US3445488A - Novel 5beta,10alpha-steroids - Google Patents
Novel 5beta,10alpha-steroids Download PDFInfo
- Publication number
- US3445488A US3445488A US471704A US3445488DA US3445488A US 3445488 A US3445488 A US 3445488A US 471704 A US471704 A US 471704A US 3445488D A US3445488D A US 3445488DA US 3445488 A US3445488 A US 3445488A
- Authority
- US
- United States
- Prior art keywords
- compounds
- steroids
- trans
- novel
- estran
- 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
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- 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
- This invention relates to a group of novel estranes having a heretofore unknown configuration at the A-B ring junction.
- this invention provides a group of novel steroids having the following formula:
- Y is CHOH- or R is hydrogen, acetyl or m-hydroxyacetyl; R is hydrogen, C C alkyl, vinyl ethinyl, or halo-ethinyl, and R" is acetyl or a-hydroxyacetyl.
- protecting groups are the tetrahydropyranyl, acetyl, benzoyl, succinoyl, methyl, ethyl, propionyl and other like groups.
- compounds represented by the above formula which have one or more of the added conventional ring substituents, such as a fluoro, chloro, or methyl at the 6 position, hydroxy or keto at the 11 position, methyl or fluoro at the 16 position, methylene at the 2 position, etc.
- thermodynamically-less stable SIS-compounds are formed.
- the starting materials for the above-mentioned Birch reduction process which leads to the compounds of this invention can be named either l9-I10r-10a-St6l0ids or 19- nor-lO-isosteroids.
- the synthesis of many of these steroids is fully described in my co-pending application, Ser. No. 389,484, filed Aug. 13, 1964, now Patent No. 3,341,558.
- the synthetic procedure used to prepare these compounds involves a catalytic hydrogenation of the corresponding A -diene with palladium-on-carbon at atmospheric pressure.
- the resulting ketone at C can now be reacted with sodium acetylide or sodium chloracetylide to form the 17a-ethinyl or 17a-chlorethinyl-17B-hydroxy steroid. Additionally, the ethinyl group can 'be semi-hydrogenated at this point to a vinyl group to produce the 17ot-vinyl derivative. Hydrolysis of the protecting ketal group with acid then yields the desired l7ethinyl or 17- vinyl steroid reaction product.
- SflJOu-estrane-Bp,17,3-diol as well as the a isomer are prepared from 5 9,l0a-estran-l7fi-ol-3-one by reduction with lithium aluminum hydride or other appropriate hydride reducing agent.
- Example II 17a methyl-5 3,l0a-estran-1718-01-3-one Following the procedure of Example I, 17u-I1'16thyll'9-nor-l0-isotestosterone was reduced by the action of lithium in liquid ammonia solvent to yield 17a-methyl-5 3, l0a-estran-17fi-ol-3-one, which was isolated and purified by the procedure of the same example. l7a-methyl-5p, l Cm-estran-l7 3-ol-3-one thus prepared melted at about 139441 C. after recrystallization from an ether-hexane solvent mixture.
- R is hydrogen, acetyl 0r a-hydroxyacetyl
- R is hydrogen, C -C alkyl, vinyl, ethinyl or halo-ethinyl
- R" is acetyl or a-hydroxyacetyl.
Description
United States Patent 3,445,488 NOVEL 5fl,10oc-STEROIDS Eugene Farkas, Indianapolis, Ind., assignor to Eli Lilly and Company, Indianapolis, Ind., a corporation of Indiana No Drawing. Filed July 13, 1965, Ser. No. 471,704 Int. Cl. C07c 169/66, 169/10; A61k 27/00 US. Cl. 260-397.4 3 Claims ABSTRACT OF THE DISCLOSURE Novel 5,3,10a-estranes and l9-norpregnanes useful as anti-hormones.
This invention relates to a group of novel estranes having a heretofore unknown configuration at the A-B ring junction.
