N-substituted-N′-substituted urea derivatives and...

Details N-substituted-N′-substituted urea derivatives and... N-substituted-N′-substituted urea derivatives and...

2001-10-04

2004-01-27

Davis, Brian (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Esters having the thiocarboxylate group, -cx-, wherein the...

C560S009000, C560S015000, C560S016000, C560S029000, C560S034000, C564S047000, C564S056000, C564S057000, C564S059000, C562S621000, C562S623000

Reexamination Certificate

active

06683200

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a novel N-substituted-N′-substituted urea derivative as well as a pharmaceutical composition, a TNF-&agr; production inhibitory agent and a therapeutic agent for treating an autoimmune disease, which contain the compounds.
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).
On the other hand, the compounds represented by the following general formula I, in which R
1
, R
3
and R
4
simultaneously represent hydrogen atoms and R
6
and R
7
are both methyl groups, are disclosed in Japanese Un-Examined Patent Publication No. Hei 1-224758 as sensitizing dyes (II-40). In addition, the compounds represented by the following general formula I, in which R
1
is an aryl group or a furanylmethyl group, R
3
is an isopropyl group and R
6
and R
7
are both methyl groups, are disclosed in Japanese Un-Examined Patent Publication No. Sho 57-209267 as examples of the compounds having an effect as an antiarrhythmic agent (Examples 1, 2, 34, 37, 52 and 58).
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, a TNF-&agr; production inhibitory agent and a therapeutic agent for treating autoimmune diseases, which comprise the foregoing compounds.
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 and 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 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 if both R
6
and R
7
are methyl groups, R
1
, R
3
and R
4
do not simultaneously represent hydrogen atom, or if R
3
is an isopropyl group and both R
6
and R
7
are methyl groups, R
1
does not represent an aryl group and a furanylmethyl group.
According to the present invention, there are also provided N-substituted-N′-substituted urea derivatives represented by the following general formula III and 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 with for 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-methyltlimethylene 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 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 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.
When the compound represented by the general formula I according to the present invention has thiol, hydroxyl and/or amino groups, these groups may be protected with commonly used protective groups.
Examples of protective groups for thiol gr

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