Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-23
2001-02-06
Kight, John (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S277400
Reexamination Certificate
active
06184238
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel N-hydroxyurea derivative and pharmaceutical composition containing the same. These compounds have a lipoxygenase inhibitory activity and a thromboxane synthase inhibitory activity, so are useful in treating or alleviating allergic diseases or inflammatory diseases.
BACKGROUND ART
In recent years, the role of chemical mediators in asthma and other allergic diseases has been quickly elucidated. In addition to histamine, PAF, leukotrienes, thromboxane A
2
, etc. have become known. It has been shown that leukotrienes are biosynthesized by the action of 5-ipoxygenase from arachidonic acid, and thromboxane A
2
is biosynthesized by thromboxane synthase after the catabolism with cyclooxygenase from arachidonic acid. Further, leukotrienes and thromboxane A
2
have both been found to be important chemical mediators in allergic reactions causing various diseases such as asthma, psoriasis, enteritis, nephritis, ulcers, and ischemia. Therefore, if it were possible to inhibit the biosynthesis of both chemical mediators, a greater effect could be obtained in treating or alleviating the above diseases when compared with the inhibition of single mediator.
Recently, as compounds for inhibiting the biosynthesis of such two mediators, benzothiazole derivatives (Japanese Unexamined Patent Publication (Kokai) No. 5-178855), quinone derivatives (Japanese Unexamined Patent Publication (Kokai) No. 5-78321), imidazolylphenol derivatives (Japanese Unexamined Patent Publication (Kokai) No. 6-9571), and N-hydroxyurea derivatives (WO96/23772) have become known.
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide compounds capable of inhibiting both the biosynthesis of leukotrienes and thromboxane A
2
, that is, novel compounds having both the dual inhibition against lipoxygenase and thromboxane synthase at the same time.
In accordance with the present invention, there are provided N-hydroxyurea derivatives having the formula (I):
wherein, either one of R
1
, R
3
and R
4
represents A, either one of the other groups of R
1
, R
3
, and R
4
and R
2
represents a 3-pyridyl group or 3-pyridyl alkyl group, the remaining groups of R
1
, R
2
, R
3
, and R
4
independently represent a hydrogen atom, halogen atom, or a substituted or unsubstituted C
1
to C
8
alkyl group where the substituent represents a halogen atom, cyano group, phenyl group, carboxyl group, or lower alkoxycarbonyl group, R
5
represents a hydrogen atom or lower alkyl group, R
6
represents a hydrogen atom, lower alkyl group, C
3
to C
7
cycloalkyl group, or a substituted or unsubstituted phenyl group, where the substituent represents a halogen atom, lower alkyl group, or lower alkoxy group, B indicates a bond, C
1
to C
20
alkylene group, C
2
to C
8
alkenylene group, or C
2
to C
8
alkynylene group or B—C(R
5
) represents a C
2
to C
6
alkylene group having a benzene ring in the middle thereof.
In accordance with the present invention, there is further provided a pharmaceutical composition comprising this N-hydroxyurea derivative or its optically active substances, pharmaceutically acceptable salts, or the hydrates or solvates thereof as an active principle, in particular an antiasthmatic or anti-inflammatory drug.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention will now be explained in further detail.
The present invention is as explained above, but as preferable compounds, N-hydroxyurea derivatives wherein, in the formula (I), either one of R
1
, R
3
, and R
4
represents A, either one of the other groups of R
1
, R
3
, and R
4
and R
2
represents a 3-pyridyl group or 3-pyridyl lower alkyl group, especially a 3-pyridyl group or 3-pyridylmethyl group, the remaining groups of R
1
, R
2
, R
3
, and R
4
independently represent a hydrogen atom, halogen atom, or a substituted or unsubstituted C
1
to C
5
alkyl group where the substituent represents a carboxyl group, methoxycarbonyl group, or ethoxycarbonyl group etc., R
5
represents a hydrogen atom, methyl group, or ethyl group, R
6
represents a hydrogen atom, methyl group, ethyl group, or C
3
to C
6
cycloalkyl group, B represents a bond, C
1
to C
12
alkylene group, C
2
to C
5
alkenylene group, or C
2
to C
5
alkynylene group, or B—C(R
5
) represents a C
2
to C
4
alkylene group having a benzene ring in the middle thereof may be mentioned.
