The present invention relates to novel cinnamide compounds that are useful for treating inflammatory and immune diseases, to pharmaceutical compositions comprising these compounds, and to methods of inhibiting inflammation or suppressing immune response in a mammal.
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0. 28. A compound of formula I:
##STR00031##
or a pharmaceutically-acceptable salt or pharmaceutically-acceptable prodrug of a compound of formula I,
wherein r1, r2, r4, and r5 are each independently selected from
a. hydrogen,
b. halogen,
c. alkyl,
d. haloalkyl,
e. alkoxy,
f. cyano,
g. nitro, and
h. carboxaldehyde,
where r3 is a “cis-cinnamide” or “trans-cinnamide”, defined as
##STR00032##
where r8 and r9 are each independently selected from
a. hydrogen,
b. alkyl,
c. carboxyalkyl,
d. alkylaminocarbonylalkyl, and
e. dialkylaminocarbonylalkyl,
r10 and r11 are taken together with the N to form an unsubstituted heterocyclyl group, or a substituted heterocyclyl group, where the substituted heterocyclyl group is substituted by one or more than one substituent, where the substituents are each independently selected from
1) alkyl,
2) alkoxy,
3) alkoxyalkyl,
4) cycloalkyl,
5) aryl,
6) heterocyclyl,
7) heterocyclylcarbonyl,
8) heterocyclylalkylaminocarbonyl,
9) hydroxy,
10) hydroxyalkyl,
11) hydroxyalkoxyalkyl,
12) carboxy,
13) carboxycarbonyl,
14) carboxaldehyde,
15) alkoxycarbonyl,
16) arylalkoxycarbonyl,
17) aminoalkanoyl,
18) carboxamido,
19) alkoxycarbonylalkyl,
20) carboxamidoalkyl,
21) alkanoyl,
22) hydroxyalkanoyl,
23) alkanoyloxy,
24) alkanoylamino,
25) alkanoyloxyalkyl, and
26) alkylsulfonyl,
and Ar is an unsubstituted aryl group, an unsubstituted heteroaryl group, a substituted aryl group, or a substituted heteroaryl group, where the substituted aryl group and the substituted heteroaryl group are substituted by one or more than one substituent, where the substituents are each independently selected from
a. halogen,
b. alkyl,
c. aryl,
d. haloalkyl,
e. hydroxy,
f. alkoxy,
g. alkoxycarbonyl,
h. alkoxyalkoxy,
i. hydroxyalkyl,
j. aminoalkyl,
k. alkyl(alkoxycarbonylalkyl)aminoalkyl,
l. unsubstituted heterocyclylalkyl,
m. substituted heterocyclylalkyl,
n. carboxaldehyde,
o. carboxaldehyde hydrazone,
p. carboxamide,
q. alkoxycarbonylalkyl,
r. hydroxycarbonylalkyl(carboxyalkyl),
s. cyano,
t. amino,
u. heterocyclylalkylamino, and
v. “trans-cinnamide”.
0. 23. A compound of formula I:
##STR00027##
or a pharmaceutically-acceptable salt or pharmaceutically-acceptable prodrug of a compound of formula I,
wherein r1, r2, r4, and r5 are independently selected from
a. hydrogen,
b. halogen,
c. alkyl,
d. haloalkyl,
e. alkoxy,
f. cyano,
g. nitro, and
h. carboxaldehyde,
where r3 is a “cis-cinnamide” or “trans-cinnamide”, defined as
##STR00028##
where r8 and r9 are each independently selected from
a. hydrogen,
b. alkyl,
c. carboxyalkyl,
d. alkylaminocarbonylalkyl, and
e. dialkylaminocarbonylalkyl,
r10 and r11 are each independently selected from
a. hydrogen,
b. alkyl,
c. cycloalkyl,
d. alkoxycarbonylalkyl,
e. hydroxyalkyl, and
f. heterocyclylalkyl,
or r10 and r11 are taken together with the N to form an unsubstituted heterocyclyl group, or a substituted heterocyclyl group, where the substituted heterocyclyl group is substituted by one or more than one substituent, where the substituents are each independently selected from
1) alkyl,
2) alkoxy,
3) alkoxyalkyl,
4) cycloalkyl,
5) aryl,
6) heterocyclyl,
7) heterocyclylcarbonyl,
8) heterocyclylalkylaminocarbonyl,
9) hydroxy,
10) hydroxyalkyl,
11) hydroxyalkoxyalkyl,
12) carboxy,
13) carboxycarbonyl,
14) carboxaldehyde,
15) alkoxycarbonyl,
16) arylalkoxycarbonyl,
17) aminoalkanoyl,
18) carboxamido,
19) alkoxycarbonylalkyl,
20) carboxamidoalkyl,
21) alkanoyl,
22) hydroxyalkanoyl,
23) alkanoyloxy,
24) alkanoylamino,
25) alkanoyloxyalkyl, and
26) alkylsulfonyl,
and Ar is an unsubstituted heteroaryl group, a substituted aryl group, or a substituted heteroaryl group, where the substituted aryl group and the substituted heteroaryl group are substituted by one or more than one substituent, where the substituents are each independently selected from
a. halogen,
b. alkyl,
c. aryl,
d. haloalkyl,
e. hydroxy,
f. alkoxy,
g. alkoxycarbonyl,
h. alkoxyalkoxy,
i. hydroxyalkyl,
j. aminoalkyl,
k. alkyl(alkoxycarbonylalkyl)aminoalkyl,
l. unsubstituted heterocyclylalkyl,
m. substituted heterocyclylalkyl,
n. carboxaldehyde,
o. carboxaldehyde hydrazone,
p. carboxamide,
q. alkoxycarbonylalkyl,
r. hydroxycarbonylalkyl(carboxyalkyl),
s. cyano,
t. amino,
u. heterocyclylalkylamino, and
v. “trans-cinnamide”,
wherein when Ar is pyridyl, Ar is substituted by two or more than two substituents.
0. 26. A compound of formula I:
##STR00029##
or a pharmaceutically-acceptable salt or pharmaceutically-acceptable prodrug of a compound of formula I,
wherein r1, r2, r4, and r5 are independently selected from
a. hydrogen,
b. halogen,
c. alkyl,
d. haloalkyl,
e. alkoxy,
f. cyano,
g. nitro, and
h. carboxaldehyde,
subject to the proviso that one or more than one of r1, r2, r4, and r5 are other than hydrogen,
where r3 is a “cis-cinnamide” or “trans-cinnamide”, defined as
##STR00030##
where r8 and r9 are each independently selected from
a. hydrogen,
b. alkyl,
c. carboxyalkyl,
d. alkylaminocarbonylalkyl, and
e. dialkylaminocarbonylalkyl,
r10 and r11 are each independently selected from
a. hydrogen,
b. alkyl,
c. cycloalkyl,
d. alkoxycarbonylalkyl,
e. hydroxyalkyl, and
f. heterocyclylalkyl,
or r10 and r11 are taken together with the N to form an unsubstituted heterocyclyl group, or a substituted heterocyclyl group, where the substituted heterocyclyl group is substituted by one or more than one substituent, where the substituents are each independently selected from
1) alkyl,
2) alkoxy,
3) alkoxyalkyl,
4) cycloalkyl,
5) aryl,
6) heterocyclyl,
7) heterocyclylcarbonyl,
8) heterocyclylalkylaminocarbonyl,
9) hydroxy,
10) hydroxyalkyl,
11) hydroxyalkoxyalkyl,
12) carboxy,
13) carboxycarbonyl,
14) carboxaldehyde,
15) alkoxycarbonyl,
16) arylalkoxycarbonyl,
17) aminoalkanoyl,
18) carboxamido,
19) alkoxycarbonylalkyl,
20) carboxamidoalkyl,
21) alkanoyl,
22) hydroxyalkanoyl,
23) alkanoyloxy,
24) alkanoylamino,
25) alkanoyloxyalkyl, and
26) alkylsulfonyl,
and Ar is an unsubstituted aryl group, an unsubstituted heteroaryl group, a substituted aryl group, or a substituted heteroaryl group, where the substituted aryl group and the substituted heteroaryl group are substituted by one or more than one substituent, where the substituents are each independently selected from
a. halogen,
b. alkyl,
c. aryl,
d. haloalkyl,
e. hydroxy,
f. alkoxy,
g. alkoxycarbonyl,
h. alkoxyalkoxy,
i. hydroxyalkyl,
j. aminoalkyl,
k. alkyl(alkoxycarbonylalkyl)aminoalkyl,
l. unsubstituted heterocyclylalkyl,
m. substituted heterocyclylalkyl,
n. carboxaldehyde,
o. carboxaldehyde hydrazone,
p. carboxamide,
q. alkoxycarbonylalkyl,
r. hydroxycarbonylalkyl(carboxyalkyl),
s. cyano,
t. amino,
u. heterocyclylalkylamino, and
v. “trans-cinnamide”.
0. 21. A compound of formula I:
##STR00023##
or a pharmaceutically-acceptable salt or pharmaceutically-acceptable prodrug of a compound of formula I,
wherein r1, r2, r3, r4, and r5 are independently selected from
a. hydrogen,
b. halogen,
c. alkyl,
d. haloalkyl,
e. alkoxy,
f. cyano,
g. nitro, and
h. carboxaldehyde,
with the proviso that at least one of r1 and r3 is a “cis-cinnamide” or a “trans-cinnamide”, defined as
##STR00024##
where r8 and r9 are each independently selected from
a. hydrogen,
b. alkyl,
c. carboxyalkyl,
d. alkylaminocarbonylalkyl, and
e. dialkylaminocarbonylalkyl,
r10 and r11 are each independently selected from
a. hydrogen,
b. alkyl,
c. cycloalkyl,
d. alkoxycarbonylalkyl,
e. hydroxyalkyl, and
f. heterocyclylalkyl,
or r10 and r11 are taken together with the N to form an unsubstituted heterocyclyl group, or a substituted heterocyclyl group, where the substituted heterocyclyl group is substituted by one or more than one substituent, where the substituents are each independently selected from
1) alkyl,
2) alkoxy,
3) alkoxyalkyl,
4) cycloalkyl,
5) aryl,
6) heterocyclyl,
7) heterocyclylcarbonyl,
8) heterocyclylalkylaminocarbonyl,
9) hydroxy,
10) hydroxyalkyl,
11) hydroxyalkoxyalkyl,
12) carboxy,
13) carboxycarbonyl,
14) carboxaldehyde,
15) alkoxycarbonyl,
16) arylalkoxycarbonyl,
17) aminoalkanoyl,
18) carboxamido,
19) alkoxycarbonylalkyl,
20) carboxamidoalkyl,
21) alkanoyl,
22) hydroxyalkanoyl,
23) alkanoyloxy,
24) alkanoylamino,
25) alkanoyloxyalkyl, and
26) alkylsulfonyl,
and Ar is an unsubstituted aryl group, an unsubstituted heteroaryl group, a substituted aryl group, or a substituted heteroaryl group, where the substituted aryl group and the substituted heteroaryl group are substituted by one or more than one substituent, where the substituents are each independently selected from
a. halogen,
b. alkyl,
c. aryl,
d. haloalkyl,
e. hydroxy,
f. alkoxy,
g. alkoxycarbonyl,
h. alkoxyalkoxy,
i. hydroxyalkyl,
j. aminoalkyl,
k. alkyl(alkoxycarbonylalkyl)aminoalkyl,
l. unsubstituted heterocyclylalkyl,
m. substituted heterocyclylalkyl,
n. carboxaldehyde,
o. carboxaldehyde hydrazone,
p. carboxamide,
q. alkoxycarbonylalkyl,
r. hydroxycarbonylalkyl(carboxyalkyl),
s. cyano,
t. amino,
u. heterocyclylalkylamino, and
v. “trans-cinnamide”,
subject to the proviso that when r3 is a “cis-cinnamide” or a “trans-cinnamide,” as defined above, one or more than one of the following conditions is fulfilled:
(A) r1, as defined above, is other than hydrogen;
(B) r8 and r9 are both hydrogen and Ar is not pyridyl; and
(C) r10 and r11 are taken together with N to form a substituted or unsubstituted heterocyclyl group, as defined above.
0. 22. A compound of formula I:
##STR00025##
or a pharmaceutically-acceptable salt or pharmaceutically-acceptable prodrug of a compound of formula I,
wherein r1, r2, r3, r4, and r5 are independently selected from
a. hydrogen,
b. halogen,
c. alkyl,
d. haloalkyl,
e. alkoxy,
f. cyano,
g. nitro, and
h. carboxaldehyde,
with the proviso that at least one of r1 and r3 is a “cis-cinnamide” or a “trans-cinnamide”, defined as
##STR00026##
where r8 and r9 are each independently selected from
a. hydrogen,
b. alkyl,
c. carboxyalkyl,
d. alkylaminocarbonylalkyl, and
e. dialkylaminocarbonylalkyl,
r10 and r11 are each independently selected from
a. hydrogen,
b. alkyl,
c. cycloalkyl,
d. alkoxycarbonylalkyl,
e. hydroxyalkyl, and
f. heterocyclylalkyl,
or r10 and r11 are taken together with the N to form an unsubstituted heterocyclyl group, or a substituted heterocyclyl group, where the substituted heterocyclyl group is substituted by one or more than one substituent, where the substituents are each independently selected from
1) alkyl,
2) alkoxy,
3) alkoxyalkyl,
4) cycloalkyl,
5) aryl,
6) heterocyclyl,
7) heterocyclylcarbonyl,
8) heterocyclylalkylaminocarbonyl,
9) hydroxy,
10) hydroxyalkyl,
11) hydroxyalkoxyalkyl,
12) carboxy,
13) carboxycarbonyl,
14) carboxaldehyde,
15) alkoxycarbonyl,
16) arylalkoxycarbonyl,
17) aminoalkanoyl,
18) carboxamido,
19) alkoxycarbonylalkyl,
20) carboxamidoalkyl,
21) alkanoyl,
22) hydroxyalkanoyl,
23) alkanoyloxy,
24) alkanoylamino,
25) alkanoyloxyalkyl, and
26) alkylsulfonyl,
and Ar is an unsubstituted aryl group, an unsubstituted heteroaryl group, a substituted aryl group, or a substituted heteroaryl group, where the substituted aryl group and the substituted heteroaryl group are substituted by one or more than one substituent, where the substituents are each independently selected from
a. halogen,
b. alkyl,
c. aryl,
d. haloalkyl,
e. hydroxy,
f. alkoxy,
g. alkoxycarbonyl,
h. alkoxyalkoxy,
i. hydroxyalkyl,
j. aminoalkyl,
k. alkyl(alkoxycarbonylalkyl)aminoalkyl,
l. unsubstituted heterocyclylalkyl,
m. substituted heterocyclylalkyl,
n. carboxaldehyde,
o. carboxaldehyde hydrazone,
p. carboxamide,
q. alkoxycarbonylalkyl,
r. hydroxycarbonylalkyl(carboxyalkyl),
s. cyano,
t. amino,
u. heterocyclylalkylamino, and
v. “trans-cinnamide”,
subject to the proviso that one or more than one of the following conditions is fulfilled:
(A) Ar is an unsubstituted heteroaryl group, a substituted heteroaryl group, or a substituted aryl group;
(B) two or more than two of r1, r2, r3, r4, and r5, as defined above, are other than hydrogen; and
(C) r10 and r11 are taken together with N to form a substituted or unsubstituted heterocyclyl group, as defined above.
