JP3080131B2 - Pyridazinone derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to a novel anti-allergic, anti-allergic and / or anti-platelet agent having a bronchodilator effect.
The present invention relates to a (2H) -pyridazinone derivative and, where possible, a pharmaceutically acceptable salt, a method for producing the same, and a pharmaceutical composition containing these as an active ingredient.

[0002]

2. Description of the Related Art

1) Bronchodilators Bronchial asthma, bronchitis and adult respiratory distress syndrome (Adult R)
In the treatment of chronic reversible obstructive respiratory disease such as espiratory DistressSyndrome), airway remission during an attack is important,
Bronchodilators have been used for such purposes. The main bronchodilators currently in clinical use are roughly classified into β-stimulants such as salbutamol and xanthine drugs represented by theophylline. The former has the drawback that its efficacy is diminished with intractable disease, and furthermore, there is a concern that in the treatment of bronchial asthma, the symptoms may be worsened by frequent long-term administration (The New England Journal of the Medicine (The New E
ngland Journal of Medicine, Volume 321, pp. 1517-1527,
1989)]. On the other hand, at present, the theophylline-based drugs have a narrow safety margin and are restricted in terms of use.

2) Antiallergic field In the immediate allergic diseases such as bronchial asthma, allergic rhinitis, urticaria and hay fever, various biochemical mediators are considered to be involved, and histamine is important among them. An antihistamine has been used as an antiallergic agent for a long time.
However, many antihistamine antiallergic agents have central side effects such as drowsiness. As for the treatment of asthma, drugs that have a bronchodilator effect as well as antiallergic effects are of great therapeutic and economic significance, but at present the drugs with such functions have not been clinically developed. is there.

[0005] 3) Antiplatelet agent field [0005] Platelets play an important role in the formation of blood clots through activation by stimulation, adhesion to blood vessel walls, and aggregation, in relation to the pathological condition. ing. Thrombotic diseases caused by thrombus formation include cerebral thrombosis, pulmonary thrombosis, myocardial infarction, angina, peripheral arterial occlusion, etc., all of which require the development of useful drugs. It is a disease area that is said to be. Antiplatelet agents having a platelet aggregation inhibitory action have attracted attention as preventive and therapeutic agents for these thrombosis. The effects of aspirin have been widely studied so far, and ticlopidine and cilostazol have recently been clinically developed. However, at present, more potent drugs are desired in terms of efficacy.

[0006] In addition to the above-mentioned various thrombosis diseases, various diseases suggested to be involved in platelets have been pointed out. These diseases include nephritis and cancer cell metastasis. Recently, extensive research has been conducted on the preventive and therapeutic effects of antithrombotic agents having an inhibitory effect on platelet function against these diseases, mainly. [Journal of Royal College of Physicians (Jour
nal of Royal College of Physicians), Volume 7, Issue 1,
5-18 pages, 1972; Japanese clinical study, 4, 6, 13
0-136, 1988; Anticancer Research, 6, 543-548,
1986].

The 5- (ω-aminoalkyleneoxy or ω-aminocarbonylalkyleneoxy-substituted benzylamino) -3 (2H) -pyridazinone derivatives of the general formula [I] and the salts thereof and the compounds described in the known literature Is described below. Compounds of the type in which the 5-position of the 3 (2H) -pyridazinone ring relatively similar to the compound of the present invention is bonded by a substituted benzylamino group are described in the following literature.

(A) Japanese Patent Publication, Japanese Patent Publication No. 6-41455, European Patent Publication 186817, US Pat.
2) is a lower alkyl group, the 4 position is a chlorine atom or a bromine atom, the 5 position is an alkyloxy group, an ω-aminoalkyl group, an ω-carbamoylalkyleneoxy group, an ω-
Compounds including N-mono-lower alkylaminocarbonylalkyleneoxy group, benzylamino group in which a substituent containing an aminocarbonyl group is substituted on a benzene ring, 3 (2H) -pyridazinone derivative in which the 6-position is a hydrogen atom, and compounds thereof There are descriptions of pharmaceutical uses and pharmacological activities as anti-SRS-A agents.

(B) Japanese Unexamined Patent Publication, JP-A-62-03076
9, European Patent Publication 201765, U.S. Pat.
Reference 2) states that a hydrogen atom is substituted at the 2-position, a chlorine atom and a bromine atom at the 4-position, and an alkyloxy group, an ω-phenylalkyleneoxy group and a dialkylamino group are substituted at the 5-position on the benzene ring. Compounds containing 3 (2H) -pyridazinone derivatives having a benzylamino group and a hydrogen atom at the 6-position, and their pharmaceutical use and pharmacological activity as anti-SRS-A agents are described.

(C) Japanese Unexamined Patent Publication, JP-A-63-30187
0, European Patent Publication 275997, U.S. Pat.
Reference 2) states that a substituent containing a hydrogen atom, a lower alkyl group at the 2-position, a chlorine atom, a bromine atom at the 4-position, an alkyloxy group, an ω-phenylalkyleneoxy group, and a dialkylamino group at the 5-position is a benzene ring. A benzylamino group substituted above, a halogen atom at the 6-position, a nitro group, an amino group,
There are descriptions of compounds containing an alkoxy group 3 (2H) -pyridazinone derivative and their pharmaceutical use and pharmacological activity as anti-SRS-A agents.

(D) WO91 / 16314, European Patent Publication
No. 482208, US Pat. No. 5,202,323 (hereinafter referred to as reference d)
Is a ω-phenylalkyleneoxy in which a 2-position is a hydrogen atom, a lower alkyl group, a 4-position is a chlorine atom or a bromine atom, and a 5-position is an alkyloxy group, an alkyl group or a halogen atom which may be substituted on a benzene ring. Group, ω-alkoxycarbonylalkyleneoxy group, benzylamino group in which substituents including ω-aminocarbonylalkyleneoxy group are substituted on the benzene ring, and 6-position is an alkyleneoxy group having various functional groups at ω-position. Compounds containing 3 (2H) -pyridazinone derivatives and their antithrombotic agents, cardiotonic agents,
There is a description of pharmaceutical uses and pharmacological activities as vasodilators and anti-SRS-A agents.

[0012]

As a result of intensive studies, the present inventors have surprisingly found that the 3 (2H) -pyridazinone derivatives of the present invention and salts thereof which are different from any of the compounds disclosed in the references a to d. Are more excellent compounds as bronchodilators, antiallergic agents, and antiplatelet agents, and exhibit particularly excellent oral activity, and the above-mentioned respiratory diseases, immediate allergic diseases, and thrombotic diseases It has been found that the active ingredient can be used as an active ingredient of a prophylactic or therapeutic agent, and the present invention has been completed.

That is, the present invention provides a compound represented by the general formula [I]:

[0014]

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Wherein R ¹ , R ² and R ³ each independently represent a hydrogen atom or a C _1-4 alkyl group. X represents a chlorine atom or a bromine atom. Y ¹ represents a hydrogen atom, a halogen atom, a nitro group, an amino group, or a C _1-4 alkoxy group. Y ² is
Hydrogen atom, halogen atom, hydroxyl group, C _1-4 alkyl group or
C _{1-4 represents an} alkoxy group. A represents a C _1-5 alkylene chain which may be substituted with a hydroxyl group. B is carbonyl or
_{Shows a} methylene chain which may be substituted with a C _1-4 alkyl group.

R ⁴ and R ⁵ each independently represent a C _1-4 alkyl group, or R ⁴ is a hydrogen atom and R ⁵ is -Z-Ar (Z is C
_{In the 1-5} alkylene chain, Ar represents an aromatic 6-membered ring which may contain a nitrogen atom. ), R ⁴ and R ⁵ together form a C _2-6 cyclic alkylene, or

[0017]

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[0018] {R ⁶ is, C _1-4 alkyl group (the alkyl group, C _1-4 alkyl group, an optionally substituted phenyl group Y ³ (Y ³ is a hydrogen atom, a halogen atom, C _1-4 alkyl group, C _1-4 alkoxy group, amino group, N-formyl group or
C _{1-4 represents} an alkylcarbonylamino group. ),

[0019]

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(R ⁷ and R ⁸ each represent a hydrogen atom or, together with the carbon atom to which each is attached, represents a benzene ring.
B, C and D each independently represent a nitrogen atom or a carbon atom. )as well as

[0021]

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(Y ³ is the same as above. R ⁹ may be substituted with a C _1-4 alkyl group or a C _1-4 alkyl group, a C _1-4 alkoxy group or a halogen atom on the benzene ring. A benzyl group.) May be substituted with one or more substituents. ) Or -COR ¹⁰ (R ¹⁰ represents a hydrogen atom or a C _1-4 alkyl group). Forming a 4-substituted piperazine ring represented by｝,

[0023]

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[0024] {R ¹¹ is, C _1-4 alkyl group (said alkyl group, one of the same.) And Substituent group a hydroxyl group to Y ³ phenyl group (Y ³ may be substituted with the above Or a plurality of substituents). To form a 4-substituted piperidine represented by｝. 3
The present invention relates to a (2H) -pyridazinone derivative and a salt thereof, a production method thereof, and a pharmaceutical composition containing these as an active ingredient.

