US3234093A - 6-chloro-1, 2alpha-methylene-delta6-17alpha-hydroxyprogesterone compounds and compositions - Google Patents

6-chloro-1, 2alpha-methylene-delta6-17alpha-hydroxyprogesterone compounds and compositions Download PDF

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Publication number
US3234093A
US3234093A US189724A US18972462A US3234093A US 3234093 A US3234093 A US 3234093A US 189724 A US189724 A US 189724A US 18972462 A US18972462 A US 18972462A US 3234093 A US3234093 A US 3234093A
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United States
Prior art keywords
methylene
compounds
hydroxyprogesterone
progestational
chloro
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US189724A
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English (en)
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Wiechert Rudolf
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Bayer Pharma AG
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Schering AG
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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
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general

Definitions

  • the present invention relates to new progestational agents and treatments therewith, and more particularly to new 6-position halogenated l,2a-methylene-A -l7ahyd-roxyprogesterones which have an unusually high proge'stational action, even upon peroral administration, to these new compounds, methods of producing the same, progesta'tional compositions containing the same, and progestational treatments using these compounds.
  • lt is-a primary object of the present invention to provide a new series of compounds with progestational activity.
  • the present invention also has as its object the provision of progestational compositions containing the compounds of the present invention as the active ingredient thereof, and also the treatment of patients requiring progestational effect.
  • the present invention mainly comprises a compound of the formula:
  • X is a halogen
  • R is selected from the group consisting of hydrogen and acyl wherein acyl is derived from a carboxylic acid.
  • esters of the present invention i.e., compounds of the above formula wherein R is acyl derived from a carboxylic acid
  • R is acyl derived from a carboxylic acid
  • the most preferred progestational compounds of the present invention are the 6-position halogenated-liar-methylene- 3,Z34,@93 Patented Feb. 8, 1965 ice N-l7whydroxyprogesterone esters of carboxylic acids.
  • the invention is in general applicable to all o-halogenated compounds of the above group, it is most preferred from the point of view of high progestational action that the halogen in the 6-position be chlorine.
  • the 6-brominated compounds are also active progestati-onal compounds, the action thereof is considerably less than the 6-chlorinated corresponding compounds.
  • the present invention is in general applicable to all types of carboxylic acid esters of 6-hal'ogen-l,2a-methylene-A -l7a-hydroxyprogesterone, including aliphatic acid esters, alicyclic acid esters, aromatic acid esters and mixed open chain-cyclic carboxylic acid esters. All of these esters may be produced in analogous manner to the production of the esters of the present invention which will be shown in the examples given below.
  • the preferred esters from the point of View of the progestational activity of the present invention are the aliphatic carboxylic acid esters of up to 10 carbon atoms, such as the acetate, propionate, valerate, capronate, enanthate, etc.
  • the acetate exhibits a particularly high degree of progestational activity, particularly upon peroral administration
  • the higher homologous esters exhibit a similar high degree of progestational activity, which, particularly in the case of peroral administration, is higher than that of known progestational compounds.
  • the higher homologs starting with the enanthate, there is in addition a valuable protraction of the p'rogestational activity.
  • the alicyclic and mixed open chain-cyclic carboxylic' acid esters such as the cyclopentlypropionate.
  • the compounds of the present invention may be incorporated into progestational compositions of all type, e.g., for injection purposes, such as by subcutaneous injection, or for peroral administration.
  • progestational compositions of all type e.g., for injection purposes, such as by subcutaneous injection, or for peroral administration.
  • the compounds thereof have a highly superior progestational activity upon peroral administration, it is apparent that this invention should not be limited to the use of the compounds for peroral administration because the compounds can'also be used by injection, by per os administration, for example in the form of suppositories, etc.
  • compositions-with the progestational compounds of the present invention can be used as active ingredient with any normal pharmaceutical carrier or excipient for administration by injection, for peroral administration in the form of tablets, dragecs, emulsions, for rectal administration suppositories, etc.
  • the pharmaceutical carriers and excipients would include diluents and absorbents such as amidone, sugar, carbon-ates, kaolin, etc.; agglutinants such as carboxymethyl cellulose, alginates, gums, sorbitol, polyvinylpyrrolidone, pectins, etc.; lubricants such as talc, stearic acid, stearates, etc.; wetting agents such as sorbi't'an, mono-oleate, oleates or ste-arates of triethanolamine, etc.; buffering substances such as calcium salts, glyoocols, mag
