Патент USA US3071588код для вставки
aired tat Pte IQQ Patented Jan. 1, 1953 1 2 pared by the process illustrated by the following equa tion: 3,071,578 ANDROSTANE-i6,1l7-DICOXYLIC ACED IMHDES Pierre (Irahhé, Mexico (Iity, Mexico, assignor, by mesne 5 $12, assignments, to Syntex Corporation, a corporation of Panama No Drawing. Filed .lnly 19, 1961, Ser. No. 125,106 19 Qlaims. (ill. 260-2395) The present invention relates to novel cyclopentano phenanthrene compounds and to a process for the pro duction thereof. 10 More particularly the present invention relates to novel androstane-lG?,17,8-dicarboxylic acid imide derivatives 15 and to novel intermediates for the production thereof. The novel compounds of the present invention which are anti-epileptic and central nervous system depressant agents and which also exhibit anti-ovulatory activity, are represented by the following formulas: / \\i iii, Cm mm\I toz/ @x Z 30 mm mm n" Y 4-0 In the above formulas Z represents a double bond for a saturated linkage between C—4 and C——5; Y represents a double bond or a saturated linkage between C-5 and 0-6; X represent the group 50 in the doling-positions, wherein R1 may be hydrogen, 55 a lower alkyl, di(lower alkyl) amino, lower alkyl, aryl or aralkyl group, each containing up to 8 carbon atoms; R represents hydrogen or a hydrocarbon carboxylic acyl group of less than 12 carbon atoms. The acyl group is derived from hydrocarbon carboxylic 60 acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by ‘functional groups such as hydroxy, alkoxy containing 65 up to 5 carbon atoms, aeyioxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethyl acetate, t-butylacetate, phenoxyacetate, cyclopentylpropi onate, aminoacetate and ?-chloropropionate. any 20 cox 0e g so“ ' The novel compounds of the present invention are pre l = __ 3,071,578 4 In the above formulas R1 has the same meaning as hereinabove set forth; Ac represents an acyl group, prefer ably the acetyl group. 1 In practicing the process outlined above the starting compound (I) 1‘6a-cyano-A5-pregnen-3,8-ol-20-one 3-ace tate [1. Romo, Tetrahedron 3, 37 (1958)], is hydrolyzed in a basic medium, such as methanolic potassium hy droxide, affording A5-17a-pregnen-3?-ol-20-one-lGB-car concentrated solution poured into water. The formed pre cipitate was ?ltered off, washed with water and dried in vacuo. Recrystallization from acetone-hexane afforded A5-androsten-3/8-ol-l6/3,17,8-dicarboxylic acid. M.P. 312 314° C.; [oc]D —63° (pyridine). Example II By reversing the steps described in the preceding Ex ample, 5 g. of 16u-cyano-A5-pregnen-3?-ol-ZO-one 3-ace boxylic acid (II). This compound is treated with an alkali metal hypohalogenite such as sodium hypobromite 10 tate was ?rst hydrolyzed with 4% methanolic potassium hydroxide as described in Example I to afford A5-17oc at a lower temperature, approximately 0° C., for a period pregnen-B/i-ol-ZO-one-16/3-carboxylic acid, identical with of time of the order of 2 hours, thus giving A5-androsten an authentic specimen. 3,6-01-165,17,3-dicarboxylic acid (III). Upon re?ux of Upon further treatment with sodium hydroxide and this compound with acetic anhydride there is obtained the anhydride of A5-androsten-3?-ol-16B,'17,B-dicarboxylic acid 15 bromine as described in Example I and working up the product as set forth in that example, there was afforded 3-acetate (IV). A5-androsten-3B-ol-165,17,8-dicarboxylic acid. M.P. 307 Alternatively the starting compound (I) is treated with 309° 0., identical with the above obtained diacid. an alkali metal hypohalogenite, such as sodium hypo brornite, at a low temperature, approximately 0° C., for Example III a period of time of the order of 2 hours, thus furnishing 20 ‘l6a-cyano-A5-androsten-3,B-ol-l7?