Hereinafter, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , A, B, X, Y ¹ and Y ² in the compound of the formula (I) will be described.

Specific examples of R ¹ , R ² and R ³ include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group and a sec-butyl group. ,
A t-butyl group is exemplified, and a hydrogen atom is more preferred.

A is an alkylene chain having a total of 1 to 5 carbon atoms which may be substituted at any position by a hydroxyl group or an alkyl group, and includes a methylene group, an ethylene group, a propylene group,
Examples include bonding species such as a butylene group and a pentylene group, and more preferably a straight-chain alkylene having 1 to 4 carbon atoms.

Examples of B include a methylene chain-bonded species which may be substituted with a carbonyl or C _1-4 alkyl group.

X includes a chlorine atom and a bromine atom.

Y ¹ represents a hydrogen atom, chlorine atom, bromine atom, iodine atom, nitro group, amino group, methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-
Butoxy group, i-butoxy group, sec-butoxy group, t-
Butoxy groups.

As Y ² , a hydrogen atom, chlorine atom, bromine atom, iodine atom, hydroxyl group, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec- Butyl, t-butyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy groups.

R ⁴ and R ⁵ are as follows.

(1) a C _1-4 alkyl group, which represents 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, a t-butyl group Is mentioned.

(2) R ⁴ is a hydrogen atom and R ⁵ is -Z-Ar (Z
Represents a C _1-5 alkylene chain, and Ar represents an aromatic 6-membered ring which may contain a nitrogen atom. ), A phenyl group, a 2-pyridyl group, a 3-pyridyl group,
4-pyridyl group, 3-pyridazinyl group, 4-pyridazinyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-
Examples include a pyrimidinyl group and a 2-pyrazinyl group.

(3) R ⁴ and R ⁵ together form a C _2-6 cyclic alkylene, and together with the nitrogen atom to which they are attached, an aziridine ring, an azetidine ring, a pyrrolidine ring, a piperidine ring, a homopiperidine ring Form a ring.

(4) R ⁴ and R ⁵ are taken together with a nitrogen atom to form a 4-substituted piperazine

[0037]

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Or 4-substituted piperidine

[0039]

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Is shown.

R ⁶ represents a C _1-4 alkyl group or —COR ¹⁰ (R ¹⁰ represents a hydrogen atom or a C _1-4 alkyl group). A methyl group is preferable as the C _1-4 alkyl group represented by R ⁶ , and may have a substituent, and the substituent includes a C _1-4 alkyl group and phenyl optionally substituted with Y ^3. A group (Y ³ represents a hydrogen atom, a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, an amino group, an N-formyl group or a C _1-4 alkylcarbonylamino group),

[0042]

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(R ⁷ and R ⁸ each represent a hydrogen atom or, together with the carbon atom to which each is attached, represents a benzene ring.
B, C and D each independently represent a nitrogen atom or a carbon atom. )as well as

[0044]

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(Y ³ is the same as above. R ⁹ represents a C _1-4 alkyl group or a C _1-4 alkyl group, a C _1-4 alkoxy group or a benzyl group optionally substituted with a halogen atom. .)
Are listed. One or more substituents may be present.

Specific examples of R ⁶ include o-, m-, p-
A benzyl group which may have a halogen atom which can be bonded at any position on the benzene ring, an α, α-diphenylmethyl group, or a substituent at any position at the 2-, 3-, or 4-position. A pyridylmethyl group, a pyrimidylmethyl group,
Pyrazylmethyl group, pyridazylmethyl group, quinolylmethyl group, isoquinolylmethyl group, quinoxalylmethyl group,
A quinazolylmethyl group, a benzimidazolylmethyl group having a C _1-4 alkyl group at the N-position or a benzyl group which may be substituted on the benzene ring with a halogen atom, and α, α-phenyl-pyridyl in which those aromatic rings are combined Methyl group, α, α-phenyl-pyrimidylmethyl group,
α, α-phenyl-pyrazylmethyl group, α, α-phenyl-pyridylmethyl group, α, α-phenyl-quinolylmethyl group, α, α-phenyl-isoquinolylmethyl group,
Examples of the substituent include an α, α-phenyl-quinoxalylmethyl group and an α, α-phenyl-quinazolylmethyl group.

[0047] R ¹¹ represents a C _1-4 alkyl group, the alkyl group may have a substituent, Examples of the substituent group, an optionally substituted phenyl group Y ³ (Y ³ is the same as described above) and a hydroxyl group.
There may be several or each.

Specific examples of R ¹¹ include a benzyl group and an α, α-diphenylmethyl group which may have a halogen atom on the benzene ring which can be bonded at any position of o-, m- and p-positions. And each substituent such as α, α, α-hydroxy-diphenylmethyl group.

Preferred examples of R ⁴ and R ⁵ include 4-substituted piperazin-1-yl and 4-substituted piperidin-1-yl described above.

In the above description, n is normal, i is
Is iso, sec is secondary, t is tertiary, o
Is ortho, m is meta, and p is para.

Preferred compounds in the compound of the present invention of the general formula [I] include the following compounds.

(1) A compound [I] wherein R ² and R ³ are a hydrogen atom and Y ¹ is a hydrogen atom, a halogen atom, a nitro group or a C _1-4 alkoxy group.

(2) R ⁴ and R ⁵ are taken together with a nitrogen atom to which each is bonded.

[0054]

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[0055] [R ¹² is, C _1-4 alkyl group {said alkyl group, C _1-4 alkyl group, an optionally substituted phenyl group Y ³ (Y ³ is a hydrogen atom, a halogen atom, C _1-4 alkyl group, C _1-4 alkoxy group, amino group, N-formyl group or
C _{1-4 represents} an alkylcarbonylamino group. ),

[0056]

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(R ⁷ and R ⁸ each represent a hydrogen atom or, together with the carbon atom to which each is attached, represents a benzene ring.
B, C and D each independently represent a nitrogen atom or a carbon atom. )as well as

[0058]

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(Y^ThreeIs the same as above. R⁹Is C_1-4Alkyl group
Or, C on the benzene ring_1-4Alkyl group, C_1-4Alkoxy
Substituted or unsubstituted by a halogen atom
Represents a hydroxyl group. )) To one or more of the substituents
It may be more substituted. ｝ Or -COR ^Ten(R^TenIs hydrogen
Atom or C_1-4Represents an alkyl group. ). ]
Forming a 4-substituted piperazine ring,

[0060]

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[0061] [R ¹¹ is, C _1-4 alkyl group {said alkyl group, Y ³ optionally substituted by a phenyl group (Y ³ are the same. Above) one of the and a hydroxyl substituent or It may be substituted with a plurality of substituents. Represents｝. The compound [I] according to the above (1), which forms a 4-substituted piperidine represented by the following formula:

(3) R ⁴ and R ⁵ are taken together with a nitrogen atom to which each is bonded.

[0063]

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[0064] [R ¹³ is a methyl group {said methyl group, Y ³ phenyl group (Y ³ may be substituted with a hydrogen atom, a halogen atom, C _1-4 alkyl, C _1-4 alkoxy Group, amino group, N-formyl group or C _1-4 alkylcarbonylamino group.),

[0065]

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(R ⁷ and R ⁸ each represent a hydrogen atom or, together with the carbon atom to which each is attached, represents a benzene ring.
B, C and D each independently represent a nitrogen atom or a carbon atom. )as well as

[0067]

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(Y ³ is the same as above. R ⁹ may be a C _1-4 alkyl group or a C _1-4 alkyl group, a C _1-4 alkoxy group or a halogen atom on the benzene ring. A benzyl group.) May be substituted with one or more substituents. Represents — or —COR ¹⁰ (R ¹⁰ represents a hydrogen atom or a C _1-4 alkyl group). The compound according to the above (2), which forms a 4-substituted piperazine ring represented by the following formula:

(4) The compound according to the above (3), wherein Y ² is a halogen atom or a C _1-4 alkoxy group.

(5) R ⁴ and R ⁵ are taken together with a nitrogen atom to which each is bonded.

[0071]

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[R ¹⁴ is

[0073]

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(Y ⁴ represents a hydrogen atom, a halogen atom, an amino group, an N-formyl group or a C _1-4 alkylcarbonylamino group),

[0075]

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(R ¹⁵ represents a benzyl group which may be substituted with a halogen atom.) The compound according to the above (4), which is represented by the formula:

The compounds of the present invention represented by the general formula [I] include optical isomers and stereoisomers based on 1 to 5 asymmetric carbon atoms.

The compound represented by the formula [I] of the present invention is
If desired, a pharmacologically acceptable non-toxic salt can be prepared using an appropriate acid. The compound represented by the formula [I] can be used for the purpose of the present invention either in a free form or a pharmacologically acceptable salt thereof. Examples of such base salts include, for example, mineral salts (hydrochloride, hydrobromide, sulfate, hydrogen sulfate, nitrate, phosphate, hydrogen phosphate, dihydrogen phosphate, etc.), organic acids Salts (formate, acetate, propionate, succinate, malonate, oxalate, maleate, fumarate,
Malate, citrate, tartrate, lactate, glutamate, aspartate, picrate, carbonate, etc.), sulfonate (methanesulfonate, benzenesulfonate, toluenesulfonate, etc.) Can be given. Each of these salts can be produced by known means.

