Immunosuppressant tricyclic compounds

A compound of structural Formula I:

• ##STR72## or a pharmaceutically acceptable salt, crystal form, or hydrate thereof, wherein:
• a, b and c are independently a single bond or a double bond, and represented by in the structure above;
• n is:
• 0, 1 or 2;
• r is:
• 0 or 1;
• s is:
• 0 or 1;
• R.sup.1 and R.sup.2 are independently:
• (1) hydroxyl,
• (2) (C.sub.1 -C.sub.6)-alkyloxy,
• (3) H,
• (4) OCO(C.sub.1 -C.sub.6)-alkyl,
• (5) (C.sub.1 -C.sub.6)-alkyl,
• (6) R.sup.1 and R.sup.2 taken together is an exo-methylene group,
• (7) R.sup.1 and R.sup.2 taken together is .dbd.O,
• (8) (C.sub.1 -C.sub.6)-alkylaryl, wherein aryl is as defined in R.sup.11 below, or
• (9) (C.sub.2 -C.sub.8)alkenyl;
• with the proviso that R.sup.2 is absent when a is a double bond;
• R.sup.3 and R.sup.4 are independently:
• (1) hydroxyl,
• (2) (C.sub.1 -C.sub.6)-alkyloxy,
• (3) H,
• (4) OCO(C.sub.1 -C.sub.6)-alkyl,
• (5) (C.sub.1 -C.sub.6)-alkyl,
• (6) phenyl,
• (7) R.sup.3 and R.sup.5 taken together is an oxirane group when b is a single bond, or
• (8) (CH.sub.2).sub.n aryl, wherein aryl is as defined below;
• with the proviso that R.sup.4 is absent when b is a double bond, additionally, R.sup.3 and R.sup.4 can be taken together to be .dbd.O when b is a single bond;
• R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are independently selected from the group consisting of:
• (1) O[(C.dbd.O)O.sub.r ].sub.s R.sup.13,
• (2) O[(C.dbd.O)O.sub.r ].sub.s -aryl, aryl as defined below,
• (3) O[(C.dbd.O)O.sub.r ].sub.s -heteroaryl,
• (4) hydrogen, provided that R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are not all hydrogen at the same time when c is a single bond,
• (5) (C.sub.1 -C.sub.6)alkylaryl, wherein aryl is as defined below, and
• (6) hydroxyl;
• R.sup.9 is:
• (1) H,
• (2) OH,
• (3) .dbd.O,
• (4) O[(C.dbd.O)O.sub.r ].sub.s (C.sub.1 -C.sub.6)-alkyl, alkyl as defined below,
• (5) O[(C.dbd.O)O.sub.r ].sub.s (C.sub.2 -C.sub.6)-alkenyl, as defined below,
• (6) O[(C.dbd.O)O.sub.r ].sub.s -aryl, aryl as defined below,
• (7) O[(C.dbd.O)O.sub.r ].sub.s -heteroaryl,
• (8) O(CH.sub.2).sub.n -heteroaryl,
• (9) O(CH.sub.2).sub.n -aryl, aryl as defined below, or
• (10) R.sup.9 and R.sup.12 are connected to form ##STR73## when R.sup.10 is methyl and R.sup.11 is H;
• R.sup.10 is:
• (1) CH.sub.3, or
• (2) H;
• R.sup.11 is chosen from the group consisting of:
• (1) H,
• (2) (C.sub.1 -C.sub.6)-alkyl, wherein alkyl is unsubstituted or substituted with one or two of the substituents selected from the group consisting of:
• (a) halo, wherein halo is fluoro, chloro, bromo, or iodo,
• (b) hydroxy,
• (c) oxo,
• (d) (C.sub.1 -C.sub.6)-alkyloxy,
• (e) (C.sub.1 -C.sub.6)-alkyl--S(O).sub.n --,
