Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-04
2003-03-18
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S237800, C514S252120, C514S331000, C514S428000, C540S609000, C540S610000, C544S168000, C544S400000, C546S231000, C546S233000, C546S332000, C546S336000, C546S337000, C548S565000, C548S567000
Reexamination Certificate
active
06534499
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a novel N-substituted-N′-substituted urea derivative, a pharmaceutical composition containing the same, a TNF-&agr; production inhibitory agent and a therapeutic agent for treating an autoimmune disease.
TNF-&agr; (Tumor Necrosis Factor-&agr;) has presently been recognized as a cytokine strongly correlated with biological protection-immunological mechanism, but the continuous and excess production of TNF-&agr; causes various tissue disorders and this accordingly becomes a principal cause of a variety of diseases and exacerbation. For instance, examples of pathogenesis associated with TNF-&agr; include articular rheumatism, systemic erythematodes (SLE), dyscrasia, acute infectious diseases, allergy, fever, anemia and diabetes (YAMAZAKI, Clinical Immunology, 1995, 27:1270). Moreover, it has also been reported that TNF-&agr; plays an important role in the crisis of chronic rheumatism and Crohn's disease, which are autoimmune diseases (Andreas Eigler et al., Immunology Today, 1997, 18:487).
Accordingly, a compound capable of inhibiting the production of TNF-&agr; or controlling the action thereof would be effective in the treatment of the foregoing diseases and therefore, a variety of investigations have been done to obtain such a compound (the foregoing articles: YAMAZAKI, Clinical Immunology, 27; Andreas Eigler et al., Immunology Today, 18).
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a novel compound having an activity of inhibiting TNF-&agr; production.
It is another object of the present invention to provide an intermediate useful in the preparation of the foregoing compound.
It is a further object of the present invention to provide a pharmaceutical composition containing the foregoing compound, a TNF-&agr; production inhibitory agent and a therapeutic agent for treating autoimmune diseases.
The inventors of this invention have conducted intensive studies to synthesize a compound having a urea structure as a basic structure, which has not conventionally been investigated as a drug, have established a large number of novel compounds, have found that N-substituted-N′-substituted urea derivatives represented by the following general formula I among the foregoing novel compounds show an excellent TNF-&agr; production inhibitory activity and thus have completed the present invention on the basis of the foregoing finding.
More specifically, the present invention herein provides an N-substituted-N′-substituted urea derivative represented by the following general formula I as well as a pharmaceutically acceptable salt thereof:
wherein R
1
represents a hydrogen atom, a lower alkyl group, an aryl group or a group represented by the following general formula II:
wherein R
2
represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a carboxyl group or an ester group, or R
2
may form a ring together with R
1
; R
3
and R
4
may be the same or different and each represents a hydrogen atom, a lower alkyl group, a cycloalkylalkyl group, an adamantylalkyl group, an arylalkyl group, a cycloalkyl group or an aryl group; R
5
represents a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group or an aryl group; R
6
and R
7
may be the same or different and each represents a hydrogen atom, a lower alkyl group, a cycloalkylalkyl group, a cycloalkyl group or an aryl group; A
1
and A
2
may be the same or different and each represents a lower alkylene group, provided that R
5
and either R
6
or R
7
together or R
6
and R
7
together form a 5- to 7-membered ring and that either of the substituents R
3
and R
4
represents a cycloalkylalkyl group, an adamantylalkyl group or an arylalkyl group.
According to the present invention, there are also provided N-substituted-N′-substituted urea derivatives represented by the following general formula III as well as salts thereof:
The present invention likewise provides a pharmaceutical composition, a TNF-&agr; production inhibitory agent and a therapeutic agent for treating autoimmune diseases, which comprise the foregoing N-substituted-N′-substituted urea derivative or a pharmaceutically acceptable salt thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
In the present invention, the lower alkyl group may be, for instance, linear or branched alkyl groups having 1 to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl and isohexyl groups, with alkyl groups having 1 to 6 being preferred. The lower alkyl group is more preferably those having 1 to 3 carbon atoms, in particular, methyl group. Examples of cycloalkyl groups are those having 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups, with those having 3 to 6 carbon atoms being preferred and cyclohexyl group being particularly preferred. Examples of lower alkoxy groups include linear or branched alkoxy groups having 1 to 8 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and hexyloxy groups, with those having 1 to 5 carbon atoms being preferred and those having 1 to 3 carbon atoms being particularly preferred.
These lower alkyl, cycloalkyl and lower alkoxy groups may be substituted wiTNFor instance, halogen atoms (such as fluorine, chlorine, iodine and bromine atoms) and/or a hydroxyl group. Moreover, the cycloalkyl group may be substituted with a lower alkyl group and/or a lower alkoxy group.
Examples of lower alkylene groups are linear or branched alkylene groups having 1 to 8 carbon atoms such as methylene, ethylene, propylene, isopropylene, methylmethylene, tetramethylene, 2-methyltrimethylene and hexamethylene groups, with those having 1 to 5 carbon atoms being preferred. The lower alkylene group is more preferably those having 2 to 4 carbon atoms and in particular, those having 2 to 3 carbon atoms.
In addition, examples of aryl groups are phenyl groups, naphthyl groups and aromatic heterocyclic groups having 6 to 12 carbon atoms, which may be substituted or unsubstituted and the aryl group is preferably a substituted or unsubstituted phenyl group and particularly preferably an unsubstituted phenyl group or a biphenylyl group. In this respect, the substituent may be, for instance, a halogen atom (such as fluorine, chlorine, iodine or bromine atom), a hydroxyl group, an amino group, a lower alkyl group, a lower alkoxy group, a cycloalkyl group or a phenyl group.
Examples of cycloalkylalkyl, adamantylalkyl and arylalkyl groups are linear or branched alkyl groups having 1 to 8 carbon atoms, preferably alkyl groups having 1 to 5 carbon atoms, more preferably alkyl groups having 1 to 3 carbon atoms and most preferably ethyl group, to which the foregoing cycloalkyl, adamantly or aryl group is bonded.
Examples of ester groups are lower alkyl esters, benzyl esters and phenyl esters.
Examples of rings formed by the combination of substituents R
2
and R
1
are 5- and 6-membered non-aromatic hetero rings including the sulfur atom to which R
1
is bonded as a member of the rings, such as tetrahydrothiophene, thiolactone and dithiolan.
Examples of 5- to 7-membered rings formed by the combination of R
6
with R
6
or R
7
or the combination of R
6
and R
7
are non-aromatic hetero rings having a nitrogen atom or a combination of a nitrogen atom and an oxygen or sulfur atom in the ring, with those having one or two nitrogen atoms and those having a nitrogen atom and an oxygen atom being more preferred. Specific examples thereof include pyrroline, pyrrolidine, oxazoline, oxazolidine, thiazoline, thiazolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine; piperidine, piperazine, morpholine, homo-piperazine and homo-piperidine rings. Among these rings, preferred are pyrroline, pyrrolidine, tetrahydropyridine, piperidine, piperazine, morpholine and homo-piperidine rings, with pyrrolidine, piperidine, piperazine, tetrahydropyridine and homo-piperidine rings being more preferred. Parti
Ban Masakazu
Horiuchi Masato
Mita Shiro
Suhara Hiroshi
Rao Deepak
Santen Pharmaceutical Co. Ltd.
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