1. A compound of the formula I:
##STR00013##
e####
or a pharmaceutically-acceptable salt or pharmaceutically-acceptable prodrug thereof of a compound of formula I,
wherein r1, r2, r3, r4, and r5 are independently
selected from
a. hydrogen,
b. halogen,
c. alkyl,
d. haloalkyl,
e. alkoxy,
f. cyano,
g. nitro, and
h. carboxaldehyde, and
with the proviso that at least one of r1 or and r3 is a “cis-cinnamide” or a “trans-cinnamide”, defined as
##STR00014##
wherein r8 and r9 are each independently selected from
a. hydrogen, and
b. alkyl,
c. carboxy alkyl,
d. alkylaminocarbonyl alkyl, and
e. dialkylaminocarbonyl alkyl,
and r10 and r11 are each independently selected from
a. hydrogen,
b. alkyl,
c. cycloalkyl,
d. alkoxycarbonylalkyl,
e. hydroxyalkyl, and
f. heterocyclylalkyl,
or where NR10r11 is r10 and r11 are taken together with the N to form an unsubstituted heterocyclyl group, or a substituted heterocyclyl, where the substituted heterocyclyl group is substituted by one or more than one substituent, where the substituents are each independently selected from
1) alkyl,
2) alkoxy,
3) alkoxyalkyl,
4) cycloalkyl,
5) aryl,
6) heterocyclyl,
7) heterocyclylcarbonyl,
8) heterocyclylalkylaminocarbonyl,
9) hydroxy,
10) hydroxyalkyl,
11) hydroxyalkoxyalkyl,
12) carboxy,
13) carboxycarbonyl,
14) carboxaldehyde,
15) alkoxycarbonyl,
16) arylalkoxycarbonyl,
17) aminoalkanoyl,
18) carboxamido,
19) alkoxycarbonylalkyl,
20) carboxamidoalkyl,
21) alkanoyl,
22) hydroxyalkanoyl,
23) alkanoyloxy,
24) alkanoylamino,
25) alkanoyloxyalkyl, and
26) alkylsulfonyl,
and wherein Ar is an unsubstituted aryl group, an unsubstituted heteroaryl group, a substituted aryl group, or a substituted heteroaryl group, where the substituted aryl group and the substituted heteroaryl group are substituted by one or more than one substituent, where substitutions the substituents are each independently selected from
a. hydrogen,
b a. halogen,
c b. alkyl,
d c. aryl,
e d. haloalkyl,
f e. hydroxy,
g f. alkoxy,
h g. alkoxycarbonyl,
i h. alkoxyalkoxy,
j i. hydroxyalkyl,
k j. aminoalkyl,
l k. alkyl(alkoxycarbonylalkyl)aminoalkyl,
m l. unsubstituted heterocyclylalkyl,
n m. substituted heterocyclylalkyl,
o n. carboxaldehyde,
p o. carboxaldehyde hydrazone,
q p. carboxamide,
r q. alkoxycarbonyl alkyl,
s r. hydroxycarbonylalkyl (carboxyalkyl),
t s. cyano,
u t. amino,
v u. heterocyclylalkylamino, and
w v. “trans-cinnamide”,
or a pharmaceutically-acceptable salt or prodrug thereof.
subject to the proviso that when r3 is a “cis-cinnamide” or a “trans-cinnamide,” as defined above, one or more than one of the following conditions is fulfilled:
(A) Ar is an unsubstituted heteroaryl group, a substituted heteroaryl group, or a substituted aryl group wherein when Ar is a pyridyl group, Ar is substituted and Ar is not substituted by only one alkyl group;
(B) one or more than one of r1, r2, r4, and r5, as defined above, are other than hydrogen; and
(C) r10 and r11 are taken together with N to form a substituted or unsubstituted heterocyclyl group, as defined above.
2. A compound according to
3. A compound according to
4. A compound according to
7. A compound according to
8. A compound according to
9. A compound according to
10. A compound according to
11. A compound according to claim 8 4 wherein Ar is selected from substituted phenyl, 1,3-benzimidazol-2-one, 1,4-benzodioxane, 1,3-benzodioxole, 1-benzopyr-2-en-4-one, indole, isatin, 1,3-quinazolin-4-one, and quinoline.
12. A compound according to
13. A compound according to
14. A compound according to
15. A composition comprising a compound of according to
16. A method of inhibiting inflammation comprising the administration of a compound of
or a pharmaceutically-acceptable salt or pharmaceutically-acceptable prodrug of a compound of formula I,
wherein r1, r2, r3, r4, and r5 are independently selected from
a. hydrogen,
b. halogen,
c. alkyl,
d. haloalkyl,
e. alkoxy,
f. cyano,
g. nitro, and
h. carboxaldehyde,
with the proviso that at least one of r1 and r3 is a “cis-cinnamide” or a “trans-cinnamide”, defined as
##STR00016##
where r8 and r9 are each independently selected from
a. hydrogen,
b. alkyl,
c. carboxyalkyl,
d. alkylaminocarbonylalkyl, and
e. dialkylaminocarbonylalkyl,
r10 and r11 are each independently selected from
a. hydrogen,
b. alkyl,
c. cycloalkyl,
d. alkoxycarbonylalkyl,
e. hydroxyalkyl, and
f. heterocyclylalkyl,
or r10 and r11 are taken together with the N to form an unsubstituted heterocyclyl group, or a substituted heterocyclyl group, where the substituted heterocyclyl group is substituted by one or more than one substituent, where the substituents are each independently selected from
1) alkyl,
2) alkoxy,
3) alkoxyalkyl,
4) cycloalkyl,
5) aryl,
6) heterocyclyl,
7) heterocyclylcarbonyl,
8) heterocyclylalkylaminocarbonyl,
9) hydroxy,
10) hydroxyalkyl,
11) hydroxyalkoxyalkyl,
12) carboxy,
13) carboxycarbonyl,
14) carboxaldehyde,
15) alkoxycarbonyl,
16) arylalkoxycarbonyl,
17) aminoalkanoyl,
18) carboxamido,
19) alkoxycarbonylalkyl,
20) carboxamidoalkyl,
21) alkanoyl,
22) hydroxyalkanoyl,
23) alkanoyloxy,
24) alkanoylamino,
25) alkanoyloxyalkyl, and
26) alkylsulfonyl,
and Ar is an unsubstituted aryl group, an unsubstituted heteroaryl group, a substituted aryl group, or a substituted heteroaryl group, where the substituted aryl group and the substituted heteroaryl group are substituted by one or more than one substituent, where the substituents, are each independently selected from
a. halogen,
b. alkyl,
c. aryl,
d. haloalkyl,
e. hydroxy,
f. alkoxy,
g. alkoxycarbonyl,
h. alkoxyalkoxy,
i. hydroxyalkyl,
j. aminoalkyl,
k. alkyl(alkoxycarbonylalkyl)aminoalkyl,
l. unsubstituted heterocyclylalkyl,
m. substituted heterocyclylalkyl,
n. carboxaldehyde,
o. carboxaldehyde hydrazone,
p. carboxamide,
q. alkoxycarbonylalkyl,
r. hydroxycarbonylalkyl(carboxyalkyl),
s. cyano,
t. amino,
u. heterocyclylalkylamino, and
v. “trans-cinnamide”.
17. A method of inhibiting inflammation comprising the administration of a composition comprising a compound of
or a pharmaceutically-acceptable salt or pharmaceutically-acceptable prodrug of a compound of formula I,
wherein r1, r2, r3, r4, and r5 are independently selected from
a. hydrogen,
b. halogen,
c. alkyl,
d. haloalkyl,
e. alkoxy,
f. cyano,
g. nitro, and
h. carboxaldehyde,
with the proviso that at least one of r1 and r3 is a “cis-cinnamide” or a “trans-cinnamide”, defined as
##STR00018##
where r8 and r9 are each independently selected from
a. hydrogen,
b. alkyl,
c. carboxyalkyl,
d. alkylaminocarbonylalkyl, and
e. dialkylaminocarbonylalkyl,
r10 and r11 are each independently selected from
a. hydrogen,
b. alkyl,
c. cycloalkyl,
d. alkoxycarbonylalkyl,
e. hydroxyalkyl, and
f. heterocyclylalkyl,
or r10 and r11 are taken together with the N to form an unsubstituted heterocyclyl group, or a substituted heterocyclyl group, where the substituted heterocyclyl group is substituted by one or more than one substituent, where the substituents are each independently selected from
1) alkyl,
2) alkoxy,
3) alkoxyalkyl,
4) cycloalkyl,
5) aryl,
6) heterocyclyl,
7) heterocyclylcarbonyl,
8) heterocyclylalkylaminocarbonyl,
9) hydroxy,
10) hydroxyalkyl,
11) hydroxyalkoxyalkyl,
12) carboxy,
13) carboxycarbonyl,
14) carboxaldehyde,
15) alkoxycarbonyl,
16) arylalkoxycarbonyl,
17) aminoalkanoyl,
18) carboxamido,
19) alkoxycarbonylalkyl,
20) carboxamidoalkyl,
21) alkanoyl,
22) hydroxyalkanoyl,
23) alkanoyloxy,
24) alkanoylamino,
25) alkanoyloxyalkyl, and
26) alkylsulfonyl,
and Ar is an unsubstituted aryl group, an unsubstituted heteroaryl group, a substituted aryl group, or a substituted heteroaryl group, where the substituted aryl group and the substituted heteroaryl group are substituted by one or more than one substituent, where the substituents, are each independently selected from
a. halogen,
b. alkyl,
c. aryl,
d. haloalkyl,
e. hydroxy,
f. alkoxy,
g. alkoxycarbonyl,
h. alkoxyalkoxy,
i. hydroxyalkyl,
j. aminoalkyl,
k. alkyl(alkoxycarbonylalkyl)aminoalkyl,
l. unsubstituted heterocyclylalkyl,
m. substituted heterocyclylalkyl,
n. carboxaldehyde,
o. carboxaldehyde hydrazone,
p. carboxamide,
q. alkoxycarbonylalkyl,
r. hydroxycarbonylalkyl(carboxyalkyl),
s. cyano,
t. amino,
u. heterocyclylalkylamino, and
v. “trans-cinnamide”
and a pharmaceutically-acceptable carrier.
18. A method of suppressing immune response comprising the administration of a compound of
or a pharmaceutically-acceptable salt or pharmaceutically-acceptable prodrug of a compound of formula I,
wherein r1, r2, r3, r4, and r5 are independently selected from
a. hydrogen,
b. halogen,
c. alkyl,
d. haloalkyl,
e. alkoxy,
f. cyano,
g. nitro, and
h. carboxaldehyde,
with the proviso that at least one of r1 and r3 is a “cis-cinnamide” or a “trans-cinnamide”, defined as
##STR00020##
where r8 and r9 are each independently selected from
a. hydrogen,
b. alkyl,
c. carboxyalkyl,
d. alkylaminocarbonylalkyl, and
e. dialkylaminocarbonylalkyl,
r10 and r11 are each independently selected from
a. hydrogen,
b. alkyl,
c. cycloalkyl,
d. alkoxycarbonylalkyl,
e. hydroxyalkyl, and
f. heterocyclylalkyl,
or r10 and r11 are taken together with the N to form an unsubstituted heterocyclyl group, or a substituted heterocyclyl group, where the substituted heterocyclyl group is substituted by one or more than one substituent, where the substituents are each independently selected from
1) alkyl,
2) alkoxy,
3) alkoxyalkyl,
4) cycloalkyl,
5) aryl,
6) heterocyclyl,
7) heterocyclylcarbonyl,
8) heterocyclylalkylaminocarbonyl,
9) hydroxy,
10) hydroxyalkyl,
11) hydroxyalkoxyalkyl,
12) carboxy,
13) carboxycarbonyl,
14) carboxaldehyde,
15) alkoxycarbonyl,
16) arylalkoxycarbonyl,
17) aminoalkanoyl,
18) carboxamido,
19) alkoxycarbonylalkyl,
20) carboxamidoalkyl,
21) alkanoyl,
22) hydroxyalkanoyl,
23) alkanoyloxy,
24) alkanoylamino,
25) alkanoyloxyalkyl, and
26) alkylsulfonyl,
and Ar is an unsubstituted aryl group, an unsubstituted heteroaryl group, a substituted aryl group, or a substituted heteroaryl group, where the substituted aryl group and the substituted heteroaryl group are substituted by one or more than one substituent, where the substituents, are each independently selected from
a. halogen,
b. alkyl,
c. aryl,
d. haloalkyl,
e. hydroxy,
f. alkoxy,
g. alkoxycarbonyl,
h. alkoxyalkoxy,
i. hydroxyalkyl,
j. aminoalkyl,
k. alkyl(alkoxycarbonylalkyl)aminoalkyl,
l. unsubstituted heterocyclylalkyl,
m. substituted heterocyclylalkyl,
n. carboxaldehyde,
o. carboxaldehyde hydrazone,
p. carboxamide,
q. alkoxycarbonylalkyl,
r. hydroxycarbonylalkyl(carboxyalkyl),
s. cyano,
t. amino,
u. heterocyclylalkylamino, and
v. “trans-cinnamide”.
19. A method of suppressing immune response comprising the administration of a composition comprising a compound of
or a pharmaceutically-acceptable salt or pharmaceutically-acceptable prodrug of a compound of formula I,
wherein r1, r2, r3, r4, and r5 are independently selected from
a. hydrogen,
b. halogen,
c. alkyl,
d. haloalkyl,
e. alkoxy,
f. cyano,
g. nitro, and
h. carboxaldehyde,
with the proviso that at least one of r1 and r3 is a “cis-cinnamide” or a “trans-cinnamide”, defined as
##STR00022##
where r8 and r9 are each independently selected from
a. hydrogen,
b. alkyl,
c. carboxyalkyl,
d. alkylaminocarbonylalkyl, and
e. dialkylaminocarbonylalkyl,
r10 and r11 are each independently selected from
a. hydrogen,
b. alkyl,
c. cycloalkyl,
d. alkoxycarbonylalkyl,
e. hydroxyalkyl, and
f. heterocyclylalkyl,
or r10 and r11 are taken together with the N to form an unsubstituted heterocyclyl group, or a substituted heterocyclyl group, where the substituted heterocyclyl group is substituted by one or more than one substituent, where the substituents are each independently selected from
1) alkyl,
2) alkoxy,
3) alkoxyalkyl,
4) cycloalkyl,
5) aryl,
6) heterocyclyl,
7) heterocyclylcarbonyl,
8) heterocyclylalkylaminocarbonyl,
9) hydroxy,
10) hydroxyalkyl,
11) hydroxyalkoxyalkyl,
12) carboxy,
13) carboxycarbonyl,
14) carboxaldehyde,
15) alkoxycarbonyl,
16) arylalkoxycarbonyl,
17) aminoalkanoyl,
18) carboxamido,
19) alkoxycarbonylalkyl,
20) carboxamidoalkyl,
21) alkanoyl,
22) hydroxyalkanoyl,
23) alkanoyloxy,
24) alkanoylamino,
25) alkanoyloxyalkyl, and
26) alkylsulfonyl,
and Ar is an unsubstituted aryl group, an unsubstituted heteroaryl group, a substituted aryl group, or a substituted heteroaryl group, where the substituted aryl group and the substituted heteroaryl group are substituted by one or more than one substituent, where the substituents, are each independently selected from
a. halogen,
b. alkyl,
c. aryl,
d. haloalkyl,
e. hydroxy,
f. alkoxy,
g. alkoxycarbonyl,
h. alkoxyalkoxy,
i. hydroxyalkyl,
j. aminoalkyl,
k. alkyl(alkoxycarbonylalkyl)aminoalkyl,
l. unsubstituted heterocyclylalkyl,
m. substituted heterocyclylalkyl,
n. carboxaldehyde,
o. carboxaldehyde hydrazone,
p. carboxamide,
q. alkoxycarbonylalkyl,
r. hydroxycarbonylalkyl(carboxyalkyl),
s. cyano,
t. amino,
u. heterocyclylalkylamino, and
v. “trans-cinnamide”
and a pharmaceutically-acceptable carrier.
