Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-12-02
2004-10-26
Desai, Rita (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S080000, C546S116000
Reexamination Certificate
active
06809203
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to oxazolo, thiazolo and selenazolo[4,5-c]-quinolin-, tetrahydroquinolin-4-amines and hetero analogs thereof, and to intermediates used in their preparation. The invention also relates to pharmaceutical compositions containing the above compounds as well as the use of these compounds as immunomodulators and for inducing cytokine biosynthesis, including interferon-&agr; biosynthesis and/or tumor necrosis factor-&agr; biosynthesis.
BACKGROUND OF THE INVENTION AND RELATED PRIOR ART
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 have been reported. For example, Jain et al.,
J. Med. Chem.
11, pp. 87-92 (1968), has 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), and Berenyi et al.,
J. Heterocyclic Chem.
18, 1537-1540 (1981), have reported certain 2-oxoimidazo[4,5-c]quinolines.
Following the above report, 1H-imidazo[4,5-c]quinolin-4-amines and 1- and 2-substituted derivatives thereof were found to be useful as antiviral agents, bronchodilators and immunomodulators. These are described in U.S. Pat. Nos. 4,689,338; 4,698,348; 4,929,624; 5,037,986; 5,266,675; 5,268,376; 5,346,905; 5,389,640; 5,605,899; 5,352,784; 5,446,153; and 5,482,936. Shen et al., U.S. Pat. Nos. 4,038,396 and 4,131,677, describe certain oxazolo-and thiazolopyridines as having antiinflammatory, analgesic, and antipyretic properties.
SUMMARY OF THE INVENTION
The present invention provides compounds of the Formula I
wherein:
R
1
is selected from the group consisting of oxygen, sulfur and selenium;
R
2
is selected from the group consisting of
-hydrogen;
-alkyl;
-alkyl-OH;
-haloalkyl;
-alkenyl;
-alkyl-X-alkyl;
-alkyl-X-alkenyl;
-alkenyl-X-alkyl;
-alkenyl-X-alkenyl;
-alkyl-N(R
5
)
2
;
-alkyl-N
3
;
-alkyl-O—C(O)—N(R
5
)
2
;
-heterocyclyl;
-alkyl-X-heterocyclyl;
-alkenyl-X-heterocyclyl;
-aryl;
-alkyl-X-aryl;
-alkenyl-X-aryl;
-heteroaryl;
-alkyl-X-heteroaryl; and
-alkenyl-X-heteroaryl;
R
3
and R
4
are each independently:
-hydrogen;
-X-alkyl;
-halo;
-haloalkyl;
—N(R
5
)
2
;
or when taken together, R
3
and R
4
form a fused aromatic, heteroaromatic, cycloalkyl or heterocyclic ring;
X is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —OC(O)—, and a bond; and
each R
5
is independently H or C
1-8
alkyl;
with the proviso that when R
1
is sulfur, R
3
is not —NH
2
; or a pharmaceutically acceptable salt thereof.
As a second aspect, the present invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula I(a) and a pharmaceutically acceptable vehicle:
wherein:
R
1
is selected from the group consisting of oxygen, sulfur and selenium;
R
2
is selected from the group consisting of
-hydrogen;
-alkyl;
-alkyl-OH;
-haloalkyl;
-alkenyl;
-alkyl-X-alkyl;
-alkyl-X-alkenyl;
-alkenyl-X-alkyl;
-alkenyl-X-alkenyl;
-alkyl-N(R
5
)
2
;
-alkyl-N
3
;
-alkyl-O—C(O)—N(R,)
2
;
-heterocyclyl;
-alkyl-X-heterocyclyl;
-alkenyl-X-heterocyclyl;
-aryl;
-alkyl-X-aryl;
-alkenyl-X-aryl;
-heteroaryl;
-alkyl-X-heteroaryl; and
-alkenyl-X-heteroaryl;
R
3
and R
4
are each independently:
-hydrogen;
-X-alkyl;
-halo;
-haloalkyl;
—N(R
5
)
2
;
or when taken together, R
3
and R
4
form a fused aromatic, heteroaromatic, cycloalkyl or heterocyclic ring;
X is selected from the group consisting of —O—, —S—, —NR
5
—, —C(O)—, —C(O)O—, —OC(O)—, and a bond; and
each R
5
is independently H or C
1-8
alkyl; or a pharmaceutically acceptable salt thereof.
The compounds of Formula I(a) are useful in inducing the biosynthesis of certain cytokines in animals, including humans. Cytokines that may be induced by the compounds of the invention include but are not limited to, interferons, particularly interferon-&agr;, and tumor necrosis factor-&agr;. The invention therefore also provides a method of inducing cytokine biosynthesis in an animal by administering to the animal an effective amount of a composition comprising a compound of Formula I(a). Because of their ability to induce cytokine biosynthesis the compounds of the invention are useful in the treatment of a variety of conditions, including viral and neoplastic diseases, and the invention further provides a method of treating such conditions in a subject by administering a therapeutically effective amount of a composition comprising a compound of Formula I(a) to the subject.