• (f) aryl-(C.sub.1 -C.sub.6)-alkyloxy, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two or three of the substituents selected from the group consisting of:
• (a') halo, wherein halo is fluoro, chloro, bromo, or iodo,
• (b') hydroxy,
• (c') (C.sub.1 -C.sub.6)-alkyl,
• (d') (C.sub.1 -C.sub.4)-perfluoroalkyl,
• (e') (C.sub.1 -C.sub.6)-alkenyl,
• (f') (C.sub.1 -C.sub.6)-alkynyl,
• (g') (C.sub.1 -C.sub.6)-alkyloxy,
• (h') (C.sub.1 -C.sub.6)-alkyl--S(O).sub.n --,
• (i') phenyl,
• (j') phenoxy,
• (k') cyano,
• (l') nitro,
• (m') CO.sub.2 H,
• (n') CO(C.sub.1 -C.sub.6)-alkyl,
• (o') CO.sub.2 (C.sub.1 -C.sub.6)-alkyl,
• (p') CONR.sup.13 R.sup.14,
• (q') NR.sup.13 R.sup.14,
• (r') NR.sup.13 CO(C.sub.1 -C.sub.6)-alkyl,
• (s') (C.sub.1 -C.sub.6)-alkenyloxy, and
• (t') benzyloxy;
• (g) cyano,
• (h) nitro,
• (i) vinyl,
• (j) NR.sup.13 R.sup.14,
• (k) NR.sup.13 CO(C.sub.1 -C.sub.6)-alkyl,
• (l) CHO,
• (m) CO.sub.2 H,
• (n) CO(C.sub.1 -C.sub.6)-alkyl,
• (o) CO.sub.2 (C.sub.1 -C.sub.6)-alkyl,
• (p) CONR.sup.13 R.sup.14,
• (q) aryl, wherein aryl is as defined above,
• (r) OCOCH.sub.3, and
• (s) (CH.sub.2).sub.n O(CO)CH(SPh).sub.2 ;
• (3) (C.sub.2 -C.sub.6)-alkenyl, wherein alkenyl is unsubstituted or substituted with one or two of the substituents selected from the group consisting of:
• (a) halo, wherein halo is fluoro, chloro, bromo, or iodo,
• (b) hydroxy,
• (c) oxo,
• (d) (C.sub.1 -C.sub.6)-alkyloxy,
• (e) (C.sub.1 -C.sub.6)-alkyl--S(O).sub.n --,
• (f) phenyl-(C.sub.1 -C.sub.6)-alkyloxy,
• (g) cyano,
• (h) nitro,
• (i) vinyl,
• (3) NR.sup.13 R.sup.14,
• (k) NR.sup.13 CO(C.sub.1 -C.sub.6)-alkyl,
• (l) CHO,
• (m) CO.sub.2 H,
• (n) CO(C.sub.1 -C.sub.6)-alkyl,
• (o) CO.sub.2 (C.sub.1 -C.sub.6)-alkyl,
• (p) CONR.sup.13 R.sup.14,
• (q) aryl, wherein aryl is as defined above,
• (r) heteroaryl, and
• (s) OCOCHC.sub.3,
• (4) (CH.sub.2 ).sub.n O(C.sub.2 -C.sub.6)-alkenyl, wherein alkenyl is as defined above,
• (5) CHO,
• (6) COOH,
• (7) CONR.sup.13 R.sup.14,
• (8) O[(C.dbd.O)O.sub.r ].sub.s (C.sub.1 -C.sub.6)-alkyl, alkyl as defined above,
• (9) (CH.sub.2 ).sub.n S(C.sub.1 -C.sub.6)-alkyl, wherein alkyl is as defined above,
• (10) (CH.sub.2 ).sub.n S(C.sub.2 -C.sub.6)-alkenyl, wherein alkenyl is as defined above,
• (11) (CH.sub.2 ).sub.n S-aryl, wherein aryl is as defined above, or
• (12) (CO)(C.sub.1 -C.sub.6)-alkyl, wherein alkyl is as defined above;
• R.sup.12 is as defined above for R.sup.11 or
• (1) .dbd.O,
• (2) .dbd.CH--(C.sub.1 -C.sub.6)-alkyl, wherein alkyl is as defined above,
• (3) .dbd.CH--(C.sub.1 -C.sub.6)-alkenyl, wherein alkenyl is as defined above,
• (4) .dbd.CH-aryl, wherein aryl is as defined above,
• (5) hydroxyl, or
• (6) R.sup.9 and R.sup.12 are connected to form ##STR74## when R.sup.10 is methyl;
• and R.sup.11 is H;
• R.sup.13 and R.sup.14 are independently:
• (1) hydrogen,
• (2) (C.sub.1 -C.sub.6)-alkyl, or
• (3) phenyl.