Further, in the present invention, as preferable compounds in the case where R
1
is A, N-hydroxyurea derivatives where either one of R
2
, R
3
, and R
4
represents a 3-pyridyl group or 3-pyridylmethyl group, the other groups of R
2
, R
3
, and R
4
preferably represent a hydrogen atom, halogen atom, or a substituted or unsubstituted C
1
to C
5
alkyl group where the substituent represents a carboxyl group, methoxycarbonyl group, or ethoxycarbonyl group, especially a hydrogen atom, chlorine atom, fluorine atom, methyl group, carboxyalkyl group such as a carboxypentyl group, or lower alkoxycarbonylalkyl group such as an ethoxycarbonylbutyl group, R
5
preferably represents a hydrogen atom or lower alkyl group such as a methyl group or ethyl group, especially a hydrogen atom or methyl group, R
6
preferably represents a hydrogen atom, or lower alkyl group such as a methyl group or ethyl group, or C
3
to C
6
cycloalkyl group, especially a hydrogen atom or cyclohexyl group, B preferably represents a C
1
to C
15
alkylene group or C
2
to C
8
alkenylene group, more preferably a C
1
to C
12
alkylene group, particularly preferably a C
1
to C
6
linear alkylene group may be mentioned.
As preferable compounds in the case where R
3
is A, N-hydroxyurea derivatives where, in the formula (I), either one of R
1
, R
2
, and R
4
represents a 3-pyridyl group, 3-pyridylmethyl group, or 3-pyridylpropyl group, the other groups of R
1
, R
2
, and R
4
each preferably represents a hydrogen atom, halogen atom, or C
1
to C
5
alkyl group, especially a hydrogen atom, halogen atom, or methyl group, R
5
preferably represents a hydrogen atom or lower alkyl group such as a methyl group or ethyl group, especially a hydrogen atom or methyl group, R
6
preferably represents a hydrogen atom, lower alkyl group such as a methyl group or ethyl group, or C
3
to C
6
cycloalkyl group, especially a hydrogen atom, B preferably represents a bond, C
1
to C
5
alkylene group, C
2
to C
5
alkenylene group, especially a bond or vinylene group, or B—C(R
5
) represents a C
1
to C
4
alkylene group having a benzene ring in the middle thereof may be mentioned.
As preferable compounds in the case where R
4
is A, N-hydroxyurea derivatives where, in the formula (I), either one of R
1
, R
2
, and R
3
represents a 3-pyridyl group, 3-pyridylmethyl group, or 3-pyridylpropyl group, the other groups of R
1
, R
2
, and R
3
each preferably represents a hydrogen atom, halogen atom, or a substituted or unsubstituted C
1
to C
5
alkyl group where the substituent represents a carboxyl group, methoxycarbonyl group, or ethoxycarbonyl group, especially a hydrogen atom, methyl group, carboxybutyl group, or ethoxycarbonylbutyl group, R
5
preferably represents a hydrogen atom or lower alkyl group such as a methyl group or ethyl group, especially a hydrogen atom or methyl group, R
6
preferably represents a hydrogen atom, lower alkyl group such as a methyl group or ethyl group, or C
3
to C
6
cycloalkyl group, especially a hydrogen atom, B preferably represents a bond, C
1
to C
8
alkylene group, C
2
to C
5
alkenylene group, or C
2
to C
5
alkynylene group, especially a bond, ethylene group, vinylene group, or ethynylene group may be mentioned.
Further, in the present invention, the N-hydroxyurea derivatives represented by the formula (I) may be pharmacologically acceptable salts, specifically an inorganic acid salt formed from hydrochloric acid, hydrobromic acid, sulfuric acid, bisulfuric acid, or phosphoric acid or an organic acid salt formed from formic acid, acetic acid, citric acid, fumaric acid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaric acid, methanesulfonic a
Kawahara Yoshikazu
Komatsu Toshiya
Takano Michika
Christie Parker & Hale LLP
Kight John
Nikken Chemicals Co., Ltd.
Robinson Binta
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