0. 20. A compound according to
(2,4-Dichlorophenyl)[2-(E-((6-hydroxyhexylamino)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-(E-((3-(1-imidazolyl)propylamino)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((2-hydroxyethylamino)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((6-hydroxyhexylamino)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((bis-(2-hydroxyethyl)ainino)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((3-(2-oxopyrrolidin-1-yl)propylamino)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-methylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-pyridyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-(Hydroxymethyl)phenyl) (2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-hydroxyethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-hydroxyethoxyethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((3-(hydroxymethyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((2-(hydroxymethyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((3-acetamidopyrrolidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((4-(hydroxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((3-carboxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-carboxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((4-acetylhomopiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((thiomorpholin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((4-(2-oxo,-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((2-tetrahydroisoquinolinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((2-(1-morpholinyl)ethylamino)carbonyl)ethenyl)phenyl]sulfide;
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((4-phenylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((3-(2-oxopyrrolidin-1-yl)propylamino)carbonyl)ethenyl)phenyl]sulfide;
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((cyclopropylamino)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)2-nitro-4-(E-((3-(2-oxopyrrolidin-1-yl)propylamino)carbonyl)ethenyl)phenyl]sulfide;
(2,3-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(4-Bromophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(4-Methylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(tert-butoxycarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(2-furoylcarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(methanesulfonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(diethylaminocarbonylmethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(diethylaminocarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl) (2-nitro-4-(E-((4-(carboxycarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(carboxymethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Chlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Aminophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Hydroxymethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Ethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-iso-Propylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-tert-Butylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Chlorophenyl)[2-chloro-4-(E-((4-acetylpiperain-1-yl)carbonyl))2-propenyl)phenyl]sulfide;
(2-(1-Morpholinylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-(4-(1,3-Benzodioxolyl-5-methyl)piperazin-1-ylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-(4-(iso-Propylaminocarbonylmethyl)piperazin-1-ylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-((N-Ethoxycarbonylmethyl-N-methyl)aminomethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-Formylphenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-(4-Formylpiperazin-1-ylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-(E-((1-Morpholinyl)carbonyl)ethenyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-Formylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Formylphenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide, N,N-dimethyl hydrazone;
(2-((3-(1-Morpholinyl)propyl)-1-amino)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-bromo-4-(E-((3-(2-oxopyrrolidin-1-yl)propylamino)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-formyl-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide; and
(2-Chloro-6-formylphenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide.
0. 24. A compound according to
0. 25. A compound according to
0. 27. A compound according to
0. 29. A compound according to
wherein X* and Z* are independently selected from —CH2—, —CH2NH—, —CH2O—, —NH—, and —O— with the proviso that at least one of X* and Z* is not —CH2—, and Y* is selected from —C(O)— and —(C(R″)2)v— where R′ is hydrogen or C1-4 alkyl and v is 1-3.
0. 30. A compound according to
wherein X* and Z* are independently selected from —CH2—, —CH2NH—, —CH2O—, —NH—, and —O— with the proviso that at least one of X* and Z* is not —CH2—, and Y* is selected from —C(O)— and —(C(R″)2)v— where R′ is hydrogen or C1-4 alkyl and v is 1-3.
0. 31. A compound according to
wherein X* and Z* are independently selected from —CH2—, —CH2NH—, —CH2O—, —NH—, and —O— with the proviso that at least one of X* and Z* is not —CH2—, and Y* is selected from —C(O)— and —(C(R″)2)v— where R′ is hydrogen or C1-4 alkyl and v is 1-3.
0. 32. A compound according to
wherein X* and Z* are independently selected from —CH2—, —CH2NH—, —CH2O—, —NH—, and —O— with the proviso that at least one of X* and Z* is not —CH2—, and Y* is selected from —C(O)— and —(C(R″)2)v— where R′ is hydrogen or C1-4 alkyl and v is 1-3.
0. 33. A compound according to
wherein X* and Z* are independently selected from —CH2—, —CH2NH—, —CH2O—, —NH—, and —O— with the proviso that at least one of X* and Z* is not —CH2—, and Y* is selected from —C(O)— and —(C(R″)2)v— where R′ is hydrogen or C1-4 alkyl and v is 1-3.
0. 34. A compound according to
wherein X* and Z* are independently selected from —CH2—, —CH2NH—, —CH2O—, —NH—, and —O— with the proviso that at least one of X* and Z* is not —CH2—, and Y* is selected from —C(O)— and —(C(R″)2)v— where R′ is hydrogen or C1-4 alkyl and v is 1-3.
0. 35. A compound according to
wherein X* and Z* are independently selected from —CH2—, —CH2NH—, —CH2O—, —NH—, and —O— with the proviso that at least one of X* and Z* is not —CH2—, and Y* is selected from —C(O)— and —(C(R″)2)v— where R′ is hydrogen or C1-4 alkyl and v is 1-3.
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The present invention relates to compounds that are useful for treating inflammatory and immune diseases, to pharmaceutical compositions comprising these compounds, and to methods of inhibiting inflammation or suppressing immune response in a mammal.
Inflammation results from a cascade of events that includes vasodilation accompanied by increased vascular permeability and exudation of fluid and plasma proteins. This disruption of vascular integrity precedes or coincides with an infiltration of inflammatory cells. Inflammatory mediators generated at the site of the initial lesion serve to recruit inflammatory cells to the site of injury. These mediators (chemokines such as IL-8, MCP1, MIP-1, and RANTES, complement fragments and lipid mediators) have chemotactic activity for leukocytes and attract the inflammatory cells to the inflamed lesion. These chemotactic mediators which cause circulating leukocytes to localize at the site of inflammation require the cells to cross the vascular endothelium at a precise location. This leukocyte recruitment is accomplished by a process called cell adhesion.
Cell adhesion occurs through a coordinately regulated series of steps that allow the leukocytes to first adhere to a specific region of the vascular endothelium and then cross the endothelial barrier to migrate to the inflamed tissue (Springer, T. A., (2,4-Dichlorophenyl)[2-chloro-4-(E-((3-(1-pyrrolidin-2-only)propylamino)carbonyl)ethenyl)phenyl]sulfide;
The present invention also provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more pharmaceutically-acceptable carriers.The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.
The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray. The term “parenteral” administration as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically-acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservative preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like, . Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically-acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (I i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifing and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers sucha s cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically-acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
The compounds of the present invention may be used in the form of pharmaceutically-acceptable salts derived from inorganic or organic acids. By “pharmaceutically-acceptable salt” is meant those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically-acceptable salts are well-known in the art. For example, S. M. Berge, et al. Describe , describe pharmaceutically-acceptable salts in detail in J. Pharmaceutical Sciences , J. Pharmaceutical Sciences (1977) 1977, 66; 1 et seq. The salts may be prepared in situ in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water Water-soluble, or oil-soluble, or dispersible products are thereby obtained. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
Basic addition salts can be prepared in situ in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically-acceptable basic addition salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and , aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically-acceptable carrier and any needed preservatives, buffers, or propellants which may be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
Generally dosage levels of about 0.1 to about 50 mg, more preferably of about 5 to about 20 mg of active compound per kilogram of body weight per day are administered orally or intravenously to a mammalian patient. If desired, the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.
Preparation of Compounds of this Invention
The compounds and processes of the present invention may be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the invention can be prepared. ##STR00005## ##STR00006##
Scheme 1 describes the synthesis of a typical cinnamide-substituted diaryl sulfide 4 through an aldehyde intermediate 2. Aldehyde 2 is prepared by reaction of a thiophenol (for example 2,4-dichlorothiophenol, 2-bromothiophenol, or the like) with halo-substituted benzaldehyde derivative 1 (e.g. 2-chlorobenzaldehyde, 3-chloro,4-fluorobenzaldehyde, or the like) in the presence of base (e.g. sodium carbonate, triethylamine, or the like) and a polar solvent (e.g. dimethylformamide, dimethylsulfoxide, or the like). The aldehyde group is homologated to the corresponding cinnamic acid 3, using an acetate equivalent (for example, malonic acid, triethoxyphosphonoacetate, or the like) in the presence of an appropriate base and solvent. In some cases, it may be necessary to hydrolyze an intermediate ester (for example using sodium hydroxide in alcohol). The acid group is activated (for example using thionyl chloride, or dicyclohexylcarbodiimide and N-hydroxysuccinimide, or the like) and reacted with a primary or secondary amine (for example, 6-aminohexanol, pyrrolidone-3-propylamine, or the like) to provide the desired analog 4. In one variant, a haloacetophenone can replace benzaldehyde 2; the resultant cinnamides 4 are substituted with a methyl group at the 3-position. ##STR00007## ##STR00008##
Alternatively, the order of these coupling steps may be reversed (Scheme 2). A substituted halocinnamic acid 5 (e.g. 3-chloro,2-nitrocinnamic acid or the like) may be coupled with a primary or secondary amine (e.g. N-acetylpiperazine or the like) as described above to give the corresponding amide 6. The halo-group can then be displaced with a substituted thiophenol in the presence of base to provide the product 7. ##STR00009##
A number of the compounds described herein may be prepared from intermediate benzylic alcohols like 8 (Scheme 3) Activation of the alcohol moiety (for example, using phosphorus tribromide or methanesulfonyl chloride and lithium halide in dimethylformamide) and displacement with a primary or secondary amine (e.g. morpholine, N-formylpiperazine or the like) provides analogs with structures related to 9. Alternatively the alcohol may be oxidized (for example using TPAP or PCC or the like) to give aldehyde 10. ##STR00010##
Cinnamides like 13 may be prepared from halo-substituted derivatives 11 by palladium-mediated coupling [e.g. using tetrakis (o-tolyl phosphine) palladium (0), Pd2 (dba)3, or the like] with acrylamide derivatives 12 (Scheme 4). In similar manner, anilino-cinnamides like 16 can be prepared by palladium-mediated coupling of amines 15 with halo-cinnamides 14. ##STR00011##
In some cases, functional groups on the aromatic rings can be modified to produce new analogs (Scheme 5). For example, a nitro group in compounds like 17 may be reduced (for example, with tin(II) chloride, or by catalytic hydrogenation, or the like) to the corresponding amine 18. This amine may then itself be converted to a halogen, for example by diazotization using nitrous acid or t-butyl nitrite in the presence of a metal halide salt like cupric bromide, providing analog 19. ##STR00012##
It is also possible to assemble cinnamide-substituted diaryl sulfides in a “reverse” sense (Scheme 6). Thus, for example, compound 20, prepared as described in Scheme 1, may be deprotected by treatment with base (e.g. potassium t-butoxide or the like) to provide thiolate anion 21, which may be reacted with an activated haloarene (e.g. 2,3-dichlorobenzaldehyde, 3-chloro,4-fluorobenzaldehyde or the like) to provide the corresponding product 22.
The compounds and processes of the present invention will be better understood in connection with the following examples which are intended as an illustration of and not a limitation upon the scope of the invention.
To a stirred solution of 2,4-dichlorothiophenol (2.0 g, 11.2 mmol) in 25 mL of anhydrous DMF was added potassium carbonate (3.09 g, 22.4 mmol), followed by 2-chlorobenzaldehyde (1.26 mL, 11.3 mmol). The mixture was then heated under nitrogen atmosphere at 70° C. for 5 hours. The reaction mixture was then allowed to cool to room temperature and partitioned between ether and water. The aqueous layer was extracted with ether once and the combined organic layer was washed with water and brine, dried over sodium sulfate and condensed in vacuo. The crude product was purified via silica gel flash chromatography, eluting with 5-10% ether/hexanes, to give 2.62 g (9.25 mmol, 83%) of the desired aldehyde as a colorless oil, which solidified slowly upon standing at room temperature.
A mixture of the aldehyde (1.50 g, 5.3 mmol) from Example 1A, malonic acid (1.21 g, 11.6 mmol), piperidine (78.6 μL, 0.80 mmol) in 8.0 mL of anhydrous pyridine was heated at 110° C. for 2 hours. Gas evolution ceased during this period. Pyridine was then removed under vacuum. Water and 3N aq. HCl were then added with stirring. The desired cinnamic acid was then collected through filtration, washed with cold water and dried in a vacuum oven overnight to give 1.56 g (4.8 mmol, 91%) of white solid.
A suspension of the acid (284 mg, 0.87 mmol) from Example 1B in 5 mL of methylene chloride was stirred with (COCl)2 (84 μL, 0.97 mmol), and one drop of DMF under nitrogen atmosphere for 90 minutes. The solvent was then removed under vacuum. The residue (COCl)2 was removed with benzene (2×) in vacuo. To a separate flask, previously filled with 6-amino-1-hexanol (12 mg, 0.10 mmol), Hunig's base (22.8 μL, 0.13 mmol) and DMAP (1.1 mg, 0.008 mmol) in 2.0 mL of CH2Cl2, the acid chloride (30 mg, 0.087 mmol) in 1.0 mL of CH2Cl2 was then dropped in slowly. After 30 minutes, the reaction mixture was poured into 3N HCl and extracted with ethyl aceetate (EtOAc). The organic layer was washed with brine, dried with Na2SO4, condensed under reduced pressure. The crude product was purified by preparative TLC to give 21.0 mg (90%) of the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 1.31-1.48 (m, 4H), 1.48-1.70 (m, 4H), 3.37 (q, J=6.7 Hz, 2H), 3.65 (t, J=6.3 Hz, 2H), 5.63 (br s, 1H), 6.36 (d, J=15.9 Hz, 1H), 6.71 (d, J=9.3 Hz, 1H), 7.95 (dd, J=2.4, 8.7 Hz, 1H), 7.31-7.49 (m, 4H), 7.65 (dd, J=2.1, 7.5 Hz, 1H), 7.99 (d, J=15.9 Hz, 1H). MS (DSI/NH3) (M+NH4)+ at m/z 441, 443, 445.
