Patent ID: 6011023
Filing Date: 2000-01-04
Classification: A61K,C07J

Abstract:
A method for preventing and treating neovascularization, which comprises: administering a therapeutically effective amount of a composition comprising a compound of the formula: ##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)N(R).sub.2 or--OC(.dbd.O)OR.sub.7, and R is hydrogen, alkyl (C.sub.1 -C.sub.4), or phenyl and each R is the same or different, and R.sub.7 is 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.26R.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;R.sub.23 is --OH, O--C(.dbd.O)--R.sub.11, --OP(O)--(OH).sub.2, --O--C(.dbd.O)--(CH.sub.2).sub.t COOH or R.sub.23 with R.sub.10 forms a cyclic phosphate 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;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 --N(R.sub.21)CH(R.sub.22)COOH 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 .alpha.-F, R.sub.9 is .beta.-CH.sub.3, R.sub.10 is .alpha.-OH, R.sub.13 and R.sub.15 are .dbd.O and R.sub.23 is --OP(O)--(OH).sub.2,R.sub.24 is C, C.sub.1 -C.sub.2 double bond, O;R.sub.25 is 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(O)R.sub.27, C(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 is C.sub.1 -C.sub.6 (alkyl, branched alkyl, cycloalkyl, haloalkyl, aralkyl, aryl); R.sub.27 is R.sub.26 or OR.sub.26 ; R.sub.28 is H, C1-C6 (alkyl, branched alkyl, cycloalkyl);excepted from the compounds of Structure [A] are the compounds wherein R.sub.23 is OH, OC(.dbd.O)R.sub.11, OP(O)(OH).sub.2, or OC(.dbd.O)(CH.sub.2).sub.t COOH;also excepted from the compounds of Structure are the compound 3,11.beta.,17.alpha.,21-tetrahydroxy-5-pregnane-20-one (the 3-.alpha., 5-.beta.; 3-.alpha., 5-.alpha.; 3-.beta., 5-.alpha.; and 3-.beta., 5-.beta. isomers of tetrahydrocortisol) wherein R.sub.15 is .dbd.O, R.sub.10 is .alpha.-OH, R.sub.1 is .beta.-CH.sub.3, R.sub.3 is .beta.-OH, R.sub.2 is H, R.sub.4 is H, R.sub.13 is .alpha.- or .beta.-OH, R.sub.14 is H, R.sub.12 is .alpha.- or .beta.-H, R.sub.5 is H, R.sub.6 is H, R.sub.9 is H, R.sub.24 is C, and R.sub.23 is OH; and methyltestosterone, wherein R.sub.1 is .beta.-CH.sub.3, R.sub.2 is H, R.sub.3 is H, R is H, R.sub.5 is H, R.sub.6 is H, R.sub.9 is H, R.sub.10 is .alpha.-CH.sub.3, R.sub.12 and R.sub.14 form a C.sub.4 -C.sub.5 double bond, R.sub.13 is .dbd.O, R.sub.24 is C and R.sub.25 is .beta.-OH; dihydrotestosterone, wherein R.sub.1 is .beta.-CH.sub.3, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.9, R.sub.10, and R.sub.14 are H, R.sub.12 is .alpha.-H, R.sub.13 is .dbd.O, R.sub.24 is C, and R.sub.25 is .beta.-OH; dromostanolone propionate, wherein R.sub.1 is .beta.-CH.sub.3,R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.9, R.sub.10, and R.sub.14 are H, R.sub.12 is .alpha.-H, R.sub.13 is .dbd.O, R.sub.24 is C and R.sub.25 is .beta.-OC(.dbd.O)CH.sub.2 CH.sub.3 ; methandrostenelone, wherein R is .beta.-CH.sub.3, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, and R.sub.9 are H, R.sub.10 is .alpha.-CH.sub.3, R.sub.12 and R.sub.14 form a C.sub.4 C.sub.5 double bond, R.sub.13 is .dbd.O, R.sub.24 is C.sub.1 C.sub.2 double bond, and R.sub.25 is .beta.-OH; testosterone, wherein R.sub.1 is .beta.-CH.sub.3, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.9, and R.sub.10 are H, R.sub.12 and R.sub.14 form a C.sub.4 C.sub.5 double bond, R.sub.13 is .dbd.O, R.sub.24 is C, and R.sub.25 is .beta.-OH; norethandrolone, wherein R.sub.1 is CH.sub.3 (C.sub.13) and H(C.sub.10), R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, and R.sub.9 are H, R.sub.10 is .alpha.-CH.sub.2 CH.sub.3, R.sub.12 and R.sub.14 form a C.sub.4 -C.sub.5 double bond, R.sub.13 is .dbd.O, R.sub.24 is C, and R.sub.25 is .beta.-OH; bolasterone, wherein R.sub.1 is .beta.-CH.sub.3, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.9 are H, R.sub.6 is .alpha.-CH.sub.3, R.sub.10 is .alpha.-CH.sub.3, R.sub.13 is .dbd.O, R.sub.12 and R.sub.14 form a C.sub.4 C.sub.5 double bond, C.sub.24 is C and R.sub.25 is .beta.-OH; and oxandrolone, wherein R.sub.1 is .beta.-CH.sub.3, R.sub.2, R.sub.3, R.sub.5, R.sub.6, R.sub.9, and R.sub.14 are H, R.sub.10 is .alpha.CH.sub.3, R.sub.12 is .alpha.-H, R.sub.13 is .dbd.O, R.sub.24 is O, and R.sub.25 is .beta.-OH; also excepted from the compounds of Structure A are 4,9(1 1)-Pregnadien-17.alpha.,21-diol-3,20-dione-21 acetate, 4,9(11)-Pregnadiene-17.alpha.,21-diol-3,20-dione, 11-epicortisol, 17.alpha. hydroxyprogesterone, and tetrahydrocortexolone.