US 5,208,228 A · Aminomacrolides and derivatives having immunosuppressive activity

Abstract

Aminomacrolides of the general structural Formula I: ##STR1## have been prepared from suitable precursors by incorporation of a nitrogen substituent 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.

A compound of formula I:

##STR16## or a pharmaceutically acceptable salt thereof, wherein:
R is
1) methyl,
2) ethyl,
3) propyl, or
4) allyl;
R.sup.1 and R.sup.2 are, independently,
1) --N.sub.3 ;
2) --NHCN;
3) --NR.sup.5 R.sup.6, wherein R.sup.5 and R.sup.6 are independently,
a) hydrogen,
b) C.sub.1 -C.sub.12 alkyl, unsubstituted or substituted with R.sup.7 and R.sup.8, wherein R.sup.7 and R.sup.8 are independently selected from the group consisting of:
i) hydrogen,
ii) --OH,
iii) C.sub.1 -C.sub.6 alkoxy,
iv) --O--CO--C.sub.1 -C.sub.6 alkyl,
v) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are independently, hydrogen, or C.sub.1 -C.sub.6 alkyl, unsubstituted or substituted with phenyl
vi) --CONR.sup.9 R.sup.10,
vii) --CO.sub.2 H,
viii) --CO--O--C.sub.1 -C.sub.6 alkyl,
ix) --S--C.sub.1 -C.sub.6 alkyl,
x) --SO--C.sub.1 -C.sub.6 alkyl,
xi) --SO.sub.2 --C.sub.1 -C.sub.6 alkyl,
xii) halo,
xiii) --C.sub.3 -C.sub.7 -cycloalkyl,
xiv) phenyl, unsubstituted or substituted with M, W and Y, wherein M, W and Y are independently selected from the group consisting of:
A) hydrogen,
B) C.sub.1 -C.sub.6 alkyl,
C) --OH,
D) C.sub.1 -C.sub.6 alkoxy,
E) --O--CO--C.sub.1 -C.sub.6 alkyl,
F) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,
G) --CONR.sup.9 R.sup.10,
H) --CO.sub.2 H,
I) --CO--O--C.sub.1 -C.sub.6 alkyl,
J) halo,
K) --NO.sub.2,
L) --CN, and
N) --CF.sub.3,
xv) naphthyl, unsubstituted or substituted with M, W and Y, wherein M, W and Y are as defined above, and
xvi) --CF.sub.3,
c) C.sub.3 -C.sub.12 alkenyl, unsubstituted or substituted with R.sup.7 and R.sup.8, wherein R.sup.7 and R.sup.8 are as defined above,
d) C.sub.3 -C.sub.7 cycloalkyl, unsubstituted or substituted with R.sup.7 and R.sup.8, wherein R.sup.7 and R.sup.8 are as defined above,
e) phenyl, unsubstituted or substituted with M, W and Y, wherein M, W and Y are as defined above,
f) naphthyl, unsubstituted or substituted with M, W and Y, wherein M, W and Y are as defined above,
g) --SO.sub.2 -phenyl, wherein phenyl is unsubstituted or substituted with with M, W and Y, wherein M, W and Y are as defined above,
h) --SO.sub.2 --C.sub.1 -C.sub.6 alkyl,
i) or where R.sup.5 and R.sup.6 and the N to which they are attached may form an unsubstituted or substituted 3- to 7-membered heterocyclic ring which may include one or two additional heteroatoms independently selected from the group consisting of O, S, or NR.sup.9, wherein R.sup.9 is as defined above, and where the substituent(s), attached to the carbon atom(s) in the heterocyclic ring is/are independently selected form the group consisting of:
i) hydrogen,
ii) --OH,
iii) C.sub.1 -C.sub.6 alkoxy,
iv) --O--CO--C.sub.1 -C.sub.6 alkyl,
v) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are independently, hydrogen, or C.sub.1 -C.sub.6 alkyl, unsubstituted or substituted with phenyl,
vi) --CONR.sup.9 R.sup.10,
vii) --CO.sub.2 H,
viii) --CO--O--C.sub.1 -C.sub.6 alkyl,
ix) --SH,
x) halo,
xi) phenyl, unsubstituted or substituted with M, W and Y, wherein M, W and Y are as defined above,
xii) naphthyl, unsubstituted or substituted with M, W and Y, wherein M, W and Y are as defined above, and
xiii) --CF.sub.3 ;
4) --N(R.sup.5)CO--O--R.sup.11, wherein R.sup.5 is as defined above and R.sup.11 is C.sub.1 -C.sub.12 alkyl, unsubstituted or substituted with R.sup.7 and R.sup.8, wherein R.sup.7 and R.sup.8 are as defined above;
5) --N(R.sup.5)CO--R.sup.12, wherein R.sup.5 is as defined above and R.sup.12 is
a) hydrogen,
b) C.sub.1 -C.sub.12 alkyl, unsubstituted or substituted with R.sup.7 and R.sup.8, wherein R.sup.7 and R.sup.8 are as defined above,
