US3890356A - 7-Alkyl-{66 {hu 3,5{b -steroids - Google Patents

7-Alkyl-{66 {hu 3,5{b -steroids Download PDF

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US3890356A
US3890356A US344838A US34483873A US3890356A US 3890356 A US3890356 A US 3890356A US 344838 A US344838 A US 344838A US 34483873 A US34483873 A US 34483873A US 3890356 A US3890356 A US 3890356A
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dien
solution
alkyl
methyl
acetone
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US344838A
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Joyce F Grunwell
John O Johnston
Vladimir Petrow
Philip M Weintraub
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Richardson Vicks Inc
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Richardson Merrell Inc
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Priority to ZA00740932A priority patent/ZA74932B/en
Priority to AU65584/74A priority patent/AU6558474A/en
Priority to CA192,667A priority patent/CA1027929A/en
Priority to JP49028209A priority patent/JPS49126661A/ja
Priority to GB1236874A priority patent/GB1410294A/en
Priority to DE2413559A priority patent/DE2413559A1/en
Priority to FR7409975A priority patent/FR2223014A1/fr
Priority to BE142453A priority patent/BE812836A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J11/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 3
    • 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
    • C07J1/0003—Androstane derivatives
    • C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
    • 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
    • C07J1/0003—Androstane derivatives
    • C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
    • C07J1/0022—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
    • 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
    • C07J1/0003—Androstane derivatives
    • C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
    • C07J1/0022—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
    • C07J1/0029—Ethers
    • 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
    • C07J1/0003—Androstane derivatives
    • C07J1/0033—Androstane derivatives substituted in position 17 alfa and 17 beta
    • C07J1/0037—Androstane derivatives substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being a saturated hydrocarbon group
    • 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
    • C07J1/0051—Estrane derivatives
    • C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
    • C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
    • 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
    • C07J1/0051—Estrane derivatives
    • C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
    • C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
    • C07J1/0074—Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton

Definitions

  • follicle-stimulating hormone FSH
  • FSH follicle-stimulating hormone
  • the follicle also produces estrogen which stimulates the conversion of the uterine endometrium into a proliferative phase.
  • the ovum is released and the follicle is converted into a corpus luteum which in addition to estrogen now produces progesterone.
  • the ovum is released into the Fallopian tube and may be subsequently fertilized within a period of from 12 to 24 hours.
  • the fertilized ovum enters the uterus and by day 21 /2 to day 24 /2 the ovum or blastocyst nidates within the uterine lining and begins to implant.
  • This implantation process is completed with the establishment of the fetal-placental circulation which occurs at about day 35.
  • a proper estrogen-progesterone balance is required.
  • rapid placental development occurs, and by day 70 to day 75 the placenta produces all of the progesterone required to maintain pregnancy.
  • the removal of the corpus luteum prior to day 70 results in a rapid drop in progesterone levels and the expulsion of the uterine contents during a menstrual bleed.
  • the corpus luteum is removed 70 days after the onset of menstruation, pregnancy will continue.
  • This invention relates to new steroids, to their preparation and to their use as pharmaceutical agents. More particularly, the novel compounds of the present invention are 7-alkyl-A -unsaturated steroids useful as antiprogestational agents represented by the general formula:
  • R R R and R are each hydrogen or methyl
  • R is selected from the group consisting of hydrogen
  • R is lower alkyl having from I to 3 carbon atoms
  • R is selected from the group consisting of hydrogen, lower alkyl having from 1 to 6 carbon atoms, lower alkenyl and lower alkynyl having from 2 to 6 carbon atoms, lower alkenynyl and lower alkadiynyl having from 4 to 6 carbon atoms;
  • R is selected from the group consisting of hydrogen
  • R is selected from the group consisting of hydrogen
  • novel compounds of the present invention are prepared in solution from their corresponding 7-alkyl-4-en-3-ones, 7-alkyl-4-en-3-ols and 7-alkyl-5- en-3-ols using a variety of dehydrating reagents. halo/enolizing reagents and organolithium or Grignard reagents, and isolating the products therefrom.
  • This invention also relates to the discovery that the novel compounds described in formula (l), in addition to certain compounds described in the prior art, are
  • R R R and R are each hydrogen or methyl
  • R is selected from the group consisting of hydrogen
  • R is lower alkyl having from 1 to 3 carbon atoms
  • R is selected from the group consisting of hydrogen, lower alkyl having from 1 to 6 carbon atoms, lower alkenyl and lower alkynyl having from 2 to 6 carbon atoms, lower alkenynyl and lower alkadiynyl having from 4 to 6 carbon atoms;
  • R is selected from the group consisting of hydrogen
  • acyl having from 2 to 12 carbon atoms, 2- tetrahydropyranyl, trimethylsilyl, l-cycloalkenyl having from 5 to 8 carbon atoms, 1- methoxycycloalkyl and l-ethoxyeycloalkyl in which the cycloalkyl group has from 5 to 8 carbon atoms, and the groups R and OR when taken together are 0x0 or a cyclic acetal; and
  • R is selected from the group consisting of hydrogen
  • the novel compounds of the present invention all contain an alkyl substituent in the 7 -position of the steroid nucleus.
  • This substituent consists of either the methyl, ethyl, propyl or isopropyl groups and may be present in either the a or ,B-configuration as indicated by the wave-like bond at the point of attachment.
  • the compounds of the present invention also have unsaturation in common at both the 3 and 5-positions of the steroid nucleus. Consequently, all of these novel compounds can be named as either 7-alkyl-3,5- androstadienes. estradienes or gonadienes. It should be noted, however, that with respect to the 7-alkyl-3,5- estradienes, all must possess at least a mono-substituent in one of the 1,3,4 or 6-positions of the steroid nucleus, i.e., R R R and R cannot all be hydrogen.
  • the 3-position of the steroid nucleus is either unsubstituted or substituted with a halogen, aliphatic, phenyl or substituted phenyl group.
  • the usual halogen substituents at the 3-position include the chloro or bromo radieals.
  • the aliphatic group present at the 3-position comprises a lower alkyl group having from I to 4 carbon atoms and includes such groups as methyl, ethyl, propyl, butyl, isobutyl and t-butyl.
  • a phenyl group when present can be either unsubstituted or monosubstituted.
  • the substituents on the phenyl nucleus include such groups as halogen, as represented by fluorine, chlorine and bromine, or a hydroxyl, methyl and methoxy group.
  • halogen as represented by fluorine, chlorine and bromine
  • a hydroxyl, methyl and methoxy group Illustrative of compounds containing a substituted phenyl radical in the 3-position are: 7a ethyl-3-(4-methoxyphenyl)estra-3,5-dien-l7B-ol and 7a-ethyl-3-(3-chlorphenyl)androsta-3,5-dien-l7B-ol.
  • the compounds represented by formula (I) include derivatives in which the ll-position of the steroid nucleus, represented by the symbol R is either unsubstituted or is substituted with a hydroxy or an oxo group.
  • Illustrative of such compounds are: 7,8-methylandrosta- 3,5-dienl 7B-ol, 7/3-methylandrosta-3 ,S-diene-l 1,8, l7B-diol, 7B-methylandrosta-3,S-diene-1la, l7B-diol, and 7B-methylandrosta-3,5-diene-l l,l7-dione.
  • the compounds of the present invention can be either monosubstituted or disubstituted in the l7-position of the steroid nucleus, i.e., they may be l7B-and/or l7aderivatives.
  • the l7a-position may be either substituted or unsubstituted.
  • the compounds of this invention are substituted with either a saturated or an unsaturated aliphatic hydrocarbon chain having from I to 6 carbon atoms.
  • alkyl radicals straight or branched chain alkyl radicals, as for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isoamyl, n-pentyl and n-hexyl.
  • alkenyl groups which may be present are the vinyl, allyl, lbutenyl, l-pentenyl and l-hexenyl radicals.
  • alkynyl groups present are ethynyl, l-propynyl, l-butynyl, and l-hexynyl.
  • unsaturated conjugated hydrocarbon radicals present are the groups l,3-butenynyl, 1,3-pentenynyl, 1,3-butadiynyl and 2,4-hexadiynyl.
  • Substituents in the I7B-position include esters and ethers of the free alcohol.
  • R is hydrogen
  • the free alcohol is present, as for example, the compound la,7a-dimethylestra-3 ,S-dien-l 7,8-01.
  • the acyl esters which are present are derived from hydrocarbon acyl radicals having from 2 to 12 carbon atoms inclusively.
  • the organic acyl groups include those of saturated and unsaturated aliphatic acids and aromatic acids such as acetic, propionic, butyric, isobutyric, valeric, isovaleric, caproic, caprylic, decanoic,
  • the compounds of this invention also include certain l7B-ethers.
  • Such ethers include unsaturated cyeloalkane ethers having from 5 to 8 carbon atoms in which the unsaturation is present in a position alpha to the ether oxygen.
  • Illustrative ot such unsaturated ethers are the I-cyclopentene. I-cyclohexene or I-cyelooetene radicals.
  • the corresponding saturated cycloalkanes are also considered to be within the scope of this invention wherein the cycloalkane group is further substituted with either a methoxy or an ethoxy radical at its point of attachment.
  • Illustrative substituted cycloalkanc ethers include: 7a-ethyl-l7Bt l methoxyeyclopentyloxy)-estra-3.5-diene 7a-ethyl I 7B( I '-ethoxycyclohexyloxy )-estra-3.5-diene. 70!- methyl-I7fi( l '-methoxycycloheptyloxy)-estra-3,5- diene and 7a-methyI-I7B( l -ethoxycycltmctyloxy)- estra-3,5-diene.
  • the 178- class ol ethers also includes saturated heterocyelic ethers.
  • Both the I701 and l7B-positions may be combined to represent a ketone.
  • the compounds of this invention include I 1 and/or l7-ketones. as for example. 173- hydroxy. 'lfi-methylestra-Z.S-dien-l I-one. 7,8- methylcstra-3,S-dien-l7-one and 7/3-methylestra-3.5- diene-I l.l7-dione.
  • 1701 and l7B-positions may be taken together to form a I.3-dioxolane or other cyclic acetal.
  • Illustrative of such compounds are 7a-propylandrosta- 3,5-dien-I7-one cycie I7-(ethylene acetal) and 3- chlore-7oz-methyl-estra-B,S-dien-l7-one cyclic l7- (ethylene acetal).
  • a preferred group of compounds is obtained when the 3-position of the steroid nucleus contains a methyl substituent.
  • the 7-position contains a methyl group in the a-configuration and the l7a-position of the steroid nucleus remains unsubstituted. i.e.. R is methyl, R is a a-methyl and R is hydrogen.
  • R is methyl, R is a a-methyl and R is hydrogen.
  • R OR l lll wherein R R R,. R... R,.. R and R have the values previously assigned.
  • the compounds of the present invention are prepared by methods analogous to those in the art.
  • the 3- chIoro-3.5-dienes are prepared by reacting a A"-3-keto steroid with at least one equivalent of a chloro/enolizing agent such as phosphouous oxychloride.
  • a chloro/enolizing agent such as phosphouous oxychloride.
  • prosphorous pentachloride or oxalyl chloride generally in the presence of an acid catalyst such acetic acid, oxalic acid. p-toluene-sulfonic acid.
  • the Vilsmeier reagent phosphorous oxychloride in dimethylformamide. may be employed.
  • the reaction proceeds at temperatures ranging from about 0 to l()()C.. although temperatures near room temperature are preferred.
  • Suitable inert solvents include benzene, heptane, toluene. dimethylformamide and acetic acid.
  • the 3-bromo-3,5-dienes are prepared in a similar fashion substituting a bromo/enolizing agent such as phosphorous tribromide or oxalyl bromide in the above procedure.
  • the 3.5-dienes wherein R is hydrogen arc synthesized by elimination ofthe elements of water from a A- B-hydroxy or A -3-hydroxy steroid.
  • a A -3- hydroxy steroid is treated with an acid such as hydrochloric acid.
  • methanesulfonic acid, sulfuric acid or acetic acid is a solvent such as acetone.
  • Water may also be utilized as a co-solvent and the temperature can vary from about C. to the reflux temperature of the particular solvent employed.
  • halides of inorganic acids such as phosphorous oxy chloride and thionyl chloride in the presence of a tertiary amine such as triethylamine or pyridine may be utilized to effect these dehydrations in such solvents as ether, dioxane or tetrahydrofuran.
  • Basic reagents such as aluminum oxide are also successfully employed to effect dehydration.
  • the A -3-hydroxy steroids can be converted to the 3-tosylate .of 3-mesylate in the usual manner by treatment with p-toluenesulfonylchloride or methylsulfonylchloride in pyridine at 0C.
  • Elimination of the tosylate or mesylatc is effected with alkaline reagents in neutral solvents such as potassium t-butoxide in dimethylsulfoxide or lithium bromide and lithium carbonate in dimethylformamide.
  • neutral solvents such as potassium t-butoxide in dimethylsulfoxide or lithium bromide and lithium carbonate in dimethylformamide.
  • An ester residue can also be eliminated by pyrolysis from the 3-xanthate. phenylcarbamate, ethylcarbonate derivatives of A' -3- ols to produce the desired 3,5-dienes. Using these procedures 7a-ethyl-3,5-androstadiene-l 7,B-ol.
