US3354185A - 1, 2, methylene androstane derivatives - Google Patents

1, 2, methylene androstane derivatives Download PDF

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Publication number
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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United States
Prior art keywords
methylene
androstane
acid
solution
group
Prior art date
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Expired - Lifetime
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US448854A
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English (en)
Inventor
Wiechert Rudolf
Mueller Hans
Neumann Friedmund
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Bayer Pharma AG
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Schering AG
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Classifications

    • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
US448854A 1964-04-25 1965-04-16 1, 2, methylene androstane derivatives Expired - Lifetime US3354185A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DESCH35037A DE1226574B (de) 1964-04-25 1964-04-25 Verfahren zur Herstellung von 1, 2alpha-Methylen-5alpha-androstanderivaten

Publications (1)

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US3354185A true US3354185A (en) 1967-11-21

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US448854A Expired - Lifetime US3354185A (en) 1964-04-25 1965-04-16 1, 2, methylene androstane derivatives

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US (1) US3354185A (de)
CH (1) CH471828A (de)
DE (1) DE1226574B (de)
GB (1) GB1029749A (de)
NL (1) NL6505072A (de)

Cited By (1)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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 (de) 1966-10-13
GB1029749A (en) 1966-05-18
CH471828A (de) 1969-04-30
NL6505072A (de) 1965-10-26

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