EP0156643A2 — Ester prodrugs of steroids

USPTO Abstract

A compound of the formula wherein the dotted line between positions C-1 and C-2 means the presence or absence of a double bond; wherein R, is CH 3 or -C 2 H 5 ; wherein R 2 is H, and R 3 is in the a-position and is -OH, -O-alkyl(C 1 -C 12 ) wherein aryl is furyl, thienyl, pyrrolyl, or pyridyl wherein each of said hetero moiety is optionally substituted with one or two (C 1 -C 4 )- alkyl groups or aryl is -(CH 2 ) 1 -phenyl wherein f is 0 to 2 and wherein the phenyl ring is optionally substituted with 1 to 3 groups selected from chlorine, fluorine, bromine, alkyl (C,-C 3 ), alkoxy (C 1 -C 3 ), thioalkoxy (C 1 -C 3 ), Cl 3 C-, F 3 C-, -NH 2 , and -NHCOCH 3 and wherein R is hydrogen, alkyl (C 1 -C 4 ), or phenyl and each R can be the same or different; and wherein R, is aryl as herein defined or alkyl (C 1 -C 12 ); or wherein R 2 is α-Cl and R 3 is β-Cl; or wherein R 2 and R 3 taken together are oxygen (-0-) bridging positions C-9 and C-11; or wherein R 2 and R 3 taken together form a double bond be-tween positions C-9 and C-11; wherein R 4 is H, CH 3 , Cl or F; wherein R 5 is H, OH, F, Cl, Br, CH 3 , phenyl, vinyl or allyl; wherein R 6 is H or CH 3 ; wherein R, is H, OH, CH 3 , F or = CH,; wherein R 10 is H, OH, CH 3 or R 10 forms a second bond between positions C-16 and C-17; wherein R,, is -CH 2 CH 2 COOH, -Y-(CH 2 ) n -X-(CH 2 ) m -SO 3 H, -Y'-(CH 2 ) P -X'-(CH 2 ) q -NR 12 R 13 or -Z(CH 2 ),O, wherein Y is a bond or -0-; Y' is a bond, -0-, or -S-; each of X and X' is a bond, -CON(R 14 )-, -N(R 14 )CO-, -O-, -S-, -S(0)-, or -S(O 2 )-; R 14 is hydrogen or alkyl (C 1 -C 4 ); each of R 12 and R 13 is a lower alkyl group of from 1 to 4 carbon atoms optionally substituted with one hydroxyl or R 12 and R 13 taken together with the nitrogen atom to which each is attached forms a monocyclic heterocyclic selected from pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino or N(lower)alkylpiperazino wherein alkyl has from 1 to 4 carbon atoms; n is an integer of from 4 to 9; m is an integer of from 1 to 5; p is an integer of from 2 to 9; q is an integer of from 1 to 5; Z is a bond or -0-; r is an integer of from 2 to 9; and 0 is (1) -R 15 -CH 2 COOH wherein R 15 is -S-, -S(0)-, -S(O 2 -, -SO 2 N-(R 16 )-, or-N(R 16 )SO 2 -; and R 15 is hydrogen or lower alkyl (C 1 -C 4 ); with the proviso that the total number of carbon atoms in R 15 and (CH 2 ), is not greater than 10; (2) -CO-COOH; or (3) -CON(R 17 )CH(R 18 )COOH wherein R 17 is H and R 18 is H, CH,, -CH,COOH, -CH 2 CH 2 COOH, -CH 2 OH, -CH 2 SH, -CH 2 CH 2 SCH 3 , or CH 2 Ph-OH wherein Ph is phenyl and Ph-OH is p-hydroxyphenyt; or R 17 is CH 3 and R 18 is H; or R 17 and R 18 taken together are -CH 2 CH 2 CH 2 -; or -N(R 17 )- CH(R 18 )COOH taken together is -NHCH 2 CONHCH 2 COOH; and pharmaceutically acceptable salts thereof; with the further provisos that: (a) when n is 2, R 14 is other than hydrogen; (b) the sum of m and n is not greater than 10; (c) the sum of p and q is not greater than 10; (d) when X is a bond the sum of m and n is from 5 to 10; (e) when X' is a bond the sum of p and q is from 4 to 9; (f) when R 4 is Cl or F, the C-1 position is saturated; and (g) when R, is =CH 2 , R 10 is other than a second bond between positions C-16 and C-17; excepting the following compounds: 21-(3-Carboxy-1-oxopropoxy)-6a-fluoro-17a-hydroxy-16α-methylpregna-1,3,9(11)triene-3,20-dione, sodium salt; 21-(3-carboxy-1-oxopropoxy)-17α-hydroxy-16β-methyl- pregna-1,4,9(11 )triene-3,20-dione; 21-(3-carboxy-1-oxopropoxy)-17a-hydroxy-16a-methyl- pregna-1,4,9(11)triene-3,20-dione, sodium salt; 21-(3-carboxy-1-oxopropoxy)-17a-hydroxy-16a-methyl- pregna-4,9(11)diene-3,20-dione, sodium salt; N-methyltaurine amide ofl7a-hydroxypregna-4,9(11)diene-3,20-dione-21-hemisuberate, sodium salt; N-methyltaurine amide of 17a-hydroxypregna-1,4,9 (11)triene-6a-3,20-dione-21 - hemisuberate, sodium salt.