IE58147B1 - 13 alpha -alkyl-17 beta-(3acyloxypropyl)-gonanes - Google Patents
13 alpha -alkyl-17 beta-(3acyloxypropyl)-gonanesInfo
- Publication number
- IE58147B1 IE58147B1 IE316985A IE316985A IE58147B1 IE 58147 B1 IE58147 B1 IE 58147B1 IE 316985 A IE316985 A IE 316985A IE 316985 A IE316985 A IE 316985A IE 58147 B1 IE58147 B1 IE 58147B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- gonadiene
- hydroxy
- general formula
- examples
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0077—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom
- C07J41/0083—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom substituted in position 11-beta by an optionally substituted phenyl group not further condensed with other rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
1. 13 alpha-alkylgonanes of general formula I see diagramm : EP0186834,P6,F4 wherein R represents an acyl radical having up to 10 C atoms and X represents an oxygen atom or the grouping N apprch OH.
Description
The invention relates to new 13°(-alkyl-17B-(3-acyloxy-propyl) gonanes, a process for their manufacture and pharmaceutical preparations containing these compounds. 130C-alkyl-17B- (3-hydroxypropyl)-4,9-gonadiene-3-ones are 5 known from; European Patent Application No. 84730062.1.
These compounds have a strong affinity for gestagen receptors without themselves having any gestagenic activity. They are competitive antagonists of progesterone (antigestagens) and are suitable for inducing abortions since they displace the progesterone necessary for maintenance of pregnancy from the receptor. The compounds are thus valuable and of interest from the point of view of their use for postcoital (p.c.) control of fertility.
It has now been found that their bio-availability can,sur15 prisingly, be considerably enhanced by converting these compounds into the 13d-alkyl-17B-(3-acyloxypropyl)-gonanes' of general formula I. In comparison to the previously known 13 Furthermore, they possess excellent chemical stability.
They can be stored without difficulty for a long period of time at room temperature without decomposing.
According to one aspect the invention provides a compound of the general formula I where R represents an acyl radical having up to 10 C-atoms and X represents an oxygen atom or the grouping N~0H.
The acyl radical R may contain up to 10 C-atoms. Possible acyl radicals are, for example, the formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, glycoloyl, cyclopentylacetyl, mono-, di-, trichcloroacetyl, benzoyl, trifluoromethylbenzoyl and nicotinovl radicals; preferred are the acetyl and benzoyl radicals.
X represents an oxygen atom or the group N*^0H, with the hydroxyimino radical being in the syn or anti position.
In another aspect the invention provides a method of preparing a compound of general formula I wherein a compound of the general formula II ch2 - ch2-oh (II) is reacted with an acid chloride or an acid anhydride of 5 general formula III or IV respectively II R-C-Cl (III) II (R-C)2O (IV) where R represents an acyl radical having up to 10 C-atoms, in the 10 presence of bases at a temperature of between O and 60°C and, if desired subsequently reacting with hydroxylamine hydrochloride in the presence of tertiary amines at a temperature of between -20 and 4o°C. The preferred bases for esterification are tertiary amines such as pyridine. The preferred tertiary amine during conversion for the preparation of oximes is pyridine.
Further suitable tertiary bases are, for example, trimethylamine, triethylamine, Ν,Ν-dimethylamino pyridine, 1,5-diazabicyclo [4.3.0} nonene-5 (DBN) and 1.5-diazabicyclo[5.4.0) undecene-5 (DBU).
The 13a-alkylgonanes of general formula I can be used in the form of pharmaceutical preparations. The preparations are manufactured by the methods generally known in galenics by mixing with organic or inorganic inert carrier material suitable for enteral, percutaneous or parenteral application .
For humans the dosage of the active ingredients in accordance with the invention amounts to approximately 10 to 1000 mg per day.
The invention will be more clearly understood from the following examples which, however, are given without limitation to the scope of the invention.
Example 1 A solution of 2.4 g of 11 6- (4-dimethylaminophenyl)-1 7o(hydroxy-1 3o(-niethyl-176 (3-hydroxypropyl)-4,9-gonadiene3-one in 7 ml of pyridine and 14 ml of acetanhydride is stirred for 14 hours at 25 °C. This mixture is then poured into warm water (100 ml) at a temperature of approx. 50 °C stirred for 15 minutes and the cooled emulsion extracted with methylene chloride. The methylene chloride phase is washed neutral with NaHCO. solution, dried over Na_SO, and concentrated. Crystallization of the crude product from ethylacetate/diisopropyl ether yields 2.24 g of 176(3-acetoxypropyl)-116- (4-dimethylaminophenyl)-17 -hydroxy 130(-methyl-4,9-gonadiene-3-one with a melting point of 162 - 164 °C. [a]p5 + 436.5° (CHC13, c = 0.515).
