Sulfonamide and sulfamide substituted imidazoquinolines

Details Sulfonamide and sulfamide substituted imidazoquinolines Sulfonamide and sulfamide substituted imidazoquinolines

2003-04-28

2004-01-13

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...

C514S228500, C514S253030, C546S082000, C544S060000, C544S361000, C544S364000

Reexamination Certificate

active

06677349

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to imidazoquinoline compounds that have sulfonamide or sulfamide substitution at the 1-position and to pharmaceutical compositions containing the 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, as seen for example in WO 98/30562, EP 894 797 and WO 00/09506. EP 894 797 discloses amide substituted imidazoquinoline compounds that are disclosed to be useful as immune response modifying compounds, while WO 00/09506 discloses imidazoquinoline compounds that contain a sulfonamide substituent wherein the sulfonamide nitrogen is part of a saturated heterocyclic ring. Despite these efforts, however, 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 compounds of Formula I:
wherein R, R
1
and R
2
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 reponse 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 pharmaceutial compositions containing a therapeutically effective amount of a compound of Formula I and methods of inducing cytokine biosynthesis in an animal, treating a viral infection and/or treating a neoplastic disease in an animal by administering a effective amount of a compound of Formula I to the animal.
In addition, methods of synthesizing compounds of Formula I and intermediates useful in the synthesis of these compounds are provided.
DETAILED DESCRIPTION OF THE INVENTION
As mentioned earlier, the invention provides compounds of Formula I:
wherein
R
1
is -alkyl-NR
3
—SO
2
—X—R
4
or -alkenyl-NR
3
—SO
2
—X—R
4
;
X is a bond or —R
5
—;
R
4
is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from the group consisting of:
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-substituted aryl;
-substituted heteroaryl;
-substituted heterocyclyt;
-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
-R
3
R
3
;
-(alkyl)
0-1
-NR
3
—CO—O-alkyl;
-(alkyl)
0-1
-NR
3
—CO-alkyl;
-(alkyl)
0-1
-NR
3
—CO-aryl;
-(alkyl)
0-1
-NR
3
—CO-substituted aryl;
-(alkyl)
0-1
-R
3
—CO-heteroaryl;
-(alkyl)
0-1
-R
3
—CO-substituted heteroaryl;
—N
3
;
-halogen;
-haloalkyl;
-haloalkoxy;
—CO-haloalkoxy;
—NO
2
;
—CN;
—OH;
—SH; and in the case of alkyl alkenyl, or heterocyclyl, oxo;
R
2
is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-substituted aryl;
-heteroaryl;
-substituted heteroaryl;
-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;
—
3
;
-aryl;
-substituted aryl;
-heteroaryl;
-substituted heteroaryl;
-heterocyclyl;
-substituted heterocyclyl;
—CO-aryl;
—CO-(substituted aryl);
—CO-heteroaryl; and
—CO-(substituted heteroaryl);
each R
3
is independently selected from the group consisting of hydrogen and C
1-10
alkyl;
R
5
is selected from the group consisting of hydrogen and C
1-10
alkyl, or R
4
and R
5
can combine to form a 3 to 7 membered heterocyclic or substituted heterocyclic ring;
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.
Preparation of the Compounds
Imidazoquinolines of the invention can be prepared according to Reaction Scheme I where R, R
1
, R
2
and n are as defined above.
In step (1) of Reaction Scheme I a 4-chloro-3-nitroquinoline of Formula II is reacted with an amine of Formula R
1
NH
2
where R
1
is as defined above to provide a 3-nitroquinolin-4-amine of Formula III. The reaction can be carried out by adding amine to a solution of a compound of Formula II in a suitable solvent such as chloroform or dichloromethane and optionally heating. Many quinolines of Formula II are known compounds (see for example, U.S. Pat. No. 4,689,338 and references cited therein).
In step (2) of Reaction Scheme I a 3-nitroquinolin-4-amine of Formnula III is reduced to provide a quinoline-3,4-diamine of Formula IV. Preferably, the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon or palladium on carbon. The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as isopropyl alcohol or toluene.
In step (3) of Reaction Scheme I a quinoline-3,4-diamine of Formula IV is reacted with a carboxylic acid or an equivalent thereof to provide a 1H-imidazo[4,5-c]quinoline of Formula V. Suitable equivalents to carboxylic acid include acid halides, orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired R
2
substituent in a compound of Formula V. For example, triethyl orthoformate will provide a compound where R
2
is hydrogen and triethyl orthoacetate will provide a compound where R
2
is methyl. The reaction can be run in the absence of solvent or in an inert solvent such as toluene. The reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction.
In step (4) of Reaction Scheme I a 1H-imidazo[4,5-c]quinoline of Formula V is oxidized to provide a 1H-imidazo[4,5-c]quinoline-5N-oxide of Formula VI using a conventional oxidizing agent that is capable of forming N-oxides. Preferred reaction conditions involve reacting a solution of a compound of Formula V in chloroform with 3-chloroperoxybenzoic acid at ambient conditions.
In step (5) of Reaction Scheme I a 1H-imidazo[4,5-c]quinoline-5N-oxide of Formula VI is aminated to provide a

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