Hereinafter, typical compounds included in the 3 (2H) -pyridazinone derivatives represented by the general formula [I] and the salts thereof, which are the compounds of the present invention, are shown in Table I, but the present invention is not limited by these. It is not what is done In Table I, n represents normal, i represents iso, t represents tertiary, Me represents a methyl group, Et represents an ethyl group, Pr represents a propyl group, Bu represents a butyl group, and Ph represents a phenyl group.

Further, Q1 to Q42 in Table I are groups represented by the following formulas.

[0081]

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[0082]

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Table I

[0084]

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[0085]

[Table 1] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 1 HHH Br H 4-OMe 3-Q1 CH ₂ Q10 ・ HCl 2 HHH Cl Cl 4-OMe 3-Q1 CH ₂ Q10 ・ HCl 3 HHH Cl NO ₂ 4-OMe 3-Q1 CH ₂ Q10 ・ HCl 4 HHH Cl H 4-OMe 3-Q1 CH ₂ Q19 ・ 2HCl 5 HHH Br H 4 -OMe 3-Q1 CH ₂ Q19 ・ 2HCl 6 HHH Br H 4-OMe 3-Q1 CH ₂ Q19 ・ Q35 7 HHH Br H 4-OMe 3-Q1 CH ₂ Q21 ・ 2HCl 8 HHH Br H 4-OMe 3-Q1 CH ₂ Q21 ・ Q35 9 HHH Br H 4-OMe 3-Q1 CH ₂ Q21 ・ H ₂ SO ₄ 10 HHH Cl H 4-OMe 3-Q1 CH ₂ Q21 ・ 2HCl 11 HHH Cl H 4-OMe 3-Q1 CH ₂ Q21 ・ H ₂ SO ₄ 12 HHH Cl H 4-OMe 3-Q1 CH ₂ Q21 ・ Q35 13 HHH Br H 4-OMe 3-Q1 CH ₂ Q20 ・ 2HCl 14 HHH Br H 4-OMe 3-Q1 CH ₂ Q20 ・Q35 15 HHH Cl H 4-OMe 3-Q1 CH ₂ Q20 ・ 2HCl 16 HHH Cl H 4-OMe 3-Q1 CH ₂ Q20 ・ Q35 17 Et HH Cl H 4-OMe 3-Q1 CH ₂ Q20 ・ 2HCl 18 HHH Br H 4-OMe 3-Q2 CH ₂ Q10 ・ HCl 19 HHH Cl Cl 4-OMe 3-Q2 CH ₂ Q10 ・ HCl 20 HHH Cl H 4-OMe 3-Q2 CH ₂ Q16 ・ 2HCl 21 HHH Cl H 4-OMe 3-Q2 CH ₂ Q17 ・ 2HCl 22 HHH Br H 4-OMe 3-Q2 CH ₂ Q19 ・ 2HCl 23 HHH Cl H 4-OMe 3-Q2 CH ₂ Q19 ・ 2HCl ── ────────────────────────────

[0086]

[Table 2] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 24 HHH Cl NO ₂ 4-OMe 3-Q2 CH ₂ Q19 ・ 2HCl 25 HHH Cl Cl 4-OMe 3-Q2 CH ₂ Q19 ・ 2HCl 26 HHH Cl H 4-OMe 3-Q2 CH ₂ Q20 ・ 2HCl 27 Et HH Cl H 4-OMe 3-Q2 CH ₂ Q20 ・ 2Q35 28 ⁱ Pr HH Cl H 4-OMe 3-Q2 CH ₂ Q20 ・ 2Q35 29 HHH Cl NO ₂ 4-OMe 3-Q2 CH ₂ Q21 ・ 2HCl 30 HHH Cl Cl 4-OMe 3-Q2 CH ₂ Q21 ・ 2HCl 31 HHH Cl H 4- OMe 3-Q1 CO Q37 ・ HCl 32 HHH Cl H 4-OMe 3-Q1 CO Q16 ・ HCl 33 HHH Br H 4-OMe 3-Q1 CO Q16 ・ HCl 34 HHH Br H 4-OMe 3-Q1 CO Q23 ・ 2HCl 35 HHH Cl H 4-OMe 3-Q1 CO Q23 ・ 2HCl 36 HHH Cl H 4-OMe 3-Q1 CO Q19 ・ Q35 37 HHH Cl H 4-OMe 3-Q1 CO Q19 ・ HCl 38 HHH Br H 4-OMe 3 -Q1 CO Q19 ・ Q35 39 HHH Cl H 4-OMe 3-Q1 CO Q20 ・ Q35 40 HHH Cl H 4-OMe 3-Q1 CO Q20 ・ HCl 41 Et HH Cl H 4-OMe 3-Q1 CO Q20 ・ Q36 42 ⁱ Pr HH Cl H 4-OMe 3-Q1 CO Q20 ・ Q35 43 HHH Br H 4-OMe 3-Q1 CO Q20 ・ Q35 4 4 HHH Br H 4-OMe 3-Q1 CO Q20 ・ HCl 45 HHH Cl H 4-OMe 3-Q3 CO Q23 ・ 2HCl 46 HHH Cl H 4-OMe 3-Q3 CO Q16 ・ HCl ──────── ──────────────────────

[0087]

[Table 3] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 47 HHH Cl H 4-OMe 3-Q3 CO Q19 ・ HCl 48 HHH Br H 4-OMe 3-Q3 CO Q19 ・ HCl 49 HHH Cl H 4-OMe 3-Q4 CO Q19 ・ HCl 50 CONH ₂ HH Cl H 4-OMe 3-Q1 CO Q20 ・ Q35 51 HHH Cl H 4-OMe 3 -Q1 CO Q21 ・ Q35 52 HHH Cl H 4-OMe 3-Q5 CO Q20 ・ Q35 53 HHH Cl H 4-OMe 3-Q8 CH ₂ Q20 ・ 2Q35 54 HHH Cl H 4-OMe 3-Q2 CH ₂ Q19 ・ 2Q35 55 HHH Cl H 4-OMe 3-Q5 CH ₂ Q20 ・ 2Q35 56 HHH Cl H 4-OMe 3-Q7 CO Q20 ・ Q35 57 HHH Cl H 4-OMe 3-Q7 CH ₂ Q20 ・ 2Q35 58 HHH Cl H 4- OMe 3-Q8 CH ₂ Q29 ・ 2Q35 59 HHH Cl H 4-OMe 3-Q2 CH ₂ Q29 ・ 2Q35 60 HHH Cl H 4-OMe 3-Q2 CH ₂ Q34 ・ 2Q35 61 HHH Cl H 4-OMe 3-Q1 CO Q29 ・ Q35 62 HHH Cl H 4-OMe 3-Q1 CO Q27 63 HHH Cl H 4-OMe 3-Q1 CH ₂ Q27 ・ Q35 64 HHH Cl OEt 4-OMe 3-Q1 CO Q20 ・ Q35 65 HHH Cl OEt 4- OMe 3-Q1 CH ₂ Q20 ・ 2Q35 66 HHH Cl OEt 4-OMe 3-Q1 CO Q19 ・ Q35 67 HHH Cl OE t 4-OMe 3-Q1 CO Q29 ・ Q36 68 HHH Cl OEt 4-OMe 3-Q5 CO Q20 ・ Q35 69 HHH Cl OEt 4-OMe 3-Q7 CO Q20 ・ Q35 ─────────── ───────────────────

[0088]

[Table 4] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 70 HHH Cl OEt 4-OMe 3-Q5 CH ₂ Q29 ・ 2Q35 71 HHH Cl OEt 4-OMe 3-Q2 CH ₂ Q29 ・ 2Q35 72 HHH Cl OEt 4-OMe 3-Q2 CH ₂ Q34 ・ 2Q35 73 HHH Cl OEt 4-OMe 3-Q1 CO Q34 ・ Q35 74 HHH Cl OEt 4-OMe 3-Q1 CO Q27 75 HHH Cl OEt 4-OMe 3-Q1 CH ₂ Q27 ・ Q35 76 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q20 ・ Q35 77 HHH Cl O ⁱ Pr 4-OMe 3-Q8 CH ₂ Q25 ・ 2Q35 78 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q24 79 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q25 ・ Q35 80 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q26 ・ Q35 81 HHH Cl H 4-OMe 3-Q3 CH ₂ Q42 82 HHH Cl H 4-OMe 3-Q1 CH ₂ Q12 ・ HCl 83 HHH Cl H 4-OMe 3-Q1 CH ₂ Q14 ・ HCl 84 HHH Cl H 4-OMe 3 -Q1 CH ₂ Q16 ・ 2HCl 85 HHH Cl H 4-OMe 3-Q1 CH ₂ Q18 ・ 2HCl 86 HHH Cl H 4-OMe 3-Q1 CH ₂ Q22 ・ 2HCl 87 HHH Cl H 4-OMe 3-Q1 CH ₂ Q23・ 3HCl 88 HHH Cl H 4-OMe 3-Q1 CH ₂ Q28 ・ HCl 89 HHH Cl H 4-OMe 3-Q1 CH ₂ Q37 ・ 2HCl 90 HHH Cl H 4-OMe 3-Q1 CH ₂ Q39 ・ HCl 91 HHH Cl H 4-OMe 3-Q1 CH ₂ Q40 ・ 3HCl 92 HHH Cl H 4-OMe 3-Q1 CH ₂ Q29 ・ 2HCl ── ────────────────────────────

