Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-02-25
2001-09-04
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S238000
Reexamination Certificate
active
06284758
ABSTRACT:
TECHNICAL FIELD
The present invention relates to angiogenesis promoters and angiogenesis potentiators, which contain, as an active ingredient, a specific pyridazinone compound or a pharmacologically acceptable salt thereof.
BACKGROUND ART
The below-noted specific pyridazinone compound in the present invention is known to have superior platelet aggregation inhibitory effect, cardiotonic effect, vasodilating effect, anti-SRS-A (Slow Reacting Substances of Anaphylaxis) effect, thromboxane A
2
synthase inhibitory effect and the like (JP-B-7-107055, JP-A-7-285869), and is a drug expected to be an antiplatelet agent and the like.
However, there has not been any report on the effect of the pyridazinone compound on angiogenesis.
DISCLOSURE OF THE INVENTION
The present inventors have conducted various studies of the effect of the pyridazinone compound on the angiogenesis and found that the pyridazinone compound promotes angiogenesis and potentiates an angiogenic effect of a drug having such effect, which resulted in the completion of the present invention.
Accordingly, the present invention provides the following.
An angiogenesis promoter containing a pyridazinone compound of the formula (I)
wherein R
1
, R
2
and R
3
are each independently a hydrogen atom or a lower alkyl, X is a halogen atom, cyano or a hydrogen atom, Y is a halogen atom, trifluoromethyl or a hydrogen atom, and A is C
1
-C
8
alkylene optionally substituted by hydroxyl group, or a pharmacologically acceptable salt thereof (hereinafter to be referred to as pyridazinone compounds) as an active ingredient.
A method of promoting angiogenesis, which comprises administering a pyridazinone compound.
Use of a pyridazinone compound for the production of an angiogenesis promoter.
A pharmaceutical composition for promoting angiogenesis, which comprises a pyridazinone compound and a pharmaceutically acceptable carrier.
A commercial package comprising the above-mentioned pharmaceutical composition, and a written matter associated therewith, the written matter stating that the pharmaceutical composition can or should be used for promoting angiogenesis.
A potentiator of a drug having an angiogenic effect, which contains a pyridazinone compound as an active ingredient.
A method of potentiating an angiogenic effect of a drug having such effect, which comprises administering a pyridazinone compound.
Use of a pyridazinone compound for the production of a potentiator of a drug having an angiogenic effect.
A pharmaceutical composition for potentiating an angiogenic effect of a drug having such effect, which contains a pyridazinone compound and a pharmaceutically acceptable carrier.
A commercial package comprising the above-mentioned pharmaceutical composition, and a written matter associated therewith, the written matter stating that the pharmaceutical composition can or should be used for potentiating an angiogenic effect of a drug having such effect.
The pyridazinone compound in the present invention is preferably a compound of the formula (I), wherein R
1
and R
2
are each hydrogen atom, R
3
is hydrogen atom or alkyl having 1 to 4 carbon atoms, X is halogen atom, Y is halogen atom or hydrogen atom and A is C
1
-C
5
alkylene optionally substituted by hydroxyl group.
Particularly preferable pyridazinone compound of the formula (I) (hereinafter to be referred to as pyridazinone compound (I)) is, for example, 4-bromo-6-[3-(4-chlorophenyl)-propoxy]-5-(3-pyridylmethylamino)-3-(2H)-pyridazinone.
Angiogenesis means that endothelial cells bud from an existing blood vessel and form a new blood vessel. The process of the formation is complicated and is an important phenomenon observed in various aspects in the living body, such as angiogenesis for development and growth, pathologic angiogenesis (e.g. growth of tumor, diabetic retinopathy) and the like.
Administration of an angiogenesis promoter to the patients with cancer or diabetic retinopathy is prohibited because it promotes pathologic angiogenesis.
However, an angiogenesis promoter is useful in that it complements and potentiates the efficacy of a pharmaceutical agent that directly acts on the mainly diseased artery (artery mainly causing the disease), because it forms a collateral circulatory path irrespective of the mainly diseased artery.
The symbols used in this specification are explained in the following.
The lower alkyl at R
1
, R
2
and R
3
has 1 to 6 carbon atoms and may be linear or branched. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl and the like.
R
1
and R
2
are each preferably a hydrogen atom and R
3
is preferably a hydrogen atom or alkyl having 1 to 4 carbon atoms.
The alkyl having 1 to 4 carbon atoms at R
3
is exemplified by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and the like.
The halogen atom at X and Y means fluorine atom, chlorine atom, bromine atom or iodine atom.
Preferable X is a halogen atom and preferable Y is a halogen atom and a hydrogen atom.
The C
1
-C
8
alkylene optionally substituted by hydroxyl group at A may be linear or branched and is exemplified by methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, 2,2-dimethylethylene, 2,2-diethylethylene, 2,2-di-n-propylethylene, hydroxymethylene, 1-hydroxyethylene, 2-hydroxyethylene, 3-hydroxypropylene and the like.
Preferable A is C
1
-C
5
alkylene optionally substituted by hydroxyl group.
In the formula (I), methylene group and pyridine ring may be bonded at any position, but preferably bonded at the 3-position relative to the nitrogen atom of the pyridine ring.
Y may be substituted at any position on the benzene ring, but preferably at the 4-position.
Particularly, the pyridazinone compound of the formula (I) wherein R
1
and R
2
are hydrogen atoms, R
3
is hydrogen atom or alkyl having 1 to 4 carbon atoms, X is halogen atom, Y is halogen atom or hydrogen atom and A is C
1
-C
5
alkylene optionally substituted by hydroxyl group is preferable.
More preferable pyridazinone compounds (I) include 4-bromo-6-(3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-(3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-[3-(4-chlorophenyl)propoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)propoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-(2,2-dimethyl-3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-(2,2-dimethyl-3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)-2,2-dimethylpropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-[3-(4-chlorophenyl)-2,2-dimethylpropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)-3-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-[3-(4-chlorophenyl)-3-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)-2-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone and 4-chloro-6-[3-(4-chlorophenyl)-2-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone.
The pyridazinone compound (I) in the present invention encompasses stereoisomers and optical isomers.
The pyridazinone compound (I) can be produced by a method disclosed in, for example, JP-B-7-107055, U.S. Pat. No. 5,314,883, EP-A-482208, JP-A-7-252237, U.S. Pat. No. 5,750,523 and EP-A-742211.
The pharmacologically acceptable salts of pyridazinone compound (I) include salts with inorganic acid (e.g., hydrochloride, hydrobromide, phosphate, sulfate and the like), salts with organic acid (e.g., acetate, succinate, maleate, fumarate, malate, tartrate and the like), and the like.
The pyridazinone compound (I) can be converted to the above-mentioned salts by known methods.
The pyridazinone compound (I) and pharmacologically acceptable salts thereof can be used as an angiogenesis promoter by themselves. They may be also used as a potentiator of the angiogenic
Egi Yasuhiro
Hayashi Kazutaka
Kido Hideaki
Kubo Yoshiji
Nakamura Norifumi
Liu Hong
Raymond Richard L.
Welfide Corporation
Wenderoth , Lind & Ponack, L.L.P.
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