US3758588A - New a-nor-b-homo-steroids - Google Patents

New a-nor-b-homo-steroids Download PDF

Info

Publication number
US3758588A
US3758588A US00840025A US3758588DA US3758588A US 3758588 A US3758588 A US 3758588A US 00840025 A US00840025 A US 00840025A US 3758588D A US3758588D A US 3758588DA US 3758588 A US3758588 A US 3758588A
Authority
US
United States
Prior art keywords
dioxo
oxo
homo
solution
hydroxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US00840025A
Other languages
English (en)
Inventor
O Jeger
K Schaffner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis Corp
Original Assignee
Ciba Geigy Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CH353362A external-priority patent/CH412876A/de
Application filed by Ciba Geigy Corp filed Critical Ciba Geigy Corp
Application granted granted Critical
Publication of US3758588A publication Critical patent/US3758588A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J69/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by contraction of only one ring by one atom and expansion of only one ring by one atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general

Definitions

  • R for H, lower alkyl or OR R for H, lower alkyl or OR 0 0-K OR R3 for 0, lower alkylene, or O H R being -H, an acyl group or a hydrocarbon radical.
  • These compounds have progestative, anti-inflammatory and/or glucocorticoid action.
  • the present invention relates to the manufacture of A-nor-B-homosteroids, more particularly 3-oxoand 3:6-dioxo-A-nor-B-homosteroids, starting from 3-oxo- 4:5-oxidosteroids, and to new compounds of this class which are biologically active or represent intermediates for the manufacture of biologically active compounds.
  • A-nor-B-homosteroids more particularly 3-oxoand 3:6-dioxo-A-nor-B-homosteroids, starting from 3-oxo- 4:5-oxidosteroids, and to new compounds of this class which are biologically active or represent intermediates for the manufacture of biologically active compounds.
  • new compounds of this class which are biologically active or represent intermediates for the manufacture of biologically active compounds.
  • the 3:6-dioxo-A-nor-B-homo-androstanes and -A-androstenes which have in position 175 a free or esterified hydroxyl group, and also the corresponding 3-mono-oxo-compounds; they display a high anabolic activity coupled with a very low androgenic activity.
  • the 3:6-dioxo-A-nor-B-homopregnane compounds more especially those which contain in position 20, and possibly in position ll, an oxo group, in positions 17 and/or 21 and 1 1/3 hydroxyl groups, are of very special importance as novel compounds having a progestative or anti-inflammatory action respectively.
  • the hitherto known steroids having the A-nor-B-' 6-oxo-A-nor-B- and homo skeleton namely homocholestane and 6-oxo-l7B-hydroxy-5a- -SB-A-nor-B-homo-androstane and their l7-benzoates
  • the 3-oxo-4a:5aand 4B:5fi-oxidosteroids, saturated in positions I and 2 used as starting materials can be prepared in the manner known per se from the corresponding A-3-oxo compounds, for example by treatment with alkaline hydrogen peroxide or per-acids, or by hydrogenation of A -3-oxo-4:5-oxidosteroids.
  • the last-mentioned starting materials are new; surprisingly, they can be obtained directly from A'-3-oxosteroiddienes by treatment with per-acids, for example with organic per-acids, such as lower aliphatic or aromatic per-acids, for example with peracetic, perbenzoic and monoperphthalic acid, or by dehydrogenation of the above-mentioned 1:2-satu rated 3 -oxo-4 5 oxidosteroids, for example with selenium dioxide or dicyano-dichloroquinone.
  • per-acids for example with organic per-acids, such as lower aliphatic or aromatic per-acids, for example with peracetic, perbenzoic and monoperphthalic acid
  • dehydrogenation of the above-mentioned 1:2-satu rated 3 -oxo-4 5 oxidosteroids for example with selenium dioxide or dicyano-dichloroquinone.
  • the irradiation according to the invention o f 3-oxo- 4:5-oxidosteroids is advantageously performed in an organic solvent, for example in an aliphatic or cycloaliphatic hydrocarbon such as pentane, hexane or methylcyclohexane.
  • organic solvent for example in an aliphatic or cycloaliphatic hydrocarbon such as pentane, hexane or methylcyclohexane.
  • aliphatic and cyclic ethers such, for instance, as diethyl ether or dioxane.
  • Suitable light is artificial or strong natural light; it is advantageous to use ultra-violet light such as is emitted by mercury low-pressure or high-pressure burners, or strong sunlight.
  • the irradiation is advantageously performed at a temperature ranging from 0 to +C.
  • any present ester or protective groups such, for example, as ketals or bismethylenedioxy groups, may be split hydrolytically and free hydroxyl groups may be oxidized to oxo groups.
  • the products of the present process may be converted in the known manner into their functional ketone derivatives derived from the enol form, or into metal salts.
  • acylation for example treatment with a carboxylic anhydride, such as acetic or propionic anhydride
  • etherifying agents such, for example, as alcohols or thioalcohols in the presence of an acid catalyst
  • the enolethers and, respectively, thioenolethers are obtained.
  • cyclic hydrazones are obtained which may also be looked upon as pyrazole derivatives.
  • Reaction with cupric salts furnishes the corresponding copper complexes.
  • the 5 -3-oxo-6-acyloxy-A-nor-B-homosteroids prepared by the present process can be converted into the corresponding saturated -unsubstituted 3-oxo-A-nor- B-homosteroids by catalytic hydrogenation in a manner known per se, such as hydrogenation, for example, in benzene or alcohol, with palladium carbon or palladium-barium carbonate catalyst.
