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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US3234093A
US3234093A US18972462A US3234093A US 3234093 A US3234093 A US 3234093A US 18972462 A US18972462 A US 18972462A US 3234093 A US3234093 A US 3234093A
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methylene
compounds
hydroxyprogesterone
progestational
chloro
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Wiechert Rudolf
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Bayer Pharma AG
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J53/00Steroids 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J7/00Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J75/00Processes for the preparation of steroids in general

Description

United States Patent 3,234,093 6-CHLORO-LZa-METHYLENE-A -l7oL-HYDRQXY- PRQGESTERONE COMPQUNDS AND CQM- POSITIONS Rudolfi Wiechert, Berlin-Lichterfelde, Germany, assignor to 'Schering Aktiengesellschaft, Berlin, Germany No Drawing. Filed Apr. 24, 1962, Ser. No. 189,724 Claims priority, application Germany, Apr. 29, 1961, Sch 29,643 The portion of the term of the patent subsequent to Mar. 31, 1981-, has been disclaimed 12 Claims. (Cl. 161-74) 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.

It is another object of the present invention to provide 6-position halogenated 1,Zu-methyIene-A -l7a-hydroxyprogesterone esters which have a remarkably high progestational activity.

It is yet another object of the present invention to provide for the production of these new compounds.

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.

Other objects and advantages of the present invention will be apparent from a further reading of the specification and of the appended claims.

With the above and other objects in view, the present invention mainly comprises a compound of the formula:

wherein X is a halogen, and wherein R is selected from the group consisting of hydrogen and acyl wherein acyl is derived from a carboxylic acid.

The esters of the present invention, i.e., compounds of the above formula wherein R is acyl derived from a carboxylic acid, have been found to have a surprisingly high degree of progestational action, which is in many cases equal to and superior to the progestational action of known compounds used for this purpose, and particularly upon peroral administration is in many cases several times greater than the progestational action of known compounds used for this purpose. Accordingly, 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.

Although 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. Thus, for example, although 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, and 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. In the case of the higher homologs, starting with the enanthate, there is in addition a valuable protraction of the p'rogestational activity. Also preferred for the purposes of the present invention are 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. Although it is a particular advantage of the present invention that 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.

In preparing compositions-with the progestational compounds of the present invention, these compounds 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. Thus, for example, in the manufacture of tablets and dragees 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.

As indicated above, a particular advantage of the adequate. positive Clauberg test on infantile rabbits.

present invention is that the composition thereof can: be administered in the form of capsules, tablets, dragees,

marked superior activity of the compound of the' present invention:

The preferred daily dose of the pro- 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. In accordance with the method of the present invention 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:

CH3 CH3' (5: =0

n 93 O=ci -wherein R and X have the same definitions as above.

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.

.Ketosteroids.

The surprisingly strong progestational action, particularly upon peroral administratoim of the compounds of the present-invention, is illustrated by the following comparative tests wherein 6-chloro-1,2a-methylene-Ai17oc hydroxyprogesteroneaacetate was compared with cornpoundsknown to have a verystrong progestational action. amount of the; tested compound sufficient to achieve an The results are summarized in the .table'below, and show the In these tests there was determined the.- minimum Necessary dose in mg. upon administration Compound Subcutaneous Peroral progesterone-acetate 0.003 0. 01 19-nor-17a-hydroxy-progesterone-acetate a 0.003 0.1 17u-Hydroxy-progesterone-acetate 0.03. 0. 9 19-nor-l7a-ethinyl-testosterone 0.06 0.1 19-nor-17cv-ethinyl-testosterone-acetate 0. 03 I, 0.03

Example 1 v 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.

solution is stored for 16 hours ata+5 C. and 7 hoursFat room temperature. It :is then diluted with methylene chloride and, with-aqueous ferrous sulfate 1solution,"so-

dium .bicarbonate solution and with water washed into neutral.

