US3354185A - 1, 2, methylene androstane derivatives - Google Patents
1, 2, methylene androstane derivatives Download PDFInfo
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- US3354185A US3354185A US448854A US44885465A US3354185A US 3354185 A US3354185 A US 3354185A US 448854 A US448854 A US 448854A US 44885465 A US44885465 A US 44885465A US 3354185 A US3354185 A US 3354185A
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- methylene
- androstane
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
-
- 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
- C07J11/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Definitions
- steroids 1,2a-methylene-l7a-methyl-u-androstane-l7fl-ol.
- the compound has a strong anabolic and ovulation in- Q hibiting action.
- the invention relates to 1,2a-methylene-5u-androstane derivatives of the general formula wherein R is a member selected from the group consisting of hydrogen and acyl, acyl being derived from an aliphatic, carboxylic acid having from 1 to 11 carbon atoms and R is a member selected from the group consisting of lower alkyl, lower alkenyl and lower alkinyl containing from 1 to 4 carbon atoms.
- Another object of the invention is to improve the ovulation inhibitory activity of androstane type steroids.
- a more specific object of the invention is the provision of a methylene substituted androstane type steroid with marked anabolic and ovulation inhibiting action.
- the acyl group that may be present as R in this formula may consist of any of the acid residues that are commonly used in steroid chemistry.
- Preferred acyl groups are the acid residues of aliphatic carboxylic acids and particularly those having 1 to 11 carbon atoms. Examples of such acids 'ice are acetic acid, propionic acid, caproic acid, enanthic acid and undecylic acid. These acid residues can of course also be substituted in the usual manner.
- R groups in the above stated formula may particularly be those having between 1 and 4 carbon atoms such as methyl, ethyl, ethinyl or vinyl.
- Table 1 shows the strong oral anabolic action of the new compounds in item IV, relating to the 1,20; methylene 17cc methyl-Sa-andrOStane-l7fi-ol.
- the oral anabolic and androgenic activity of the orally administered compound was determined by comparison with the corresponding activity of 17a-methyltestosterone (item I), and of the well known anabolic agents II and III.
- the tests were carried out by standard methods using castrated rats and the Levator-ani and semicle vesicle test.
- Table 1 clearly demonstrates the superiority of the new compounds in respect of their anabolic efficiency.
- the eX- tremely high dissociation between anabolic and androgenic action is illustrated by the subsequent Table 2.
- the 1,20: methylene-17ot-alkyl-5a-androstane-17,8-01 compounds of the invention and their l7-esters, in addition to their anabolic action, are strong ovulation inhibitors. If we compare for instance the specific compound listed as IV with conventional ovulation inhibitors as shown below in Table 3 as items V to VIII we find a 10 to 3-0 times increased activity after oral application to normal female rats. The positive or negative ovulation in these tests was determined by tube inspection.
- the new 1,2a-methylene-5ot-androstane derivatives may be combined for therapeutical use with the additives, vehicles, taste modifiers, etc. common in galenic pharmacy and may be prepared in the form of tablets, lozenges, capsules, pills or also as suspensions or solutions.
- concentration of active ingredient in drugs of this type depends of course on the indication for which it is intended.
- Oral anabolic agents for instance should contain about 1 to 20 mg. and ovulation inhibitors should contain about 0.5 to 5 mg. active substance.
- the novel 1,2otmethylene-5a-androstane derivatives may for instance be made in the following manner.
- LZwmCthYlCIIE-Saandrostane-l7-one may be subjected to reaction with a Grignard agent in conventional manner in order to introduce an alkyl or alkenyl group in the place of the 17 keto group.
- an alkinyl group be introduced, for instance the ethinyl group, which can then be reduced to the corresponding vinyl group or to a saturated alkyl group.
- R a reactive derivative of such acid.
- desired acid should be understood as implying all .acids conventionally used in steroid chemistry for the purpose of esterification of steroid alcohols.
- the starting product of this process the 1,2a-methylene- 5a-androstane-17-one has not heretofore been described, .as far as we are aware.
- This compound can for instance be made as follows from 1,Ze-methylene-Sot-androstanel7fi-ol-3-one-l7-acetate using conventional methods.
