Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-08
2002-12-10
Rao, Deepak R. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S255010, C514S583000, C514S595000, C544S374000, C544S391000, C564S047000, C564S059000
Reexamination Certificate
active
06492370
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel urea derivatives which have TNF-&agr; production inhibitory effects and are useful as therapeutic agents for various diseases, particularly as therapeutic agents for autoimmune diseases such as rheumatoid arthritis, and to novel compounds which are useful as synthetic intermediates thereof.
BACKGROUND ART
TNF-&agr; (tumor necrosis factor-&agr;) was found as a factor which induces hemorrhagic necrosis at tumor sites, and it is now recognized as a cytokine which widely participates in biophylaxis-immune mechanism through inflammation. However, prolonged and excessive production of TNF-&agr; causes tissue disorders and is a factor which brings about causes and exacerbation of various diseases. Accordingly, it is reported that it is important to suppress the excessive production of TNF-&agr; in morbidity where TNF-&agr; is excessively produced (Yamazaki, Clinical Immunology, 27, 1270, 1995). The above-mentioned literature recites many pathema such as arthrorheumatism, systemic lupus erythematosus (SLE), cachexia, acute infectious disease, allergy, pyrexia, anemia and diabetes as examples of pathema in which TNF-&agr; participates.
It is reported that TNF-&agr; plays an important role in crises of rheumatoid arthritis and Crohn's disease, which are autoimmune diseases (Andreas Eigler et al., Immunology Today, 18, 487, 1997).
TNF-&agr; is known to participate in various diseases as well as autoimmune diseases such as rheumatoid arthritis, Crohn's disease and systemic lupus erythematosus as reported in the above-mentioned literatures and the like. Compounds which inhibit its production or suppress its effect are expected to be useful for treatment of various diseases, and many studies have been done. Outlines of these studies of drugs are introduced in the above-mentioned literatures (Yamazaki, Clinical Immunology, 27, 1270, 1995, Andreas Eigler et al., Immunology Today, 18, 487, 1997). Recently, it was found that a proteolytic enzyme participating in secretion of TNF-&agr; is metalloprotease, and a study of TNF-&agr; production inhibitory effects of metalloprotease inhibitors is also reported. (Published Japanese Translation of PCT No. 508115/1997).
Various drugs having the TNF-&agr; production inhibitory effects have been studied as mentioned above. Focusing attention on chemical structure of the drugs, however, no drug having a chemical structural feature of compounds of the present invention is known at all. The chemical structural feature of the compounds of the present invention is that the compounds have urea structure as basic structure and have a sulfur atom and an amide bond in side chains. Few studies of such drugs having the urea structure as basic skeleton have been reported. Moreover, no drug having a sulfur atom in a side chain has hitherto practically been reported.
Since the compounds having the urea structure as the basic structure and having a sulfur atom and the amide bond in the side chains have not practically been reported as mentioned above, a study of synthesis of such compounds and a study of pharmacological actions, particularly the TNF-&agr; production inhibitory effects of the compounds were very interesting subjects.
DISCLOSURE OF THE INVENTION
The present inventors focused attention on urea structure of which application to drugs had hardly been studied, made studies on synthesis of novel urea derivatives wherein sulfur is introduced into one side chain thereof and an amide bond is introduced into the other side chain thereof, and succeeded in preparing many novel compounds. The present inventors further studied pharmacological actions of the compounds and found that these novel compounds have excellent TNF-&agr; production inhibitory effects. In a process of the study on preparing the above-mentioned novel urea derivatives, the present inventors succeeded also in preparing novel compounds which are useful as synthetic intermediates of the derivatives.
The present invention relates to compounds represented by the following general formula [I] and salts thereof (hereinafter referred to as “the present compound” as far as there is no proviso), medicinal compositions containing it as an active ingredient, and compounds which are represented by the general formula [III] and are useful as synthetic intermediates of the present compounds and salts thereof (hereinafter referred to as “the present synthetic intermediate” as far as there is no proviso).
wherein
R
1
is hydrogen, lower alkyl, an aromatic group, R
A
—CO—, R
C
—S— or a group of the following formula [II].