  • the 3-oxo-4a:5aand 4B5B-oxidosteroids used as starting materials in the present process belong preferably to the androstane, pregnane, cholane, cholestane, spirostane or cardanolide series or to the corresponding l9-nor series and may contain, in addition to the aforementioned groupings, in one or more than one of the positions 1, 6, 7, 8, 9, l1, 12, 14, 15 2i further substituents such as alkyl (for example methyl) groups and/or halogen atoms, free or functionally converted oxo groups, or free, esterified or etherified hydroxyl groups.
  • the starting materials may coni i TR. 8:
  • Particularly important starting materials are, for example, the following compounds: 5 3-oxo-4a5a-oxidoand -4B:5B-oxido-l7- hydroxyandrostane and its esters, 3:l7-dioxo-4a:5a-oxidoand -4B:5/3-oxidoandrostane and its l7-ethyleneketal,
  • Another object of the invention are the 3:6-dioxo-A- nor-B-homosteroids, obtained by the present process, and their functional derivatives such, for example, as their enolesters (derived from the tautomeric enol a form) of organic, more especially lower aliphatic or aromatic carboxylic or sulfonic acids, such, for example, as acetic, propionic, butyric, benzoic, para-toluenesulfonic acid, and enolethers and enolthioethers, for example lower alkyl ethers and thioethers (such as methyl-, ethyland propyl-ether and thioether) as well as the corresponding metal salts, for example copper complexes.
  • their enolesters derived from the tautomeric enol a form
  • organic more especially lower aliphatic or aromatic carboxylic or sulfonic acids, such, for example, as acetic, propi
  • Especially valuable compounds are such of the formulae l and ll I i R5 ...R
  • H H H and R and R for a member selected from the group consisting of. H, lower alkyl and O R, R together with R a member selected from the group consisting of for a member selected from the group consisting of 0,
  • R for a member selected from the group consisting of -H and -O-R and R is a member selected from the group consisting of -H, an acyl group, a hydrocarbon radical, X and Y each is a member selected from the group consisting of hydrogen and methyl, and the ldehydro derivatives, tautomeric forms and the enol esters and ethers thereof, with the proviso that R in 1,2-
  • saturated compounds be different from when X is hydrogen, that R be different from acyl in R and R when taken together and that the ether groups are derived from alcohols having from one to 8 carbon atoms and the esters are derived from acids having from one to 15 carbon atoms.
  • R stands for a free' or esterified or etherified hydroxyl group together with a hydrogen atom or a lower alkyl group exhibit a high anabolic action.
  • R stands for a free' or esterified or etherified hydroxyl group together with a hydrogen atom or a lower alkyl group
  • the anabolic action develops also upon peroral administration.
  • These compounds are therefore suitable for use as medicaments for the treatment of all conditions requiring an increased protein synthesis, such as chronic loss in weight, post-operative and postinfection conditions, anorexia and osteoporosis, more especially in geriatry.
  • Particularly suitable are the following compounds: 3z6-dioxo-l7B-hydroxy-A-nor-B-homo-androstane and its esters,
  • the anabolic effect may be measured pharmacologically in fully grown, male castrated rats by the socalled levator-ani test, by giving the animals increasing doses of the substance to be tested and measuring the increasing weight of the involuted levator ani muscle.
  • An optimal effect may be considered that which represents a full restitution of the muscle to the weight of that muscle in normal control animals.
  • Such complete restitution is attained with very small doses of the substances of the present invention. For instance, when 3 :6-dioxol 7B-hydroxyl 7a-methyl-A-nor-B-homoandrostane is administered subcutaneously, the optimal anabolic effect corresponding to said complete restitution is attained with a dose of approximately 0,3 mg/kg daily, for days.
  • the androgenic effect of the substance may similarly be measured by determining the increase in weight of the involuted seminal vesicles of the castrated animals.
  • the optimal androgenic dose viz. that provoking a complete weight restitution of the seminal vesicles, as compared to the controls, is evaluated.
  • this androgenic dose is 13 to times higher than the optimal anabolic dose when the administration is effected by the subcutaneous route.
  • the absolute value of the anabolic effect is extremely high with this compound, the optimal dose under the afore-mentioned experimental conditions being 0'.03 mg/kg body weight daily for 15 days when given subcutaneously and 1.0 mg/kg daily for 15 days when given orally.
  • R stands for a free or esterified or etherified hydroxyl group together with an unsaturated hydrocarbon radical, especially a vinyl, allyl, ethinyl or propinyl group, which may also be halogenated, e.g., fluorinated, show a gestagenic or ovulation inhibiting action.
  • oestrane compounds and their l-dehydro derivatives for example A -3 :6-dioxol 7,6-hydroxyl 7a-vinyland 1 7aethinyl-A-nor-B-homo-androstene and their esters and A -3:6-dioxo-l7B-hydroxy-l 7a-vinyland -l 7aethinyl-A-nor-B-homo-oestrene and their esters.
  • A'-3z6:20-trioxo-A-nor-B-homo-pregnene A-3 26:20-trioxol 7a-hyd roxy-A-nor-B-homopregnene and its esters, 3:6:20-trioxo l6, l7 dihydroxy-A-nor-"B-homopregnane, and their 6-enol-esters and/or l7 esters or ethers, for example the 6- or l7a-acetates or 16a, 17aacetonides of the 1601, l7a-dihydroxy derivatives.
  • R represents a hydrogen atom or a methyl group and R is a free or esterified hydroxyl group as well as 6-enol-esters or 6-enol-ethers thereof.
  • R represents a hydrogen atom or a methyl group and R is a free or esterified hydroxyl group as well as 6-enol-esters or 6-enol-ethers thereof.
