JPH07107055B2 - Pyridazinone derivatives - Google Patents

Description

Detailed Description of the Invention Technical Field The present invention relates to novel 3(2H) steroid compounds having platelet aggregation inhibitory activity, cardiotonic activity, vasodilatory activity and/or anti-SRS-A activity.
- pyridazinone derivatives and, where possible, their pharmaceutically acceptable salts, their preparation process and pharmaceutical compositions containing them as active ingredients.

Background Art 1) Field of Antithrombotic Agents: It has been revealed that platelet aggregation plays an important role in thrombus formation in terms of its relationship to pathology. Major thrombotic diseases caused by thrombus formation include cerebral thrombosis, pulmonary thrombosis, myocardial infarction, angina pectoris, and peripheral arterial occlusion, all of which are disease areas in which the development of effective drugs is required. Antithrombotic agents with platelet aggregation inhibitory effects have attracted attention as preventive and therapeutic agents for these thrombi. The effects of aspirin have been widely studied, and more recently, ticlopidine and cilostazol have been clinically developed, but there is currently a demand for drugs with even stronger efficacy.

In addition to the above-mentioned thrombotic diseases, various other diseases have been suggested to be related to platelets. These diseases include nephritis and cancer cell metastasis, and recently, extensive research has been conducted on the preventive and therapeutic effects of antithrombotic agents that inhibit platelet function on these and other diseases (Journal of the Royal Society of
Journal of Royal College of Physicians
Physicians), Volume 7, No. 1, pp. 5-18, 1972
Japanese Clinical Journal, Vol. 4, No. 6, pp. 130-136, 1988; Anticancer Research, 6
Vol. 1, pp. 543-548, 1986].

2) Cardiotonic Agents Cardiotonic agents that increase myocardial contractility have long been used as treatments for congestive heart failure. However, previous cardiac glycosides such as digitalis, aminophylline, and catecholamines have had severe side effects, and more recently, drugs such as milrinone and denopamine have been clinically developed.

3) Vasodilators: Although numerous vasodilators have been known to date, there are currently few well-balanced drugs that combine powerful and desirable effects as circulatory system agents, such as platelet aggregation inhibition.

4) Anti-SRS-A Agents: SRS-A (Slow Reacting Substances of Anaphylaxis)
is a chemical mediator that is released together with histamine during allergic reactions, and its existence has long been known from the developmental standpoint as a physiologically active substance that induces strong and sustained contraction of airway smooth muscle.

In 1979, the main component of SRS-A was identified as leukotriene _C4 (hereinafter referred to as L
TC ₄ ), leukotriene D ₄ (hereinafter referred to as LTD ₄ )
and leukotriene E ₄ (hereinafter referred to as LTE ₄ ) (collectively referred to as peptide leukotrienes).

SRS-4 has been extensively studied in terms of its relationship with pathological conditions, and as a result, its relationship with immediate-type allergies such as bronchial asthma, allergic rhinitis, urticaria, and hay fever is becoming clear.

Furthermore, its association with various inflammatory diseases, ischemic diseases, etc. has also been suggested.

Therefore, drugs that inhibit the action of SRS-A include _LTC4 , _LTD4 , and L
These compounds are expected to be useful as preventive or therapeutic agents for diseases caused by any one of _TE4 or a mixture thereof.

So far, a large number of drugs have been reported to inhibit the action of SRS-A (Drugs of the
Drugs of the Future, Vol. 12, 453-47
4, 1987; Annual Reports in Medicinal Chemistry
Annual Reviews in Pharmacological Toxicology, Vol. 22, pp. 73-84, 1987;
Reviews in Pharmacological Toxicology), Volume 29, 123
- p. 143, 1989].

However, none of these drugs have yet been put to clinical use.

The relationship between the 6-ω-substituted alkyleneoxy-3(2H)-pyridazinone derivatives of the general formula [I] of the present invention and, if possible, their pharmaceutically acceptable salts, and the compounds described in the publicly known literature will be explained below.

(a) German Patent Publication No. 1670169 (hereinafter referred to as Document A) describes a compound in which the 2-position of 3(2H)-pyridazinone is a hydrogen atom, an aliphatic, or a cycloaliphatic.
chloro, bromine or aromatic groups with a chlorine atom or bromine atom at the 4-position and a
There is a description of 3(2H)-pyridazinone derivatives in which the first position is substituted with an amino group including an aralkylamino group and the second position is substituted with a chlorine atom, a bromine atom, a hydroxyl group or an alkoxy group having 1 to 4 carbon atoms.

However, there is only a description of the synthesis of 3(2H)-pyridazinone derivatives, their use as agricultural chemicals, medicines, dyes and other intermediates, and there is no description of examples, examples of compounds or pharmaceutical activity.

(b) In Japanese Patent Publication No. 58-183675 (hereinafter referred to as document b), the 2-position is a lower alkyl group, and the 4-position is a
a 3-substituted alkyl group having a hydrogen atom at the 5-position, a substituted or unsubstituted anilino group at the 6-position, and a hydroxyl group or a lower alkoxy group at the 7-position;
(2H)-pyridazinone derivatives are described.

The uses of the 3(2H)-pyridazinone derivative are clearly stated to be analgesic, anti-inflammatory, antiallergic and antirheumatic effects, but there is no description of its specific pharmacological activity.

(c) Japanese Patent Publication No. 63-30187 and European Patent Publication No. 0275997 (hereinafter referred to as Document c) disclose 6-substituted alkoxy-5-(2-methyl-2-propanol)-1-(2-methyl-2-propanol)-1-(2-methyl-2-propanol)-2 ...
-substituted benzylamino-3(2H)-pyridazinone derivatives and their use as anti-SRS-A agents are described.

Disclosure of the Invention The present inventors have conducted extensive research and have unexpectedly found that
The compounds of the present invention are different from any of the compounds disclosed in
The present inventors have found that (2H)-pyridazinone derivatives and pharmaceutically acceptable salts thereof are excellent compounds as antithrombotic agents, cardiac stimulants, vasodilators, and/or anti-SRS-A agents, and that they can serve as active ingredients in preventive or therapeutic drugs for the above-mentioned various thrombotic diseases, congestive heart failure, hypertension, asthma, immediate-type allergic diseases, and the like, and have completed the present invention.

That is, the present invention provides a compound of the general formula [I] wherein R ¹ is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, an alkenyl group having 3 to 4 carbon atoms, or (CH ₂ ) _n
CO ₂ R ⁵ (n is an integer of 1 to 4, and R ⁵ is a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms).

^R2 represents ^A1 - ^Y1 ( ^A1 represents a linear or branched alkylene group having 1 to 12 carbon atoms, ^Y1 represents _CO2R5 ( ^R5 is the same as above), a cyano group, ^OR6 ( ^R6 represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms ^, or a phenyl group), or a thienyl group or pyridyl group which may be substituted at any position; ( ^R7 and ^R8 each independently represent a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a cyclic alkyl group having 3 to 8 carbon atoms, a phenyl group, or a thiazolyl group or thiadiazolyl group which may be substituted at any position, or ^R7 and ^R8 together form an alkylene group having 2 to 8 carbon atoms which may be substituted with a linear or branched alkyl group having 1 to 3 carbon atoms or a phenyl group, or form a morpholine ring together with the nitrogen atom.) ( ^R5 is the same as above, and ^R9 represents a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkyl group having 1 to 4 carbon atoms, or a phenyl group which may be substituted with a halogen atom.) ( ^R10 and ^R11 each independently represent a hydrogen atom, a halogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, an acylamino group having 1 to 4 carbon atoms, ^OR5 ( ^R5 is the same as above), _NHSO2R9 ( ^R9 is the same as above) ^, or S(O) _m - ^R12
(m is an integer of 0 to 2, and ^R12 is a linear or branched alkyl group having 1 to ⁴ carbon atoms).
¹¹ does not simultaneously represent a hydrogen atom.) ( ^R13 represents a hydrogen atom, ^R14 represents a phenyl group, or ^R13 and ^R14 together form an alkylene having 2 to 8 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms.) ( ^R15 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, ^R16 represents a linear or branched alkyl group having 1 to 4 carbon atoms, or ^R15 and ^R16 together form an alkylene having 2 to 8 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms.) ( ^R17 and ^R18 each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms, or ^R17 and ^R18 together form an alkylene group having 2 to 8 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms.) (1 is 1 or 2, k is an integer of 0 to 3, and R ¹⁹ is a hydrogen atom or a halogen atom), or or ^A2 - ^Y2 ( ^A2 represents an alkylene group having 2 to 10 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms, except when the carbon chain connecting the oxygen atom and ^Y2 has one carbon atom, and ^Y2 represents a phenyl group).

^R3 and ^R4 are each independently a hydrogen atom or a group having 1 to 3 carbon atoms.
represents a straight or branched chain alkyl group.

X represents a chlorine atom, a bromine atom, a hydrogen atom or a cyano group.

Ar [j is 0 or 1, R ²⁰ is a hydrogen atom, a halogen atom or O
R ¹² (wherein R ¹² is the same as above). ( ^Z1 represents an oxygen atom or a sulfur atom.) [ ^R21 represents a hydrogen atom or ^OR5 ( ^R5 is the same as defined above)], or [ ^Z2 and ^Z3 each independently represent a hydrogen atom, a halogen atom,
a straight or branched alkyl group having 1 to 4 carbon atoms, OR ²² (R
²² represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms; O-A ¹ -Y ³ (A ¹ is the same as above);
^Y3 is a linear or branched alkyl group having 1 to 4 carbon atoms or a phenyl group which may be substituted with a halogen atom;
^{2R5 ,} (R ⁵ , R ⁷ and R ⁸ are the same as above.) or Z ² and
^Z3 together with the benzene ring (W represents an alkylene group having 1 to 8 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms.) } and, if possible, a pharmaceutically acceptable salt thereof, a method for producing the same, and a pharmaceutical composition containing the same as an active ingredient.

Hereinafter, R ¹ in the compound of the present invention represented by the above general formula [I],
R ² , R ³ , R ⁴ , X and Ar will be explained.