Several years ago, it was determined that many of the structural features of the naturally occurring steroidal hormones were not necessary for hormonal activity. For example, it was found that 19-norprogesterone was somewhat rnore active as a progestational agent than the naturally occurring hormone, progesterone. Furthermore, A cortisol (prednisolone) is a far more powerful anti-infiammatory agent than cortisol iself as is the 6a-fiuoro-l6amethyl derivative of prednisolone. Such discoveries have led to tremendous advances in the field of steroidal hormone therapy, particularly among the antiinfiammatory agents wherein substitution of fluorine for its isostere hydrogen as well as introduction of additional double bonds have been particularly profitable research areas.
In addition to the above cited modifications, another method of varying the structure of the steroidal hormones has been to change the spatial orientation of various groups or atoms, particularly those at ring junction carbons. This line of attack has not been as fruitful as the others, largely because the non-natural configuration thus produced is thermodynamically unstable compared with the naturally occurring configuration.
In general, most naturally occurring steroids have a trans-anti-trans configuration for the AB and B-C ring junctures; that is to say, the A-B and B-C rings are both trans-fused, and the atoms or groups at the 9 and 10 positions are trans (anti) to one another. Furthermore, each of the A, B and C rings is able to be in the more stable chair configuration when the rings are fused trans to one another as in the normal steroid. Deviation from the natural configuration gives rise to various forces which tend to render a non-natural configuration relatively unstable. These forces are largely the result of steric and/ or torisonal strains and can result in forcing one of the rings into the relatively unstable boat conformation, or in deforming the steroid molecule from the essentially planar conformation of the naturally occurring trans-anti-trans steroids.
Despite the fact that non-natural ring juncture configu rations result in a steroid which is relatively more strained compared to a steroid with a natural configuration, it has been possible to synthesize many of the non-natural steroid A-BC ring systems. In general, however, these syntheses have been carried out on 19-nor compounds because of the great difiiculty in synthesizing compounds with a methyl group at the ring junction. The fully hydrogenated l9-nor compounds, or estranes, have been prepared by reduction of the corresponding estratrienes, many of which are naturally occurring female hormones. For example,
3,445,488 Patented May 20, 1969 Birch reduction of estrone followed by hydrolysis of the reduction product to a 3-keto-A compound and subsequent elimination of the A bond by reduction yields a 3-ketoestrane having a normal 5a,10fi,9u,8B-configuration (transanti-trans). The 5a,10a,9a,8 8-configuration (cis-syn-trans) has been prepared by Farkas and Ra-pala (see US. Patent 3,015,666) by reduction of an estratriene using a highly active rhodium or ruthenium catalyst. This type of reduction yields only compounds having hydrogen on the alpha side of the ring since the beta methyl group at C effectively blocks the estratriene from approaching the catalyst from the beta side. Another isomer, the one with the 5 8,10/3,9a,8B-configuration (cis-syn-trans), has been prepared by the reduction of estrone with platinum oxide in acetic acid, among other methods. Thus, there have been prepared only three of the four possible configurations at the A-'B ring junction in steroids having natural stereochemistry at the B-C ring junctions-the 5a,10/3,9a,8;3, the 5oz,10a,9oc,8,8, and the 5,8,10B,9ot,85.
It is an object of this invention to provide 19-nor steroids having the heretofore unknown 5fi,10u,9u,8[3 configuration (trans-syn-trans). It is a further object of this invention to provide a process for the preparation of 55,10a-estr2nes. Other objects of this invention will become apparent from the description which follows.
In fulfillment of the above and other objects, this invention provides a group of novel steroids having the following formula:
wherein Y is CHOH- or R is hydrogen, acetyl or m-hydroxyacetyl; R is hydrogen, C C alkyl, vinyl ethinyl, or halo-ethinyl, and R" is acetyl or a-hydroxyacetyl. Also included within the scope of this invention are compounds having protecting ester or ether groups replacing the hydrogen of the hydroXyl at 3 or 17. Among such protecting groups are the tetrahydropyranyl, acetyl, benzoyl, succinoyl, methyl, ethyl, propionyl and other like groups. Also included within the scope of this invention are compounds represented by the above formula which have one or more of the added conventional ring substituents, such as a fluoro, chloro, or methyl at the 6 position, hydroxy or keto at the 11 position, methyl or fluoro at the 16 position, methylene at the 2 position, etc.
