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
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • 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 present invention relates to 11 ⁇ -substituted 14,17-ethanoestratrienes of the general formula I.
• R 1 represents a hydrogen atom, a C 1 -C 12 alkanoyl, a benzoyl, a straight or branched chain C 1 -C 12 alkyl, a C 3 -C 7 cycloalkyl or a C 4 - C 8 -alkylcycloalkyl group
• R 2 for a hydrogen atom or a C 1 -C 12 alkanoyl group
• R 3 for a grouping stand, where n is 0, 1 or 2 and R 4 and R 5 independently of one another
• Hydrogen atom or a straight-chain or branched C 1 -C 8 -alkyl group which may also be partially fluorinated, mean a process for their preparation, pharmaceutical preparations containing these compounds, and their use for the production of medicaments.
• R 1 and / or R 2 stands for an alkanoyl group, primarily an acetyl or propionyl group is intended; for R 1 in the meaning of an alkyl group, the methyl or ethyl group are particularly suitable.
• R 1 and / or R 2 stands for an alkanoyl group, primarily an acetyl or propionyl group is intended; for R 1 in the meaning of an alkyl group, the methyl or ethyl group are particularly suitable.
• R 1 is, for example, the cyclopropyl, cyclopentyl and
• the partially fluorinated alkyl groups R 4 and R 5 are primarily 2,2,3,3,4,4,4-heptafluorobutyl and 4,4,5,5,5-pentafluoropentyl.
• EP-A 0 138504 Steroidal antiestrogens which are essentially free of a residual estrogenic effect (pure antiestrogens) are disclosed in EP-A 0 138504 and EP 0384842. From the multitude of substances described in EP-A 0 138504
• the compounds of general formula I according to the invention have a particularly high degree of similarity to the estrogen receptor and, when administered orally, are pure antiestrogens with a very strong antiestrogenic effect.
• the compounds according to the invention are therefore suitable for the therapy of
• estrogen-dependent diseases for example anvulatory mertility
• Prostatic hyperplasia breast cancer, endometrial cancer and melanoma.
• the daily dose for the treatment of the diseases mentioned is typically
• a dose unit contains 5 to 500 mg of one or more compounds of the general formula I.
• the compounds according to the invention are suitable for the production of pharmaceutical compositions and preparations
• compositions or medicaments contain one or more of the inventive substances as active ingredient.
• Compounds optionally in a mixture with other pharmacologically or pharmaceutically active substances.
• the pharmaceuticals are produced in a known manner, the known and customary pharmaceutical auxiliaries and other customary carriers and
• Diluents can be used.
• auxiliaries include, for example, those which are recommended or indicated in the following references as auxiliaries for pharmacy, cosmetics and related fields: Ullmans Encyklopadie der Technische Chemie, Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 ff., H. v. Czetsch-Lindenwald, auxiliaries for pharmacy and neighboring areas; Pharm. Ind., Issue 2, 1961, page 72 u. ff .: Dr. H. P. Fiedler, Lexicon of auxiliaries for pharmacy, cosmetics and related
• the compounds can be administered orally or parenterally, for example intraperitoneally, intramuscularly, subcutaneously or percutaneously.
• the connections can also be implanted into the tissue. The amount to be administered
• Compound fluctuates within a wide range and can cover any effective amount.
• the amount of the compound administered can be 0.01-100 mg / kg body weight, preferably 0.1-20 mg / kg body weight, per day.
• the dosage units can contain a pharmaceutically acceptable carrier, such as, for example, starch, sugar, sorbitol, gelatin, lubricant, silica, talc, etc.
• a pharmaceutically acceptable carrier such as, for example, starch, sugar, sorbitol, gelatin, lubricant, silica, talc, etc.
• the active ingredients can be dissolved or suspended in a physiologically acceptable diluent.
• a physiologically acceptable diluent Oils with or without the addition of a solubilizer, a surface-active agent, a suspending or emulsifying agent are very often used as diluents Games for oils used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.
• the compounds can also be in the form of a depot injection or
• Implant preparations that can be formulated so that a delayed release of the active ingredient is made possible.
• Implants can contain, for example, biodegradable polymers as inert materials or synthetic silicones such as silicone rubber.
• Active ingredients can also be incorporated into a plaster for percutaneous application, for example.
• R 3 has the meanings given in formula I.
• the flavoring is carried out with an acid halide / acid anhydride.
• Lithium aluminum hydride or similar reducing agents are also carried out by conventional methods.
• R 4 represents a partially fluorinated alkyl group
• MgX- (CH 2 ) 9 - (CH 2 ) n + 1 -OL wherein X is a chlorine, bromine or iodine atom, L is a hydroxy protecting group such as the tertiary-butyl-dimethylsilyl group and n is 0, 1 or 2 or MgX- (CH 2 ) 9 -SR 4 , in which X has the meaning given above and R 4 has the meaning given in formula I.
• the 4,9-diene-3-one structure is then established by treating the Grignard addition product in a moderately acidic medium (for example in a mixture of tetrahydrofuran and semi-concentrated acetic acid), the terminal hydroxyl protective group L which may be present also being split off. If desired, the ⁇ -hydroxy group can then be oxidized to the corresponding carboxylic acid by conventional methods (e.g. with Jones' reagent). The ⁇ -hydroxy group or carboxyl group is then terminated with an amine
• this sulfide must also be oxidized to give the corresponding sulfoxide -SR 4 , for example with sodium periodate, in order to obtain a compound of the general formula.