[0089]

[Table 5] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 93 HHH Cl H 4-OMe 3-Q1 CH ₂ Q30 ・ 3HCl 94 HHH Cl H 4-OMe 3-Q1 CH ₂ Q31 ・ 3HCl 95 HHH Cl H 4-OMe 3-Q1 CH ₂ Q32 ・ 3HCl 96 HHH Cl H 4-OMe 3-Q1 CH ₂ Q33 ・ 2HCl 97 HHH Cl H 4- OMe 3-Q1 CH ₂ Q24 ・ 3HCl 98 HHH Cl H 4-OMe 3-Q1 CH ₂ Q25 ・ 2HCl 99 HHH Cl H 4-OMe 3-Q1 CH ₂ Q26 ・ 2HCl 100 HHH Cl H 4-OMe 3-Q1 CH ₂ Q34 ・ 2HCl 101 HHH Cl H 4-OMe 3-Q2 CH ₂ Q19 ・ 2HCl 102 HHH Cl H 4-OMe 3-Q2 CH ₂ Q21 ・ 2HCl 103 HHH Cl H 4-OMe 3-Q2 CH ₂ Q23 ・ 3HCl 104 HHH Cl H 4-OMe 3-Q2 CH ₂ Q24 ・ 3HCl 105 HHH Cl H 4-OMe 3-Q2 CH ₂ Q25 ・ 2HCl 106 HHH Cl H 4-OMe 3-Q2 CH ₂ Q26 ・ 2HCl 107 HHH Cl H 4- OMe 3-Q2 CH ₂ Q28 ・ HCl 108 HHH Cl H 4-OMe 3-Q2 CH ₂ Q29 ・ 3HCl 109 HHH Cl H 4-OMe 3-Q2 CH ₂ Q33 ・ 2HCl 110 HHH Cl H 4-OMe 3-Q2 CH ₂ Q34 ・ 2HCl 111 HHH Cl H 4-OMe 3-Q5 CH ₂ Q10 ・ HCl 112 HHH Cl H 4-OMe 3-Q5 CH ₂ Q17 ・ 2HCl 113 HHH Cl H 4-OMe 3-Q5 CH ₂ Q19 ・ 2HCl 114 HHH Br H 4-OMe 3-Q1 CH ₂ Q11 ・ HCl 115 Me HH Br H 4-OMe 3 -Q1 CH ₂ Q11 ・ HCl ──────────────────────────────

[0090]

[Table 6] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 116 H Me H Br H 4-OMe 3-Q1 CH ₂ Q11 ・HCl 117 HHH Br H 4-OMe 3-Q1 CH ₂ Q17 ・ 2HCl 118 HHH Br NH ₂ 4-OMe 3-Q1 CH ₂ Q17.2HCl 119 HHH Br Br 4-OMe 3-Q1 CH ₂ Q17 ・ 2HCl 120 HHH Br H 4-Cl 3-Q1 CH ₂ Q19 ・ 2HCl 121 HHH Br HH 3-Q1 CH ₂ Q20 ・ 2HCl 122 HHH Br H 4-OEt 3-Q1 CH ₂ Q20 ・ 2HCl 123 HHH Br H 4-OMe 3-Q1 CH ₂ Q22 ・ 2HCl 124 HHH Br H 4-OMe 3-Q1 CH ₂ Q23 ・ 3HCl 125 HHH Br H 4-OMe 3-Q1 CH ₂ Q38 ・ 2HCl 126 HHH Br H 4-OMe 3-Q1 CH ₂ Q40 ・ 3HCl 127 HHH Cl H 4-OMe 3-Q2 CH ₂ Q9 ・ HCl 128 HH Me Cl H 4-OMe 3-Q2 CH ₂ Q9 ・ HCl 129 HHH Cl Cl 4-OMe 3-Q2 CH ₂ Q9 ・ HCl 130 ^t Bu HH Cl H 4-OMe 3-Q2 CH ₂ Q9 ・ HCl 131 HHH Cl H 4-OH 3-Q2 CH ₂ Q9 ・ HCl 132 HHH Cl H 4-OMe 3-Q2 CH ₂ Q13 ・ HCl 133 HHH Cl H 4-OMe 3 -Q2 CH ₂ Q14 ・ HCl 134 HHH Cl H 4-OMe 3-Q2 CH ₂ Q15 ・ HCl 135 HHH Cl H 4-OMe 3-Q2 CH ₂ Q28 ・ HCl 136 HHH Cl H 4-OMe 3-Q2 CH ₂ Q41 ・ HCl 137 HHH Br H 4-OMe 3-Q2 CH ₂ Q12 ・ HCl 138 ⁱ Pr HH Br H 4- OMe 3-Q2 CH ₂ Q14 ・ HCl ──────────────────────────────

[0091]

[Table 7] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 139 HHH Br H 4-Cl 3-Q2 CH ₂ Q14 ・ HCl 140 HHH Br H 4-OMe 3-Q2 CH ₂ Q18 ・ 2HCl 141 HHH Br H 4-OMe 3-Q2 CH ₂ Q20 ・ 2HCl 142 HHH Br Br 4-OMe 3-Q2 CH ₂ Q20 ・ 2HCl 143 H Me H Br H 4-OMe 3-Q2 CH ₂ Q20 ・ 2HCl 144 HHH Br H 4-OH 3-Q2 CH ₂ Q20 ・ 2HCl 145 HHH Br HH 3-Q2 CH ₂ Q20 ・ 2HCl 146 HHH Br H 4-OMe 3-Q2 CH ₂ Q21 ・ 2HCl 147 HHH Br H 4-OMe 2-Q2 CH ₂ Q21.2HCl 148 HHH Br H 4-OMe 3-Q2 CH ₂ Q23.3HCl 149 HHH Cl H 4-OMe 3-Q3 CH ₂ Q10 ・ HCl 150 HHH Cl Cl 4-OMe 3-Q3 CH ₂ Q10 ・ HCl 151 Et HH Cl H 4-OMe 3-Q3 CH ₂ Q10 ・ HCl 152 HHH Cl H 4-OMe 3-Q3 CH ₂ Q13 ・ HCl 153 HHH Cl H 4- OMe 3-Q3 CH ₂ Q15 ・ 2HCl 154 HHH Cl H 4-OEt 3-Q3 CH ₂ Q19 ・ 2HCl 155 HHH Cl H 4-OMe 3-Q3 CH ₂ Q21 ・ 2HCl 156 HHH Cl H 4-OMe 3-Q3 CH ₂ Q22 ・ 2HCl 157 HHH Cl H 4-OMe 3-Q3 CH ₂ Q23 ・ 3HCl 158 HHH C l H 4-OMe 3-Q3 CH ₂ Q37 ・ 2HCl 159 HHH Cl H 4-OMe 3-Q3 CH ₂ Q40 ・ 3HCl 160 HHH Cl H 4-OMe 3-Q3 CH ₂ Q41 ・ HCl 161 HHH Br H 4-OMe 3-Q4 CH ₂ Q9 ・ HCl ──────────────────────────────

[0092]

[Table 8] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 162 HHH Br H 4-OMe 3-Q4 CH ₂ Q12 ・ HCl 163 HHH Br H 4-OMe 3-Q4 CH ₂ Q14 ・ HCl 164 HHH Br H 4-OMe 3-Q4 CH ₂ Q16 ・ 2HCl 165 HHH Br H 4-OMe 3-Q4 CH ₂ Q20 ・ 2HCl 166 HHH Br H 2- OMe 3-Q4 CH ₂ Q20 ・ 2HCl 167 HHH Br H 4-OMe 3-Q4 CH ₂ Q28 ・ HCl 168 HHH Br H 4-OMe 3-Q4 CH ₂ Q39 ・ HCl 169 HHH Cl H 4-OMe 3-Q5 CH ₂ Q11 ・ HCl 170 HHH Cl H 4-OMe 3-Q5 CH ₂ Q13 ・ HCl 171 HHH Cl H 4-OMe 3-Q5 CH ₂ Q16 ・ 2HCl 172 HHH Cl H 4-OMe 3-Q5 CH ₂ Q18 ・ 2HCl 173 HHH Cl H 4-OMe 3-Q5 CH ₂ Q19 ・ 2HCl 174 HHH Cl H 4-OMe 3-Q5 CH ₂ Q20 ・ 2HCl 175 HHH Cl H 4-OEt 3-Q5 CH ₂ Q20 ・ 2HCl 176 HHH Cl H 4- O ^t Bu 3-Q5 CH ₂ Q20 ・ 2HCl 177 HHH Cl H 4-OMe 3-Q5 CH ₂ Q23 ・ 3HCl 178 HHH Br H 4-OMe 3-Q6 CH ₂ Q10 ・ HCl 179 ⁱ Pr HH Br H 4-OMe 3-Q6 CH ₂ Q14 ・ HCl 180 HHH Br H 4-OMe 3-Q6 CH ₂ Q17 ・ 2HCl 181 H HH Br H 4-OMe 3-Q6 CH ₂ Q21 ・ 2HCl 182 HHH Br H 4-OMe 3-Q6 CH ₂ Q39 ・ HCl 183 HHH Cl H 4-OMe 3-Q1 CO Q10 184 HHH Cl H 4-OMe 3- Q1 CO Q12 ──────────────────────────────

