Patent ES-356956-A1 (ES)
Title: Novel halogenated steroids and a process for the manufacture thereof
IPC: C07J5/00
Filed: 1968-08-06
Abstract: The invention comprises steroids of formula wherein R1 is F, Cl, Br or C 1-8 alkyl, and A represents one of the following entities wherein R2 is H or F R3 is H, OH, C 1-8 alkoxy, C 1-8 alkanoyloxy, COCHF 2 , COCHCl 2 or C 1-8 alkyl R4 is C 1-7 alkylidene or [alpha]-CH 2 Cl, (the latter, only when n is 0 or 1, X is a #1-unsaturation or 2-chloro group, R2 is H and R3 is OH or C 1-8 alkanoyloxy) or R3 + R4 together form a 11-alkyl-alkylidenedioxy group R5 is H or C 1-8 alkanoyl R6 is H, C 1-8 alkyl or optionally halo-substituted C 2-7 monounsaturated aliphatic hydrocarbyl R7 is H or CH 3 R8 is [alpha]-H, [alpha]-F, [alpha]-Cl or [alpha]-Br R9 is H, a hydroxy group, the dihydrogen phosphate ester thereof or an alkali metal salt thereof, or a C 1-8 alkanoyloxy group R10 is C 1-7 alkylidene, [alpha]-CH 2 Cl, [alpha]-CH 2 F, [alpha]-Cl or [alpha]-F R11 is OH or C 1-8 alkanoyloxy or, when R9 is H, R10 + R11 together form a 11-alkylalkylidenedioxy group or R9 + R11 together form a 11-alkoxy-alkylidenedioxy group n is 0 or 1 X is a #1-unsaturation or a 2-chloro or 1[alpha],2[alpha]-methylene group X1 is a #1-unsaturation or a 2-chloro group Y is CH 2 , CHOH or CO Z is CHOH, CO, [alpha]-(alkyl- or aryl-sulphonyloxy) - methylene or, (when R8 is [alpha]-H and R9 is other than H), methylene, or, (when R8 = Cl), #-chloromethylene or x + R8 together represent a #9(11)-unsaturation or a 9#, 11#-epoxy group. The above compounds are prepared (i) by chlorination of the corresponding 4-unsubstituted compounds and (ii) the action of a strong acid on a steroid of formula to obtain the corresponding 16-methylene-17[alpha]- hydroxy-steroid. Product interconversions described are 2-chlorination 1,2-dehydrogenation oxidation of 11-OH to 11-OXO sulphonation of 11[alpha]-OH dehydration of a 9[alpha]-H-11#-OH compound or desulphonation of a 9[alpha]-H-11[alpha]- sulphonyloxy compound to yield a #9(11)- compound treatment of #9(11)-compounds with HOCl or HOBr to give 9[alpha]-(Cl or Br)-11-OH compounds dehydrohalogenating 9[alpha]-(Cl or Br)-11-OH compounds to 9#,11#-epoxy compounds treatment of 9#,11#-epoxy compounds with HF, HCl, HBr or a chlorinating agent to give 9[alpha]-halo-11-OH or 9[alpha],11#-dichloro compounds esterification of 17- and/or 21-hydroxy groups and saponification of 17- and/or 21-alkanoyloxy groups. 6 - Fluoro - 16[alpha],17[alpha] - isopropylidenedioxypregna - 4,6 - diene - 3,11,20 - trione, 21 - acetoxy - 6 - fluoro - 16[alpha] - fluoromethyl - 17[alpha] - hydroxy - pregna - 4,6 - diene 3,11,20 - triene and 21 - acetoxy - 6,16[alpha] - difluoro - 17[alpha] - hydroxypregna - 4,6 - diene - 3,11,20 - trione are prepared by 6,7-dehydrogenation of the corresponding pregn-4-enes. 6 - Chloro - 16[alpha] - chloromethyl - 17[alpha] - acetoxypregna - 4,6 - diene - 3,20 - dione is prepared from 16[alpha] - chloromethyl - 17[alpha] - acetoxy - pregn- 4 - ene - 3,20 - dione via 17[alpha] - acetoxy - 16[alpha] chloromethyl - 3 - ethoxy - pregna - 3,5 - dien - 20- one and 6# - chloro - 16[alpha] - chloromethyl - 17[alpha]- acetoxy - pregn - 4 - ene - 3,20 - dione. 21 - Acetoxy - 6 - chloro - 17[alpha] - hydroxy - 16- methylene - pregna - 4,6 - diene - 3,11,20 - trione is prepared from 21-acetoxy-17[alpha]-hydroxy-16- methylene - pregn - 4 - ene - 3,11,20 - trione via 21 - acetoxy - 3 - ethoxy - 17[alpha] - hydroxy - 16- methylene - pregna - 3,5 - diene - 11,20 - dione and 21 - acetoxy - 6# - chloro - 17[alpha] - hydroxy - 16- methylene - pregn - 4 - ene - 3,11,20 - trione. 4,6 - Dichloro - 21 - acetoxy - 16[alpha],17[alpha] - epoxy- 16# - methyl - pregna - 4,6 - diene - 3,11,20- trione (X) is prepared by the sequence: 21- acetoxy - 6 - chloro - 17[alpha] - hydroxy - pregna - 4,6- diene - 3,11,20 - trione (XI) # the 3,20 - bis- (semicarbazone) of XI # 21 - acetoxy - 6- chloro - pregna - 4,6,16 - triene - 3,11,20 - trione 3,20 - bis(semicarbazone) # 21 - hydroxy - 6- chloro - pregna - 4,6,16 - triene - 3,11,20 - trione (XII) # the 21-acetate of XII # 6-chloro-21- acetoxy - 16[alpha],17[alpha] - methyleneazo - pregna - 4,6- diene - 3,11,20 - trione # 6 - chloro - 21 - acetoxy - 16 - methyl - pregna - 4,6,16 - triene- 3,11,20 - trione # an unidentified trichloro intermediate (by treatment with Cl 2 /CCl 4 ) # an unidentified oil (by treatment with Na 2 HPO 4 / CF 3 CO 3 H) # X (by treatment with pyridine). 2#,4,6 - Trichloro - 21 - acetoxy - 16[alpha],17[alpha]- epoxy - 16# - methyl - pregna - 4,6 - diene- 3,11,20-trione is prepared by chlorination of the corresponding 2-dechloro compound. The compounds of Formula I are stated to possess progestational, glucocorticoid, mineralocorticoid, anti inflammatory and thymolytic activities, and may be made up with carriers into pharmaceutical compositions for oral, parenteral and topical administration.