Illustrative compounds included within the scope of this invention include the following:
5 8, 1 Oa-estran- 17a-Ol-3 -one 53, l0a-estrane-3B,17a-diol 5,8,10m-estrane-3 8,17;8-dio1 6a-fiuoro-17a-chlorethinyl-5fi,10a-estrane-1 lB,17;8-diol-3- onel7/3-acetate 17a-n-propyl-5 8, 1 0a-estrane-3 [3, 1 7B-dio1 17m-methyl-5/3, 10a-estran-17B-ol-3-one-17fl-benzoate 19-nor-5fi,10a-pregna-3 ,20-dione 19-nor-5B,10a-pregna-3 6,11B,17u,21-tetrol-20-one 19-nor-5fi,10a-pregna-3B,21-diol-3,20-dione Compounds represented by the above formulas are highmelting white crystalline solids soluble in most polar organic solvents. They are readily prepared by reducing a 3-keto-A -19-nor-l0-isosteroid by means of lithium in liquid ammonia-a standard Birch reduction. The compounds are isolated from the reaction mixture by conventional processes and can either be crystallized directly or after purification by chromatography.
It is quite surprising that Birch reduction of a A -10u,9a, 8/3-steroid would yield the SB-derivative inasmuch as it is generally believed that the Six-steroid would be more stable thermodynamically. Specifically, the transsyn-trans conformation of the steroids of this invention is theoretically less stable thermodynamically than the cis-syn-trans conformation (the 5a,10a,9a,8,8-configuration) which would be a possible product of a Birch reduction of a 3-keto-A l9-nor-10-isosteroid. Furthermore, it has generally been held that the Birch reduction, inasmuch as it is a oneelectron reduction, would yield the thermodynamically more stable derivative, although there has been a recent exception found to this rule. Nevertheless, in the synthetic process of this invention, quite surprisingly, the thermodynamically-less stable SIS-compounds are formed.
Compounds represented by the above formula are in general anti-hormones. When Z in the above formula is either R is hydrogen and R is defined as above, the resulting compounds are anti-androgens or, in some cases, antiprogesterones. The compounds in which Z is R 'OH R" H or C and R and R" are either acetyl or a-hydroxyacetyl have the same carbon skeleton as progesterone and cortisone and thus these tend to have an anti-progestational or anticortisone action, depending on the structure of the C side chain. Among the compounds of this invention, 5,9,10aestran-l7fl-ol-3-one, in particular, is an extremely potent anti-androgen.
The starting materials for the above-mentioned Birch reduction process which leads to the compounds of this invention can be named either l9-I10r-10a-St6l0ids or 19- nor-lO-isosteroids. The synthesis of many of these steroids is fully described in my co-pending application, Ser. No. 389,484, filed Aug. 13, 1964, now Patent No. 3,341,558. In this application, I used the preferred nomenclature, calling the compounds 19-nor-IO-isotestosterones, 19-nor- 10-iso-4-androsten-3-ones, 19-nor-10-isoprogesterones, etc. The synthetic procedure used to prepare these compounds involves a catalytic hydrogenation of the corresponding A -diene with palladium-on-carbon at atmospheric pressure.
Certain of the starting materials, particularly those containing a vinyl or ethinyl group at 0, cannot be prepared directly by the above catalytic hydrogenation procedure, and it is necessary to prepare these starting materials in a somewhat round about fashion. A particularly useful synthetic procedure which can be applied to the synthesis of many of the compounds having unsaturation at C is the following: 8,l0a-estran-17,8-ol-3-one is reacted with ethylene glycol in the presence of acid to form a protective ketal grouping for the C ketone. With the C ketone protected, the hydroxyl at 17 can then readily be oxidized, using chromium trioxide in pyridine as the oxidizing agent. The resulting ketone at C can now be reacted with sodium acetylide or sodium chloracetylide to form the 17a-ethinyl or 17a-chlorethinyl-17B-hydroxy steroid. Additionally, the ethinyl group can 'be semi-hydrogenated at this point to a vinyl group to produce the 17ot-vinyl derivative. Hydrolysis of the protecting ketal group with acid then yields the desired l7ethinyl or 17- vinyl steroid reaction product.