-carboxylic acid 3-ace tate (IX). Hydrolysis of this compound in a basic me dium such as methanolic potassium hydroxide, affords the The foregoing compound, A5-androsten-3?-ol-16?,17,9 dicarboxylic acid was re?uxed for 10 minutes with 60 cc. of acetic anhydride. 'Ihe acetic anhydride was then evaporated under vacuum and the residue recrystallized above obtained A5-androsten-3B-ol-11613,17?-dicarboxylic 25 from methylene-chloride-hexane affording the anhydride acid (III). of the A5-androsten-3/8-ol-16p,17,8-dicarboxylic acid 3 The anhydride of A5-andr0sten-3/8-o1-1618,17?-dicarbox acetate. M.P. 171-175° C.; [1x113 —83° (CHCl3). ylic acid 3-acetate compound (IV) is treated with a pri mary amine, as for example, methylamine, ethylamine, Example IV propylamine, aniline, benzylamine or ammonia, thus giv ing the corresponding A5-androsten-3?-ol-l6p,17,8#dicar 30 boxylic acid imide 3-acetate derivative (V) which upon saponi?cation in a mild alkaline medium, such as potas sium carbonate solution, affords the corresponding free 3,8-alcohol (VI). This free alcohol is oxidized under 2 g. of this last anhydride was treated with a solution of 2 g. of propylamine in methylene chloride. The reac tion mixture was allowed to-stand at room temperature overnight. The solvent was then evaporated and the resi due recrystallized from acetone-hexane affording N Oppenauer conditions to the corresponding A4-androsten 35 propyl-A5-androsten-3/8-ol-16,8,17,8-dicar-boxylic acid imide 3-acetate. 3-one-16?,17?-dicarboxylic acid amide derivative (VII) Example V which is hydrogenated to the ‘respective saturated 3-ketone androstane (VIII). " , > 2 g. of the anhydride of A5-androsten-3)3—ol-l6?,17;8-di The A5-313-alcoho1 derivative (VI) is hydrogenated to the corresponding androstan-3l3-ol-li6?,17?-dicarboxylic acid amide derivative. The above obtained compounds containing a free sec ondary hydroxyl group at C-3 are conventionally acylated in pyridine with a hydrocarbon carboxylic acid anhydride or chloride containing up to 12 carbon atoms of the type 45 mentioned previously to furnish the corresponding 35 acyloxy derivative. The following speci?c examples serve to illustrate but are not intended to limit the scope of the present inven tion: - Example I carboxylic acid 3-acetate was treated following the tech nique described in Example IV except that propylamine was substituted by N,N-diethylamino-ethylamine, giving N - (N',N' - diethylaminoethyl)-A5-androsten-3?-ol-16B, 17,6-dicarboxylic acid imide 3-acetate. Example VI 2 g. of the anhydride of A5-androsten-3B-ol-16?,17,8 dicarboxylic acid 3-acetate was treated following the technique described in Example IV except that‘ propyl— amine was substituted by aniline affording N-phenyl-A5 androsten-3?-ol-165,175-dicarboxylic acid imide 3-acetate. Example VII 2 g. of the anhydride of A5-androsten~3?-ol-16/8,17? 5 g. of 16a-cyano-A5-pregnen-3,8-ol-2O-one 3-acetate [1. Romo, Tetrahedron 3, 37 (1958)], were dissolved in dicarboxylic acid 3-acetate were treated with 50 cc. of 200 cc. of dioxane. A solution, prepared by dissolving 55 a saturated solution of ammonia in anhydrous ethanol. 7 g. of sodium hydroxide in 60 cc. of water and 40 cc. The reaction mixture was kept in a closed vessel at room temperature for 24 hours. It was then evaporated to dry ' mine, was added to the steroid solution, the operation ness and the residue recrystallized from acetone thus being conducted at —5° C. The resulting mixture was affording A5 - androsten-3?-ol-l6?,l7?