dose unit contains about 0.1-100 mg of active ingredient (s).
- the dosage of the compounds according to the invention in humans is about 0.1-1000 mg per day.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU59838/98A AU5983898A (en) | 1996-12-06 | 1997-12-08 | Steroid esters, method for the manufacture thereof and their pharmaceutical use |
EP97954725A EP0942920B1 (de) | 1996-12-06 | 1997-12-08 | Steroidester, verfahren zu ihrer herstellung und ihre pharmazeutische verwendung |
DE59706268T DE59706268D1 (de) | 1996-12-06 | 1997-12-08 | Steroidester, verfahren zu ihrer herstellung und ihre pharmazeutische verwendung |
AT97954725T ATE212640T1 (de) | 1996-12-06 | 1997-12-08 | Steroidester, verfahren zu ihrer herstellung und ihre pharmazeutische verwendung |
JP52522098A JP2001505212A (ja) | 1996-12-06 | 1997-12-08 | ステロイドエステル、その製造方法及びその調剤学的使用 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19652408A DE19652408C2 (de) | 1996-12-06 | 1996-12-06 | Steroidester, Verfahren zu ihrer Herstellung und ihre Verwendung zur Herstellung von Arzneimitteln |
DE19652408.3 | 1996-12-06 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1998024803A1 true WO1998024803A1 (de) | 1998-06-11 |
WO1998024803A9 WO1998024803A9 (de) | 1998-10-08 |
Family
ID=7814943
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1997/006829 WO1998024803A1 (de) | 1996-12-06 | 1997-12-08 | Steroidester, verfahren zu ihrer herstellung und ihre pharmazeutische verwendung |
Country Status (10)
Country | Link |
---|---|
US (1) | US6096732A (de) |
EP (1) | EP0942920B1 (de) |
JP (1) | JP2001505212A (de) |
AR (1) | AR008706A1 (de) |
AT (1) | ATE212640T1 (de) |
AU (1) | AU5983898A (de) |
DE (2) | DE19652408C2 (de) |
TW (1) | TW427998B (de) |
WO (1) | WO1998024803A1 (de) |
ZA (1) | ZA9710972B (de) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011119194A1 (en) | 2010-03-22 | 2011-09-29 | Repros Therapeutics Inc. | Compositions and methods for non-toxic delivery of antiprogestins |
EP2974772A1 (de) | 2008-04-28 | 2016-01-20 | Repros Therapeutics Inc. | Progesteronantagonist cdb-4124 bei der behandlung von brustkrebs |
EP3263112A1 (de) | 2006-10-24 | 2018-01-03 | Repros Therapeutics Inc. | Zusammensetzungen und verfahren zum unterdrücken der endometrialen proliferation |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0283428A1 (de) * | 1987-03-18 | 1988-09-21 | Schering Aktiengesellschaft | 19,11beta-Überbrückte Steroide, deren Herstellung und diese enthaltende pharmazeutische Präparate |
DE4434488A1 (de) * | 1994-09-14 | 1996-03-21 | Schering Ag | Steroidester und -amide, Verfahren zu ihrer Herstellung und ihre pharmazeutische Verwendung |
WO1996019997A1 (de) * | 1994-12-23 | 1996-07-04 | Schering Aktiengesellschaft | Progesteronantagonistisch- und antiöstrogen wirksame verbindungen zur gemeinsamen verwendung für die weibliche kontrazeption |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3633244A1 (de) * | 1986-09-26 | 1988-03-31 | Schering Ag | Antigestagene zur hemmung der uterinen prostaglandinsynthese |
US5446178A (en) * | 1987-03-18 | 1995-08-29 | Schering Aktiengesellschaft | Process for preparing 19,11β-bridged steroids |
US5439913A (en) * | 1992-05-12 | 1995-08-08 | Schering Aktiengesellschaft | Contraception method using competitive progesterone antagonists and novel compounds useful therein |
DE4434448C2 (de) * | 1994-09-27 | 1996-10-17 | Richard Halm | Naßläufer-Spaltrohrmotor für Pumpen |
-
1996
- 1996-12-06 DE DE19652408A patent/DE19652408C2/de not_active Expired - Fee Related
-
1997
- 1997-12-05 AR ARP970105724A patent/AR008706A1/es not_active Application Discontinuation
- 1997-12-05 ZA ZA9710972A patent/ZA9710972B/xx unknown
- 1997-12-06 TW TW086118397A patent/TW427998B/zh not_active IP Right Cessation
- 1997-12-08 AU AU59838/98A patent/AU5983898A/en not_active Abandoned
- 1997-12-08 EP EP97954725A patent/EP0942920B1/de not_active Expired - Lifetime
- 1997-12-08 DE DE59706268T patent/DE59706268D1/de not_active Expired - Fee Related
- 1997-12-08 AT AT97954725T patent/ATE212640T1/de not_active IP Right Cessation
- 1997-12-08 US US08/986,592 patent/US6096732A/en not_active Expired - Fee Related
- 1997-12-08 JP JP52522098A patent/JP2001505212A/ja not_active Ceased
- 1997-12-08 WO PCT/EP1997/006829 patent/WO1998024803A1/de active IP Right Grant
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0283428A1 (de) * | 1987-03-18 | 1988-09-21 | Schering Aktiengesellschaft | 19,11beta-Überbrückte Steroide, deren Herstellung und diese enthaltende pharmazeutische Präparate |
DE4434488A1 (de) * | 1994-09-14 | 1996-03-21 | Schering Ag | Steroidester und -amide, Verfahren zu ihrer Herstellung und ihre pharmazeutische Verwendung |
WO1996019997A1 (de) * | 1994-12-23 | 1996-07-04 | Schering Aktiengesellschaft | Progesteronantagonistisch- und antiöstrogen wirksame verbindungen zur gemeinsamen verwendung für die weibliche kontrazeption |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3263112A1 (de) | 2006-10-24 | 2018-01-03 | Repros Therapeutics Inc. | Zusammensetzungen und verfahren zum unterdrücken der endometrialen proliferation |
EP3693376A1 (de) | 2006-10-24 | 2020-08-12 | Allergan Pharmaceuticals International Limited | Zusammensetzungen zur unterdrückung der endometriumproliferation |
EP2974772A1 (de) | 2008-04-28 | 2016-01-20 | Repros Therapeutics Inc. | Progesteronantagonist cdb-4124 bei der behandlung von brustkrebs |
WO2011119194A1 (en) | 2010-03-22 | 2011-09-29 | Repros Therapeutics Inc. | Compositions and methods for non-toxic delivery of antiprogestins |
EP3865502A1 (de) | 2010-03-22 | 2021-08-18 | Allergan Pharmaceuticals International Limited | Zusammensetzungen und verfahren zur nicht-toxischen verabreichung von cdb-2914 |
Also Published As
Publication number | Publication date |
---|---|
DE19652408C2 (de) | 2002-04-18 |
DE59706268D1 (de) | 2002-03-14 |
DE19652408A1 (de) | 1998-06-10 |
AU5983898A (en) | 1998-06-29 |
ZA9710972B (en) | 1998-06-15 |
TW427998B (en) | 2001-04-01 |
EP0942920A1 (de) | 1999-09-22 |
JP2001505212A (ja) | 2001-04-17 |
US6096732A (en) | 2000-08-01 |
ATE212640T1 (de) | 2002-02-15 |
EP0942920B1 (de) | 2002-01-30 |
AR008706A1 (es) | 2000-02-09 |
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