US 5,208,241 A · N-heteroaryl, N-alkylheteroaryl, N-alkenylheteroaryl and N-alkynylheteroarylmacrolides having immunosuppressive activity

Abstract

N-Heteroaryl, N-alkylheteroaryl, N-alkenylheteroaryl and N-alkynylheteroaryl macrolides of the general structural Formula I: ##STR1## have been prepared from suitable precursors by amination, alkylation and/or arylation at C-3" and/or C-4" of the cyclohexyl ring. These macrolide immunosuppressants are useful in a mammalian host for the treatment of autoimmune diseases, infectious diseases and/or the prevention of rejection of foreign organ transplants. In addition, these macrolide immunosuppressants are useful in the topical treatment of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses. Also, these macrolides are useful in the treatment of reversible obstructive airways disease, particularly asthma. Furthermore, these macrolides are useful as hair revitalizing agents, especially in the treatment of male pattern alopecia or alopecia senilis.

A compound of Formula I:

##STR14## or a pharmaceutically acceptable salt thereof, wherein:
R.sup.1 is selected from:
(1) --NR.sup.6 R.sup.7,
(2) --NR.sup.6 COR.sup.7,
(3) --NR.sup.7 CO.sub.2 R.sup.6,
(4) --NR.sup.7 CO.sub.2 R.sup.6,
(5) --NR.sup.6 CO.sub.2 R.sup.7, and
(6) --NR.sup.6 CHR.sup.6 R.sup.7 ;
R.sup.6 is selected from
(1) heteroaryl, wherein heteroaryl is selected from the group consisting of:
##STR15## wherein Q is N(R.sup.8)--, --O--, or --S--;
(2) substituted heteroaryl, wherein heteroaryl is as defined above, and in which the substituents are X, Y and Z;
(3) heteroaryl-C.sub.1-10 alkyl, wherein heteroaryl is as defined above;
(4) substituted heteroaryl-C.sub.1-10 alkyl, wherein heteroaryl is as defined above and in which the heteroaryl group is substituted by X, Y and Z and the alkyl portion may be substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) oxo,
(c) C.sub.1-6 alkoxy,
(d) phenyl-C.sub.1-3 alkoxy,
(e) substituted phenyl-C.sub.1-3 alkoxy, in which the substituents on phenyl are X, Y and Z,
(f) --OCO--C.sub.1-6 alkyl,
(g) --NR.sup.8 R.sup.9, wherein R.sup.8 and R.sup.9 are independently selected from
(i) hydrogen,
(ii) C.sub.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.sub.1-6 alkoxy,
(d') --CO.sub.2 H,
(e') --CO.sub.2 --C.sub.1-6 alkyl,
(f') --C.sub.3-7 cycloalkyl, and
(g') --OR.sup.11,
(iii) C.sub.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.sub.1-6 alkoxy,
(d') --CO.sub.2 H,
(e') --CO.sub.2 --C.sub.1-6 alkyl,
(f') --C.sub.3-7 cycloalkyl, and
(g') --OR.sup.11,
(iv) or where R.sup.8 and R.sup.9 and the N to which they are attached may form a heterocyclic ring selected from the group consisting of:
morpholine, thiomorpholine, piperidine, and piperizine,
(h) --NR.sup.8 CO--C.sub.1-6 alkyl-R.sup.9, wherein R.sup.9 is as defined above,
(i) --NR.sup.8 CO.sub.2 --C.sub.1-6 alkyl-R.sup.9,
(j) --NR.sup.8 CONR.sup.8 R.sup.9,
(k) --OCONR.sup.8 R.sup.9,
(l) --COOR.sup.8,
(m) --CHO,
(n) phenyl,
(o) substituted phenyl in which the substituents are X, Y and Z,
(p) --S(O).sub.p --C.sub.1-6 alkyl, and
(q) --OR.sup.11 ;
(5) heteroaryl-C.sub.1-10 alkyl wherein heteroaryl is as defined above and one or more of the alkyl carbons is replaced by a group selected from:
--NR.sup.8 --, --O--, --S(O).sub.p --, --CO.sub.2 --, --O.sub.2 C--, --CONR.sup.8 --, --NR.sup.8 CO--, --NR.sup.8 CONR.sup.9 --;
(6) substituted heteroaryl-C.sub.1-10 alkyl wherein heteroaryl is as defined above and one or more of the alkyl carbons is replaced by a group selected from:
--NR.sup.8 --, --O--, --S(O).sub.p --, --CO.sub.2 --, --O.sub.2 C--, --CONR.sup.8 --, --NR.sup.8 CO--, and --NR.sup.8 CONR.sup.9 --, the heteroaryl group is substituted with X, Y, and Z, and the alkyl group may be substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) oxo,