-dicarboxylic acid 60 stirred for 2 hours, maintaining the temperature under imide 3-acetate. of dioxane and further adding dropwise 3.2 cc. of bro 5° C. It was then treated with 50 cc. of a saturated solution of sodium sul?te in water, re?uxed for 15 min utes, acidi?ed with concentrated hydrochloric acid, satur ated with sodium chloride and extracted with ethyl ace Example VIII 1.5 g. of A5-androsten-3?-ol-16/3,17/3-dicarboxylic acid imide 3-acetate in 50 cc. of methanol were treated with tate. The extract was washed with water, dried over an 65 0.5 g. of potassium carbonate in 2.5 cc. of water. The hydrous sodium sulfate and evaporated to dryness thus affording 16a-cyano - A5 - androsten-B’?-ol-17,8-carboxylic acid B-acetate. M.P. 259—261° C.; ]; -62° (pyri dine). By alkaline hydrolysis the 3?-alcohol was ob tained: M.P. 271—274°; [oc]D —-71° (pyridine). The foregoing compound was re?uxed for 10 hours with 250‘ cc. of 4% methanolic potassium hydroxide solution and then neutralized with acetic acid. Part of the solvent was removed under reduced pressure and the 75 mixture was re?uxed for 30 minutes, then poured into ice water and the precipitate collected, washed with water and dried, thus producing a crude product which upon recrystallization from acetone-hexane afforded A5-andro sten-3B-ol-16p,17B-dicarboxylic acid imide. When applying this selective saponi?cation to N-pro pyl-M-androsten-SB-ol-16/3,17/8-dicarboxylic acid imide 3~acetate, N-(N’,N'-diethylaminoethyl)-A5-androsten-3B o1-16;8,l7?-dicarboxylic acid imide B-acetate, N-phenyl~ 5 3,071,578 6 A5-androsten-3?-ol-1613,1713-dicarboxylic acid imide 3-ace dried. Recrystallization from acetone-hexane afforded A5 tate, there were respectively obtained A5-androsten-3?-ol androsten-3l3-ol-l 65,17,8-dicarboxylic acid imide 3-propi 165,175-dicarboxylic acid imide, N-propyl-M-androsten 35-01-16?,17/3-dicarboxylic acid imide, N-(N’,N'-diethyl aminoethyl)-A5~androsten-3,8-ol‘165,17?-dicarboxylic acid imide and N-phenyl-A5-androsten-318-01-16,8,l7?-dicarb0x onate. Following the above technique were treated the starting materials listed below, with the acylating agent indicated, furnishing the corresponding products hereinafter set forth. ylic acid imide. Example IX A solution of 1 g. of A5-androsten-3/3-ol-16,8,17?-di 10 carboxylic acid imide in 80 cc. of toluene and 20 cc. of cyclohexanone was dried by distilling oif 10‘ cc. of the Starting compound Acylating agent Product solvent. A solution of 1 g. of aluminum isopropoxide in A?-androsten-ii?-olcaproic anhydride___ 3-caproate of A5 7 cc. of anhydrous toluene was then added and the mix acid imide. 16B,17?-dicarb0xylic ture was re?uxed for 45 minutes. 15 acid imide. 4 cc. of acetic acid were added and the solvents re Do ________________ l_ cyclopentylpropl3-cyclopentylpropio onic anhydn'de. nate of AE-andro moved by steam distillation. The product was extracted steu-3B-ol-16B,17?~ several times with ethyl acetate and the organic extracts washed with 1% hydrochloric acid solution, water, 10% sodium carbonate solution and water until neutral, dried 20 over anhydrous sodium sulfate and evaporated to dryness. Crystallization from methanol afforded A4-androsten-3 one-165,17/3-dicarboxylic acid imide. Upon oxidation by the same technique of N-propyl-A5 androsten~3?-ol-16,8,175-dicarboxylic acid imide, N-(N', N-propyl-N-androsten- 3B-0l-16B,l7?-dicar- imide. dride. ' 3-propionate of N propyl-As-andro Sten-3B-0l-16?,175 dicarboxylic acid 25 irnid-e. N- (N ’ N’-diethy1ami- carboxylic acid imide, N-phenyl-A5-androsten-318-01-l6B, noethyD-N-andro- 17B-dicarboxylic acid imide, there were correspondingly formed A4-androsten-3-one-l6p,17B-dicarboxylic acid im dicarb oxylic acid imide. androstan-3B-o1-16?,17?dicarboxylic acid 35 imide. ‘ caproic anhydride..