Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-02-20
2004-03-09
Desai, Rita (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S082000, C546S083000, C546S084000
Reexamination Certificate
active
06703402
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
5
—, —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
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
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:
-hyhrogen;
-X-alkyl;
-halo;
-haloalkyl;
or when taken together, and 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.
DETAILED DESCRIPTION OF THE INVENTION
This invention includes compounds of Formula I, pharmaceutical compositions containing compounds of Formula I(a) and therapeutic methods using compounds of Formula I(a) as well as intermediate compounds of Formula II that are used to prepare the compounds of Formulae I and I(a).
The terms “alkyl” and “alkenyl” as used herein refer to a straight or branched hydrocarbon group, or a cyclic group (i.e., cycloalkyl and cycloalkenyl) that contains from 1 to 20, preferably 1 to 10, more preferably 1 to 8 carbon atoms, unless otherwise specified. Typical alkyl groups are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Exemplary cyclic groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl and adamantyl. The prefix “alk,” when used, e.g. for “alkoxy” and the like, also has the same meaning.
The term “aryl” refers to a carbocyclic aromatic ring or ring system. The aryl group is preferably a six-membered ring, such as phenyl, or an aromatic polycyclic ring system, such as naphthyl. The most preferred aryl group is phenyl which may be unsubstituted or substituted by one or more substituents as defined below. Examples of other suitable aryl groups include biphenyl, fluorenyl and indenyl.
The term “heteroaryl” refers to an aromatic ring or ring system that contains one or more heteroatoms, in which the heteroatoms are selected from nitrogen, oxygen and sulfur. Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, tetrazolyl, imidazo, and so on. In the case where R
3
and R
4
are taken together and form a 5- or 6-membered heteroaromatic ring, the heteroatom is nitrogen, oxygen or sulfur and the ring may contain one or more of such atoms. Preferably, the heteroatom is nitrogen or sulfur. Preferred heteroaromatic rings formed by R
3
and R
4
are illustrated by the following formulae where the two lines indicate where they are fused.
The terms “heterocyclic” and “heterocyclyl” refer to non-aromatic rings or ring systems that contain one or more ring heteroatoms (e.g., O, S, N). Exemplary heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidino, piperazino, thiazolidinyl, imidazolidinyl, and the like.
All of the above rings and ring system
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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