Amide substituted imidazoquinolines

Details Amide substituted imidazoquinolines Amide substituted imidazoquinolines

2001-12-21

2004-06-29

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S082000

Reexamination Certificate

active

06756382

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to imidazoquinoline compounds that have an amide containing substituent at the 1-position, and to pharmaceutical compositions containing such compounds. A further aspect of this invention relates to the use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals, and in the treatment of diseases, including viral and neoplastic diseases.
BACKGROUND OF THE INVENTION
The first reliable report on the 1H-imidazo[4,5-c]quinoline ring system, Backman et al.,
J. Org. Chem
. 15, 1278-1284 (1950) describes the synthesis of 1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]quinoline for possible use as an antimalarial agent. Subsequently, syntheses of various substituted 1H-imidazo[4,5-c]quinolines were reported. For example, Jain et al.,
J. Med. Chem
. 11, pp. 87-92 (1968), synthesized the compound 1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline as a possible anticonvulsant and cardiovascular agent. Also, Baranov et al.,
Chem. Abs
. 85, 94362 (1976), have reported several 2-oxoimidazo[4,5-c]quinolines, and Berenyi et al.,
J. Heterocyclic Chem
. 18, 1537-1540 (1981), have reported certain 2-oxoimidazo[4,5-c]quinolines.
Certain 1H-imidazo[4,5-c]quinolin-4-amines and 1- and 2-substituted derivatives thereof were later found to be useful as antiviral agents, bronchodilators and immunomodulators. These are described in, inter alia, U.S. Pat. Nos. 4,689,338; 4,698,348; 4,929,624; 5,037,986; 5,268,376; 5,346,905; and 5,389,640, all of which are incorporated herein by reference.
There continues to be interest in the imidazoquinoline ring system. For example, EP 894 797 describes imidazoquinoline compounds that bear an amide containing substituent at the 1-position. The active compounds of this series require a terminal amine substituent that may be incorporated into a heterocyclic ring. As another example, WO 00/09506 describes imidazopyridine and imidazoquinoline compounds that may have an amide or urea containing substituent at the 1-position. The compounds described in this publication as having utility contain a 1-substituent wherein the amide or urea nitrogen is part of a heterocyclic ring. Despite these attempts to identify compounds that are useful as immune response modifiers, there is a continuing need for compounds that have the ability to modulate the immune response, by induction of cytokine biosynthesis or other mechanisms.
SUMMARY OF THE INVENTION
We have found a new class of compounds that are useful in inducing cytokine biosynthesis in animals. Accordingly, this invention provides imidazoquinoline-4-amine and tetrahydroimidazoquinoline-4-amine compounds that have an amide containing substituent at the 1-position. The compounds which have been found to be useful inducers of cytokine biosynthesis are defined by Formulae (I), (Ia), and (Ib), which are defined in more detail infra. These compounds share the general structural formula (I):
wherein R
1
, R
2
, and R are as defined herein for each class of compounds having formulas (I), (Ia), and (Ib). The invention also provides novel compounds of formulas (Ic), (Id), and (Ie) as defined herein, which compounds are also useful as immune response modifiers and which also have the same general structural formula (I) above.
The compounds of Formulae (I), (Ia), (Ib), (Ic), (Id), and (Ie) are useful as immune response modifiers due to their ability to induce cytokine biosynthesis and otherwise modulate the immune response when administered to animals. This makes the compounds useful in the treatment of a variety of conditions such as viral diseases and tumors that are responsive to such changes in the immune response.