Specific examples of ^R1 include a hydrogen atom, a methyl group, an ethyl group,
n-propyl group, i-propyl group, n-butyl group, i-
butyl group, sec-butyl group, t-butyl group, 2-propenyl group, 2-methyl-2-propenyl group, carboxymethyl group, 2-carboxyethyl group, 3-carboxypropyl group, 4-carboxybutyl group, methoxycarbonylmethyl group, 2-methoxycarbonylethyl group, 3-methoxycarbonylpropyl group, 4-methoxycarbonylbutyl group, ethoxycarbonylmethyl group, 2-ethoxycarbonylethyl group, 3-ethoxycarbonylpropyl group, 4-ethoxycarbonylbutyl group, n-propoxycarbonylmethyl group, i-propoxycarbonylmethyl group, 2-n-propoxycarbonylethyl group, 2-i-
propoxycarbonylethyl group, 3-n-propoxycarbonylpropyl group, 3-i-propoxycarbonylpropyl group, 4-n-propoxycarbonylbutyl group, 4
-i-propoxycarbonylbutyl group, n-butoxycarbonylmethyl group, i-butoxycarbonylmethyl group,
sec-butoxycarbonylmethyl group, i-butoxycarbonylmethyl group, 2-n-butoxycarbonylethyl group, 2-i-butoxycarbonylethyl group, 2-sec-
butoxycarbonylethyl group, 2-t-butoxycarbonylethyl group, 3-n-butoxycarbonylpropyl group, 3-i-butoxycarbonylpropyl group, 3-sec
-butoxycarbonylpropyl group, 3-t-butoxycarbonylpropyl group, 4-n-butoxycarbonylbutyl group, 4-i-butoxycarbonylbutyl group, 4-sec
Examples of the alkyl group include a 4-t-butoxycarbonylbutyl group, a 4-t-butoxycarbonylbutyl group, and the like, and preferably a hydrogen atom, an ethyl group, or an i-propyl group, and more preferably a hydrogen atom.

^R2 includes the type ^A1 - ^Y1 or ^A2 - ^Y2 .
Here, ^A1 represents a linear or branched alkylene having 1 to 12 carbon atoms, and ^A2 represents an alkylene having 2 to 10 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms, except when the carbon chain connecting the oxygen atom and ^Y2 has one carbon atom.

Specific examples of Y ¹ include a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an i-propoxycarbonyl group, an n-butoxycarbonyl group, an i-butoxycarbonyl group, a sec-butoxycarbonyl group, a t-butoxycarbonyl group, a 2-thienyl group, a 3-thienyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a cyano group, a hydroxy group, a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, a t-butoxy group, a phenoxy group, a carbamoyl group, an N-methylaminocarbonyl group, an N-ethylaminocarbonyl group, an N-n-propylaminocarbonyl group,
N-i-propylaminocarbonyl group, N-n-butylaminocarbonyl group, N-i-butylaminocarbonyl group, N-sec-butylaminocarbonyl group, N-t-butylaminocarbonyl group, N-cyclopropylaminocarbonyl group, N-cyclobutylaminocarbonyl group, N
-cyclopentylaminocarbonyl group, N-cyclohexylaminocarbonyl group, N-cycloheptylaminocarbonyl group, N-cyclooctylaminocarbonyl group,
N-phenylaminocarbonyl group, N-2-thiazolylaminocarbonyl group, N-4-thiazolylaminocarbonyl group, N-5-thiazolylaminocarbonyl group, N-
a 2-thiadiazolylaminocarbonyl group, an N-5-thiadiazolylaminocarbonyl group, a 1-aziridinocarbonyl group, a 1-azetidinocarbonyl group, a 1-pyrrolidinocarbonyl group, a 1-piperidinocarbonyl group, a 1-homopiperidinocarbonyl group, a 1-(2,5-dimethyl)pyrrolidinocarbonyl group, a 1-(2,6-dimethyl)piperidinocarbonyl group, a 1-(3-phenyl)pyrrolidinocarbonyl group, a 1-(4-phenyl)piperidinocarbonyl group, an N-methylsulfonylamino group, an N-ethylsulfonylamino group, an N-n-propylsulfonylamino group,
N-i-propylsulfonylamino group, N-n-butylsulfonylamino group, N-i-butylsulfonylamino group, N-sec-butylsulfonylamino group, N-t-butylsulfonylamino group, 1-morpholinocarbonyl group, N-phenylsulfonylamino group, methyl group, ethyl group at the ortho-position, meta-position or para-position on the benzene ring, n
-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, fluorine atom,
an N-substituted phenylsulfonylamino group substituted with a chlorine atom, a bromine atom, or an iodine atom; or an N-substituted phenylsulfonylamino group substituted with a methyl group, an ethyl group, or an N-substituted phenylsulfonylamino group substituted with a chlorine atom, a bromine atom, or an iodine atom; ...
-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, fluorine atom,
Chlorine atom, bromine atom, iodine atom, formylamino group,
Acetylamino group, propionylamino group, butyrylamino group, methylsulfonylamino group, ethylsulfonylamino group, N-n-propylsulfonylamino group, N-
i-propylsulfonylamino group, N-n-butylsulfonylamino group, N-i-butylsulfonylamino group,
N-sec-butylsulfonylamino group, N-t-butylsulfonylamino group, N-phenylsulfonylamino group, hydroxy group, methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, sec-butoxy group, t-butoxy group, N-substituted phenylsulfonylamino group substituted at the ortho-, meta- or para-position on the benzene ring by methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, fluorine atom, chlorine atom, bromine atom or iodine atom, methylthio group, ethylthio group, n-propylthio group, i-propylthio group, n-butylthio group, i-butylthio group, sec-
butylthio group, t-butylthio group, methylsulfoxy group, ethylsulfoxy group, n-propylsulfoxy group,
i-propyl sulfoxy group, n-butyl sulfoxy group,
i-butyl sulfoxy group, sec-butyl sulfoxy group,
a substituted phenyl group substituted with a t-butylsulfoxy group, a methylsulfonyl group, an ethylsulfonyl group, an n-propylsulfonyl group, an i-propylsulfonyl group, an n-butylsulfonyl group, an i-butylsulfonyl group, a sec-butylsulfonyl group, or a t-butylsulfonyl group, or an N-phenylcarbonylamino group, 1-(2-oxo)
an azetidinyl group, a 1-(2-oxo)pyrrolidinyl group,
a 1-(2-oxo)piperidinyl group, a 1-(2-oxo)homopiperidinyl group, a 1-(2-oxo-3,3-dimethyl)pyrrolidinyl group, a 1-(2-oxo-5,5-dimethyl)pyrrolidinyl group, an N-methoxycarbonylamino group, an N-ethoxycarbonylamino group, an N-n-propoxycarbonylamino group, an N-i-propoxycarbonylamino group, an N-n-butoxycarbonylamino group,
N-i-butoxycarbonylamino group, N-sec-butoxycarbonylamino group, N-t-butoxycarbonylamino group, 3-(2-oxo)oxazolidinyl group, 3
-(2-oxo-5,5-dimethyl)oxazolidinyl group, 3-(2-oxo-4,4-diethyl)oxazolidinyl group, 3-(2-oxo-5,5-diethyl)oxazolidinyl group, or methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, se
N,N in which c-butyl and t-butyl groups are optionally combined
-disubstituted amino group, 1-azetidino group, 1-pyrrolidino group, 1-piperidino group, 1-(2,5-dimethyl)pyrrolidino group, 1-(3,4-dimethyl)pyrrolidino group, 1-
(4,4-dimethyl)piperidino group, 1-(4-phenylmethyl)piperazino group, 1-(4-diphenylmethyl)
piperazino group or 1-(4-substituted phenylmethyl)piperazinyl group or 1-(4-di-substituted phenylmethyl)piperazinyl group in which the ortho-, meta- or para-position on the benzene ring is substituted with a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; phenylaminocarboxyl group or N,N-disubstituted aminocarbonyl group in which a chain or cyclic alkyl group, a phenyl group, a thiazolyl group or a thiadiazolyl group is optionally combined on the N-substituted aminocarbonyl group described above; N-alkyl-N-phenylsulfonylamino groups in which a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms is further substituted on the nitrogen atom of the N-phenylsulfonylamino groups, N-alkylsulfonylamino groups or N-alkoxycarbonylamino groups described above, N,N-dialkylsulfonylamino groups or N-
a halogen atom on the alkyl-N-alkoxycarbonylamino group or the substituted phenyl group described above,
Examples include di-substituted phenyl groups in which any combination of a chain alkyl group, an acylamino group, a hydroxy group, an alkoxy group, an N-phenylsulfonylamino group, an N-alkylsulfonylamino group, a chain alkylthio group, or a chain alkylsulfonyl group is substituted at any position, such as the ortho-position, meta-position, or para-position, on a benzene ring.

^Y2 may be a phenyl group.

Specific examples of ^R3 and ^R4 include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, and an i-propyl group, and preferably a hydrogen atom.

Specific examples of X include a hydrogen atom, a chlorine atom, a bromine atom,
Examples thereof include a cyano group, and preferably each substituent except a hydrogen atom.

Specific examples of Ar include a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, and groups at the 2-, 3-, and 4-positions on the pyridine ring.
a fluorine atom, a chlorine atom, or a bromine atom at the 5th, 6th, or 7th positions;
a substituted 2-pyridyl group, 3-pyridyl group, or 4-pyridyl group substituted with an iodine atom, a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, or a t-butoxy group, or an N-oxidepyridyl group corresponding to the pyridyl group or substituted pyridyl group described above, a 2-furyl group, a 3-pyridyl group, or a 4-pyridyl group;
1-naphthyl group, 2-thienyl group, 3-thienyl group, 1-naphthyl group, 2-naphthyl group, 1-naphthyl group or 2-naphthyl group substituted at any position on the naphthalene ring with hydroxy group, methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, sec-butoxy group or t-butoxy group, or substituted phenyl groups substituted at any position and in any combination with one or two of the following substituents. Specific examples of the substituents include hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butoxy group, phenyl ...
Examples of the alkyl group include a c-butyl group, a t-butyl group, a hydroxyl group, an alkoxy group consisting of a linear or branched alkyl group having 1 to 8 carbon atoms, or a dioxymethylene group, 1,2-dioxyethylene group, 1,3-dioxypropylene group, or an O- ^A1 - ^Y3 group in which two adjacent substituents are joined together, where ^A1 represents a linear or branched alkylene group having 1 to 10 carbon atoms, and ^Y3 represents a phenyl group, or a group selected from the group consisting of a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, an aryl ...
a t-butyl group, a substituted phenyl group substituted with a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, or a carboxyl group or an alkoxycarbonyl group described in the section of ^Y1 above,
It refers to a 1-cyclic aminocarbonyl group, a 1-morpholinocarbonyl group, or a carbamoyl group in which a nitrogen atom is substituted in any combination with two substituents selected from a hydrogen atom, a linear, branched, or cyclic alkyl group, a phenyl group, a thiazolyl group, and a thiadiazolyl group, and an N-substituted or N,N-disubstituted aminocarbonyl group. Of these, preferred are a 3-pyridyl group or a 3-substituted-4-methoxyphenyl type, but the present invention is not limited to these specific examples.

