Thioether substituted imidazoquinolines

Details Thioether substituted imidazoquinolines Thioether substituted imidazoquinolines

2002-06-07

2003-12-23

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S082000, C546S084000, C546S159000, C544S316000, C514S293000

Reexamination Certificate

active

06667312

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to imidazoquinoline compounds that have thioether 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.
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.
Certain 1H-imidazo[4,5-c]naphthyridine-4-amines, 1H-imidazo[4,5-c]pyridin-4-amines, and 1H-imidazo[4,5-c]quinolin-4-amines having an ether containing substituent at the 1 position are known. These are described in U.S. Pat. Nos. 5,268,376; 5,389,640; 5,494,916; and WO 99/29693.
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 a thioether containing substituent at the 1-position. The compounds are defined by Formulas (I) and (II), which are defined in more detail infra. These compounds share the general structural formula:
wherein X, Z, R
1
, R
2
, and R are as defined herein for each class of compounds having Formulas (I) and (II).
The compounds of formulas (I) and (II) 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) or (II) to the animal.
In addition, the invention provides methods of synthesizing the compounds of the invention.
DETAILED DESCRIPTION OF THE INVENTION
As mentioned earlier, we have found certain compounds that induce cytokine biosynthesis and modify the immune response in animals. Such compounds are represented by Formulas (I) and (II) as shown below.
Imidazoquinoline compounds of the invention, which have thioether functionality at the 1-position are represented by Formula (I):
wherein:
X is —CHR
3
—, —CHR
3
-alkyl-, or —CHR
3
-alkenyl-;
Z is —S—, —SO—, or —SO
2
—;
R
1
is selected from the group consisting of:
-alkyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkenyl;
—R
4
-aryl;
—R
4
-heteroaryl;
—R
4
-heterocyclyl;
R
2
is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y-alkenyl;
-alkyl-Y-aryl; 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;
-heteroaryl;
-heterocyclyl;
—CO-aryl; and
—CO-heteroaryl;
each R
3
is independently H or C
1-10
alkyl;
R
4
is alkyl or alkenyl;
each Y is independently —O— or —S(O)
0-2
—;
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, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
The invention also includes tetrahydroimidazoquinoline compounds that bear a thioether containing substituent at the 1-position. Such tetrahydroimidazoquinoline compounds are represented by Formula (II):
wherein:
X is —CHR
3
—, —CHR
3
-alkyl-, or —CHR
3
-alkenyl-;
Z is —S—, —SO—, or —SO
2
—;
R
1
is selected from the group consisting of:
-alkyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkenyl;
—R
4
-aryl;
—R
4
-heteroaryl; and
—R
4
-heterocyclyl;
R
2
is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y-alkenyl;
-alkyl-Y-aryl; 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;
-heteroaryl;
-heterocyclyl;
—CO-aryl; and
—CO-heteroaryl;
each R
3
is independently H or C
1-10
alkyl;
R
4
is alkylene or alkenylene;
Y is —O— or —S(O)
0-2
—;
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, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof
Preparation of the Compounds
Compounds of the invention can be prepared according to Reaction Scheme I where R, R
1
, R
2
, X and n are as defined above.
In step (1) of Reaction Scheme I a 4-chloro-3-nitroquinoline of Formula X is reacted with an amine of formula HO—X—NH
2
to provide a 3-nitroquinolin-4-amine of Formula XI. The reaction can be carried out by adding the amine to a solution of a compound of Formula X in a suitable solvent such as chloroform or dichloromethane in the presence of triethylamine and optionally heating. Many quinolines of Formula X are known compounds (see for example, U.S. Pat. No. 4,689,338 and references cited therein). Many amines of formula HO—X—NH
2
are commercially available; others can be readily prepared using known synthetic routes.
In step (2) of Reaction Scheme I a 3-nitroquinolin-4-amine of Formula XI is chlorinated to provide a 3-nitroquinolin-4-amine of Formula XII. Conventional chlorinating agents can be used. Preferably the reaction is carried out by combining a compound of Formula XI with thionyl chloride in a suitable solvent such as dichloromethane. The reaction may be run at ambient temperature or it may be heated. Alternatively the reaction may be run neat.
In step (3) of Reaction Scheme I a 3-nitroquinolin-4-amine of Formula XII is reduced to provide a quinoline-3,4-diamine of Formula XIII. Preferably, the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon. The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as toluene.
In step (4) of Reaction Scheme I a quinoline-3,4-diamine of Formula XIII is reacted with a carboxylic acid or an equivalent thereof to provide a 1H-imidazo[4,5-c]quinoline of Formula XIV. Suitable equivalents to a carboxylic acid include orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired R
2
substitue

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