[0093]

[Table 9] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 185 HHH Cl H 4-OMe 3-Q1 CO Q14 186 HHH Cl H 4-OMe 3-Q1 CO Q17 ・ HCl 187 HHH Cl H 4-OH 3-Q1 CO Q20 ・ HCl 188 HHH Cl H 4-Cl 3-Q1 CO Q20 ・ HCl 189 HHH Cl NO ₂ 4-OMe 3-Q1 CO Q20 ・ HCl 190 HHH Cl H 4-OMe 3-Q1 CO Q21 ・ HCl 191 HHH Cl H 4-OMe 3-Q1 CO Q23 ・ 2HCl 192 HHH Cl H 4-OMe 3-Q1 CO Q39 193 HHH Cl H 4-OMe 3-Q1 CO Q41 194 HHH Br H 4-OMe 3-Q1 CO Q11 195 HHH Br H 4-OMe 3-Q1 CO Q13 196 Me HH Br H 4-OMe 3-Q1 CO Q16 ・ HCl 197 HHH Br H 4- Cl 3-Q1 CO Q19 ・ HCl 198 HHH Br H 2-OMe 3-Q1 CO Q19 ・ HCl 199 HHH Br NO ₂ 4-OMe 3-Q1 CO Q19 ・ HCl 200 HHH Br NH ₂ 4-OMe 3-Q1 CO Q19・ HCl 201 HHH Br H 4-OMe 3-Q1 CO Q21 ・ HCl 202 HMe H Br H 4-OMe 3-Q1 CO Q21 ・ HCl 203 HHH Br H 4-OEt 3-Q1 CO Q21 ・ HCl 204 HHH Cl H 4-OMe 3-Q2 CO Q10 205 HHH Cl H 4-OMe 3-Q2 CO Q14 206 HHH Cl H 4-OM e 3-Q2 CO Q17 ・ HCl 207 HHH Cl H 4-OMe 3-Q2 CO Q19 ・ HCl ──────────────────────────── ──

[0094]

[Table 10] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 208 HHH Cl H 4-OMe 3-Q2 CO Q20 ・ HCl 209 HHH Cl H 4-Cl 3-Q2 CO Q20 ・ HCl 210 HHH Cl HH 3-Q2 CO Q20 ・ HCl 211 HHH Cl H 4-F 3-Q2 CO Q20 ・ HCl 212 Et HH Cl H 4-OMe 3-Q2 CO Q20・ HCl 213 HHH Cl H 4-OMe 3-Q2 CO Q21 ・ HCl 214 HHH Cl NO ₂ 4-OMe 3-Q2 CO Q21 ・ HCl 215 HHH Cl Cl 4-OMe 3-Q2 CO Q21 ・ HCl 216 Me HH Cl H 4-OMe 3-Q2 CO Q21 ・ HCl 217 HHH Cl H 4-OMe 2-Q2 CO Q21 ・ HCl 218 HHH Cl H 4-OMe 3-Q2 CO Q22 ・ HCl 219 HHH Br H 4-OMe 3-Q2 CO Q9 220 HHH Br H 4-OMe 3-Q2 CO Q15 221 HHH Br H 4-OMe 3-Q2 CO Q18 ・ HCl 222 HHH Br H 4-OMe 3-Q2 CO Q20 ・ HCl 223 HHH Br H 4-OMe 3-Q2 CO Q23 ・ 2HCl 224 HHH Br H 4-OMe 3-Q2 CO Q28 225 HHH Br H 4-OMe 3-Q2 CO Q37 ・ HCl 226 HHH Br H 4-OMe 3-Q2 CO Q39 227 HHH Cl H 4-OMe 3 -Q3 CO Q11 228 HHH Cl H 4-OMe 3-Q3 CO Q17 ・ HCl 229 HHH Cl H 4 -OMe 3-Q3 CO Q20 ・ HCl 230 HHH Cl Cl 4-OMe 3-Q3 CO Q20 ・ HCl ─────────────────────────── ───

[0095]

[Table 11] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 231 HHH Cl NH ₂ 4-OMe 3-Q3 CO Q20 ・ HCl 232 HH Me Cl H 4-OMe 3-Q3 CO Q20 ・ HCl 233 HHH Cl Cl 4-Cl 3-Q3 CO Q20 ・ HCl 234 HHH Br H 4-OMe 3-Q4 CO Q10 235 HHH Br H 4-OMe 3-Q4 CO Q12 236 HHH Br H 4-OMe 3-Q4 CO Q13 237 HHH Br H 4-OMe 3-Q4 CO Q18 ・ HCl 238 HHH Br H 4-OMe 3-Q4 CO Q19 ・ HCl 239 HHH Br H 4-OMe 3 -Q4 CO Q21 ・ HCl 240 HHH Br H 4-OMe 3-Q4 CO Q23 ・ 2HCl 241 HHH Br H 4-OMe 3-Q4 CO Q38 ・ HCl 242 HHH Br H 4-OMe 3-Q4 CO Q40 ・ 2HCl 243 HHH Cl H 4-OMe 3-Q5 CO Q9 244 HHH Cl H 4-OMe 3-Q5 CO Q16 ・ HCl 245 HHH Cl H 4-OMe 3-Q5 CO Q19 ・ HCl 246 HHH Cl Cl 4-OMe 3-Q5 CO Q19 · HCl 247 HHH Cl H 4- O n Bu 3-Q5 CO Q19 · HCl 248 HHH Cl H 2-OMe 3-Q5 CO Q19 · HCl 249 HHH Cl H 4-OMe 3-Q5 CO Q20 · HCl 250 HHH Cl H 4-OMe 3-Q5 CO Q21 · HCl 251 HHH Cl NO 2 4-OMe 3-Q5 CO Q21 HCl 252 HHH Cl H 4-Cl 3-Q5 CO Q21 ・ HCl 253 Et HH Cl H 4-OMe 3-Q5 CO Q21 ・ HCl ──────────────────── ──────────

[0096]

[Table 12] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 254 HHH Cl H 4-OMe 3-Q5 CO Q23.2HCl 255 HHH Br H 4-OMe 3-Q6 CO Q10 256 HHH Br H 4-OMe 3-Q6 CO Q15 257 HHH Br H 4-OMe 3-Q6 CO Q18 ・ HCl 258 HHH Br H 4-OMe 3-Q6 CO Q19 ・ HCl 259 HHH Br H 4-OMe 3-Q6 CO Q20 ・ HCl 260 HHH Br Br 4-OMe 3-Q6 CO Q20 ・ HCl 261 HHH Br NH ₂ 4-OMe 3-Q6 CO Q20 ・ HCl 262 HHH Br H 4-OMe 3-Q6 CO Q21 ・ HCl 263 HHH Br H 4-Cl 3-Q6 CO Q21 ・ HCl 264 ⁱ Bu HH Cl H 4-OMe 3-Q6 CO Q19 ・ HCl 265 HHH Cl H 4-OMe 3-Q6 CO Q20 ・HCl 266 HHH Cl Cl 4-OMe 3-Q6 CO Q20 ・ HCl 267 HHH Cl H 4-OMe 3-Q6 CO Q21 ・ HCl 268 HHH Cl H 4-OMe 3-Q6 CO Q23.2HCl 269 HHH Cl H 4-OMe 3-Q6 CO Q37 ・ HCl 270 HHH Cl H 4-OMe 3-Q6 CO Q41 271 HHH Cl H 4-OMe 3-Q5 CH ₂ Q21 ・ 2HCl 272 HHH Cl H 4-OMe 3-Q5 CH ₂ Q23 ・ 3HCl 273 HHH Cl H 4-OMe 3-Q5 CH ₂ Q24 ・ 3HCl 274 HHH Cl H 4-OMe 3 -Q5 CH ₂ Q25 ・ 2HCl 275 HHH Cl H 4-OMe 3-Q5 CH ₂ Q26 ・ 2HCl 276 HHH Cl H 4-OMe 3-Q5 CH ₂ Q27 ・ 2HCl ───────────── ─────────────────

[0097]

