Патент USA US3076809код для вставки
United States Patent " / 3,076,802 ‘ Patented Feb. 5, 1963' 2 1 droxide and dioxane. This chloroamide is allowed to re 3,076,802 20-[w-(TERTIARY-AMINO)LOWER ALKANOYLAMI D0] PREGN-S-EN-Zi?-OLS, ESTERS CORRESPOND act with dimethylamine in butanone to produce ZO?-(di methylaminoacetamido)pregn-S-en-S?-ol. The instant 3/3-hydroxy compounds can, alternatively, be obtained by hydrolysis of the corresponding 3-esters. ING, AND INTERMEDIATES THERETO Raymond E. Counsel], Skokie, Ill., assignor to G. D. Typically, 20oz-(dimethylaminoacetamido)pregn-S-en-Ii? Searle & Co., Chi. ago, Ill., a corporation of Delaware No Drawing. Filed Dec. 1, 1961, Ser. No. 156,475 11 Claims. (Cl. 260—239.5) ol B-acetate is allowed to react with aqueous potassium amino-amides of the pregnane series and, more particu ols, suitably by reaction with a lower alkanoic acid an hydride in pyridine. 20cc - (dimethylaminoacetamido) hydroxide in dioxane to yield the free 313-01. The 3/8-(lower alkanoates) of this invention can be The present invention is concerned with novel steroidal 10 manufactured also by acylation of the corresponding 3,6’ larly, with 20-[w-(tertiary-amino)lower alkanoylamido] pregn-S-en-‘s‘?-ol, for example, is treated with propionic anhydride and pyridine to afford the corresponding 3 pregn-5-en-3B-ols and esters thereof, which are repre sented by the structural formula propionate. CH3 CH3 The compounds of this invention display valuable phar macological properties. They are, for example, hypo CHM/v NHCOAlk-Z chlolesterolemic agents as is evidenced by their ability CH3 to inhibit the hepatic synthesis of cholesterol. They are 20 also antibiotic agents in view of their ability to inhibit ' the growth of Chlorella vulgaris. In addition, these com pounds are intermediates in the manufacture of the N substituted 20-aminopregn~5~en-3?-ols and corresponding esters of my copending application Serial No. 81,254, 2.5 ?led January 9, 1961, now Patent No. 3,013,008, of which wherein R is hydrogen or a lower alkanoyl radical, Alk is a lower alkylene radical, Z is the residue of a secondary amine selected from the group consisting of di-(lower the present application is a continuation-in-part. The invention is disclosed in further detail by the fol lowing examples which represent speci?c embodiments of this invention, without, however, limiting it either in alky1)amines, cycloalkylamines, morpholine, and N-alkyl 3.0 spirit or in scope. Amounts of materials are given in‘ piperazines, and the wavy line indicates the alternative or or p con?guration of the substituent at carbon atom 20 parts by weight and temperatures are given in degrees centrigrade (° 0.). Example 1 The lower alkanoyl radicals encompassed by the R term are exempli?ed by formyl, acetyl, propionyl, butyryl, 35 To a solution of 18 parts of 20ot-aminopregn-5-en-3? valeryl, caproyl, and the branched-chain isomers thereof, ol 3-acetate in 240 parts of benzene containing 7.3 parts and the lower alkylene radicals represented by Alk are exempli?ed by methylene, ethylene, trimethylene, tetra of triethylamine is added dropwise a solution of 7.5 parts of chloroacetyl chloride in 20 parts of benzene, and methylene, pentamethylene, and the branched-chain radi this mixture is stirred and heated at re?ux for about one 40 hour, then cooled and ?ltered. The ?lter cake is washed cals isomeric therewith. Equivalent to the organic bases of this invention are the with benzene, and the ?ltrate is washed successively with corresponding non-toxic salts, which are exempli?ed by dilute hydrochloric acid, aqueous sodium bicarbonate, the citrate, tartrate, maleate, ascorbate, gluconate, lactate, and water, dried over anhydrous sodium sulfate contain _ succinate, phosphate, sulfate, hydrobromide, and hydro ing decolorizing carbon, and stripped of solvent at re 45 chloride. duced pressure. The residue is crystallized from ethanol Starting materials suitable for the manufacture of the to yield 20w(chloroacetamido)pregn-5-en-3B-ol S-acetate, instant compounds are the 20-aminopregn-S-en-B‘?