(c) C.sub.1-6 alkoxy,
(d) phenyl-C.sub.1-3 alkoxy,
(e) substituted phenyl-C.sub.1-3 alkoxy, in which the substituents on phenyl are X, Y and Z,
(f) --OCO--C.sub.1-6 alkyl,
(g) --NR.sup.8 R.sup.9, wherein R.sup.8 and R.sup.9 are as defined above,
(h) --NR.sup.8 CO--C.sub.1-6 alkyl, wherein R.sup.8 is as defined above,
(i) --NR.sup.8 CO.sub.2 --C.sub.1-6 alkyl,
(j) --NR.sup.8 CONR.sup.8 R.sup.9,
(k) --OCONR.sup.8 R.sup.9,
(l) --COOR.sup.8,
(m) --CHO,
(n) phenyl,
(o) substituted phenyl in which the substituents are X, Y and Z,
(p) --S(O).sub.p --C.sub.1-6 alkyl, and
(q) --OR.sup.11 ;
(7) heteroaryl-C.sub.3-10 alkenyl wherein heteroaryl is as defined above and alkenyl contains one to four double bonds;
(8) heteroaryl-C.sub.3-10 alkenyl wherein heteroaryl is as defined above and alkenyl contains one to four double bonds and wherein one or more of the alkyl carbons is replaced by a group selected from:
--NR.sup.8 --, --O--, --S(O).sub.p --, --CO.sub.2 --, --O.sub.2 C--, --CONR.sup.8 --, --NR.sup.8 CO--, and --NR.sup.8 CONR.sup.9 --;
(9) substituted heteroaryl-C.sub.3-10 alkenyl wherein heteroaryl is as defined above and alkenyl contains one to four double bonds and wherein one or more of the alkyl carbons may be replaced by a group selected from:
--NR.sup.8 --, --O--, --S(O).sub.p --, --CO.sub.2 --, --O.sub.2 C--, --CONR.sup.8 --, --NR.sup.8 CO--, --NR.sup.8 CONR.sup.9, --NR.sup.8 CONR.sup.9, the heteroaryl group is substituted with X, Y, and Z, and the alkyl group may be substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) oxo,
(c) C.sub.1-6 alkoxy,
(d) phenyl-C.sub.1-3 alkoxy,
(e) substituted phenyl-C.sub.1-3 alkoxy, in which the substituents on phenyl are X, Y and Z,
(f) --OCO--C.sub.1-6 alkyl,
(g) --NR.sup.8 R.sup.9, wherein R.sup.8 and R.sup.9 as defined above,
(h) --NR.sup.8 CO--C.sub.1-6 alkyl, wherein R.sup.8 is as defined above,
(i) --NR.sup.8 CO.sub.2 --C.sub.1-6 alkyl,
(j) --NR.sup.8 CONR.sup.9,
(k) --OCONR.sup.8 R.sup.9,
(l) --COOR.sup.8,
(m) --CHO,
(n) phenyl,
(o) substituted phenyl in which the substituents are X, Y and Z,
(p) --S(O).sub.p --C.sub.1-6 alkyl, and
(q) --OR.sup.11 ;
R.sup.2 is independently selected from:
(1) the definitions of R.sup.1 ;
(2) hydroxy;
(3) phenyloxy;
(4) substituted phenyloxy in which the substituents are X, Y and Z;
(5) 1- or 2-naphthyloxy;
(6) substituted 1- or 2-naphthyloxy in which the substituents are X, Y and Z;
(7) biphenyloxy;
(8) substituted biphenyloxy in which the substituents are X, Y and Z;
(9) C.sub.1-10 alkoxy;
(10) substituted-C.sub.1-10 alkoxy in which one or more substituent(s) is(are) selected from:
(a) hydroxy,
(b) oxo,
(c) C.sub.1-6 alkoxy,
(d) phenyl-C.sub.1-3 alkoxy,
(e) substituted phenyl-C.sub.1-3 alkoxy, in which the substituents on phenyl are X, Y and Z,
(f) --OCO--C.sub.1-6 alkyl,
(g) --NR.sup.8 R.sup.9, wherein R.sup.8 and R.sup.9 are as defined above
(h) --NR.sup.6 CO--C.sub.1-6 alkyl, wherein R.sup.6 is as defined above,
(i) --COOR.sup.6, wherein R.sup.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.sup.11, and
(r) --S(O).sub.p --C.sub.1-6 alkyl;
(11) C.sub.3-10 alkenyloxy;
(12) substituted C.sub.3-10 alkenyloxy in which one or more substituent(s) is(are) selected from:
(a) hydroxy,
(b) oxo,
(c) C.sub.1-6 alkoxy,
(d) phenyl-C.sub.1-3 alkoxy,
(e) substituted phenyl-C.sub.1-3 alkoxy, in which the substituents on phenyl are X, Y and Z,
(f) --OCO--C.sub.1-6 alkyl,
(g) --NR.sup.8 R.sup.9, wherein R.sup.8 and R.sup.9 are as defined above
(h) --NR.sup.8 CO--C.sub.1-6 alkyl, wherein R.sup.8 is as defined above,
(i) --COOR.sup.8, wherein R.sup.8 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.sup.11, and
(r) --S(O).sub.p --C.sub.1-6 alkyl;