  • the preparation of the 3,5-dienes wherein R is lower alkyl or phenyl proceeds by treating the corresponding 4-en-3-one with an appropriate organometallic reagent, as for example, an organolithium reagent or a Grignard reagent.
  • organometallic reagent as for example, an organolithium reagent or a Grignard reagent.
  • Anhydrous solvents such as ether or tetrahydrofuran are generally employed.
  • the intermediate tertiary allylic alcohol which forms. is subsequently dehydrated to form the 3-alkyl or 3-phenyl-3,5-
  • allylic alcohol intermediate may also be directly dehydrated without isolation by addition of the Grignard reaction mixtureto an aqueous mineral acid orby heating with acidic alumina in a solvent such as aqueous alcohol.
  • the dehydration of the tertiary allylie alcohol may be affected by treatment with an acid halide and a tertiary base, as for example, phosphorus oxychloride andtriethylamine or pyridine, in inert solvent such as ether or dioxane.
  • an acid halide and a tertiary base as for example, phosphorus oxychloride andtriethylamine or pyridine, in inert solvent such as ether or dioxane.
  • the staring materials for the compounds of the present invention are 7-alkyl-4-en-3-ones, 7-alkyl-4-en-3- ols and 7-alkyl-5-en-3-ols. These compounds are best prepared from the corresponding 7-alkyl-5-en 3 ones available in good yield from the reaction of a ditlower alkyl) copper lithium with a 4,6-dien-3-one in an inert solvent such as ether. tetrahydrofuran, hexane or mixtures thereof at temperatures ranging from 78 to 25C.
  • the initially formed enolate anion is quenched by addition to a protonating agent such as saturated solution of ammonium chloride, oxalic acid or boric acid to provide the desired 7-alkyl-5-en-3-one.
  • the 7-alkyl-5-en-3-one is reduced to the 7-alkyl-5- en-3-ol by reducing agents such as sodium borohydride, lithium aluminum hydride and lithium tri-ttutoxyaluminum hydride by procedures well known to also betreducedby reagents such as lithium aluminum hydride, lithium tri-t-butoxy-aluminum hydride so- .dium borohydrideto form. the desired7-alkyl-4'en-3! .01.
  • reducing agents such as sodium borohydride, lithium aluminum hydride and lithium tri-ttutoxyaluminum hydride by procedures well known to also betreducedby reagents such as lithium aluminum hydride, lithium tri-t-butoxy-aluminum hydride so- .dium borohydrideto form.
  • The.halo-3,5-dienes are preferably prepared .from
  • the ketone can be reduced to the'al'cohol bymetallo-hydride reagents "such as lithium aluminum hydride or sodium borohydride.
  • the ketone can be alkylated to form a :l 7a-alkyl. alkenyLor alkynyl 17B-ol by reaction with an-appropriate organometallie;reagent. asrfor exampleumethylmagnesium bromide or propinyl llithium.
  • the free hydroxy group may be acylated by means of an acid hal ide or acid anhydride in the presence of a'tertiar y base such as pyridine.
  • Suitable acid moieties include acetic, .propionic, decanoic and cyclohexane darboxylie acids.
  • the tetrahydropyranyl ether is p'repared by the action of dihydropyran in the presence of an acid catalyst such as p-toluenesulfonic acid or pho:phoro'us oxychloride with a3',5-dienl7B-ol.
  • the l-alkoxycycloalkoxy derivatives of this invention are prepared by reaction of a'3,5-diehl7B-ol'with a loweralkylk etal of a cycloalkanone or the lower a]- 'kylen'olether of a cycloalkanone 'or a mixture of these in the'presence of an. acid catalyst preferably pyridine ptoluenesulfonate in solvents such as dioxane, tbutanol, or methylene chloride. Temperatures during the reaction can vary from about 20 to C. with the lower temperatures preferred.
  • Suitable cycloalkyl derivatives include, for example, cyclopentanone diethylketal and l-methoxy-l-cyclohexene.
  • the l-cycloalkenylethers are directly prepared. Suitable solvents include benzene and dimethylformamide.
  • the l-cycloalkenylethers are prepared by pyrolysis of the isolated l-alkoxycycloalkoxy steroid in the presence of a trace of an organic base such a pyridine in a high boiling solvent such toluene. benzene. dimethylformarnide.
  • the 3.5-dien-l7-ol is oxidized to the 3,5-dien-l7-one by means of the op- -penauer reaction or the Pfitzer-Moffatt procedure which utilizes dicyclohexylcarbodiimide, dimethylsulfoxide, pyridine and trifluoroacetic acid.
  • the antiprogestational effect of the compounds represented by Formula l l is demonstrated by observing the decidual cell reaction of a traumatized uterine horn of an immature female rat receiving progesterone. Traumatization of the uterine horn simulates a pseudoimplantation. The increase in tissue weight of the traumatized horn in comparison to the untraumatized contralateral control uterine horn, measures progesterone stimulated growth. Conversely, a reduction of this progesterone-primed decidual response is an in vivo biological measure of the antiporgestational activity of these compounds.
  • Mated female hamsters considered to be pregnant by the presence of sperm in a post-estrus vaginal levage, are treated subcutaneously with the test compound during days 38 of pregnancy. This period of gestation in the hamster relates from a point just prior to implantation of a fertilized ovum to a point after which implantation has occured and placental circulation is now complete. Treated animals are sacrificed one day prior to parturition and the total number of live feti is compared to those in a control group of mated female hamsters.
  • fertile female refers to any female mammal that can reproduce and that requires progesterone for reproduction and gestation.
  • illustrative of such species are mice, rats, guinea pigs, rabbits, ferrets, dogs, cats, cows, horses and primates, including monkeys, baboons and humans.
  • the 7-alkyl-3,5-unsaturated steroids are variously administered in order to achieve their antiprogestational effect.
  • women are administered prior to ovulation either daily to weekly in small doses which do not interfere with ovulation.
  • these agents are administered in small doses, i.e., a mini-pill" type of regimen, fertility is inhibited without inhibiting or interfering with the ovulatory process.
  • the 7-alkyl-3,5-unsaturated steroids are administered in one or more larger doses following ovulation, but prior to the occurrence of the progesterone ovarian/placental shift, which takes place approximately 55 days after ovulation.
  • ovulation varies, of course, from species t species. In women ovulation occurs on or about day or during the period from about day 14 to about of the menstrual cycle. After this period the placenta independently supplies the necessary progesterone, and the instant compounds are no longer significantly effective as antiprogestational agents. Failure of the fertilized ovum to implant insures the lack of further development into a mature fetus. in the higher primates there results a menstrual bleed which indicates the lack of pregnancy.
  • the contranidative effect of these 7-alkyl-3,5- unsaturated steroids can be utilized to insure the failure of a fertilized ovum to implant in any fertile female mammal as previously defined.
  • the present invention is useful for reducing the fertility in such commercially valuable species as dogs, cats, cows and horses.
  • the compounds are administered for a period of time not exceeding 50% of the gestation period for the particular species.
  • the compounds are administered during the first quarter of the gestation period.
  • the particular dosage of the active ingredient depends upon such factors as the route of administration, age, weight of the mammal being treated and the frequency of dosing.
  • a post-ovulatory dosage unit of the therapeutic steroid contains from about 0.1 milligrams to about 3.0 grams of the active ingredient per administration with dosages repeated as necessary.
  • Dosage units administered prior to ovulation using a mini-pill type of regimen contain from 0.1 mg to L0 mg, de pending upon the particular steroid employed.
  • a dosage unit of from 0.1 mg to 0.5 mg, and even more particularly from 0.1 mg to 0.25 mg is employed.
  • the actual amount required varies from compound to compound but is an amount which is insufficient to inhibit ovulation, but which is nevertheless sufficient to maintain adequate antiprogestational effects that will prevent nidation from occurring and that will produce menstrual bleeding in fertile female women.
  • amounts up to 3.0 grams of the active ingredient can be administered once or twice a year.
  • the compoundsof the present invention are administered in various dosage unit forms such as tablets, capsules, powders, granules, oral solutions or suspensions, sterile solutions or suspensions for parenteral use, sublingual and intrabuccal preparations, aerosols and sprays'for inhalation and insufflation therapy, creams, lotions, and ointments for topical use, intravaginal and rectal suppositories, vaginal rings, impregnated with the active ingredient, intrauterine devices, subcutaneous and intramuscular implants, depot preparations and as further illustrated in the Examples.
  • compositions such as tablets
  • the principal active ingredient is mixed with conventional pharmaceutical excipients such as gelatin. starches, lactose, magnesium stearate, talc, acacia, di-- calcium phosphate and functionally similar materials. Tablets can be laminated coated or otherwise compounded to provide for a prolonged or delayed action or to release a predetermined successive amount of medication.
  • Capsules are prepared by mixing the steroid with an inert pharmaceutical filler or diluent and filled in either hard gelatin capsules or machine encapsulated soft gelatin capsules. Syrups or elixirs can contain the active ingredients together with sucrose or other sweetening agent, methyl and propyl parabens as preservatives, and suitable color and flavoring agents.
  • Parenteral fluid dosage forms are prepared by utilizing the active ingredient in a sterile liquid vehicle, the preferred vehicle being water or saline solution.
  • the parenteral formulations include those administerable by a jet gun.
  • Compositions having the desired clarity, stability and adaptability for parenteral use are obtained by dissolving from about 0.1 milligram to about 3 grams of the active ingredient in a vehicle consisting of a mixture of nonvolatile. liquid polyethylene glycols which are soluble in water and organic liquids. and which have molecular weight ranging from about 200 to about 1500.
  • the solutions may advantageously contain suspending agents, such as sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or polyvinyl alcohol.
  • parenteral compositions may contain bactericidal and fungicidal agents, as for example, parabens, benzyl alcohol, phenol or thimerosal.
  • isotonic agents can be included such as sugar or sodium chloride, as well as local anesthetics, stabilizing or buffering agents.
  • the parenteral compositions may be frozen after filling and water removed by freeze-drying techniques well known in the art. Such dry, lyophilized powders are generally reconstituted immediately prior to use.
  • Topical ointments are prepared by dispensing the active ingredient in a suitable ointment base such as petrolatum, lanolin, polyethylene glycols or mixtures thereof. Generally, the steroid is finely divided by milling or grinding. Creams and lotions are prepared by dispersing the active ingredient in an oily phase and subsequently forming an emulsion thereof.
  • a suitable ointment base such as petrolatum, lanolin, polyethylene glycols or mixtures thereof.
  • the steroid is finely divided by milling or grinding.
  • Creams and lotions are prepared by dispersing the active ingredient in an oily phase and subsequently forming an emulsion thereof.
  • the active ingredient can also be compressed into pellets and implanted subcutaneously or intramuscularly as a depot injection or implant. Implantation re sults in a slow but predetermined rate of absorption from the site of implantation. Such implants may additionally employ inert materials, as for example, biodegradable polymers and synthetic silicone polymer rubbers.
  • the instant compounds can also be mixed with a silicone polymer and molded in the form of cylindrical rings, loops, coils, petals or other shapes which can be inserted directly into the uterus.
  • the active ingredient diffuses through the permeable polymeric material at a relatively slow and constant rate thereby enabling its antiprogestational effects to be available directly at the site of severe activity.
  • the residual oil is stirred for a period of sixteen hours in 50 ml pyridine and 50 ml acetic anhydride and poured onto an ice/water mixture and extracted with ether. The ether extract is dried over magnesium sulfate and filtered. Additional ether is added to bring the total volume to 300 m1 and the solution cooled to C. Triethylamine 1.63 g (0.016 mole) and phosphorous oxychloride 2.45 g (0.016 mole) are added all at once and the resultant mixture is stirred for 30 minutes at 0C. The suspension is filtered and the filtrate washed well with water, dried over magnesium sulfate and distilled to dryness.
  • the residue is purified by chromatography on a silica gel column, eluting the column with methylene chloride and recrystallizing from a hexane solution to yield 3,7a-dimethylestra-3,S-dien-l 78-01, acetate, m.p. l14-115C..
  • the organic layer is separated, dried over magnesium sulfate and concentrated in vacuo resulting in the formation of 3,4,7a-trimethylandrost-4-ene-3,l7,8-diol as a glass.
  • This material is dissolved in 250 ml of acetone, treated with 15 ml ofa 10% aqueous hydrochloric acid solution and heated at its reflux temperature for 0.5 hour. The solution is concentrated in vacuo, thhe residue dissolved in benzene, the benzene solution is washed with water, ,dried over magnesium sulfate and concentrated in vacuo.
  • EXAMPLE 1V 3-Chloro-7a-methylandrosta-3 .S-dien- 1 713-01 acetate 7a-methyltestosterone acetate, 4.4 g (12.7 mole) in 25 ml of acetic acid is treated with phosphorous trichloride, (2 ml). After 18 hours, the solid is filtered and crystallized from acetone to yield 3-chloro-7a methylandrosta-3,5-dien-l7,8-01 acetate, (1.0 g 21.6%), m.p. 178-180C.
  • the resulting solution is concentrated and diluted with water.
  • the solid which forms is filtered and purified by chromatography on a silica gel column, eluting with a mixture of benzene/10% acetone.
  • the eluate is concentrated to dryness in vacuo and the residue crystallized from aqueous acetone to yield 3,7a-dimethylandrosta-3,S-dien-l 1,8,17B-diol, m.p.
