Patent CA-1310009-C (CA)
Title: Ester prodrugs of steroids
Inventor: BRAUGHLER JOHN M
IPC: C07J5/00
Filed: 1985-03-13
Granted: 1992-11-10
Abstract: ABSTRACT ESTER PRODRUGS OF STEROIDS     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 R1 is CH3 or -C2H5; wherein  R2  is  H,  and  R3  is  in  the  .alpha.-position  and  is  -OH, -O-alkyl(C1-C12), -O?alkyl(C1-C12),     =O?aryl,     -C?N(R)2,     or -O?OR7 wherein aryl is furyl, thienyl, pyrrolyl, or pyridyl wherein each of said hetero moiety is optionally substituted with one or two (C1-C4)-alkyl groups or aryl is -(CH2)f-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(C1-C3), alkoxy(C1-C3), thio-alkoxy(C1-C3), Cl3C-, F3C-, -NH2 and -NHCOCH3 and wherein R is hydro-gen, alkyl(C1-C4), or phenyl and each R can be the same or different; and wherein R7 is aryl as herein defined or alkyl(C1-Cl2); or wherein R2 is .alpha.-Cl and R3 is .beta.-Cl; or wherein R2 and R3 taken together are oxygen (-O-) bridging positions C-9 and C-11; or wherein R2 and R3 taken together form a double bond between positions C-9 and C-11. wherein R4 is H, CH3, Cl or F; wherein R5 is H, OH, F, Cl, Br, CH3, phenyl, vinyl or allyl; wherein R6 is H or CH3;     wherein R9 is H, OH, CH3, F or =CH2; wherein R10 is H, OH, CH3 or R10 forms a second bond between positions C-16 and C-17; wherein R11  is  -CH2CH2COOH,  -Y-(CH2)n-X-(CH2)m-SO3H,  -Y'-(CH2)p-X'-(CH2)q-NR12R13 or -Z(CH2)rQ, wherein Y is a bond or -O-; Y' is a bond, -O-, or -S-; each of X and X' is a bond, -CON(R14)-, -N(R14)CO-, -O-, -S-, -S(O)-, or -S(O2)-; R14 is hydrogen or alkyl(C1-C4); each of R12 and R13 is a lower alkyl group of from 1 to 4 carbon atoms optionally substituted with one hydroxyl or R12 and R13 taken together with the nitrogen atom to which each is attached forms a monocyclic hetero-cyclic selected from pyrrolidino, piperidino, morpholino, thiomorpho-lino, 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 -O-; r is an integer of from 2 to 9; and Q is (1)  -R15-CH2COOH wherein R15  is  -S-,  -S(O)-,  -S(O)2-,  -SO2N-(R16)-, or -N(R16)SO2-; and R16 is hydrogen or lower alkyl(C1-C4); with the proviso that the total  number of carbon atoms in R16 and (CH2)r is not greater than 10;     (2) -CO-COOH; or (3) -CON(R17)CH(R18)COOH wherein R17 is H and R18 is H, CH3, CH2COOH,  -CH2CH2COOH,  -CH2OH,  -CH2SH,  -CH2CH2SCH3, or -N(R17)-wherein Ph is phenyl and Ph-OH is p-hydroxyphenyl; or R17 is CH3 and R18 is H; or R17 and R18 taken together are -CH2CH2CH2-; or -N(R17)-CH(R18)COOH taken together is -NHCH2CONHCH2COOH; and pharmaceutically acceptable salts thereof; with the further provisos that:         (a) when n is 2, R14 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 R4 is Cl or F, the C-1 position is saturated; and (g) when R9 is =CH2, R10 is other than a second bond between positions C-16 and C-17; excepting the following compounds: 21-(3-Carboxy-1-oxopropoxy)-6.alpha.-fluoro-17.alpha.-hydroxy-16.alpha.-methyl-pregna-1,3,9(11)triene-3,20-dione, sodium salt; 21-(3-carboxy-1-oxopropoxy)-17.alpha.-hydroxy-16.beta.-methylpregna-1,4,9-(11)triene-3,20-dione;     21-(3-carboxy-1-oxopropoxy)-17.alpha.-hydroxy-l6.alpha.-methylpregna-1,4,9 (11)triene-3,20-dione, sodium salt; 21-(3-carboxy-1-oxopropoxy)-17.alpha.-hydroxy-16.alpha.-methylpregna-4,9(11)-diene-3,20-dione, sodium salt; N-methyltaurine  amide  of  17.alpha.-hydroxypregna-4,9(11)diene-3,20-dione-21-hemisuberate, sodium salt; N-methyltaurine  amide  of  17.alpha.-hydroxypregna-1,4,9(11)triene-6.alpha.-3,20-dione-21-hemisuberate, sodium salt.