4 This invention is further illustrated by the following specific examples:
One hundred milliliters of redistilled liquid ammonia were placed in a three-neck flask and 0.4 g. of lithium were added in small pieces. Next, a solution of 0.2 g. of 19-nor-IO-isotestosterone in 3 0 ml. of anhydrous tetrahydrofurane was added. The resulting reaction mixture was stirred for about 20 minutes, after which time excess ammonium chloride was added. The reaction mixture was allowed to warm up to room temperature while the ammonia evaporated. A mixture of ml. of water and 100 ml. of methylene dichloride was added. The organic layer was separated, and the aqueous layer was extracted twice more with 100 ml. portions of methylene dichloride. The organic extracts were combined, were washed with 100 ml. of saturated sodium chloride solution and were dried. Evaporation of the resulting solution to dryness yielded an orange-yellow residue which was ldlSSO1Vd in 20 ml. of a 3 :1 benzene-hexane solvent mixture, and the resulting solution was chromatographed over 20 g. of Grade III neutral alumina. Fifty milliliter eluate fractions were obtained and numbered serially. The organic solvent was removed by evaporation in vacuo from each fraction. The residue from fractions 7-11 were combined and recrystallized from a mixture of ether and hexane, thus yielding 5B, 10a-estran-l7-ol-3-one, which melted in the range 122- 123 C. The material gave a single spot on thin layer chromatography. An optically rotatory dispersion curve of the compound was a typically negative CE curve with minimum value of M=l'0 22, a value consistant with the 55, 10a-steroid structure.
Recrystallization of the material thus obtained from the same solvent system as above yielded purified material, 5 3,LOa-estran-l7fl-ol-3-one, melting in the range -137" C.
The above reaction was repeated employing 19-nor-l0- isotestosterone acetate as a starting material. The acetate group was hydrolized during the reaction and the same product was obtained as above.
SflJOu-estrane-Bp,17,3-diol as well as the a isomer are prepared from 5 9,l0a-estran-l7fi-ol-3-one by reduction with lithium aluminum hydride or other appropriate hydride reducing agent.
Example II.17a methyl-5 3,l0a-estran-1718-01-3-one Following the procedure of Example I, 17u-I1'16thyll'9-nor-l0-isotestosterone was reduced by the action of lithium in liquid ammonia solvent to yield 17a-methyl-5 3, l0a-estran-17fi-ol-3-one, which was isolated and purified by the procedure of the same example. l7a-methyl-5p, l Cm-estran-l7 3-ol-3-one thus prepared melted at about 139441 C. after recrystallization from an ether-hexane solvent mixture. Similar compounds in which the methyl is replaced by either n-propl, n-butyl, ethyl or the like, or in which the grouping at C is p-acetyl or ,B-(ahydroxyacetyl), with or without an a-hydroxyl at the 17 position, are also readily prepared by a Birch reduction of the corresponding 3-keto-A -19-nor-l0-isosteroid.
I claim:
1. A steroid of the formula wherein Y is CHOI-I- or R on HO IR R" n -h-;z is o" o" or o" 5 R is hydrogen, acetyl 0r a-hydroxyacetyl; R is hydrogen, C -C alkyl, vinyl, ethinyl or halo-ethinyl; and R" is acetyl or a-hydroxyacetyl.
2. 5.1 10a-estran-17B-o1-3-one. 3. 17a-methyl-5 3,l0a-estran-17B-01-3-one.
References Cited UNITED STATES PATENTS 1/1962 Farkas et a1. 260397.5 10
6 OTHER REFERENCES Counsell I, Tetrahedron, 1961, vol. 15, pp. 202211.
LEWIS GOTTS, Primary Examiner.
ETHEL G. LOVE, Assistant Examiner.
US. Cl. X.R.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US47170465A | 1965-07-13 | 1965-07-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
US3445488A true US3445488A (en) | 1969-05-20 |
Family
ID=23872693
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US471704A Expired - Lifetime US3445488A (en) | 1965-07-13 | 1965-07-13 | Novel 5beta,10alpha-steroids |
Country Status (1)
Country | Link |
---|---|
US (1) | US3445488A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012083201A1 (en) * | 2010-12-17 | 2012-06-21 | Harbor Biosciences, Inc. | Steroid tetrol solid state forms-2 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3014935A (en) * | 1960-06-15 | 1961-12-26 | Searle & Co | 5alpha-estrane-3alpha, 17beta-diols and esters thereof |
US3015666A (en) * | 1958-06-16 | 1962-01-02 | Lilly Co Eli | Novel 5alpha, 10alpha-19-nor steroids and method for their preparation |
-
1965
- 1965-07-13 US US471704A patent/US3445488A/en not_active Expired - Lifetime
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3015666A (en) * | 1958-06-16 | 1962-01-02 | Lilly Co Eli | Novel 5alpha, 10alpha-19-nor steroids and method for their preparation |
US3014935A (en) * | 1960-06-15 | 1961-12-26 | Searle & Co | 5alpha-estrane-3alpha, 17beta-diols and esters thereof |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012083201A1 (en) * | 2010-12-17 | 2012-06-21 | Harbor Biosciences, Inc. | Steroid tetrol solid state forms-2 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Djerassi et al. | Steroids. LIV. 1 Synthesis of 19-Nov-17α-ethynyltestosterone and 19-Nor-17α-methyltestosterone2 | |
US3166577A (en) | 1, 2-dimethyl estrogens and intermediates used in the production thereof | |
US3445489A (en) | 9beta,10alpha-steroids,intermediates therefor and pharmaceutical preparations containing these compounds as an active ingredient | |
US3385871A (en) | Halogenated cyclopropyl and cyclopropenyl estratrienes and process for their preparation | |
US3357888A (en) | 4, 7-dimethyl androstene derivatives | |
US3380886A (en) | 7alpha-methyl-3beta-hydroxy-5-androstenes | |
US3275666A (en) | 16-methylene steroids of the esterne series | |
US3445488A (en) | Novel 5beta,10alpha-steroids | |
US3032552A (en) | 1-methyl steroids of the androstane series | |
US3290297A (en) | Tetrahydrofuranyl ethers of delta1, 3, 5(10)-estratriene | |
US3574197A (en) | Process of producing 1-hydroxy-7alpha-methyl-estradiol derivatives | |
US3515719A (en) | 7-methyl-6,19-epoxy steroids of the androstane series | |
US3636011A (en) | 11beta-fluoro-19-nor-steroids and process for their preparation | |
US3510556A (en) | 17alpha-ethers of 16-methylene-19-nor-progesterones | |
US3442918A (en) | 17alpha-alka-1',3'-diynyl steroids | |
US3383384A (en) | Process and intermediates for manufacture of 19-norsteroids | |
US3202684A (en) | 17alpha-chlorethynyl steroids and process for their preparation | |
US3127428A (en) | Process for converting a 3-keto-delta-steroid to the corresponding 3-keto delta-compound | |
US3527778A (en) | 3,17 - bisoxygenated 11betamethyl - 19 - norpregn - 4 - en - 20 - ones and derivatives thereof | |
US3264331A (en) | Androstane hydrazone derivatives and methods for their manufacture | |
US3365445A (en) | 1beta, 2beta-methylene steroids of the androstane series | |
US3374228A (en) | 14beta-estra-1, 3, 5(10)-trienes | |
US3083199A (en) | delta3-5alpha-steroids and 3alpha-hydroxy-5alpha-steroids and the preparation thereof | |
US3484464A (en) | Novel 19-nor-9-isosteroids | |
US3472882A (en) | 7-halomethyl-19-nor steroids and processes for their preparation |