O-aryl, O-alkyl, O-alkenyl and O-alkynylrapamycin derivatives

Claim 2

A compound of formula I: ##STR12## or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 are independently selected from: (1) hydrogen; (2) phenyl; (3) substituted phenyl in which the substituents are X, Y and Z; (4) 1- or 2- naphthyl; (5) substituted 1- or 2- naphthyl in which the substituents are X, Y and Z; (6) biphenyl; (7) substituted biphenyl in which the substituents are X, Y and Z; (8) C 1-10 alkyl; (9) substituted C 1-10 alkyl in which one or more substituent(s) is(are) selected from: (a) hydroxy, (b) oxo, (c) C 1-6 -alkoxy, (d) phenyl-C 1-3 alkoxy, (e) substituted phenyl-C 1-3 alkoxy, in which the substituents on phenyl are X, Y and Z, (f) --OCO--CL alkyl, (g) --NR 6 R 7 , wherein R 6 and R 7 are independently selected from (i) hydrogen, (ii) C 1-10 alkyl unsubstituted or substituted with one or more of the substituent(s) selected from: (a') phenyl, which is unsubstituted or substituted with X, Y and Z, (b') --OH, (c') C 1-6 alkoxy, (d') --CO 2 H) (e') --CO 2 -C 1-6 alkyl, (f') --C 3-7 cycloalkyl, and (g') --OR 11 , (iii)C 3-10 alkenyl unsubstituted or substituted with one or more of the substituent(s) selected from: (a') phenyl, which is unsubstituted or substituted with X, Y and Z, (b') --OH, (C') C 1-6 alkoxy, (d') --CO 2 H, (e') --CO 2 --C 1-6 alkyl, (f') --C 3-7 cycloalkyl, and (g') --OR 11 , (iv)or where R 6 and R 7 and the N to which they are attached can form a 3-7-membered saturated heterocyclic ring, unsubstituted or substituted with C 1-6 alkyl or phenyl, the ring being selected from the group consisting of: aziridine, morpholine, thiomorpholine, thiomorpholine-oxide, thiomorpholine-dioxide, piperidine, pyrrolidine, and piperizine, (h) --NR 6 CO--C 1-6 alkyl--R 7 , wherein R 6 is as defined above, (i) --NR 6 CO 2 --C 1-6 alkyl--R 7 , (j) --NR 6 CONR 6 R 7 , (k) --OCONR 6 R 7 , (l) --COOR 6 , (m) --CHO, (n) phenyl, (o) substituted phenyl in which the substituents are X, Y and Z, (p) phenyloxy, (q) substituted phenyloxy in which the substituents are X, Y and Z, (r) 1- or 2- naphthyl, (s) substituted 1- or 2- naphthyl in which the substituents are X, Y and Z, (t) biphenyl (u) substituted biphenyl in which the substituents are X, Y and Z; (v) --OR 11 , and (w) --S(O) p --C 1-6 alkyl; (10) C 3-10 alkenyl; (11) substituted C 3-10 alkenyl in which one or more substituent(s) is(are) selected from: (a) hydroxy, (b) oxo, (c) C 1-6 alkoxy, (d) phenyl-C 1-3 alkoxy, (e) substituted phenyl-C 1-3 alkoxy, in which the substituents on phenyl are X, Y and Z, (f) --OCO--C 1-6 alkyl, (g) --NR 6 R 7 , wherein R 6 and R 7 are as defined above (h) --NR 6 CO--C 1-6 alkyl, wherein R 6 is as defined above, (i) --COOR 6 , wherein R 6 is as defined