Example 2 0.36 ml of benzoyl chloride in 4 ml of methylene chloride are dripped, ice-cooled, into a solution of 700 mg of 116(4-dimethylaminophenyl)-17«-hydroxy-1J^-methy1-176-(3-hydroxypropyl) -4 , 9-gonadiene-3-one. The mixture is stirred for 60 minutes at +5 °C, then poured into saturated NaHCO^ solution and extracted with ethyl acetate. Crystallization of the crude product from hexane/diisopropyl ether yields 630 mg of 176-(3-benzoyloxypropyl)-116-(4-dimethylaminophenyl) -17«-hydroxy-13g-methyl-4,9-gonadiene-3-one with a melting point of 114 - 116 °C.
Example 3 A solution of 630 mg of 176-(3-acetoxypropyl)-118-(4-dimethylaminophenyl)-17«-hydroxy-1 3 0 °C after the addition of 600 mg of hydroxylamine hydrochloride. The mixture is subsequently poured into a mixture of ice water and saturated NH^Cl solution and extracted with ethyl acetate. After chromatography on silica gel with hexane/ethyl acetate 410 mg of 1 7fi-(3-acetoxypropyl)-11 ΒΙΟ (4-dimethyl-aminophenyl )-1 7c(-hydroxy-1 3(X-meth yl-4,9-gonadiene 3-one-anti-oxime are obtained with a melting point of 201 - 204 °C.
UV (MeOH): λ = 288 nm (£ = 27400). max Example 4 Composition of a tablet with the prefered compound 178-(3Acetoxypropyl)-118-(4-N,N-Dimethylamino)-Phenyl)-17a-hydroxy13a-methyl-4,9-gonadiene-3-one for oral application. .0 mg 17 8-3 (-acetoxypropy 1-118-(4-N,N-Dimethylamino)-phenyl)17ct-hydroxy-13a-methyl-4,9-gonadiene-3-one 140.5 mg Lactose 69.5 mg Corn Starch 2.5 mg Polyvinylpyrrolidone 2.0 mg Aerosl1 0.5 mg Magnesium Stearate 225.0 mg
Claims (5)
1. 1 3 oC-alkylgonanes of general formula I where 5 R represents an acyl radical having up to 10 C-atoms and X represents an oxygen atom or the grouping N OH.
2. A compound as claimed in claim 1 wherein R is acetyl or benzoyl.
3. 17 8-(3-acetoxypropyl)-116-(4-dimethylaminophenyl)17a-hydroxy-13a-methyl-4,9-gonadiene-3-one.
4. 176-(3-benzoyloxypropyl)-118-(4-dimethylaminophenyl)17a-hydroxy-13a-methyl-4,9-gonadiene-3-one. 5. 176-(3-acetoxypropyl)-116-(4-dimethylaminophenyl)17a-hydroxy-13a-methyl-4,9-gonadiene-3-one-anti-oxime. 6. A process for the preparation of 13ff-alkylgonanes of general formula I where 5 R and X have the meaning given in Claim 1, characterized in that a compound of the formula II (II) is reacted with an acid chloride or an acid anhydride of general formula III or IV respectively II R-C-Cl (HI) (R-C) 2 O (IV) 5 where R has the meaning given in Claim 1, in the presence of bases at a temperature of between 0 and 60°C and, if desired subsequently reacting with hydroxylamine hydrochloride in the presence of tertiary amines at a 10 temperature of between -20 and +40°C. 7. A pharmaceutical preparation comprising a compound as claimed in any of Claims 1 to 5 and a pharmaceutically acceptable carrier. 8. Use of compounds of Claims 1 to 5 for the manufacture of pharmaceuticals. 15 9. A method of medical treatment or prophylaxis comprising the step of administering an effective amount of a compound as claimed in any of Claims 1 to 5 or a composition as claimed in Claim 7. 10. The use of a compound as claimed in any of claims 1 to 9 20 for the manufacture of a pharmaceutical composition for use in a method of medical treatment or prophylaxis. 11. A compound substantially as hereinbefore described with reference to the Examples. 12. A process substantially as hereinbefore described with reference to the Examples. 13. A pharmaceutical preparation substantially as hereinbefore described with reference to the Examples.