In the above explanation, n stands for normal, i stands for iso, and sec stands for sec.
means secondary and t means tertiary.

Preferred compounds of the present invention represented by the general formula [I] include compounds represented by the general formula [IC] wherein R ^1C represents a hydrogen atom.

^R2 ' is ^A1 - ^Y3 ' ( ^A1 represents a linear or branched alkylene group having 1 to 12 carbon atoms, ^Y3 ' represents _CO2R5 ^' ( ^R5 ' represents a linear or branched alkyl group having 1 to 4 carbon atoms), (R ⁷ and R ⁸ ′ are each independently a hydrogen atom, a group having 1 to 4 carbon atoms,
^R7 ' and ^R8 ' together form an alkylene group having 2 to 8 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms or a phenyl group, or form a morpholine ring together with the nitrogen atom. ( ^R5 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and R9 ^' represents a linear or branched alkyl group having 1 to 4 carbon atoms or a phenyl group which may be substituted with a halogen atom.) ( ^R10 ' and ^R11 ' each independently represent a hydrogen atom, a halogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, an acylamino group having 1 to 4 carbon atoms, ^OR5 ( ^R5 is the same as above), _NHSO2R9 " ( ^{R9 "} represents a linear or branched alkyl group having 1 to 4 carbon atoms), or S(O) _m - ^R12 (m is 0 or 2, and ^R12 represents a linear or branched alkyl group having 1 to 4 carbon atoms), provided that ^R10 ' and ^R11 ' do not simultaneously represent a hydrogen atom.) (R ¹³ ′ represents a hydrogen atom, R ¹⁴ ′ represents a phenyl group, or R
^{R 13} ' and R ¹⁴ ' together form an alkylene having 2 to 5 carbon atoms. (R ¹⁵ ′ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, R ¹⁶ ′ represents a linear or branched alkyl group having 1 to 4 carbon atoms, or R ¹⁵ ′ and R ¹⁶ ′ together form an alkylene group having 2 to 6 carbon atoms.) (R ¹⁷ ′ and R ¹⁸ ′ each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms, or R ¹⁷ ′ and R ¹⁸ ′ together form an alkylene group having 2 to 6 carbon atoms.) (1 represents 1 or 2, and R ¹⁹ represents a hydrogen atom or a halogen atom), or or ^A2 - ^Y2 ( ^A2 represents an alkylene group having 2 to 8 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms, except when the carbon chain connecting the oxygen atom and ^Y2 has one carbon atom, and ^Y2 represents a phenyl group).

Xc' represents a chlorine atom, a bromine atom or a cyano group.

Ar' is a 3-pyridyl group or [ ^Z3 is a halogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, ^OR22 ( ^R22 is a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms),
8 represents a straight or branched chain alkyl group.) or O-A ^3
-Y3 ( ^A3 is an alkylene having 1 to 4 carbon atoms, ^Y3 is a phenyl group, _CO2R5 ^' , (R ⁵ ', R ⁷ ' and R ⁸ ' are the same as above.) ) ) ] ] } can be mentioned.

The compounds of the present invention represented by the general formula [I] include optical isomers and stereoisomers based on 1 to 6 asymmetric carbon atoms.

The compounds of the present invention, which are represented by the general formula [I], are shown below.
Representative compounds encompassed by the (2H)-pyridazinone derivatives and, where possible, pharmaceutically acceptable salts thereof are shown in Table I, but the present invention is not limited thereto.

In Table I, n is normal, i is iso, sec is secondary, Me is methyl, Et is ethyl, Pr is propyl.
Bu is a butyl group, Pen is a pentyl group, Hex is a hexyl group, He
p is a heptyl group, Oct is an octyl group, Ac is an acetyl group, Ph
means a phenyl group.

Furthermore, Q1 to Q108 in Table I are groups represented by the following formulae:

The method for producing the compound of the present invention will be explained below.

The 3(2H)-pyridazinone derivatives of the general formula [I] of the present invention and, if possible, pharmaceutically acceptable salts thereof, are
For example, it can be produced by the methods shown in the following reaction schemes (1) to (9).

(wherein X ¹ represents a chlorine atom or a bromine atom, X ² represents a chlorine atom, a bromine atom or a hydrogen atom, R ¹ , R ² , R ³ , R ⁴ and
The production method according to reaction scheme (1) involves reacting a 4,5-dihalo- or 5-halo-3(2H)-pyridazinone compound represented by general formula [IIA] with an arylmethylamine derivative of general formula [III] or a salt thereof in an inert solvent, if necessary, in the presence of a hydrogen halide scavenger, to obtain the compound of the present invention represented by general formula [I] in which the 4-position is X ²
This is a method for producing a compound of general formula [IA] in which the ring is bonded with the ring.

In the above reaction formula (1), when ^X2 in [IIA] is a chlorine atom or a bromine atom, a compound of the general formula [VA] in which an arylmethylamino group is substituted at the 4-position, which is a positional isomer of the compound of the general formula [IA], can be obtained. (wherein R ¹ , R ² , R ³ , R ⁴ , X ¹ and Ar are the same as above) is produced as a by-product, but the ratio of the compound of general formula [IA] to the compound of general formula [VA] produced is mainly affected by the polarity of the solvent used.

That is, when a solvent with high polarity is used, the production rate of the compound of general formula [IA] of the present invention tends to be high, and conversely, when a solvent with low polarity (benzene, toluene, hexane, etc.) is used, the production rate of the compound of general formula [VA] tends to be high.

Therefore, solvents that can be suitably used to suppress the by-production of [VA] and efficiently produce the compound of the general formula [IA] of the present invention include ether solvents (tetrahydrofuran, 1,4-
dioxane, etc.), amide solvents (formamide, N,N-
Dimethylformamide, N,N-dimethylacetamide,
Examples of suitable solvents include organic solvents such as N-methylpyrrolidone, acetonitrile, dimethyl sulfoxide, alcoholic solvents (methanol, ethanol, propanol, etc.), organic amine solvents (pyridine, triethylamine, N,N-dimethylaminoethanol, triethanolamine, etc.), water, and mixtures thereof.

As a method for separating and purifying the compound of general formula [IA] of the present invention from a mixture of the compound of general formula [IA] and the compound of general formula [VA], a method known per se in organic synthesis such as fractional recrystallization or various types of chromatography using silica gel can be adopted.

5-halo-3(2)-(2-methyl-2-phenyl-2-propanol) in which X ² in the general formula [IIA] is a hydrogen atom
When H)-pyridazinone is used, in addition to the above-mentioned solvents, benzene, toluene, xylene, n-hexane, n-heptane, etc. may also be used as the reaction solvent without any problem.

In the reaction of the compounds of the general formulas [IIA] and [III], hydrogen chloride or hydrogen bromide is produced. The yield is generally improved by adding a hydrogen halide scavenger to the reaction system to trap this hydrogen halide.

Preferred hydrogen halide removal agents are any that are not involved in the reaction and can trap hydrogen halide, such as inorganic bases such as potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate; N,N-
Examples of the organic base include dimethylaniline, N,N-diethylaniline, trimethylamine, triethylamine, N,N-dimethylaminoethanol, and pyridine.

Furthermore, the arylmethylamine derivative of the general formula (III) itself may be used in excess as a hydrogen halide removing agent, and this may even improve the yield.

The reaction temperature can usually be in the range of from 10° C. to the boiling point of the solvent used in the reaction.

The molar ratio of the raw materials can be set arbitrarily. However, it is preferable to use an arylmethylamine derivative of the general formula [III] or a salt thereof in the reaction of a compound of the general formula [II]
A], usually 1 to 10 times by mole, preferably 1.2 times by mole,
A molar equivalent of about 5 is sufficient.

4,5-dihalo- or 5-halo-3(2H) of the general formula [IIA]
The pyridazinone derivatives can be produced, for example, by applying the following known production methods or known organic reactions.

That is, 4,5-dihalo- or 5-halo-3-( ...
The (2H)-pyridazinone derivatives can be prepared by utilizing or adapting the method described in Reference c.

Among the arylmethylamine derivatives of the general formula [III] in reaction scheme (1) or salts thereof, those which are not commercially available can be prepared according to the method described in JP-A-61-267560.

(In the formula, ^R1 , ^R2 , ^R3 , ^R4 , ^X1 and Ar are the same as above.) Reaction formula (2) is a method for producing a 4-cyano-5-arylmethylamino derivative represented by general formula [IB], which is the compound of the present invention, using a halogen substitution reaction between a 4-halo-5-arylmethylamino derivative represented by general formula [IB-a] and a metal cyanide represented by general formula [IV].

Examples of the metal M include a lithium atom, a sodium atom, a potassium atom, and a copper atom.

The reaction solvents include N,N-dimethylformamide, N,N-
Amide solvents such as dimethylacetamide and N-methylpyrrolidone, alcohol solvents such as methanol, ethanol, n-propanol and n-butanol, dimethyl sulfoxide, and aqueous solvents thereof are preferably used.

The reaction temperature varies depending on the reactant, but
Generally, the reaction can be carried out at a temperature ranging from room temperature to the boiling point of the solvent used. Generally, the reaction proceeds under milder temperature conditions for a bromine atom than for a chlorine atom as the halogen atom at the 4-position.

The molar ratio of the raw materials can be arbitrarily set, but it is preferable to use the metal cyanide compound of the general formula [IV] in combination with the 4-halo-5-
Usually, it is sufficient to use the compound in an amount of 1.2 to 10 times by mole relative to the arylmethylamino derivative.

Methods for isolating and purifying the target product include known methods in organic synthesis such as recrystallization, various types of chromatography using silica gel, and distillation.

(wherein ^R1 ' represents a linear or branched alkyl group having 1 to 4 carbon atoms, an alkenyl group having 3 ^to ₄ carbon atoms or ( _CH2 ) _nCO2R5 ; hal represents a chlorine atom, a bromine atom, an iodine atom or other leaving functional group; n, ^R2 , ^R3 , ^R4 , ^R5 , X and Ar are the same as above.) Reaction formula (3) shows a reaction of the compound of the present invention of the general formula [I], which is a compound of the general formula [I-a] in which the 2-position of pyridazinone is a hydrogen atom, with a halogeno derivative represented by the general formula ^R1' -hal,
This method involves reacting the compound with a reactive derivative having a leaving group, such as an alkylsulfonate derivative or a phenylsulfonate derivative, to produce a 2-position-substituted compound of the general formula [I-b], which is the compound of the present invention.