• magnesium shavings are placed in 70 ml of tetrahydrofuran and with a solution of 108 g of 11-bromundecyl tertiary butyldimethylsilyl ether in 140 ml
• Tetrahydrofuran added within 1.5 h. After 1 h at 40 ° C, the mixture is cooled to 0 ° C, 1.3 g of copper (I) chloride are added, the mixture is stirred at 0 ° C for 0.5 h, a solution of 10 g of 3.3- (2.2- Dimethyltrimethylenedioxy) -5 ⁇ , 10 ⁇ -epoxy-14,17-ethanoestr-9 (11) - en-17-ol (Scholz, S. et al. Liebigs Ann. Chem., (1989), p. 151 (13b)) added dropwise in 80 ml of tetrahydrofuran and stirring was continued at 0 ° C. for 0.5 h. A saturated ammonium chloride solution is then added, and the mixture is stirred at 0 ° C. for 0.25 h
• This crude product is stirred in 10 ml of a 1 normal methanolic potassium hydroxide solution for 1 h at 25 ° C. Then it is neutralized with in hydrochloric acid, concentrated in vacuo on water, extracted four times with dichloromethane, washed with brine, dried over sodium sulfate, concentrated in vacuo to dryness and Chromatographed on silica gel with dichloromethane / acetone.
• This crude amide is stirred in 10 ml of a 1 normal methanolic potassium hydroxide solution at 25 ° C. for 1 h.
• the mixture is then neutralized with in hydrochloric acid, concentrated in vacuo, poured onto water, extracted four times with dichloromethane, washed with brine, dried over sodium sulfate, concentrated to dryness in vacuo and chromatographed on silica gel with dichloromethane / acetone.
• the 4,4,5,5,5-pentafluoropentyl-1-thioacetate thus obtained is stirred with 100 ml of a 2N sodium hydroxide solution at 100 ° C.
• magnesium shavings are placed in 6 ml of tetrahydrofuran and with a solution of 10 g of 9-bromo-nonyl-4,4,5,5,5-pentafluoropentyl sulfide in 14 ml
• Tetrahydrofuran added within 1.5 h After 1 h at 40 ° C., the mixture is cooled to 0 ° C., 0.13 g of copper (I) chloride is added, and the mixture is stirred at 0 ° C. for 0.5 h, a solution of 1.0 g 3 , 3- (2,2-Dimethyltrimethylenedioxy) -5 ⁇ , 10 ⁇ -epoxy-14,17-ethanoestr-9 (11) - en-5 ⁇ , 17 ⁇ -diol (Scholz, S. et al. Liebigs Ann. Chem., (1989 ), P.
• the crude sulfide is stirred in 7 ml of tetrahydrofuran with 8 ml of glacial acetic acid and 4 ml of water for 1.5 h at a bath temperature of 50 ° C. Then it is diluted with ethyl acetate, washed four times with sodium hydrogen carbonate and brine, dried over sodium sulfate, concentrated in vacuo to dryness in 15 ml of methanol dissolved, treated with 440 mg sodium periodate, diluted with ethyl acetate, four times with
• This crude product is stirred in 10 ml of a 1 normal methanolic potassium hydroxide solution at 25 ° C. for 1 h. Then it is neutralized with in hydrochloric acid, concentrated in vacuo, poured into water, extracted four times with dichloromethane, washed with brine, dried over sodium sulfate, concentrated to dryness in vacuo and chromatographed on silica gel with dichloromethane / acetone.
• the 11- (14,17-ethano-3,17-dihydroxyestra-1,3,5 (10) -trien-11 ⁇ -yl) -decanoic acid is used instead of 11-bromundecyl tertiarybutyldimethylsilyl ether by using 10-bromodecyl tertiary butyldimethylsilyl ether - (N-methyl-N-isopropyl) -amide obtained as colorless crystals with a melting point of 112-4 ° C.
• the 11- (14,17-ethano-3,17-dihydroxyestra-1,3,5 (10) -trien-11 ⁇ -yl) is used instead of 11-bromundecyl tertiary butyldimethylsilyl ether by using 12-bromo-dodecyl tert-butyldimethylsilyl ether.
• -decanoic acid- (N-methyl-N-isopropyl) -amide obtained as colorless crystals with a melting point of 107-9 ° C.
• the compound of Example 4 can also be prepared according to the invention as described below:

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• Steroid Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Hydrogenated Pyridines (AREA)
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• 1991
  • 1991-09-24 DE DE4132182A patent/DE4132182A1/de not_active Withdrawn
• 1992
  • 1992-09-24 DE DE59207687T patent/DE59207687D1/de not_active Expired - Lifetime
  • 1992-09-24 US US08/211,173 patent/US5502046A/en not_active Expired - Fee Related
  • 1992-09-24 DK DK92920370.1T patent/DK0642529T3/da active
  • 1992-09-24 ES ES92920370T patent/ES2097924T3/es not_active Expired - Lifetime
  • 1992-09-24 EP EP92920370A patent/EP0642529B1/de not_active Expired - Lifetime
  • 1992-09-24 JP JP5505804A patent/JPH07501792A/ja active Pending
  • 1992-09-24 WO PCT/EP1992/002210 patent/WO1993006124A1/de not_active Ceased
  • 1992-09-24 CA CA002119780A patent/CA2119780A1/en not_active Abandoned
  • 1992-09-24 AT AT92920370T patent/ATE146185T1/de not_active IP Right Cessation
  • 1992-09-24 EP EP92203021A patent/EP0546591A2/de active Pending
• 1997
  • 1997-02-27 GR GR970400373T patent/GR3022692T3/el unknown

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