- Example 1 A Grignard solution was prepared from 4.49 g. magnesium filings in 5-0 ml. abs. ether and 11.6 ml. methyliodide in 32.4 ml. abs. ether. 4.0 g. LZOL-ITICthYlCIlB-Sotandrostane-17-one in 140 ml. abs. benzene were then added by dropping to the Grignard solution and were stirred for 4 hours at room temperature in a nitrogen atmosphere. Concentrated aqueous ammonium chloride solution was then cautiously added to the reaction mixture upon cooling with ice. The product was finally slightly acidified with dilute hydrogen chloride and extracted with ether. After separation the ether phase was washed until neutral, dried and concentrated by evaporation. The
- Example 2 Acetylene was passed for 30 minutes upon cooling into 133 ml. abs. tetrahydrofurane, A Grignard solution was prepared from 9.26 g. magnesium filings in 114 ml. abs. tetrahydrofurane and 29 ml. ethylbromide in 114 ml. abs. tetrahydrofurane. The cooled Grignard solution was added to the above solution of tetrahydrofurane resulting in a temperature rise to C. The introduction of acetylene was continued until the reaction temperature went down again. 4.8 g. of 1,2a-methylene-5ot-and-rostane-17-one in 114 ml. abs.
- Example 4 312 mg. of 1,2a-methylene-17a-ethinyl-5tx-androstanel7fi-ol were hydrogenated in 30 ml. thiophene-free benzene in the presence of 2x312 mg.
- Example 5 A mixture of 500 mg. Ila-methylene-l7m-ethinyl-5w androstane-l7B-ol, 2.5 ml. pyridine and 2.5 ml. acetic acid anhydride were heated for 4 hours to l40 C. The reaction mixture was then stirred into an iced sodium chloride solution and was extracted with ether. After neutral washing, drying and concentration by evaporation of the separated ether solution there were obtained 425 mg. 1,2oz methylene a e-thinyl 5a androstane 17B- ol-l7-acetate in the form of an oil.
- R is a member selected from the group consisting of lower alkyl, lower alkenyl and lower alkinyl containing from 1 to 4 carbon atoms.
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Description
United States Patent C) F ABSTRACT OF THE DISCLOSURE A steroid compound having the general structural formula I Q2 Q3 wherein R is a member selected from the group consisting of hydrogen and acyl, acyl being derived from an aliphatic carboxylic acid having from 1 to 4 carbon atoms, and R is a member selected from the group consisting of lower alkyl, lower alkenyl and lower alkinyl containing from 1 to 4 carbon atoms.
An example of the steroids is 1,2a-methylene-l7a-methyl-u-androstane-l7fl-ol.
The compound has a strong anabolic and ovulation in- Q hibiting action.
The invention relates to 1,2a-methylene-5u-androstane derivatives of the general formula wherein R is a member selected from the group consisting of hydrogen and acyl, acyl being derived from an aliphatic, carboxylic acid having from 1 to 11 carbon atoms and R is a member selected from the group consisting of lower alkyl, lower alkenyl and lower alkinyl containing from 1 to 4 carbon atoms.
It is an object of the present invention to improve the anabolic efliciency of steroids, particularly in case of oral 5 application.
Another object of the invention is to improve the ovulation inhibitory activity of androstane type steroids.
A more specific object of the invention is the provision of a methylene substituted androstane type steroid with marked anabolic and ovulation inhibiting action.
These and other objects, as will be apparent from the following description of the invention, are accomplished by the compounds of the general formula above stated. The acyl group that may be present as R in this formula may consist of any of the acid residues that are commonly used in steroid chemistry. Preferred acyl groups are the acid residues of aliphatic carboxylic acids and particularly those having 1 to 11 carbon atoms. Examples of such acids 'ice are acetic acid, propionic acid, caproic acid, enanthic acid and undecylic acid. These acid residues can of course also be substituted in the usual manner. As examples in this respect are mentioned phenyl acetic acid, cyclopentylpropionic acid, halogenoacetic acid, amino-acetic acid, hydroxypropionic acid, etc.
7 The R groups in the above stated formula may particularly be those having between 1 and 4 carbon atoms such as methyl, ethyl, ethinyl or vinyl.
The following Table 1 shows the strong oral anabolic action of the new compounds in item IV, relating to the 1,20; methylene 17cc methyl-Sa-andrOStane-l7fi-ol. The oral anabolic and androgenic activity of the orally administered compound was determined by comparison with the corresponding activity of 17a-methyltestosterone (item I), and of the well known anabolic agents II and III. The tests were carried out by standard methods using castrated rats and the Levator-ani and semicle vesicle test.
