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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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/xx
Priority to AU65584/74A priority patent/AU6558474A/en
Priority to CA192,667A priority patent/CA1027929A/fr
Priority to JP49028209A priority patent/JPS49126661A/ja
Priority to GB1236874A priority patent/GB1410294A/en
Priority to DE2413559A priority patent/DE2413559A1/de
Priority to FR7409975A priority patent/FR2223014A1/fr
Priority to BE142453A priority patent/BE812836A/fr
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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.

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
US344838A 1973-03-26 1973-03-26 7-Alkyl-{66 {hu 3,5{b -steroids Expired - Lifetime US3890356A (en)

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US344838A US3890356A (en) 1973-03-26 1973-03-26 7-Alkyl-{66 {hu 3,5{b -steroids
ZA00740932A ZA74932B (en) 1973-03-26 1974-02-12 7-alkyl-delta3,5-steroids
AU65584/74A AU6558474A (en) 1973-03-26 1974-02-14 7-alkyl-delta 3,5-steroids
CA192,667A CA1027929A (fr) 1973-03-26 1974-02-15 7-alkyle-.delta.3,5-steroides
JP49028209A JPS49126661A (fr) 1973-03-26 1974-03-13
GB1236874A GB1410294A (en) 1973-03-26 1974-03-20 7-alkyl-delata3,5-steroids
DE2413559A DE2413559A1 (de) 1973-03-26 1974-03-21 Neue steroide, verfahren zu deren herstellung und diese enthaltende pharmazeutische praeparate
FR7409975A FR2223014A1 (fr) 1973-03-26 1974-03-22
BE142453A BE812836A (fr) 1973-03-26 1974-03-26 Alkyl-7 delta exp.3

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5175154A (en) * 1987-11-25 1992-12-29 Research Corporation Technologies, Inc. 5 α-pregnan-20-ones and 5-pregnen-20-ones and related compounds
WO1994018982A1 (fr) * 1993-02-19 1994-09-01 The Medical College Of Hampton Roads Procede prevenant ou inhibant la fecondite
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
US6340688B1 (en) 1992-05-02 2002-01-22 Schering Aktiengesellschaft Contraception method using competitive progesterone antagonists and novel compounds useful therein
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
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

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3246022A (en) * 1964-06-04 1966-04-12 Searle & Co 3-aryl-17beta-oxy (androsta/estra)-3, 5-dienes
US3351639A (en) * 1963-03-20 1967-11-07 American Cyanamid Co 17-alkyl-20-keto substituted pregnenes, pregnadienes and methods of preparing the same
US3471531A (en) * 1966-04-07 1969-10-07 Herchel Smith Synthesis of gona-3,5-dienes
US3522281A (en) * 1966-10-28 1970-07-28 Ciba Geigy Corp Delta**3,5-7alpha-methyloestradienes
US3553213A (en) * 1969-03-17 1971-01-05 American Home Prod 17-alpha-aminoalkynyl-3-chloro 19-norsteroidal 3,5-dienes

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3351639A (en) * 1963-03-20 1967-11-07 American Cyanamid Co 17-alkyl-20-keto substituted pregnenes, pregnadienes and methods of preparing the same
US3246022A (en) * 1964-06-04 1966-04-12 Searle & Co 3-aryl-17beta-oxy (androsta/estra)-3, 5-dienes
US3471531A (en) * 1966-04-07 1969-10-07 Herchel Smith Synthesis of gona-3,5-dienes
US3522281A (en) * 1966-10-28 1970-07-28 Ciba Geigy Corp Delta**3,5-7alpha-methyloestradienes
US3553213A (en) * 1969-03-17 1971-01-05 American Home Prod 17-alpha-aminoalkynyl-3-chloro 19-norsteroidal 3,5-dienes

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5175154A (en) * 1987-11-25 1992-12-29 Research Corporation Technologies, Inc. 5 α-pregnan-20-ones and 5-pregnen-20-ones and related compounds
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
US6340688B1 (en) 1992-05-02 2002-01-22 Schering Aktiengesellschaft Contraception method using competitive progesterone antagonists and novel compounds useful therein
US20050026885A1 (en) * 1992-05-12 2005-02-03 Krzysitof Chwalisz Contraception method using competitive progesterone antagonists and novel compounds useful therein
US6608074B2 (en) 1992-05-12 2003-08-19 Schering Ag Contraception method using competitive progesterone antagonists and novel compounds useful therein
US7297702B2 (en) 1992-05-12 2007-11-20 Schering Aktiengesellschaft Contraception method using competitive progesterone antagonists and novel compounds useful therein
AU692150B2 (en) * 1993-02-19 1998-06-04 Eastern Virginia Medical School Method of preventing or inhibiting fertilization
EP1159965A3 (fr) * 1993-02-19 2002-05-22 The Medical College Of Hampton Roads Procédé de prévention ou d'inhibition de la fertilisation
US5516769A (en) * 1993-02-19 1996-05-14 The Medical College Of Hampton Roads Method of inhibiting fertilization
WO1994018982A1 (fr) * 1993-02-19 1994-09-01 The Medical College Of Hampton Roads Procede prevenant ou inhibant la fecondite
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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BE812836A (fr) 1974-07-15
ZA74932B (en) 1975-01-29
FR2223014A1 (fr) 1974-10-25
DE2413559A1 (de) 1974-10-17
GB1410294A (en) 1975-10-15
CA1027929A (fr) 1978-03-14
AU6558474A (en) 1975-08-14

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