This reaction can usually be carried out in the presence of an inorganic base such as potassium carbonate, sodium carbonate, lithium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, or lithium hydroxide, or an organic base such as triethylamine or tri-n-propylamine.

In the compound of the general formula [Ia], when R ³ is an alkyl group, in addition to the above inorganic bases, metal hydrides such as sodium hydride and n-butyllithium, and organometallic compounds can be used.

As the reaction solvent, when an inorganic base or an organic base is used, ketone solvents (acetone, methyl ethyl ketone, diethyl ketone, etc.), amide solvents (formamide, N,N-dimethylformamide, N,N-dimethylacetamide, etc.), alcohol solvents (methanol, ethanol, etc.), water, etc., and mixed solvents thereof are preferably used, while when a metal hydride is used, ether solvents are usually preferably used.

The reaction temperature can usually be in the range of 0°C to the boiling point of the solvent when an inorganic base or an organic base is used, and can usually be in the range of -78°C to 60°C when a metal hydride or an organometallic compound is used.

The molar ratio of the raw materials can be set ^arbitrarily .
It is sufficient to use the reactive derivative represented by the formula (Ia) in an amount of 1 to 5 times by mole relative to the compound of the formula (Ia).

The target product can be isolated and purified in accordance with the method shown in reaction formula (2).

(wherein ^R1 , ^R2 , ^R3 , ^R4 , X, Ar and hal are the same as above.) Reaction formula (4) is a method for producing the compound of the present invention of general formula [I] by reacting a 6-hydroxy-5-arylmethylamino derivative represented by general formula [IC-a] with a reactive derivative represented by ^R2 -hal.
The arylmethylamino derivatives can be prepared by the methods described in Reference c and the above-mentioned reaction scheme (2).

The reaction conditions can be set to the same as those for the reaction formula (3).

(wherein ^M1 represents an alkali metal atom, R1 ^" represents a protecting group, and ^R1 , ^R2 , ^R3 , ^R4 , X and Ar are the same as above.) Reaction formula (5) corresponds to general formula [ID-a] or general formula [ID-b].
This method is a method for producing the 6-alkoxy-5-arylmethylamino derivatives of the general formula [I] or [I-a], which are the compounds of the present invention, by using a substitution reaction of the nitro group between the 6-nitro-5-arylmethylamino derivatives of the general formula [I] and the alkali metal alkoxides of the general formula [VI].
The nitro derivatives can be prepared by the method described in reference c.

To obtain the target compound in which the 2-position of pyridazinone is a hydrogen atom, a direct method in which R ¹ of [ID-a] and [I] is a hydrogen atom in reaction formula (5)-(i) can be adopted. Alternatively, a 6-position of general formula [ID-b] in which the 2-position is protected by an R ¹ ″ group as in reaction formula (5)-(ii) can be adopted.
-nitro-5-arylmethylamino derivatives,
Alternatively, a production method can be adopted in which the compound of general formula [ID-c] is first derived and then the R ¹ ″ group is deprotected, and the latter method is often more efficient.

Examples of the protecting group R ¹ ″ include a tetrahydropyranyl group, a tetrahydrofuranyl group, a 2-trimethylsilylethoxymethyl group (Me ₃ SiCH ₂ CH ₂ OCH ₂ —), a pivaloyloxymethyl group (Me ₃ C—CO ₂ CH ₂ —), and a benzyloxymethyl group. Hydroxymethyl group, methoxymethyl group, (MeOCH
₂ -), CO ₂ R (R is a lower alkyl group), etc. are preferably used.

The protecting group R ¹ ″ can be easily deprotected using deprotection conditions commonly used for the respective protecting groups.

Alkali metals ^M1 include lithium atoms, sodium atoms, and potassium atoms.

Therefore, the alkali metal alkoxide of the general formula [VI], which is a nucleophilic agent, corresponds to the reactive species of the metal alkoxide defined by the above ^M1 and ^R2 .

The reaction solvent may be an amide solvent (N-methylpyrrolidone, formamide, N,N-dimethylformamide, N,N-
There are no particular limitations on the solvent, as long as it is inert to the reaction, and examples thereof include ether solvents (diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, etc.), benzene solvents (benzene, toluene, xylene, etc.), and mixed solvents thereof.

The reaction temperature varies depending on the reactants and cannot be generalized, but generally, a temperature between -15°C and the boiling point of the solvent used in the reaction can be used.

The molar ratio of the raw materials can be set arbitrarily, but it is usually sufficient to use 1.2 to 10 times the molar amount of the alkali metal alkoxide of general formula [VI] relative to the 6-nitro-5-arylmethylamino derivative of general formula [ID-a] or general formula [ID-b].

Methods for isolating and purifying the target product include known methods in organic synthesis such as recrystallization, various types of chromatography using silica gel, and distillation.

(In the formula, ^R1 , ^R2 , ^R3 , ^R4 , ^X1 and Ar are the same as above.) Reaction formula (6) is a method for reductively removing the halogen atom of a 4-halo derivative of general formula [IB-a] to produce compounds of general formula [IE], which are the compounds of the present invention, in which the 4-position is a hydrogen atom.

The most commonly used reduction method is catalytic hydrogenation, which uses palladium, platinum oxide, Raney nickel, etc. as catalysts and proceeds relatively quickly at hydrogen pressures of 1 to 10 atmospheres.

When ^R2 contains an atom that acts as a catalyst poison, particularly good results may be obtained by using a metal hydride such as tri-n-butyltin hydride or lithium aluminum hydride.

As the solvent used in the reaction, a protic solvent is usually preferably used in the case of catalytic hydrogenation, and an ether solvent is usually preferably used in the case of using a metal hydride.

The reaction temperature can usually be in the range of -10 to 100°C, and the reaction generally proceeds relatively rapidly.

(In the formula, ^R1 , ^R3 , ^R4 , ^R5 , ^R7 , ^R8 , ^A1 , X and Ar are the same as above.) Reaction formula (7) is a method for producing a 6-aminocarbonylalkyleneoxy derivative of general formula [IF-b] by subjecting a 6-ω-carboxyalkyleneoxy derivative or a 6-ω-alkoxycarbonylalkyleneoxy derivative of general formula [IF-a] to a condensation reaction by dehydration or dealcoholization with an amine compound represented by general formula [VII].

When ^R5 is a hydrogen atom, a wide variety of condensation methods known in peptide synthesis can be used as the condensation method, including the acid chloride method, the mixed acid anhydride method, and condensation methods using condensing agents such as dicyclohexylcarbodiimide, carbonyldiimidazole, N-hydroxysuccinimide, etc., and an appropriate condensation method can be selected depending on the reactivity of the amines of general formula [VII]. As for reaction conditions, conditions usually used may be used without any problem.

Furthermore, when reacting with nucleophilic amines among the amines represented by general formula [VII], the condensation reaction proceeds even when an ester in which ^R5 is an alkyl group is used. In this case, there are no particular restrictions on the solvent, and most solvents can be used as long as they are not involved in the reaction. In addition, it is often possible to carry out the reaction without a solvent. The reaction temperature can be set in the range of room temperature to 200°C, but is usually 50 to 150°C.
It is often performed in the range of °C.

(wherein ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R7 , ^R8 , X, ^Z2 and ^A1 are the same as above.) Reaction formula (8) shows a process for condensing a 5-(ω-carboxyalkyleneoxy)phenylmethylamino derivative or a 5-(ω-alkoxycarbonylalkyleneoxy)phenylmethylamino derivative of the general formula [IG-a] with an amine compound of the general formula [VII] to give the corresponding compound of the general formula [IG
-b)].

This reaction can be carried out in the same manner as explained in reaction scheme (7).

(Wherein, ^R1 , ^R2 , ^R3 , ^R4 , ^R20 and X are the same as above.) Reaction formula (9) shows a method for producing an N-oxypyridylmethylamino derivative of general formula [IH-b] by oxidizing the nitrogen atom on the pyridine ring of a 5-pyridylmethylamino derivative of general formula [IH-a]. Examples of oxidizing agents include performic acid, peracetic acid, perbenzoic acid, metachloroperbenzoic acid, t-butyl hydroperoxide, and aqueous hydrogen peroxide.

Examples of reaction solvents include halogen-based solvents (carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane, etc.), ether-based solvents (diethyl ether, tetrahydrofuran, 1,4-dioxane, etc.), benzene-based solvents (benzene, toluene, etc.), alcohol-based solvents (methanol, ethanol, t-butanol, etc.), acetic acid, formic acid, etc. In some cases, a transition metal complex may be added as a catalyst.

The reaction temperature can usually be in the range of from -20°C to the boiling point of the solvent used in the reaction.

The molar ratio of the raw materials can be set arbitrarily, but it is sufficient to use the oxidizing agent in an amount of usually 1 to 10 times, preferably 1.2 to 5 times, the molar amount of the 5-pyridylmethylamino derivative of the general formula [IH-a].

Methods for isolating and purifying the target product include known methods in organic synthesis such as recrystallization, various types of chromatography using silica gel, and distillation.

The administration forms of the 3(2H)-pyridazinone derivatives of general formula [I] of the present invention and, if possible, pharmaceutically acceptable salts thereof, include parenteral administration by injection (subcutaneous, intravenous, intramuscular, intraperitoneal injection), ointment, suppository, aerosol, etc., and oral administration by tablets, capsules, granules, pills, syrup, liquid, emulsion, suspension, etc.

The above-mentioned pharmaceutical composition containing the compound of the present invention contains the compound of the present invention in an amount of about 0.1 to 99.5%, preferably about 0.5 to 95%, based on the weight of the total composition.

In addition to the compounds of the present invention or compositions containing the compounds of the present invention, other pharmaceutically active compounds may be included.

Alternatively, these compositions may contain more than one compound of the invention.

The clinical dose of the compound of the present invention varies depending on the age, body weight, sensitivity of the patient, severity of symptoms, etc., but the generally effective dose is about 0.003 to 1.5 g, preferably about 0.01 to 0.6 g, per day for an adult.

However, amounts outside the above ranges can be used if desired.

The compounds of the present invention may be formulated for administration in any conventional pharmaceutical manner.

That is, tablets, capsules, granules, and pills for oral administration contain excipients such as sucrose, lactose, glucose, starch, and mannitol; binders such as syrup, gum arabic, gelatin, sorbitol, tragacanth, methylcellulose, and polyvinylpyrrolidone; disintegrants such as starch, carboxymethylcellulose or calcium salts thereof, microcrystalline cellulose, and polyethylene glycol; lubricants such as talc,
It is prepared using magnesium or calcium stearate, silica; lubricants such as sodium laurate, glycerol, etc.