above, (j) --CHO, (k) phenyl, (l) substituted phenyl in which the substituents are X, Y and Z, (m) 1- or 2-naphthyl, (n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z, (o) biphenyl, (p) substituted biphenyl in which the substituents are X, Y and Z, (q) --OR 11 , and (r) --S(O) p--C 1-6 alkyl; (12) C 3-10 alkynyl; (13) substituted C 3-10 alkynyl in which one or more substituent(s) is(are) selected from: (a) hydroxy, (b) oxo, (c) C 1-6 alkoxy, (d) phenyl-C alkoxy, (e) substituted phenyl-C 1-3 alkoxy, in which the substituents on phenyl are X, Y and Z, (f) --OCO--C 1-6 alkyl, (g) --NR 6 R , wherein R and R are as defined above, (h) --NR 6 CO--C 1-6 alkyl, wherein R 6 is as defined above, (i) --COOR 6 , wherein R 6 is as defined above, (j) --CHO, (k) phenyl, (l) substituted phenyl in which the substituents are X, Y and Z, (m) 1- or 2-naphthyl, (n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z, (o) biphenyl, (p) substituted biphenyl in which the substituents are X, Y and Z, and (q) --OR 11 ; with the proviso that R 1 and R 2 are not simultaneously hydrogen; R 11 is selected from: (a) --PO(OH)O - M + , wherein M + is a positively charged inorganic or organic counterion, (b) --SO 3 - M + , (c) --CO(CH 2 ) q CO 2 - M + , wherein q is 1-3, and (d) --CO--C 1-6 alkyl-NR 6 R 7 , wherein R 6 and R 7 are as defined above and the alkyl is unsubstituted or substituted with one or more substituents selected from: (i) hydroxy, (ii) C 1-6 alkoxy, (iii) --NR 16 R 17 , wherein R 16 and R 17 are independently selected from: (a') hydrogen, and (b') C 1-6 alkyl, (iv) --COOR 6 , wherein R 6 is as defined above, (v) phenyl, (vi) substituted phenyl in which the substituents are X, Y and Z, (vii) --SH, and (viii) --S--C 1-6 alkyl; X, Y and Z independently are selected from: (a) hydrogen, (b) C 1-7 alkyl, (c) C 2-6 alkenyl, (d) halogen, (e) --(CH 2 ) m --NR 6 R 7 , wherein R 6 and R 7 are as defined above, and m is 0 to 2, (f) --CN, (g) --CHO, (h) --CF 3 ) (i) --SR 8 , wherein R 8 is hydrogen, C 1-6 alkyl, trifluoromethyl, or phenyl, (j) --SOR 8 , wherein R 8 is as defined above, (k) --SO 2 R 8 , wherein R 8 is as defined above, (l) --CONR 6 R 7 , wherein R 6 and R 7 are as defined above, (m) R 9 O(CH 2 ) m - wherein R 9 is hydrogen, C 1-3 alkyl, hydroxy-C 2-3 alkyl, trifluoromethyl, phenyl or naphthyl and m is as defined above, (n) --CH(OR 12 )(OR 13 ), wherein R 12 and R 13 are C 1-3 alkyl or taken together form an ethyl or propyl bridge, (o) ##STR13## wherein R 9 and m are as defined above, and (p) ##STR14## wherein R 9 and m are as defined above, and (q) --OR 11 ; or any two of adjacent X, Y and Z can be joined to form a ring selected from the group consisting of: dioxolanyl, dihydrofuranyl, dihydropyranyl, and dioxanyl.