The invention further provides pharmaceutical compositions containing the immune response modifying compounds, and methods of inducing cytokine biosynthesis in an animal, treating a viral infection in an animal, and/or treating a neoplastic disease in an animal by administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) to the animal.
In addition, methods of synthesizing the compounds of the invention and intermediates useful in the synthesis of these compounds are provided.
DETAILED DESCRIPTION OF THE INVENTION
As mentioned earlier, we have found that certain compounds induce cytokine biosynthesis and modify the immune response in animals. Such compounds are represented by Formulae (I), (Ia), (Ib), (Ic), (Id), and (Ie), as shown below.
The invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula (I):
wherein
R
1
is -alkyl-NR
3
—CO—R
4
or -alkenyl-NR
3
—CO—R
4
wherein R
4
is aryl, heteroaryl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from the group consisting of:
-alkyl;
-alkenyl;
-alkynyl;
-(alkyl)
0-1
-aryl;
-(alkyl)
0-1
-(substituted aryl);
-(alkyl)
0-1
-heteroaryl;
-(alkyl)
0-1
-(substituted heteroaryl);
—O-alkyl;
—O-(alkyl)
0-1
-aryl;
—O-(alkyl)
0-1
-(substituted aryl);
—O-(alkyl)
0-1
-heteroaryl;
—O-(alkyl)
0-1
-(substituted heteroaryl);
—CO-aryl;
—CO-(substituted aryl);
—CO-heteroaryl;
—CO-(substituted heteroaryl);
—COOH;
—CO—O-alkyl;
—CO-alkyl;
—S(O)
0-2
-alkyl;
—S(O)
0-2
-(alkyl)
0-1
-aryl;
—S(O)
0-2
-(alkyl)
0-1
-(substituted aryl);
—S(O)
0-2
-(alkyl)
0-1
-heteroaryl;
—S(O)
0-2
-(alkyl)
0-1
-(substituted heteroaryl);
—P(O)(OR
3
)
2
;
—NR
3
—CO—O-alkyl;
—N
3
;
-halogen;
—NO
2
;
—CN;
-haloalkyl;
—O-haloalkyl;
—CO-haloalkyl;
—OH;
—SH; and in the case of alkyl, alkenyl, or heterocyclyl, oxo;
or R
4
is
wherein R
5
is an aryl, (substituted aryl), heteroaryl, (substituted heteroaryl), heterocyclyl or (substituted heterocyclyl) group;
R
2
is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-(substituted aryl);
-heteroaryl;
-(substituted heteroaryl);
-heterocyclyl;
-(substituted heterocyclyl);
-alkyl-O-alkyl;
-alkyl-O-alkenyl; and
-alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
—OH;
-halogen;
—N(R
3
)
2
;
—CO—N(R
3
)
2
;
—CO—C
1-10
alkyl;
—CO—O—C
1-10
alkyl;
—N
3
;
-aryl;
-(substituted aryl);
-heteroaryl;
-(substituted heteroaryl);
-heterocyclyl;
-(substituted heterocyclyl);
—CO-aryl; and
—CO-heteroaryl;
each R
3
is independently selected from the group consisting of hydrogen; C
1-10
alkyl-heteroaryl; C
1-10
alkyl-(substituted heteroaryl); C
1-10
alkyl-aryl; C
1-10
alkyl-(substituted aryl) and C
1-10
alkyl;
n is 0 to 4;
and each R present is independently selected from the group consisting of C
1-10
alkyl, C
1-10
alkoxy, halogen and trifluoromethyl, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective carrier.
The invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula (Ia):
wherein
R
1
is -alkyl-NR
3
—CO—R
4
or -alkenyl-NR
3
—CO—R
4
wherein R
4
is aryl, heteroaryl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from the group consisting of:
-heterocyclyl;
-(substituted heterocyclyl);
-(alkyl)
0-1
heterocyclyl;
-(alkyl)
0-1
(substituted heterocyclyl);
—O-(alkyl)
0-1
heterocyclyl;
—O-(alkyl)
0-1
(substituted heterocyclyl);
—S(O)
0-2
-(alkyl)
0-1
heterocyclyl; and
—S(O)
0-2
-(alkyl)
0-1
(substituted heterocyclyl);
R
2
is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-(substituted aryl);
-heteroaryl;
-(substituted heteroaryl);
-heterocyclyl;
-(substituted heterocyclyl);
-alkyl-O-alkyl;
-alkyl-O-alkenyl; and
-alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
—OH;
-halogen;
—N(R
3
)
2
;
—CO—N(R
3
)
2
;
—CO—C
1-10
alkyl;
—CO—O—C
1-10
alkyl;
—N
3
;
-aryl;
-(substituted aryl);
-heteroaryl;
-(substituted heteroaryl);
-heterocyclyl;
-(substituted heterocyclyl);
—CO-aryl; and
—CO-heteroaryl;
each R
3
is independently selected from the group consisting of hydrogen; C
1-10
alkyl-heteroaryl; C
1-

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