Quinoline derivatives

Details Quinoline derivatives Quinoline derivatives

2002-04-25

2003-07-15

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...

C514S232800, C514S291000, C544S128000, C546S090000, C546S155000

Reexamination Certificate

active

06593343

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel substituted quinoline-3-carboxamide derivatives, to methods for their preparation, to compositions containing them, and to methods and use for clinical treatment of disease resulting from autoimmunity, such as multiple sclerosis, insulin-dependent diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and psoriasis and, furthermore, diseases where pathologic inflammation plays a major role, such as asthma, atherosclerosis, stroke and Alzheimer's disease. More particularly, the present invention relates to novel quinoline derivatives suitable for the treatment of, for example, multiple sclerosis and its manifestations.
BACKGROUND OF THE INVENTION
Autoimmune diseases, e.g. multiple sclerosis (MS), insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus (SLE), rheumatoid arthritis (R
A
), inflammatory bowel disease (IBD) and psoriasis represent assaults by the body's immune system which may be systemic in nature, or else directed at individual organs in the body. They appear to be diseases in which the immune system makes mistakes and, instead of mediating protective functions, becomes the aggressor (1).
MS is the most common acquired neurologic disease of young adults in Western Europe and North America. It accounts for more disability and financial loss, both in lost income and in medical care, than any other neurologic disease of this age group. There are approximately 250.000 cases of MS in the United States.
Although the cause of MS is unknown, advances in brain imaging, immunology, and molecular biology have increased researchers' understanding of this disease. Several therapies are currently being used to treat MS, but no single treatment has demonstrated dramatic treatment efficacy. Current treatment of MS falls into three categories: treatment of acute exacerbations, modulation of progressive disease, and therapy for specific symptoms.
MS affects the central nervous system and involves a demyelination process, i.e., the myelin sheaths are lost whereas the axons are preserved. Myelin provides the isolating material that enables rapid nerve impulse conduction. Evidently, in demyelination, this property is lost. Although the pathogenic mechanisms responsible for MS are not understood, several lines of evidence indicate that demyelination has an immunopathologic basis. The pathologic lesions, the plaques, are characterized by infiltration of immunologically active cells such as macrophages and activated T cells (2).
In U.S. Pat. No. 4,547,511 and in U.S. Pat. No. 4,738,971 and in EP 59,698 some derivatives of N-aryl-1,2-dihydro-4-substituted-1-alkyl-2-oxo-quinoline-3-carboxamide are claimed as enhancers of cell-mediated immunity. The compound
known as roquinimex (Merck Index 12
th
Ed., No. 8418; Linomide®, LS2616, N-phenyl-N-methyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide) belongs to this series of compounds. Roquinimex has been reported to have multiple immunomodulatory activities not accompanied with general immunosuppression (3-12).
Furthermore, in U.S. Pat. No. 5,580,882 quinoline-3-carboxamide derivatives are claimed to be useful in the treatment of conditions associated with MS. The particular preferred compound is roquinimex. In U.S. Pat. No. 5,594,005 quinoline-3-carboxamide derivatives are claimed to be useful in the treatment of type I diabetes. The particular preferred compound is roquinimex.
In WO 95/24195 quinoline-3-carboxamide derivatives are claimed to be useful in the treatment of inflammatory bowel disease. Particularly preferred compounds are roquinimex or a salt thereof. In WO95/24196 quinoline-3-carboxamide derivatives are claimed to be useful in the treatment of psoriasis. Particularly preferred compounds are roquinimex or a salt thereof.
In clinical trials comparing roquinimex to placebo, roquinimex was reported to hold promise in the treatment of conditions associated with MS (13,14). There are, however, some serious drawbacks connected to roquinimex. For example, it has been found to be teratogenic in the rat, and to induce dose-limiting side effects in man, e.g. a flu-like syndrome, which prevents from using the full clinical potential of the compound.
Further, in WO 92/18483 quinoline derivatives substituted in the 6-position with a RAS(O)
n
-group (R
A
=lower alkyl or aryl; n=0-2) are claimed, which posses an immunomodulating, anti-inflammatory and anti-cancer effect.
The substitution, i.e., type and pattern, of the above, specifically mentioned, compounds in the prior art places them outside the scope of the present invention.
DESCRIPTION OF THE INVENTION
A primary objective of the present invention is to provide structurally novel quinoline compounds which by virtue of their pharmacological profile, with high potency in experimental models and low level of side-effects, are considered to be of value in the treatment of disease resulting from autoimmunity and pathologic inflammation. Examples of such disease are multiple sclerosis, insulin-dependent diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and psoriasis and other diseases where inflammation plays a major role, such as asthma, atherosclerosis, stroke and Alzheimer's disease. More particularly, the present invention relates to novel quinoline derivatives suitable for the treatment of, for example, multiple sclerosis and its manifestations.
The term “treatment” as used herein includes prophylaxis as well as relieving the symptoms of disease.
It has now surprisingly been found that the novel compounds of general formula (I)
wherein
R is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl and allyl;
R′ is selected from methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, and OCH
x
F
Y
,
wherein x=0-2,
y=1-3 with the proviso that
x+y=3;
R″ is selected from hydrogen, fluoro and chloro, with the proviso that R″ is selected from fluoro and chloro only when R′ is selected from fluoro and chloro;
R
4
is selected from hydrogen and pharmaceutically acceptable inorganic cations, such as sodium, potassium and calcium, and organic cations such as monoethanolamine, diethanolamine, dimethylaminoethanol, morpholine and the like;
R
5
is selected from ethyl, n-propyl, iso-propyl, methoxy, ethoxy, chloro, bromo, trifluoromethyl, and OCH
x
F
y
, and OCH
2
CH
x
F
y
wherein x=0-2,
y=1-3 with the proviso that
x+y=3;
R
6
is hydrogen; or
R
5
and R
6
taken together are methylenedioxy;
are unexpectedly effective and specific in the treatment of individuals suffering from autoimmune and inflammatory diseases.
The compounds of general formula (I) may exist in different tautomeric forms and all such forms where such forms exist are included herein.
In a preferred embodiment of the invention R
4
is selected from hydrogen or sodium,
R
5
is selected from ethyl, methoxy, chloro and trifluoromethyl,
R
5
and R
6
taken together are methylenedioxy,
R′ is selected from methyl, methoxy, fluoro, chloro and trifluoromethyl when R″ is hydrogen and
R″ is selected from metal- and para-fluoro provided that R′ is ortho-fluoro.
Among the most preferred compounds of general formula (I) according to the present invention are:
N-ethyl-N-(3-fluoro-phenyl)-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxamide,
N-ethyl-N-(4-methoxy-phenyl)-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxamide,
N-methyl-N-(2,4-difluoro-phenyl)-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxamide,
N-methyl-N-(2,5-difluoro-phenyl)-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxamide,
N-ethyl-N-(3-methoxy-phenyl)-1,2-dihydro-4-hydroxy-5-ethyl-1-methyl-2-oxo-quinoline-3-carboxamide,
N-methyl-N-(2-fluoro-phenyl)-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,
N-methyl-N-(2,4-difluoro-phenyl)-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-o

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