[Table 13] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 277 HHH Cl H 4-OMe 3-Q5 CH ₂ Q28 ・ HCl 278 HHH Cl H 4-OMe 3-Q5 CH ₂ Q29 ・ 3HCl 279 HHH Cl H 4-OMe 3-Q5 CH ₂ Q33 ・ 2HCl 280 HHH Cl H 4-OMe 3-Q5 CH ₂ Q34 ・ 2HCl 281 HHH Cl H 4- OMe 3-Q7 CH ₂ Q10 ・ HCl 282 HHH Cl H 4-OMe 3-Q7 CH ₂ Q17 ・ 2HCl 283 HHH Cl H 4-OMe 3-Q7 CH ₂ Q19 ・ 2HCl 284 HHH Cl H 4-OMe 3-Q7 CH ₂ Q21 ・ 2HCl 285 HHH Cl H 4-OMe 3-Q7 CH ₂ Q23 ・ 3HCl 286 HHH Cl H 4-OMe 3-Q7 CH ₂ Q24 ・ 3HCl 287 HHH Cl H 4-OMe 3-Q7 CH ₂ Q25 ・ 2HCl 288 HHH Cl H 4-OMe 3-Q7 CH ₂ Q26 ・ 2HCl 289 HHH Cl H 4-OMe 3-Q7 CH ₂ Q27 ・ HCl 290 HHH Cl H 4-OMe 3-Q7 CH ₂ Q28 ・ HCl 291 HHH Cl H 4- OMe 3-Q7 CH ₂ Q29 ・ 3HCl 292 HHH Cl H 4-OMe 3-Q7 CH ₂ Q33 ・ 2HCl 293 HHH Cl H 4-OMe 3-Q7 CH ₂ Q34 ・ 2HCl 294 HHH Cl H 4-OMe 3-Q8 CH ₂ Q10 ・ HCl 295 HHH Cl H 4-OMe 3-Q8 CH ₂ Q17 ・ 2HCl 296 HH H Cl H 4-OMe 3-Q8 CH ₂ Q19 ・ 2HCl 297 HHH Cl H 4-OMe 3-Q8 CH ₂ Q21 ・ 2HCl 298 HHH Cl H 4-OMe 3-Q8 CH ₂ Q2 ・ 3HCl 299 HHH Cl H 4- OMe 3-Q8 CH ₂ Q24 ・ 3HCl ──────────────────────────────

[0098]

[Table 14] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 300 HHH Cl H 4-OMe 3-Q8 CH ₂ Q25 ・ 2HCl 301 HHH Cl H 4-OMe 3-Q8 CH ₂ Q26 ・ 2HCl 302 HHH Cl H 4-OMe 3-Q8 CH ₂ Q27 ・ HCl 303 HHH Cl H 4-OMe 3-Q8 CH ₂ Q28 ・ HCl 304 HHH Cl H 4- OMe 3-Q8 CH ₂ Q33 ・ 2HCl 305 HHH Cl H 4-OMe 3-Q8 CH ₂ Q34 ・ 2HCl 306 HHH Cl H 4-OMe 3-Q1 CO Q24 ・ HCl 307 HHH Cl H 4-OMe 3-Q1 CO Q25・ 2HCl 308 HHH Cl H 4-OMe 3-Q1 CO Q26 ・ HCl 309 HHH Cl H 4-OMe 3-Q1 CO Q33 ・ HCl 310 HHH Cl H 4-OMe 3-Q1 CO Q34 ・ HCl 311 HHH Cl H 4- OMe 3-Q3 CO Q20 ・ HCl 312 HHH Cl H 4-OMe 3-Q3 CO Q21 ・ HCl 313 HHH Cl H 4-OMe 3-Q3 CO Q24 ・ 2HCl 314 HHH Cl H 4-OMe 3-Q3 CO Q25 ・ HCl 315 HHH Cl H 4-OMe 3-Q3 CO Q26 ・ HCl 316 HHH Cl H 4-OMe 3-Q3 CO Q27 317 HHH Cl H 4-OMe 3-Q3 CO Q28 318 HHH Cl H 4-OMe 3-Q3 CO Q29・ 2HCl 319 HHH Cl H 4-OMe 3-Q3 CO Q33 ・ HCl 320 HHH Cl H 4 -OMe 3-Q3 CO Q34 ・ HCl 321 HHH Cl H 4-OMe 3-Q5 CO Q24 ・ 2HCl 322 HHH Cl H 4-OMe 3-Q5 CO Q25 ・ HCl ───────────── ─────────────────

[0099]

[Table 15] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 323 HHH Cl H 4-OMe 3-Q5 CO Q26 ・ HCl 324 HHH Cl H 4-OMe 3-Q5 CO Q27 325 HHH Cl H 4-OMe 3-Q5 CO Q28 326 HHH Cl H 4-OMe 3-Q5 CO Q29 ・ 2HCl 327 HHH Cl H 4-OMe 3-Q5 CO Q53 ・ HCl 328 HHH Cl H 4-OMe 3-Q5 CO Q54 ・ HCl 329 HHH Cl H 4-OMe 3-Q7 CO Q10 330 HHH Cl H 4-OMe 3-Q7 CO Q16 ・ HCl 331 HHH Cl H 4-OMe 3-Q7 CO Q19 ・ HCl 332 HHH Cl H 4-OMe 3-Q7 CO Q21 ・ HCl 333 HHH Cl H 4-OMe 3-Q7 CO Q23 ・ 2HCl 334 HHH Cl H 4-OMe 3-Q7 CO Q24 ・ 2HCl 335 HHH Cl H 4-OMe 3-Q7 CO Q25 ・ 2HCl 336 HHH Cl H 4-OMe 3-Q7 CO Q26 ・ 2HCl 337 HHH Cl H 4-OMe 3-Q7 CO Q27 338 HHH Cl H 4-OMe 3-Q7 CO Q28 339 HHH Cl H 4-OMe 3-Q7 CO Q29 ・ 2HCl 340 HHH Cl H 4-OMe 3-Q7 CO Q33 ・ HCl 341 HHH Cl H 4-OMe 3-Q7 CO Q34 ・ HCl 342 HHH Cl OEt 4-OMe 3-Q1 CH ₂ Q10 343 HHH Cl OEt 4-OMe 3-Q1 CH ₂ Q16 ・ HCl 344 HH H Cl OEt 4-OMe 3-Q1 CH ₂ Q19 ・ HCl 345 HHH Cl OEt 4-OMe 3-Q1 CH ₂ Q21 ・ HCl ───────────────────── ─────────

[0100]

[Table 16] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 346 HHH Cl OEt 4-OMe 3-Q1 CH ₂ Q23 ・ 3HCl 347 HHH Cl OEt 4-OMe 3-Q1 CH ₂ Q24 ・ 3HCl 348 HHH Cl OEt 4-OMe 3-Q1 CH ₂ Q25 ・ 2HCl 349 HHH Cl OEt 4-OMe 3-Q1 CH ₂ Q26 ・ 2HCl 350 HHH Cl OEt 4- OMe 3-Q1 CH ₂ Q29 ・ 2HCl 351 HHH Cl OEt 4-OMe 3-Q1 CH ₂ Q33 ・ HCl 352 HHH Cl OEt 4-OMe 3-Q1 CH ₂ Q34 ・ HCl 353 HHH Cl OEt 4-OMe 3-Q2 CH ₂ Q10 354 HHH Cl OEt 4-OMe 3-Q2 CH ₂ Q16 ・ HCl 355 HHH Cl OEt 4-OMe 3-Q2 CH ₂ Q19 ・ HCl 356 HHH Cl OEt 4-OMe 3-Q2 CH ₂ Q20 ・ 2HCl 357 HHH Cl OEt 4-OMe 3-Q2 CH ₂ Q21 ・ 2HCl 358 HHH Cl OEt 4-OMe 3-Q2 CH ₂ Q23 ・ 3HCl 359 HHH Cl OEt 4-OMe 3-Q2 CH ₂ Q24 ・ 3HCl 360 HHH Cl OEt 4-OMe 3 -Q2 CH ₂ Q25 ・ 2HCl 361 HHH Cl OEt 4-OMe 3-Q2 CH ₂ Q26 ・ 2HCl 362 HHH Cl OEt 4-OMe 3-Q2 CH ₂ Q27 ・ HCl 363 HHH Cl OEt 4-OMe 3-Q2 CH ₂ Q28・ HCl 364 HHH Cl OEt 4-O Me 3-Q2 CH ₂ Q33 ・ 2HCl 365 HHH Cl OEt 4-OMe 3-Q5 CH ₂ Q10 366 HHH Cl OEt 4-OMe 3-Q5 CH ₂ Q16 ・ HCl 367 HHH Cl OEt 4-OMe 3-Q5 CH ₂ Q19・ HCl 368 HHH Cl OEt 4-OMe 3-Q5 CH ₂ Q2 ・ 2HCl ──────────────────────────────

[0101]