  • EXAMPLE XII 104,3 ,7a-Trimethylandrosta-3,S-dien-173-01 A stirred solution of 1a,7a-dimethyltestosterone, 1.7 g (5.38 m mole) in 130 ml tetrahydrofuran is treated with ml of ethereal 1.85 M methyl lithium. After minutes, the reaction is poured onto saturated aqueous ammonium chloride, diluted with ether and the organic layer separated, dried over magnesium sulfate and concentrated under vacuum. The diol so obtained is refluxed in a mixture of 250 ml of acetone and 50 ml of a 10% aqueous hydrochloric acid solution for a period of one hour.
  • the reaction mixture is concentrated, poured into water and filtered.
  • the crude diene so obtained is chromatographed on a silica gel column (60 g) eluting with a mixture of benzene containing 5% acetone.
  • the eluate is evaporated to dryness in vacuo and crystallized from aqueous acetone to yield la,3,7atrimethylandrosta-3,5-dien-1713-01, (0.8 g, 47.3%) m.p.
  • EXAMPLE X111 701,17a-Dimethylandrosta-3,S-dien-1 7-01 A solution of 7a-mcthylandrosta-3.S-dien-l7-one 2.84 g 10 m mole), in a mixture of ml of ether and 50 ml of tetrahydrofuran is treated with 40 ml of 1.6 M ethereal methyl lithium (40 ml). After 1 hour, the mixture is poured onto saturated aqueous ammonium sulfate, diluted with benzene and the organic layer separate, dried over magnesium sulfate and concentrated in vacuum. The residue is dissolved in benzene and purified by chromatography on a silica gel column.
  • the 70,17a-dimethylandrosta-3,S-dien- 175-01 so obtained, m.p. 7C. has the following properties: ir (KBr) 3420, 1645 (w), 1625 (2), 1150, 860 cm; uv max (EtOH) 228 (6 14,600) 236 (e 15,900), 244 nm (6 10.600); nmr (CDCl 6 0.78 (M d, C7aCH 0.91 (S, C,,,H,,), 1.01 (S, C, -H 1.23 (S, C CH 5.41 (d, C,,H), 5.60-5.78 (m, C ,H), 5.98 (d, C H).
  • This material is dissolved in 500 ml of acetone, treated with 50 ml ofa 10% aqueous hydrochloric acid solution and heated at its reflux temperature for a period of 1 hour.
  • the solution is concentrated in vacuum and the residue twice extracted with methylene chloride.
  • the combined extracts are washed with water, dried over magnesium sulfate, treated with charcoal, filtered and concentrated under vacuum to an orange liquid which is dissolved in benzene and purified by chromatography on a silica gel chromatographic column.
  • the eluate is evaporated to dryness and recrystalizeed from an aqueous acetone to yield 3,713- dimethy1androsta-3,5-dien-175-01, m.p.
  • a solution of l01,75-dimethyltestosterone, 1.5 g (4.75 m mole) in tetrahydrofuran ml) is added to a stirred suspension of lithium aluminum hydride in 200 m1 of tetrahydrofuran. After standing for a period of 18 hours, water is added to the reaction mixture. The salts are removed by filtration, the filtrate is dried over magnesium sulfate and the solvent removed under vacuum. The residue is dehydrated in 300 ml of refluxing acetone which contains 50 m1 ofa 10% aqueous hydrochloric acid solution. The solution is concentrated, diluted with water and filtered.
  • the solid is purified by chromatography on a silica gel column (50 g), eluting with a mixture of benzene 5% acetone. The eluate is evaporated to dryness and crystallized from aqueous acetone to yield l0:,7B-dimethylandrosta-3,S-dien-l 7B- 0], m.p. l48150C.; ir (KBr) 3360, 1645 (w) cm; uv
  • Phosphorous oxychloride is added to a solution of 3.- 7a-dimethyl-androsta-3.5-dien-17B-o1 in 2.3- dihydropyran. After standing at room temperature for a period of 72 hours, the solution is diluted with ether, washed with aqueous sodium carbonate and water, dried over sodium sulfate and evaporated to dryness under vacuum. Crystallization of the residue from hexane results in the formation of 3,7oz-dimethyl-17B-(2- tetrahydropyranyloxy)androsta-3,5-diene.
  • the mixture is partially distilled and then diluted with water, extracted with ether and the combined extracts are washed with water, dried and chilled to 0C. Phosphorous oxychloride and triethylamine are added which form a precipitate instantly. After 30 minutes. the suspension is filtered. the ether solution washed with water, sodium bicarbonate, dried over sodium sulfate and evaporated to dryness. The residue is chromatographed on a silica gel column, eluting the column with methyleneehloride. The eluate is evaporated to dryness and the residue crystallized from aqueous acetone to yield 13-ethy1-3,7adimethy1gona-3,5-dien-17B-o1 acetate.
  • EXAMPLE XXIV 17/3-( 1 Methoxycyclohexyloxy)-3,7a-dimethylandrosta-3,5-diene The compound 3,7a-dimcthylandrosta-3 .5-dien-17B- o1 is dissolved in anhydrous dioxane and treated with pyridine p-toluenesulfonate and cyclohexanone methyl enolether. Stirring is continued for a period of 3 hours.
  • EXAMPLE XXVI Preparation of a tablet formulation
  • One thousand tablets for oral use, each containing 5 mg of 13-ethy1-3,7a-dimethy1gona-3,S-dien-175-01 acetate are prepared according to the following formulation:
  • the l 3-ethy1-3,7a-dimethy1gona-3,S-dien-17,8-01 acetate and dicalcium phosphate are mixed well, granulated with a 7.5% aqueous solution of methylcellulose, passed through a No. 8 screen and carefully dried. The dried granules are passed through a No. 12 screen, blended with talc and calcium stearate and compressed into tablets.
  • one-piece soft gelatin capsules can be prepared in which the above formulation can be granulated, slugged or compressed directly into a rotary die or plate mold in which the capsule is formed.
  • the above excipients may be omitted and the active ingredient dispensed as a powder directly into the capsule.
  • EXAMPLE XXVlll Preparation of a parenteral injectable solution
  • a sterile aqueous suspension suitable for injection is prepared from the following ingredients 7a-Methylandrosta3,S dienl 7Bol l Polyethylene glycol 4000, U.S.P. 3 Sodium chloride 0.9 Polyoxyethylene derivatives of sorbitan monooleate (TWEEN 80) L'.S.P.
  • EXAMPLE xxx Preparation of an intrauterine device
  • a mixture of 1.0 gram of l3ethyl-7oz-methylg0na- 3,5-dien-l7B-ol and 18 grams of synthetic silicone polymer rubber, Silastic, Dow-Corning Medical Silastic 382 elastomer, and 3 drops of stannous octoate are mixed and placed in a toroidal mold.
  • the mold is cured at 40 for 4 hours, cooled, and the elastic toroidal rings so prepared are trimmed of excess polymer. Suitable rings having an outside diameter of 65 mm and weighing approximately 18 grams each can be prepared in this manner.
  • filler such as 10 micron size amorphous silica may be incorporated in the silicone rubber to control the rate and degree of permeability of diffusion.
  • a 7-alkyl-3,5-unsaturated steroid having the general formula:
  • R R R and R are each hydrogen or methyl
  • R is selected from the group consisting of hydrogen
  • R is lower alkyl having from 1 to 3 carbon atoms
  • R is selected from the group consisting of CH CHOH and C O;
  • R is selected from the group consisting of hydrogen, lower alkyl having from 1 to 6 carbon atoms, lower alkenyl and lower alkynyl having from 2 to 6 carbon atoms, lower alkenynyl and lower alkadiynyl having from 4 to 6 carbon atoms;
  • R is selected from the group consisting of hydrogen
  • acyl having from 2 to 12 carbon atoms, 2- tetrahydropyranyl, trimethylsilyl, l-cycloalkenyl having from 5 to 8 carbon atoms, 1- methoxycycloalkyl and l-ethoxycycloalkyl in which the cycloalkyl group has from 5 to 8 carbon atoms, and the groups R andOR when taken together are oxo or a cyclic acetal; and
  • R is hydrogen with the proviso that when R and R,
  • R R R and R are hydrogen, R R R R and R, cannot all be hydrogen at the same time.
  • R is alpha-methyl and R is hydrogen.
  • a compound of claim 1 which is 3,7a-dimethylestra-3 ,5-dienl 7B-ol.
  • a compound of claim 1 which is 3,7a-dimethylestra-3,5-dien-l7B-ol, acetate.

Abstract

Novel steroids of the class of 7-alkyl-3,5-androstadienes, estradienes and gonadienes are prepared which are useful as antiprogestational and antifertility agents.

Description

United States Patent [1 1 Grunwell et a1.
[ 7-ALKYL-A -STEROIDS 22 Filed: Mar. 26, 1973 21 Appl. No.: 344,838
[52] US. Cl 260/397.5; 260/239.55 R; 260/239.55 C; 260/397.3; 260/397.45;
[51] Int. Cl. C07C 167/00; C07C 169/00 [58] Field of Search Machine Searched Steroids 1 June 17, 1975 [56] References Cited UNITED STATES PATENTS 3,246,022 4/1966 Chinn 260/3975 3,351,639 11/1967 Allen et a1. 260/3973 3,471,531 10/1969 Hughes et al.. 260/3973 3,522,281 7/1970 Anner et a1 260/3975 3,553,213 1/1971 Oliver et al. 260/2395 Primary ExaminerE1bert L. Roberts Attorney, Agent, or Firm-William J. Stein; Eugene O. Retter; George W. Rauchfuss, Jr.
[5 7 ABSTRACT Novel steroids of the class of 7-a1kyl-3,5- androstadienes, estradienes and gonadienes are prepared which are useful as antiprogestational and antifertility agents.
5 Claims, N0 Drawings 1 7-ALKYL-A3'5-STEROIDS BACKGROUND OF THE INVENTION Progesterone is unique among the steroid hormones by virtue of the fact that its presence is essential with most female mammals, including women, for the maintenance of a successful pregnancy. A loss of interference with progesterone during the early stages of pregnancy prevents the continuation of gestation.
In women the typical menstrual cycle is 28 days with the onset of menstruation counted as day one. During the interval from day to day 12, follicle-stimulating hormone (FSH) from the pituitary gland stimulates the growth of the primordial follicles of the ovary with the result that by day 12 of the cycle a mature Graafian follicle is ready to rupture and release a mature ovum. In addition to the formation of an ovum, the follicle also produces estrogen which stimulates the conversion of the uterine endometrium into a proliferative phase. On day 14 the ovum is released and the follicle is converted into a corpus luteum which in addition to estrogen now produces progesterone. These two hormones stimulate the endometrial growth of the uterine lining converting it by day 19 from its proliferative phase into its secretory stage.
The ovum is released into the Fallopian tube and may be subsequently fertilized within a period of from 12 to 24 hours. At about day 18 /2, the fertilized ovum enters the uterus and by day 21 /2 to day 24 /2 the ovum or blastocyst nidates within the uterine lining and begins to implant. This implantation process is completed with the establishment of the fetal-placental circulation which occurs at about day 35. In order for successful implantation to occur, a proper estrogen-progesterone balance is required. Subsequent to the implantation period, rapid placental development occurs, and by day 70 to day 75 the placenta produces all of the progesterone required to maintain pregnancy. Thus, the removal of the corpus luteum prior to day 70 results in a rapid drop in progesterone levels and the expulsion of the uterine contents during a menstrual bleed. However, if in a pregnant woman the corpus luteum is removed 70 days after the onset of menstruation, pregnancy will continue.
Applicants have made the important discovery that compounds of this invention possess marked antiprogestational properties. Thus they are able to reduce fertility when administered without interfering with normal ovulation. In this regard these compounds differ from the contraceptive steroids of the prior art, which inhibit ovulation or which interfere with ovum transport by virtue of their progestational and/or estrogenic properties.
Administration of the antiprogestational agents of the present invention throughout the normal mammalian menstrual cycle results in a desynchronization of the maturing uterine mucosa relative to the 0vulation process, thereby preventing nidation or implantation of the fertilized ovum. In women the withdrawal of progesterone from a progesterone-primed uterine endometrium results in menstrual bleeding. Thus, the
monthly administration of the instant antiprogestational agents following ovulation insures menstrual cyclicity.
DESCRIPTION OF PRIOR ART US. Pat. No. 3,522,281 represents the closest art known to applicants and disclosures A""7a-methylestradienes as estrogenic agents, antigonadotrophic agents and as ovulation inhibitors. Thus, the importance of these novel products antifertility agents resides in their ability to inhibit ovulation. In contrast thereto, applicants have made the important discovery that the chemically distinct and novel compounds of the present invention have novel antiprogestational activity. Applicants have further discovered that both the novel compounds of this invention as well as the prior art compounds described above are useful as antiprogestational agents in reducing the fertility of fertile females without inhibiting or interfering with ovulation.
US. Pat. No. 3,246,022 describes certain 3-aryl-l7B- hydroxy-androsta-3,S-dienes and 3-aryl-l7B-hydroxyestra-3,5-dienes which are stated to reduce edema formation associated with the inflammatory response to tissue insult. Additionally the compounds described therein are stated to share with estrone a capacity to inhibit uterine response to progesterone. The compounds of the present invention taken as a whole are all substituted in the 7-position of the steroid nucleus. Thus, they are distinct chemical entities from those described in the prior art. In addition. there is no indication in the prior art that these compounds when administered to fertile mammals, mammels, including women, inhibit nidation or prevent implantation, thereby reducing fertility in such females.