The title compound was prepared by the procedures described in Example 1C substituting 6-amino-1-hexanol with 1-(3-aminopropyl)imidazole. White powder; 1H NMR (d6-DMSO, 300 MHz) δ 1.88 (p, J=7.7 Hz, 2H), 3.11 (q, J=7.7 Hz, 2H), 3.97 (t, J=7.7 Hz, 2H), 6.63 (d, J=15.9 Hz, 1H), 6.70 (d, J=8.7 Hz, 1H), 6.89 (d, J=0.9 Hz, 1H), 7.17 (d, J=0.9 Hz, 1H), 7.33 (dd, J=2.7, 8.7 Hz, 1H), 7.46-7.65 (m, 4H), 7.72 (d, J=2.7 Hz, 1H), 7.78 (d, J=15.9 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 8.24 (t, J=5.9 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/z 448, 450, 452. Analysis calculated for C21H19N3O1Cl3S1.0.87H2O: C, 56.30; H, 4.67; N, 9.38. Found: C, 56.30; H, 4.56; N, 9.27.
The title compound was prepared by the procedures described in Example 1 substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with ethanolamine. Colorless oil; 1H NMR (CDCl3, 300 MHz) δ 3.57 (q, J=7.65 Hz, 2H), 3.71 (q, J=7.65 Hz, 2H), 6.06 (br s, 1H), 6.40 (d, J=15.3 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 7.22-7.30 (m, 4H), 7.49-7.60 (m, 1H), 7.55 (d, J=15.3 Hz, 1H). MS (APCI) (M+H)+ at m/z 402, 404, 406, 408. Analysis calculated for C17H14N1O2Cl3S1.0.25H2O: C, 50.14; H, 3.59; N, 3.44. Found: C, 50.16; H, 3.62; N, 3.29.
The title compound was prepared by the procedures described in Example 1 substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-4-fluoro-benzaldehyde. Colorless oil; 1H NMR (CDCl3, 300 MHz) δ 1.42 (m, 4H), 1.58 (m, 4H), 3.40 (q, J=6.7 Hz, 2H), 3.65 (br m, 2H), 5.60 (br t, 1H), 6.35 (d, J=15.3 Hz, 1H), 6.98 (d, J=8.7 Hz, 1H), 7.22-7.30 (m, 4H), 7.49-7.60 (m, 1H), 7.55 (d, J=15.3 Hz, 1H). MS (APCI) (M+H)+ at m/z 458, 460, 462, 464. Analysis calculated for C21H22N1O2Cl3S1.0.27H2O: C, 54.39; H, 4.90; N, 3.02. Found: C, 54.40; H, 4.85; N, 2.71.
The title compound was prepared by the procedures described in Example 1 substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with diethanolamine. Colorless oil; 1H NMR (CDCl3, 300 MHz) δ 2.99 (br s, 2H), 3.67 (br m, 4H), 3.88 (t, J=5.1 Hz, 2H), 3.94 (t, J=5.1 Hz, 2H), 6.94 (d, J=1.53 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 7.21-7.32 (m, 3H), 7.50-7.54 (m, 1H), 7.58 (d, J=2.4 Hz, 1H), 7.58 (d, J=15.3 Hz, 1H). MS (APCI) (M+H)+ at m/z 446, 448, 450, 452. Analysis calculated for C19H18N1O3Cl3S1.1.09H2O: C, 48.93; H, 4.36; N, 3.00. Found: C, 48.88; H, 4.00; N, 3.01.
The title compound was prepared by the procedures described in Example 1 substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with 1-(3-aminopropyl)-2-pyrrolidinone. Colorless oil; 1H NMR (CDCl3, 300 MHz) δ 1.74 (qu, J=6.0 Hz, 2H), 2.09 (qu, J=7.5 Hz, 2H), 2.45 (t, J=8.25 Hz, 2H), 3.33 (q, J=6.0 Hz, 2H), 3.42 (q, J=8.25 Hz, 4H), 6.46 (d, J=15.6 Hz, 1H), 7.02 (d, J=8.7 Hz, 1H), 7.14-7.23 (m, 2H), 7.30 (dd, J=2.4, 8.7 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H). 7.51 (d, J=15.6 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/z 483, 485, 487, 489. Analysis calculated for C22H21N2O2Cl3S1.0.57H2O: C, 53.48; H, 4.52; N, 5.67. Found: C, 53.49; H, 4.60; N, 5.65.
The title compound was prepared by the procedures described in Example 1 substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with morpholine. White solid; 1H NMR (CDCl3, 300 MHz) δ 3.59-3.80 (m, 8H), 6.83 (d, J=15.6 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 7.16-7.32 (m, 3H), 7.49-753 (m, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.59 (d, J=15.6 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/z 428, 430, 432, 434. Analysis calculated for C19H16N1O2Cl3S1.0.46H2O: C, 52.22; H, 3.90; N, 3.20. Found: C, 52.20; H, 3.76; N, 3.12.
The title compound was prepared by the procedures described in Example 1 substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with 1-methylpiperazine. Colorless oil; 1H NMR (CDCl3, 300 MHz) δ 2.37 (s, 3H), 2.51 (br m, 4H), 3.64-3.87 (br m, 4H), 6.85 (d, J=15.6 Hz, 1H), 6.98 (d, J=8.7 Hz, 1H), 7.19-7.25 (m, 2H), 7.27 (dd, J=2.1, 8.7 Hz, 1H), 7.52 (t, J=0.9 Hz, 1H), 7.57 (d, J=15.6 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/z 441, 443, 445, 447. Analysis calculated for C20H19N2O1Cl3S1.0.45H2O: C, 53.39; H, 4.46; N, 6.23. Found: C, 53.37; H, 4.46; N, 6.07.
The title compound was prepared by the procedures described in Example 1 substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with 1-acetylpiperazine. White solid; 1H NMR (CDCl3, 300 MHz) δ 2.15 (s, 3H), 3.50-3.58 (m, 2H), 3.58-3.85 (m, 6H), 6.85 (d, J=15.3 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 7.24-7.36 (m, 3H), 7.54 (dd, J=2.4 Hz, 1H), 7.61 (d, J=15.3 Hz, 1H), 7.61 (d, J=2.1 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/z 486, 488, 490, 492. Analysis calculated for C21H19N2O2Cl3S1.0.85H2O: C, 51.99; H, 4.30; N, 5.77. Found: C, 52.03; H, 4.27; N, 5.67.
The title compound was prepared by the procedures described in Example 1 substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with 1-(2-pyridyl)piperazine. White solid; 1H NMR (CDCl3, 300 MHz) δ 3.59 (br m, 2H), 3.69 (br m, 2H), 3.78 (br m, 2H), 3.86 (br m, 2H), 6.64-6.72 (m, 2H), 6.90 (d, J=15.6 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 7.22-7.25 (m, 2H), 7.31 (dd, J=2.4, 8.7 Hz, 1H), 7.49-7.57 (m, 2H), 7.61 (d, J=15.6 Hz, 1H), 7.62 (d, J=2.4 Hz, 1H), 8.19-8.24 (m, 1H). MS (DCI/NH3) (M+H)+ at m/z 504, 506, 508, 510. Analysis calculated for C24H20N3O1Cl3S1: C, 57.10; H, 3.99; N, 8.32. Found: C, 57.12; H, 4.06; N, 8.29.
The title compound was prepared by the procedures described in Example 1 substituting 2,4-dichlorothiophenol with 2-mercaptobenzyl alcohol, 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with morpholine. White solid; 1H NMR (CDCl3, 300 MHz) δ 3.50-3.62 (br m, 6H), 3.65-3.74 (br m, 2H), 4.54 (d, J=5.7 Hz, 2H), 5.33 (t, J=5.7 Hz, 1H), 6.62 (d, J=8.7 Hz, 1H), 7.28 (d, J=15.0 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.42 (d, J=15.0 Hz, 1H), 7.43 (dd, J=1.8, 8.7 Hz, 1H), 7.50 (dd, J=2.1, 8.7 Hz, 1H), 7.55 (dd, J=2.1, 7.8 Hz, 1H), 7.68 (dd, J=1.5, 8.1 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/z 390, 392. Analysis calculated for C20H20N1O3Cl1S1.0.09H2O: C, 61.35; H, 5.20; N, 3.58. Found: C, 61.37; H, 5.48; N, 3.81.
The title compound was prepared by the procedures described in Example 1 substituting 2,4-dichlorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with morpholine. White solid; 1H NMR (d6-DMSO, 300 MHz) δ 3.50-3.66 (br m, 6H), 3.66-3.79 (br m, 2H), 7.05 (d, J=8.7 Hz, 1H), 7.26 (dd, J=2.1, 8.1 Hz, 1H), 7.33 (dd, J=2.1, 8.1 Hz, 1H), 7.36 (d, J=15.6 Hz, 1H), 7.39 (dd, J=1.8, 12.0 Hz, 1H), 7.45 (dd, J=1.8, 6.3 Hz, 1H), 7.48 (d, J=15.6 Hz, 1H), 7.64 (dd, J=2.1, 8.7 Hz, 1H), 7.80 (dd, J=2.8, 8.7 Hz, 1H), 8.09 (d, J=2.1 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/z 438, 440, 442.
The title compound was prepared by the procedures described in Example 1 substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with 1-hydroxyethylpiperazine. Colorless oil; 1H NMR (CDCl3, 300 MHz) δ 2.85-3.20 (br m, 6H), 3.84-4.29 (m, 6H), 6.80 (d, J=15.3 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 7.72-7.38 (m, 3H), 7.50-7.56 (m, 1H), 7.56-7.62 (m, 1H), 7.60 (d, J=15.3 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/z 471, 473, 475, 477.
The title compound was prepared by the procedures described in Example 1 substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with 1-[2-(2-hydroxyethoxy)ethyl]piperazine. Colorless oil; 1H NMR (CDCl3, 300 MHz) δ 2.73 (br m, 6H), 3.58-3.68 (m, 2H), 3.68-4.00 (m, 8H), 6.84 (d, J=15.3 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 7.20-7.34 (m, 3H), 7.54 (d, J=7.5 Hz, 1H), 7.58 (d, J=15.3 Hz, 1H), 7.58-7.65 (overlapping d, 1H). MS (DCIINH3) (M+H)+ at m/z 515, 517, 519, 521.
The title compound was prepared by the procedures described in Example 1 substituting 2,4-dichlorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with 3-hydroxymethylpiperidine. 1H NMR (DMSO-d6, 300 MHz) δ 8.07 (d, J=17.7 Hz, 1H), 7.80 (d, J=7.7 Hz, 1H), 7.63 (br d, J=7.7 Hz, 1H), 7.44 (d, J=7.0 Hz, 1H), 7.40 (br s, 2H), 7.35 (m, 1H), 7.25 (dd 7.7, 1.5, 1H), 7.06 (dd, J=8.1 2.9, 1H), 4.57 (m, 1H), 4.45 (m, 1H), 4.16 (br m, 2H), 1.2-1.8 (m, 8H). HRMS calculated for C21H21N1O2S1Br1Cl1: 466.0243. Observed: 466.0247.
The title compound was prepared by the procedures described in Example 1 substituting 2,4-dichlorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with 2-hydroxymethylpiperidine. 1H NMR (DMSO-d6, 300 MHz) δ 8.03 (m, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.61 (m, 1H), 7.30-7.45 (m, 4H), 7.23 (m, 1H), 7.07 (m, 1H), 4.79 (m, 2H), 4.61 (m, 2H), 4.10 (m, 1H), 1.50 (m, 6H). HRMS calculated for C21H21N1O2S1Br1Cl1: 466.0243. Observed: 466.0247.
The title compound was prepared by the procedures described in Example 1 substituting 2,4-dichlorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with 3-acetamidopyrrolidine. 1H NMR (DMSO-d6, 300 MHz) δ 8.14 (m, 1H), 8.07 (dd, J=9.8, 1.7 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.64 (dd, J=8.1, 1.7 Hz, 1H), 7.25-7.47 (m, 4H), 7.10 (t, J=7.8 Hz, 1H), 7.03 (dd, J=8.1, 1.7 Hz, 1H), 3.45-4.34 (m, 6H), 2.02 (m, 2H), 1.81 (ap d, J=1.4 Hz, 1H), HRMS calculated for C21H20N2O2S1Br1Cl1: 479.0196. Observed: 479.0183.
The title compound was prepared by the procedures described in Example 1 substituting 2,4-dichlorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with 4-hydroxypiperidine. 1H NMR (DMSO-d6, 300 MHz) δ 8.08 (d, J=1.7 Hz, 1H), 7.80 (dd, J=8.0, 1.5 Hz, 1H), 7.63 (dd, J=8.3, 1.9 Hz, 1H), 7.44 (ap dd, J=7.5, 1.4 Hz, 2H), 7.40 (ap d, J=3.7 Hz 2H), 7.34 (dt, J=7.6, 1.8 Hz, 1H), 7.25 (dd, J=7.5, 1.7 Hz 1H), 7.05 (d, J=8.1 Hz, 1H), 4.76 (br s, 1H), 4.01 (m, 2H), 3.72 (m, 1H), 3.12 (m, 1H), 1.75 (m, 2H), 1.32 (m, 2H). HRMS calculated for C20H19N1O2S1Br1Cl1: 452.0087. Observed: 452.0076.
The title compound was prepared by the procedures described in Example 1 substituting 2,4-dichlorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with piperidine. 1H NMR (DMSO-d6, 300 MHz) δ 8.08 (d, J=1.7 Hz, 1H), 7.80 (dd, J=8.1, 1.4 Hz, 1H), 7.63 (dd, J=8.1, 1.7 Hz, 1H), 7.44 (ap dd, J=7.6, 1.5 Hz, 1H), 7.39 (ap d, J=4.8 Hz, 2H), 7.34 (dt, J=7.5, 1.6, 1H), 7.24 (dd, J=7.5, 1.7, 1H), 7.05 (d, J=8.1 Hz, 1H), 3.65 (br m, 2H), 3.53 (br m, 2H), 1.62 (br m, 2H), 1.50 (br m, 4H). HRMS calculated for C20H19N1O1S1Br1Cl1: 436.0130. Observed: 436.0122.
The title compound was prepared by the procedures described in Example 1 substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with nipecotic acid. Colorless oil; 1H NMR (CDCl3, 300 MHz) δ 1.44-1.68 (br m, 1H), 1.68-2.00 (br m, 2H), 2.51-2.67 (br m, 1H), 3.13-3.37 (br m, 1H), 3.80-4.12 (br m, 1H), 4.30-5.00 (br m, 3H), 6.86 (d, J=15.3 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 7.16-7.24 (m, 2H), 7.29 (d, J=8.7 Hz, 1H), 7.47-7.55 (m, 1H), 7.55 (d, J=15.3 Hz, 1H), 7.60 (br d, 1H). MS (APCI) (M+H)+ at m/z 470, 472, 474, 476.
The title compound was prepared by the procedures described in Example 1 substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with isonipecotic acid. Colorless oil; 1H NMR (CDCl3, 300 MHz) δ 1.68-1.85 (m, 2H), 1.98-2.09 (m, 2H), 2.60-2.72 (m, 1H), 2.90-3.13 (br m, 1H), 3.17-3.38 (br, m, 1H), 3.93-4.12 (br m, 1H), 4.38-4.59 (br m, 1H), 6.86 (d, J=15.3 Hz, 1H), 6.99 (dd, J=8.7 Hz, 1H), 7.20-7.25 (m, 2H), 7.28 (dd, J=1.8,8.7 Hz, 1H), 7.49-7.53 (m, 1H), 7.56 (d, J=15.3 Hz, 1H), 7.60 (d, J=1.8 Hz, 1H). MS (APCI) (M+H)+ at m/z 470, 472, 474, 476.
The title compound was prepared by the procedures described in Example 1 substituting 2,4-dichlorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-3-fluoro-benzaldehyde, and 6-amino-1-hexanol with 4-acetylhomopiperazine. 1H NMR (DMSO-d6, 300 MHz) δ 8.10 (m, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.64 (m, 1H), 7.24-7.51 (m, 5H), 7.05 (m, 1H), 3.39-3.77 (m, 8H), 1.97 (m, 3H), 1.68 (m, 2H). HRMS calculated for C22H22N2O2S1Br1Cl1: 493.0352. Observed: 493.0352.
The title compound was prepared by the procedures described in Example 1 substituting 2,4-dichlorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-3-fluoro-benzaldehyde, and 6-amino-1-hexanol with thiomorpholine. 1H NMR (DMSO-d6, 300 MHz) 68.10 (d, J=1.5 Hz, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.64 (dd, J=8.1, 1.5 Hz, 1H), 7.31-7.48 (m, 4H), 7.36 (m, 1H), 7.26 (dd, J=8.1, 1.8 Hz, 1H), 7.05 (d J=8.1 Hz, 1H), 3.96 (m, 2H), 3.82 (m, 2H), 2.62 (m, 4H). HRMS calculated for C19H17N1O1S2Br1Cl1: 455.9681. Observed: 455.9676.
The title compound was prepared by the procedures described in Example 1 substituting 2,4-dichlorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-3-fluoro-benzaldehyde, and 6-amino-1-hexanol with 4-(1-benzimidazol-2-only)piperidine 4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine. 1H NMR (DMSO-d6, 300 MHz) δ 8.14 (d, J=1.5 Hz, 1H), 7.80 (dd, J=7.9, 1.3 Hz, 1H), 7.67 (dd, J=8.1, 1.8 Hz, 1H), 7.48 (ap s, 2H), 7.44 (dt, J=7.5, 1.2, 1H), 7.34 (dt, J=7.6, 1.6, 1H), 7.26 (dd, J=7.7, 1.8 Hz, 1H), 7.22 (m, 1H), 7.06 (d, J=8.1, 1H), 6.97 (ap d, J=2.6, 3H), 4.64 (m, 1H), 4.48 (m, 2H), 2.79 (m, 2H), 2.29 (m, 2H), 1.78 (m, 2H). HRMS calculated for C27H23N3O2SBr1Cl1: 568.0461. Observed: 568.0477.
The title compound was prepared by the procedures described in Example 1 substituting 2,4-dichlorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde 3-chloro-3-fluoro-benzaldehyde, and 6-amino-1-hexanol with tetrahydroisoquinoline. 1H NMR (DMSO-d6, 300 MHz) δ 8.12 (d, J=7.4 Hz, 1H), 7.81 (dd, J=7.7. 1.1 Hz, 1H), 7.67 (dd, J=8.3, 1.3 Hz, 1H), 7.47 (m, 2H), 7.43 (dd, J=7.5, 1.3 Hz, 2H), 7.34 (dt, J=7.6, 1.7 Hz, 1H), 7.27 (d 7.7 Hz, 1H), 7.19 (m, 4H), 7.05 (d, J=8.1 Hz, 1H), 4.92 (s, 1H), 4.72 (s, 1H), 3.95 (t, J=5.9 Hz, 1H), 3.78 (t, J=5.7 Hz, 1H), 2.89 (t, J=5.3 HZ, 1H), 2.83 (t, J=3.7, 1H). HRMS calculated for C24H19N1O2S1Br1Cl1: 484.0138. Observed: 484.0128.
The title compound was prepared by the procedures described in Example 1 substituting 2,4-dichlorothiophenol with 2-methylthiophenol, 2-chlorobenzaldehyde with 4-fluoro-3-trifluoromethylbenzadehyde 4-fluoro-3-trifluoromethylbenzaldehyde, and 6-amino-1-hexanol with 1-acetylpiperazine. 1H NMR (CDCl3, 300 MHz) δ 7.79 (s, 1H); 7.63 (d, J=15.4 Hz, 1H); 7.51 (d, J=6.8 Hz, 1H); 7.41-7.33 (m, 3H); 7.28 (m, 1H); 6.83 (d, J=15.4 Hz, 1H); 6.79 (d, J=6.8 Hz, 1H); 3.80-3.60 (m, 6H); 3.57-3.50 (m, 2H); 2.34 (s, 3H); 2.14 (s, 3H). MS (ESI) m/z 919 (2M+Na)+, 897 (2M+H)+, 471 (M+Na)+, 449 (M+H)+.
The title compound was prepared by the procedures described in Example 1 substituting 2,4-dichlorothiophenol with 2-methylthiophenol, 2-chlorobenzaldehyde with 4-fluoro-3-trifluoromethylbenzadehyde 4-fluoro-3-trifluoromethylbenzaldehyde, and 6-amino-1-hexanol with morpholine. 1H NMR (DMSO-d6, 300 MHz) δ 7.79 (s, 1H); 7.63 (d, J=14.0 Hz, 1H); 7.52 (d, J=7.6 Hz, 1H); 7.40-7.30 (m, 3H); 7.28 (m, 1H); 6.87 (d, J=14.0 Hz, 1H); 6.84 (d, J=7.6 Hz, 1H); 3.73 (br s, 8H); 2.34 (s, 3H). MS (ESI) m/z 837 (2M+Na)+, 815 (2M+H)+, 408 (M+H)+.
The title compound was prepared by the procedures described in Example 1 substituting 2,4-dichlorothiophenol with 2-methylthiophenol, 2-chlorobenzaldehyde with 4-fluoro-3-trifluoromethylbenzadehyde 4-fluoro-3-trifluoromethylbenzaldehyde, and 6-amino-1-hexanol with 2-(1-morpholinyl)ethylamine. 1H NMR (CDCl3, 300 MHz) δ 7.80 (s, 1H); 7.56 (d, J=15.8 Hz, 1H); 7.50 (d, J=8.1 Hz, 1H); 7.40-7.32 (m, 3H); 7.28 (m, 1H); 6.79 (d, J=15.8 Hz, 1H); 6.40 (d, J=8.1 Hz, 1H); 3.75 (t, J=4.6 Hz, 4H); 3.51 (q, J=5.5 Hz, 2H), 2.57 (t, J=5.8 Hz, 2H); 2.55-2.48 (m, 4H); 2.34 (s, 3H ). MS (ESI) m/z 923 (2M+Na)+, 473 (M+Na)+, 451 (M+H)+.
The title compound was prepared by the procedures described in Example 1 substituting 2,4-dichlorothiophenol with 2-methylthiophenol, 2-chlorobenzaldehyde with 4-fluoro-3-trifluoromethylbenzadehyde 4-fluoro-3-trifluoromethylbenzaldehyde, and 6-amino-1-hexanol with 4-phenylpiperazine. 1H NMR (CDCl3, 300 MHz) δ 7.81 (s, 1H); 7.64 (d, J=16.0 Hz, 1H); 7.51 (d, J=8.2 Hz, 1H); 7.40-7.27 (m, 6H); 6.98-6.90 (m, 4H); 6.80 (d, J=8.2 Hz, 1H); 3.88 (br s, 4H); 2.23 (br s, 4H); 2.34 (s, 3H). MS (ESI) m/z 987 (2M+Na)+, 965 (2M+H)+, 505 (M+Na)+, 483 (M+H)+, 451.
The title compound was prepared by the procedures described in Example 1 substituting 2,4-dichlorothiophenol with 2-methylthiophenol, 2-chlorobenzaldehyde with 4-fluoro-3-trifluoromethylbenzadehyde 4-fluoro-3-trifluoromethylbenzaldehyde, and 6-amino-1-hexanol with 1-pyrrolidin-2-only)propylamine 3-(2-oxopyrrolidin-1-yl)propylamine. 1H NMR (CDCl3, 300 MHz) δ 7.78 (s, 1H); 7.53 (d, J=15.6 Hz, 1H); 7.49 (d, J=7.2 Hz, 1H); 7.40-7.33 (m, 3H); 7.14 (m, 1H); 6.80 (d, J=8.2 Hz, 1H); 6.43 (d, J=15.6 Hz, 1H); 3.41 (m, 4H); 3.32 (q, J=6.1 Hz, 2H); 2.43 (t, J=6.6 Hz, 2H); 2.34 (s, 3H), 2.08 (m, 2H), 1.75 (m, 2H). MS (ESI) m/z 947 (2M+Na)+, 925 (2M+H)+, 4.85 (M+Na)+, 463 (M+H)+.
The title compound was prepared by the procedures described in Example 1 substituting 2,4-dichlorothiophenol with 2-methylthiophenol, 2-chlorobenzaldehyde with 4-fluoro-3-trifluoromethylbenzadehyde 4-fluoro-3-trifluoromethylbenzaldehyde, and 6-amino-1-hexanol with cyclopropylamine. 1H NMR (CDCl3, 300 MHz) δ 7.76 (s, 1H); 7.56 (d, J=15.4 Hz, 1H); 7.50 (d, J=8.4 Hz, 1H); 7.40-7.30 (m, 3H); 7.28 (m, 1H); 6.88 (d, J=8.4 Hz, 1H); 6.30 (d, J=15.4 Hz, 1H); 5.70 (br s, 1H), 2.95 (m, 1H); 2.34 (s, 3H); 0.85 (m, 2H); 0.57 (m, 2H). MS (ESI) m/z 777 (2M+Na)+, 755 (2M+H)+, 400 (M+Na)+, 378 (M+H)+.
To a stirred solution of trans-4-chloro-3-nitrocinnamic acid (1.50 g, 6.59 mmol) and 1-acetylpiperazine (0.89 g, 6.94 mmol) in 20 mL of DMF at room temperature was added EDAC (1.4 g, 7.30 mmol). The mixture was then stirred at room temperature for 2 hours. TLC indicated the complete consumption of the acid. Water was then added to quench the reaction and to precipitate out the product. Cinnamide was then collected through filtration and washed with cold water. The light yellow product was dried in a vacuum oven overnight at 40° C. to give 2.04 g (6.03 mmol, 91.6%) of the title compound.
To a stirred solution of 4-chloro-3-nitro-cinnamide (275 mg, 0.814 mmol) from Example 32A in 1.0 mL of DMF was added potassium carbonate (169 mg, 1.22 mmol), followed by the dropwise addition of 2,4-dichlorothiophenol (146 mg, 0.815 mmol). The mixture was then stirred at room temperature for 60 minutes. Completion of the reaction was indicated by the TLC. Water was then added to precipitate the product. Filtration, washing with cold water, and drying in a vacuum oven afforded 350 mg (0.728 mmol, 89%) of the titled title compound as a light yellow solid. 1H NMR (d6-DMSO, 300 MHz) δ 2.05 (s, 3H), 3.42-3.50 (br m, 4H), 3.50-3.64 (br m, 2H), 3.64-3.79 (br m, 2H), 6.83 (d, J=8.7 Hz, 1H), 7.44 (d, J=15.3 Hz, 1H), 7.55 (d, J=15.3 Hz, 1H), 7.63 (dd, J=2.7, 8.7 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.96 (d, J=2.7 Hz, 1H), 8.69 (d, J=1.8 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/z 497, 499, 501. Analysis calculated for C21H19N3O4Cl2S1.0.82H2O: C, 50.94; H, 4.20; N, 8.49. Found: C, 50.91; H, 4.21; N, 8.69.
The title compound was prepared by the procedures described in Example 32 substituting 1-acetylpiperazine with 1-(3-aminopropyl)-2-pyrrolidinone. Light-yellow powder; 1H NMR (d6-DMSO, 300 MHz) δ 1.64 (p, J=7.1 Hz, 2H), 1.91 (p, J=7.5 Hz, 2H), 2.21 (t, J=8.3 Hz, 2H), 3.15 (q, J=6.3 Hz, 2H), 3.21 (dd, J=9.9, 17.7 Hz, 2H), 3.32 (overlapping t, J=8.4 Hz, 2H), 6.72 (d, J=15.6 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 7.46 (d, J=15.6 Hz, 1H), 7.63 (dd, J=2.4, 8.1 Hz, 1H), 7.79 (dd, J=2.4, 8.7 Hz, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.96 (d, J=2.4 Hz, 1H), 8.18 (t, J=6.0 Hz, 1H), 8.46 (d, J=2.1 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/z 494, 496.
The title compound was prepared by the procedures described in Example 32B substituting 2,4-dichlorothiophenol with 2,3-dichlorothiophenol. Light-yellow powder; 1H NMR (d6-DMSO, 300 MHz) δ 2.04 (s, 3H), 3.42-3.50 (br m, 4H), 3.50-3.64 (br m, 2H), 3.64-3.79 (br m, 2H), 6.88 (d, J=8.7 Hz, 1H), 7.45 (d, J=15.6 Hz, 1H), 7.55 (t, J=7.65 Hz, 1H), 7.57 (d, J=15.6 Hz, 1H), 7.78 (dd, J=1.8, 8.1 Hz, 1H), 7.87 (dd, J=1.8, 8.1 Hz, 1H), 7.95 (dd, J=2.7, 9.0 Hz, 1H), 8.69 (d, J=1.8 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/z 497, 499, 501.
The title compound was prepared by the procedures described in Example 32 substituting 2,4-dichlorothiophenol with 4-bromothiophenol. Light-yellow powder; 1H NMR (d6-DMSO, 300 MHz) δ 2.04 (s, 3H), 3.47 (br m, 4H), 3.52 (br m, 1H), 3.60 (br m, 1H), 3.68 (br m, 1H), 3.74 (br m, 1H), 6.90 (d, J=8.7 Hz, 1H), 7.43 (d, J=15.0 Hz, 1H), 7.54 (d, J=15.0 Hz, 1H), 7.58 (d, J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.92 (dd, J=2.1, 9.0 Hz, 1H), 8.65 (d, J=2.1 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/z 507, 509.
The title compound was prepared by the procedures described in Example 32 substituting 2,4-dichlorothiophenol with p-thiocresol. Light-yellow powder; 1H NMR (d6-DMSO, 300 MHz) δ 2.04 (s, 3H), 2.39 (s, 3H), 3.47 (br m, 4H), 3.52 (br m, 1H), 3.60 (br m, 1H), 3.68 (br m, 1H), 6.89 (d, J=8.7 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 7.39 (d, J=8.4 Hz, 2H), 7.40 (d, J=15.0 Hz, 1H), 7.53 (d, J=15.0 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.89 (dd, J=2.1, 8.7 Hz, 1H), 8.64 (d, J=2.1 Hz, 1H). MS (DCI/NH3) (M+NH4)+ at m/z 443.