5. 14. A method substantially as hereinbefore described with reference to the Examples.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843446661 DE3446661A1 (en) | 1984-12-18 | 1984-12-18 | NEW 13 (ALPHA) -ALKYL-17 (BETA) - (3-ACYLOXYPROPYL) GONANA |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE853169L IE853169L (en) | 1986-06-18 |
| IE58147B1 true IE58147B1 (en) | 1993-07-14 |
Family
ID=6253403
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE316985A IE58147B1 (en) | 1984-12-18 | 1985-12-16 | 13 alpha -alkyl-17 beta-(3acyloxypropyl)-gonanes |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0186834B1 (en) |
| JP (1) | JPH0662665B2 (en) |
| AT (1) | ATE45957T1 (en) |
| AU (1) | AU580646B2 (en) |
| CA (1) | CA1262894A (en) |
| DD (1) | DD242231A5 (en) |
| DE (2) | DE3446661A1 (en) |
| DK (1) | DK166502B1 (en) |
| ES (1) | ES8701194A1 (en) |
| FI (1) | FI83089C (en) |
| GR (1) | GR853017B (en) |
| HU (1) | HU193357B (en) |
| IE (1) | IE58147B1 (en) |
| NO (1) | NO163014C (en) |
| NZ (1) | NZ214449A (en) |
| PT (1) | PT81690B (en) |
| ZA (1) | ZA859666B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4434488A1 (en) | 1994-09-14 | 1996-03-21 | Schering Ag | Steroid esters and amides, processes for their preparation and their pharmaceutical use |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA8231B (en) * | 1981-01-09 | 1982-11-24 | Roussel Uclaf | New 11 -substituted steroid derivatives, their preparation, their use as medicaments, the compositions containing them and the new intermediates thus obtained |
| EP0116974B1 (en) * | 1983-02-18 | 1986-10-29 | Schering Aktiengesellschaft | 11-beta-aryl-estradienes, process for their preparation and pharmaceutical compositions containing them |
| ES533260A0 (en) * | 1983-06-15 | 1985-02-01 | Schering Ag | PROCEDURE FOR THE PREPARATION OF 13A-ALQUILGONANOS |
-
1984
- 1984-12-18 DE DE19843446661 patent/DE3446661A1/en not_active Withdrawn
-
1985
- 1985-12-03 FI FI854788A patent/FI83089C/en not_active IP Right Cessation
- 1985-12-05 NZ NZ214449A patent/NZ214449A/en unknown
- 1985-12-13 AT AT85115925T patent/ATE45957T1/en not_active IP Right Cessation
- 1985-12-13 DE DE8585115925T patent/DE3572670D1/en not_active Expired
- 1985-12-13 EP EP85115925A patent/EP0186834B1/en not_active Expired
- 1985-12-16 IE IE316985A patent/IE58147B1/en not_active IP Right Cessation
- 1985-12-16 DD DD85284398A patent/DD242231A5/en not_active IP Right Cessation
- 1985-12-16 ES ES549998A patent/ES8701194A1/en not_active Expired
- 1985-12-16 GR GR853017A patent/GR853017B/el unknown
- 1985-12-17 JP JP60282175A patent/JPH0662665B2/en not_active Expired - Lifetime
- 1985-12-17 DK DK587585A patent/DK166502B1/en not_active IP Right Cessation
- 1985-12-17 CA CA000497807A patent/CA1262894A/en not_active Expired
- 1985-12-17 HU HU854813A patent/HU193357B/en not_active IP Right Cessation
- 1985-12-17 NO NO855090A patent/NO163014C/en unknown
- 1985-12-17 PT PT81690A patent/PT81690B/en not_active IP Right Cessation
- 1985-12-18 AU AU51436/85A patent/AU580646B2/en not_active Ceased
- 1985-12-18 ZA ZA859666A patent/ZA859666B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GR853017B (en) | 1986-04-15 |
| AU5143685A (en) | 1986-06-26 |
| DE3446661A1 (en) | 1986-06-19 |
| AU580646B2 (en) | 1989-01-19 |
| DD242231A5 (en) | 1987-01-21 |
| JPS61145197A (en) | 1986-07-02 |
| ES549998A0 (en) | 1986-12-01 |
| DK587585A (en) | 1986-06-19 |
| PT81690A (en) | 1986-01-01 |
| ATE45957T1 (en) | 1989-09-15 |
| IE853169L (en) | 1986-06-18 |
| FI854788A0 (en) | 1985-12-03 |
| FI83089C (en) | 1991-05-27 |
| NO855090L (en) | 1986-06-19 |
| PT81690B (en) | 1988-02-17 |
| HU193357B (en) | 1987-09-28 |
| DK166502B1 (en) | 1993-06-01 |
| NO163014B (en) | 1989-12-11 |
| EP0186834A3 (en) | 1986-11-26 |
| FI83089B (en) | 1991-02-15 |
| EP0186834A2 (en) | 1986-07-09 |
| DK587585D0 (en) | 1985-12-17 |
| HUT40138A (en) | 1986-11-28 |
| JPH0662665B2 (en) | 1994-08-17 |
| NZ214449A (en) | 1989-01-06 |
| FI854788A (en) | 1986-06-19 |
| DE3572670D1 (en) | 1989-10-05 |
| ES8701194A1 (en) | 1986-12-01 |
| CA1262894A (en) | 1989-11-14 |
| ZA859666B (en) | 1986-08-27 |
| NO163014C (en) | 1990-03-21 |
| EP0186834B1 (en) | 1989-08-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |