Urea substituted imidazopyridines

Details Urea substituted imidazopyridines Urea substituted imidazopyridines

2003-02-04

2004-04-06

Aulakh, Charanjit S. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S296000, C546S290000

Reexamination Certificate

active

06716988

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to imidazopyridine compounds that have urea or thiourea functionality 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. The invention also provides methods of making the compounds and intermediates useful in their synthesis.
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.
Substituted 1H-imidazopyridine-4-amine compounds useful as immune response modifiers are described in U.S. Pat. Nos. 5,446,153; 5,494,916; and
5,644,063. The compounds described in these patents do not have amine containing substitution at the
1-position. Certain 1H-imidazo[4,5-c]quinolin-4-amines that have amide, sulfonamide, and urea functionality at the 1-position are described in PCT Publications WO 00/76505, WO 00/76518 and U.S. Pat. No. 6,331,539. All of the above-mentioned patents and published patent applications are incorporated herein by reference.
Despite these recent discoveries of 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 imidazopyridine-4-amine compounds that have urea or thiourea functionality at the 1-position. The compounds which have been found to be useful inducers of cytokine biosynthesis are defined by Formula (I), which is described in more detail infra. Formula (I) is as follows:
wherein X, Y, Z, R
1
, R
2
, R
3
, R
4
, and R
5
are as defined herein.
The compounds of Formula (I) 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) to the animal.
In addition, the invention provides methods of synthesizing the compounds of the invention and intermediates useful in the synthesis of these compounds.
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 Formula (I) below:
wherein
X is alkylene or alkenylene;
Y is —CO— or —CS—;
Z is —NR
6
—; —NR
6
—CO—; —NR
6
—SO
2
—; or —NR
7
—;
R
1
is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of:
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-substituted cycloalkyl;
-substituted aryl;
-substituted heteroaryl;
substituted heterocyclyl;
—O-alkyl;
—O-(alkyl)
0-1
-aryl;
—O-(alkyl)
0-1
-substituted aryl;
—O-(alkyl)
0-1
-heteroaryl;
—O-(alkyl)
0-1
-substituted heteroaryl;
—O-(alkyl)
0-1
-heterocyclyl;
—O-(alkyl)
0-1
-substituted heterocyclyl;
—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;
—S(O)
0-2
-(alkyl)
0-1
-heterocyclyl;
—S(O)
0-2
-(alkyl)
0-1
-substituted heterocyclyl;
-(alkyl)
0-1
-N(R
6
)
2
;
-(alkyl)
0-1
-NR
6
—CO—O-alkyl;
-(alkyl)
0-1
-NR
6
—CO-alkyl;
-(alkyl)
0-1
-NR
6
—CO-aryl;
-(alkyl)
0-1
-NR
6
—CO-substituted aryl;
-(alkyl)
0-1
-NR
6
—CO-heteroaryl;
-(alkyl)
0-1
-NR
6
—CO-substituted heteroaryl;
P(O)(Oalkyl)
2
;
—N
3
;
-halogen;
-haloalkyl;
-haloalkoxy;
—CO-haloalkyl;
—CO-haloalkoxy;
—NO
2
;
—CN;
—OH;
—SH; and in the case of alkyl, alkenyl, and heterocyclyl, oxo;
R
2
is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-substituted aryl;
-heteroaryl;
-substituted heteroaryl;
-alkyl-O-alkyl;
-alkyl-S-alkyl;
-alkyl-O-aryl;
-alkyl-S-aryl:
-alkyl-O-alkenyl;
-alkyl-S— alkenyl; and
-alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
—OH;
-halogen;
—N(R
6
)
2
;
—CO—N(R
6
)
2
;
—CS—N(R
6
)
2
;
—SO
2
—N(R
6
)
2
;
—NR
6
—CO—C
1-10
alkyl;
—NR
6
—CS—C
1-10
alkyl;
—NR
6
—SO
2
—C
1-10
alkyl;
—CO—C
1-10
alkyl;
—CO—O—C
1-10
alkyl;
—N
3
;
-aryl;
-substituted aryl;
-heteroaryl;
-substituted heteroaryl;
-heterocyclyl;
-substituted heterocyclyl;
-CO-aryl;
—CO-(substituted aryl);
—CO-heteroaryl; and
—CO-(substituted heteroaryl);
R
3
and R
4
are independently selected from the group consisting of hydrogen, alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthio;
R
5
is H or C
1-10
alkyl, or R
5
can join with X to form a ring that contains one or two hetero atoms;
each R
6
is independently H or C
1-10
alkyl;
R
7
is H or C
1-10
alkyl which may be interrupted by one or more heteroatoms or when R
1
is alkyl, R
7
and R
1
can join to form a ring;
or a pharmaceutically acceptable salt thereof.
Preparation of the Compounds
Compounds of the invention can be prepared according to Reaction Scheme I where R
1
, R
2
, R
3
, R
4
, R
5
, X, Y and Z are as defined above, Bn is benzyl and R′ is alkyl of one to four carbon atoms, perfluoroalkyl of one to four carbon atoms, phenyl, or phenyl substituted by halogen or alkyl of one to four carbon atoms.
In step (I) of Reaction Scheme I a 3-nitropyridine-2,4-disulfonate of Formula X is reacted with an amine of Formula R
1
-Z-Y—N(R
5
)—X—NH
2
to provide a 3-nitro-4-aminopyridine-2-sulfonate of Formula XI. Due to the presence of two sulfonate groups that could in principle be displaced, the reaction may provide a mixture of products that can be readily separated using conventional techniques such as column chromatography. The reaction is preferably carried out by adding the amine to a solution of a compound of Formula X in a suitable solvent such as dichloromethane in the presence of a tertiary amine such as triethylamine. As the sulfonate group is a relatively facile leaving group, the reaction can be run at a reduced temperature (0° C.) in order to decrease the amount of undesired 2-aminated and 2,4-diaminated side products. 3-Nitropyridine-2,4-disulfonates are known and can be readily prepared using known synthetic methods, see for example, Lindstom et al., U.S. Pat. No. 5,446,153 and the references cited therein.
In step (2) of Reaction Scheme I a 3-nitro-4-am

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