Injections, solutions, emulsions, suspensions, syrups and aerosols contain a solvent for the active ingredient, such as water, ethyl alcohol, isopropyl alcohol, propylene glycol,
1,3-butylene glycol, polyethylene glycol;
They are prepared using surfactants such as sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene ethers of hydrogenated castor oil, and lecithin; suspending agents such as cellulose derivatives such as carboxymethylcellulose sodium salt and methylcellulose, and natural gums such as tragacanth and gum arabic; and preservatives such as esters of parahydroxybenzoic acid, benzalkonium chloride, and sorbic acid salts.

Suppositories are prepared using, for example, polyethylene glycol, lanolin, coconut oil, and the like.

BEST MODE FOR CARRYING OUT THE INVENTION Examples (Synthesis Examples, Formulation Examples, Test Examples) The present invention will be described in detail below with reference to examples (synthesis examples, formulation examples, test examples), but the present invention is not limited to these examples in any way.

The symbols "NMR,""IR," and "MS" in the Synthesis Examples and Table II represent "nuclear magnetic resonance spectrum,""infrared absorption spectrum," and "mass spectrum," respectively.
Unless otherwise specified, the infrared absorption spectrum is in KB
rThe nuclear magnetic resonance spectrum was measured in deuterated chloroform using the tablet method.

In Table II, "MS" indicates only the parent peak or a representative fragment peak.

Synthesis Example 1 4-chloro-5-(3,4-dimethoxybenzylamino)
-6-(5-methoxycarbonylpentyloxy)-3
(2H)-pyridazinone (Compound No. 1) A mixture of 4.13 g of 4,5-dichloro-6-(5-methoxycarbonylpentyloxy)-3(2H)-pyridazinone, 6.70 g of 3,4-dimethoxybenzylamine, 130 mL of 1,4-dioxane, and 130 mL of water was heated to reflux overnight with stirring. The solvent was removed by distillation under reduced pressure, and the resulting residue was poured into water and extracted with chloroform. The extract was washed successively with dilute hydrochloric acid, water, and saturated brine, dried over sodium sulfate, and the solvent was removed by distillation. The resulting residue was crystallized from chloroform-n-hexane-diethyl ether to give 5.28 g of the title compound as colorless crystals with a melting point of 111-112 °C.

NMR δ:11.71(1H,broad s),6.71(3H,s),5.02(1H,colla
pesd t),4.76(2H,d),4.11(2H,t),3.80(6H,s),3.
57 (3H, s), 2.26 (2H, t), 2.1-1.2 (6H, m). MS (m/e): 439 (M ⁺ ), 404, 151 (100%). Synthesis Example 2 4-chloro-5-(3,4-dimethoxybenzylamino)
-6-(5-carboxypentyloxy)-3(2H)-
Pyridazinone (Compound No. 2) 4-chloro-5-(3,4-dimethoxybenzylamino)-6-(5-methoxycarbonylpentyloxy)-3(2H)-pyridazinone (Compound No.
1) A mixture of 240 mg of benzoyl perfluorooctanoate, 65 mg of sodium hydroxide, 10 mL of methanol, and 1 mL of water is stirred at 60-70°C for 1 hour. The reaction mixture is evaporated under reduced pressure, and water is poured into the resulting residue. The pH is adjusted with dilute hydrochloric acid.
After diluting the mixture to 1-2, extract with chloroform. The extract is washed with water and then saturated brine, dried over sodium sulfate, and the solvent is removed by distillation. The residual solid is crystallized from chloroform-diethyl ether to give 192 mg of the title compound as colorless crystals with a melting point of 150.5-151.5°C.

NMR δ:6.70(3H,s),5.14(1H,collapsed t),4.75(2H,
d), 4.10 (2H, t), 3.79 (6H, s), 2.29 (2H, t), 2.0~1.
2 (6H,m). MS (m/e): 425 (M ⁺ ), 390, 151 (100%). Synthesis Example 3 4-bromo-5-(3-pyridylmethylamino)-6-
(3-Phenylpropoxy)-3(2H)-pyridazinone hydrochloride (Compound No. 85) 4-Bromo-5-(3-pyridylmethylamino)-6-
2.50 g of (3-phenylpropoxy)-3(2H)-pyridazinone (Compound No. 101) was dissolved in 10% hydrogen chloride methanol solution.
The mixture was dissolved in 50 mL of HCl and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the resulting residue was crystallized from methanol-diethyl ether to give 2.68 g of the title compound as colorless crystals having a melting point of 203-205°C.

MS (m/e): 414 (M ⁺ −HCl), 335, 322, 296, 217, 118 (100
%). Synthesis Example 4 4-chloro-5-(3,4-dimethoxybenzylamino)
-6-(5-N,N-diethylaminocarbonylpentyloxy)-3(2H)-pyridazinone (Compound No. 12) 200mM of 4-chloro-5-(3,4-dimethoxybenzylamino)-6-(5-carboxypentyloxy)-3(2H)-pyridazinone (Compound No. 2) prepared in Synthesis Example 2
g, 60 mg of triethylamine and 10 mL of tetrahydrofuran
To this mixture, 60 mg of ethyl chlorocarbonate was added under ice cooling, and the mixture was stirred at the same temperature for 1.5 hours. Subsequently, 100 mg of diethylamine was added. The ice bath was removed, and the mixture was stirred for 2.5 hours. The solvent was then evaporated under reduced pressure. Water was poured into the residue, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The resulting residue was crystallized from chloroform-diethyl ether to yield 209 mg of the title compound as colorless crystals with a melting point of 148-149.5°C.

NMR δ:6.75(3H,s),5.15(1H,collapsed t),4.79(2H,
d),4.15(2H,t),3.83(6H,s),3.81,3.76(2H,q each),
2.27 (2H, t), 2.1~1.9 (6H, m), 1.15, 1.10 (3H each,
t). MS (m/e): 480 (M ⁺ ), 445, 310, 275, 170 (100%), 151. Synthesis Example 5 4-chloro-5-(3,4-dimethoxybenzylamino)
-6-(5-N-methylaminocarbonylpentyloxy)-3(2H)-pyridazinone (Compound No. 8) 4-chloro-5-(3,4-dimethoxybenzylamino)-6-(5-methoxycarbonylpentyloxy)-3(2H)-pyridazinone (Compound No.
1) 200 mg, 2 mL of 40% methylamine aqueous solution and 6 mL of methanol
The mixture was heated to reflux for 8 hours, the reaction mixture was evaporated under reduced pressure, and the resulting residue was extracted with chloroform.
The extract was washed with water and saturated brine in that order, dried over sodium sulfate, and the solvent was removed by distillation. The residue was crystallized from chloroform-diethyl ether to give 146 mg of the title compound as colorless crystals having a melting point of 103-104°C.

NMR δ:11.65(1H,broad s),6.73(3H,s),6.0~5.5(1H,b
road m),5.02(1H,collapsed t),4.76(2H,d),4.10
(2H,t),3.81(6H,s),2.74(3H,d),2.12(2H,collap
sed t), 1.9-1.3 (6H, m). MS (m/e): 438 (M ⁺ ), 403, 310, 274, 151 (100%), 128. Synthesis Example 6 4-chloro-5-(3-pyridylmethylamino)-6-
[5-(1-piperidinocarbonylpentyloxy)]
-3(2H)-pyridazinone fumarate (Compound No. 73) 4-chloro-5-(3-pyridylmethylamino)-6-
[5-(1-piperidinocarbonylpentyloxy)]
A mixture of 1.0 g of 3(2H)-pyridazinone (Compound No. 33), 268 mg of fumaric acid, and 20 mL of methanol was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure, and the resulting solid was crystallized from chloroform-ethyl acetate.
1.06 g of the title compound was obtained as colorless crystals at 156-158°C.

MS (m/e):433[M ⁺ −(CH−CO ₂ H) ₂ ],398,287,251,216,
182 (100%). Synthesis Example 7 4-cyano-5-(3-pyridylmethylamino)-6-
[3-(4-chlorophenylpropoxy)]-3(2H)
-Pyridazinone (Compound No. 107) 4-Bromo-5-(3-pyridylmethylamino)-6-
[3-(4-chlorophenylpropoxy)]-3(2H)
- Pyridazinone (compound No. 106) 1.0 g, copper cyanide 587 m
A mixture of 20 g and 20 mL of N-methylpyrrolidone was heated at 120-130°C.
The mixture was stirred at rt for 6 hours. After cooling to room temperature, saturated aqueous ammonium chloride was added and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation. The residue was crystallized from acetonitrile to give 313 mg of the title compound as pale yellowish-white crystals with a melting point of 188-190°C.

MS (m/e): 395 (M ⁺ ), 350, 243, 152 (100%), 124. Synthesis Example 8 2-ethoxycarbonylmethyl-4-bromo-5-(3,
4-Dimethoxybenzylamino)-6-[3-(4-chlorophenylpropoxy)]-3(2H)-pyridazinone (Compound No. 238) 4-Bromo-5-(3,4-dimethoxybenzylamino)
-6-[3-(4-chlorophenylpropoxy)]-3
(2H)-pyridazinone (compound No. 239) 100 mg, potassium carbonate 33 mg, ethyl bromoacetate 49 mg, sodium iodide
A mixture of 316 mg of this product and 5 mL of methyl ethyl ketone was heated to reflux for 5 hours. After filtering off the insoluble material, the solvent was evaporated under reduced pressure. Water was poured into the resulting residue, which was then extracted with chloroform. After washing with saturated brine and drying over sodium sulfate, the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1) to yield 82 mg of the title compound as a colorless oil.

MS (m/e): 593 (M ⁺ ), 514, 288, 259, 151 (100%). Synthesis Example 9 2-carboxymethyl-4-bromo-5-(3,4-dimethoxybenzylamino)-6-[3-(4-chlorophenylpropoxy)]-3(2H)-pyridazinone (compound
No.227) 2-Ethoxycarbonylmethyl-4- ...
-bromo-5-(3,4-dimethoxybenzylamino)-
6-[3-(4-chlorophenylpropoxy)]-3
A mixture of 80 mg of (2H)-pyridazinone (Compound No. 238), 16 mg of sodium hydroxide, 2 mL of methanol, and 0.2 mL of water was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, and water was poured into the resulting residue. The pH was adjusted to 1-2 with dilute hydrochloric acid, and then the residue was extracted with chloroform. The extract was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The residue was crystallized from chloroform-diethyl ether, giving a melting point of 140-141.
49 mg of the title compound was obtained as colorless crystals at ℃.