c) C.sub.3 -C.sub.12 cycloalkyl, unsubstituted or substituted with R.sup.7 and R.sup.8, wherein R.sup.7 and R.sup.8 are as defined above,
d) phenyl, unsubstituted or substituted with M, W and Y, wherein M, W and Y are as defined above,
e) naphthyl, unsubstituted or substituted with M, W and Y, wherein M, W and Y are as defined above, or
f) where R.sup.5 and R.sup.12 and the --NCO-- to which they are attached may form an unsubstituted or substituted 5- to 7-membered heterocyclic ring which may include one or two additional heteroatoms independently selected from the group consisting of O, S, or NR.sup.9, wherein R.sup.9 is as defined above;
6) --N(R.sup.13)COCH(R.sup.17)NR.sup.5 R.sup.6 wherein R.sup.5 and R.sup.6 are as defined above, R.sup.13 is selected from the definitions of R.sup.5, and R.sup.17 is:
a) hydrogen,
b) C.sub.1 -C.sub.4 alkyl, unsubstituted or substituted with R.sup.18, wherein R.sup.18 is selected from the group consisting of:
i) --OH,
ii) C.sub.1 -C.sub.6 alkoxy,
iii) --O--CO--C.sub.1 -C.sub.6 alkyl,
iv) --SH,
v) --S--C.sub.1 -C.sub.6 alkyl,
vi) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,
vii) --CO.sub.2 H,
viii) --CONH.sub.2,
ix) imidazolyl,
x) indolyl,
xi) phenyl, and
xii) p-hydroxyphenyl, or
c) phenyl;
7) --N(R.sup.13)CO(CH.sub.2).sub.m NR.sup.5 R.sup.6, wherein m is 0 or 2-6, R.sup.5 and R.sup.6 are as defined above, and R.sup.13 is selected from the definitions of R.sup.5, or where R.sup.13 and R.sup.5 and the --NCO(CH.sub.2).sub.m N-- to which they are attached may form an unsubstituted or substituted 5- to 7-membered heterocyclic ring;
8) --N.dbd.C(R.sup.13)--NR.sup.5 R.sup.6, wherein R.sup.5 and R.sup.6 are as defined above, and R.sup.13 is selected from the definitions of R.sup.5, and wherein if either R.sup.5 or R.sup.6 are hydrogen, the tautomeric structure --NHC(R.sup.13).dbd.NR.sup.5or6 is also possible;
9) --N(R.sup.14).sub.3.sup.+ A.sup.-, wherein R.sup.14 is C.sub.1 -C.sub.6 alkyl, unsubstituted or substituted with phenyl or naphthyl, and wherein A.sup.- is a counterion;
10) ##STR17## wherein R.sup.15 and R.sup.16 are independently, a) hydrogen,
b) phenyl, unsubstituted or substituted with M, W and Y, wherein M, W and Y are as defined above,
c) naphthyl, unsubstituted or substituted with M, W and Y, wherein M, W and Y are as defined above,
d) --CN,
e) --CF.sub.3,
f) --CO--C.sub.1 -C.sub.6 alkyl, or
g) --CO--O--C.sub.1 -C.sub.6 alkyl;
11) hydroxy or C.sub.1 -C.sub.6 alkoxy, with the proviso that R.sup.1 and R.sup.2 are not simultaneously hydroxy, C.sub.1 -C.sub.6 alkoxy, or combinations thereof;
or
12) where R.sup.1 and R.sup.2 may both be connected to form a 3- to 7-membered heterocyclic ring of the form:
##STR18## wherein p is zero or one, R.sup.5 is as defined above, and Z is a) --CO--,
b) --CS--,
c) --CO--C.sub.1 -alkyl,
d) --CS--C.sub.1 -alkyl, or
e) C.sub.1 -C.sub.2 -alkyl, wherein the alkyl may be unsubstituted or substituted with one or more of the following:
i) --OH,
ii) C.sub.1 -C.sub.6 alkyl,
iii) C.sub.1 -C.sub.6 alkoxy,
iv) --O--CO--C.sub.1 -C.sub.6 alkyl,
v) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,
vi) --CONR.sup.9 R.sup.10,
vii) --CO.sub.2 H,
viii) --CO--O--C.sub.1 -C.sub.6 alkyl,
ix) --S--C.sub.1 -C.sub.6 alkyl,
x) --SO--C.sub.1 -C.sub.6 alkyl,
xi) --SO.sub.2 --C.sub.1 -C.sub.6 alkyl,
xii) halo,
xiii) phenyl, unsubstituted or substituted with M, W and Y, wherein M, W and Y are as defined above, or
xiv) naphthyl unsubstituted or substituted with M, W and Y, wherein M, W and Y are as defined above;
R.sup.3 is hydrogen, hydroxy, or C.sub.1 -C.sub.6 alkoxyl;
R.sup.4 is hydrogen, or R.sup.3 and R.sup.4 taken together form a double bond;
X is 0 or (H,OH);
and
n is 1 or 2.

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Aminomacrolides and derivatives having immunosuppressive activity

Life of this patent

Aminomacrolides and derivatives having immunosuppressive activity

Life of this patent

Abstract

Claims27