- 3-caproate of N (N’,N’-diethylami sten-3B-ol-16B,17?- ide, N-propyl-A4-androsten-3-one-16p},175 - dicarboxylic 30 N- (N’,N’-dicthy1a1ninoethyD-N-androacid imide, N-(N',N'-diethylaminoethyl)-A4-androsten~3 sten-3B-ol-16?,17§one-165,17l3-dicarboxylic acid imide and N-phenyl-M- an dicarboxylic acid. A solution of 800 mg. of A4-androsten-3-one-163,175 dicarboxylic acid imide in 40 cc. of ethyl acetate was propyl-Ai-andro stem-318014612175 dicarboxylic acid boxylic acid imide. Do ________________ __ propionic anhy- N’-diethylaminoethyl)-A5 - androsten - 3p3~o1-16B,17B - di drosten-3-one-163,17,8-dicarboxylic acid imide. Example X dicarboxylic acid imide. benzoyl ch1oride_____ B-bcnzoate of N noethyD-M-andro sten-3B-0L16BJ7B dicarboxylic acid imide. cyclopentylpropi- 3-cyclopenty1propio onic anhydride. nate of N-(N’ , N’ diethylaminoethyD 168,17/3-dicarboxyl1c N-androstcn-SB-ol acid imide. propionic anhydride. 3-pr0pionate of an drostan-3B-oi 163,17B-dicarboxy1ic cyclopentylpropi- 3‘cyclopentylpr0pio onic anhydrid e. nate oi androstan acid imide. D0 ________________ .. shaken with 50 mg. of 5% palladium-charcoal catalyst in a hydrogen atmosphere, until 1 mol. of gas was consumed. N- (N ’,N'-diethylam1~ The catalyst was ?ltered off and the ?ltrate evaporated to 40 noethyD-androstan 3B-o1-16?,17B-dicar dryness. Recrystallization from methanol-benzene af boxylic acid imide. forded androstan-3-one-16,8,17,8-dicarboxylic acid imide. Following the same technique were hydrogenated N-pro 3B-ol~1618,17B-dicar boxylic acid imide. caproic anhydride.__ S-caproate of N (N’,N’-diethy1ami noethyl)-audro~ stan-3B-ol-16/9J7? dicarboxylic acid im e. Do ________________ __ pyl-A4-androsten-3-one-163,17,8-dicarboxylic acid imide, beuzoyl chloride .... -. S-benzoate of N (N’ ,N’-diethylami nocthyD-andro stan-3?-ol-16B,17?~ N-(N’,N’-diethylaminoethyl)-A4-androsten-3 - one - 16,8, 17?-dicarboxy1ic acid imide, N-phenyl-A4—androsten-3-or1e dicarboxylic acid 16,8,17B-dicarboxylic acid imide giving respectively an N -phenyl-androstan drostan-3-one-166,17?-dicarboxylic acid imide, N-propyl androstan-3-one-16,8,17?-dicarboxylic acid imide, N-(N', propionic anhy 3B-0l-l6/3,17B-dicar dride . boxylic acid imide. N’-diethylaminoethyl)-androstan-3 - one - 165,17}? - dicar Do ________________ __ benzoyl chloride".. boxylic acid imide and N-phenyl-androstan-3one-16p}, 17?-dicarboxylic acid imide. imide. 3-propionate of N phenyl-androstan 3B-ol-16BJ76-dicar boxylic acid imide. 3-benzoate of N phenyl-androstan 3B-ol-16B,17?'dicar— boxylic acid imide. Example X1 800 mg. of A5-androsten-3/3-ol-16,8,17,3-dicarboxylic acid imide were hydrogenated following the technique de Example XIII By substituting in the method of Example IV the pro pylamine by other alkylamines such as methylamine, scribed in Example X, giving androsten-350L165,17,6-di carboxylic acid imide. When applying this procedure to N-propyl-As-androsten 3,8-01-16/5’,17,6-dicarboxylic acid imide, N-(N',N’-diethyl— aminoethyl)-A5-androsten-3B-ol-16,8,17,5-dicarboxylic acid ethylamine or heptylamine, there was obtained the corre 60 sponding N-methyl, N-ethyl, and N-heptyl derivatives of acid imide, there were correspondingly formed androstan A5-androsten-3/S-ol~16,8,17,8-dicarboxylic acid imide 3~ acetate which upon selective saponi?cation by the method described in Example VIII were transformed into the 3/3-o1-16l3,17B-dicarboxylic acid imide, N-propyl-andro stan-3?