  • A'-3:6:l 1:20-tetraoxol 701:2 l -dihydroxy-A-nor-B- homo-pregnene its lower aliphatic carboxylic acid es ters, such as the acetate, the trimethylacetate, the propionate, valerate caproate etc., and the 7-methylderivatives of these compounds.
  • All compounds of formulae 1 and [1 above may also be employed in veterinary medicine, e.g., as additives to animal fodder.
  • acyl radicals in the above-mentioned esters are more especially those of aliphatic, cycloaliphatic, araliphatic, aromatic or heterocyclic carboxylic acids containing one to 15 carbon atoms, for example formiates, acetates, propionates, butyrates, trimethylacetates, caproates, valerates, oenanthates, decanoates, undecylenates, cyclopentylpropionates, hexahydrobenzoates,
  • phenylpropionates benzoates, furoates, trifluoracetates, ethyl or methyl carbonates, or the like.
  • Ethers are primarily derived from aliphatic, araliphat'ic, cycloaliphatic or heterocyclic alcohols preferably having from 1 to 8 carbon atoms, for example from methanol, ethanol, propanol, benzyl alcohol, cyclopentanol or tetrahydropyranol, e.g., the radical therefrom may be methyl, ethyl, propyl, benzyl, cyclopentyl or tetrahydropyranyl.
  • 6-mono-esters and. 6-monoethers as derived from the enol form of the steroids said, as well as 17-mono-est ers or ethers or 6, 17- diesters or diethers may be prepared from the unesterified compounds.
  • acylation of a 3 ,6-dioxo-17a-a1kyl-17B-hydroxy-androstane or oestrane compound for example, by treatment with carboxylic acid anhydride such as acetic or propionic anhydride at room temperature, the 6-enolesters are obtained, whereas treatment with an etherifying agent, for example, by acylation of a 3 ,6-dioxo-17a-a1kyl-17B-hydroxy-androstane or oestrane compound, for example, by treatment with carboxylic acid anhydride such as acetic or propionic anhydride at room temperature, the 6-enolesters are obtained, whereas treatment with an etherifying agent, for example, by acylation of a 3 ,6-dioxo-17a-a1kyl-17B-hydroxy-androstane or oestrane compound, for example, by treatment with carboxylic acid anhydride such as acetic or propionic anhydride at room temperature, the 6-
  • an alcohol such as an alkanol
  • an acidic catalyst gives rise to the corresponding enolethers.
  • the acylation is preferably performed at elevated temperature. In the 6, 17-diesters thus obtained it is possible to liberate the 6-enol ester group by acid hydrolysis, thus rendering accessible the 17-monoesters.
  • the acylation affords preferably the 6, 17a-diesters, from which there are obtained 6- mono-esters by mild alkaline hydrolysis and 17-monoesters by acidic hydrolysis.
  • the new pharmacologically active compounds can be used for the manufacture of pharmaceutical preparations. These contain said active compounds together with a solid or liquid medicinal excipient. More particularly the preparations of the present invention are characterized by the content of one of the new A-nor- B-homo-steroids.
  • the preparations are made by as such known methods, for example, with the use of pharmaceutical organic or inorganic excipients, suitable for parenteral, enteral' and particularly oral, or'also topic administration.
  • Suitable excipients are substances that do not react with the new compounds such, as for example, water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatine, lactose, starch, magnesium stearate, talc, white petroleum jelly, cholesterol or other medicinal excipients. More especially, preparations are made which are suitable for parenteral administration, preferably solutions, above all oily or aqueous solutions: furthermore suspensions, emulsions or implants;
  • the preparations may be sterilized or they may contain assistantssuch as preserving, stabilizing, wetting or emulsifying agents, salts for regulating the osmotic pressure or buffers. They may also contain 8 other therapeutically active compounds. They are prepared in the known manner.
  • the content of the active substance in these preparations, such as of a tablet, is preferably 0.01-20 mg or 0.03 50%, especially 0.1 to 10 by weight.
  • Said pharmaceutical preparations can be used in human or veterinary medicine.
  • the irradiation with ultra-violet rays is performed under nitrogen in a quartz vessel in which the source of light is centrally disposed and which'is cooled by means ,of water.
  • the light sources used are low-pressure burn- EXAMPLE 1
  • a mixture of 15 grams of l-dehydrotestosterone acetate and a solution of perbenzoic acid in ml of chloroform (8.5 mg per ml) is kept for 4 days in the dark at room temperature.
  • the reaction solution is then diluted with ether and agitated successively with aqueous solutions of potassium iodide and sodium thiosulfate.
  • a partially crystalline crude product is obtained which is chromatographed on alumina.
  • a 2:1-mixture of benzene and hexane elutes 3.6 grams of a crystalline fraction, while a 1:1-mixture of benzene and 'ether elutes 7.5 grams of unchanged startingmaterial.
  • the first fraction is recrystallized four times from acetone+hexane and furnishes 2.15 grams of A -3-ox0- 4B:5B-oxido-17B-acetoxyandrostene. Constant melting point: 144 C. Optical rotation [(110 +250 (c 1.02). Ultra-violet spectrum: A 232 p. (log or 3.96). Infra-red spectrum (in chloroform): 11 1,725, 1,680, 1,623, 1255 cm.
  • EXAMPLE 4 A solution of 2.0 grams of A-3-oxo-4B:5fl-oxido- 17B-acetoxyandrostene in 200 ml of dioxane is irradi ated for 40 hours with a low-pressure burner, and then evaporated under vacuum. In the thin-layer chromatogram [eluantz benzene+methanol 19:1] of the crystalline residue no starting material can be detected. After three recrystallizations from methylene chloride+methanol there are obtained 1.60 grams of A-3:6-dioxo- 17B-acetoxy-A-nor-B-homoandrostene (constant melting point+ 171 172C). Ferric chloride test: positive.
  • EXAMPLE 6 450 mg of A'-3:6-dioxo-17B-acetoxy-A-nor B- homoandrostene are hydrogenated in the presence of 450 mg of palladium black of 5% strength in 50 ml of benzene. When the absorption of hydrogen has ceased (1 mol, after 30 minutes) the solution is filtered through Celit and the filtrate is evaporated under vacuum. The residue is chromatographed on silica gel.
  • EXAMPLE 7 1.20 grams of 3-oxo-4B:5fl-oxido-l7B-acetoxyandrostane in 120 ml of dioxane are irradiated for 54 hours with a low-pressure burner, and the solution is then evaporatedunder vacuum. According to its thinlayer chromatogram leluant: 19:1-mixture of benzene and methanol] the residue contains starting material and about 25% of 3:6-dioxo-l7B-acetoxy-A-nor-B- homoandrostane. Ferric chloride test: positive. Ultraviolet spectrum: )t 293 p. (log e 3.32). The two compounds are very difficult to separate by chromatography on silica gel.
  • EXAMPLE 8 crystals which, after three recrystallizations from methylene chlofifie-l rnethanol, melt at 154-156C (100 mg) and according to their mixed melting point and infrared spectrum are identical with the compound described in Example 6.
  • the compound According to its mixed melting point, infra-red spectrum and ultraviolet spectrum (A 291 t, log 6 3.97), the compound is identical with 3:6-dioxo-l7B-acetoxy-A-nor- B-homoandrostane.
  • EXAMPLE 10 440 mg of A-3:6-dioxo-17B-acetoxy-A-nor-B- homoandrostene are kept for 6 days at room temperature in 10ml of a 1:1-mixture of acetic anhydride and pyridine. The solution is then evaporated to dryness under vacuum and the crystalline residue is dissolved in 9:1 benzene+ ether and filtered through silica gel, to yield 350 mg of A -3-oxo-6:17B-diacetoxy-A-nor-B- homoandrostadiene which, after three recrystallizations from acetone+hexane, melts at 120 121C. Ferric chloride test: negative.
  • a solution of 80 mg of A-3:6-dioxo-17B-acetoxy-A- nor-B-homoandrostene in '20 ml of ethanol is mixed with a solution of 0.5 gram of copper acetate and 2 grams of sodium acetate in 20 m1 of water, whereupon the reaction solution turns instantaneously green. After minutes it is poured into water and extracted with benzene. Evaporation of the organic phase under vacuum yields 94 mg of green crystals which, according to their thin-layer chromatogram [eluant: benzene:methanol 19:1], are uniform.
  • EXAMPLE 13 A solution of 80 mg of 3:6-dioxo-l 7B-acetoxy-A-nor- B-homoandrostane in ml of ethanol is mixed with a solution of 0.5 gram of copper acetate and 2 grams of sodium acetate in 20 ml 'of water. The solution immediately turns green and after '15 minutes it is poured into water, and with benzene 90 mg of green crystals are isolated which, according to their thin-layer chromatogram [eluant benzene+methanol 19:1], are uniform.
  • EXAMPLE 16 3 grams of 3-oxo-4Bz5B-oxido 1 7B- acetoxyandrostane and 900 mg of selenium dioxide are mixed with 150 ml of tertiary butanol and 1.5 ml of glacial acetic acid. The suspension is reflexed for 24 hours under nitrogen, then another 900 mg of selenium dioxide are added and the whole is boiled for 24 hours longer. The cooled solution is freed by decantation from the precipitated selenium, evaporated and the residue is dissolved in ethyl acetate.
  • EXAMPLE 17 9 grams of A -3-oxo-l7a-methyl-l7B-hydroxyandrostadiene in a solution of perbenzoic acid in 140 ml of chloroform (35 mg per ml) are kept for 4 days in the dark at room temperature. The reaction solution is then diluted with ether and agitated with aqueous potassium iodide solution and then with aqueous sodium thiosulfate solution, to yield 9.1 grams of a crude product which is chromatographed on neutral alumina (activity Ill; 30 times the amount).
  • the product is a mixture of 85% of 3-oxo-4flz5floxido-l7fl-hydroxy-17a-methyl-A -androstene and 15% of 3oxo-4a:5cz-oxido-'17B-hydroxy-l7a-methyl- A -androstene.
  • EXAMPLE 18 Under the conditions described in Example 4 the bismethylenedioxy compound of prednisolone yields via the corresponding 4az5a-oxido or 413:5]S-oxido compound (prepared as described in Example 1) the 17 :20- ;20:2l-bis-methylenedioxy compound of A-3:6:20- trioxo-l 16:1701:2l-trihydroxy-A-nor-Bhomopregnene which, on hydrolysis, furnishes free A-3:6:20 trioxol 1B:1701:2l-trihydroxy-A-nor-B-homopregnene.
  • EXAMPLE 250 mg of A -3-oxo-6:l7-diacetoxy-A-nor-B- homoandrostadiene are hydrogenated in 20 ml of henzene with 250 mg of palladium black of 5% strength. The absorption of hydrogen is ml in 20 minutes. After the solution has been freed from the catalyst, it is evaporated under vacuum and the residue is chromatographed on 7 grams of acid alumina (activity 11). 85 mg of crystals are isolated with a lzl-m'ixture of hexane and benzene, which, after two recrystallizations from etherzpentane and sublimation under high vacuum, melt at 139 -l40C. Optical rotation [a],, 1 12 (c 0:49). The compound is'pure 3-oxo-17B- acetoxy-A nor-B-homoandrostane.
  • EXAMPLE 21 l7B-acetoxy-A-nor-B-homoandrostane which is recrystallized twice from etherl pentane and sublimed in a high vacuum. the melting point is 139 140C. Optical rotation [01],, 1 16 (c 0.43). Infra-red spectrum in chloroformzh 1727, 1258 cm. The compound is identical with the compound described in Example 20.
  • EXAMPLE 22 1.5 g of A -3:20dioxo-4:5-oxido-17a-acetoxy pregnene in 500 ml of dioxane are irradiated for 72 hours at 26 to 29C with a low-pressure burner, and the solution is then evaporated under vacuum. The residue is dissolved in 50 ml of alcohol, diluted with 150 ml of ether and agitated in a separating funnel with 10 ml of ice-cold sodium hydroxide solution of 10% strength in 50 ml of water.
  • the share that does not react with sodium hydroxide solution amounts to 0.5 g and is unreacted starting material.
  • the starting material may be prepared thus:
  • a solution of 10 g of A-3:20-dioxo-17aacetoxypregnene in 100 ml of methylene chloride and 300 ml of methanol is mixed at 0C dropwise with 60 ml of hydrogen peroxide of 30% strength and 20 ml of sodium hydroxide solution of 10% strength and stirred for 27 hours at 0C.
  • the reaction mixture is then poured into ice water and extracted with methylene chloride and ether. After washing neutral, drying and evaporating under vacuum there are obtained 9 g of crude 3:20-dioxol 7a-acetoxy-4:5-oxidopregnane which is used as it is, without purification, for the following step.
  • a solution of 5.16 g of crude 3:20-dioxo-17aacetoxy-4:5-oxidopregnane in ml of tertiary amyl alcohol is mixed with 2.5 ml of glacial acetic acid and 0.5 g of mercury, heated to the boil, and a solution of 2.5 g of selenium dioxide in 32 ml of tertiary amyl alcohol is vigorously stirred in dropwise. After 14 hours, the batch is cooled, filtered through a layer of Norite and the filtrate is evaporated under vacuum.
  • the catalyst is filtered off and the filtrate-is evaporated. The residue constitutes 3:6:2-
  • EXAMPLE 25 4.15 g of A -3-oxo-4z5-oxido-l7a-methyl-l7fiacetoxyandrostene in 500 ml of dioxane are irradiated for 72 hours at 26 to 30C with a low-pressure burner,
  • Example 23 The share soluble in sodium hydroxide solution amounts to 3.63 g and constitutes A'-3:6-dioxo-l7amethyl- 1 7B-acetoxy-A-nor-B-homoandrostene which, after recrystallization from methylene chloride-l-ether, melts at 206 210C.
  • A-3-oxo-20B-hydroxypregnene (melting at 167 170C) is oxidized with alkaline hydrogen peroxide as described in Example 23, the resulting product is treated with acetic anhydride-lrpyridine, and the 3-oxo- 4:5-oxido-ZOB-acetoxypregniirie so formed is dehydrogenated with selenium dioxide to furnish A 3- oxo-4:5- oxido fl-acetoxypregnene.
  • EXAMPLE 28 800 mg of A-3:6-dioxo-20fi-hydroxy-A-nor-B- ho'mopregnene in 200 ml of benzene are hydrogenated in the presence of 800 mg of palladium carbon of 5% strength; When the amount of hydrogen calculated'for 1 mol has been abs'orbed,the catalyst is filtered'off and the filtrate is evaporated under. VacuumL The resulting 3:6-dioxo 20BhydroXy-A-nor-B-homopregnane melts at l 17 to 118C after crystallization from ether-I-pentane.
  • EXAMPLE 29 1.5 g of the lactone of A -3-oxo-4z5-oxide-l7fihydroxy-17a (fl-carboxyethyl)-androstene in 500 m1 of dioxane are irradiated for 72 hours at 26 to 29C with a low-pressureburner; the solution is then evaporated under vacuum and the residue is treated as described in Example 23.
  • the extract obtained with sodium hydroxide solution is the lactone of A -3z6- dioxo-l7flhydroxy-1.7d-(B-carboxyethyl)-A-nor-B- v v I homoandrostene; it melts after recrystallization from methylene chloride-etherat 185 186C, [01],, +85.
  • the starting material can bep repared from the lactone of A -3-oxo-l7B-hydroxy-l7a-(B-carboxyethyl)- androstene by oxidation with-hydrogen peroxide and subsequent dehydrogenation with selenium dioxide as described in Example 23.
  • EXAMPLE 32 dium hydroxide solution'and the extract acidified with EXAMPLE 33 1.5 grams of A -3-oxo-4:5-oxido-7a-methyl-17B- acetoxy-androstene in 500 cc of dioxane are irradiated as described in Example 23, A -3z6-dioxo-7aa-methyl- 17/3-acetoxy-A-nor-B-homo-androstene being obtained.
  • a dimethyl-17p-hydroxy-androstene is converted into A -3 :6-dioxo-7aa 17B-dimethyl-17,8-hydroxy-A-norf B-homo-androstene.
  • EXAMPLE 34 In the catalytic hydrogenation according to Example 6 there are obtained from the compounds listed under A the hydrogenation products listed under B A. Starting materials A'-3:6:20-trioxo 1 7acapronyloxy-A-nor-B- homo-pregnene A'-3:6:20-trioxo-l7amethyl-A-nor-B-homopregnene A-3:6-dioxo-7aa-methyll7B-acetoxy-A-nor-B- B.
  • EXAMPLE 35 1.5 grams of A-3:20-dioxo-4z5-oxido-1lfizl'la-dihydroxy-21-acetoxy-pregnene are irradiated and worked up as described in Example 23, A -3:620 trioxo-l 15:1 7a-di-hydroxy-21-acetoxy-A-nor-B-homopregnene being obtained and A'-3:6:20-trioxo- 1 1 B: l 711:2 l trihydroxy-A-nor-B-homopregnene formed by partial hydrolysis during extraction with so dium hydroxide solution.
  • the sodium hydroxide extract is acidified with dilute hydrochloric acid, axtracted with methylene chloride and evaporated, to yield 310 mg of crude A -3,6,l 1,20-tetraoxo-l 7,2 l -dihydroxy-A-nor- B-homopregnene. (The 21-acetate is hydrolysed during the working up).
  • the product is purified by chromatography on 30 times its own weight of silica gel. Elution with benzene and with benzene+ether yields about 60 mg of oily products; elution with ether furnishes the pure compound which, after having been recrystallised from methylene chloride+ether, melts at 184 186C.
  • the crystalline residue is twice recrystallised from aqueous methanol, whereupon it melts at 132C, and is A3,6-dioxo-l7B-acetoxy-l-methyl-A-nor-B- homo-androstene or A- -3-oxo-6-hydroxy-17B- acetoxyl -methy1-A-nor-B-homo-androstadiene respectively.
  • a specimen is sublimed in a high vacuum at 125C.
  • the starting material is prepared as follows:
  • EXAMPLE 39 350 mg of A-3-oxo-4,5-oxido-17B-acetoxy-oestrene in 70 ml of dioxane are irradiated for 3hours with a mercury vapour low-pressure burner, and the solution is then evaporated under vacuum. The residue is taken up in ether and the ethereal solution washed with icecold 2N-sodium hydroxide solution. The basic equeous extracts are immediately acidified with dilute sulphuric acid and then extracted with ether.
  • the resulting organic phase is washed with water until neutral, dried and evaporated, to leave 200 mg of crystalline photoproduct, namely A-3,6-dioxo-l7B-acetoxy-A-nor-B-- -homo-oestrene or A -3-oxo-6-hydroxy-l7fl-acetoxy- A-nor-B-homo-oestradiene respectively.
  • the product is treated for a short time in benzene with active carbon and then dissolved in a 9:1-mixture of benzene and ether and filtered through neutral silica gel. After having been recrystallised three times from methylene chloride+methanol the product melts at 171 172C.
