Angiostatic agents and methods and compositions for controlling ocular hypertension

A method for treating GLC1A glaucoma which comprises administering to a person in need thereof a pharmaceutically effective amount of angiostatic agent that has the following structure:

• ##STR3## wherein R.sub.1 is H, .beta.-CH.sub.3 or .beta.-C.sub.2 H.sub.5 ;
• R.sub.2 is F, C.sub.9 -C.sub.11 double bond, C.sub.9 -C.sub.11 epoxy, H or Cl;
• R.sub.3 is H, OR.sub.26, OC(.dbd.O)R.sub.27, halogen, C.sub.9 -C.sub.11 double bond, C.sub.9 -C.sub.11 epoxy, .dbd.O, --OH, --O-alkyl(C.sub.1 -C.sub.12), --OC(.dbd.O)alkyl(C.sub.1 -C.sub.12), --OC(.dbd.O)ARYL, --OC(.dbd.O)N(R).sub.2 or --OC(.dbd.O)OR.sub.7, wherein ARYL is furyl, thienyl, pyrrolyl, or pyridyl and each of said moieties is optionally substituted with one or two (C.sub.1 -C.sub.4)alkyl groups, or ARYL is --(CH.sub.2).sub.f -phenyl wherein f is 0 to 2 and the phenyl ring is optionally substituted with 1 to 3 groups selected from chlorine, fluorine, bromine, alkyl(C.sub.1 -C.sub.3), alkoxy(C.sub.1 -C.sub.3), thioalkoxy-(C.sub.1 -C.sub.3), Cl.sub.3 C--, F.sub.3 C--, --NH.sub.2 and --NHCOCH.sub.3 and R is hydrogen, alkyl (C.sub.1 -C.sub.4), or phenyl and each R can be the same or different, and R.sub.7 is ARYL as herein defined, or alkyl(C.sub.1 -C.sub.12);
• R.sub.4 is H, CH.sub.3, Cl or F;
• R.sub.5 is H, OH, F, Cl, Br, CH.sub.3, phenyl, vinyl or allyl;
• R.sub.6 is H or CH.sub.3 ;
• R.sub.9 is CH.sub.2 CH.sub.2 OR.sub.26, CH.sub.2 CH.sub.2 OC(.dbd.O)R.sub.27, H, OH, CH.sub.3, F, .dbd.CH.sub.2, CH.sub.2 C(.dbd.O)OR.sub.28, OR.sub.26, O(C.dbd.O)R.sub.27 or O(C.dbd.O)CH.sub.2 (C.dbd.O)OR.sub.26
• R.sub.10 is --C.tbd.CH, --CH.dbd.CH.sub.2, halogen, CN, N.sub.3, OR.sub.26, OC(.dbd.O)R.sub.27, H, OH, CH.sub.3 or R.sub.10 forms a second bond between positions C-16 and C-17;
• R.sub.12 is H or forms a double bond with R.sub.1 or R.sub.14 ;
• R.sub.13 is halogen, OR.sub.26, OC(.dbd.O)R.sub.27, NH.sub.2, NHR.sub.26, NHC(.dbd.O)R.sub.27, N(R.sub.26).sub.2, NC(.dbd.O)R.sub.27, N.sub.3, H, --OH, .dbd.O, --O--
• P(.dbd.O)(OH).sub.2, or --O--C(.dbd.O)--(CH.sub.2).sub.t COOH where t is an integer from 2 to 6;
• R.sub.14 is H or forms a double bond with R.sub.12 ;
• R.sub.15 is H, .dbd.O or --OH;
• and R.sub.23 with R.sub.10 forms a cyclic phosphate;
• wherein R.sub.9 and R.sub.15 have the meaning defined above;
• or wherein R.sub.23 is --OH, O--C(.dbd.O)--R.sub.11, --OP(O)--(OH).sub.2, or --O--C(.dbd.O)--(CH.sub.2).sub.t COOH wherein t is an integer from 2 to 6;
• and R.sub.11 is --Y--(CH.sub.2).sub.n --X--(CH.sub.2).sub.m --SO.sub.3 H, --Y'--(CH.sub.2).sub.p --X'--(CH.sub.2).sub.q --NR.sub.16 R.sub.17 or --Z(CH.sub.2).sub.r Q,
• wherein Y is a bond or --O--;
• Y' is a bond, --O--, or --S--;
• each of X and X' is a bond, --CON(R.sub.18)--, --N(R.sub.18)CO--, --O--, --S--, --S(O)--, or --S(O.sub.2)--;