  • esium trisilicate, etc. coating substances such as gluten, cellulose acetophthalate, methyl phthalate, ethyl phthalate, etc.; carriers and excipients for emulsions, such as polyethylene-glycol, carboxymethyl cellulose, methyl cellulose, sorbitan mono-o leate, interesterified oils, etc.; and carriers and excipien-ts for suppositories such as cocoa butter, ynthetic semi-glycerides, etc.
  • coating substances such as gluten, cellulose acetophthalate, methyl phthalate, ethyl phthalate, etc.
  • carriers and excipients for emulsions such as polyethylene-glycol, carboxymethyl cellulose, methyl cellulose, sorbitan mono-o leate, interesterified oils, etc.
  • carriers and excipien-ts for suppositories such as cocoa butter, ynthetic semi-glycerides, etc.
  • composition thereof can: be administered in the form of capsules, tablets, dragees,
  • the compounds of the present invention are produced 1 by introducing a halogen atom into the 6-position of. the; chosen L'Za-methylene-A -l7u-hydroxyprogesterone ester.
  • the LZa-rmethylene-A -l7a-hydroxyprogesterone ester is first converted in known manner, preferably by means of pere carboxylic acids, particularly perbenzoic acid, into the: corresponding 6,7a-epoxide, which is then treated with the hydrohalic acid, preferably in glacial acetic acid solution, whereby in a single operation the cyclopropane ring is opened with the formation of a lot-halogen methyl group, and the epoxy ring is opened with the splitting-off ofwater and the formation of the 6-halogen-Ni-grouping.
  • the lot-halogen. methyl group of the. reaction product is then subsequently re-converted into the 1,2wmethylene group, preferably by means of organic bases, particularly collidine. This method is illustrated by the following general equations:
  • the starting compounds for the method of the present invention may be produced in accordance with the methods shown in German Patent No. 1,072,991, German Patent No. 1,096,353, and US. patent application Serial No. 60,812, now US. "3,127,396 filed. October 6, 1960,: for Production of 1,2-Methylene and 16,17-Methylene.
  • Example 1 2.34 g. of 1,2ot-methylene-A -pregnadiene-Not-016,20- dioneel7-acetate are dissolved in 18.25 cc.v of ethylene chloride; which contains 844 mg. of perbenzoic acid.: The.
  • Example 2 8.7 g. of 1,2u-methylene-At -pregnadiene:17a-ol-3,20 dione-17-capronate (produced according to the methods; of German Patent No. 1,072,99l and German Patent No. 1,096,353 )1 and 2.77 g. :of perbenzoic acid in-52.9cc. of
  • Example 3 This example describes the production of tablets.
  • 1 g. of 1,2zxmethylene-6-chloro-A-l7a-hydroxyprogesterone-17-acetate are granulated in normal manner with 36 g. of lactose, 25.6 g. of corn starch and with 1.4 g. of gelatin with the addition of 0.035 g. of peroxy-benzoic acid methyl ester/propylester, and after the addition of 6 g. of talcum pressed into tablets in the usual manner, each tablet weighing about 120 mg. and containing about 1 mg. of the active ingredient.
  • Example 4 970 mg. of 1,2tat-methylene-d -pregnadiene-17u-ol-3, 20-dione-l7-propionate (M.P. 1925-1955”) [produced according to the methods of German Patent No. 1,072,991 and German Patent No. 1,096,353] are treated with perbenzoic acid as described in Example 2 and worked up. After recrystallisation from ethylacetate 538 mg. 1,2a methylene 6,70: oXido A pregnene 17oz o1 3,20-dione-l7-propionate (M.P. 199-202”) are obtained and reacted in the same manner as described in Examp le 2.
  • Example 5 5 g. 1,Za-methylene-A -pregnadiene-17a-ol-3,20-dione- 17-valerate [produced according to the methods of German Patent No. 1,072,991 and German Patent No. 1,096,353] are reacted in the same manner as described in Example 1. After chromatography over silica gel 2 g. 6 chlor 1,204 methylene A*- pregnadiene 1701-01- 3,20-dione-17-valerate are obtained as an oil.
  • Example 6 5 g. l,2a-methylene-A -pregnadiene-17m-ol-3,20-dione- 17-cyclopentylpropionate [produced according to the methods of German Patent No. 1,072,991 and German Patent No. 1,096,353] are reacted in the same manner as described in Example 1. After chromatography over silica gel 1.8 g. 6-chlor-1,2wmethylene-A -pregnadiene- 17u-ol-3,20-dione-17-cyclopentylpropionate are obtained as an oil.
  • X is chlorine; and wherein R is selected from the group consisting of hydrogen and acyl wherein acyl is derived from a hydrocarbon aliphatic carboxylic acid of up to 10 carbon atoms.
  • a progestational composition in daily dose form comprising between about 1 mg. and 6 mg. of the 6-chloro- 1,2a-rnethylene-A -17 a-hydroxyprogesterone ester of a hydrocarbon aliphatic carboxylic acid of up to 10 carbon atoms as active ingredient; and a pharmaceutical carrier.
  • a progestational composition in daily dose form comprising between about 1 mg. and 6mg. of 6-ch1oro- 1,2a-methyleneA -17a-hydroxyprogesterone-acetate in an amount sufficient to achieve a progestational effect as ac tive ingredient; and a pharmaceutical carrier.
  • a progest-ational composition in daily dose form comprising between about 1 mg. and 6 mg. of 6-chlorol,2a-methylene-A -17a-hydroxyprogesterone-capronate in an amount sutficient to achieve a progestational effect as active ingredient; and a pharmaceutical carrier.
  • a progestational composition in daily dose form for peroral administration comprising between about 1 mg. and 6 mg. of the 6-oh1oro-1,2a-methylene-M-17ot-hydroxyprogesterone ester of a hydrocarbon aliphatic carboxylic acid of up to 10 carbon atoms as active ingredient in an amount suflicient to achieve a progestational effect; and a pharmaceutical carrier adapted for peroral administration.