(13) C.sub.3-10 alkynyloxy;
(14) substituted C.sub.3-10 alkynyloxy in which one or more substituent(s) is(are) selected from:
(a) hydroxy,
(b) oxo,
(c) C.sub.1-6 alkoxy,
(d) phenyl-C.sub.1-3 alkoxy,
(e) substituted phenyl-C.sub.1-3 alkoxy, in which the substituents on phenyl are X, Y and Z,
(f) --OCO--C.sub.1-6 alkyl,
(g) --NR.sup.8 R.sup.9, wherein R.sup.8 and R.sup.9 are as defined above,
(h) --NR.sup.8 CO--C.sub.1-6 alkyl, wherein R.sup.8 is as defined above,
(i) --COOR.sup.8, wherein R.sup.8 is as defined above,
(j) --CHO,
(k) phenyl,
(l) substituted phenyl in which the substitutents 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.sup.11 ;
and
(15) --OR.sup.11 ;
R.sup.7 is selected from
(1) hydrogen, and
(2) C.sub.1-10 alkyl, unsubstituted or substituted with, one or more of the substitutent(s) selected from:
(a) hydroxy,
(b) oxo,
(c) C.sub.1-6 alkoxy,
(d) phenyl-C.sub.1-3 alkoxy,
(e) substituted phenyl-C.sub.1-3 alkoxy, in which the substituents on phenyl are X, Y and Z,
(f) --OCO--C.sub.1-6 alkyl, and
(g) --NR.sup.8 R.sup.9, wherein R.sup.8 and R.sup.9 are as defined above;
R.sup.3 is hydrogen, hydroxy, --OR.sup.11, or C.sub.1-6 alkoxy;
R.sup.4 is hydrogen, or R.sup.3 and R.sup.4 taken together form a double bond;
R.sup.5 is
1) methyl,
2) ethyl,
3) propyl, or
4) allyl;
R.sup.10 is hydrogen, hydroxy, --OR.sup.11 or fluoro;
R.sup.11 is selected from:
(a) --PO(OH)O.sup.- M.sup.+, wherein M.sup.+ is a positively charged inorganic or organic counterion selected from the group consisting of:
ammonium, sodium, lithium, potassium, calcium, magnesium, dicyclohexylamine, N-methyl-D-glucamine, arginine and lysine,
(b) --SO.sub.3 .sup.- M.sup.+,
(c) --CO(CH.sub.2).sub.q CO.sub.2.sup.- M.sup.+, wherein q is 1 to 3, and
(d) --CO--C.sub.1-6 alkyl-NR.sup.8 R.sup.9, wherein R.sup.8 and R.sup.9 are as defined above and the alkyl is unsubstituted or substituted with one or more substituents selected from:
(i) hydroxy,
(ii) C.sub.1-6 alkoxy,
(iii) --NR.sup.16 R.sup.17 , wherein R.sup.16 and R.sup.17 are independently selected from:
(a') hydrogen, and
(b') C.sub.1-6 alkyl,
(iv) --COOR.sup.6, wherein R.sup.6 is as defined above,
(v) phenyl,
(iv) substituted phenyl in which the substituents are X, Y and Z,
(vii) heteroaryl,
(viii) --SH, and
(ix) --S--C.sub.1-6 alkyl;
W is 0 or (H,OH);
X, Y and Z independently are selected from:
(1) hydrogen,
(2) C.sub.1-7 alkyl,
(3) C.sub.2-6 alkenyl,
(4) halogen,
(5) --(CH.sub.2).sub.m --NR.sup.8 R.sup.9, wherein R.sup.8 and R.sup.9 are as defined above, and m is 0, 1 or 2,
(6) --CN,
(7) --CHO,
(8) --CF.sub.3,
(9) --SR.sup.12, wherein R.sup.12 is hydrogen, C.sub.1-6 alkyl, trifluoromethyl, or phenyl,
(10) --SOR.sup.12, wherein R.sup.12 is as defined above,
(11) --SO.sub.2 R.sup.12, wherein R.sup.12 is as defined above,
(12) --CONR.sup.8 R.sup.9, wherein R.sup.8 and R.sup.9 are as defined above,
(13) R.sup.13 O(CH.sub.2).sub.m -- wherein R.sup.13 is hydrogen, C.sub.1-3 alkyl, hydroxy-C.sub.2-3 alkyl, phenyl, R.sup.11 or naphthyl and m is as defined above,
(14) --CH(OR.sup.14)(OR.sup.15), wherein R.sup.14 and R.sup.15 are C.sub.1-3 alkyl or taken together form an ethyl or propyl bridge, ##STR16## wherein R.sup.13 and m are as defined above, ##STR17## wherein R.sup.13 and m are as defined above, and (17) --OR.sup.11 ;
or any two of X, Y and Z may be joined to form a saturated ring dioxolanyl or dioxanyl;
and
n is 1 or 2.

214 more elements

N-heteroaryl, N-alkylheteroaryl, N-alkenylheteroaryl and N-alkynylheteroarylmacrolides having immunosuppressive activity

Life of this patent

N-heteroaryl, N-alkylheteroaryl, N-alkenylheteroaryl and N-alkynylheteroarylmacrolides having immunosuppressive activity

Life of this patent

Abstract

Claims32