The title compound was prepared by the procedures described in Example 32 substituting 1-acetylpiperazine with tert-butyl piperazine carboxylate. Light-yellow powder; 1H NMR (d6-DMSO, 300 MHz) δ 1.42 (s, 9H), 3.36 (overlapping m, 4H), 3.55 (br m, 2H), 3.70 (br m, 2H), 6.83 (d, J=8.7 Hz, 1H), 7.42 (d, J=15.6 Hz, 1H), 7.54 (d, J=15.6 Hz, 1H), 7.63 (dd, J=2.4, 8.4 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.92 (dd, J=2.4, 8.7 Hz, 1H), 7.96 (d, J=2.7 Hz, 1H), 8.68 (d, J=2.4 Hz, 1H). MS (APCI) (M+H)+ at m/z 538, 540, 542.
Trifluoroacetic Acid Salt
The compound (100 mg, 0.186 mmol) from Example 37 was dissolved in 0.5 mL of neat trifluoroacetic acid (TFA). The mixture was stirred at room temperature for 1 hour. The TFA was then removed under vacuum to give the title compound (105 mg) as a yellow solid.
To a stirred solution of piperazine TFA salt (35 mg, 0.067 mmol) from Example 38A in 2.0 mL of CH2Cl2 was added Et3N (23 μL, 0.17 mmol), 4-dimethylaminopyridine (DMAP) (1.0 mg, 0.0082 mmol), and furyl chloride (8.0 μL, 0.080 mmol). The mixture was then stirred at room temperature for 30 minutes before the solvent was removed. The crude product was purified with Gilson HPLC system, YMC C-18 column, 75×30 mm I.D., S-5 μM, 120 Å, and a flow rate of 25 mL/min, λ=214, 245 nm; mobile phase A, 0.05 M NH4Oac NH4OAc, and B, CH3CN; linear gradient 20-100% of B in 20 minutes to give the title compound (24 mg, 67%) as a light-yellow powder; 1H NMR (d6-DMSO, 300 MHz) δ 3.62-3.87 (br m, 8H), 6.66 (q, J=2.1 Hz, 1H), 6.84 (d, J=8.7 Hz, 1H), 7.04 (d, J=3.3 Hz, 1H), 7.44 (d, J=15.3 Hz, 1H), 7.56 (d, J=15.3 Hz, 1H), 7.63 (dd, J=2.4, 8.1 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.87 (d, J=2.1 Hz, 1H), 7.92 (dd, J=2.1, 12.0 Hz, 1H), 7.96 (d, J=2.1 Hz, 1H), 8.70 (d, J=2.1 Hz, 1H). MS (APCI) (M+H)+ at m/z 532, 534, 536.
The title compound was prepared by the procedures described in Example 38B substituting furoyl chloride with methanesulfonyl chloride. Light-yellow powder; 1H NMR (d6-DMSO, 300 MHz) δ 2.90 (s, 3H), 3.25 (br m, 4H), 3.68 (br m, 2H), 3.83 (br m, 2H), 6.84 (d, J=9.0 Hz, 1H), 7.45 (d, J=15.6 Hz, 1H), 7.56 (d, J=15.6 Hz, 1H), 7.63 (dd, J=2.4, 8.7 Hz, 1H), 7.83 (d, J=9.0 Hz, 1H), 7.93 (dd, J=2.1, 9.0 Hz, 1H), 7.95 (d, J=2.7 Hz, 1H), 8.70 (d, J=2.1 Hz, 1H). MS (ESI) (M+H)+ at m/z 516, 518, 520.
The title compound was prepared by the procedures described in Example 38B substituting furoyl chloride with 2-chloro-N,N-diethylacetamide. Light-yellow powder; 1H NMR (d6-DMSO, 300 MHz) δ 1.01 (t, J=7.2 Hz, 3H), 1.13 (t, J=7.2 Hz, 3H), 2.46 (br m, 4H), 3.16 (s, 2H), 3.24 (q, J=7.2 Hz, 2H), 3.37 (q, J=7.2 Hz, 2H), 3.56 (br m, 2H), 3.69 (br m, 2H), 6.83 (d, J=9.0 Hz, 1H), 7.46 (d, J=15.3 Hz, 1H), 7.52 (d, J=15.3 Hz, 1H), 7.62 (dd, J=2.4, 8.7 Hz, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.92 (dd, J=2.1, 9.0 Hz, 1H), 7.95 (d, J=2.7 Hz, 1H), 8.67 (d, J=2.1 Hz, 1H). MS (ESI) (M+NH4)+ at m/z 573, 575, 577.
The title compound was prepared by the procedures described in Example 38B substituting furoyl chloride with N,N-diethylcarbamyl chloride. Light-yellow powder; 1H NMR (d6-DMSO, 300 MHz) δ 1.06 (t, J=6.9 Hz, 6H), 3.12 (br m, 4H), 3.15 (q, J=6.9 Hz, 4H), 3.58 (br m, 2H), 3.72 (br m, 2H), 6.83 (d, J=8.7 Hz, 1H), 7.42 (d, J=15.6 Hz, 1H), 7.53 (d, J=15.6 Hz, 1H), 7.63 (dd, J=2.7, 9.0 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.92 (dd, J=2.4, 8.7 Hz, 1H), 7.95 (d, J=2.7 Hz, 1H), 8.68 (d, J=2.1 Hz, 1H). MS (APCI) (M+H)+ at m/z 537, 539, 541.
The title compound was prepared by the procedures described in Example 38B substituting CH2CL2 with CH3CN as solvent, and furoyl chloride with tert-butyl bromoacetate. Light-yellow powder; 1H NMR (CDCl3, 300 MHz) δ 1.47 (s, 9H), 2.70 (br m, 4H), 3.21 (s, 2H), 3.74 (br m, 2H), 3.82 (br m, 2H), 6.73 (d, J=8.7 Hz, 1H), 6.92 (d, J=15.0 Hz, 1H), 7.39 (dd, J=2.4, 8.7 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.61 (d, J=15.0 Hz, 1H), 7.62 (d, J=2.4 Hz, 1H), 7.66 (d, J=8.7 Hz, 1H), 8.43 (br d, 1H). MS (APCI) (M+H)+ at m/z 552, 554, 556.
The title compound was prepared by the procedures described in Example 38B substituting furoyl chloride with ethyl oxalyl chloride.
To a stirred solution of the ethyl ester (40 mg, 0.074 mmol) from Example 43A in 2 mL of ethanol was added saturated LiOH (0.25 mL). The mixture was then stirred at room temperature for 2 hours. Water (2 mL) was then added to the reaction mixture, which was then acidified to pH=2 with concentrated HCl. The precipitates were collected through filtration, washed with cold water, dried under vacuum to give the titled title compound (30 mg, 79%) as a light yellow solid. 1H NMR (d6-DMSO, 300 MHz) δ 3.52 (br m, 4H), 3.62 (br m, 2H), 3.76 (br m, 2H), 6.84 (d, J=9.0 Hz, 1H), 7.46 (d, J=15.3 Hz, 1H), 7.56 (d, J=15.3 Hz, 1H), 7.63 (dd, J=2.7, 8.7 Hz, 1H), 7.83 (d, J=9.0 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.96 (d, J=2.7 Hz, 1H), 8.70 (br d, 1H). MS (APCI) (M—COO)+ at m/z 466, 468, 470.
The title compound was prepared by the procedures described in Example 38A substituting compound from Example 37 with compound from Example 42. Light-yellow powder; 1H NMR (d6-DMSO, 300 MHz) δ 3.14 (s, 2H), 3.40 (overlapping br m, 4H), 3.44 (br m, 1H), 3.51 (br m, 1H), 3.57 (br m, 1H), 3.71 (br m, 1H), 6.82 (d, J=8.7 Hz, 1H), 7.42 (d, J=15.6 Hz, 1H), 7.52 (d, J=15.6 Hz, 1H), 7.63 (dd, J=2.4, 8.7 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.92 (dd, J=2.4, 8.7 Hz, 1H), 7.96 (d, J=2.4 Hz, 1H), 8.68 (d, J=2.4 Hz, 1H). MS (APCI) (M+H)+ at m/z 496, 498, 500.
The title compound was prepared by the procedures described in Example 32 substituting 2,4-dichlorothiophenol with o-thiocresol. Light-yellow powder; 1H NMR (d6-DMSO, 300 MHz) δ 2.03 (s, 3H), 2.29 (s, 3H), 3.47 (br m, 4H), 3.53 (br m, 1H), 3.60 (br m, 1H), 3.67 (br m, 1H), 3.83 (br m, 1H), 6.64 (d, J=8.7 Hz, 1H), 7.40 (d, J=15.0 Hz, 1H), 7.36-7.42 (m, 1H), 7.46-7.57 (m, 3H), 7.63 (d, J=6.9 Hz, 1H), 7.89 (dd, J=2.4, 9.0 Hz, 1H), 8.66 (d, J=2.4 Hz, 1H). MS (APCI) (M+H)+ at m/z 426.
The title compound was prepared by the procedures described in Example 32 substituting 2,4-dichlorothiophenol with 2-chlorothiophenol. Light-yellow powder; 1H NMR (d6-DMSO, 300 MHz) δ 2.04 (s, 3H), 3.47 (br m, 4H), 3.52 (br m, 1H), 3.60 (br m, 1H), 3.68 (br m, 1H), 3.73 (br m, 1H), 6.75 (d, J=9.0 Hz, 1H), 7.43 (d, J=15.3 Hz, 1H), 7.54 (d, J=15.3 Hz, 1H), 7.55 (dd, J=1.8, 8.1 Hz, 1H), 7.64 (t, J=1.8, 8.1 Hz, 1H), 7.76 (d, J=1.8, 8.1 Hz, 1H), 7.82 (d, J=1.8, 8.1 Hz, 1H), 7.93 (dd, J=2.4, 9.0 Hz, 1H), 8.68 (d, J=2.4 Hz, 1H). MS (APCI) (M+H)+ at m/z 446, 448, 450.
The title compound was prepared by the procedures described in Example 32 substituting 2,4-dichlorothiophenol with 2-aminothiophenol. Light-yellow powder; 1H NMR (d6-DMSO, 300 MHz) δ 2.04 (s, 3H), 3.47 (br m, 4H), 3.52 (br m, 1H), 3.60 (br m, 1H), 3.68 (br m, 1H), 3.74 (br m, 1H), 5.58 (s, 2H), 6.65 (td, J=1.5, 15.0 Hz, 1H), 6.72 (dd, J=1.5, 8.7 Hz, 1H), 7.00 (dd, J=1.8, 8.7 Hz, 1H), 7.27 (t, J=1.5, 8.6 Hz, 1H), 7.36 (dd, J=1.5, 8.7 Hz, 1H), 7.39 (d, J=15.3 Hz, 1H), 7.53 (d, J=15.3 Hz, 1H), 7.89 (dd, J=1.8, 8.7 Hz, 1H), 8/64 (d, J=1.8 Hz, 1H). MS (APCI) (M+H)+ at m/z 427.
The title compound was prepared by the procedures described in Example 32 substituting 2,4-dichlorothiophenol with 2-mercaptobenzyl alcohol. Light-yellow powder; 1H NMR (d6-DMSO, 300 MHz) δ 2.03 (s, 3H), 3.47 (br m, 4H), 3.52 (br m, 1H), 3.60 (br m, 1H), 3.67 (br m, 1H), 3.73 (br m, 1H), 4.53 (d, J=5.7 Hz, 1H), 5.34 (t, J=5.7 Hz, 1H), 6.65 (d, J=8.7 Hz, 1H), 7.40 (d, J=15.3 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.53 (d, J=15.3 Hz, 1H), 7.59 (d, J=7.5 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.87 (dd, J=2.1, 8.7 Hz, 1H), 8.65 (d, J=2.1 Hz, 1H). MS (APCI) (M+NH4)+ at m/z 459.
The title compound was prepared by the procedures described in Example 32 substituting 2,4-dichlorothiophenol with 2-ethylthiophenol. Light-yellow powder; 1H NMR (d6-DMSO, 300 MHz) δ 1.01 (t, J=7.65 Hz, 3H), 2.04 (s, 3H), 2.69 (q, J=7.65 Hz, 2H), 3.47 (br m, 4H), 3.52 (br m, 1H), 3.59 (br m, 1H), 3.67 (br m, 1H), 3.73 (br m, 1H), 6.64 (d, J=8.7 Hz, 1H), 7.38 (dd, J=2.4, 7.5 Hz, 1H), 7.40 (d, J=15.6 Hz, 1H), 7.50-7.61 (m, 3H), 7.53 (d, J=15.6 Hz, 1H), 7.89 (dd, J=2.4, 8.7 Hz, 1H), 8.64 (d, J=2.4 Hz, 1H). MS (APCI) (M+Cl)− at m/z 474, 476.
The title compound was prepared by the procedures described in Example 32 substituting 2,4-dichlorothiophenol with 2-isopropylthiophenol. Light-yellow powder; 1H NMR (d6-DMSO, 300 MHz) δ 1.05 (d, J=6.9 Hz, 6H), 2.04 (s, 3H), 3.47 (br m, 4H), 3.52 (br m, 1H), 3.60 (br m, 1H), 3.67 (br m, 1H), 3.72 (br m, 1H), 6.64 (d, J=8.4 Hz, 1H), 7.34-7.41 (m, 2H), 7.39 (d, J=15.3 Hz, 1H), 7.52 (d, J=15.3 Hz, 1H), 7.56-7.73 (m, 2H), 7.90 (dd, J=2.1, 8.7 Hz, 1H), 8.64 (d, J=2.1 Hz, 1H). MS (APCI) (M+NH4)30 at m/z 471. Analysis calculated for C24H27N3O4S1.0.21H2O: C, 63.03; H, 5.96; N, 9.13. Found: C, 63.03; H, 6.04; N, 9.19.
The title compound was prepared by the procedures described in Example 32 substituting 2,4-dichlorothiophenol with 2-tert-butylthiophenol. Light-yellow powder; 1H NMR (d6-DMSO, 300 MHz) δ 1.46 (s, 9H), 2.04 (s, 3H), 3.47 (br m, 4H), 3.52 (br m, 1H), 3.60 (br m, 1H), 3.67 (br m, 1H), 3.73 (br m, 1H), 6.68 (d, J=8.7 Hz, 1H), 7.35 (t, J=7.5 Hz, 1H), 7.39 (d, J=15.3 Hz, 1H), 7.45-7.57 (m, 2H), 7.50 (d, J=15.3 Hz, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.88 (dd, J=2.4, 8.7 Hz, 1H), 8.64 (d, J=2.4 Hz, 1H). MS (APCI) (M+NH4)+ at m/z 485.
The title compound was prepared by the procedures described in Example 1A substituting 2,4-dichlorothiophenol with 2-chlorothiophenol, and 2-chlorobenzaldehyde with 4′-fluoro-3′-chloroacetophenone.