[Table 17] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 369 HHH Cl OEt 4-OMe 3-Q5 CH ₂ Q23 ・ 3HCl 370 HHH Cl OEt 4-OMe 3-Q5 CH ₂ Q24 ・ 3HCl 371 HHH Cl OEt 4-OMe 3-Q5 CH ₂ Q25 ・ 2HCl 372 HHH Cl OEt 4-OMe 3-Q5 CH ₂ Q26 ・ 2HCl 373 HHH Cl OEt 4- OMe 3-Q5 CH ₂ Q27 ・ HCl 374 HHH Cl OEt 4-OMe 3-Q5 CH ₂ Q28 ・ HCl 375 HHH Cl OEt 4-OMe 3-Q5 CH ₂ Q29 ・ 3HCl 376 HHH Cl OEt 4-OMe 3-Q5 CH ₂ Q33 ・ 2HCl 377 HHH Cl OEt 4-OMe 3-Q5 CH ₂ Q34 ・ 2HCl 378 HHH Cl OEt 4-OMe 3-Q7 CH ₂ Q10 379 HHH Cl OEt 4-OMe 3-Q7 CH ₂ Q16 ・ 2HCl 380 HHH Cl OEt 4-OMe 3-Q7 CH ₂ Q19 ・ 2HCl 381 HHH Cl OEt 4-OMe 3-Q7 CH ₂ Q20 ・ 2HCl 382 HHH Cl OEt 4-OMe 3-Q7 CH ₂ Q21 ・ 2HCl 383 HHH Cl OEt 4-OMe 3 -Q7 CH ₂ Q23 ・ 3HCl 384 HHH Cl OEt 4-OMe 3-Q7 CH ₂ Q24 ・ 3HCl 385 HHH Cl OEt 4-OMe 3-Q7 CH ₂ Q25 ・ 2HCl 386 HHH Cl OEt 4-OMe 3-Q7 CH ₂ Q26・ 2HCl 387 HHH Cl OEt 4-OMe 3-Q7 CH ₂ Q27 ・ HCl 388 HHH Cl OEt 4-OMe 3-Q7 CH ₂ Q28 ・ HCl 389 HHH Cl OEt 4-OMe 3-Q7 CH ₂ Q29 ・ 3HCl 390 HHH Cl OEt 4-OMe 3- Q7 CH ₂ Q33 ・ 2HCl 391 HHH Cl OEt 4-OMe 3-Q7 CH ₂ Q3 ・ 2HCl ───────────────────────────── ─

[0102]

[Table 18] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 392 HHH Cl OEt 4-OMe 3-Q8 CH ₂ Q10 393 HHH Cl OEt 4-OMe 3-Q8 CH ₂ Q16 ・ 2HCl 394 HHH Cl OEt 4-OMe 3-Q8 CH ₂ Q19 ・ 2HCl 395 HHH Cl OEt 4-OMe 3-Q8 CH ₂ Q20 ・ 2HCl 396 HHH Cl OEt 4-OMe 3 -Q8 CH ₂ Q21 ・ 2HCl 397 HHH Cl OEt 4-OMe 3-Q8 CH ₂ Q23 ・ 3HCl 398 HHH Cl OEt 4-OMe 3-Q8 CH ₂ Q24 ・ 3HCl 399 HHH Cl OEt 4-OMe 3-Q8 CH ₂ Q26・ 2HCl 400 HHH Cl OEt 4-OMe 3-Q8 CH ₂ Q27 ・ HCl 401 HHH Cl OEt 4-OMe 3-Q8 CH ₂ Q28 ・ HCl 402 HHH Cl OEt 4-OMe 3-Q8 CH ₂ Q29 ・ 3HCl 403 HHH Cl OEt 4-OMe 3-Q8 CH ₂ Q33 ・ 2HCl 404 HHH Cl OEt 4-OMe 3-Q8 CH ₂ Q34 ・ 2HCl 405 HHH Cl OEt 4-OMe 3-Q1 CO Q10 406 HHH Cl OEt 4-OMe 3-Q1 CO Q16 ・ 2HCl 407 HHH Cl OEt 4-OMe 3-Q1 CO Q21 ・ 2HCl 408 HHH Cl OEt 4-OMe 3-Q1 CO Q23 ・ 2HCl 409 HHH Cl OEt 4-OMe 3-Q1 CO Q24 ・ 3HCl 410 HHH Cl OEt 4 -OMe 3-Q1 CO Q2 5.2HCl 411 HHH Cl OEt 4-OMe 3-Q1 CO Q26 ・ 2HCl 412 HHH Cl OEt 4-OMe 3-Q1 CO Q27 413 HHH Cl OEt 4-OMe 3-Q1 CO Q28 414 HHH Cl OEt 4-OMe 3- Q1 CO Q3 ・ 2HCl ──────────────────────────────

[0103]

[Table 19] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 415 HHH Cl OEt 4-OMe 3-Q3 CO Q10 416 HHH Cl OEt 4-OMe 3-Q3 CO Q16 ・ HCl 417 HHH Cl OEt 4-OMe 3-Q3 CO Q19 ・ HCl 418 HHH Cl OEt 4-OMe 3-Q3 CO Q20 ・ HCl 419 HHH Cl OEt 4-OMe 3-Q3 CO Q21・ 2HCl 420 HHH Cl OEt 4-OMe 3-Q3 CO Q23 ・ 2HCl 421 HHH Cl OEt 4-OMe 3-Q3 CO Q24 ・ 3HCl 422 HHH Cl OEt 4-OMe 3-Q3 CO Q25 ・ 2HCl 423 HHH Cl OEt 4- OMe 3-Q3 CO Q26 ・ 2HCl 424 HHH Cl OEt 4-OMe 3-Q3 CO Q27 425 HHH Cl OEt 4-OMe 3-Q3 CO Q28 426 HHH Cl OEt 4-OMe 3-Q3 CO Q29 ・ 3HCl 427 HHH Cl OEt 4-OMe 3-Q3 CO Q33 ・ 2HCl 428 HHH Cl OEt 4-OMe 3-Q3 CO Q34 ・ 2HCl 429 HHH Cl OEt 4-OMe 3-Q5 CO Q10 430 HHH Cl OEt 4-OMe 3-Q5 CO Q16 ・ HCl 431 HHH Cl OEt 4-OMe 3-Q5 CO Q19 ・ HCl 432 HHH Cl OEt 4-OMe 3-Q5 CO Q21 ・ 2HCl 433 HHH Cl OEt 4-OMe 3-Q5 CO Q23 ・ 2HCl 434 HHH Cl OEt 4-OMe 3 -Q5 CO Q24 3HCl 435 HHH Cl OEt 4-OMe 3-Q5 CO Q25 ・ 2HCl 436 HHH Cl OEt 4-OMe 3-Q5 CO Q26 ・ 2HCl 437 HHH Cl OEt 4-OMe 3-Q5 CO Q27 ───────── ─────────────────────

[0104]

[Table 20] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 438 HHH Cl OEt 4-OMe 3-Q5 CO Q28 439 HHH Cl OEt 4-OMe 3-Q5 CO Q29 ・ 3HCl 440 HHH Cl OEt 4-OMe 3-Q5 CO Q33 ・ 2HCl 441 HHH Cl OEt 4-OMe 3-Q5 CO Q34 ・ 2HCl 442 HHH Cl OEt 4-OMe 3-Q7 CO Q10 443 HHH Cl OEt 4-OMe 3-Q7 CO Q16 ・ HCl 444 HHH Cl OEt 4-OMe 3-Q7 CO Q19 ・ HCl 445 HHH Cl OEt 4-OMe 3-Q7 CO Q21 ・ 2HCl 446 HHH Cl OEt 4-OMe 3 -Q7 CO Q23 ・ 2HCl 447 HHH Cl OEt 4-OMe 3-Q7 CO Q24 ・ 3HCl 448 HHH Cl OEt 4-OMe 3-Q7 CO Q25 ・ 2HCl 449 HHH Cl OEt 4-OMe 3-Q7 CO Q26 ・ 2HCl 450 HHH Cl OEt 4-OMe 3-Q7 CO Q27 451 HHH Cl OEt 4-OMe 3-Q7 CO Q28 452 HHH Cl OEt 4-OMe 3-Q7 CO Q29 ・ 3HCl 453 HHH Cl OEt 4-OMe 3-Q7 CO Q33 ・ 2HCl 454 HHH Cl OEt 4-OMe 3-Q7 CO Q34 ・ 2HCl 455 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q10 456 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q17 ・ 2HCl 457 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q19 ・ 2HCl 458 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q20 ・ 2HCl 459 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q21 ・ 2HCl 460 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q23 ・2HCl ──────────────────────────────

[0105]

[Table 21] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 461 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q24 ・ 2HCl 462 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q25 ・ 2HCl 463 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q26 ・ 2HCl 464 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q27 ・ HCl 465 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q28 ・ HCl 466 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q29 ・ 3HCl 467 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q33 ・ 2HCl 468 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q34 ・ 2HCl 469 HHH Cl O ⁱ Pr 4-OMe 3-Q2 CO Q10 470 HHH Cl O ⁱ Pr 4-OMe 3-Q2 CO Q17 ・ 2HCl 471 HHH Cl O ⁱ Pr 4- OMe 3-Q2 CO Q19 ・ 2HCl 472 HHH Cl O ⁱ Pr 4-OMe 3-Q2 CO Q20 ・ 2HCl 473 HHH Cl O ⁱ Pr 4-OMe 3-Q2 CO Q21 ・ 2HCl 474 HHH Cl O ⁱ Pr 4-OMe 3 -Q2 CO Q23 ・ 2HCl 475 HHH Cl O ⁱ Pr 4-OMe 3-Q2 CO Q24 ・ 2HCl 476 HHH Cl O ⁱ Pr 4-OMe 3-Q2 CO Q25 ・ 2HCl 477 HHH Cl O ⁱ Pr 4-OMe 3-Q2 CO Q26 ・ 2HCl 478 HHH Cl O ⁱ Pr 4-OMe 3-Q2 CO Q27 ・ H Cl 479 HHH Cl O ⁱ Pr 4-OMe 3-Q2 CO Q28 ・ HCl 480 HHH Cl O ⁱ Pr 4-OMe 3-Q2 CO Q29 ・ 3HCl 481 HHH Cl O ⁱ Pr 4-OMe 3-Q2 CO Q33 ・ 2HCl 482 HHH Cl O ⁱ Pr 4-OMe 3-Q2 CO Q34 ・ 2HCl 483 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q10 ───────────────────── ─────────