  • the starting material is prepared as follows:
  • EXAMPLE 40 700 mg of 3-oxo-4,5-oxido-l7B-acetoxy-oestrane in 200 ml of dioxane are irradiated for 2 hours with a mercury vapour high-pressure burner. The solution is then evaporated under vacuum and the residue chromatographed on 60 times its own weight of neutral silica gel. A 9:1-mixture of benzene and ether elutes 598 mg of 3 ,6-dioxo-17B-acetoxy-A-nor-B-homo-10-oestrane or A -3-oxo-6-hydroxy-l7B-acetoxy-A-nor-B-homo-10;- oestrene respectively.
  • the starting material is prepared as follows:
  • EXAMPLE 41 500 mg of 3-oxo-4,5-oxido-l7B-hydroxy-7aa,17adimethyl-oestrane (melting at 138 140C after recrystallisation from ether) in ml of dioxane are irradiated for 13 hours with a mercury vapour high-pressure burner.
  • 3-oxo-4,5-oxido-l7B-hydroxy-17aethinylandrostane (m.p. 168-174C, from 14 chloride+ether) 3 ,6-di0xo-17B-hydroxy-17aethinyl-A-nor-B- homoandrostane or A E-0x06, l 7fl-dihydroxy- 1 7aethinyl-A-nor-B- homoandrostene (m.p. 166168C, from methylene chloride-tether).
  • EXAMPLE 42 3.45 g of 3-oxo-4,5-oxido-20-ethylenedioxy-Z1- acetoxypregnane in 255 ml of dioxane are irradiated for 13 hours with a high-pressure burner at a temperature of 17 to 18C. The solution is then evaporated, to leave as residue crude 3,6-dioxo-20-ethylenedioxy-21- acetoxy-A-nor-B-homopregnane; to purify it, it is dissolved in methylene chloride and chromatographed on silica gel (containing 5% of moisture).
  • the residue of the methylene chloride eluates is recrystallized from methanol to yield the pure product melting at 126 131C.
  • the mother liquor is evaporated, and the residue is dissolved in 60 ml of methanol, mixed with a solution of 1 g of potassium carbonate in 20 ml of water and hydrolyzed by being boiled for 2 hours under reflux.
  • the solution is evaporated under vacuum and the residue agitated with ethyl acetate.
  • the ethyl acetate solutions are combined, washed with water, dried and evaporated under vacuum.
  • the residue is taken up in a 1:3-mixture of methylene chloride and ether and repeatedly agitated with ice-cold 2N-sodium hydroxide solution.
  • the combined sodium hydroxide extracts are adjusted at 0C with phosphoric acid to pH 4 to 5 and exhaustively extracted with methylene chloride.
  • the methylene chloride solutions are washed with water, dried and evaporated under vacuum. After repeated recrystallization from a mixture of methylene chloride and isopropyl ether there are obtained 1.56 g of pure 3,6- dioxo-20-ethylene-dioxy-2 l -hydroxy-A-nor-B-homopregnane melting at 164 165C.
  • the starting material used above is obtained from the known A -3,20-bisethylenedioxy-2 l -acetoxypregnene by partial deketalization in 3-position with a mixture of paratoluenesulfonic acid and acetic acid in acetone.
  • the resulting monoketal is mixed with hydrogen peroxide in the presence of alkali and the hydrolyzed 21- acetoxy group is finally reacetylated with acetic anhydride in the presence of pyridine.
  • Irradiation as described above may also be performed with 3-oxo-4,5-0xido-20-ethylenedioxy-21- hydroxypregnane, whereupon 3,6-dioxo-- ethylenedioxy-21-hydr0xy-A-nor-B-hompregnane is obtained as irradiation product.
  • EXAMPLE 44 5 g of 3-Oxo-4,5-oxido-20-ethylenedioxypregnane in 900 ml of dioxane are irradiated for 48 hours with a high-pressure burner at 17 to 18C. The solution is evaporated and the residue dissolved in a 1:3-mixture of methylene chloride and ether, and the solution is repeatedly agitated with ice-cold 8% sodium hydroxide solution. The combined sodium hydroxide extracts are mixed at 0C with phosphoric acid to pH 4 to 5 and the whole is exhaustively extracted with methylene chloride. The methylene chloride extracts are washed with water, dried and evaporated under vacuum.
  • the above-mentioned starting material is accessible from the known A -3B-acetoxy-2O-ethylenedioxypregnene by alkaline hydrolysis, oxidation of the resulting A -3-hydroxy-compound with chromium trioxide to A 3-oxo-20-ethylene-dioxy-pregnene, followed by treatment with hydrogen peroxide in the presence of sodium hydroxide solution.
  • EXAMPLE 45 700 mg of 3-oxo-4,5-oxido-l6a,l7a-dihydroxy-20- ethylenedioxypregnane in 140 ml of dioxane are irradiated for 13 hours with a high-pressure burner at 20C. The solution is evaporated and the residue dissolved in ether and repeatedly agitated with ice-cold 2% sodium hydroxide solution. The aqueous extracts are combined, adjusted at 0C with phosphoric acid to pH 4 to 5 and exhaustively extracted by agitation with methylene chloride. The methylene chloride solutions are combined, washed with water, dried and evaporated under vacuum.
  • the starting material used above is obtained from A -3B-acetoxy-2O-ethylenedioxypregnadiene by alkaline hydrolysis and Oppenauer oxidation to A"-3-ox0- 20-ethylenedioxypregnadiene, oxidation with hydrogen peroxide to the corresponding 4,5-oxido compound, followed by hydroxylation of the 16,17-double bond with osmium tetroxide.
  • EXAMPLE 46 A solution of 2.168 g of 3-oxo-4,5-oxido-l 1B- hydroxyl 7d,20;20,2 l -bismethylenedioxypregnane (mixture of the 4a,5aand 4B,5B-oxido compounds) in 500 ml of pure dioxane is vigorously stirred at 18 to 22C while being irradiated with a mercury vapour high-pressure lamp until a specimen of the reaction mixture reveals that the infrared absorption has reached a maximum at 6.08 and 6.24p.. This is generally the case after 8 to 16 hours. The solution is then benzene+ethyl acetate (85:15) fractions.
  • the extracts are washed with 0.4N-sodium bicarbonate solution and with water, dried over sodium sulfate and evaporated to yield 0.372 g of a crystalline crude product; for purification it is dissolved in 100 ml of benzene and the solution is filtered through a column of 10 g of silica gel prepared with benzene, while being further eluted with benzene+ethyl acetate mixtures 95:5, 85:15 and 50:50.