MS (m/e): 486 (M ⁺ -Br), 427,371,151 (100%). Synthesis Example 10 4-Bromo-5-[3-(N-oxypyridylmethylamino)]-6-(3-phenylpropoxy)-3(2H)
-Pyridazinone (Compound No. 230) 4-Bromo-5-(3-pyridylmethylamino)-6-
A mixture of 250 mg of (3-phenylpropoxy)-3(2H)-pyridazinone (Compound No. 101), 167 mg of metachloroperbenzoic acid, and 10 mL of dichloromethane is stirred at room temperature for 6 hours. A saturated aqueous solution of sodium bicarbonate and chloroform are added, and the organic layer is separated. The aqueous layer is extracted with chloroform, and the combined organic layer is washed with water and saturated brine, in that order, dried over sodium sulfate, and the solvent is evaporated. The residual solid is crystallized from chloroform-diethyl ether, giving a melting point of 191
The title compound was obtained as colorless crystals at ∼192°C.

MS (m/e): 414 (M ⁺ −O), 335, 323, 295, 217, 91 (100
%). Compounds synthesized according to the above synthesis examples are shown in Table II. The structures of the compounds are referenced by the compound numbers shown in Table I. The rightmost column in the table lists the numbers of the synthesis examples that were applied.

Formulation Example 1 Tablets Compound No. 85 10 g Lactose 20 g Starch 4 g Starch (for gluing) 1 g Magnesium stearate 0.1 g Carboxymethylcellulose calcium 7 g Total 42.1 g The above ingredients were mixed in a conventional manner and then made into sugar-coated tablets each containing 50 mg of the active ingredient.

Formulation Example 2 Capsules Compound No. 88 10 g Lactose 20 g Microcrystalline cellulose 10 g Magnesium stearate 1 g Total 41 g The above ingredients were mixed in a conventional manner and then filled into gelatin capsules to give capsules containing 50 mg of the active ingredient per capsule.

Formulation Example 3 Soft Capsules Compound No. 94 10 g Corn oil 35 g Total 45 g The above ingredients were mixed and then made into soft capsules by a conventional method.

Formulation Example 4 Ointment Compound No. 55 1.0 g Olive oil 20 g White petrolatum 79 g Total 100 g The above ingredients were mixed in a conventional manner to give a 1% ointment.

Formulation Example 5 Aerosol Suspension (A) Compound No. 11 0.25% Isopropyl myristate 0.10% Ethanol 26.40% (B) 60-40% mixture of 1,2-dichlorotetrafluoroethane and 1-chloropentafluoroethane 73.25% The above composition (A) is mixed, the resulting mixture is charged into a container equipped with a valve, and the propellant (B) is added at a temperature of about 2.46-2.25% at 20°C.
The mixture was injected through the valve nozzle up to a cage pressure of 81 mg/cm ² to form an aerosol suspension.

Test method I. Platelet aggregation inhibitory effect 1. In vitro test (A) Rabbit platelet aggregation inhibitory effect Nine doses of 3.8% sodium citrate were injected into the abdominal aorta of a Japanese white male rabbit (body weight 1.8-2.5 kg) using a syringe containing one volume of 3.8% sodium citrate.
A volume of blood was collected and centrifuged at 200×g for 7 minutes at room temperature to obtain platelet-rich plasma (PRP).
Platelet-poor plasma (PPP) was prepared by centrifugation at 1000 × g for 10 minutes. For the measurement, PRP and PPP diluted to 300,000/ ^mm3 were used. PRP and PPP were placed in the aggregation cell, and the transmittance measurement range was set to PR.
After adjusting P to 0% and PPP to 100%, the test drug dissolved in 100% dimethyl sulfoxide (DNSO) was added to the PRP (final concentration of DMSO was 0.25%). After incubation at 37°C, 900 rpm for 2 minutes, an aggregating agent was added and the aggregation curve was recorded. The aggregation inhibitory effect of the test drug was expressed as the concentration that inhibited 50% of the aggregation of the control ( _IC50 : μM). Aggregating agent
ADP and arachidonic acid (AA) were used at the minimum concentrations that showed maximum aggregation (ADP: 5-10 μM; AA: 0.2-0.3 mM).
Platelet aggregation was measured using NBS HEMA TRACER 601.

(B) Inhibitory effect on platelet aggregation in guinea pigs. Blood was similarly collected from the abdominal aorta of male Hartley guinea pigs (weighing approximately 300 g) and centrifuged at 160 x g for 10 minutes at room temperature to obtain PRP. The residue was further centrifuged at 3,000 x g for 15 minutes to prepare PPP. The PRP for measurement was prepared in the same manner as in the rabbit test.
The test drug was dissolved in 100% DMSO (final DMSO concentration: 0.5%), and the _IC50 value, the concentration at which 50% of the aggregation was inhibited relative to the control, was calculated.
AA was used.

2. In vivo test (A) Inhibitory effect on platelet aggregation in rabbits Male Japanese white rabbits (weight 1.8-2.5 kg) were fasted for 18 hours, and the test drug suspended in 0.5% methylcellulose was orally administered. After administration, blood samples were taken from the auricular artery at regular intervals, and in vitro
PRP was prepared in the same manner as in the ro test, and platelet aggregation due to each aggregating agent was measured.
The aggregation rate was measured when it was set at 100%, and the inhibition rate was calculated.

(B) Inhibitory effect on guinea pig platelet aggregation (1) Hartley male guinea pigs (weight approximately 350 g)
The subjects were fasted for 18 hours, and the test drug suspended in 5% gum arabic solution was orally administered. After administration, blood was collected from the abdominal aorta at regular intervals, and PRP was prepared in the same manner as in the in vitro test.
Platelet aggregation caused by each aggregating agent was measured. The effect of the drug was evaluated by measuring the aggregation rate, with the aggregation rate before administration set at 100%, and calculating the inhibition rate.

(2) Hartley male guinea pig (weight approximately 350g)
The subjects were fasted for 18 hours, and the test drug suspended in 5% gum arabic solution was orally administered. One hour after administration, blood was collected from the abdominal aorta, PRP was prepared in the same manner as in the in vitro test, and platelet aggregation induced by each aggregating agent was measured. The effect of the drug was measured by measuring the aggregation rate, with aggregation before administration set at 100%, and the inhibition rate was calculated.

(C) Mouse thrombocytopenia model: Collagen (Holm) diluted with saline was administered at 1 mg/5 mL/kg via the tail vein to male ICR mice (weight 24-30 g). Five minutes later, under pentobarbital anesthesia, 9 volumes of blood were collected from the lower femoral vein using a plastic syringe containing 1 volume of 3.8% sodium citrate. The drug was orally administered 1 hour before collagen administration. Blood was diluted to 20 ml with Isotone II.
The diluted solution was centrifuged at 60×g for 5 minutes, and the upper layer was further purified with Isotone.
The platelets were diluted with II and the platelet count was measured using a Coulter counter (model ZM).

In the above tests I-1 and I-2, ticlopidine hydrochloride (Daiichi Pharmaceutical Co., Ltd.) and cilostazol (Otsuka Pharmaceutical Co., Ltd.) were used as control drugs.

II. Cardiotonic Action Male guinea pigs (Hartley strain, 250-400 g) were sacrificed by exsanguination, and the hearts were extracted and placed in a nutrient solution (Kreb's-Hens) aerated with oxygen (containing 5% carbon dioxide) prepared in advance.
Eleit solution: NaCl 118.4mM, KCl 4.7mM, MgSO ₄・7H ₂ O 1.18
mM,CaCl ₂・2H ₂ O 2.5mM,KH ₂ PO ₄ 1.2mM,NaHCO ₃ 24.9mM,G
The heart was then immediately immersed in a nutrient solution containing 11.1 mM lucose. The heart was then transferred to a petri dish filled with aerated nutrient solution and the oxygen was continuously supplied to the dish. After quickly separating the atria and ventricles,
Papillary muscle specimens were prepared from the right ventricle and suspended in an organ bath filled with oxygenated nutrient solution kept at 31°C, and a tension of 500 mg was applied.

The papillary muscle preparations were suspended for 20 and 40 minutes, and the nutrient solution was replaced.
After observing for another 20 minutes, isoproterenol was cumulatively administered (final concentration: 3×10 ⁻⁷ M) and the effect on contractile force was observed.
After 40 minutes, the nutrient solution was replaced and observed for another 20 minutes.
The test drugs were administered cumulatively. The effect of each test drug on contractile force was calculated by dividing the difference in contractile force after the second isoproterenol administration by 100.
The rate of change due to the test drug when the activity was measured as % was expressed as a percentage, and the concentration EC ₃₀ (μM) required for 30% enhancement was calculated.

Contractile force was measured by applying square-wave electrical stimulation [vo] to the papillary muscles via bipolar platinum electrodes using an electrical stimulator (Nihon Kohden SEN-3201).
ltage: threshold x 2 (V), duration: 3 (msec), frequency:
1 (Hz)] was applied, and the generated tension was recorded on a recorder via an FD pickup and a strain pressure amplifier.

The control drug used was the cardiac stimulant milrinone (Winthrop).

III. Vasodilatory effect Male rabbits (Japanese white, 2-2.5 kg) were anesthetized with intravenous injection of Nembutal [body weight (kg) x 0.5 + 0.5 mL]. After blood loss, the thoracic aorta was excised and aliquots of the rabbits were placed in a nutrient solution (Kreb's-Henseleit) aerated with oxygen (containing 5% carbon dioxide) prepared in advance.
Solution: NaCl 118.4mM, KCl 4.7mM, MgSO ₄・7H ₂ O 1.188mM, Ca
Cl ₂・2H ₂ O 2.5mM, KH ₂ PO ₄ 1.2mM, NaHCO ₃ 24.9mM, Glucose
The blood vessels were then immediately immersed in a nutrient solution containing 11.1 mM sodium. The vessels were then transferred to a petri dish filled with aerated oxygenated nutrient solution, and both ends of the vessels were fixed with insect pins, and fat and connective tissue were removed. The vessels were then cut into spirals (3 mm wide, 1 cm long) using scissors at an angle.
Both sides of the specimen were fixed with clips, suspended in an organ bath filled with oxygenated nutrient solution kept at 37°C, and subjected to a tension of 2 g.

