Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-21
2002-07-02
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S336000
Reexamination Certificate
active
06413995
ABSTRACT:
This application is a 35 USC §371 of PCT/JP00/0082 filed on Jan. 11, 2000, which in turn claims the benefit of Japanese Application No. 4384/1999 filed on Jan. 11, 1999.
TECHNICAL FIELD
The present invention relates to cinnamamide derivatives and pharmaceutical compositions containing them. In particular, the present invention relates to an immunomodulatory agent and/or a prophylactic or therapeutic agent for nephrotic syndrome, circulatory disorders or respiratory diseases.
BACKGROUND ART
Interleukin 12 (IL-12) is currently known to play an important role in the differentiation of CD4
+
T lymphocytes into Th1 cells, and is also suggested to be a relevant to diseases associated with cellular immunity. Interleukin 6 (IL-6) is also known to induce cell growth of various cell types, as well as B cell growth and differentiation. On the contrary, Interleukin 10 (IL-10) is reported to have an inhibitory activity against cellular immunity. It is pointed out that IL-10 is relevant to diseases resulting from suppressed immunity. Accordingly, compounds which control the production of IL-6, IL-10 and IL-12 may be revolutionary new drugs that are expected to be effective in the treatment of diseases including autoimmune diseases resulting from excessive immunity (e.g., nephrotic syndrome, immunological rejection in transplantation, rheumatism, allergy), diabetes, liver disorders and tumors.
Since thromboxane A
2
, which is produced in platelets, the lungs and the like, has strong platelet aggregation and smooth muscle constrictor activities, the regulation of thromboxane A
2
production influences blood pressure, bronchial asthma and/or blood coagulation. Accordingly, compounds which inhibit thromboxane A
2
synthase may be revolutionary new drugs that are expected to be effective for circulatory disorders (e.g., ischemic heart disease, thromboembolic disorder, disorder of cerebral circulation) and respiratory diseases (e.g., asthma).
Steroids are used as a first-choice drug for the treatment of nephrotic syndrome, but there is a problem that steroids cause disturbances in growth because nephrotic syndrome is often found in children. Cyclosporine is used for the treatment of intractable nephrosis, but cyclosporine is required to be administered while monitoring its blood level because it causes renal disorders including decreased renal function and hypertension. Under these circumstances, it is also desirable to develop an effective and less toxic therapeutic agent for nephrotic syndrome in the medical aspect.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide novel cinnamamide derivatives and pharmaceutical compositions containing them, in particular, to provide an immunomodulatory agent and a prophylactic or therapeutic agent for nephrotic syndrome, circulatory disorders or respiratory diseases.
The present invention encompasses the following embodiments.
(1) A cinnamamide derivative having the following formula (I):
wherein
R
1
represents a hydroxyl group, a C
1-6
-alkoxy group, an arylalkoxy group or a substituted or unsubstituted amino group;
R
2
and R
3
are same or different, each of which represents a hydrogen atom, a halogen atom or a C
1-4
-alkyl group;
R
4
represents a hydrogen atom or a C
1-6
-alkyl group;
R
5
represents a hydrogen atom, a C
1-6
-alkyl group or an aryl group;
R
6
represents a hydrogen atom, a C
1-6
-alkyl group, a cyano group or a C
1-6
-alkoxy-carbonyl group;
W represents an oxygen atom, a sulfur atom, an imino group, a methylene group, a hydroxymethylene group (—CH(OH)—) or a carbonyl group (—CO—);
X and Y are same or different, each of which represents an oxygen atom or a sulfur atom;
m represents an integer of 0 to 2;
n represents an integer of 1 to 3; and
when m is 0, a group: —C(R
2
)(R
3
)—W— may represent a vinylene group (—CH═CH—);
or a pharmaceutically acceptable salt thereof.