  • the starting material used in the above Example can be prepared as follows:
  • the alkali is neutralized at C with 62.5 ml of 1.5N-orthophosphoric acid; the-reaction solution is poured over a mixture of 250 g of ice and 500 ml of ice-cold water and extracted by agitation with ice-cold methylene chloride. The ice-cold extracts are washed with water,
  • the mixture of the active ingredient, lactose and wheat starch is moistened with a gelatine solution of 10% strength to form a slightly plastic mass, and then granulated in the usual manner. After being dried at 40C, the mass is brought into the usual grain size by being passed through a sieve. Arrowroot, magnesium stearate and talc are added to the dried mass and the mixture is then compressed into tablets of 7 mm in diameter.
  • EXAMPLE 48 1,000 Tablets each containing 1 mg of the active substance. Ingredients:
  • EXAMPLE 49 1,000 Tablets each containing 1 mg of the active sub- 50 stance. Ingredients:
  • EXAMPLE 50 In the manner described in Examples 47 to 49 tablets can be prepared each containing 25 mg of the lactone of A-3:6-dioxo-l7B-hydroxy-17a-(B-carboxy-ethyl)- A-nor-B-homo-androstene or 1 to 5 mg of the active products described in the following Examples.
  • the mixture of the active substance with lactose is moistened with an aqueous solution of saccharose and granulated in the usual manner. After being dried, the sieved granulate is mixed with stearic acid and talc and then compressed into linguettes.
  • EXAMPLE 52 100 Oil ampoules each containing 25 mg/ml of the active substance. Ingredients:
  • the active ingredient is dissolved in benzyl alcohol and the stirred solution diluted with hot sterilized sesame oil. 1 ml of this solution containing the ingredients in the above given amounts is filled in ampoules which are sterilized at 160C for 1.5 hours.
  • EXAMPLE 53 100 Oil ampoules each containing 10 mg/ml of the active substance. Ingredients:
  • the active substance is dissolved in 5 to ml of pure acetone and the acetone evaporated. The residue is then dissolved in the sesame oil which has been purified and sterilized by heating it to 180C for two hours. The solution obtained is filtered through a glass filter and 1 ml of the filtrate is filled in ampoules which are sterilized at 160C for L5 hours.
  • EXAMPLE 54 in the manner described in Examples 52 and 53 oil ampoules can be prepared each containing 10 to 25 mg of Ai -3 -oxo-6: l 7B-diacetoxy-A-nor-B-homoandrostadiene, A-3:6-dioxo-l7B-acetoxy-l9-nor-A- nor-B-homo-androstene, A-3:6:20-trioxo-l7acapronyloxy-A-nor-B-homo-pregnene or 3:6-dioxo- 7aa-methyli 7fl-acetoxy-A-nor-B-homo-androstane.
  • EXAMPLE 55 1,000 Tablets of an anabolic preparation containing 3 ,o-dioxo-l 7/3-hydroxy-7aa l 7a-dimethyl-A-nor-B- homo-oestrane are manufactured from the following ingredients:
  • Oil ampoules each containing 0.05 mg/ml of the active substance Oil ampoules each containing 0.05 mg/ml of the active substance. Ingredients:
  • EXAMPLE 56 100 Oil ampoules of an anabolic preparation for parenteral administration, each containing 25 mg per ml of A'-3,6-dioxo-l7B-acetoxy-l-methyl-A-nor-B-homoandrostene are manufactured from the following ingredients:
  • A-3,6dioxol 7B-acetoxy- 1 -methyl- A-nor-B-homo-androstene 2.5 g benzyl alcohol l0 ml sesame oil 90 ml
  • the active principle is dissolved in the benzyl alcohol and the stirred solution is diluted with sesame oil sterilised at an elevated temperature. 1 ml of this solution, which contains the above proportions of the ingredients, is charged into ampoules which are then sterilised for l '12 hours at C.
  • anabolic preparations can be prepared which are suitable for parenteral administration and contain as active principle A-3,6-dioxo-17B- acetoxy-A-nor-B-homo-oestrene or 3,6-dioxo-17B- acetoxy-A-nor-B-homol 0-oestrane.
  • EXAMPLE 57 1000 Tablets of a gestagenic pharmaceutical preparation each containing mg of 3,6-dioxo-l7B-hydroxy- 17a-ethinyl-A-nor-B-homo-oestrane are manufactured from the following ingredients:
  • gestagenic preparations for oral administration containing 3,6-dioxo-l7fihydroxy-17a-ethinyl-A-nor-B-homoandrostane as active principle, can be manufactured.
  • EXAMPLE 58 1,000 Tablets of a pharmaceutical preparation for use as an antiphlogistic, each containing 1 mg of A 3 ,6,1 l, ZO-tetraoxo- 1 701,2 1 -dihydroxy-A-nor-B- homopregnene, are manufactured from the following ingredients:
  • EXAMPLE 59 1,000 Tablets of an anabolic preparation each containing 5 mg of 3,6-dioxo-l7B-hydroxy-l7a-methyl-A- nor-B-homo-androstane are manufactured from the following ingredients:
  • acyl radical is that of an acid selected from the group consisting of formic, acetic, propionic, butyric, trimethylacetic, caproic, valeric, oenanthic, decanoic, undecylenoic, cyclopentyl proprionic, hexahy drobenzoic, phenylpropionic, benzoic, furoic, trifluo- I roacetic, ethyl carbonic and methyl carbonic acids.
  • the acyl radical is that of an acid selected from the group consisting of formic, acetic, propionic, butyric, trimethylacetic, caproic, valeric, oenanthic, decanoic, undecylenoic, cyclopentyl proprionic, hexahydrobenzoic, phenylprop
  • X is a member of the group consisting of hydrogen and methyl, the corresponding l-dehydro compounds the enol esters of acids selected from the group consisting of acetic, propionic, butyric, benzoic, and para-toluenesulfonic acids and the lower alkyl enol ethers and thioethers thereof, with the proviso that R be different from acyl in R and R when taken together.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US00840025A 1962-03-23 1969-07-08 New a-nor-b-homo-steroids Expired - Lifetime US3758588A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CH353362A CH412876A (de) 1962-03-23 1962-03-23 Verfahren zur Herstellung neuer 3,6-Dioxo-A-nor-B-homo-steroide
CH984462 1962-08-17
CH1442262 1962-12-07
CH288063 1963-03-07