• R.sub.18 is hydrogen or alkyl (C.sub.1 -C.sub.4);
• each of R.sub.16 and R.sub.17 is a lower alkyl group of from 1 to 4 carbon atoms optionally substituted with one hydroxyl or R.sub.16 and R.sub.17 taken together with the nitrogen atom to which each is attached forms a monocyclic heterocycle selected from pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino or N(lower)alkyl-piperazino 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 one of the following:
• (1) --R.sub.19 --CH.sub.2 COOH wherein R.sub.19 is --S--, --S(O)--, --S(O).sub.2 --, --SO.sub.2 N(R.sub.20)--, or N(R.sub.20)SO.sub.2 --;
• and R.sub.20 is hydrogen or lower alkyl-(C.sub.1 -C.sub.4);
• with the proviso that the total number of carbon atoms in R.sub.20 and (CH.sub.2).sub.r is not greater than 10;
• or
• (2) --CO--COOH;
• or
• (3) CON(R.sub.21)CH(R.sub.22)COOH wherein R.sub.21 is H and R.sub.22 is H, CH.sub.3, --CH.sub.2 COOH, --CH.sub.2 CH.sub.2 COOH, --CH.sub.2 OH, --CH.sub.2 SH, --CH.sub.2 CH.sub.2 SCH.sub.3, or --CH.sub.2 Ph-OH wherein Ph-OH is p-hydroxyphenyl;
• or R.sub.21 is CH.sub.3 and R.sub.22 is H;
• or R.sub.21 and R.sub.22 taken together are --CH.sub.2 CH.sub.2 CH.sub.2 --;
• or --N(R.sub.21)CH(R.sub.22)COOH taken together is --NHCH.sub.2 CONHCH.sub.2 COOH;
• and pharmaceutically acceptable salts thereof;
• with the proviso that if R.sub.23 is a phosphate, it must form a cyclic phosphate, with R.sub.10 when R.sub.13 is .dbd.O, except for the compound wherein R.sub.1 is .beta.-CH.sub.3, R.sub.2 and R.sub.3 taken together form a double bond between positions 9 and 11, R.sub.4 and R.sub.6 are hydrogen, R.sub.12 and R.sub.14 taken together form a double bond between positions 4 and 5, R.sub.5 is .varies.--F, R.sub.9 is .beta.-CH.sub.3, R.sub.10 is .varies.-OH, R.sub.13 and R.sub.15 are .dbd.O and R.sub.23 is --OP(O)--(OH).sub.2,
• R.sub.24 =C, C.sub.1 -C.sub.2 double bond, O;
• R.sub.25 =C(R.sub.15)CH.sub.2 --R.sub.23, OH, OR.sub.26, OC(.dbd.O)R.sub.27, R.sub.26, COOH, C(.dbd.O)OR.sub.26, CHOHCH.sub.2 OH, CHOHCH.sub.2 OR.sub.26, CHOHCH.sub.2 OC(.dbd.O)R.sub.27, CH.sub.2 CH.sub.2 OH, CH.sub.2 CH.sub.2 OR.sub.26, CH.sub.2 CH.sub.2 OC(.dbd.O)R.sub.27, CH.sub.2 CN, CH.sub.2 N.sub.3, CH.sub.2 NH.sub.2, CH.sub.2 NHR.sub.26, CH.sub.2 N(R.sub.26).sub.2, CH.sub.2 OH, CH.sub.2 OR.sub.26, CH.sub.2 O(C.dbd.O)R.sub.27, CH.sub.2 O(P.dbd.O)(OH).sub.2, CH.sub.2 O(P.dbd.O)(OR.sub.26).sub.2, CH.sub.2 SH, CH.sub.2 S--R.sub.26, CH.sub.2 SC(.dbd.O)R.sub.27, CH.sub.2 NC(.dbd.O)R.sub.27, C(.dbd.O)CHR.sub.28 OH, C(.dbd.O)CHR.sub.28 OR.sub.26, C(.dbd.O)CHR.sub.28 OC(.dbd.O)R.sub.27 or
• R.sub.10 and R.sub.25 taken together may be .dbd.C(R.sub.28).sub.2, that is, an optionally alkyl substituted methylene group;
• wherein R.sub.26 =C.sub.1 -C.sub.6 (alkyl, branched alkyl, cycloalkyl, haloalkyl, aralkyl, aryl);
• R.sub.27 =R.sub.26 +OR.sub.26 ;
• R.sub.28 =H, C.sub.1 -C.sub.6 (alkyl, branched alkyl, cycloalkyl).