Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-21
2001-11-06
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...
C514S341000, C546S275100, C546S336000
Reexamination Certificate
active
06313153
ABSTRACT:
TECHNICAL FIELD
The present invention relates to pyridylacrylamide derivatives and anti nephritic agents and TGF-&bgr; inhibitors comprising the compounds.
BACKGROUND ART
There is no effective method or drug for treating nephritis and artificial dialysis is carried out in patients with chronic nephritis and reduced renal function. Chronic glomerulonephritis is said to play a main role in introducing the artificial dialysis and amounts to about 40% of the original diseases of patients introducing the artificial dialysis. Under these circumstances, the development of excellent agents for treating nephritis is expected from the standpoint of medical administration.
TGF-&bgr; (transforming growth factor-&bgr;) acts on various cells such as fibroblasts to enhance the production of extracellular matrices such as collagen, and prevents the degradation of the extracellular matrices by proteases. Further, it has been reported to promote the deposition of the extracellular matrices onto cell surfaces. Thus, diseases associated with TGF-&bgr; may include liver cirrhosis, pulmonary or other fibrosis, nephritis, chronic renal insufficiency, diabetic nephropathy, and retinopathy.
Therefore, it is expected that any substances inhibiting TGF-&bgr; would be effective for such fibrous diseases.
Japanese Patent Laid Open Publication No. 8-333249 discloses that compounds represented by the following formula (A):
wherein A is a single bond or —NH—, E is —OCO— or —COO—, Phe is a 1,4-phenylene group, Ar—R
1
is a phenyl group substituted a group represented by the following formula:
in which Z is a single bond, or a methylene, ethylene or vinylene group, R
2
is a hydrogen atom or a C
1-4
alkyl or —CH
2
CONR
3
R
4
group, R
3
and R
4
independently being a hydrogen atom or a C
1-4
alkyl group, R
5
and R
6
independently are a hydrogen atom or a C
1-4
alkyl group, R
7
is a C
2-6
alkenyl group, and R
8
is —(CH
2
)
n
—COOR
9
, n being 0 or an integer of 1 to 4 and R
9
being a hydrogen atom or a C
1-4
alkyl group, or salts thereof are useful agents for inhibiting release, activation and synthesis of TGF-&bgr;. However, there is no description on the pyridylacrylamide derivatives represented by the formula (I) below which are used as effective ingredients in the pharmaceutical compositions of the present invention.
With respect to the pyridylacrylamide derivatives, on the other hand, WO93/04035 (Japanese Patent Laid Open Publication No. 6-510030) describes the compound represented by the following formula (B):
Ar
3
—CH═CH—CO—NHCH
2
—Ar
4
(B)
wherein Ar
3
is a 3-pyridyl group and Ar
4
is a 3,5-di-tert-butyl-4-hydroxyphenyl group as an example of many 3,5-di-tert-butyl-4-hydroxyphenyl derivatives, and shows that the compound is useful as agents for treating metabolic diseases, such as anti-atherosclerosis agents, and may act anti-inflammatory and cytophylatically as well as antasthmatically. However, there is no description suggesting that the compound (B) is useful as anti nephritic agents or TGF-&bgr; inhibitors.
DISCLOSURE OF THE INVENTION
It is an object of the present invention to provide a novel pyridylacrylamide derivative and a anti nephritic agent and TGF-&bgr; inhibitor comprising the novel or known pyridylacrylamide derivative.
The present inventors have continued researches and studies to develop anti nephritic agents and TGF-&bgr; inhibitors and found that specific pyridylacrylamide derivatives are effective as anti nephritic agents and TGF-&bgr; inhibitors. Thus, the present invention has been completed.