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  • 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)
US189724A 1961-04-29 1962-04-24 6-chloro-1, 2alpha-methylene-delta6-17alpha-hydroxyprogesterone compounds and compositions Expired - Lifetime US3234093A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DESCH29643A DE1158966B (de) 1961-04-29 1961-04-29 Verfahren zur Herstellung von 6-Chlor-1, 2ª‡-methylen-í¸-17ª‡-hydroxyprogesteronestern

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US (1) US3234093A (fr)
BE (1) BE616989A (fr)
BR (1) BR6238435D0 (fr)
CH (1) CH417576A (fr)
DE (1) DE1158966B (fr)
GB (1) GB973908A (fr)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3401163A (en) * 1965-10-21 1968-09-10 Squibb & Sons Inc Preparation of methylene steroids
US3423507A (en) * 1966-02-25 1969-01-21 Schering Corp Method of treating benign prostratic hypertrophy
US3439093A (en) * 1964-10-13 1969-04-15 Schering Ag 6 - halogen - 1alpha,2alpha - methylene - 16alpha - methyl - delta**4,6 - pregnadiene - 17alpha - ol - 3,20 - diones and the 17-esters
US3895110A (en) * 1973-09-06 1975-07-15 Schering Ag Methods for the treatment of psychic disturbances
FR2384794A1 (fr) * 1977-03-21 1978-10-20 Schering Ag Methylene-1a,2a steroides et medicaments qui en contiennent
US4367227A (en) * 1976-03-11 1983-01-04 Lever Brothers Company Method and cosmetic composition for reducing sebum secretion
EP0143888A3 (en) * 1983-09-01 1985-10-09 Schering Aktiengesellschaft Berlin Und Bergkamen Process for the preparation of 17-alpha-acyloxy-6-chloro-1-alpha,2-alpha-methylene-4,6-pregnadiene-3-20-diones
US5439901A (en) * 1993-07-23 1995-08-08 The Procter & Gamble Company Cyproterone thiopivalate
EP0696686A1 (fr) 1994-08-10 1996-02-14 Fatigue Technology, Inc. Assemblage écrou mur
US6165504A (en) * 1998-09-23 2000-12-26 Barr Laboratories, Inc. Methods for treating hot flashes and improving the quality of life of castrated prostatic cancer patients
US6613758B1 (en) 1999-04-02 2003-09-02 Barr Laboratories, Inc. Method for treating osteoporosis in castrated prostatic cancer patients
JP2005523927A (ja) * 2002-04-29 2005-08-11 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 酢酸シプロテロンの改良された合成
US20060211873A1 (en) * 2002-04-29 2006-09-21 Boehringer Ingelheim International Gmbh Synthesis of cyproterone acetate
US20060247272A1 (en) * 2004-09-23 2006-11-02 Pfizer Inc 4-Amino Substituted-2-Substituted-1,2,3,4-tetrahydroquinoline Compounds
WO2007050425A2 (fr) 2005-10-21 2007-05-03 Bristol-Myers Squibb Company Modulateurs de lxr
WO2007062314A2 (fr) 2005-11-23 2007-05-31 Bristol-Myers Squibb Company Inhibiteurs de cetp heterocycliques
WO2008070496A2 (fr) 2006-12-01 2008-06-12 Bristol-Myers Squibb Company Inhibiteurs d'amino cetp étendus
US20090258040A1 (en) * 2008-04-09 2009-10-15 Pherin Pharmaceuticals, Inc. Steroid treatment for hot flashes
WO2010093601A1 (fr) 2009-02-10 2010-08-19 Metabasis Therapeutics, Inc. Nouveaux thyromimetiques contenant de l'acide sulfonique et methodes d'utilisation associees
EP2428516A1 (fr) 2003-11-19 2012-03-14 Metabasis Therapeutics, Inc. Nouvelles substances thyromimetiques contenant du phosphore
WO2014087298A1 (fr) 2012-12-03 2014-06-12 Pfizer Inc. Nouveaux modulateurs androgéniques sélectifs
US11617751B2 (en) 2006-07-06 2023-04-04 Bayer Pharma AG Pharmaceutical composition containing a tetrahydrofolic acid