Claim 3

The compound of claim 1 wherein: R 1 and R 2 are independently selected from: (1) hydrogen; (2) methyl; (3) phenyl; (4) substituted phenyl in which the substituents are X, Y and Z; (5) 1- or 2- naphthyl; (6) substituted 1- or 2- naphthyl in which the substituents are X, Y and Z; (7) biphenyl; and (8) substituted and biphenyl in which the substituents are X, Y and Z; with the proviso that R 1 and R 2 are not simultaneously hydrogen; X, Y and Z are independently, selected from: (a) hydrogen, (b) C 1- 7 alkyl, (c) C 2-6 alkenyl, (d) halogen, (e) --(CH 2 ) m -NR 6 R 7 , wherein R 6 and R 7 are, independently selected from (i) hydrogen, or (ii) C 1-6 alkyl unsubstituted or substituted with phenyl, and m is 0 to 2, (f) --CN, (g) --CHO, (h) --CF 3 , (i) --SR 8 , wherein R 8 is hydrogen, C 1-6 alkyl, trifluoromethyl, or phenyl, (j) --SOR 8 , wherein R 8 is as defined above, (k) --SO 2 R 8 , wherein R 8 is as defined above, (l) --CONR 6 R 7 , wherein R 6 and R 7 are as defined above, (m) R 9 O(CH 2 ) m - wherein R 9 is hydrogen, C 1-3 alkyl, hydroxy-C 2-3 alkyl, trifluoromethyl, phenyl or naphthyl and m is as defined above, (n) --CH(OR 12 )(OR 13 ), wherein R 12 and R 13 are C 1-3 alkyl or taken together form an ethyl or propyl bridge, (o) ##STR15## wherein R 9 and m are as defined above, and (p) ##STR16## wherein R 9 and m are as defined above, and (q) --OR 11 ; or any two of adjacent X, Y and Z can be joined to form a ring selected from the group consisting of: dioxolanyl, dihydrofuranyl, dihydropyranyl, and dioxanyl.