To a stirred suspension of NaH (60% in mineral oil, 121 mg, 3.03 mmol) in 20 mL of anhydrous THF under nitrogen atmosphere was added triethyl phosphonoacetate dropwise. After 20 minutes, the acetophenone (600 mg, 2.02 mmol) from Example 52A in THF (5 mL) was added in one portion. The resulting clear solution was then stirred at room temperature for 7 hours. Reaction was then stopped, most of the solvent was evaporated, and the residue was partitioned between EtOAc (2×20 mL) and water. The combined organic layer was washed with water and brine, dried over Na2SO4, concentrated in vacuo. The crude product was purified using silica gel flash column chromatography eluting with 5-10% Et2O in hexanes to give the (E)-isomer of the cinnamate (500 mg, 68%) as a white solid.
A mixture of the cinnamate (500 mg, 1.37 mmol) from Example 52B in 5 mL of EtOH/THF (4:1) was stirred with sat. LiOH solution (0.50 mL) at 50° C. for 2 hours. The mixture was then acidified with 3N HCl and extracted with CH2Cl2 (3×10 mL). The combined organic layer was dried over MgSO4, concentrated under reduced pressure to give the titled title compound (450 mg, 97%) as a white solid.
The title compound was prepared using the cinnamic acid from Example 52C by the procedures described in Example 1C substituting 6-amino-1-hexanol with 1-acetylpiperazine. White solid; 1H NMR (CDCl3, 300 MHz) δ 2.10-2.20 (m, 3H), 2.25 (s, 3H), 3.40-3.80 (m, 8H), 6.28 (s, 1H), 7.00 (d, J=8.7 Hz, 1H), 7.19-7.36 (m, 4H), 7.46-7.56 (m, 2H). MS (APCI) (M+NH4)+ at m/z 466, 468, 470.
To a stirred solution of benzyl alcohol (195 mg, 0.32 mmol) from Example 11 in 2.0 mL of anhydrous DMF was added LiBr (48 mg, 0.35 mmol). The mixture was then cooled in an ice-water bath, and PBr3 (60 μL, 0.40 mmol) was dropped in slowly. The ice bath was then removed and the mixture was stirred at room temperature for 1 hour. Water was then added, the mixture was then partitioned between EtOAc and aqueous NaHCO3. The aqueous layer was extracted with EtOAc once. The combined organic layer was washed with water and brine, dried over Na2SO4, concentrated on a rotavap. The crude bromide (230 mg) was used directly for the alkylation without purification.
To a stirred solution of morpholine (10 μL, 0.11 mmol) in 0.5 mL of CH3CN was added Hunig base (23.7 μL, 0.14 mmol), followed by the bromide (40 mg, 0.091 mmol). The mixture was then stirred at room temperature for 2 hours. Solvent was then removed and the crude product was purified with Gilson Preparative HPLC as described in Example 38B to give the titled title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 2.33 (br t, 4H), 3.45 (br t, 4H), 3.50-3.65 (m, 6H), 3.56 (s, 2H), 3.65-3.80 (br m, 2H), 6.74 (d, J=8.7 Hz, 1H), 7.30 (d, J=15.3 Hz, 1H), 7.35-7.41 (m, 2H), 7.43 (d, J=15.3 Hz, 1H), 7.46 (td, J=2.4, 8.1 Hz, 1H), 7.52 (dd, J=2.1, 8.7 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/z 459, 461.
The title compound was prepared by the procedures described in Example 53B substituting morpholine with 1-piperonylpiperazine. White solid; 1H NMR (d6-DMSO, 300 MHz) δ 2.13-2.40 (br m, 8H), 3.28 (s, 2H), 3.49-3.64 (br m, 6H), 3.54 (s, 2H), 3.70 (br m, 2H), 5.97 (s, 2H), 6.69 (dd, J=1.8, 8.1 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 6.79 (d, J=1.8 Hz, 1H), 6.81 (d, J=8.1 Hz, 1H), 7.39 (d, J=15.3 Hz, 1H), 7.33-7.38 (m, 2H), 7.38-7.50 (m, 2H), 7.43 (d, J=15.3 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 8.00 (d, J=2.1 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/z 592, 594.
The title compound was prepared by the procedures described in Example 53B substituting morpholine with N-isopropyl-1-piperazineacetamide. White solid; 1H NMR (d6-DMSO, 300 MHz) δ 1.04 (d, J=6.3 Hz, 6H), 2.20-2.42 (br m, 8H), 2.78 (s, 2H), 3.47-3.64 (br m, 6H), 3.56 (s, 2H), 3.64-3.76 (br m, 2H), 3.85 (qd, J=6.3, 8.1 Hz, 1H), 6.73 (d, J=8.7 Hz, 1H), 7.29 (d, J=15.6 Hz, 1H), 7.31-7.39 (m, 2H), 7.43 (d, J=15.6 Hz, 1H), 7.45 (td, J=2.7, 6.3 Hz, 1H), 7.50 (dd, J=2.1, 8.7 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 8.00 (d, J=2.1 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/z 557, 559.
The title compound was prepared by the procedures described in Example 53B substituting morpholine with ethyl sarcosinate hydrochloride. White solid; 1H NMR (d6-DMSO, 300 MHz) δ 1.16 (t, J=7.2 Hz, 3H), 2.27 (s, 2H), 3.30 (s, 2H), 3.51-3.66 (br m, 6H), 3.66-3.75 (br m, 2H), 3.78 (s, 2H), 4.05 (q, J=7.2 Hz, 2H), 6.75 (d, J=8.7 Hz, 1H), 7.30 (d, J=15.3 Hz, 1H), 7.33-7.38 (m, 2H), 7.42-7.50 (m, 2H), 7.43 (d, J=15.3 Hz, 1H), 7.53 (dd, J=2.1, 8.7 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/z 489, 491.
To a stirred solution of the alcohol (368 mg, 0.94 mmol) from Example 11 in 5 mL of anhydrous acetonitrile was added activated 4 Å molecular sieves, TPAP (3.3 mg, 0.0094 mmol), and NMO (110 mg, 1.03 mmol). The mixture was then stirred at room temperature for 3 hours. The reaction mixture was then quenched with dimethyl sulfide (100 μL). The crude product was filtered through celite, washed with acetonitrile, and condensed in vacuo. The titled title compound was purified by silica gel column chromatography to give a white solid (216 mg, 59%). 1H NMR (d6-DMSO, 300 MHz) δ 3.60 (br m, 6H), 3.73 (br m, 2H), 7.00 (d, J=8.4 Hz, 1H), 7.40 (d, J=15.3 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.51 (d, J=15.3 Hz, 1H), 7.52 (td, J=1.8, 8.1 Hz, 1H), 7.61 (td, J=1.8, 8.1 Hz, 1H), 7.71 (dd, J=2.1, 8.4 Hz, 1H), 8.02 (dd, J=2.1, 8.4 Hz, 1H), 8.14 (d, J=2.1 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/z 388, 390.
The title compound was prepared by the procedures described in Example 53B substituting morpholine with 1-formyl piperazine. White solid; 1H NMR (d6-DMSO, 300 MHz) δ 2.20-2.32 (m, 6H), 2.74 (br m, 2H), 3.48 (s, 2H), 3.59 (m, 6H), 3.70 (br m, 2H), 6.74 (d, J=8.7 Hz, 1H), 7.29 (d, J=15.6 Hz, 1H), 7.35-7.41 (m, 2H), 7.42 (d, J=15.6 Hz, 1H), 7.45-7.52 (m, 3H), 7.98 (d, J=2.1, 1H). MS (DCI/NH3) (M+H)+ at m/z 486, 488.
A mixture of bromide (80 mg, 0.18 mmol) from Example 12, acryloylmorpholine (33 mg, 0.23 mmol), Pd(Oac)2 (2.0 mg, 0.009 mmol), P(o-tolyl)3 (17 mg, 0.056 mmol), Et3N (39 μL, 0.27 mmol), and anhydrous DMF (1.0 mL) in a pressure tube was flushed with nitrogen for 5 minutes before it was capped and heated at 110° C. over night overnight. TLC indicated almost complete consumption of the starting bromide. The reaction mixture was then allowed to cool down to room temperature, and partitioned between EtOAc and water. The aqueous layer was extracted once with EtOAc. The combined organic layer was washed with water and brine, dried over Na2SO4, and condensed under reduced pressure. The crude product was purified with Gilson Preparative HPLC as described in Example 38B to give the titled title compound as a light-brown solid (35 mg, 39%). 1H NMR (d6-DMSO, 300 MHz) δ 3.43-3.88 (m, 16H), 6.58 (d, J=8.7 Hz, 1H), 7.30 (d, J=15.3 Hz, 2H), 7.43 (d, J=15.3 Hz, 1H), 7.47-7.64 (m, 4H), 7.86 (d, J=15.3 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.14 (d, J=7.5 Hz, 1H). MS (DCI/NH3) (M+NH4)+ m/z 516, 518. Analysis calculated for C26H27N2O4Cl1S1.0.46H2O: C, 61.56; H, 5.55; N, 5.21. Found: C, 61.56; H, 5.50; N, 5.43.
The title compound was prepared by the procedures described in Example 57 substituting compound from Example 11 with compound from Example 48. Yellow solid; 1H NMR (d6-DMSO, 300 MHz) δ 2.04 (s, 3H), 3.47 (br m, 4H), 3.52 (br m, 1H), 3.60 (br m, 1H), 3.68 (br m, 1H), 3.74 (br m, 1H), 6.85 (d, J=8.4 Hz, 1H), 7.44 (d, J=15.6 Hz, 1H), 7.55 (d, J=15.6 Hz, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.73 (t, J=7.5 Hz, 1H), 7.80 (td, J=2.4, 7.5 Hz, 1H), 7.92 (dd, J=2.1, 9.0 Hz, 1H), 8.04 (dd, J=2.4, 7.5 Hz, 1H), 8.66 (d, J=2.1 Hz, 1H), 10.29 (s, 1H). MS (APCI) (M+Cl)− at m/z 474, 476.
A mixture of the aldehyde (20 mg, 0.052 mmol) from Example 57, 1,1-dimethyl hydrazine (3.9 μL, 0.052 mmol) in 0.5 mL of EtOH with a tiny amount of AcOH was stirred at room temperature over night overnight. The solvent was then removed and the product was purified by preparative TLC to give the titled title compound (20 mg, 90%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ 2.91 (s, 6H), 3.55-3.82 (br m, 8H), 6.64 (d, J=8.7 Hz, 1H), 6.76 (d, J=15.3 Hz, 1H), 7.05 (dd, J=1.8, 8.7 Hz, 1H), 7.26 (td, J=1.8, 7.8 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.47-7.57 (m, 2H), 7.54 (m, 2H), 8.04 (dd, J=1.8, 8.7 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/z 430, 432, 434, 436.
A mixture of bromide (60 mg, 0.14 mmol) from Example 12, aminopropylmorpholine (24 μL, 0.17 mmol), Pd2(dba)3 (1.2 mg, 0.0013 mmol), BINAP (2.5 mg, 0.004 mmol), NaOt-Bu (19 mg, 0.20 mmol), 18-crown-6 (50 mg, 0.20 mmol), and anhydrous toluene (1 mL) in a pressure tube was flushed with nitrogen for 3 minutes before it was capped and heated at 80° C. over night overnight. The reaction was then stopped, and allowed to cool down to room temperature. The reaction mixture was partitioned between EtOAc and water, and the aqueous layer was extracted once with EtOAc. The combined organic layer was then washed with water and brine, dried over Na2SO4, and condensed under reduced pressure. The crude product was purified with Gilson Preparative HPLC as described in Example 38B to give the titled title compound as a light-brown oil (30 mg, 44%). 1H NMR (d6-DMSO, 300 MHz) δ 1.62 (quintet, J=6.5 Hz, 2H), 2.15-2.26 (m, 8H), 3.17 (q, J=6.5 Hz, 2H), 3.22-3.76 (m, 12H), 3.50 (t, J=6.5 Hz, 2H), 5.72 (t, J=5.7 Hz, 1H), 6.47 (d, J=8.7 Hz, 1H), 6.68 (t, J=7.2 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 7.26 (d, J=15.6 Hz, 1H), 7.35-7.42 (m, 2H), 7.43 (d, J=15.6 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 8.00 (d, J=2.1 Hz, 1H). MS (APCI) (M+H)+ at m/z 502, 504.
A mixture of nitro compound (780 mg, 1.58 mmol) from Example 33, SnCl2 (1.50 g, 7.91 mmol) in 25 mL of anhydrous EtOH was refluxed under nitrogen atmosphere for 90 minutes. The reaction was then allowed to cool down to room temperature, quenched with sat. NaHCO3, and extracted with EtOAc (2×50 mL). The combined organic layer was washed with water and brine, dried over Na2SO4, and condensed in vacuo to give the crude aniline as a yellowish brown solid, which was converted to the bromide without purification.
To a stirred solution of t-butyl nitrite (57 μL, 0.48 mmol), CrBr2 (87 mg, 0.39 mmol) in 2.0 mL of CH3CN at room temperature was added a solution of aniline from Example 63A (150 mg, 0.323 mmol) in 1.0 mL of CH3CN. The dark green solution was then heated at 65° C. under nitrogen atmosphere for 90 minutes. The reaction mixture was then allowed to cool down to room temperature, and partitioned between EtOAc and 3N HCl. The organic layer was then washed with brine, dried over Na2SO4, and condensed in vacuo. The crude product was then purified with Gilson Preparative HPLC as described in Example 38B to give the titled title compound as a light-brown solid (50 mg, 29%). Colorless oil; 1H NMR (d6-DMSO, 300 MHz) δ 1.63 (quintet, J=7.2 Hz, 2H), 1.91 (quintet, J=8.4 Hz, 2H), 2.22 (t, J=8.4 Hz, 2H), 3.09-3.47 (m, 6H), 6.67 (d, J=15.3 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.38 (d, J=15.3 Hz, 1H), 7.50 (dd, J=2.4, 8.7 Hz, 1H), 7.57 (dd, J=2.1, 8.4 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.96 (d, J=2.1 Hz, 1H), 8.13 (t, J=6.0 Hz, 1H). MS (ESI) (M+H)+ at m/z 527, 529, 531, 533.
The title compound was prepared by the procedures described in Example 59 substituting the bromide from Example 12 with 2-fluoro-5-bromobenzaldehyde.
The title compound was prepared by the procedures described in Example 32 substituting 4-chloro-3-nitro-cinnamide with the compound from Example 64A. White solid: 1H NMR (d6-DMSO, 300 MHz) δ 3.60 (br m, 6H), 3.71 (br m, 2H), 6.82 (d, J=8.7 Hz, 1H), 7.35 (d, J=15.6 Hz, 1H), 7.54 (d, J=15.6 Hz, 1H), 7.55 (dd, J=2.4, 8.7 Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.86 (dd, J=2.4, 8.4 Hz, 1H), 7.91 (d, J=2.4 Hz, 1H), 8.41 (d, J=2.1 Hz, 1H), 10.19 (s, 1H). MS (DCI/NH3) (M+H)+ at m/z 422, 424, 426, 428.
The title compound was prepared by the procedures described in Example 1 substituting 2,4-dichlorothiophenol with methyl 3-mercaptopropionate, and 6-amino-1-hexanol with 1-acetyl piperazine.