-ol-16?,l7,B-dicarboxylic acid imide, N-(N’,N’-di corresponding free 3,3-alcohols. By following the technique described in Example ‘IX ethylarninoethyl)-androstan - 3?-ol-16[3,l7[3 » dicarboxylic the thus :formed 3B~alcohols were oxidized to the cor~ acid imide and N-phenyl-androstan-3,8-01-165,17,B-dicar boxylic acid imide. Example XII responding 3-ketones, namely the N-methyl, N-ethyl and N-hepty-l derivatives of A4~androstene-3-one-16?,173-di imide, N-phenyl-A5-androsten-31301-165,175-dicarboxylic carboxylic acid imide. 70 500 mg. of A5-androsten-3?-ol-16,8,17,8-dicarboxylic acid imide in 5 cc. of pyridine were treated with 1 cc. of propionic anhydride. The reaction mixture was left over Example XIV By substituting in Example VI the aniline by benzyl amine or phenethylamine, there were obtained the corre night at room temperature, then poured into ice water, the formed precipitate ?ltered 0E, washed with water and 75 sponding N-benzyl and N-phenethyl derivatives. 3,071,578 7 a , l 8 . . between C—5 and C—6; R is selected from the group con I claim: 1. A compound selected from the group consisting of the following formula: sisting of hydrogen and a hydrocarbon carboxylic acyl group of ‘less than 12 carbon atoms and R1 is selected from the group consisting of hydrogen, alkyl, dialky‘l aminoalkyl, avryl and aralkyl radicals each containing up 0=O—N-—R1 to 8 carbon atoms. 8. Androstan-3/8-ol-1618,17p-dicarboxylic acid imide. 9. Nwpropylaandrostan-fi,B-ol-1616,l7?-dicarboxylic acid imide. 11. The 3-acetate of A5-androsten-3l3-ol-165,17B-dicar boxy-lie acid imide. 12. The 3-propionate of N-propyl-A5-androsten-3?-ol wherein Z is selected ‘from the group consisting of a double bond between 0-4 and C~5 and a saturated link 15 16,8,17?-dicarboxylic acid imide. 13. The 3-caproate of N-(N',N’-diethy1aminoethyl)-A5 age between 0-4 and C-5 and R1 is selected from the group ‘consisting of hydrogen, alkyl, dialkylaminoalkyl, aryl and aralkyl radicals each containing up to 8 car bon atoms. I 2. Meandrosten-B-one-l65,1713-dicarboxylic acid imide. 20 3. l7?-dicarboxylic acid imide. l6. A5-androsten-3B-ol-1613,l7?-dicarboxylic acid. 17. The acetate of A5-androsten-35-ol-16B,17,8-dicar N-(NQN’aiiethylaminoethyl)-A4-androsten - 3 - one 165,17B-dicarboxylic acid imide. androsten-S‘?-ol-IQB,l7?—dicarboxylic acid imide. 14. The S-propionate of N-pheny1-androstan-3 5-01-1653 17,8-dicarboxylic acid imide. 15. The B-benzoate of N-phenyl-androstan-3?-ol-16/3, ' 4. N-phenyl-A4-androsten-3one-16,3,175 - dicarboxylic acid imide. b‘oxylic acid anhydride. 18. A process for the production of androstan-l6?,17,8 5. Androstan-3-one-16,B,17B-dicarboxylic acid imide. 25 dicarboxyllic acid imide derivatives which comprises treat 6. Nqpropyl-androstan-3-one-165,17B-dicarboxylic acid ing the corresponding 16ot-cyano-pregnan-20-one com imide. pound with an alkali metal hypohalogenite, hydrolyzing 7. A compound selected from the group consisting of the 1éa-cyano-androstan-l6,6-carboxylic acid thus formed the following ?ormula: 30 in a basic medium, re?uxing the obtained dicarboxylic acid with an acid anhydride and treating the formed steroid anhydride with a primary amine selected from the R0 Y group consisting of alkylamine, dialkylaminoalkylamine, arylamine and aralkyyamine each containing up to 8 car 35 bon atoms and ammonia. 119. The process of claim 18 wherein the alkali metal hypohalogenite is sodium hypobromite, the basic medium is dilute methanolic potassium hydroxide, the anhydride is acetic anhydride and the amine is propylamine. wherein Y is selected from the group consisting of a 40 double bond between 0-5 and C-6 and a single bond No reference cited.