SUMMARY OF THE INVENTION This invention relates to new steroids, to their preparation and to their use as pharmaceutical agents. More particularly, the novel compounds of the present invention are 7-alkyl-A -unsaturated steroids useful as antiprogestational agents represented by the general formula:
wherein R R R and R are each hydrogen or methyl;
R is selected from the group consisting of hydrogen,
chloro, bromo, lower alkyl having from I to 4 carbon atoms, phenyl, halophenyl, hydroxyphenyl, tolyl, and methoxyphenyl;
R is lower alkyl having from I to 3 carbon atoms;
R,- is selected from the group consisting of CH Cl-IOH and C=O;
R is selected from the group consisting of hydrogen, lower alkyl having from 1 to 6 carbon atoms, lower alkenyl and lower alkynyl having from 2 to 6 carbon atoms, lower alkenynyl and lower alkadiynyl having from 4 to 6 carbon atoms;
R,, is selected from the group consisting of hydrogen,
alcyl having from 2 to 12 carbon atoms, 2-
3 tetrahydropyranyl, trimethylsilyl, l-cycloalkenyl having from to 8 carbon atoms, 1- methoxycycloalky and l-ethoxy-cycloalkyl in which the cycloalkyl group has from 5 to 8 carbon atoms, and the groups R and OR when taken together are 0x0 or a cyclic acetal; and
R is selected from the group consisting of hydrogen,
methyl and ethyl with the proviso that when R and R are hydrogen, R R R 3 and R cannot all be hydrogen at the same time.
In general the novel compounds of the present invention are prepared in solution from their corresponding 7-alkyl-4-en-3-ones, 7-alkyl-4-en-3-ols and 7-alkyl-5- en-3-ols using a variety of dehydrating reagents. halo/enolizing reagents and organolithium or Grignard reagents, and isolating the products therefrom.
This invention also relates to the discovery that the novel compounds described in formula (l), in addition to certain compounds described in the prior art, are
useful in reducing the fertility of fertile females in a manner other than by ovulation inhibition. More particularly, this enlarged class of compounds is represented by the general formula: I
wherein R R R and R are each hydrogen or methyl;
R is selected from the group consisting of hydrogen,
chloro, bromo, lower alkyl having from I to 4 carbon atoms, phenyl, halophenyl, hydroxyphenyl, tolyl, and methoxyphenyl;
R is lower alkyl having from 1 to 3 carbon atoms;
R is selected from the group consisting of CH CHOH and C=O;
R is selected from the group consisting of hydrogen, lower alkyl having from 1 to 6 carbon atoms, lower alkenyl and lower alkynyl having from 2 to 6 carbon atoms, lower alkenynyl and lower alkadiynyl having from 4 to 6 carbon atoms;
R,, is selected from the group consisting of hydrogen,
acyl having from 2 to 12 carbon atoms, 2- tetrahydropyranyl, trimethylsilyl, l-cycloalkenyl having from 5 to 8 carbon atoms, 1- methoxycycloalkyl and l-ethoxyeycloalkyl in which the cycloalkyl group has from 5 to 8 carbon atoms, and the groups R and OR when taken together are 0x0 or a cyclic acetal; and
R is selected from the group consisting of hydrogen,
methyl and ethyl.
DETAILED DESCRIPTION OF THE INVENTION As illustrated in general formula l above, the novel compounds of the present invention all contain an alkyl substituent in the 7 -position of the steroid nucleus. This substituent consists of either the methyl, ethyl, propyl or isopropyl groups and may be present in either the a or ,B-configuration as indicated by the wave-like bond at the point of attachment.
The compounds of the present invention also have unsaturation in common at both the 3 and 5-positions of the steroid nucleus. Consequently, all of these novel compounds can be named as either 7-alkyl-3,5- androstadienes. estradienes or gonadienes. It should be noted, however, that with respect to the 7-alkyl-3,5- estradienes, all must possess at least a mono-substituent in one of the 1,3,4 or 6-positions of the steroid nucleus, i.e., R R R and R cannot all be hydrogen.
The 3-position of the steroid nucleus is either unsubstituted or substituted with a halogen, aliphatic, phenyl or substituted phenyl group. The usual halogen substituents at the 3-position include the chloro or bromo radieals. The aliphatic group present at the 3-position comprises a lower alkyl group having from I to 4 carbon atoms and includes such groups as methyl, ethyl, propyl, butyl, isobutyl and t-butyl. A phenyl group when present can be either unsubstituted or monosubstituted. The substituents on the phenyl nucleus include such groups as halogen, as represented by fluorine, chlorine and bromine, or a hydroxyl, methyl and methoxy group. Illustrative of compounds containing a substituted phenyl radical in the 3-position are: 7a ethyl-3-(4-methoxyphenyl)estra-3,5-dien-l7B-ol and 7a-ethyl-3-(3-chlorphenyl)androsta-3,5-dien-l7B-ol.
The compounds represented by formula (I) include derivatives in which the ll-position of the steroid nucleus, represented by the symbol R is either unsubstituted or is substituted with a hydroxy or an oxo group. Illustrative of such compounds are: 7,8-methylandrosta- 3,5-dienl 7B-ol, 7/3-methylandrosta-3 ,S-diene-l 1,8, l7B-diol, 7B-methylandrosta-3,S-diene-1la, l7B-diol, and 7B-methylandrosta-3,5-diene-l l,l7-dione.
As illustrated in formula (1) above, the compounds of the present invention can be either monosubstituted or disubstituted in the l7-position of the steroid nucleus, i.e., they may be l7B-and/or l7aderivatives. Thus, the l7a-position may be either substituted or unsubstituted. When substituted, the compounds of this invention are substituted with either a saturated or an unsaturated aliphatic hydrocarbon chain having from I to 6 carbon atoms. Illustrative of such groups are straight or branched chain alkyl radicals, as for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isoamyl, n-pentyl and n-hexyl. lllustrative of the alkenyl groups which may be present are the vinyl, allyl, lbutenyl, l-pentenyl and l-hexenyl radicals. Illustrative of the alkynyl groups present are ethynyl, l-propynyl, l-butynyl, and l-hexynyl. Illustrative of the unsaturated conjugated hydrocarbon radicals present are the groups l,3-butenynyl, 1,3-pentenynyl, 1,3-butadiynyl and 2,4-hexadiynyl.
Substituents in the I7B-position include esters and ethers of the free alcohol. When R is hydrogen, the free alcohol is present, as for example, the compound la,7a-dimethylestra-3 ,S-dien-l 7,8-01.
The acyl esters which are present are derived from hydrocarbon acyl radicals having from 2 to 12 carbon atoms inclusively. The organic acyl groups include those of saturated and unsaturated aliphatic acids and aromatic acids such as acetic, propionic, butyric, isobutyric, valeric, isovaleric, caproic, caprylic, decanoic,
dodecanoic. acrylic. crotonic. c vclobutaneearlmsylie. cyclopentaneearboxylic. eyclopentenecarboxylic. cyclohexanecarboxylic. benxoic. toluic. naphthoic. ethylbcnzoie. phenylaeetic. naphthaleneaeetic. phenylvaleric, cinnamie, phenylpropionic. p-propyloxyphenylpropionic and p-butyloxyphenylacetic acid.
The compounds of this invention also include certain l7B-ethers. Such ethers include unsaturated cyeloalkane ethers having from 5 to 8 carbon atoms in which the unsaturation is present in a position alpha to the ether oxygen. Illustrative otsuch unsaturated ethers are the I-cyclopentene. I-cyclohexene or I-cyelooetene radicals. The corresponding saturated cycloalkanes are also considered to be within the scope of this invention wherein the cycloalkane group is further substituted with either a methoxy or an ethoxy radical at its point of attachment. Illustrative substituted cycloalkanc ethers include: 7a-ethyl-l7Bt l methoxyeyclopentyloxy)-estra-3.5-diene 7a-ethyl I 7B( I '-ethoxycyclohexyloxy )-estra-3.5-diene. 70!- methyl-I7fi( l '-methoxycycloheptyloxy)-estra-3,5- diene and 7a-methyI-I7B( l -ethoxycycltmctyloxy)- estra-3,5-diene. The 178- class ol ethers also includes saturated heterocyelic ethers. illustratively. 3.7adimethyl-l 7B-t 2'-tetrahydropyranyloxy )-androst-3,5- diene and la, 7adimethyI-l7B-(2- tetrahydropyranyloxy)-estra-3.5-diene. Ethers such as trimethylsilyl ethers likewise fall within the purview of the present invention.
Both the I701 and l7B-positions may be combined to represent a ketone. Thus, the compounds of this invention include I 1 and/or l7-ketones. as for example. 173- hydroxy. 'lfi-methylestra-Z.S-dien-l I-one. 7,8- methylcstra-3,S-dien-l7-one and 7/3-methylestra-3.5- diene-I l.l7-dione.
Additionally the 1701 and l7B-positions may be taken together to form a I.3-dioxolane or other cyclic acetal. Illustrative of such compounds are 7a-propylandrosta- 3,5-dien-I7-one cycie I7-(ethylene acetal) and 3- chlore-7oz-methyl-estra-B,S-dien-l7-one cyclic l7- (ethylene acetal).
A preferred group of compounds is obtained when the 3-position of the steroid nucleus contains a methyl substituent. the 7-position contains a methyl group in the a-configuration and the l7a-position of the steroid nucleus remains unsubstituted. i.e.. R is methyl, R is a a-methyl and R is hydrogen. This group is illustrated by the formula:
R OR l lll wherein R R R,. R... R,.. R and R have the values previously assigned.
The following compounds further illustrate the species represented by general formula (I) above: 17al'-butynyl )-3- I01. 7a-dimethylandrosta-3.5-dien-I 7B- ol. la, 7a-dimethyl-3'phenylandrosta-3.S-dien-l7B-ol butyratc. 701,13-diethylgona-3.S-dien-17,8-ol. I3-ethyl- 7a,] 7a-dimethylgonal-3.S-dien-l 7B-ol. 17,8-( 1 cycIopentenyloxy)-l 3-ethyI-7a-methylgona-3,S-diene. 4.7a-dimethylestra3.5-dien-I7B-ol. 3.7a-dimethyll7B-( l-methoxycyclohexyloxy)-estra-3.5-diene. 3.7adimethyI-l7B( l cyclohexenyloxy)-estra3.5dienc. 3.7a, I 7a-trimethyI-estra-3,S-dien- I 7Bol, 3,704,170!- trimethylestra-3.S-dien-I7B-ol heptanoate. 3.701.170!- trimethyIestra-3,S-dien-l 7B-ol propionate. 3,701- dimethylestra-3,5-dien-I 7-onc, 3.7oz-dimethyl- 1 7a( I propynyl )estra-3,5-dien- I 7/3-ol, 4,6,7atrimethylandrosta-3,S-dien-I7,B-ol, 4,6.7atrimethyIandrosta-3.S-dien-l7B-ol dodecanoate, 111,6,- 7a-trimethylandrosta-3,S-dien- I 7-onc. 7B-ethyI-3- phenylandrosta-3.S-dien- I 7B-ol. 7,8-ethyl-3- phenylandrosta-3,S-dien-I7B-ol decanoate. 3-methyl- 7a-propyIandrosta-3,S-dienl 7-one. l7a-ethinyl-7amethyl-3( p-methoxyphenyl)-androst-3.5-dien-l 7,8-ol. 7B-ethyl-3t m-methoxyphenyl )-androsta-3,5-dien l7-one. 7a, 1 7a-dimethyl-3tp-fluorophenyl J-androsta- 3,5-dien-17B-ol. 7ot-methyl-3(p-fluorophenyU-estra- 3.5-dien-I7-one, I01,7,8-dimethyl-3-phenylandrosta- 3.5-dien- I 7-one. 4.7B-dimethylandrosta-3,S-dienl7-one, la4.7a-trimethyIandrosta-3,S-dien- I 7B-ol. 7a-
methyl-1 7a-vinyIandrosta-3 ,S-dien-l 7,8-ol, 3.7adimethyl- I 7a-vinyl-estra-3.5-dien- I 7,8-0]. la,7adimethyl- 1 7a-vinylandrosta-3.S-dien- I 78-01 acetate,
and la,7a-dimethyl- I 7B-tetra-hydropyranyloxyandrosta-3,5-diene.
The compounds of the present invention are prepared by methods analogous to those in the art. The 3- chIoro-3.5-dienes are prepared by reacting a A"-3-keto steroid with at least one equivalent of a chloro/enolizing agent such as phosphouous oxychloride. prosphorous pentachloride or oxalyl chloride generally in the presence of an acid catalyst such acetic acid, oxalic acid. p-toluene-sulfonic acid. Alternatively. the Vilsmeier reagent. phosphorous oxychloride in dimethylformamide. may be employed. The reaction proceeds at temperatures ranging from about 0 to l()()C.. although temperatures near room temperature are preferred. Suitable inert solvents include benzene, heptane, toluene. dimethylformamide and acetic acid. The 3-bromo-3,5-dienes are prepared in a similar fashion substituting a bromo/enolizing agent such as phosphorous tribromide or oxalyl bromide in the above procedure. In this manner I7oz-ethinyl-l7/3-hydroxy-7amethyl-4-androsten-3-one acetate, I7B-hydroxy-7amethyI-4-estren-3-one acetate and l3-ethyl-l7B- hydroxy-7a-methyl-4-gonen-3-one acetate and converted in good yield to 3-chloro-I7a-ethinyl-7amethyl-3,S-androstadien-I7B-ol acetate, 3-bromo-7amethyl-3.5-estradien-l7B-ol acetate and 3-chloro-l3- ethyl-7a-methyl-3.S-gonadicn-l78-0] acetate. respectively.
The 3.5-dienes wherein R is hydrogen arc synthesized by elimination ofthe elements of water from a A- B-hydroxy or A -3-hydroxy steroid. Preferably. a A -3- hydroxy steroid is treated with an acid such as hydrochloric acid. p-toluenesulfonic acid. methanesulfonic acid, sulfuric acid or acetic acid is a solvent such as acetone. methanol. ethanol. dioxane or tetrahydrofuran. Water may also be utilized as a co-solvent and the temperature can vary from about C. to the reflux temperature of the particular solvent employed. Alternatively, halides of inorganic acids such as phosphorous oxy chloride and thionyl chloride in the presence of a tertiary amine such as triethylamine or pyridine may be utilized to effect these dehydrations in such solvents as ether, dioxane or tetrahydrofuran. Basic reagents such as aluminum oxide are also successfully employed to effect dehydration. The A -3-hydroxy steroids can be converted to the 3-tosylate .of 3-mesylate in the usual manner by treatment with p-toluenesulfonylchloride or methylsulfonylchloride in pyridine at 0C. Elimination of the tosylate or mesylatc is effected with alkaline reagents in neutral solvents such as potassium t-butoxide in dimethylsulfoxide or lithium bromide and lithium carbonate in dimethylformamide. An ester residue can also be eliminated by pyrolysis from the 3-xanthate. phenylcarbamate, ethylcarbonate derivatives of A' -3- ols to produce the desired 3,5-dienes. Using these procedures 7a-ethyl-3,5-androstadiene-l 7,B-ol. 7a, 170(- dimethyl-3,5-estradien-l7B-ol and 6,7a-dimethyl-3.5- androstadien-I7B-ol are synthesized from "laethylandrost-4-en-3B,l7B-ol. 7a,l70z-dimethyl-4-estrene- 35, 173-01, and 6,7a-dimethylandrost-4-ene-3B, 1 7pdiol. respectively. y i
The preparation of the 3,5-dienes wherein R is lower alkyl or phenyl proceeds by treating the corresponding 4-en-3-one with an appropriate organometallic reagent, as for example, an organolithium reagent or a Grignard reagent. Anhydrous solvents such as ether or tetrahydrofuran are generally employed. The intermediate tertiary allylic alcohol which forms. is subsequently dehydrated to form the 3-alkyl or 3-phenyl-3,5-
dicne. This dehydration is catalyzed by hydrogen ions.
as for example, hydrochloric acid, p-toluenesulfonic acid, acetic aeidin such solvents as acetone, methanol, ethanol, dioxane, tetrahydrofuran and aqueous mixtures thereof. The allylic alcohol intermediate may also be directly dehydrated without isolation by addition of the Grignard reaction mixtureto an aqueous mineral acid orby heating with acidic alumina in a solvent such as aqueous alcohol. Additionally the dehydration of the tertiary allylie alcohol may be affected by treatment with an acid halide and a tertiary base, as for example, phosphorus oxychloride andtriethylamine or pyridine, in in inert solvent such as ether or dioxane. Following these procedures the compounds 7a,l7a-dimethyl-3- (p-methoxyphenyl)-3,5estradiene-l7B-ol, 7B-ethyl-3 -(p-chlorophenyl)-3,5-androsta-dien-l 713-01 and 3,6,7- a,l7oz-tetramethyl-3,S-androstadien-l7B-ol are obtained from 701,17a-dimethyl-l7B-hydroxyestr4-en- 3-one, 7B-ethyl-l7B-hydroxy-androst-4-en-3-one and 6,7a-dimethyl-androst-4-ene-3,l7-dione, respectively.
The staring materials for the compounds of the present invention are 7-alkyl-4-en-3-ones, 7-alkyl-4-en-3- ols and 7-alkyl-5-en-3-ols. These compounds are best prepared from the corresponding 7-alkyl-5-en 3 ones available in good yield from the reaction of a ditlower alkyl) copper lithium with a 4,6-dien-3-one in an inert solvent such as ether. tetrahydrofuran, hexane or mixtures thereof at temperatures ranging from 78 to 25C. The initially formed enolate anion is quenched by addition to a protonating agent such as saturated solution of ammonium chloride, oxalic acid or boric acid to provide the desired 7-alkyl-5-en-3-one.
The 7-alkyl-5-en-3-one is reduced to the 7-alkyl-5- en-3-ol by reducing agents such as sodium borohydride, lithium aluminum hydride and lithium tri-ttutoxyaluminum hydride by procedures well known to also betreducedby reagents such as lithium aluminum hydride, lithium tri-t-butoxy-aluminum hydride so- .dium borohydrideto form. the desired7-alkyl-4'en-3! .01.
The.halo-3,5-dienes are preferably prepared .from
l7B hydroxy-4 en3-one, acylates; 1or 4-en13 l7-dione lTi-ketals whereas the 3,5-dienes. .3-alkyl-3.5-dienes and 3-aryl-3.5-.dienes are preferably obtained from intermediates containing a l 'l-ketal. or.a .free' I 7-hydroxy groups These various ketals, alcoholstand esters lare readily. removed,.,oxidized, reduced, -a'cylated, .alkylated and etherified using standard. methods known to i the art. For exainple..the ketonercan beireadilytregenerated from thexketal under acid conditions. The ketone can be reduced to the'al'cohol bymetallo-hydride reagents "such as lithium aluminum hydride or sodium borohydride. The ketone can be alkylated to form a :l 7a-alkyl. alkenyLor alkynyl 17B-ol by reaction with an-appropriate organometallie;reagent. asrfor exampleumethylmagnesium bromide or propinyl llithium. The free hydroxy group may be acylated by means of an acid hal ide or acid anhydride in the presence of a'tertiar y base such as pyridine. Suitable acid moietiesinclude acetic, .propionic, decanoic and cyclohexane darboxylie acids. The tetrahydropyranyl ether is p'repared by the action of dihydropyran in the presence of an acid catalyst such as p-toluenesulfonic acid or pho:phoro'us oxychloride with a3',5-dienl7B-ol. The l-alkoxycycloalkoxy derivatives of this invention are prepared by reaction of a'3,5-diehl7B-ol'with a loweralkylk etal of a cycloalkanone or the lower a]- 'kylen'olether of a cycloalkanone 'or a mixture of these in the'presence of an. acid catalyst preferably pyridine ptoluenesulfonate in solvents such as dioxane, tbutanol, or methylene chloride. Temperatures during the reaction can vary from about 20 to C. with the lower temperatures preferred. Suitable cycloalkyl derivatives include, for example, cyclopentanone diethylketal and l-methoxy-l-cyclohexene. Following essentially the same procedure but varying the reaction solvents in order to obtain reaction temperatures above 70C., the l-cycloalkenylethers are directly prepared. Suitable solvents include benzene and dimethylformamide. Alternatively, the l-cycloalkenylethers are prepared by pyrolysis of the isolated l-alkoxycycloalkoxy steroid in the presence of a trace of an organic base such a pyridine in a high boiling solvent such toluene. benzene. dimethylformarnide. The 3.5-dien-l7-ol is oxidized to the 3,5-dien-l7-one by means of the op- -penauer reaction or the Pfitzer-Moffatt procedure which utilizes dicyclohexylcarbodiimide, dimethylsulfoxide, pyridine and trifluoroacetic acid.
Applicants have discovered that the 7-alkyl-A"' steroids represented by formula (11) above possess antiprogestational activity. Administration to fertile female mammals prior to the decline in ovarian dependence for progesterone insures the absence of an'implanted ovum. In women the ovarian/placental shift of progesterone synthesis occurs about 55 days following ovulation or on about day 70, if counted from the onset of the last menstruation. By insuring the absence of an implanted ovum, estrus in fertile female mammals. or menstrual cyclicity in fertile female primates, such as monkeys, baboons and humans, will occur.
The antiprogestational effect of the compounds represented by Formula l l is demonstrated by observing the decidual cell reaction of a traumatized uterine horn of an immature female rat receiving progesterone. Traumatization of the uterine horn simulates a pseudoimplantation. The increase in tissue weight of the traumatized horn in comparison to the untraumatized contralateral control uterine horn, measures progesterone stimulated growth. Conversely, a reduction of this progesterone-primed decidual response is an in vivo biological measure of the antiporgestational activity of these compounds.
The effect of these compounds upon nidation and implantation is demonstrated by their administration to pregnant hamsters at a point immediately and subsequent to nidation and observing their prepartum effects. Mated female hamsters, considered to be pregnant by the presence of sperm in a post-estrus vaginal levage, are treated subcutaneously with the test compound during days 38 of pregnancy. This period of gestation in the hamster relates from a point just prior to implantation of a fertilized ovum to a point after which implantation has occured and placental circulation is now complete. Treated animals are sacrificed one day prior to parturition and the total number of live feti is compared to those in a control group of mated female hamsters.
The term fertile female as used herein refers to any female mammal that can reproduce and that requires progesterone for reproduction and gestation. illustrative of such species are mice, rats, guinea pigs, rabbits, ferrets, dogs, cats, cows, horses and primates, including monkeys, baboons and humans.
The 7-alkyl-3,5-unsaturated steroids are variously administered in order to achieve their antiprogestational effect. In women they are administered prior to ovulation either daily to weekly in small doses which do not interfere with ovulation. When these agents are administered in small doses, i.e., a mini-pill" type of regimen, fertility is inhibited without inhibiting or interfering with the ovulatory process. Administered in this fashion, the maturation of the uterine lining is forced out of phase with the ovulation process, thereby preventing nidation or implantation of the fertilized egg. Alternatively, the 7-alkyl-3,5-unsaturated steroids are administered in one or more larger doses following ovulation, but prior to the occurrence of the progesterone ovarian/placental shift, which takes place approximately 55 days after ovulation. Such doses, administered subsequent to ovulation, halt further nidation or implantation. y
The onset of ovulation varies, of course, from species t species. In women ovulation occurs on or about day or during the period from about day 14 to about of the menstrual cycle. After this period the placenta independently supplies the necessary progesterone, and the instant compounds are no longer significantly effective as antiprogestational agents. Failure of the fertilized ovum to implant insures the lack of further development into a mature fetus. in the higher primates there results a menstrual bleed which indicates the lack of pregnancy.
The contranidative effect of these 7-alkyl-3,5- unsaturated steroids can be utilized to insure the failure of a fertilized ovum to implant in any fertile female mammal as previously defined. Thus the present invention is useful for reducing the fertility in such commercially valuable species as dogs, cats, cows and horses. Generally the compounds are administered for a period of time not exceeding 50% of the gestation period for the particular species. Preferably the compounds are administered during the first quarter of the gestation period.
The particular dosage of the active ingredient depends upon such factors as the route of administration, age, weight of the mammal being treated and the frequency of dosing. A post-ovulatory dosage unit of the therapeutic steroid contains from about 0.1 milligrams to about 3.0 grams of the active ingredient per administration with dosages repeated as necessary. Dosage units administered prior to ovulation using a mini-pill type of regimen contain from 0.1 mg to L0 mg, de pending upon the particular steroid employed. Preferably a dosage unit of from 0.1 mg to 0.5 mg, and even more particularly from 0.1 mg to 0.25 mg is employed. The actual amount required varies from compound to compound but is an amount which is insufficient to inhibit ovulation, but which is nevertheless sufficient to maintain adequate antiprogestational effects that will prevent nidation from occurring and that will produce menstrual bleeding in fertile female women. In the case of a subcutaneous, depot preparation or medicated intrauterine device, amounts up to 3.0 grams of the active ingredient can be administered once or twice a year.
The compoundsof the present invention are administered in various dosage unit forms such as tablets, capsules, powders, granules, oral solutions or suspensions, sterile solutions or suspensions for parenteral use, sublingual and intrabuccal preparations, aerosols and sprays'for inhalation and insufflation therapy, creams, lotions, and ointments for topical use, intravaginal and rectal suppositories, vaginal rings, impregnated with the active ingredient, intrauterine devices, subcutaneous and intramuscular implants, depot preparations and as further illustrated in the Examples.
In the preparation of solid compositions such as tablets, the principal active ingredient is mixed with conventional pharmaceutical excipients such as gelatin. starches, lactose, magnesium stearate, talc, acacia, di-- calcium phosphate and functionally similar materials. Tablets can be laminated coated or otherwise compounded to provide for a prolonged or delayed action or to release a predetermined successive amount of medication. Capsules are prepared by mixing the steroid with an inert pharmaceutical filler or diluent and filled in either hard gelatin capsules or machine encapsulated soft gelatin capsules. Syrups or elixirs can contain the active ingredients together with sucrose or other sweetening agent, methyl and propyl parabens as preservatives, and suitable color and flavoring agents.
Parenteral fluid dosage forms are prepared by utilizing the active ingredient in a sterile liquid vehicle, the preferred vehicle being water or saline solution. The parenteral formulations include those administerable by a jet gun. Compositions having the desired clarity, stability and adaptability for parenteral use are obtained by dissolving from about 0.1 milligram to about 3 grams of the active ingredient in a vehicle consisting of a mixture of nonvolatile. liquid polyethylene glycols which are soluble in water and organic liquids. and which have molecular weight ranging from about 200 to about 1500. The solutions may advantageously contain suspending agents, such as sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or polyvinyl alcohol. Additionally, they may contain bactericidal and fungicidal agents, as for example, parabens, benzyl alcohol, phenol or thimerosal. If desired, isotonic agents can be included such as sugar or sodium chloride, as well as local anesthetics, stabilizing or buffering agents. In order to further enhance stability, the parenteral compositions may be frozen after filling and water removed by freeze-drying techniques well known in the art. Such dry, lyophilized powders are generally reconstituted immediately prior to use.
Topical ointments are prepared by dispensing the active ingredient in a suitable ointment base such as petrolatum, lanolin, polyethylene glycols or mixtures thereof. Generally, the steroid is finely divided by milling or grinding. Creams and lotions are prepared by dispersing the active ingredient in an oily phase and subsequently forming an emulsion thereof.
The active ingredient can also be compressed into pellets and implanted subcutaneously or intramuscularly as a depot injection or implant. Implantation re sults in a slow but predetermined rate of absorption from the site of implantation. Such implants may additionally employ inert materials, as for example, biodegradable polymers and synthetic silicone polymer rubbers.
The instant compounds can also be mixed with a silicone polymer and molded in the form of cylindrical rings, loops, coils, petals or other shapes which can be inserted directly into the uterus. The active ingredient diffuses through the permeable polymeric material at a relatively slow and constant rate thereby enabling its antiprogestational effects to be available directly at the site of severe activity.
The following preparation and examples are illustrative of the novel compounds of the present invention, their preparation, compositions and use in accordance with the above.
EXAMPLE 1 3,7a-Dimethylestra-3,5-dien-173-01 acetate A solution of 50 ml (0.8 mole) of 1.6M methyllithium in ether is added to 4.7 g (0.015 mole) 17B- hydroxy-7a-methylestr-4-en-3-one in 150 ml tetrahydrofuran over a period of 10 minutes and the resultant solution is stirred for 3 hours at room temperature. The mixture is poured onto an aqueous ammonium chloride solution and the organic layer washed well with water, dried and evaporated under reduced pressure. The residual oil is stirred for a period of sixteen hours in 50 ml pyridine and 50 ml acetic anhydride and poured onto an ice/water mixture and extracted with ether. The ether extract is dried over magnesium sulfate and filtered. Additional ether is added to bring the total volume to 300 m1 and the solution cooled to C. Triethylamine 1.63 g (0.016 mole) and phosphorous oxychloride 2.45 g (0.016 mole) are added all at once and the resultant mixture is stirred for 30 minutes at 0C. The suspension is filtered and the filtrate washed well with water, dried over magnesium sulfate and distilled to dryness. The residue is purified by chromatography on a silica gel column, eluting the column with methylene chloride and recrystallizing from a hexane solution to yield 3,7a-dimethylestra-3,S-dien-l 78-01, acetate, m.p. l14-115C..
Anal. Calcd. for C H O C,80.43; H982. Found: C,80.58; H.967.
EXAMPLE 1 l 7a-Methyl-3-phenylestra-3,5-dien-17,8-01
A solution of 7a-methyl-l9-nortestosterone 2.8 g 10 m mole) in a mixture of 50 ml of tetrahydrofuran and ml of ether is treated with 24 ml of a solution of 25% phenyl magnesium chloride in C 11,, (24 ml). After 1 hour, the reaction is poured onto aqueous ammonium chloride. The benzene extract is washed with water, dried over magnesium sulfate and taken to dryness under reduced pressure. The diol so obtained is dehydrated by refluxing for 1 hour in an acetone (250 ml)- 1072 aqueous hydrochloric acid (15 ml) solution. This solution is concentrated under reduced pressure and chromatographed on a silica gel column (50 g) eluting with benzene-5% acetone and crystallizing from aqueous methanol to yield 7a-methyl-3-phenylestra-3,5- dien-l7B-ol, (2.0 g 57.5%). m.p. 148C., ir (KBr), 3470, 1590 (m) cm; uv max (EtOH) 228 (6 10,300), (6 9,700), 287 nm (6 16,400); nmr (CDCl;,) 5 0.78 (S, C ,,H 0.88 1d, J 71-12, C7ozCH,,), 5.625.78 (m .05, C,,H), 6.60 (br s, 0.5, C,-*H). 7.17-7.67 (m, 5, AR-H.)
Anal. Calcd. for C H O: C, 86.15; H. 9.25. Found: C, 86.20; H. 9.19.
EXAMPLE Ill 3,4,7a-Trimethylandrosta-3,S-dien- 1 73-01 A solution of 4,7a-dimethyl-17B-hydroxyandrost-4- en-3-one, 1.5 g (4.75 m mole) in a mixture of 50 m1 ether and 30 ml tetrahydrofuran is treated with 30 ml of 1.6 M etheral methyl lithium. After 1.5 hours, the mixture is poured onto a saturated aqueous ammonium chloride solution and diluted with benzene. The organic layer is separated, dried over magnesium sulfate and concentrated in vacuo resulting in the formation of 3,4,7a-trimethylandrost-4-ene-3,l7,8-diol as a glass. This material is dissolved in 250 ml of acetone, treated with 15 ml ofa 10% aqueous hydrochloric acid solution and heated at its reflux temperature for 0.5 hour. The solution is concentrated in vacuo, thhe residue dissolved in benzene, the benzene solution is washed with water, ,dried over magnesium sulfate and concentrated in vacuo. The residue is purified by chromatography on a silica gel column (60 g), eluting with C H -5% acetone and crystallizing from an aqueous acetone to give 3,4,7a-trimethylandrosta-3,5-dien-17,8-01, m.p. -160C.; ir (KBr) 3480, 1630(w) cm; uv max (EtOH) 236 (6 18,300), 243 nm (e 18,900); nmr
EXAMPLE 1V 3-Chloro-7a-methylandrosta-3 .S-dien- 1 713-01 acetate 7a-methyltestosterone acetate, 4.4 g (12.7 mole) in 25 ml of acetic acid is treated with phosphorous trichloride, (2 ml). After 18 hours, the solid is filtered and crystallized from acetone to yield 3-chloro-7a methylandrosta-3,5-dien-l7,8-01 acetate, (1.0 g 21.6%), m.p. 178-180C.
Anal. Calcd. for C H ClO C, 72.79; H, 8.61; Cl, 9.78. Found: C, 72.60; H, 8.68; Cl, 9.75.
EXAMPLE V 3,7a,17a-Trimethylandrosta-3,S-dien-17B-ol A solution of 1.4 g 3,7a-dimethylandrosta-3,5-dienl7-one (4.7 m mole) is heated with 15 ml of ethereal 1.6 M. methyl lithium. After 1 hour, the mixture is poured onto a saturated aqueous ammonium chloride solution and diluted with benzene. The organic layer is separated, dried over magnesium sulfate and concentrated in vacuum. The residue is chromatographed on a silica gel column and crystallized from aqueous acetone to yield 3,704, l7a-trimethylandrosta-3,5-dien- 17,8-01 (0.8 g, 54.2%) m.p. ll8-l2lC.; ir (KBr) 3,360,1620(w)cm;uv max (EtOH) 232 (6 23,200), 238 (6 24,500), 248 nm (6 15,700); nmr(CDCl31 6 0.78, (Vzd, C7a-CH 0.88 (S, C CH3), 1.72 (S, C,-CH, 5.26 (d, 1, J Hz, C,,H), 5.67 s, 1, C -H).
Anal. Calcd. for C H O: C, 84.02; H, 10.90. Found: C, 83.54; H, 10.96.
EXAMPLE VI 7a-Methylandrosta-3,S-diene-1 lB,l7,B-diol To a stirred suspension of 7a-methylandrosta-4-ene- 3,11,17-trione, 10.5 g (34.4 m mole) is added 3.0 g of lithium aluminum hydride in tetrahydrofuran 100 ml). After 18 hours, the excess hydride is decomposed by the cautious addition of water. Magnesium sulfate is added, the insoluble salts filtered and solution distilled to dryness under vacuum. The resulting triol is dissolved in a mixture of 500 ml of acetone and 50 m1 of a hydrochloric acid solution and the solution refluxed for 1 hour. The solution is concentrated, diluted with water and the resulting solid filtered and crystallized from aqueous methanol to yield 704- methylandrosta-3,S-diene-l 1,8,17B-diol, m.p. l78-l80C.; ir (KBr) 3,440, 1650 (m) cm; uv max (EtOH) 229 (6 18,700), 236 (6 20,900), 245 (e 13,900); nmr (CDCl 5 0.86 (d. J-6.5 Hz, C70: CH 1.03 (S, C,,H=;). 1.26 (S, C -H 5.32 (d, l, J 41-12, C,,H), 5.69-5.85 (m, l, C -H) 5.99 (d, l, J 10Hz, C -H).
Anal. Calcd. for C H O AH O: C, 77.08; H, 9.87. Found: C, 77.21; H, 9.86.
EXAMPLE V11 3-Chloro-7a-methylandrosta-3,S-dien-175-01 A solution of 3-chloro-7a-methylandrosta-3,S-dien- 17,8-01 acetate, 3 g (8.29 m mole) in 100 ml of methanol and 10 ml of a 10% aqueous NaOH solution are heated at the reflux temperature for 4 hours and poured into ice water. The solid is filtered, washed well with water and crystallized twice from an aqueous acetone solution to yield 3-chloro-7a-methylandrosta-3,5- dien-l7B-ol (1.2 g, 45.2%), m.p. 178-180C.
Anal. Calcd. for C ,,H ClO: C, 74.84; H, 9.11; Cl, 11.06. Found: C, 74.47; H, 9.22; Cl, 10.70.
EXAMPLE Vlll 7,8-Methylandrosta-3,S-diene-1 1,8,17,8-dio1 To a stirred suspension of lithium aluminum hydride 1.0 g in tetrahydrofuran (300 ml) is added 73- methylandrost-4-ene-3,l 1,17-trione 3.4 g 10.8 m mole). After 18 hours at room temperature, the excess hydride is decomposed by the cautious addition of water. Magnesium sulfate is added, the salts filtered and the solution distilled to dryness under vacuum. The resulting triol is dehydrated in a mixture of refluxing 400 ml of acetone and 30 ml ofa 10% aqueous hydrochloric acid solution. After 30 minutes, the solution is concentrated, poured onto water and the solid filtered. The crude diene so obtained is chromatographed in a silica gel column, eluting with a benzene/15% acetone mixture. The eluate is evaporated to dryness in vacuum and the residue is crystallized from a mixture of etherhexane to yield 7,8-methylandrosta-3,S-diene-l 1,8,17,8- diol, m.p. l35-l45C. (dec); ir (KBr) 3,590, 3,420, 1,645 (w) cm; uv max (EtOH) 223 (6 17,400), 236 (6 19,700), 244 HIT1( l3,600)nmr(CDCl )6 1.05 (S, C,,,H;,), 1.13 /zd, C7,8CHZ), 1.17 (S, C -H 5.19 (d, l, J =4.5Hz, C,,-H), 5.68-5.84 (m, l. C;,-H 5.98 (ABXq, l, JAB =10Hz,JBX 1.5 Hz, C,H).
Anal. Calcd. for C ll-1300 C, 79.42; H. 10.00. Found: C, 78.93. H. 10.30.
EXAMPLE lX 7a-Methylandrosta-3,5-dien-17,801
A stirred suspension of 1.1 g oflithium aluminum hydride in tetrahydrofuran 150 ml) is treated with a solution of 7oz-methyltestosterone. After 18 hours. the excess hydride is decomposed by the cautious addition of water, magnesium sulfate is added, the salts filtered and the filtrate distilled to dryness under vacuum. The residue is dissolved in acetone (500 ml), diluted with 50 ml of a 10% aqueous hydrochloric acid solution and the solution refluxed for a period of 30 minutes. The solution is concentrated and the residue diluted with water. The resulting solid is filtered, washed with H O, dried and recrystallized from aqueous acetone to yield 7amethyl-androsta-3,S-diene-l7,8-01, m.p. 142-l44C., ir (KBr) 3340, 1645 (w) cm, uv max (EtOH) 223 (6 19,400), 236 (6 21,200), 244 nm (e 13,600); nmr (CDCl;,) 6 0.78 (S, C ,,H3), 0.88 (/2d, C7a-CH 0.98 (S, C, H3), 5.35 (cl, 1, J 5H2, C H), 5.53-5.72 (m, l, C -H), 5.92 (4, l, J =10 Hz, C -H).
Anal. Calcd. for C H O: C, 83.86; H, 10.56. Found: C, 83.66; H, 10.57.