The tension of the blood vessels was measured using an F-D pickup (Nihon Kohden 611-
T), and the strain-stress signals were recorded on a recorder (Nihon Kohden) via a strain-stress amplifier (Nihon Kohden AP-600G).

After 20 and 40 minutes of suspension, the nutrient solution was replaced and
The animals were observed for 20 minutes (tension was maintained at 2 g during this time), after which norepinephrine was administered (final concentration: 10 ⁻⁶ M).
The effect on vascular tension was observed. After the contraction stabilized, the nutrient solution was replaced, and then 20 and 40 minutes later, the nutrient solution was replaced again. After observing for another 20 minutes, the vessels were contracted with a contraction inducer.
After the contraction became stable, the test drug was administered cumulatively. After the experiment was completed, papaverine was administered (final concentration: 10 ^-4 M) to induce complete relaxation.

The effect of each test drug on the contraction caused by the inducer was expressed as a percentage change caused by the test drug, with the difference in tension after administration of papaverine compared to administration of the inducer being taken as 100%.

IV. Anti-SRS-A effect (bronchodilator effect) Drug The test drug was 100% dimethylsulfoxide (DMSO, Wako Pure Chemical Industries, Ltd.).
Leukotriene D ₄ (LTD ₄ , Ultra
fine) was diluted with distilled water.

Indomethacin (Indo, Sigma) is 100% ethanol (EtOH,
Aminophylline (AP, Sigma), hi
Stamina dihydrochloride (His, Wako Pure Chemical Industries) was dissolved in distilled water. The final concentrations of DMSO and EtOH in the bath were 0.25 and 0.5%, respectively.
The concentration was set to 0.1% v/v or less.

Method: Guinea pigs weighing 300-450 g were sacrificed by exsanguination, and the trachea was removed and removed of fat and connective tissue. The trachea was then cut into a spiral shape approximately 2 mm wide and divided into 2-3 pieces containing 4 pieces of smooth muscle tissue. The specimens were stored at 37°C in a modified endothelium aerated with 95% O ₂ + 5% CO _{2 .}
The subject was suspended in an 8 ml organ bath containing Tyrode's solution and a 1 g load was applied. Muscle relaxation was recorded using an isotonic transducer (Nihon Kohden, TD-112S) and a pen recorder (Yokogawa Hokushin Electric, Type 3066).

The composition of Modified Tyrode's solution is as follows (m
M).

NaCl 137,KCl 2.7,CaCl ₂ 1.8,MgCl ₂ 1.0,NaHCO ₃ 20,NaH
₂ PO ₄ 0.32, Glucose 11. After allowing the specimen to rest for 50-60 minutes, histamine dihydrochloride 10
After the response stabilized, the cells were washed and allowed to rest for 20-30 minutes. 5 μM indomethacin was added and the cells were incubated for another 30 minutes, after which 30 nM LTD ₄ was added to induce contraction. After the response stabilized, the test drug was applied cumulatively.
The maximum relaxation response was obtained by adding 1 mM AP.
The relaxation was expressed as a percentage when the relaxation rate was 1.0%, and the concentration causing 50% relaxation (EC ₅₀ , μM) was determined.

The control drug was FPL-55712 (Phison Corporation; Journal of Medicinal Chemistry, 2004), which is recognized as a selective SRS-A antagonist.
Chemistry, Vol. 20, pp. 371-379, 1977] was used.

Test Results I. Platelet Aggregation Inhibitory Effect 1. In vitro Test: (A), (B) Tables III-1 to III-3 show the platelet aggregation inhibitory effect of the test compounds.
The values are shown as ₅₀ μM.

2. In vivo test (A) Inhibitory effect on rabbit platelet aggregation (B) Inhibitory effect on guinea pig platelet aggregation (C) Inhibitory effect on platelet reduction in mice II. Cardiotonic action III. Vasodilatory effect IV. Anti-SRS-A effect Industrial Applicability From the above results, it is clear that the compound of the present invention has excellent platelet aggregation inhibitory activity, cardiotonic activity, vasodilatory activity, and anti-SRS-A activity. Therefore, the compound of the present invention can be a useful preventive and therapeutic drug for diseases such as thrombotic diseases, congestive heart failure, hypertension, angina pectoris, and immediate-type allergic diseases including asthma.

─────────────────────────────────────────────────────── Continued from the front page (51) Int.Cl. ⁶ Identification symbol Internal reference number FI Technical marking location A61K 31/50 ABS ACB C07D 401/12 237 401/14 237 403/12 237 405/12 237 409/12 237 409/14 237 413/12 237 413/14 237 417/12 237 (72) Inventor Ryozo Sakoda 722-1 Tsuboi-cho, Funabashi-shi, Chiba Prefecture Nissan Chemical Industries, Ltd. Central Research Institute (72) Inventor Nobutomo Mizunaru 1470 Shiraoka, Shiraoka-cho, Minamisaitama-gun, Saitama Prefecture Nissan Chemical Industry Co., Ltd. Biological Science Research Institute (72) Inventor Kenichi Shikada 1470 Shiraoka, Shiraoka-cho, Minamisaitama-gun, Saitama Prefecture Nissan Chemical Industry Co., Ltd. Biological Science Research Institute

Claims (10)

