Patent EP-0245357-B1 (EP)
IPC: C07J31/00
Filed: 1986-10-16
Granted: 1991-08-07
Abstract: This invention provides novel tetrahydro steroids which are useful in inhibiting angiogenesis and have the following structure: A compound of the formula: <CHEM>  wherein R1 is  beta -CH3 or  beta -CH2H5; wherein R2 is H, and R3 is =0, -OH, -0-alkyl(C1-C12), -OC(=0)-alkyl(C1-C12), -OC(=0)aryl, -OC(=0)N(R)2, or -OC(=0)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), thioalkoxy-(C1-C3), Cl3C-, F3C-, -NH2 and -NHCOCH3 and wherein R is hydrogen, 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-C12); or wherein R2 is  alpha -Cl and R3 is  beta -Cl, or wherein R2 and R3 taken together are oxygen (-0-) 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;  or R2 is  alpha -F and R3 is  beta -OH;  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 R12 is -H or forms a double bond with R14; wherein R13 is H, -OH, -OH, =0, -0-P(0)(OH)2, or -0-C(=0)-(CH2)tCOOH where t is an integer from 2 to 6;  wherein R14 is H or forms a double bond with R12;  wherein R15 is =0 or -OH;  wherein R23 with R10 forms a cyclic phosphate of the formula <CHEM> wherein R9 and R15 have the meaning defined above; or wherein R23 is -OH, O-C(=0)-R11, -0-P(0)(OH)2, or -0-C(=0)-(CH2)tCOOH wherein t is an integer from 2 to 6; and R11 is -Y-(CH2)n-X-(CH2)m-SO3H, -Y'-(CH2)p-X'-(CH2)q-NR16R17 or -Z(CH2)rQ, wherein Y is a bond or -0-; Y; is a bond, -0-, or -S-; each of X and X' is a bond, -CON(R18)-, -N(R18)CO-, -0-, -S-, -S(0)-, or -S(02)-; R18 is hydrogen or alkyl(C1-C4); each of R16 and R17 is a lower alkyl group of from 1 to 4 carbon atoms optionally substituted with one hydroxyl or R16 and R17 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 Q is   (1) -R19-CH2COOH wherein R19 is -S-, -S(0)-, -S(0)2-, -SO2N(R20)-, or -N(R20)SO2-; and R20 is hydrogen or lower alkyl(C1-C4); with the proviso that the total number of carbon atoms in R20 and (CH2)r is not greater than 10;   (2) -CO-COOH; or (3) -CON(R21)CH(R22)COOH wherein R21 is H and R22 is H, CH3, -CH2COOH, -CH2CH2COOH, -CH2OH, -CH2SH, -CH2CH2SCH3, or -CH2Ph-OH wherein Ph-OH is p-hydroxyphenyl; or R21 is CH3 and R22 is H; or R21 and R22 taken together are -CH2CH2CH2-; or -N(R21)CH(R22)COOH taken together is -NHCH2CONHCH2COOH; and pharmaceutically acceptable salts thereof; with the further provisos that:     (a) when n is 2, R18 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; and mono and bis salts thereof; excepting the following compound: 3 alpha ,11 beta ,17 alpha ,21-tetrahydroxy-5 beta -pregnane-20-one, and with the proviso that except for the compound 21-phosphate-6 alpha -fluoro-17-hydroxy-16 beta -methyl(pregna-4,9(11))-diene)-3,20-dione, R13 is =0 only when R23 with R10 forms the above described cyclic phosphate.   ;