(2) The cinnamamide derivative or pharmaceutically acceptable salt thereof according to (1) above, wherein the substituted amino group mentioned for R
1
is substituted with one or two groups selected from a substituted or unsubstituted C
1-6
-alkyl group, a substituted or unsubstituted C
3-6
-cycloalkyl group, a substituted or unsubstituted C
1-6
-alkoxy group and a hydroxyl group; or is a cyclic amino group.
(3) A pharmaceutical composition, which comprises as an active ingredient the cinnamamide derivative or pharmaceutically acceptable salt thereof according to (1) or (2) above.
(4) An immunomodulatory agent, which comprises as an active ingredient the cinnamamide derivative or pharmaceutically acceptable salt thereof according to (1) or (2) above.
(5) A prophylactic or therapeutic agent for nephrotic syndrome, which comprises as an active ingredient the cinnamamide derivative or pharmaceutically acceptable salt thereof according to (1) or (2) above.
(6) A prophylactic or therapeutic agent for circulatory disorders, which comprises as an active ingredient the cinnamamide derivative or pharmaceutically acceptable salt thereof according to (1) or (2) above.
(7) A prophylactic or therapeutic agent for respiratory diseases, which comprises as an active ingredient the cinnamamide derivative or pharmaceutically acceptable salt thereof according to (1) or (2) above.
In the above formula (I), a C
1-6
-alkoxy group mentioned for R
1
includes a linear or branched C
1-6
-alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy and n-hexyloxy. An arylalkoxy group mentioned for R
1
includes a C
1-3
-alkoxy group substituted with a substituted or unsubstituted aryl group (e.g., phenyl, p-methoxyphenyl, tolyl, naphthyl), for example, benzyloxy and phenethyloxy.
An amino group mentioned for R
1
may be substituted with at least one group selected from a substituted or unsubstituted C
1-6
-alkyl group, a substituted or unsubstituted C
3-6
-cycloalkyl group, a substituted or unsubstituted C
1-6
-alkoxy group and a hydroxyl group. This amino group may also be a cyclic amino group. A C
1-6
-alkyl group used as a substituent on the above amino group includes a linear or branched C
1-6
-alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl and hexyl. Such a C
1-6
-alkyl group may further be substituted with at least one group selected from, for example, a C
1-6
-alkoxy group (e.g., methoxy, ethoxy), a heterocyclic group (e.g., pyridyl, furyl), an aryl group (e.g., phenyl, p-methoxyphenyl, tolyl, naphthyl), an arylthio group (e.g., phenylthio, p-methoxyphenylthio, tolylthio, naphthylthio) and a C
1-6
-alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxy-carbonyl).
A C
3-6
-cycloalkyl group used as a substituent on the above amino group includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Such a C
3-6
-cycloalkyl group may further be substituted with at least one group selected from, for example, a C
1-6
-alkoxy group (e.g., methoxy, ethoxy), a heterocyclic group (e.g., pyridyl, furyl), an aryl group (e.g., phenyl, p-methoxyphenyl, tolyl, naphthyl), an arylthio group (e.g., phenylthio, p-methoxyphenylthio, tolylthio, naphthylthio) and a C
1-6
-alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl).
A C
1-6
-alkoxy group used as a substituent on the above amino group includes a linear or branched C
1-6
-alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy and n-hexyloxy. Such a C
1-6
-alkoxy group may further be substituted with at least one group selected from, for example, a C
1-6
-alkoxy group (e.g., methoxy, ethoxy), a heterocyclic group (e.g., pyridyl, furyl), an aryl group (e.g., phenyl, p-methoxyphenyl, tolyl, naphthyl), an arylthio group (e.g., phenylthio, p-methoxyphenylthio, tolylthio, naphthylthio) and a C
1-6
-alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl).
An amino group substituted with a substituted or unsubstituted C
1-6
-alkyl group includes methylamino, ethylamino, n-propylamino, isopropylamino, n-
Hasegawa Yoshihiro
Hattori Tomohisa
Hayakawa Hiroyuki
Horiuchi Fumiko
Kumazawa Hiroaki
Davis Zinna Northington
Fish & Richardson P.C.
Tsumura & Co.
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