Publications (1)

Publication Number Publication Date
US3758588A true US3758588A (en) 1973-09-11

Family

ID=27428524

Family Applications (1)

Application Number Title Priority Date Filing Date
US00840025A Expired - Lifetime US3758588A (en) 1962-03-23 1969-07-08 New a-nor-b-homo-steroids

Country Status (10)

Country Link
US (1) US3758588A (enrdf_load_stackoverflow)
AT (1) AT257062B (enrdf_load_stackoverflow)
BR (1) BR6347875D0 (enrdf_load_stackoverflow)
DK (1) DK117223B (enrdf_load_stackoverflow)
ES (1) ES286306A1 (enrdf_load_stackoverflow)
FR (1) FR3015M (enrdf_load_stackoverflow)
GB (1) GB1040177A (enrdf_load_stackoverflow)
MY (1) MY7000065A (enrdf_load_stackoverflow)
NL (2) NL122977C (enrdf_load_stackoverflow)
SE (1) SE314062B (enrdf_load_stackoverflow)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3040093A (en) * 1960-11-07 1962-06-19 Roussel Uclaf A-nor-b-homo-steroids and process of preparing same
US3138635A (en) * 1961-06-19 1964-06-23 Roussel Uclaf Novel alpha-nor-beta-homo-steroids
US3192266A (en) * 1961-06-16 1965-06-29 Roussel Uclaf 17alpha-ethynyl-17beta-hydroxy-a-nor-b-homoestranes and their process of preparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3040093A (en) * 1960-11-07 1962-06-19 Roussel Uclaf A-nor-b-homo-steroids and process of preparing same
US3192266A (en) * 1961-06-16 1965-06-29 Roussel Uclaf 17alpha-ethynyl-17beta-hydroxy-a-nor-b-homoestranes and their process of preparation
US3138635A (en) * 1961-06-19 1964-06-23 Roussel Uclaf Novel alpha-nor-beta-homo-steroids

Also Published As

Publication number Publication date
GB1040177A (en) 1966-08-24
FR3015M (fr) 1964-12-21
DK117223B (da) 1970-03-31
AT257062B (de) 1967-09-25
ES286306A1 (es) 1963-10-16
BR6347875D0 (pt) 1973-08-14
SE314062B (enrdf_load_stackoverflow) 1969-09-01
MY7000065A (en) 1970-12-31
NL122977C (enrdf_load_stackoverflow)
NL290562A (enrdf_load_stackoverflow)

Similar Documents

Publication Publication Date Title
Marker et al. Steroidal sapogenins1a
US3547912A (en) Derivatives of 2h-pyran-3(6h)-ones and preparation thereof
US3318926A (en) 7alpha-methyl-16alpha-hydroxy-estrones
US3254074A (en) Spiroxenones
US3380886A (en) 7alpha-methyl-3beta-hydroxy-5-androstenes
US3576828A (en) Delta**4,9,11-trienes of the 19-nor-androstene series and process for their manufacture
US3758588A (en) New a-nor-b-homo-steroids
US3504003A (en) A-nor-b-homosteroids
US3376193A (en) 17-acylates of 9alpha-fluoro-11beta, 17alpha-dihydroxy-16-methyl-1, 4-pregnadiene-3, 20-dione and corresponding-11-keto steroids and pharmaceutical compositions thereof
JPS5826899A (ja) ステロイド、その製造方法及び薬物としてのその用法
US3707537A (en) 4-chloro-4,6-diene-6-halo or lower alkyl steroids
US3711511A (en) 3-aza - 19 - hydroxy-3,19-cyclo-a-homo-steroids and process for their3-aza-19-hydroxy-3,19-cyclo-a-homosteroids and process for their manufacture
US3522157A (en) Process for the manufacture of a-nor-b-homo-steroids
US3937700A (en) Novel 1,2-methylene-17α-acyloxy (or improved hydroxy)-9β, 10α-steroid compounds of the pregnane series, pharmaceutic preparations on the basis of the novel compounds and methods of producing said compounds and preparations
US3716638A (en) 6alpha-methyl-19-nor-progesterone and a process of its manufacture
US3330728A (en) Progestational compositions comprising 17alpha-acetoxy-6, 16alpha-dimethyl pregna-4,6-diene-3, 20-dione
US3584016A (en) 18-methylene-steroids of the pregnane series
US3341411A (en) 7alpha, 17, 17-trimethyl-18-nor-delta13(14)-steroids of the androstane series
US3167547A (en) 17-tetrahydropyranyl ethers of 19-nor, 3-keto androstanes
US3296075A (en) 17alpha-acyloxy-16-methylene-pregn-4-ene-3, 20-diones, pharmaceutical preparations containing same, and intermediate thereto
US3723418A (en) Process for the manufacture beta-hydroxy-steroid-ketones
US3377343A (en) 2', 2'-bistrifluoromethyloxetano(3', 4'; 16alpha, 17alpha)derivatives of the pregnane series
US3453296A (en) Delta**1-7alpha-methyl-androstenes
US3375167A (en) 6-hydroxymethyl-3-oxo-4, 6-dienic steroids, acyl derivatives thereof, and process for preparing same
US3836526A (en) Novel 1,2-methylene-9beta,10alpha-steroid compounds,pharmaceutical preparations which contain the novel substances as active ingredients,and methods of producing the said compounds and preparations