IE853169L

IE853169L - Gonanes

Info

Publication number: IE853169L
Application number: IE853169A
Authority: IE
Original assignee: Schering Ag
Priority date: 1984-12-18
Filing date: 1985-12-16
Publication date: 1986-06-18
Also published as: EP0186834B1; ES549998A0; NO163014C; CA1262894A; FI83089C; IE58147B1; PT81690B; DD242231A5; DK587585A; NZ214449A; JPS61145197A; FI854788L; EP0186834A2; HUT40138A; DK587585D0; DK166502B1; JPH0662665B2; NO855090L; FI854788A0; EP0186834A3

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

58147 - i - I R E L A N D PATENTS ACT, 19 64 ■. i Ife A: A zib &» COMPLETE SPECIFICATION "13a-alky1-173-(3-acyloxypropyl)-gonanes" WPUCATWw Ko wrcmouMQt, snjss ItrlStt Patent Application by SCHERING AKTIENGESELLSCHAFT, a Germany Company of Berlin and Bergkamen, Federal Republic of Germany. 8147 - 2 - The invention relates to new 13o(-alkyl-178-(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 10 the progesterore 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,sur-15 prisingly, be considerably enhanced by converting these compounds into the 13S-alkyl-178-(3-acyloxypropyl)-gonanes' of general formula I. In comparison to the previously known 13 They can be stored without difficulty for a long period of time at room temperature without decomposing. - 3 - According to one aspect the invention provides a compound of the 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 IWOH.

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, 10 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. ch hh (I) 15 In another aspect the invention provides a method of - 4 - preparing a compound of general formula I wherein a compound of the general formula II ch2 - ch2 - ch2-oh (ii) is reacted with an acid chloride or an acid anhydride of 5 general formula III or IV respectively 0 II R-C-Cl (III) 0 II (R-C)20 (IV) where R represents an acyl radical having up to 10 C-atoms, in the 10 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 temperature of between -20 and 4o°C. The preferred bases for esterification are tertiary amines such as 15 pyridine. The preferred tertiary amine - 5 - during conversion for the preparation of oximes is pyridine.

Further suitable tertiary bases are, for example, tri-methylamine, triethylamine, N,N-dimethylamino pyridine, 5 1,5-diazabicyclo [4.3.ojnonene-5 (DBN) and 1.5-diazabicyclo-[5.4.6] 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 10 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 15 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. - 6 Example 1 A solution of 2.4 g of 11 B-(4-dimethylaminophenyl)-1 7o(- hydroxy-1 3o(-methyl-1 7B (3-hydroxypropyl)-4, 9-gonadiene- 3-one in 7 ml of pyridine and 14 ml of acetanhydride is 5 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. 3 2 4 10 and concentrated. Crystallization of the crude product from ethylacetate/diisopropy 1 ether yields 2.24 g of 17B-(3-acetoxypropyl)-11B- (4-dimethylaminophenyl)-17 -hydroxy-130f-methyl-4 ,9-gonadiene-3-one with a melting point of 162 - 164 °C. 15 [a]^5 + 436.5° (CHCl3, 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 11B-(4-dimethylaminophenyl)-17«-hydroxy-1S^-methyl-l7B-(3-hy-20 droxypropyl)-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 17B-(3-benzoyloxypropyl)-11B-(4-dimethylamino-25 phenyl)-1 7«-hydroxy-1 32(-inethyl-4 , 9-gonadiene-3-one with a melting point of 114 - 116 °C. - 7 - Example 3 A solution of 630 mg of 178-(3-acetoxypropyl)-116-(4-dimethylaminophenyl) -1 7oc-hydroxy-! 3

Claims

1. CLAIMS 1. 13oC-alkylgonanes of general formula I CH ^ 3 CH N CH2~CH2~CH2"0R (I) 5 3. 10 5. where R represents an acyl radical having up to '10 C-atoms and X represents an oxygen atom or the grouping N OH. A compound as claimed in claim 1 wherein R is acetyl or benzoyl. 17 8-(3-acetoxypropyl)-118-(4-dimethylaminophenyl)-17a-hydroxy-13a-methyl-4,9-gonadiene-3-one. 178-(3-benzoyloxypropyl)-113-(4-dimethylaminophenyl)-17a-hydroxy-13a-methyl-4,9-gonadiene-3-one. 17 8-(3-acetoxypropyl)-118-(4-dimethylaminophenyl)-17cx-hydroxy-13a-methyl-4,9-gonadiene-3-one-anti-oxime. - 9 - 6. A process for the preparation of 13Of-alky 1 gonanes of general formula I where 5 R and X have the meaning given in Claim 1, charac terized in that a compound of the formula ii ch2-ch2-ch2-oh - 10 - is reacted with an acid chloride or an acid anhydride of general formula III or IV respectively 0 II R-C-Cl (III) (R-C)2O (IV) 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. - 11 - 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. Dated this 16th day of December 1985 CRUICJS&HANK & CO., BV:/1 Executive Agferrt^ for the Applicant Youghal House, 13 Trinity Street, Dublin