Table 1 clearly demonstrates the superiority of the new compounds in respect of their anabolic efficiency. The eX- tremely high dissociation between anabolic and androgenic action is illustrated by the subsequent Table 2.
TABLE 2 Levator- Semicle D ose ani Vesicle N 0. Substance P.O Weight, Weight,
mg. rug/100 g. mg./100 g.
rat rat 17a-methyl-testosterone 12 x 44 370 l,2a-methylene-l7a 12 x 3 43 59 methyl-5a-androstane-17fi-ol.
The 1,20: methylene-17ot-alkyl-5a-androstane-17,8-01 compounds of the invention and their l7-esters, in addition to their anabolic action, are strong ovulation inhibitors. If we compare for instance the specific compound listed as IV with conventional ovulation inhibitors as shown below in Table 3 as items V to VIII we find a 10 to 3-0 times increased activity after oral application to normal female rats. The positive or negative ovulation in these tests was determined by tube inspection.
The following table lists the specific does (W which results in omission of ovulation in the case of of the test animals and peroral administration.
TABLE 3 PO. mg./ animal/day No. Compound Wow (continued for four days) V 17a-ethmyl-19-nor-testosterone 3 VI 17a-ethinyl-lQ-nor-testosterone- 3 acetate. VII... 17a-ethinyl-A -estrene-l7fi-ol-3- 1-10 one. VIII 6-0hlor-A -l7a-hydroxyprogesterone- 1-3 acetate. IV 1,2a-rnethylene-17a-methyl-5a- 0.1
androstanc-UB-ol.
:3 The new 1,2a-methylene-5ot-androstane derivatives may be combined for therapeutical use with the additives, vehicles, taste modifiers, etc. common in galenic pharmacy and may be prepared in the form of tablets, lozenges, capsules, pills or also as suspensions or solutions. The selection of the concentration of active ingredient in drugs of this type depends of course on the indication for which it is intended. Oral anabolic agents for instance should contain about 1 to 20 mg. and ovulation inhibitors should contain about 0.5 to 5 mg. active substance.
Regarding the process of manufacture, the novel 1,2otmethylene-5a-androstane derivatives may for instance be made in the following manner. LZwmCthYlCIIE-Saandrostane-l7-one may be subjected to reaction with a Grignard agent in conventional manner in order to introduce an alkyl or alkenyl group in the place of the 17 keto group. In a similar manner can an alkinyl group be introduced, for instance the ethinyl group, which can then be reduced to the corresponding vinyl group or to a saturated alkyl group. Depending on what type of R is desired in the final compound there may additionally be an .esterification of the primarily formed steroid alcohols with the desired acid or a reactive derivative of such acid. The term desired acid should be understood as implying all .acids conventionally used in steroid chemistry for the purpose of esterification of steroid alcohols.
The starting product of this process the 1,2a-methylene- 5a-androstane-17-one has not heretofore been described, .as far as we are aware. This compound can for instance be made as follows from 1,Ze-methylene-Sot-androstanel7fi-ol-3-one-l7-acetate using conventional methods.
5 g. of 1,2wmethylene-5a-androstane-17,8-ol-3-one-17- ;acetate [Ben 93, 1710 (60)] are heated for 20 minutes to 130 with 370 ml. ethylene-glycol and 25 ml. hydrazinhydrate of an 80% concentration. After cooling and addition of a solution of 37 g. sodium hydroxide in 37 ml. water heating is effected for two hours to 190 to 200 C. upon slow distillation. The reaction mixture is then .again cooled and poured into a slightly acidified sodium chloride solution. The precipitate that forms is filtered off and dissolved in either. After washing until neutral and \drying the ether solution is concentrated by evaporation in vacuo. The residue is subjected to chromatography over silicagel (having 5% water content) with methylene chloride/ chloroform (in a ratio of 3 to l) and is triturated with pentane. There are obtained 2.74 g. of LZa-methyl- .ene-5a-androstane-17/3-01 having a melting point between 111.5 and 112 C.
4.1 g. of this product are dissolved in 5 ml. acetone.
1.25 g. of chromium-(VI)-oxide in 4.7 ml. 8 N-sulfuric .acid are added to the solution upon stirring and external cooling in ice water. The solution is then poured into an .aqueous sodium chloride solution and is extracted with methylene chloride. After neutral washing, drying and concentration by evaporation of the methylene chloride phase there are left 4.0 g. of 1,2u-methylene-5a-andro- .stane-17-one in the form of an oil.
The following examples will illustrate the making of the compounds of the invention without being intended .as any limitation of the scope of the invention.
Example 1 A Grignard solution was prepared from 4.49 g. magnesium filings in 5-0 ml. abs. ether and 11.6 ml. methyliodide in 32.4 ml. abs. ether. 4.0 g. LZOL-ITICthYlCIlB-Sotandrostane-17-one in 140 ml. abs. benzene were then added by dropping to the Grignard solution and were stirred for 4 hours at room temperature in a nitrogen atmosphere. Concentrated aqueous ammonium chloride solution was then cautiously added to the reaction mixture upon cooling with ice. The product was finally slightly acidified with dilute hydrogen chloride and extracted with ether. After separation the ether phase was washed until neutral, dried and concentrated by evaporation. The
residue was Subject d t chromatography over silicagel 4 (containing 5% water) with methylene chloride. There were obtained 3.06 g. 1,2a-methylene-17u-rnethyl-5mandrostane-17/3-ol, M.P. 52-54 C. [111 -4.85 (chloroform). NearlR:163 and 2.21; (cyclopropane); IR: 2.93, (OH), 8.70/9.09/9.34,u. (COH).
Example 2 Acetylene was passed for 30 minutes upon cooling into 133 ml. abs. tetrahydrofurane, A Grignard solution was prepared from 9.26 g. magnesium filings in 114 ml. abs. tetrahydrofurane and 29 ml. ethylbromide in 114 ml. abs. tetrahydrofurane. The cooled Grignard solution was added to the above solution of tetrahydrofurane resulting in a temperature rise to C. The introduction of acetylene was continued until the reaction temperature went down again. 4.8 g. of 1,2a-methylene-5ot-and-rostane-17-one in 114 ml. abs. tetrahydrofurane Were then drop-added while continuing the passing of acetylene through the mixture. The reaction product was thereafter heated and stirred for 21 hours in an oil bath of a temperature of 70 C. and a nitrogen atmosphere. After cooling to 5 C. concentrated aqueous ammonium chloride solution was slowly added until there was no more reaction.
The product was thereupon extracted with ether, the separated organic phase was washed neutral with water and after drying over sodium sulfate was concentrated by evaporation in vacuo to dryness. The residue was subjected to chromatography over silicagel. By elution with carbon tetrachloride/methylenechloride (in a ratio of 2 to 1) one obtained 2.65 g. of 1,Za-methylene-17a-ethinyl- Swandrostane-Ufi-Ol; M.P. 84-86 C.
[a.] 34.1 (chloroform). Near-JR: 1.63 and 2.21,!1. (cyclopropane); IR: 2.95 (OH), 3.06 (CH of CECH), 4.77; (CEC), 9.55/9.65/9.86/9.93,u. (C-OH).
Example 3 The product was thereafter filtered ofi from the catalyst and the solution was concentrated to dryness in vacuo. There were thus obtained 300 mg. 1,2a-methylene-17avinyl-5a-androstane-17B-ol in the form of an oil. [a] 2 +5.95 (chloroform) IR: 2.91 1. (OH), 6.1,u. (C C), 9.82/10.0/10.90,u. (C-OH and CH=CH Example 4 312 mg. of 1,2a-methylene-17a-ethinyl-5tx-androstanel7fi-ol were hydrogenated in 30 ml. thiophene-free benzene in the presence of 2x312 mg. Lindlar catalyst up to step-by-step absorption of 2 m. mole of hydrogen. The solution was then filtered off from the catalyst and was concentrated to dryness at 40 in vacuo. There were thus obtained 300 mg. of 1,2a-methylene-l7a-ethyl-5oc-androstane-l7B-ol in the form of an oil. [001 2 +0.95 (chloroform). IR: 2.87;. (OH), 9.87/10.27,u (C-OH).
Example 5 A mixture of 500 mg. Ila-methylene-l7m-ethinyl-5w androstane-l7B-ol, 2.5 ml. pyridine and 2.5 ml. acetic acid anhydride were heated for 4 hours to l40 C. The reaction mixture was then stirred into an iced sodium chloride solution and was extracted with ether. After neutral washing, drying and concentration by evaporation of the separated ether solution there were obtained 425 mg. 1,2oz methylene a e-thinyl 5a androstane 17B- ol-l7-acetate in the form of an oil.
All of these examples are intended for illustration only, as has previously been noted, and we therefore do not wish to be limited otherwise than by the language of the appended claims.
5 We claim: 1. A compound having the general structural formula R, a I I wherein R is a member selected from the group consisting of hydrogen and acyl, acyl being derived from an aliphatic carboxylic acid having from 1 to 11 carbon atoms, 15
and R is a member selected from the group consisting of lower alkyl, lower alkenyl and lower alkinyl containing from 1 to 4 carbon atoms.
2. lint-methylene-17a-methyI-Sa andrOstane-17,8-01. 3. 1,2a-methy1ene-17a-ethiny1-5a-androstane-17 3-01.
UNITED STATES PATENTS 3,163,663 12/1964 Cross et al 260-397.5 10 3,242,050 3/ 1966 Wiechert 260-397.5 3,254,099 5/1966 Jolles et a1 260397.5
OTHER REFERENCES Fieser et a1.: Steroids, Reinhold Publishing Corp., New York, N.Y., 1959, pages 492, 493, 621, 627 and 630.
LEWIS GOTTS, Primary Examiner.
J. R. BROWN, Assistant Examiner. 20
Claims (1)
1. A COMPOUND HAVING THE GENERAL STRUCTURAL FORMULA
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DESCH35037A DE1226574B (en) | 1964-04-25 | 1964-04-25 | Process for the preparation of 1,2alpha-methylene-5alpha-androstane derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3354185A true US3354185A (en) | 1967-11-21 |
Family
ID=7433348
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US448854A Expired - Lifetime US3354185A (en) | 1964-04-25 | 1965-04-16 | 1, 2, methylene androstane derivatives |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US3354185A (en) |
| CH (1) | CH471828A (en) |
| DE (1) | DE1226574B (en) |
| GB (1) | GB1029749A (en) |
| NL (1) | NL6505072A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3470156A (en) * | 1967-01-30 | 1969-09-30 | Smithkline Corp | 6,6-ethylene-1,2-methylenesteroids |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3163663A (en) * | 1961-12-04 | 1964-12-29 | Syntex Corp | 2alpha-methyl-delta3-androstene-17-hydrocarbon derivatives |
| US3242050A (en) * | 1963-07-13 | 1966-03-22 | Schering Ag | 3-enolesters of 1alpha, 2alpha-methylene-3-ketosteroids |
| US3254099A (en) * | 1962-03-05 | 1966-05-31 | Rhone Poulenc Sa | 17alpha-substituted-17beta-hydroxy androstane and androstene derivatives |
-
1964
- 1964-04-25 DE DESCH35037A patent/DE1226574B/en active Pending
-
1965
- 1965-03-31 CH CH445065A patent/CH471828A/en not_active IP Right Cessation
- 1965-04-09 GB GB15230/65A patent/GB1029749A/en not_active Expired
- 1965-04-16 US US448854A patent/US3354185A/en not_active Expired - Lifetime
- 1965-04-21 NL NL6505072A patent/NL6505072A/xx unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3163663A (en) * | 1961-12-04 | 1964-12-29 | Syntex Corp | 2alpha-methyl-delta3-androstene-17-hydrocarbon derivatives |
| US3254099A (en) * | 1962-03-05 | 1966-05-31 | Rhone Poulenc Sa | 17alpha-substituted-17beta-hydroxy androstane and androstene derivatives |
| US3242050A (en) * | 1963-07-13 | 1966-03-22 | Schering Ag | 3-enolesters of 1alpha, 2alpha-methylene-3-ketosteroids |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3470156A (en) * | 1967-01-30 | 1969-09-30 | Smithkline Corp | 6,6-ethylene-1,2-methylenesteroids |
Also Published As
| Publication number | Publication date |
|---|---|
| DE1226574B (en) | 1966-10-13 |
| CH471828A (en) | 1969-04-30 |
| NL6505072A (en) | 1965-10-26 |
| GB1029749A (en) | 1966-05-18 |
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