-ols and Ml’. about 196-199"; [a]D=--44°. This compound is corresponding B-esters. The ZO-aminopregn-S-en-SB-ol 3-esters are allowed to react with a chloroalkanoyl chlo represented by the structural formula ride to afford the corresponding chloroalkanoylamido 50 compounds. Treatment of these novel intermediates with n-o-mnoocmol the appropriate secondary amine results in the tertiary amino) alkanoylamido 3-esters of this invention. These CHI me i processes are speci?cally illustrated by the acylationof ZOa-arninOpregn-S-en-3;3-ol B-acetate with chloroacetyl, 55 chloride to yield the novel 20a-chloroacetamidopregn-S en-3B-ol 3-acetate, which is treated with dimethylamine to produce 20a-(dimethylaminoacetamido)pregn-5-en-3B-ol 3-acetate. When the 20 - aminopregn-S-en-3B-ols are utilized as starting materials, two molecular equivalents 60 of the chloroalkanoyl chloride are required, resulting in acylation of the B-hydroxy group also. Treatment of these ester-amides with aqueous potassium hydroxide in dioxane results in preferential hydrolysis of the ester group to yield the chloroalkanoylamido substances, which are treated with a secondary amine, resutling in the instant (tertiary-amino)alkanoylamido-S-ols. The reaction of 20?-aminopregn-5-en-3[3-01, for example, with 2 molecular equivalents of chloroacetyl chloride affords the novel in CHsCO0- Example 2 The substitution of 15.9 parts of ZOB-arninopregn-S-en 35-01 and 16.9 parts of ?-chloropropionyl chloride in the process of Example 1 results in ZOB-(B-chloropropionyl i-amido) -pregn-5-en-3/3-o1 3- ( ?-chloropropionate) . Example 3 The reaction of 15.9 parts of ZOB-aminopregn-S-en-B? termediate, 20,8-(chloroacetamido)-pregn-5-en-3/3-ol 3 70 01 and 15.0 parts of chloroacetyl chloride by the process chloroacetate, which yields ZOB-(chloroacetamido)pregn of Example 1 results in 20B-(chloroacetamide)pregn-5 S-en-BB-ol upon hydrolysis with aqueous potassium hy 3,076,802 3 4 en-B?-ol 3-chloroacetate, which is presented by the struc with ether. The organic mixture is washed with water, dried over anhydrous potassium carbonate containing de colorizing carbon, and evaporated to dryness in vacuo. The resulting crystalline residue is recrystallized from aqueous ethanol to yield pure 20a-(pyrrolidinoacetami do)pregn-5-en-3;8-ol 3-acetate, M.P. about 157-160", which is represented by the structural formula tural formula I CHa-—(5—NHC 0 011101 CH3 H30 I i OH: / 10 ' CH] ClCHaCOO Example 4 To a solution of 49.8 parts of ZOB-(?-chloropropion 15 amido)pregn-5-en-3/8-ol 3-(?-chloropropionate) in 250 CHaCOO parts of dioxane is added 6 parts of potassium hydroxide in 2 parts of water, and the mixture is stored at room Example 8 temperature for about 16 hoursythen is extracted with 20 ether. The organic layer is washed with water, dried over By substituting 2.08 parts of morpholine and otherwise anhydrous sodium sulfate, and stripped of solvent at re proceeding. according to the processes of Example 7, 20a duced. pressure. The residue is crystallized fromwethyl (morpholinoacetamido)pregn-S-en-Zi?aol 3-acetate, M.P. acetate to produce 20p-(p-chloropropionamido)pregn-S about 173—176°, is obtained. This compound is repre en-3/3-ol. 25 sented by the structural formula Example 5 l / \ To a solution of 8.72‘ parts of 20a-(chloroacetamidoj n-o-NnooornN 0 pregn-5éen-3?-ol 3-acetate in 87 parts of toluene contain-} on, E30 ’ h“ ing 20 parts of butanone is added-a solution of 9 parts of 30 dimethylamine in 26 parts of toluene, and this mixture is heated at 50-55° in a. suitable sealed container for about 40 hours. The reaction mixture is cooled, washed with water, dried. over anhydrous potassium carbonate contain ing. decolorizing carbon, and evaporated to dryness at 35 reduced pressure. The resulting residueis crystallized from heptane to produce 20a-(dimethylaminoacetami do)pregn-5-en-3?