Claim 4

The compound of claim 1 wherein: R 1 and R 2 are independently selected from: (1) hydrogen; (2) C 1-10 alkyl; (3) substituted C 1-10 alkyl in which one or more substituent(s) is(are) selected from: (a) hydroxy, (b) oxo, (c) C 1-6 -alkoxy, (d) phenyl-C 1-3 alkoxy, (e) substituted phenyl-C 1-3 alkoxy, in which the substituents on phenyl are X, Y and Z, (f) --OCO--C 1-6 alkyl, (g) --NR 6 R 7 , wherein R 6 and R 7 are independently selected from (i) hydrogen, (ii) C 1-10 alkyl unsubstituted or substituted with one or more of the substituent(s) selected from: (a') phenyl, which is unsubstituted or substituted with X, Y and Z, (b') --OH, (c') C 1-6 alkoxy, (d') --CO 2 H, (e') --CO 2 --C 1-6 alkyl, (f') --C 3-7 cycloalkyl, and (g') --OR 11 , (iii)C 3-10 alkenyl unsubstituted or substituted with one or more of the substituent(s) selected from: (a') phenyl, which is unsubstituted or substituted with X, Y and Z, (b') --OH, alkoxy, (c') C 1-6 alkoxy, (d') --CO 2 H, (e') --CO 2 --C 1-6 alkyl, (f') --C 3-7 cycloalkyl, and (g') --OR 11 , (iv)or where R 6 and R 7 and the N to which they are attached can form a 3-7-membered saturated heterocyclic ring, unsubstituted or substituted with C 1-6 alkyl or phenyl, the ring being selected from the group consisting of: aziridine, morpholine, thiomorpholine, thiomorpholine-oxide, thiomorpholine-dioxide, piperidine, pyrrolidine, and piperazine, (h) --NR 6 CO--C 1-6 alkyl-R 7 , wherein R 6 is as defined above, (i) --NR 6 CO 2 --C 1-6 alkyl-R 7 , (j) --NR 6 CONR 6 R 7 , (k) --OCONR 6 R 7 , (l) --COOR 6 , (m) --CHO, (n) phenyl, (o) substituted phenyl in which the substituents are X, Y and Z, (p) phenyloxy, (q) substituted phenyloxy in which the substituents are X, Y and Z, (r) 1- or 2- naphthyl, (s) substituted 1- or 2- naphthyl in which the substituents are X, Y and Z, (t) biphenyl (u) substituted biphenyl in which the substituents are X, Y and Z; (v) --OR 11 , and (w) --S(O) p --C 1-6 alkyl; (4) C 3-10 alkenyl; (5) substituted C 3-10 alkenyl in which one or more substituent(s) is(are) selected from: (a) hydroxy, (b) oxo, (c) C 1-6 alkoxy, (d) phenyl-C 1-3 alkoxy, (e) substituted phenyl-C 1-3 alkoxy, in which the substituents on phenyl are X, Y and Z, (f) --OCO--C 1-6 alkyl, (g) --NR 6 R 7 , wherein R 6 and R 7 are as defined above (h) --NR 6 CO--C 1-6 alkyl, wherein R 6 is as defined above, (i) --COOR 6 , wherein R 6 is as defined above, (j) --CHO, (k) phenyl, (l) substituted phenyl in which the substituents are X, Y and Z, (m) 1- or 2-naphthyl, (n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z, (o) biphenyl, (p) substituted biphenyl in which the substituents are X, Y and Z, (q) --OR 11 , and (r) --S(O) p --C 1-6 alkyl; (6) C 3-10 alkynyl; (7) substituted C 3-10 alkynyl in which one or more substituent(s) is(are) selected from: (a) hydroxy, (b) oxo, (c) C 1-6 alkoxy, (d) phenyl-C 1-3 alkoxy, (e) substituted phenyl-C 1-3 alkoxy, in which the substituents on phenyl are X, Y and Z, (f) --OCO--C 1-6 alkyl, (g) --NR 6 R 7 , wherein R 6 and R 7 are as defined above, (h) --NR 6 CO--C 1-6 alkyl, wherein R 6 is as defined above, (i) --COOR 6 , wherein R 6 is as defined above, (j) --CHO, (k) phenyl, (l) substituted phenyl in which the substituents are X, Y and Z, (m) 1- or 2-naphthyl, (n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z, (o) biphenyl, (p) substituted biphenyl in which the substituents are X, Y and Z, and (q) --OR 11 ; with the proviso that R 1 and R 2 are not simultaneously hydrogen; R 11 is selected from: (a) --PO(OH)O - M + , wherein M + is a positively charged inorganic or organic counterion, (b) --SO 3 - M + , (c) --CO(CH 2 ) q CO 2 - M + , wherein q is 1-3, and (d) --CO--C 1-6 alkyl-NR 6 R 7 , wherein R 6 and R 7 are as defined above and the alkyl is unsubstituted or substituted with one or more substituents selected from: (i) hydroxy, (ii) C 1-6 alkoxy, (iii) --NR 16 R 17 , wherein R 16 and R 17 are independently selected from: (a') hydrogen, and (b') C 1-6 alkyl, (iv) --COOR 6 , wherein R 6 is as defined above, (v) phenyl, (vi) substituted phenyl in which the substituents are X, Y and Z, (vii) --SH, and (viii) --S--C 1-6 alkyl; X, Y and Z independently are selected from: (a) hydrogen, (b) C 1-7 alkyl, (c) C 2-6 alkenyl, (d) halogen, (e) --(CH 2 ) m --NR 6 R 7 , wherein R 6 and R 7 are as defined above, and m is 0 to 2, (f) --CN, (g) --CHO, (h) --CF 3 , (i) --SR 8 , wherein R 8 is hydrogen, C 1-6 alkyl, trifluoromethyl, or phenyl, (j) --SOR 8 , wherein R 8 is as defined above, (k) --SOR 2 R 8 , wherein R 8 is as defined above, (l) --CONR 6 R 7 , wherein R 6 and R 7 are as defined above, (m) R 9 O(CH 2 ) m - wherein R 9 is hydrogen, C 1-3 alkyl, hydroxy-C 2-3 alkyl, trifluoromethyl, phenyl or naphthyl and m is as defined above, (n) --CH(OR 12 )(OR 13 ), wherein R 12 are C 1-3 alkyl or taken together form an ethyl or propyl bridge, (o) ##STR17## wherein R 9 and m are as defined above, and (p) ##STR18## wherein R 9 and m are as defined above, and (q) --OR 11 ; or any two of adjacent X, Y and Z can be joined to form a ring selected from the group consisting of: dioxolanyl, dihydro-furanyl, dihydropyranyl, and dioxanyl.

