N-1 BRANCHED IMIDAZOQUINOLINES, CONJUGATES THEREOF, AND METHODS
Imidazoquinoline compounds, salts thereof, conjugates thereof, pharmaceutical compositions containing the compounds and conjugates, and methods of use of such compounds as immune response modifiers, for inducing cytokine biosynthesis in humans and animals.
1 . A compound of Formula (I), or salt thereof:
wherein:
n is an integer of 0 or 1;
R is selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, and —C(O)—O-alkyl;
R1 is —(C1-C3)alkylene-O—(C1-C3)alkyl; and
R2 is a —(C1-C18)alkylene group or —(C2-C18)alkenylene group, optionally including one or more catenary non-peroxidic —O— atoms.
2 . The compound of claim 1 , which is:
3 . The compound or salt of claim 1 , wherein n is 0.
4 . The compound or salt of claim 1 , wherein R1 is —CH 2 OCH 3 or —CH 2 OCH 2 CH 3 .
5 . The compound or salt of claim 1 , wherein R2 is a —(C1-C18)alkylene group, optionally including one or more catenary non-peroxidic —O— atoms.
6 . A compound of Formula (II), or salt thereof:
wherein:
n is an integer of 0 or 1;
R is selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, and —C(O)—O-alkyl;
R1 is —(C1-C3)alkylene-O—(C1-C3)alkyl;
R2 is a —(C1-C18)alkylene group or —(C2-C18)alkenylene group, optionally including one or more catenary non-peroxidic —O— atoms; and
R3 is selected from the group consisting of alkyl, aryl, and aralkyl, wherein:
the alkyl or alkyl portion of the aralkyl optionally includes one or more catenary non-peroxidic —O— atoms;
the alkyl or alkyl portion of the aralkyl optionally is terminated with a functional group selected from the group consisting of amine (—NH 2 ), carboxyl (—C(O)OH), hydroxyl (—OH), and thiol (—SH); and
the aryl or aryl portion of the aralkyl is optionally substituted with halogen, hydroxyl, alkyl, alkoxy, or combinations thereof.
7 . The compound of claim 6 , which is:
8 . The compound or salt of claim 6 , wherein n is 0.
9 . The compound or salt of claim 6 , wherein R1 is —CH 2 OCH 3 or —CH 2 OCH 2 CH 3 .
10 . The compound or salt of claim 6 , wherein R2 is a —(C1-C18)alkylene group, optionally including one or more catenary non-peroxidic —O— atoms.
11 . The compound or salt of claim 6 , wherein R3 is selected from the group consisting of —(C1-C10)alkyl, —(C6-C20)aryl, and —(C6-C20)ar-(C1-C10)alkyl, wherein:
the alkyl or alkyl portion of the aralkyl optionally includes one or more catenary non-peroxidic —O— atoms;
the alkyl or alkyl portion of the aralkyl optionally is terminated with a functional group selected from the group consisting of amine, carboxyl, hydroxyl, and thiol; and
the aryl or aryl portion of the aralkyl is optionally substituted with halogen, hydroxyl, alkyl, alkoxy, or combinations thereof.
12 . A compound of Formula (III), or salt thereof:
wherein:
n is an integer of 0 or 1;
R is selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, and —C(O)—O-alkyl;
R1 is —(C1-C3)alkylene-O—(C1-C3)alkyl;
R2 is a —(C1-C18)alkylene group or —(C2-C18)alkenylene group, optionally including one or more catenary non-peroxidic —O— atoms; and
Linker is a crosslinking group;
m is an integer of 0 or 1;
Q is a functional group for bonding to a polymeric moiety or second active moiety.
13 . The compound of claim 12 , which is:
14 . The compound or salt of claim 12 , wherein the Linker is an alkylene group, optionally including one or more catenary non-peroxidic —O— atoms, amine groups (—NH—), ester groups, amide groups (—NH—C(O)—), disulfide groups (—S—S—), carbonate groups (—O—C(O)—O—), carbamate groups (—O—C(O)—NH—), or combinations thereof.
15 . The compound or salt of claim 12 , wherein Q is selected from the group consisting of an amine (—NH 2 ), an aminooxy (—O—NH 2 ), a carboxylic acid (—C(O)OH), an acyl hydrazide (—C(O)—NHNH 2 ), a hydroxyl (—OH), an aldehyde (—C(O)H), an N-hydroxysuccinimide ester
a maleimide
and a pentafluorophenyl ester
16 . An IRM-containing conjugate of Formula (IV), or salt thereof:
wherein:
n is an integer of 0 or 1;
R is selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, and —C(O)—O-alkyl;
R1 is —(C1-C3)alkylene-O—(C1-C3)alkyl;
R2 is a —(C1-C18)alkylene group or —(C2-C18)alkenylene group, optionally including one or more catenary non-peroxidic —O— atoms;
Linker is a crosslinking group;
m is an integer of 0 or 1;
Z is a polymeric moiety or second active moiety; and
the -Linker m -Z portion of the conjugate, with or without a linker, optionally includes a labile bond.
17 . The IRM-containing conjugate of claim 16 , which is:
18 . The conjugate or salt of claim 16 , wherein m is 1.
19 . A pharmaceutical composition comprising the IRM-containing conjugate or salt of claim 16 and a pharmaceutically acceptable carrier.
20 . A method of inducing cytokine biosynthesis in a human or animal comprising administering an effective amount of a pharmaceutical composition of claim 19 to the human or animal.