To a stirred solution of the compound (105 mg, 0.26 mmol) from Example 65A in 2 mL of THF under nitrogen atmosphere at 0° C. was added t-BuOK solution (1.0M, 281 μL, 0.29 mmol). Light orange precipitates appeared immediately. After completion of the addition, the reaction mixture was stirred at room temperature for 1 hour before the solvent was removed on a rotavap under reduced pressure.
The yellow thiolate thus obtained was dissolved in 0.5 mL of DMF, and 2,3-dichlorobenzaldehyde was then added. The mixture was then heated at 80° C. under nitrogen for 2 hours. Reaction was then stopped and the solvent was removed under vacuum. The crude product was purified with Gilson Preparative HPLC as described in Example 38B to give the titled title compound as a white solid (25 mg, 21%). 1H NMR (CDCl3, 300 MHz) δ 2.05 (s, 3H), 3.48-3.58 (m, 2H), 3.58-3.84 (m, 6H), 6.53 (d, J=8.7 Hz, 1H), 6.80 (d, J=15.3 Hz, 1H), 7.19 (dd, J=1.8, 8.7 Hz, 1H), 7.51-7.62 (m, 2H), 7.60 (d, J=15.3 Hz, 1H), 7.84 (dd, J=1.8, 8.4 Hz, 1H), 7.99 (dd, J=1.8, 8.4 Hz, 1H). MS (APCI) (M+NH4)+ at m/z 480, 482, 484.
Compounds that antagonize the interaction between ICAM-1 and LFA-1 can be identified, and their activities quantitated, using both biochemical and cell-based adhesion assays. A primary biochemical assay measures the ability of the compound in question to block the interaction between the integrin LFA-1 and its adhesion partner ICAM-1, as described below:
ICAM-1/LFA-1 Biochemical Interaction Assay
In the biochemical assay, 100 μL of anti-LFA-1 antibody (ICOS Corporation) at a concentration of 5 μg/ml mL in Dulbecco's phosphate-buffered saaline (D-PBS) is used to coat wells of a 96-well microtiter plate overnight at 4° C. The wells are were then washed twice with wash buffer (D-PBS w/o Ca++ or Mg++, 0.05% Tween 20) and blocked by addition of 200 μL of D-PBS, 5% fish skin gelatin. Recombinant LFA-1 (100 μL of 0.7 μg/ml mL, ICOS Corporation) in D-PBS is was then added to each well. Incubation continues continued for 1 hour at room temperature and the wells are were washed twice with wash buffer. Serial dilutions of compounds being assayed as ICAM-1/LFA-1 antagonists, were prepared as 10 mM stock solutions in dimethyl sulfoxide (DMSO), are were diluted in D-PBS, 2 mM MgCl2, 1% fish skin gelatin and 50 μL of each dilution was added to duplicate wells. This is was followed by the addition of 50 μL of 0.8 μg/ml mL biotinylated recombinant ICAM-1/Ig (ICOS Corporation) to the wells and the plates are were incubated at room temperature for 1 hour. The wells are were then washed twice with wash buffer and 100 μL of Europium-labeled Streptavidin (Wallac Oy) diluted 1:100 in Delfia assay buffer (Wallac Oy), are was then added to the wells. Incubation proceeds proceeded for 1 hour at room temperature. The wells are were washed eight times with wash buffer and 100 μL of enhancement solution (Wallac Oy, cat. No. 1244-105) are was added to each well. Incubation proceeds proceeded for 5 minutes with constant mixing. Time-resolved fluorimetry measurements are were made using the a Victor 1420 Multilabel Counter (Wallac Oy) and the percent inhibition of each candidate compound is was calculated using the following equation:
where “background” refers to wells that are were not coated with anti-LFA-1 antibody.
Compounds of the present invention exhibit exhibited inhibitory activity in the above assay as follows:
Compound
% inhibition
of Example
@ 4 μM
1
75
2
73
3
75
4
72
5
73
6
85
7
87
8
74
9
93
10
79
11
87
12
90
13
79
14
82
15
88
16
86
17
84
18
86
19
93
20
82
21
80
22
90
23
90
24
80
25
82
26
94
27
94
28
87
29
84
30
93
31
92
32
92
33
91
34
91
35
89
36
90
37
91
38
91
39
86
40
90
41
83
42
56
43
82
44
78
45
88
46
87
47
82
48
89
49
93
50
94
51
84
52
86
53
87
54
86
55
82
56
83
57
90
58
80
59
92
60
95
61
88
62
92
63
82
64
81
65
86
Biological relevant activity of the compounds in this invention is confirmed using a cell-based adhesion assay, which measures their ability to block the adherence of JY-8 cells (a human EBV-trasformed B cell line expressing LFA-1 on its surface) to immobilized ICAM-1, as follows:
ICAM-1/JT-8 Cell Adhesion Assay
For measurment measurement of inhibotory inhibitory activity in the cell-based adhesion assay, 96-well microtiter plates are were coated with 70 μL of recombinat recombinant ICAM-1/Ig (ICOS Corporation) at a concentration of 5 μg/mL in D-PBS w/o without Ca++ or Mg++ or Mg++ overnight at 4° C. The wells are were then washed twice with D-PBS and blocked by addition of 200 μL of D-PBS, 5% fish skin gelatin by incubation for 1 hour at room temperature. Fluorescent tagged JY-8 cells (a human EBV-transformed B cell line expresing expressing LFA-1 on its surface; 50 μL at 2×106 cells/ml mL in RPMI 1640/1% fetal bovene bovine serum) are were added to the wells. For fluorescent labelind labelling of JY-8 cells, 5×106 cells washed once in RPMI 1640 are were resuspended in 1 mL of RPMI 1640 containing 2 μM Calceiun AM (Molecular Probes), are were incubated at 37° C. for 30 minutes, and washed once with RPMI-1640/1% fetal bovine serum. Dilutions of compounds to be assayed for ICAM-1/LFA-1 antagonistic activity are were prepared in RPMI-1640/1% fetal bovine serum from 10 mM stock solutions in DMSO and 50 μL are were added to duplicate wells. Microtiter plates are were incubated for 45 minutes at room temperature and the wells are were washed gently once with RPMI-1640/1% fetal bovine serum. Fluorescent intensity is was measured in a fluorescent plate reader with an excitation wavelength at 485 nM and an emission wavelength at 530 nM. The percent inhibition of a candidate compound at a given concentration is was calculated using the following equation:
and these concentration/inhibition data are were used to generate does response curves, from which IC50 values are were derived. Compounds of the present invention exhibit exhibited blocking activity in the above assay as follows:
Compound
of Example
IC50 nM
1
2,100
2
13,000
3
2,500
4
680
5
2,900
6
660
7
1,200
8
2,900
9
130
10
1,500
11
260
12
360
13
1,100
14
790
15
140
16
300
17
5,800
18
130
19
450
20
3,300
21
520
22
200
23
600
24
8,000
25
11,000
26
110
27
160
28
370
29
160
30
250
32
190
32
45
33
300
34
70
35
430
36
320
37
140
38
250
39
250
40
280
41
110
42
520
43
100
44
70
45
50
46
60
47
370
48
200
49
20
50
10
51
690
52
420
53
700
54
360
55
100
56
510
57
220
58
1,600
59
200
60
30
61
540
62
340
63
850
65
1,200
Compounds of the present invention have been demonstrated to act via interaction with the integrin LFA-1, specifically by binding to the interaction domain (I-domain), which is known to be critical for the adhesion of LFA-1 to a variety of cell adhesion molecules. As such, it is expected that these compounds should block the interaction of LFA-1 with other CAM's. This has in fact been demonstrated for the case of ICAM-3. Compounds of the present invention may be evaluated for their ability to block the adhesion of JY-8 cells (a human EBV-transformed B cell line expressing LFA-1 on its surface) to immobilized ICAM-3, as follows:
ICAM-3/JY-8 Cell Adhesion Assay
For measurement of inhibitory activity in the cell-based adhesion assay, 96-well microtiter plates are were coated with 50 μL of recombinant ICAM-3/Ig (ICOS Corporation) at a concentration of 10 μg/mL in D-PBS w/o without Ca++ or Mg++ overnight at 4° C. The wells are were then washed twice with D-PBS, blocked by addition of 100 μL of D-PBS, 1% bovine serum albumin (BSA) by incubation for 1 hour at room temperature, and washed once with RPMI-1640/5% heat-inactivated fetal bovine serum (adhesion buffer). Dilutions of compounds to be assayed for ICAM-3/LFA-1 antagonistic activity are were prepared in adhesion buffer from 10 mM stock solutions in DMSO and 100 μL are were added to duplicate wells. JY-8 cells (a human EBV-transformed B cell line expressing LFA-1 on its surface; 100 μL at 0.75×106 cells/ml mL in adhesion buffer) are were then added to the wells. Microtiter plates are were incubated for 30 minutes at room temperature; the adherent cells are were then fixed with 50 μL of 14% glutaraldehyde/D-PBS and were incubated for an additional 90 minutes. The wells are were washed gently with dH2O; 50 μL of dH2O is was added, following followed by 50 μL of 1% crystal violet. After 5 minutes the plates are were washed 3× times with dH2O; 75 μL of dH2O and 225 μL of 95% EtOH are were added to each well to extract the crystal violet from the cells. Absorbance is was measured at 570 nM in an ELISA plate reader. The percent inhibition of a candidate compound is was calculated using the following equation.
Compounds of the present invention exhibit exhibited blocking activity in the above assay as follows. :
Compound
% inhibition
Of Example
@ 0.6 μM
9
100
12
100
15
100
16
100
17
100
18
100
26
100
27
100
30
100
32
100
34
100
35
100
41
100
45
100
46
100
49
100
50
100
54
100
59
100
60
100
62
100
The ability of the compounds of this invention to treat arthritis can be demonstrated in a murine collagen-induced arthritis model according to the method of Kakimoto, et al., Cell Immunol 142: 326-337, 1992, in a rat collagen-induced arthritis model according to the method of Knoerzer, et al., Toxicol Pathol 25:13-19, 1997, in a rat adjuvant arthritis model according to the method of Halloran, et al., Arthitis Arthritis Rheum 39: 810-819, 1996, in a rat streptococcal cell wall-induced arthritis model according to the method of Schimmer, et al., J. Immunol 160: 1466-1477, 1998, or in a SCID-mouse human rheumatoid arthritis model according to the method of Oppenheimer-Marks et al., J Clin. Invest 101: 1261-1272, 1998.
The ability of the compounds of this invention to treat Lyme arthritis can be demonstrated according to the method of Gross et al., Science 281, 703-706, 1998.
The ability of compounds of this invention to treat asthma can be demonstrated in a murine allergic asthma model according to the method of Wegner et al., Science 247:456-459, 1990, or in a murine non-allergic asthma model according to the method of Bloemen et al., Am J Respir Crit Care Med 153:521-529, 1996.
The ability of compounds of this invention to treat inflammatory lung injury can be demonstrated in a murine oxygen-induced lung injury model according to the method of Wegner et al., Lung 170:267-279, 1992, in a murine immune complex-induced lung injury model according to the method of Mulligan et al., J Immunol 154:1350-1363, 1995, or in a murine acid-induced lung injury model according to the method of Nagase, et al., Am J Respir Crit Care Med 154:504-510, 1996.
The ability of compounds of this invention to treat inflammatory bowel disease can be demonstrated in a rabbit chemical-induced colitis model according to the method of Bennet et al., J Pharmacol Exp Ther 280:988-1000, 1997.
The ability of compounds of this invention to treat autoimmune diabetes can be demonstrated in an NOD mouse model according to the method of Hasagawa et al., Int Immunol 6:831-838, 1994, or in a murine streptozotocin-induced diabetes model according to the method of Herrold et al., Cell Immunol 157:489-500, 1994.
The ability of compounds of this invention to treat inflammatory liver injury can be demonstrated in a murine liver injury model according to the method of Tanaka et al., J Immunol 151:5088-5095, 1993.
The ability of compounds of this invention to treat inflammatory glomerular injury can be demonstrated in a rat nephrotoxic serum nephritis model according to the method of Kawasaki, et al., J Immunol 150:1074-1083, 1993.
The ability of compounds of this invention to treat radiation-induced enteritis can be demonstrated in a rat abdominal irradiation model according to the method of Panes et al., Gastroenterology 108:1761-1769, 1995.
The ability of compounds of this invention to treat radiation pneumonitis can be demonstrated in a murine pulmonary irradiation model according to the method of Hallahan et al., Proc Natl Acad Sci USA 94:6432-6437, 1997.
The ability of compounds of this invention to treat reperfusion injury can be demonstrated in the isolated rat heart according to the method of Tamiya et al., Immunopharmacology 29(1): 53-63, 1995, or in the anesthetized dog according to the model of Hartman et al., Cardiovasc Res 30(1): 47-54, 1995.
The ability of compounds of this invention to treat pulmonary reperfusion injury can be demonstrated in a rat lung allograft reperfusion injury model according to the method of DeMeester et al., Transplantation 62(10): 1477-1485, 1996, or in a rabbit pulmonary edema model according to the method of Horgan et al., Am J Physiol 261(5): H1578-H1584, 1991.
The ability of compounds of this invention to treat stroke can be demonstrated in a rabbit cerebral embolism stroke model according the method of Bowes et al., Exp Neurol 119(2): 215-219, 1993, in a rat middle cerebral artery ischemia-reperfusion model according to the method of Chopp et al., Stroke 25(4): 869-875, 1994, or in a rabbit reversible spinal cord ischemia model according to the method of Clark et al., Neurosurg 75(4): 623-627, 1991.
The ability of compounds of this invention to treat peripheral artery occlusion can be demonstrated in a rat skeletal muscle ischemia/reperfusion model according to the method of Gute et al., Mol Cell Biochem 179: 169-187, 1998.
The ability of compounds of this invention to treat graft rejection can be demonstrated in a murine cardiac allograft rejection model according to the method of Isobe et al., Science 255: 1125-1127, 1992, in a murine thyroid gland kidney capsule model according to the method of Talento et al., Transplantation 55: 418-422, 1993, in a cynomolgus monkey renal allograft model according to the method of Cosimi et al., J Immunol 144: 4604-4612, 1990, in a rat nerve allograft model according to the method of Nakao et al., Muscle Nerve 18: 93-102, 1995, in a murine skin allograft model according to the method of Gorczynski and Wojcik, J Immunol 152: 2011-2019, 1994, in a murine corneal allograft model according to the method of He et al., Opthalmol Vis Sci 35: 3218-3225, 1994, or in a xenogeneic pancreatic islet cell transplantation model according to the method of Zeng et al., Transplantation 58:681-689, 1994.
The ability of compounds of this invention to treat graft-vs.-host disease (GVHD) can be demonstrated in a murine lethal GVHD model according to the method of Haming et al., Transplantation 52:842-845, 1991.
The ability of compounds of this invention to treat cancers can be demonstrated in a human lymphoma metastasis model (in mice) according to the method of Aoudjit et al., J Immunol 161:2333-2338, 1998.
Liu, Gang, Xin, Zhili, Link, James T., Winn, Martin, Pei, Zhonghua, von Geldern, Tom
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