As yet another aspect, the present invention provides intermediate compounds of Formula II
wherein:
R
1
is selected from the group consisting of oxygen, sulfur and selenium;
R
2
is selected from the group consisting of
-hydrogen;
-alkyl;
-alkyl-OH;
-haloalkyl;
-alkenyl;
-alkyl-X-alkyl;
-alkyl-X-alkenyl;
-alkenyl-X-alkyl;
-alkenyl-X-alkenyl;
-alkyl-N(R
5
)
2
;
-alkyl-N
3
;
-alkyl-O—C(O)—N(R
5
)
2
;
-heterocyclyl;
-alkyl-X-heterocyclyl;
-alkenyl-X-heterocyclyl;
-aryl;
-alkyl-X-aryl;
-alkenyl-X-aryl;
-heteroaryl;
-alkyl-X-heteroaryl;
-alkenyl-X-heteroaryl;
—SO
2
CH
3
; and
—CH
2
—O—C(O)—CH
3
;
R
3
and R
4
are each independently:
-hydrogen;
-X-alkyl;
-halo;
-haloalkyl;
—N(R
5
)
2
;
or when taken together, R
3
and R
4
form a fused aromatic, heteroaromatic, cycloalkyl or heterocyclic ring;
X is selected from the group consisting of —O—, —S—, —NR
5
—, —C(O)—, —C(O)O—, and a bond; and
each R
5
is independently H or C
1-8
alkyl.
REFERENCES:
patent: 4031230 (1977-06-01), Gottschlich et al.
patent: 4038396 (1977-07-01), Shen et al.
patent: 4131677 (1978-12-01), Shen et al.
patent: 4689338 (1987-08-01), Gerster et al.
patent: 4698348 (1987-10-01), Gerster
patent: 4778811 (1988-10-01), Knoll et al.
patent: 4904669 (1990-02-01), Knoll et al.
patent: 4929624 (1990-05-01), Gerster et al.
patent: 5037986 (1991-08-01), Gerster
patent: 5268376 (1993-12-01), Gester
patent: 5312822 (1994-05-01), Albaugh
patent: 5346905 (1994-09-01), Gerster
patent: 5352784 (1994-10-01), Nikolaides et al.
patent: 5389640 (1995-02-01), Gerster et al.
patent: 5446153 (1995-08-01), Lindstrom et al.
patent: 5451585 (1995-09-01), Albaugh
patent: 5482936 (1996-01-01), Lindstrom
patent: 0 055 248 (1982-06-01), None
patent: 2 184 117 (1987-06-01), None
patent: WO 93/05042 (1993-03-01), None
patent: WO 95/02597 (1995-01-01), None
patent: WO 95/02598 (1995-01-01), None
patent: WO 98/16514 (1998-04-01), None
patent: WO 98/42712 (1998-10-01), None
Tetrahedron Letters, vol. 22, No. 22, pp 2121-2124, 1981 Printed in Great Britain.
Chem. Abstract 95:114500, (1981).
Chem. Abstract 86:16608, (1977).
Temple, Smith Kussner, and Montgomery, “Synthesis of Imidazo [4,5-b]pyridines and V-Triazolo [4,5-b]pyridines. Preparation of 1-Deaza-6-thioguanine Analogues”, J. Org. Chem, vol. 41, No. 24, 1976, pp. 3784-3788.
Bachman et al.,J. Org. Chem. 15, 1278-1284 (1950).
Jain et al.,J. Med. Chem. 11, pp. 87-92 (1968).
Baranov et al.,Chem. Abs. 85, 94362 (1976).
Berenyi et al.,J. Heterocyclic Chem. 18, 1537-1540 (1981).
Berge SM, et al., “Pharmaceutical Salts,”J. Pharm. Sci. 1977;66:1.
Bachman et al.,Journal of the American Chemical Society, 69, pp 365-371 (1947).
Ambrogi et al.,Synthesis, pp. 656-658 (1992).
Adler et al.,Journal of the Chemical Society, pp. 1794-1797 (1960).
Süs et al.,Justus Liebigs Annalen der Chemie, 583, pp. 150-160 (1953).
Süs et al.,Justus Liebigs Annalen der Chemie, 593, pp. 91-126 (1955).
G. L. Brennan and L. H. Kronenberg in “Automated Bioassay of Interferons in Micro-test Plates”, Biotechniques, Jun./Jul., 78, 1983.
Testerman et al. In “Cytokine Induction by the Immunomodulators Imiquimod and S-27609”,Journal of Leukocyte Biology, 58, 365-372 (Sep., 1995).
Gerster John F.
Lindstrom Kyle J.
Marszalek Gregory J.
Merrill Bryon A.
Mickelson John W.
3M Innovative Properties Company
Desai Rita
Ersfeld Dean A.
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