EXAMPLE X 7,8-Methylandrosta-3 ,5-dien-l 73-01 A solution of 3.02 g of 7,8-methyltestosterone (10 m mole) in m1 of tetrahydrofuran is added to a stirred suspension of 0.4 g lithium aluminum hydride in 200 ml of tetrahydrofuran. After stirring at room temperature overnight, the excess hydride is cautiously decomposed with water. The inorganic salts are removed by filtration and the filtrate is concentrated to give 73- methylandrost-4-ene-3,l7B-diol as a viscous liquid. This residue is dissolved in 450 ml of acetone, treated with a 10% aqueous hydrochloric acid solution and heated at its reflux temperature for 1 hour. The solution is concentrated in vacuum, diluted with water and the solid which forms is filtered, dissolved in benzene and purified by chromatography on a silica gel column. Concentration of the eluate and crystallization from aqueous acetone results in the formation of 7B- methylandrosta-3,5-dien-17,8-01, m.p. 159162C.; has the following spectral properties: ir (KBr) 3420, 1650 (w), 1050 865 cm: uv max (EtOH) 227 (e 20,900), 235 (6 23,400), 243 nm (6 15.300). nmr (CDC1 6 0.79 (S, C,,,-H 0.92 (S,C 9H;1). 1.03 (d, J 7Hz,C7,B--CH 5.19 (d, l, J 3H2, C,,-H), 5.635.82(m.1.C;,H), 5.97 (D, J 10Hz. C -H).
Anal. Calcd. for C- H Oz C, 83.86; H, 10.56. Found: C, 84.03: H, 10.70.
EXAMPLE X1 3,7oz-Dimethylandrosta-3,S-diene-l 18,1 7,8diol A mixture of 1 13,17B-dihydroxy-7a-methyltestosterone, 8.2 g (25.8 m mole) in tetrahydrofuran is treated with 120 ml of ethereal 1.6 M methyl lithium. After 4 hours, the reaction mixture is poured onto aqueous ammonium chloride and benzene added. The organic layer is washed with water, dried over magnesium sulfate and concentrated under vacuum. The resulting triol is dehydrated in a mixture of 50 ml of acetone and 50 ml of a 10% aqueous hydrochloric acid solution by refluxing for 1 hour. The resulting solution is concentrated and diluted with water. The solid which forms is filtered and purified by chromatography on a silica gel column, eluting with a mixture of benzene/10% acetone. The eluate is concentrated to dryness in vacuo and the residue crystallized from aqueous acetone to yield 3,7a-dimethylandrosta-3,S-dien-l 1,8,17B-diol, m.p. 199203C.; ir (KBr) 3,540, 3,480, 1,625, uv max (EtOH) 232 (e 22,100), 238 (e 23,900), 248 nm (6 15,600;) nmr (CDCl:;) 8 0.82 (d, J 6.5 Hz, C7a-CH 100 (S, C, H 1.22 (S, C H 1.73 (S, C CH 5.13 (d, l, J 4H C H), 5.63 (S, l, C,-H).
Anal. Calcd. for C H O C, 79.70; H, Found: C, 80.02; H, 10.41.
EXAMPLE XII 104,3 ,7a-Trimethylandrosta-3,S-dien-173-01 A stirred solution of 1a,7a-dimethyltestosterone, 1.7 g (5.38 m mole) in 130 ml tetrahydrofuran is treated with ml of ethereal 1.85 M methyl lithium. After minutes, the reaction is poured onto saturated aqueous ammonium chloride, diluted with ether and the organic layer separated, dried over magnesium sulfate and concentrated under vacuum. The diol so obtained is refluxed in a mixture of 250 ml of acetone and 50 ml of a 10% aqueous hydrochloric acid solution for a period of one hour. The reaction mixture is concentrated, poured into water and filtered. The crude diene so obtained is chromatographed on a silica gel column (60 g) eluting with a mixture of benzene containing 5% acetone. The eluate is evaporated to dryness in vacuo and crystallized from aqueous acetone to yield la,3,7atrimethylandrosta-3,5-dien-1713-01, (0.8 g, 47.3%) m.p. l6l165C.; ir (KBr) 3480, 1630 (w) cm; uv max (EtOH; 232 (6 23,300), 238 (6 25,000), 247 nm (6 16,000); nmr (CDC1 8 0.78 (S, C -H 0.88 /zd, C1aCH C7a-CH 1.73 (S, C CH 3.67 5.28 (d, l, J 5H2, C -H), 5.68 (S, l, C -H).
Anal. Calcd. for C H O: C, 84.02; H, 10.90. Found: C. 83.96; H, 11.13.
EXAMPLE X111 701,17a-Dimethylandrosta-3,S-dien-1 7-01 A solution of 7a-mcthylandrosta-3.S-dien-l7-one 2.84 g 10 m mole), in a mixture of ml of ether and 50 ml of tetrahydrofuran is treated with 40 ml of 1.6 M ethereal methyl lithium (40 ml). After 1 hour, the mixture is poured onto saturated aqueous ammonium sulfate, diluted with benzene and the organic layer separate, dried over magnesium sulfate and concentrated in vacuum. The residue is dissolved in benzene and purified by chromatography on a silica gel column. The eluate is evaporated to dryness in vacuo, and crystallized from benzene. The 70,17a-dimethylandrosta-3,S-dien- 175-01 so obtained, m.p. 7C. has the following properties: ir (KBr) 3420, 1645 (w), 1625 (2), 1150, 860 cm; uv max (EtOH) 228 (6 14,600) 236 (e 15,900), 244 nm (6 10.600); nmr (CDCl 6 0.78 (M d, C7aCH 0.91 (S, C,,,H,,), 1.01 (S, C, -H 1.23 (S, C CH 5.41 (d, C,,H), 5.60-5.78 (m, C ,H), 5.98 (d, C H).
Anal. Calcd. for C H O: C, 83.94; H, 10.73 Found: C, 83.76; H, 10.91.
EXAMPLE XlV 7a-Methyl-3-phenylandrosta-3,S-dicn-17B-ol A solution of 7a-methyltestosterone, 3.8 g (12.6 m mole) in a mixture of 100 m1 of ether and 50 ml of tetrahydrofuran is treated with 20 ml of 3 M ethereal phenyl magnesium chloride (60 m mole). After 2'hours, the mixture is poured onto a mixture of ice, water and concentrated hydrochloric acid, diluted with ether and the organic layer is separated, dried over magnesium sulfate and concentrated under vacuum to yield 701- methyl-3-phenylandrost-4-ene-3,l7B-diol as a solid. This residue is dissolved in acetone, diluted with a 10% aqueous hydrochloric acid solution and boiled on a steam bath for about 30 minutes. The cooled reaction mixture is diluted with water and extracted with ether. The combined organic extracts are dried over magnesium sulfate, filtered and concentrated in vacuum to yield a solid which is purified by dissolving in benzene and purifying on a silica gel chromatographic column. The eluate is evaporated to dryness in vacuo and crystallized from aqueous acetone solution to yield 7amethyl-3-phenylandrosta-3,S-dien-17B-ol having the following properties: ir (KBr) 3460, 1640 (w), 1595 (w), 755, 690 cm; uv max (EtOH) 220 (6 10,200), 228 (5 10,900). 234 nm (6 9.500); nrm (CDCl 8 0.80 (S, C, H 0.93 /zd, C7aC1-1 1.03 (S, C H 5.60 (d, C -H), 6.47 (s, C H), 7.17-7.65 (m, ArH 5).
Anal. Calcd. for C H O: C, 86.13; H, 9.45 Found: C, 85.85; H, 9.46.
EXAMPLE XV 3-Butyl-7oz-methylandrosta-3,S-dien- 178-01 A solution of 7oz-methyltestosterone 2.4 g (7.95 m mole) m1 of tetrahydrofuran is treated with 40 ml ofa 15% butyl lithium solution in hexane. After 1 hour, the mixture is poured onto an aqueous ammonium chloride solution diluted with ether. The organic layer is washed with water, dried over magnesium sulfate and the solvent removed under vacuum. The crude diol so obtained is dehydrated by refluxing in 20 ml of acetone containing 20 ml of a aqueous hydrochloric acid solution. The solution is concentrated, poured into water, and filtered. The crude dicne is chromatographed on a silica gel chromatographic column (50 g), eluting with a benzene 5% acetone solution. The eluate is evaporated to dryness and crystallized from aqueous acetone to give 3-butyl-7a-methylandrosta-3,5-dien- 17B-ol: (1.0 g, 37.9%), m.p. l21-124C.; ir (KBr) 3470, 1650 (w), 1620 (w) cm; uv max (EtOH) 233 (6 23,200), 242 (a 25,400), 249 nm (6 16,500); nrm (CDCl;,) 8 0.78 (S, C H 0.89 /2d, C7 xCH 0.95 (S, C -H 5.78 (d, l. J 5H2, C,,-H), 5.67 (S, 1, C -H).
Anal. Calcd. for C H O: C, 84.15; H, 11.18. Found: C, 84.39; H, 11.42.
EXAMPLE XVI 3,7B-Dimethylandrosta-3,5-dien-17,8-01
A solution of 7B-methyltestosterone, 4.53 g m mole) in a mixture of 200 ml of ether and 125 ml of tetrahydrofuran is treated with 41 ml of 1.6 M ethereal methyl lithium. After standing for 30 minutes, the mixture is poured into a saturated aqueous ammonium chloride solution and diluted with ether. The aqueous layer is separated and washed with ether. The combined organic layers are backwashed with a saturated ammonium chloride solution, dried over magnesium sulfate and concentrated in vacuum to yield 3,7,8-dimethylandrost-4-ene-3, 17B-diol as a yellow, viscous liquid. This material is dissolved in 500 ml of acetone, treated with 50 ml ofa 10% aqueous hydrochloric acid solution and heated at its reflux temperature for a period of 1 hour. The solution is concentrated in vacuum and the residue twice extracted with methylene chloride. The combined extracts are washed with water, dried over magnesium sulfate, treated with charcoal, filtered and concentrated under vacuum to an orange liquid which is dissolved in benzene and purified by chromatography on a silica gel chromatographic column. The eluate is evaporated to dryness and recrystalizeed from an aqueous acetone to yield 3,713- dimethy1androsta-3,5-dien-175-01, m.p. 132-134C., ir (KBr) 3340, 1635 (w), 1055, 885 cm; uv max (EtOH) 231 (6 22,800), 238 (6 25,200), 247 nm (6 16,700); nmr (CDCI 8 0.78 (s, C H 0.90 (d, C H 1.01 (d, C7,B-CH 1.73 (s, C CH 5.10 (d, C H), 5.73 (s, C H).
Anal. Calcd for C H O: C, 83.94; H, 10.73. Found: C, 84.07; H, 10.87.
EXAMPLE XVII 3,7a-Dimethy1androsta-3,S-dien-17-one A solution of 3,7a-dimethylandostra-3,S-dien-17B- 0], 4.0 g (13.3 m mole) in a mixture of ml benzene and 20 m1 dimethylsulfoxide, containing 1.0 ml of pyridine and 0.5 ml of trifluoroacetic acid is treated with v 8.35 g of dicyclohexyl carbodiimide and stirred for a period of 3 hours. The mixture is diluted with 100 ml of ethyl acetate and treated with 5.5 g of oxalic acid in 22 m1 of methanol. After 15 minutes, the solid is filtered and washed with ethyl acetate. The combined filtrate and wash is extracted with water, dried over magnesium sulfate and concentrated in vacuum. The residue is purified by chromatography on a silica gel column, the eluate evaporated to dryness and the residue crystallized from an aqueous acetone solution to yield 3,7a-dimethylandr0sta-3,5-dien-17-one, m.p. 149l52C., ir (KBr) 1730, 1630 (w) cm; uv max (McOH) 232 (6 22,200), 238 (e 23,500), 247 (a 15.700); nmr (CDCl 5 0.89 (d, J 7H2, C7aCH 0.92 (s, C,,,H;,;, 0.98 (S. l9 'H3), 1.74 (s. C CH 5.33 (d, l, .I 5 Hz, C,,H), 5.73 (s, l, C ,H).
Anal. Calcd. for Cull I300: C. 84.51; H. 10.13. Found: C, 84.28; H, 10.30.
EXAMPLE XVIII 3 ,7a-Dimethylandrosta-3,S-dien-1701-01 A solution of 7a-methyltestosterone, 6.04 g (20 m mole) in a mixture of 150 ml of tetrahydrofuran and 200 ml of ether is treated with ml of a 1.6 M. ethereal methyl lithium solution. After 30 minutes, the mixture is poured into a saturated ammonium chloride solution and the organic layer is separated, washed with a saturated aqueous ammonium chloride solution, dried and concentrated to dryness. The residue is dissolved in 500 ml of acetone which is diluted with a 10% aqueous hydrochloric solution and heated at its reflux temperature for 1 hour. The cooled solution is concentrated and the residue is diluted with water. The resulting solid is filtered, washed with water, dried and chromatographed on a silica gel column (200 g), eluting with a mixture of benzene-5% acetone. The eluate is evaporated to dryness and crystallized from aqueous acetone to yield 3,7a-dimethylandrosta-3,5-dien-17B- ol, m.p. 162166C.;ir(KBr)3500,1630(w)cm";uv max (EtOH), 232 (6 21,800), 238 (5 24,000), 247 nm (6 15,400 NMR coon a 0.78 (s, 3, C ,,H 0.88 /zd, C7aCH 0.97 (s, C -H 1.73 (s, C Cl-1 5.32 (d, 1, J 4.5Hz, C H), 5.73 (s, l,
Anal. Calcd. for C H O: C, 83.94; H, 10.73. Found: C, 83.96; H, 10.79.