Accordingly, the present invention includes the following inventions:
(1) an agent for treating nephritis comprising as an effective ingredient a pyridylacrylamide derivative represented by the following formula (I):
wherein Ar
1
is a substituted or unsubstituted pyridyl group, Ar
2
is a substituted or unsubstituted phenyl group, R
1
is a hydrogen atom, a C
1-6
alkyl group or an aryl group, R
2
is a hydrogen atom, a C
1-6
alkyl group, a cyano group or a C
1-6
alkoxy-carbonyl group, R
3
is a hydrogen atom or an optionally substituted C
1-6
alkyl group, X is an oxygen or sulfur atom, A and B are same or different and each represent a hydrogen atom, a hydroxyl group, a C
1-6
alkoxy group or a C
1-6
alkylthio group, or A and B together form an oxo or thioxo group, or a group represented by the formula: ═N—Y in which Y is a di(C
1-6
alkyl)amino, hydroxyl, aralkyloxy or C
1-6
alkoxy group, or a group represented by the formula: —Z
1
M—Z
2
— in which Z
1
and Z
2
are same or different and each represent an oxygen or sulfur atom or an imino group optionally substituted by a C
1-6
alkyl group, and M is an alkylene group having 2 to 4 chain members or a 1,2-phenylene group, or A is a hydroxyl group and B is a 1-C
1-6
alkyl-imidazol-2-yl group, and n is an integer of 1 to 3,
or a pharmaceutically acceptable salt thereof;
(2) a anti nephritic agent of (1) above wherein in the aforementioned formula (I), Ar
1
is a pyridyl group substituted by at least one selected from the group consisting of halogen atoms, C
1-6
alkyl groups, C
1-6
alkoxy groups and C
1-6
alkoxy-carbonyl groups;
(3) a anti nephritic agent of (1) above wherein in the aforementioned formula (I), Ar
2
is a phenyl group substituted by at least one selected from the group consisting of halogen atoms, a hydroxyl group, optionally substituted amino groups, optionally substituted C
1-6
alkoxy groups, C
2-6
alkenyl-oxy groups, aryloxy groups, optionally substituted C
1-6
alkyl groups, aryl groups, C
1-6
alkylthio groups, a carboxyl group, C
1-6
alkoxy-carbonyl groups, a sulfamoyl group and —O—CO—R
4
groups in which R
4
is a C
1-6
alkyl, aryl, C
1-6
alkoxy or optionally substituted amino group;
(4) a TGF-&bgr; inhibiting agent comprising a pyridylacrylamide derivative represented by the aforementioned formula (I) or a pharmaceutically acceptable salt thereof as an effective ingredient;
(5) a TGF-&bgr; inhibiting agent of (4) above which is a treating agent for a TGF-&bgr;-involving disease selected from liver cirrhosis, fibrosis, nephritis, chronic renal insufficiency, diabetic nephropathy, and retinopathy;
(6) a pyridylacrylamide derivative represented by the following formula (I′):
in Ar
1
is a substituted or unsubstituted pyridyl group, Ar
2
is a substituted or unsubstituted phenyl group, R
1
is a hydrogen atom, a C
1-6
alkyl group or an aryl group, R
2
is a hydrogen atom, a C
1-6
alkyl group, a cyano group or a C
1-6
alkoxy-carbonyl group, R
3
is a hydrogen atom or an optionally substituted C
1-6
alkyl group, X is an oxygen or sulfur atom, A and B are same or different and each represent a hydrogen atom, a hydroxyl group, a C
1-6
alkoxy group or a C
1-6
alkylthio group, or A and B together form an oxo or thioxo group, or a group represented by the formula: ═N—Y in which Y is a di(C
1-6
alkyl)amino, hydroxyl, aralkyloxy or C
1-6
alkoxy group, or a group represented by the formula: —Z
1
—M—Z
2
— in which Z
1
and Z
2
are same or different and each represent an oxygen or sulfur atom or an imino group optionally substituted by a C
1-6
alkyl group, and M is an alkylene group having 2 to 4 chain members or a 1,2-phenylene group, or A is a hydroxyl group and B is a 1-C
1-6
alkyl-imidazol-2-yl group, and n is an integer of 1 to 3, or a pharmaceutically acceptable salt thereof, provided that those compounds of the aforementioned formula (I′) wherein Ar
1
is 3-pyridyl group, Ar
2
is 3,5-di-tert-butyl-4-hydroxyphenyl group, R
1
, R
2
and R
3
each represent a hydrogen atom, X is an oxygen atom, A and B each represent a hydrogen atom, and n is 1, and salts thereof are excluded;
(7) a compound of (6) above wherein in the aforementioned formula (I′), Ar
1
is a pyridyl group substituted by at least one selected from the group consisting of halogen atoms, C
1-6
alkyl groups, C
1-6
alkoxy groups and C
1-6
alkoxy-carbonyl groups; and
(8) a compound of (6) above wherein in the aforementioned formula (I′), Ar
2
is a phenyl group substituted by
Hasegawa Yoshihiro
Hattori Tomohisa
Hayakawa Hiroyuki
Horiuchi Fumiko
Kumazawa Hiroaki
Davis Zinna Northington
Fish & Richardon P.C.
Tsumura & Co.
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