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3439093A (en) * 1964-10-13 1969-04-15 Schering Ag 6 - halogen - 1alpha,2alpha - methylene - 16alpha - methyl - delta**4,6 - pregnadiene - 17alpha - ol - 3,20 - diones and the 17-esters
US3401163A (en) * 1965-10-21 1968-09-10 Squibb & Sons Inc Preparation of methylene steroids
US3423507A (en) * 1966-02-25 1969-01-21 Schering Corp Method of treating benign prostratic hypertrophy
US3895110A (en) * 1973-09-06 1975-07-15 Schering Ag Methods for the treatment of psychic disturbances
US4367227A (en) * 1976-03-11 1983-01-04 Lever Brothers Company Method and cosmetic composition for reducing sebum secretion
FR2384794A1 (fr) * 1977-03-21 1978-10-20 Schering Ag Methylene-1a,2a steroides et medicaments qui en contiennent
EP0143888A3 (en) * 1983-09-01 1985-10-09 Schering Aktiengesellschaft Berlin Und Bergkamen Process for the preparation of 17-alpha-acyloxy-6-chloro-1-alpha,2-alpha-methylene-4,6-pregnadiene-3-20-diones
US4565657A (en) * 1983-09-01 1986-01-21 Schering Aktiengesellschaft Process for the production of 17α-acyloxy-6-chloro-1α,2α-m
US5439901A (en) * 1993-07-23 1995-08-08 The Procter & Gamble Company Cyproterone thiopivalate
EP0696686A1 (fr) 1994-08-10 1996-02-14 Fatigue Technology, Inc. Assemblage écrou mur
US6165504A (en) * 1998-09-23 2000-12-26 Barr Laboratories, Inc. Methods for treating hot flashes and improving the quality of life of castrated prostatic cancer patients
US6613758B1 (en) 1999-04-02 2003-09-02 Barr Laboratories, Inc. Method for treating osteoporosis in castrated prostatic cancer patients
JP2005523927A (ja) * 2002-04-29 2005-08-11 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 酢酸シプロテロンの改良された合成
CN1305893C (zh) * 2002-04-29 2007-03-21 贝林格尔·英格海姆国际有限公司 环丙孕酮乙酸酯的改进合成方法
US20060211873A1 (en) * 2002-04-29 2006-09-21 Boehringer Ingelheim International Gmbh Synthesis of cyproterone acetate
EP2428516A1 (fr) 2003-11-19 2012-03-14 Metabasis Therapeutics, Inc. Nouvelles substances thyromimetiques contenant du phosphore
US20060247272A1 (en) * 2004-09-23 2006-11-02 Pfizer Inc 4-Amino Substituted-2-Substituted-1,2,3,4-tetrahydroquinoline Compounds
WO2007050425A2 (fr) 2005-10-21 2007-05-03 Bristol-Myers Squibb Company Modulateurs de lxr
EP2392567A1 (fr) 2005-10-21 2011-12-07 Bristol-Myers Squibb Company Derives de benzothiazine et leurs utilisation comme modulateurs de lxr
WO2007062314A2 (fr) 2005-11-23 2007-05-31 Bristol-Myers Squibb Company Inhibiteurs de cetp heterocycliques
US11617751B2 (en) 2006-07-06 2023-04-04 Bayer Pharma AG Pharmaceutical composition containing a tetrahydrofolic acid
WO2008070496A2 (fr) 2006-12-01 2008-06-12 Bristol-Myers Squibb Company Inhibiteurs d'amino cetp étendus
US20090258040A1 (en) * 2008-04-09 2009-10-15 Pherin Pharmaceuticals, Inc. Steroid treatment for hot flashes
US8431559B2 (en) 2008-04-09 2013-04-30 Pherin Pharmaceuticals, Inc. Treatment of hot flashes
WO2010093601A1 (fr) 2009-02-10 2010-08-19 Metabasis Therapeutics, Inc. Nouveaux thyromimetiques contenant de l'acide sulfonique et methodes d'utilisation associees
WO2014087298A1 (fr) 2012-12-03 2014-06-12 Pfizer Inc. Nouveaux modulateurs androgéniques sélectifs
US9328104B2 (en) 2012-12-03 2016-05-03 Pfizer Inc. Selective androgen receptor modulators

Also Published As

Publication number Publication date
CH417576A (de) 1966-07-31
BR6238435D0 (pt) 1973-05-24
DE1158966B (de) 1963-12-12
BE616989A (fr) 1962-10-29
GB973908A (en) 1964-11-04

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