EXAMPLE XIX 1a,7,8-Dimethylandrosta-3,S-dienl 7,8-01
A solution of l01,75-dimethyltestosterone, 1.5 g (4.75 m mole) in tetrahydrofuran ml) is added to a stirred suspension of lithium aluminum hydride in 200 m1 of tetrahydrofuran. After standing for a period of 18 hours, water is added to the reaction mixture. The salts are removed by filtration, the filtrate is dried over magnesium sulfate and the solvent removed under vacuum. The residue is dehydrated in 300 ml of refluxing acetone which contains 50 m1 ofa 10% aqueous hydrochloric acid solution. The solution is concentrated, diluted with water and filtered. The solid is purified by chromatography on a silica gel column (50 g), eluting with a mixture of benzene 5% acetone. The eluate is evaporated to dryness and crystallized from aqueous acetone to yield l0:,7B-dimethylandrosta-3,S-dien-l 7B- 0], m.p. l48150C.; ir (KBr) 3360, 1645 (w) cm; uv
max (EtOH) 229 (6 20,900), 237 (6 23,200), 246 nm (6 15,200); NMR (CDCl:,) 5 0.68 /d, C7BCH 0.79 (s, C H 0.98 (s, C -H 1.07 (/2d, ClozCH 5.23 (d, l, .I 3 Hz, C -H), 5.37-5.62 (m, l, C H), 5.87 (ABX, l, JAB 9H2, JBX 3H2,
EXAMPLE XX 3 .7a-Dimethy1- 1 7B-( 2 -tetrahydropyrany1oxy )androsta-3.5-diene diene Phosphorous oxychloride is added to a solution of 3.- 7a-dimethyl-androsta-3.5-dien-17B-o1 in 2.3- dihydropyran. After standing at room temperature for a period of 72 hours, the solution is diluted with ether, washed with aqueous sodium carbonate and water, dried over sodium sulfate and evaporated to dryness under vacuum. Crystallization of the residue from hexane results in the formation of 3,7oz-dimethyl-17B-(2- tetrahydropyranyloxy)androsta-3,5-diene.
EXAMPLE XXI l3-Ethy1-3,7ot-dimethylgona-3,5-dien-l7B-o1 acetate Ethereal methyl lithium is added to a tetrahydrofuran solution of l3-ethyl-l 7B-hydroxy-7a-methy1-4-gonen- 3-one at C. The ice bath is removed and stirring continued for an additional 4 hours. The reaction mixture is poured onto an aqueous ammonium chloride solution. The ether layer is washed with water, dried over magnesium sulfate, and evaporated to dryness under reduced pressure. The residue so obtained is stirred with acetic anhydride and pyridine overnight to acylate the l7-hydroxy group. The mixture is partially distilled and then diluted with water, extracted with ether and the combined extracts are washed with water, dried and chilled to 0C. Phosphorous oxychloride and triethylamine are added which form a precipitate instantly. After 30 minutes. the suspension is filtered. the ether solution washed with water, sodium bicarbonate, dried over sodium sulfate and evaporated to dryness. The residue is chromatographed on a silica gel column, eluting the column with methyleneehloride. The eluate is evaporated to dryness and the residue crystallized from aqueous acetone to yield 13-ethy1-3,7adimethy1gona-3,5-dien-17B-o1 acetate.
EXAMPLE XXII 13-Ethyl-7a-methylgona-3.5-dien-l 78-01 A tetrahydrofuran solution of 13-ethyl-l7B-hydroxy- 7a-methyl-4-gonen-3-one is added to a stirred suspension of lithium aluminum hydride in tetrahydrofuran at room temperature. After hours, an aqueous solution of sodium potassium tartrate is slowly added and the salts removed by filtration. The organic filtrate is dried over magnesium sulfate and concentrated under vacuum. The residue so obtained is dissolved in methylene chloride, washed with water, redried over magnesium sulfate and the solvent removed under vacuum. The resulting residue is dissolved in a mixture of acetoneaqueous 10% hydrochloric acid and refluxed for a period of one hour. After concentrating the solution, it is diluted with water and the solid filtered. This crude dien obtained thereby is recrystallized from aqueous acetone to form 13-ethyl-7a-methy1gona-3,5-dien-l 7,8- 0].
EXAMPLE XXIII l3-Ethyl-7a-methylgona-3,S-dien-173-01 propionate A solution of 13-ethyl-7a-methylgona-3,S-dien-17B- 0! is stirred overnight with propionic anhydride and pyridine. The solution is poured onto icewater and ti]- tered. The solid is chromatographed on a silica gel column, eluting with methylene chloride. The eluate is evaporated to dryness and crystallized from aqueous acetone to yield 13-ethy1-7a-methy1gona-3,5-dien-17B- ol propionate.
EXAMPLE XXIV 17/3-( 1 Methoxycyclohexyloxy)-3,7a-dimethylandrosta-3,5-diene The compound 3,7a-dimcthylandrosta-3 .5-dien-17B- o1 is dissolved in anhydrous dioxane and treated with pyridine p-toluenesulfonate and cyclohexanone methyl enolether. Stirring is continued for a period of 3 hours. The solvent is removed under vacuum and the residue is crystallized from pentane resulting in the formation of l7B-( l '-methoxycyc1ohexyloxy)-3,7a-dimethy1androsta-3,5-diene.
EXAMPLE XXV 17/3-( 1 'Cyclohexenyloxy)-3,7a-dimethylandrosta-3,5- diene EXAMPLE XXVI Preparation of a tablet formulation One thousand tablets for oral use, each containing 5 mg of 13-ethy1-3,7a-dimethy1gona-3,S-dien-175-01 acetate are prepared according to the following formulation:
(a) l3-ethyI-3,7a-dimethylgona-3,S-
dien- 1 78-01 acetate 5 (b) Dicalcium phosphate 150 (e) Methylcellulose, U.S.P. l5 cps) 6.5 (d) Talc 20 (e) Calcium stearate 2.5
The l 3-ethy1-3,7a-dimethy1gona-3,S-dien-17,8-01 acetate and dicalcium phosphate are mixed well, granulated with a 7.5% aqueous solution of methylcellulose, passed through a No. 8 screen and carefully dried. The dried granules are passed through a No. 12 screen, blended with talc and calcium stearate and compressed into tablets.
EXAMPLE XXVII Preparation of a capsule formulation Onethousand two-piece hard gelatin capsules for oral use each containing 10 mg of 3,7a-dimethylestra- 3,5-dien-17B-ol acetate are prepared from the following ingredients: 1
(a) 3 .7a-dimethylestra-3 ,5-dien-17/3- ol acetate 10 (b) Lactose, U.S.P. (0) Starch, U.S.P. 10 (d) Talc, U.S.P. y 5 (e) Calcium stearate 1 The finely powdered materials are mixed until uniformlyy dispersed and filled into hard shelled gelatin capsules of the appropriate size.
In a similar fashion one-piece soft gelatin capsules can be prepared in which the above formulation can be granulated, slugged or compressed directly into a rotary die or plate mold in which the capsule is formed.
Alternatively, the above excipients may be omitted and the active ingredient dispensed as a powder directly into the capsule.
EXAMPLE XXVlll Preparation of a parenteral injectable solution A sterile aqueous suspension suitable for injection is prepared from the following ingredients 7a-Methylandrosta3,S dienl 7Bol l Polyethylene glycol 4000, U.S.P. 3 Sodium chloride 0.9 Polyoxyethylene derivatives of sorbitan monooleate (TWEEN 80) L'.S.P.
Sodium metahisulfite Methylparaben, U.S.P. Propylparaben. U.S.P.
Water for injection q.s. to 100 ml 0.4 O. l 0. l 8 0.03
( if) (g) (h) EXAMPLE XXIX Preparation of an ointment One thousand grams of an ointment for topical application containing 0.l% of l3-ethyl-7oz-methylgona-3,5- dien-l'lB-ol can be prepared from the following ingreclients:
(a) l3-cthyl-7a-methylgona-3 S-dien 173-01 1 (b) Light liquid petrolatum 250 (c) Wool fat 200 (d) White petrolatum q.s. ad 1000 The wool fat, white petrolatum and 200 gms of the light liquid petrolatum are liquified and held at 110F. The steroid is mixed with the remaining liquid petrolaturn and passed through a colloid mill. After passing through the mill, the mixture is stirred into the melt. The melt is permitted to cool with continued stirring until congealed.
EXAMPLE xxx Preparation of an intrauterine device A mixture of 1.0 gram of l3ethyl-7oz-methylg0na- 3,5-dien-l7B-ol and 18 grams of synthetic silicone polymer rubber, Silastic, Dow-Corning Medical Silastic 382 elastomer, and 3 drops of stannous octoate are mixed and placed in a toroidal mold. The mold is cured at 40 for 4 hours, cooled, and the elastic toroidal rings so prepared are trimmed of excess polymer. Suitable rings having an outside diameter of 65 mm and weighing approximately 18 grams each can be prepared in this manner. Optionally, filler such as 10 micron size amorphous silica may be incorporated in the silicone rubber to control the rate and degree of permeability of diffusion.
We claim:
1. A 7-alkyl-3,5-unsaturated steroid having the general formula:
wherein R R R and R are each hydrogen or methyl;
R is selected from the group consisting of hydrogen,
chloro, bromo, lower alkyl having from 1 to 4 carbon atoms, phenyl, halophenyl, hydroxyphenyl, tolyl, and methoxyphenyl;
R is lower alkyl having from 1 to 3 carbon atoms;
R, is selected from the group consisting of CH CHOH and C O;
R is selected from the group consisting of hydrogen, lower alkyl having from 1 to 6 carbon atoms, lower alkenyl and lower alkynyl having from 2 to 6 carbon atoms, lower alkenynyl and lower alkadiynyl having from 4 to 6 carbon atoms;
R,, is selected from the group consisting of hydrogen,
acyl having from 2 to 12 carbon atoms, 2- tetrahydropyranyl, trimethylsilyl, l-cycloalkenyl having from 5 to 8 carbon atoms, 1- methoxycycloalkyl and l-ethoxycycloalkyl in which the cycloalkyl group has from 5 to 8 carbon atoms, and the groups R andOR when taken together are oxo or a cyclic acetal; and
R is hydrogen with the proviso that when R and R,
are hydrogen, R R R and R, cannot all be hydrogen at the same time.
2. A compound of claim 1 wherein R is methyl, R
is alpha-methyl and R is hydrogen.
3. A compound of claim 1 which is 3,7a-dimethylestra-3 ,5-dienl 7B-ol.
4. A compound of claim 1 which is 3,7a-dimethylestra-3,5-dien-l7B-ol, acetate.
5. A compound of claim 1 which is 3,7adimethyl-

Claims (5)

1. A 7-ALKYL-3,5-UNSATURATED STEROID HAVING THE GENERAL FORMULA:
2. A compound of claim 1 wherein R2 is methyl, R5 is alpha-methyl and R7 is hydrogen.
3. A compound of claim 1 which is 3,7 Alpha -dimethyl-estra-3,5-dien-17 Beta -ol.
4. A compound of claim 1 which is 3,7 Alpha -dimethyl-estra-3,5-dien-17 Beta -ol, acetate.
5. A compound of claim 1 which is 3,7 Alpha -dimethyl-androsta-3,5-dien-17 Beta -ol.
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AU65584/74A AU6558474A (en) 1973-03-26 1974-02-14 7-alkyl-delta 3,5-steroids
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GB1236874A GB1410294A (en) 1973-03-26 1974-03-20 7-alkyl-delata3,5-steroids
DE2413559A DE2413559A1 (en) 1973-03-26 1974-03-21 NEW STEROIDS, THE PROCESS FOR THEIR MANUFACTURING AND THE PHARMACEUTICAL PREPARATIONS CONTAINING THEM
FR7409975A FR2223014A1 (en) 1973-03-26 1974-03-22
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US7704983B1 (en) 1992-03-02 2010-04-27 Eastern Virginia Medical School Antiprogestin method for reducing side effects associated with low dosage HRT and oral contraception
US7538099B1 (en) 1992-03-02 2009-05-26 Eastern Virginia Medical School Antiprogestin method and kit for reducing side effects associated with low dosage HRT, oral contraception and regulating menses
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US6608074B2 (en) 1992-05-12 2003-08-19 Schering Ag Contraception method using competitive progesterone antagonists and novel compounds useful therein
US5516769A (en) * 1993-02-19 1996-05-14 The Medical College Of Hampton Roads Method of inhibiting fertilization
EP1159965A3 (en) * 1993-02-19 2002-05-22 The Medical College Of Hampton Roads Method of preventing or inhibiting fertilization
EP1159965A2 (en) * 1993-02-19 2001-12-05 The Medical College Of Hampton Roads Method of preventing or inhibiting fertilization
AU692150B2 (en) * 1993-02-19 1998-06-04 Eastern Virginia Medical School Method of preventing or inhibiting fertilization
WO1994018982A1 (en) * 1993-02-19 1994-09-01 The Medical College Of Hampton Roads Method of preventing or inhibiting fertilization
US5468736A (en) * 1993-02-25 1995-11-21 The Medical College Of Hampton Road Hormone replacement therapy
US6225297B1 (en) * 1993-12-22 2001-05-01 Schering Akitiengesellschaft Combination contraceptive

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AU6558474A (en) 1975-08-14
GB1410294A (en) 1975-10-15
FR2223014A1 (en) 1974-10-25
ZA74932B (en) 1975-01-29
CA1027929A (en) 1978-03-14
JPS49126661A (en) 1974-12-04
DE2413559A1 (en) 1974-10-17
BE812836A (en) 1974-07-15

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