Claim 5

A compound which is: ##STR19## wherein R 1 and R 2 are selected from the following combinations of substituents: ______________________________________ R.sup.1 R.sup.2 ______________________________________ a) ##STR20## H b) ##STR21## H c) ##STR22## H d) ##STR23## H e) ##STR24## H f) ##STR25## H g) ##STR26## H h) ##STR27## H i) ##STR28## H j) H ##STR29## k) H ##STR30## l) H ##STR31## m) ##STR32## H n) ##STR33## H o) ##STR34## H p) ##STR35## H q) ##STR36## H r) ##STR37## H. ______________________________________

Claim 6

A compound which is: ##STR19## wherein R 1 and R 2 are selected from the following combinations of substituents: ______________________________________ R.sup.1 R.sup.2 ______________________________________ a) ##STR20## H b) ##STR21## H c) ##STR22## H d) ##STR23## H e) ##STR24## H f) ##STR25## H g) ##STR26## H h) ##STR27## H i) ##STR28## H j) H ##STR29## k) H ##STR30## l) H ##STR31## m) ##STR32## H n) ##STR33## H o) ##STR34## H p) ##STR35## H q) ##STR36## H r) ##STR37## H. ______________________________________

Claim 7

A compound which is: ##STR38## wherein R 1 and R 2 are selected from the following combinations of substituents: ______________________________________ R.sup.1 R.sup.2 ______________________________________ a) ##STR39## H b) H ##STR40## c) ##STR41## H d) H ##STR42## e) ##STR43## H f) H ##STR44## g) ##STR45## H h) ##STR46## H i) H ##STR47## j) ##STR48## H k) H ##STR49## l) ##STR50## H m) H ##STR51## n) ##STR52## H o) H ##STR53## p) ##STR54## H q) H ##STR55## r) ##STR56## H s) H ##STR57## t) ##STR58## H u) H ##STR59## v) ##STR60## H w) H ##STR61## x) ##STR62## H y) H ##STR63## z) ##STR64## H aa) ##STR65## H bb) ##STR66## H cc) ##STR67## H dd) ##STR68## H ee) ##STR69## H ff) ##STR70## H gg) ##STR71## H hh) H ##STR72## ii) ##STR73## H jj) ##STR74## H kk) H ##STR75## ______________________________________

Claim 8

A compound which is: ##STR38## wherein R 1 and R 2 are selected from the following combinations of substituents: ______________________________________ R.sup.1 R.sup.2 ______________________________________ a) ##STR39## H b) H ##STR40## c) ##STR41## H d) H ##STR42## e) ##STR43## H f) H ##STR44## g) ##STR45## H h) ##STR46## H i) H ##STR47## j) ##STR48## H k) H ##STR49## l) ##STR50## H m) H ##STR51## n) ##STR52## H o) H ##STR53## p) ##STR54## H q) H ##STR55## r) ##STR56## H s) H ##STR57## t) ##STR58## H u) H ##STR59## v) ##STR60## H w) H ##STR61## x) ##STR62## H y) H ##STR63## z) ##STR64## H aa) ##STR65## H bb) ##STR66## H cc) ##STR67## H dd) ##STR68## H ee) ##STR69## H ff) ##STR70## H gg) ##STR71## H hh) H ##STR72## ii) ##STR73## H jj) ##STR74## H kk) H ##STR75## ______________________________________

Claim 9

The compound of claim 1 which is: 42-O-phenyl rapamycin.

Claim 10

A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of the compound of claim 1.

Claim 11

A method for the treatment of immunoregulatory disorders or diseases comprising the administration to a mammalian species in need of such treatment of an effective amount of the compound of claim 1.

Claim 12

A method for the treatment of resistance to transplantation comprising the administration to a mammalian species in need of such treatment of an effective amount of the compound of claim 1.

Claim 13

A method for the treatment of inflammatory comprising the administration to a mammalian species in need of such treatment of an effective amount of the compound of claim 1.

Claim 14

A method for the treatment of autoimmune diseases comprising the administration to a mammalian species in need of such treatment of an effective amount of the compound of claim 1.

Claim 15

A method for the treatment of fungal infections comprising the administration to a mammalian species in need of such treatment of an effective amount of the compound of claim 1.