Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
  • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J75/00—Processes for the preparation of steroids in general

Definitions

• R and R can be the same or different and represent radicals selected from the group consisting of hydrogen, lower alkyl and the acyl radical of an organic carboxylic acid having from 1 to 18 carbon atoms.
• Another object of the invention is the development of processes for the preparation of the new estradiol derivatives.
• a further object of the invention is the development of a process for the improvement of estrogenic deficiency at the situs of the vaginal epithelium which comprises the administration of a safe but eifective amount of an estradiol derivative of the formula:
• R and R can be the same or different and represent radicals selected from the group consisting of hydrogen, lower alkyl and the acyl radical of an organic carboxylic acid having from 1 to 18 carbon atoms.
• a still further object of the invention is to prepare a composition having an estrogenic action on the vaginal epithelium consisting of an estradiol derivative 'of the formula:
• R and R can be the same or different and repre sent radicals selected from the group consisting of hydrogen, lower alkyl and the acyl radical of an organic carboxylic acid having from 1 to 18 carbon atoms, and a non-toxic vehicle.
• R and R can be the same or different and represent radicals selected from the group consisting of hydrogen, lower alkyl and the acyl radical of an organic carboxylic acid having from 1 to 18 carbon atoms, can be produced by heating a compound of the formula:
• R has the above assigned meanings in an inert organic solvent in the presence of a catalyst 'having a 3 action in admixture with some of the naturally occurring estradiol.
• 9fi-estradiol may be recovered from the mixed isomers by taking advantage of the property of the 175- benzoate of estradiol to form with isopropyl ether a solvate which is sparsely soluble in isopropyl ether. By this recovery process the natural isomer is removed and the 17fl-benzoate of 9fi-estradiol is recovered from the solvent by customary procedures.
• the process of the invention is advantageously exe cuted by using as the starting compound 19-nor-/9[3/,/ Nod-testosterone which can be named 19-nor-A -/9,8/, 10a/androsterene-17fl-ol-3-one.
• esters with organic carboxylic acids having from 1 to 18 carbon atoms such as the alkanoates and alkenoates, for example, the acetate, the trimethylacetate, the propionate, the 4,4-dimethyl-pentanoate, the IO-undecenoate; the cycloalkylalkanoates, for example, the fi-cyclopentylpropionate; the arylalkanoates, for example, the phenylpropionate; the cycloalkanoates, for example, the hexahydrobenzoate, the hexahydroterephthalate and other phenyl-carboxylic acids as well as its lower alkyl ethers may also be used without departing from the scope of the invention.
• the alkanoates and alkenoates for example, the acetate, the trimethylacetate, the propionate, the 4,4-dimethyl-pentanoate, the IO-undecenoate
• the dehydrogenation step is preferentially conducted in the presence of an anhydrous lower alkanol suchras ethanol as the inert organic solvent at the reflux temperature in an inert atmosphere utilizing a dehydrogenation catalyst based on palladium.
• an anhydrous lower alkanol suchras ethanol
• the palladium catalyst in the form of palladium hydroxide deposited and supported on an alkaline reacting compound such as, for example, magnesia.
• an ester of 19-nor-/9 ⁇ 3/,/mod-testosterone preferably the benzoic acid ester described in United States patent application Serial No. 111,499, noW United States Pate ent No. 3,138,617. leads directly to the l7B-benzoate ester of 9fi-estnadiol in admixture with small amounts of the benzoate of estradiol.
• the desired product can be recovered as outlined above.
• R" is selected from the group consisting of lower alkyl and the acyl radical of an organic carboxylic acid having from 1 to 18 carbon atoms, other than the benzoyl radical.
• esters of 9,8-estradiol the invention comprises particularly the esters in the 17-position, such as the acetate, the pivalate, the cyclopentylpropionate, the benzoate, the hexahydrobenzoate, etc.
• the ethereal phases were combined and brought to dryness.
• the dry residue was essentially composed of the 17,8-benzoate of 9B-estradiol.
• the crude product was triturated with ether at room temperature, then placed in a refrigerator.
• the precipitate was vacuum filtered, washed with iced ether and the ethereal phases were separated.
• the residue weighing 1.02 g. was dried.