[Claims] [Claim 1] General formula [I] wherein R ¹ is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, an alkenyl group having 3 to 4 carbon atoms, or (CH ₂ ) _n
R2 represents ^CO2R5 (n is an integer of 1 to 4, and ^R5 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms), ^R2 represents ^A1 - ^Y1 ( ^A1 represents a linear or branched alkylene group having 1 to 12 carbon atoms, and ^Y1 represents _CO2R5 ( ^R5 is the same as above), a cyano group, ^OR6 ( ^R6 represents a hydrogen atom, ^a linear or branched alkyl group having 1 to 4 carbon atoms, or a phenyl group), or a thienyl group or pyridyl group which may be substituted at any position, ( ^R7 and ^R8 each independently represent a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a cyclic alkyl group having 3 to 8 carbon atoms, a phenyl group, or a thiazolyl group or thiadiazolyl group which may be substituted at any position, or ^R7 and ^R8 together form an alkylene group having 2 to 8 carbon atoms which may be substituted with a linear or branched alkyl group having 1 to 3 carbon atoms or a phenyl group, or form a morpholine ring together with the nitrogen atom.) ( ^R5 is the same as above, and ^R9 represents a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkyl group having 1 to 4 carbon atoms, or a phenyl group which may be substituted with a halogen atom.) ( ^R10 and ^R11 each independently represent a hydrogen atom, a halogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, an acylamino group having 1 to 4 carbon atoms, ^OR5 ( ^R5 is the same as above), _NHSO2R9 ( ^R9 is the same as above) ^, or S(O) _m - ^R12
(m is an integer of 0 to 2, and ^R12 is a linear or branched alkyl group having 1 to ⁴ carbon atoms).
¹¹ does not simultaneously represent a hydrogen atom.) ( ^R13 represents a hydrogen atom, ^R14 represents a phenyl group, or ^R13 and ^R14 together form an alkylene having 2 to 8 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms.) ( ^R15 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, ^R16 represents a linear or branched alkyl group having 1 to 4 carbon atoms, or ^R15 and ^R16 together form an alkylene having 2 to 8 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms.) ( ^R17 and ^R18 each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms, or ^R17 and ^R18 together form an alkylene group having 2 to 8 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms.) (l is 1 or 2, k is an integer of 0 to 3, and R ¹⁹ is a hydrogen atom or a halogen atom), or or ^A2 - ^Y2 ( ^A2 represents an alkylene having 2 to 10 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms, except when the carbon chain connecting the oxygen atom and ^Y2 has one carbon atom, and ^Y2 represents a phenyl group). ^R3 and ^R4 each independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
3 represents a straight or branched alkyl group. X represents a chlorine atom, a bromine atom, a hydrogen atom or a cyano group. Ar represents [j is 0 or 1, R ²⁰ is a hydrogen atom, a halogen atom or O
R ¹² (wherein R ¹² is the same as above). ( ^Z1 represents an oxygen atom or a sulfur atom.) [ ^R21 represents a hydrogen atom or ^OR5 ( ^R5 is the same as defined above)], or [ ^Z2 and ^Z3 each independently represent a hydrogen atom, a halogen atom,
a straight or branched alkyl group having 1 to 4 carbon atoms, OR ²² (R
²² represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms; O-A ¹ -Y ³ (A ¹ is the same as above);
^Y3 is a linear or branched alkyl group having 1 to 4 carbon atoms or a phenyl group which may be substituted with a halogen atom;
_2R5 ^, (R ⁵ , R ⁷ and R ⁸ are the same as above.) or Z ² and
^Z3 together with the benzene ring (W represents an alkylene having 1 to 8 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms.) } and, if possible, a pharmaceutically acceptable salt thereof. 2. The 3(2H)-pyridazinone derivative according to claim 1, wherein R ⁴ is a hydrogen atom and X is a chlorine atom, a bromine atom or a cyano group, and, if possible, a pharmaceutically acceptable salt thereof. [Claim 3] General formula [IA] (wherein ^R1 represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms _, ^or ( _CH2 ) _nCO2R4 (n represents an integer of 1 to 4, and ^R4 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms); ^R2 represents ^A1 - ^Y1 (wherein ^A1 represents a linear or branched alkylene group having 1 to 12 carbon atoms, and ^Y1 represents _CO2R4 ( ^R4 is the same as ^above ), a cyano group, a phenoxy group, or a thienyl group or pyridyl group which may be substituted at any position); ( ^R5 and ^R6 each independently represent a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a cyclic alkyl group having 3 to 8 carbon atoms, a phenyl group, or a thiazolyl group or thiadiazolyl group which may be substituted at any position, or ^R5 and ^R6 together form an alkylene group having 2 to 8 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms or a phenyl group, or form a morpholine ring together with the nitrogen atom.) ( ^R4 is the same as above. ^R7 represents a linear or branched alkyl group having 1 to 4 carbon atoms or a phenyl group which may be substituted with a halogen atom.) ( ^R8 and ^R9 each independently represent a hydrogen atom, a halogen atom,
a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms,
1 to 4 acylamino groups, OR ⁴ (R ⁴ is the same as above), NHS
O ₂ R ¹⁰ (R ¹⁰ represents a linear or branched alkyl group having 1 to 4 carbon atoms) or S(O) _m -R ¹⁰ (m represents 0 or 2, and R ¹⁰
is the same as above.) However, ^R8 and ^R9 do not simultaneously represent a hydrogen atom.) (R ¹¹ represents a hydrogen atom, and R ¹² represents a phenyl group, or R ¹¹ and R ¹² together form an alkylene group having 2 to 5 carbon atoms.) ( ^R13 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and ^R14 represents a linear or branched alkyl group having 1 to 4 carbon atoms, ^{or R13} and ^R14 together form an alkylene group having 1 to 4 carbon atoms.) ( ^R15 and ^R16 each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms, or ^R15 and ^R16 together form an alkylene group having 2 to 6 carbon atoms.) (l is 1 or 2, and R ¹⁷ is a hydrogen atom or a halogen atom), or or ^A2 - ^Y2 ( ^A2 represents an alkylene having 2 to 8 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms, except when the carbon chain connecting the oxygen atom and ^Y2 has one carbon atom, and ^Y2 represents a phenyl group). ^R3 represents a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms. X represents a chlorine atom, a bromine atom, or a cyano group. Ar is [k represents 0 or 1, and ^R represents a hydrogen atom, a halogen atom, or ^OR ( ^R is the same as defined above)], ( ^Z1 represents an oxygen atom or a sulfur atom.) [R ¹⁹ represents a hydrogen atom or OR ⁴ (R ⁴ is the same as defined above)] or [ ^Z2 and ^Z3 each independently represent a hydrogen atom, a halogen atom,
a straight or branched alkyl group having 1 to 4 carbon atoms, OR ²⁰ (R
²⁰ represents a hydrogen atom or a straight or branched alkyl group having 1 to 8 carbon atoms; or O-A ³ -Y ³ (A ³ represents a straight or branched alkyl group having 1 to 8 carbon atoms).
4 alkylene, ^Y3 is a phenyl group, _CO2R4 ( ^R4 is the same as ^above ), ( ^R21 and ^R22 each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms, a cyclic alkyl group having 3 to 7 carbon atoms, or ^R21 and ^R22 taken together form an alkylene group having 2 to 6 carbon atoms), or ^Z2 and ^Z3 taken together form a benzene ring. (W represents an alkylene group having 1 to 2 carbon atoms.)
3(2H)-pyridazinone derivatives according to claim 2, which are represented by the formula: and, if possible, pharmaceutically acceptable salts thereof. 4. The 3(2H)-pyridazinone derivative according to claim 3, wherein R ¹ and R ³ are hydrogen atoms, and, if possible, a pharmaceutically acceptable salt thereof. [Claim 5] General formula [II] wherein R ¹ is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, an alkenyl group having 3 to 4 carbon atoms, or (CH ₂ ) _n
R2 represents ^CO2R5 (n is an integer of 1 to 4, and ^R5 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms), ^R2 represents ^A1 - ^Y1 ( ^A1 represents a linear or branched alkylene group having 1 to 12 carbon atoms, and ^Y1 represents _CO2R5 ( ^R5 is the same as above), a cyano group, ^OR6 ( ^R6 represents a hydrogen atom, ^a linear or branched alkyl group having 1 to 4 carbon atoms, or a phenyl group), or a thienyl group or pyridyl group which may be substituted at any position, ( ^R7 and ^R8 each independently represent a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a cyclic alkyl group having 3 to 8 carbon atoms, a phenyl group, or a thiazolyl group or thiadiazolyl group which may be substituted at any position, or ^R7 and ^R8 together form an alkylene group having 2 to 8 carbon atoms which may be substituted with a linear or branched alkyl group having 1 to 3 carbon atoms or a phenyl group, or form a morpholine ring together with the nitrogen atom.) ( ^R5 is the same as above, and ^R9 represents a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkyl group having 1 to 4 carbon atoms, or a phenyl group which may be substituted with a halogen atom.) ( ^R10 and ^R11 each independently represent a hydrogen atom, a halogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, an acylamino group having 1 to 4 carbon atoms, ^OR5 ( ^R5 is the same as above), _NHSO2R9 ( ^R9 is the same as above) ^, or S(O) _m - ^R12
(m is an integer of 0 to 2, and ^R12 is a linear or branched alkyl group having 1 to ⁴ carbon atoms).
¹¹ does not simultaneously represent a hydrogen atom.) ( ^R13 represents a hydrogen atom, ^R14 represents a phenyl group, or ^R13 and ^R14 together form an alkylene having 2 to 8 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms.) ( ^R15 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, ^R16 represents a linear or branched alkyl group having 1 to 4 carbon atoms, or ^R15 and ^R16 together form an alkylene having 2 to 8 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms.) ( ^R17 and ^R18 each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms, or ^R17 and ^R18 together form an alkylene group having 2 to 8 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms.) (l is 1 or 2, k is an integer of 0 to 3, and R ¹⁹ is a hydrogen atom or a halogen atom), or or ^A2 - ^Y2 ( ^A2 represents an alkylene having 2 to 10 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms, except when the carbon chain connecting the oxygen atom and ^Y2 has one carbon atom, and ^Y2 represents a phenyl group). ^X1 represents a chlorine atom or a bromine atom, and ^X2 represents a chlorine atom, a bromine atom, or a hydrogen atom.} with a 4,5-dihalo or 5-halo-3(2H)-pyridazinone compound represented by the general formula [III] wherein ^R3 and ^R4 each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms; Ar is [j is 0 or 1, R ²⁰ is a hydrogen atom, a halogen atom or O
R ¹² (wherein R ¹² is the same as above). ( ^Z1 represents an oxygen atom or a sulfur atom.) [ ^R21 represents a hydrogen atom or ^OR5 ( ^R5 is the same as defined above)] or [ ^Z2 and ^Z3 each independently represent a hydrogen atom, a halogen atom,
a straight or branched alkyl group having 1 to 4 carbon atoms, OR ²² (R
²² represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms; O-A ¹ -Y ³ (A ¹ is the same as above);
^Y3 is a linear or branched alkyl group having 1 to 4 carbon atoms or a phenyl group which may be substituted with a halogen atom;
_2R5 ^, (R ⁵ , R ⁷ and R ⁸ are the same as above.) or Z ² and
^Z3 together with the benzene ring (W represents an alkylene group having 1 to 8 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms.) } represents an arylmethylamine derivative or a salt thereof, if necessary, in the presence of a scavenger. [Claim 6] General formula [IB-a] wherein R ¹ is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, an alkenyl group having 3 to 4 carbon atoms, or (CH ₂ ) _n
R2 represents ^CO2R5 (n is an integer of 1 to 4, and ^R5 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms), ^R2 represents ^A1 - ^Y1 ( ^A1 represents a linear or branched alkylene group having 1 to 12 carbon atoms, and ^Y1 represents _CO2R5 ( ^R5 is the same as above), a cyano group, ^OR6 ( ^R6 represents a hydrogen atom, ^a linear or branched alkyl group having 1 to 4 carbon atoms, or a phenyl group), or a thienyl group or pyridyl group which may be substituted at any position, ( ^R7 and ^R8 each independently represent a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a cyclic alkyl group having 3 to 8 carbon atoms, a phenyl group, or a thiazolyl group or thiadiazolyl group which may be substituted at any position, or ^R7 and ^R8 together form an alkylene group having 2 to 8 carbon atoms which may be substituted with a linear or branched alkyl group having 1 to 3 carbon atoms or a phenyl group, or form a morpholine ring together with the nitrogen atom.) ( ^R5 is the same as above, and ^R9 represents a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkyl group having 1 to 4 carbon atoms, or a phenyl group which may be substituted with a halogen atom.) ( ^R10 and ^R11 each independently represent a hydrogen atom, a halogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, an acylamino group having 1 to 4 carbon atoms, ^OR5 ( ^R5 is the same as above), _NHSO2R9 ( ^R9 is the same as above) ^, or S(O) _m - ^R12
(m is an integer of 0 to 2, and ^R12 is a linear or branched alkyl group having 1 to ⁴ carbon atoms).
¹¹ does not simultaneously represent a hydrogen atom.) ( ^R13 represents a hydrogen atom, ^R14 represents a phenyl group, or ^R13 and ^R14 together form an alkylene having 2 to 8 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms.) ( ^R15 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, ^R16 represents a linear or branched alkyl group having 1 to 4 carbon atoms, or ^R15 and ^R16 together form an alkylene having 2 to 8 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms.) ( ^R17 and ^R18 each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms, or ^R17 and ^R18 together form an alkylene group having 2 to 8 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms.) (l is 1 or 2, k is an integer of 0 to 3, and R ¹⁹ is a hydrogen atom or a halogen atom), or or ^A2 - ^Y2 ( ^A2 represents an alkylene having 2 to 10 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms, except when the carbon chain connecting the oxygen atom and ^Y2 has one carbon atom, and ^Y2 represents a phenyl group). ^R3 and ^R4 each independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
X3 represents a straight or branched alkyl group. ^X3 represents a chlorine atom or a bromine atom. Ar represents [j is 0 or 1, R ²⁰ is a hydrogen atom, a halogen atom or O
R ¹² (wherein R ¹² is the same as above). ( ^Z1 represents an oxygen atom or a sulfur atom.) [ ^R21 represents a hydrogen atom or ^OR5 ( ^R5 is the same as defined above)] or [ ^Z2 and ^Z3 each independently represent a hydrogen atom, a halogen atom,
a straight or branched alkyl group having 1 to 4 carbon atoms, OR ²² (R
²² represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms; O-A ¹ -Y ³ (A ¹ is the same as above);
^Y3 is a linear or branched alkyl group having 1 to 4 carbon atoms or a phenyl group which may be substituted with a halogen atom;
_2R5 ^, (R ⁵ , R ⁷ and R ⁸ are the same as above.) or Z ² and
^Z3 together with the benzene ring (W represents an alkylene group having 1 to 8 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms.) } is reacted with a metal cyanide salt represented by the general formula [IV] M ⁺ CN ^- [IV] (wherein M represents a metal atom) to carry out a substitution reaction at the 4-position. 7. An antithrombotic agent comprising the 3(2H)-pyridazinone derivative according to claim 1, and, if possible, a pharmaceutically acceptable salt thereof, as an active ingredient. 8. A cardiac stimulant containing the 3(2H)-pyridazinone derivative according to claim 1, and if possible, a pharmaceutically acceptable salt thereof, as an active ingredient. 9. A vasodilator containing the 3(2H)-pyridazinone derivative according to claim 1, and, if possible, a pharmaceutically acceptable salt thereof, as an active ingredient. 10. An anti-SRS-A agent comprising the 3(2H)-pyridazinone derivative according to claim 1, and, if possible, a pharmaceutically acceptable salt thereof, as an active ingredient.