The organic phase .is dried over sodium sulfate and then. concentrated to dryness. 1.62 got the thus obtained crude 1,2ot-methylene-6,7a-oxid'o-A -pregnene-17aol-3,20-dione-l7-a-cetate are dissolved in 109 cc. of glacial acetic acid. Thisfsolution is then saturatedv at room temperature with hydrogen chloride gas and stored for 20 hours. It'is then diluted with methylene chloride and washed with waterpntil neutral.

The organic. phase is dried over sodium sulfate and :then concentrated to dryness. The thus; obtained. crude 6 chloro 1a chloromethyl A pregnadiene 17aol-3,20 dione-l7-acetate is heated to boiling .in 20cc. of

collidine for '20. minutes under nitrogen. After dilution with ether it is washed with 4 normal hydrochloric acid and washed'wi-th water until neutral. i

After drying over: sodium sulfate and concentration -to vacuum the remaining residue is subjected to chromatog 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

ethylene chloride are allowed to stand for 17 hours at. 1

The reaction 5 C. and :7 hours at room-- temperature. mixture is then further worked up as described in Example 1 and the obtainedcrude 1,2a-methylene-6,7a oxido- 1 A -pregnene-17d-ol-3,20-di0ne-17-capronate are dissolved in 585 ccof glacial acetic acid.

The solutionlis saturated with hydrogen chloride gas. at room temperature and allowed to stand for-20 hours. It .iS, then diluted with ,methylene. :chloride-:.and washed with water until neutral.

Theorganie phase is dried over ;sodium.sulfate and concentrated to dryness.= There is thus obtained 9.4g... of crude 6-chloro-1lx-chloromethyl-A -pregnadiene-17w.

01-3,20-dl0116r17-C3P1'0I13I6 which is dissolved in 87 cc.v

of freshly distilled collidine and heatedunder refluxing and under nitrogen for 30 minutes; The .reaction n1ix-v ture is then further worked up and subjected to chroma-..

tography as described in Example 1.

from isopropyl ether 2 There is thus obtained 3.1 g. of 6-chloro-l,2oc-rnethyloil. ene-A -pregnadiene-17ot-ol-3,ZO-dione-17-capronate as an UV: 6'2 2=17500. Analysis.Chlorine: 7.5 calculated. 7.4 found.

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.

There is thus obtained 120 mg. 6-chlor-1,2a-methylene A pregnadiene 17a o1 3,20 dione 17 propionate melting at 190.5191.5 C.

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.

Without further analysis, the foregoing will so fully reveal the gist of the present invention that others can by applying current knowledge readily adapt -it for various applications without omitting features that, from the standpoint of prior art, fairly constitute essential characteristics of the generic or specific aspects of this invention and, therefore, such adaptations should and are intended to be comprehended within the meaning and range of equivalence of the following claims.

wherein 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.

2. The up to 10 carbon atom hydrocarbon aliphatic carboxylic acid ester of 6-chloro-1,2a-methylene-A -17uhydroxyprogesterone.

3. The 6 chloro 1,2 methylene A 17oz hydroxyprogesterone ester of a hydrocarbon alicyclic carboxylic acid of up to 10 carbon atoms.

4. The compound 6-chloro-1,2oc-methylene-A -17a-hydroxyprogesterone-acetate.

5. The compound 6-chloro-1,2a-methylene-A -17a-hydroxyprogesterone-capronate.

6. The compound 6-ch1oro-l,2a-methylene-A -17a-hydroxyprogesterone-propionate.

7. The compound 6-chloro-1,2a-methylene-A -17a-hydroxyprogesterone-valerate.

8. The compound 6-chloro-1,2a-methylene-A -17a-hydroxyprogesterone-cyclopentylpropionate.

9. 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.

10. 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.

11. 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.

12. 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.

References Cited by the Examiner Ringold et al., J.A.C.S., 81, 1959, pp. 3485 and 3486. Sciaky, Gazz. Chim. ItaL, 91, 1961, pp. 545-561.

LEWIS GOTTS, Primary Examiner.