• a product slightly colored a light yellow-beige was obtained, melting at 220 C., and insoluble in ether. This was dissolved in 15 cc. of refluxing methanol, treated with carbon black and filtered.
• the spent carbon black was washed in boiling methanol.
• the methanol phases were combined, concentrated to 10 cc., 1.5 cc. of water was added, iced for one hour at 0 C., and vacuum filtered.
• the precipitate was dried.
• esters By reacting this compound with acid chlorides such as those of acetic acid, pivalic acid, cyclopentylpropionic acid, benzoic acid, hexahydrobenzoic acid, etc. in the presence of pyridine, the corresponding esters can be obtained.
• acid chlorides such as those of acetic acid, pivalic acid, cyclopentylpropionic acid, benzoic acid, hexahydrobenzoic acid, etc. in the presence of pyridine
• the 9B-estradiol, its esters and its ethers can be used for its effect on the vaginal epithelium where a simultaneous eifect on other organs ordinarily effected by estrogenic therapy is not desired.
• the 9fi-estr-adiol, its esters and its ethers' are administered orally, perlingually, transcutaneously or locally by a topical application on the skin and mucous membanes, or by rectal or vaginal methods.
• the product can be utilized in the form of extracts, of injectable solutions prepared with the usual adjuuctives, in ampules, in multiple-dose flacons, and in prepared injection syringes, in the form of implants, of tablets, of glossettes, of suppositories, of ovules and of pomades.
• the dosology is controlled between 25 'y/kg. and 2 mg./ kg. per day in the warm-blooded animal as a function of the method of administration.
• the pharmaceutical forms such as injectable solutions and suspensions, tabit lets, glossettes, suppositories, ovules and pomades are prepared according to the usual procedures.
• This test of estrogenic activity was made on lots of female rats, weighing about 200 grams. The female rats were castrated and tested three weeks thereafter by a single subcutaneous injection of 1 g. of estradiol benzoate. After a rest of three weeks, the-female rats, whose sensitivity to the estrogen was found to be normal, were divided into lots and treated with the experimental products. Vaginal smears were made every day at the same hour. Only those smears formed exclusively of keratinized cells were reported as positive.
• estradiol administered at one time gave a positive response in 50-- 75% of the cases.
• 9B-estradiol must be injected at a total dose of 750 g. at one time to give the same result.
• the ratio of the active doses of estradiol to 9p-estradiol is 1 to 150.
• the morphological aspect of the uterus and of the vagina is characteristic of this state.
• the uterus is more developed than in diestrus or in metaestrus; the motility of the musculature is increased; the chorion is oedematosed and the cylindrical endornetral epithelium shows basal nucleation; the multistratified vaginal epithelium casts off from its orifice its kerationized superficial layers by exfoliation.
• R and R can be different and represent radicals selected from the group consisting of hydrogen, lower alkyl and the acyl radical of an organic carboxylic acid having from 1 to 18 carbon atoms selected from the group consisting of alkanoic acids, alkenoic acids, cycloalkylalkanoic acids, phenyl-alkanoic acids, cycloalkanoic acids and phenyl carboxylic acids.
• estradiol derivatives selected from the group consisting of wherein R and R can be different and represent radicals selected from the group consisting of hydrogen, lower alkyl and the acyl radical of an organic carboxylic acid having from 1 to 18 carbon atoms selected from the group consisting of alkanoic acids, alkenoic acids, cycloalkylalkanoic acids, phenyl-alkanoic acids, cycloalkanoic acids and phenyl carboxylic acids which comprises the steps of heating a compound of the formula:
• R has the above assigned meanings, in an inert organic solvent in the presence of a catalyst having a palladium base, and recovering said estradiol derivatives.
• a process for the promotion of an estrogenic response on the vaginal epithelium substantially free of an estrogenic response on other sites which comprises the administration to warm-blooded animals of between 25 7/ kg. and 2 mg./kg. per day of an estradiol derivative of the formula:

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Steroid Compounds (AREA)

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Cited By (17)

• 1961
  • 1961-05-04 FR FR860746A patent/FR1368727A/fr not_active Expired
  • 1961-08-02 FR FR869787A patent/FR1444M/fr active Active
• 1964
  • 1964-07-30 US US386370A patent/US3198707A/en not_active Expired - Lifetime

Non-Patent Citations (1)

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