-ol. 3-acetate, M.P. about 159-161.5°; [a]D=—52.5°. This substance is represented ‘ by the structural formula Example 9 The substitution of 2.39 parts of N-methylpiperazine in the procedure of Example 7 results in 20a[(N-methyl piperazino)acetamido]pregn-5-en-3B-ol ,B-acetate, M.P. 9e I_H—C—NHOOCH:N(CH:)': about 145-147°. It is represented by the structural for mula on, H“? 45 N-CH) CH3 50 Example 6 The substitution of 43.2 parts of ZOa-(dimethylamino acetamido)pregn-5-en-3?~ol 3-acetate in the procedure of 55 Example 10 Example 4 results in 20a-(dimethylaminoacetamido) The substitution of 2.04 parts of piperidine in'the'pro pregn-5-en-3l3-ol, M.P. about 188-189°, which is repre ced'ure of Example 7 produces a'material, which is re sented by the structural formula crystallized from ‘methanol to a?ord 20a-(piperidino acetamido)pregn-5-en-3?-ol 3-acetate, M.P. about 171.5 on, 60 172.5‘’. It is represented by the structural formula CH3 ' / 65 Example 7 A solution of 4.4 parts of 20w(chloroacetamido)preg - 5fen-3B-ol S-acetate and 1.7 parts ;of p-yrrolidinein 44 parts of benzene is heated at re?ux for about 20. hours, Example 11 _' A solution of 9 parts of i20a-(chloroa'cetamido)-pregn then‘ is allowed to cool to room temperature‘ and is diluted 75 5;en-3B¢ol 3-acetate and 4.4 parts of'diethylamine inl54 3,076,802 5 6 parts of benzene is heated at 50—55° in a suitable sealed container for about 48 hours. The cooled mixture is ?ltered, and the ?ltrate is evaporated to dryness in vacuo. Crystallization of the solid residue from aqueous meth onate is obtained. This compound is represented by the structural formula anol a?ords 20a-(diethylaminoacetamido)pregn-S-en-BB ol S-acetate, M.P. about 147—149°, which is represented by the structural formula CH3 / CBS 1130 CHsCHrCOQ 15 / What is claimed is: 1. A compound of the structural formula CH3 CH3 GHaCOO Example 12 20 The reaction of 8.1 parts of 20?-(,B~chloropropion amido)pregn-5-en-3,6-ol with 14.6 parts of diethylamine according to the procedure of Example 5 results in 20/? (B-diethylaminopropionamido)pregn-S-en??-ol, which is 25 represented by the structural formula H 30 CH3 / 30 wherein R is selected from the group consisting of hydro gen and lower alkanoyl radicals, Alk is a lower alkylene radical, and Z is selected from the group consisting of di (lower alkyl)arnino radicals and radicals of the structural formula l N (XL, \_/ 35 wherein X is selected from the group consisting of meth ylene, epoxy, and methylimino radicals, and n is selected from the group consisting of 0 and l. 2. A compound of the structural formula HO Example 13 CH3 CH3 40 CH ~w NHC O Alli-Z A mixture of one part of 2018-(?-diethylarninopropion CH3 amido)pregn-5-en-3B—ol, 13 parts of propionic anhydride, and 20 parts of pyridine is kept at room temperature for about 16 hours, then is diluted with ice and water. The 45 resulting aqueous mixture is made alkaline to pH 9 by the addition of sodium carbonate, then is extracted with benzene. This organic solution is washed with water, / HO , N dried over anhydrous sodium sulfate, and concentrated to ryness to produce 201%(,B-diethylaminopropionamido) 50 wherein Alk is a lower alkylene radical and Z is a di pregn-S-en-SSB-ol 3-propionate. This compound is repre (lower alkyl) amino radical. sented by the structural formula 3. 200a - pyrrolidinoacetamidopregn - 5-en-313-0l 3-ace tate. H 4. 200a - morpholinoacetamidopregn - 5 - en - 3p - ol 3 acetate. 5. 20oz - [(N-methylpiperazino) acetamidoJpregn - 5 -en fl 35-01 S-acetate. 6. 20a - piperidinoacetamidopregn - 5 - en - 318 - ol 3 acetate. / 7. 20oz - diethylarninoacetamidopregn - 5 - en - 31B - ol S-acetate. CHaCHaCOO- 8. 20a-dimethylaminoacetamidopregn-5-en-3?-ol. \ 9. 20a - dimethylaminoacetamidopregn - 5 - en-3,B-ol 3 Example 14 By substituting one part of ZOa-(dimethyIaminoaceta mido)pregn-5-en~3p-ol in the procedure of Example 13,‘ 20w(dimethylaminoacetamido)pregn-S-en-B‘?-ol 3-propi 65 acetate. 10. 20a-chloroacetamidopregn-5-en-3B-ol 3-acetate. 11. 20,8-chloroacetamidopregn-S-en-BB-o1 3-chloroace tate. No references cited.