Claims (1)

  1. 9. A PROGESTATIONAL COMPOSITION IN DAILY DOSE FORM, COMPRISING BETWEEN ABOUT 1 MG. AND 6MG. OF THE 6-CHLORO1,2A-METHYLENE-$6-17A-HYDROXYPROGESTERONE ESTER OF A HYDROCARBON ALIPHATIC CARBOXYLIC ACID OF UP TO 10 CARBON ATOMS AS ACTIVE INGREDIENT; AND A PHARMACEUTICAL CARRIER.
US3234093A 1961-04-29 1962-04-24 6-chloro-1, 2alpha-methylene-delta6-17alpha-hydroxyprogesterone compounds and compositions Expired - Lifetime US3234093A (en)

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Cited By (21)

* 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 (en) * 1977-03-21 1978-10-20 Schering Ag Methylene-1a, 2a and steroid drugs which contain
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 (en) 1994-08-10 1996-02-14 Fatigue Technology, Inc. Wall nut assembly
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 (en) * 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 Improved synthesis of cyproterone acetate
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 (en) 2005-10-21 2007-05-03 Bristol-Myers Squibb Company Lxr modulators
WO2007062314A2 (en) 2005-11-23 2007-05-31 Bristol-Myers Squibb Company Heterocyclic cetp inhibitors
WO2008070496A2 (en) 2006-12-01 2008-06-12 Bristol-Myers Squibb Company N- ( (3-benzyl) -2, 2- (bis-phenyl) -propan-1-amine derivatives as cetp inhibitors for the treatment of atherosclerosis and cardiovascular diseases
US20090258040A1 (en) * 2008-04-09 2009-10-15 Pherin Pharmaceuticals, Inc. Steroid treatment for hot flashes
WO2010093601A1 (en) 2009-02-10 2010-08-19 Metabasis Therapeutics, Inc. Novel sulfonic acid-containing thyromimetics, and methods for their use
EP2428516A1 (en) 2003-11-19 2012-03-14 Metabasis Therapeutics, Inc. Novel phosphorus-containing thyromimetics
WO2014087298A1 (en) 2012-12-03 2014-06-12 Pfizer Inc. Novel selective androgen receptor modulators

Non-Patent Citations (1)

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

Cited By (25)

* 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 (en) * 1977-03-21 1978-10-20 Schering Ag Methylene-1a, 2a and steroid drugs which contain
US4565657A (en) * 1983-09-01 1986-01-21 Schering Aktiengesellschaft Process for the production of 17α-acyloxy-6-chloro-1α,2α-m
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 (en) 1994-08-10 1996-02-14 Fatigue Technology, Inc. Wall nut assembly
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
US20060211873A1 (en) * 2002-04-29 2006-09-21 Boehringer Ingelheim International Gmbh Synthesis of cyproterone acetate
JP2005523927A (en) * 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 Improved synthesis of cyproterone acetate
EP2428516A1 (en) 2003-11-19 2012-03-14 Metabasis Therapeutics, Inc. Novel phosphorus-containing thyromimetics
US20060247272A1 (en) * 2004-09-23 2006-11-02 Pfizer Inc 4-Amino Substituted-2-Substituted-1,2,3,4-tetrahydroquinoline Compounds
EP2392567A1 (en) 2005-10-21 2011-12-07 Bristol-Myers Squibb Company Benzothiazine derivatives and their use as lxr modulators
WO2007050425A2 (en) 2005-10-21 2007-05-03 Bristol-Myers Squibb Company Lxr modulators
WO2007062314A2 (en) 2005-11-23 2007-05-31 Bristol-Myers Squibb Company Heterocyclic cetp inhibitors
WO2008070496A2 (en) 2006-12-01 2008-06-12 Bristol-Myers Squibb Company N- ( (3-benzyl) -2, 2- (bis-phenyl) -propan-1-amine derivatives as cetp inhibitors for the treatment of atherosclerosis and cardiovascular diseases
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 (en) 2009-02-10 2010-08-19 Metabasis Therapeutics, Inc. Novel sulfonic acid-containing thyromimetics, and methods for their use
WO2014087298A1 (en) 2012-12-03 2014-06-12 Pfizer Inc. Novel selective androgen receptor modulators
US9328104B2 (en) 2012-12-03 2016-05-03 Pfizer Inc. Selective androgen receptor modulators

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