R
2
, R
3
and R
4
, being the same or different, are hydrogen, lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl or an aromatic group. When R
4
is lower alkyl, terminal carbon of the lower alkyl can join with carbon to which the alkyl is bonded to form a cycloalkyl ring.
R
5
and R
6
, being the same or different, are hydrogen, lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl or an aromatic group. When both R
5
and R
6
are lower alkyl, they can join each other to form a nonaromatic heterocyclic ring having nitrogen and/or oxygen in the ring, and the heterocyclic ring can be substituted by lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl, an aromatic group or R
A
—CO—.
R
7
is hydrogen, lower alkyl, cycloalkyl, hydroxy, mercapto, phenyl, R
B
—O—, R
C
—S—, R
D
—COS—, R
E
—OCO—, R
F
—N(R
G
)— or —CONHOH. R
7
can join with sulfur adjacent to A
1
to form a nonaromatic heterocyclic ring containing sulfur in the ring, and the ring can further have carbonyl in the ring.
A
1
is lower alkylene.
A
2
is lower alkylene.
Each lower alkyl defined above can be substituted by hydroxy, a nonaromatic heterocyclic ring having nitrogen and/or oxygen in the ring, cycloalkyl, cycloalkenyl, adamantyl, an aromatic group, phthalimido, guanidino which can be substituted by lower alkylsulfonyl or aromatic sulfonyl, R
A
—CO—, R
B
—O—, R
C
—S—, R
D
—COS—, R
E
—OCO—, R
F
—N(R
G
)—, R
H
—N(R
J
)CO—, R
K
—CONH— or —CONHOH.
Each lower alkenyl defined above can be substituted by hydroxy, lower alkyl, lower alkoxy, cycloalkyl, cycloalkenyl or an aromatic group.
Each cycloalkyl defined above can be substituted by lower alkyl, hydroxy, oxo or R
E
—OCO—.
Each aromatic group defined above can be substituted by lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen, nitro, an aromatic group, lower alkylsulfonyl, aromatic sulfonyl, R
E
—OCO—, R
F
—N(R
G
)— or R
K
—CONH—.
The nonaromatic heterocyclic ring having nitrogen and/or oxygen in the ring defined above can be substituted by lower alkyl, cycloalkyl, an aromatic group or R
A
—CO—, and the lower alkyl can be substituted by hydroxy, cycloalkyl, cycloalkenyl, an aromatic group, R
A
—CO—, R
B
—O—, R
E
—OCO— or R
F
—N(R
G
)—.
R
A
is lower alkyl, halogeno-lower alkyl, an aromatic group, lower alkoxy, aromatic-lower alkoxy or R
F
—N(R
G
)—. R
B
is lower alkyl or an aromatic group. R
C
is hydrogen, lower alkyl or an aromatic group. R
D
is lower alkyl or an aromatic group. R
E
is hydrogen, lower alkyl or an aromatic group. R
F
and R
G
, being the same or different, are hydrogen, lower alkyl, cycloalkyl or an aromatic group. R
H
and R
J
, being the same or different, are hydrogen, lower alkyl, cycloalkyl or an aromatic group. R
K
is lower alkyl, lower alkoxy or an aromatic group. The same definitions are applied hereinafter.]
[The same definitions are applied except for a case where R
7
joins with sulfur adjacent to A
1
to form a nonaromatic heterocyclic ring containing sulfur in the ring. Hereinafter, a definition of R
7
to be used for the synthetic intermediates is the same as that mentioned above.]
The groups defined above are hereinafter described in detail.
The lower alkyl is straight-chain or branched alkyl having one to eight carbon atoms such as methyl, ethyl, propyl, butyl, hexyl, isopropyl, isobutyl, isopentyl, isohexyl, t-butyl or 3,3-dimethylbutyl.
The lower alkenyl is straight-chain or branched alkenyl having two to eight carbon ato
Ban Masakazu
Horiuchi Masato
Mita Shiro
Suhara Hiroshi
Frishauf Holtz Goodman & Chick P.C.
Rao Deepak R.
Santen Pharmaceutical Co. Ltd.
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