[0106]

[Table 22] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 484 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q17 ・ 2HCl 485 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q19 ・ 2HCl 486 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q20 ・ 2HCl 487 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q21 ・ 2HCl 488 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q23 ・ 2HCl 489 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q24 ・ 2HCl 490 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q25 ・ 2HCl 491 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q26 ・ 2HCl 492 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q27 ・ HCl 493 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q28 ・ HCl 494 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q29 ・ 3HCl 495 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q33 ・ 2HCl 496 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q34 ・ 2HCl 497 HHH Cl O ⁱ Pr 4- OMe 3-Q7 CO Q10 498 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q17 ・ 2HCl 499 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q19 ・ 2HCl 500 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q20 ・ 2HCl 501 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q21 ・ 2 HCl 502 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q23 ・ 2HCl 503 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q24 ・ 2HCl 504 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q25 ・ 2HCl 505 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q26 ・ 2HCl 506 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q27 ・ HCl ─────────────────── ───────────

[0107]

[Table 23] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 507 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q28 ・ HCl 508 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q29 ・ 3HCl 509 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q33.2HCl 510 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q34 ・ 2HCl 511 HHH Cl O ⁱ Pr 4-OMe 3-Q8 CO Q10 512 HHH Cl O ⁱ Pr 4-OMe 3-Q8 CO Q17 ・ 2HCl 513 HHH Cl O ⁱ Pr 4-OMe 3-Q8 CO Q19 ・ 2HCl 514 HHH Cl O ⁱ Pr 4-OMe 3-Q8 CO Q20 ・ 2HCl 515 HHH Cl O ⁱ Pr 4-OMe 3-Q8 CO Q21 ・ 2HCl 516 HHH Cl O ⁱ Pr 4-OMe 3-Q8 CO Q23 ・ 2HCl 517 HHH Cl O ⁱ Pr 4- OMe 3-Q8 CO Q24 ・ 2HCl 518 HHH Cl O ⁱ Pr 4-OMe 3-Q8 CO Q26 ・ 2HCl 519 HHH Cl O ⁱ Pr 4-OMe 3-Q8 CO Q27 ・ HCl 520 HHH Cl O ⁱ Pr 4-OMe 3 -Q8 CO Q28 ・ HCl 521 HHH Cl O ⁱ Pr 4-OMe 3-Q8 CO Q29 ・ 3HCl 522 HHH Cl O ⁱ Pr 4-OMe 3-Q8 CO Q33 ・ 2HCl 523 HHH Cl O ⁱ Pr 4-OMe 3-Q8 CO Q34 ・ 2HCl 524 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q10 525 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q17 ・ HCl 526 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q19 ・ HCl 527 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q21 ・ HCl 528 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q23 ・ 2HCl 529 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q27 ─────────────────────── ───────

[0108]

[Table 24] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 530 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q28 531 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q29 ・ 3HCl 532 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q33 ・ 2HCl 533 HHH Cl O ⁱ Pr 4-OMe 3-Q1 CO Q34 ・ 2HCl 534 HHH Cl O ⁱ Pr 4-OMe 3-Q3 CO Q10 535 HHH Cl O ⁱ Pr 4-OMe 3-Q3 CO Q17 ・ HCl 536 HHH Cl O ⁱ Pr 4-OMe 3-Q3 CO Q19 ・ HCl 537 HHH Cl O ⁱ Pr 4- OMe 3-Q3 CO Q20 ・ HCl 538 HHH Cl O ⁱ Pr 4-OMe 3-Q3 CO Q21 ・ HCl 539 HHH Cl O ⁱ Pr 4-OMe 3-Q3 CO Q23 ・ 2HCl 540 HHH Cl O ⁱ Pr 4-OMe 3 -Q3 CO Q24 ・ 2HCl 541 HHH Cl O ⁱ Pr 4-OMe 3-Q3 CO Q25 ・ HCl 542 HHH Cl O ⁱ Pr 4-OMe 3-Q3 CO Q26 ・ HCl 543 HHH Cl O ⁱ Pr 4-OMe 3-Q3 CO Q27 544 HHH Cl O ⁱ Pr 4-OMe 3-Q3 CO Q28 545 HHH Cl O ⁱ Pr 4-OMe 3-Q3 CO Q29 ・ 2HCl 546 HHH Cl O ⁱ Pr 4-OMe 3-Q3 CO Q33 ・ HCl 547 HHH Cl O ⁱ Pr 4-OMe 3-Q3 CO Q34 ・ HCl 548 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q10 549 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q17 ・ HCl 550 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q19 ・ HCl 551 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q20 ・ HCl 552 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q21 ・ HCl ──────────────────────────────

[0109]

[Table 25] ────────────────────────────── No. R ¹ R ² R ³ XY ¹ Y ² -OA- B NR ⁴ R ⁵ ────────────────────────────── 553 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q23.2HCl 554 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q24 ・ 2HCl 555 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q25 ・ HCl 556 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q26 ・ HCl 557 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q27 558 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q28 559 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q29 ・ 2HCl 560 HHH Cl O ⁱ Pr 4- OMe 3-Q5 CO Q33 ・ HCl 561 HHH Cl O ⁱ Pr 4-OMe 3-Q5 CO Q34 ・ HCl 562 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q10 563 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q17 ・ HCl 564 HHH Cl O ⁱ Pr 4-OMe 3-Q3 CO Q19 ・ HCl 565 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q20 ・ HCl 566 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q21・ HCl 567 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q23 ・ 2HCl 568 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q24 ・ 2HCl 569 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q25 ・ HCl 570 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q26 ・ HCl 571 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q27 572 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q28 573 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q29 ・ 2HCl 574 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q33 ・ HCl 575 HHH Cl O ⁱ Pr 4-OMe 3-Q7 CO Q34 ・ HCl ──────────────────────────────

Hereinafter, a method for producing the compound of the present invention will be described. A 3 (2H) -pyridazinone derivative of the general formula [I] of the compound of the present invention and a pharmaceutically acceptable salt thereof where possible are produced, for example, by the methods shown in the following reaction formulas (1) to (7). can do.

[0111]

Embedded image

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X, Y ¹ ,
Y ² , A and B are the same as above. )

The production method according to the reaction formula (1) is based on the general formula [I
I], a 4,5-dihalo-3 (2H) -pyridazinone compound and an ω-aminoalkyleneoxy- or ω-aminocarbonylalkyleneoxy-substituted benzylamine derivative of the general formula [III] or a salt thereof. This is a method for producing the compound of the present invention of the general formula (I) by reacting in an inert solvent in the presence of a hydrogen halide removing agent.

In the above reaction formula (1), the general formula [I]
A compound represented by the general formula [IV] wherein the 4-position which is a positional isomer of the compound of formula (I) is substituted with an oxybenzylamino group

[0115]

Embedded image

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X, Y ¹ ,
Y ² , A and B are the same as above. )

The proportion of the compound of the formula [I] and the compound of the formula [IV] to be formed is mainly affected by the polarity of the solvent used.

That is, when a highly polar solvent is used, the proportion of the compound of the formula [I] of the present invention tends to increase. Accordingly, the solvent preferably used for suppressing the by-product of the compound [IV] and efficiently producing the compound of the general formula [I] of the present invention is an ether solvent (tetrahydrofuran, 1,4-dioxane, etc.). Amide solvents (formamide, N, N-dimethylformamide, N, N-
Dimethylacetamide, N-methylpyrrolidone, etc.), acetonitrile, dimethylsulfoxide, alcohol solvents (methanol, ethanol, propanol, etc.), organic amine solvents (pyridine, triethylamine, N, N-
Dimethylaminoethanol, triethanolamine and the like), water and the like, or a mixed solvent thereof.

The compound of the above general formula [I] and the general formula [IV]
As a method for separating and purifying the compound of the general formula [I] of the present invention from the mixture of the compounds of the formula (I), a method known per se in organic synthesis such as fractional recrystallization or various types of chromatography using silica gel can be employed.

In the reaction of the general formulas [II] and [III],
Although hydrogen chloride or hydrogen bromide is produced, the yield is generally improved by adding a hydrogen halide removing agent for trapping the hydrogen halide in the reaction system. As a preferable hydrogen halide removing agent, any agent capable of trapping hydrogen halide without participating in the reaction may be used. For example, inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, N, N -Dimethylaniline, N,
N-diethylaniline, trimethylamine, triethylamine, N, N-dimethylaminoethanol, N-methylmorpholine, pyridine, 2,6-dimethyl-4-
Organic bases such as N, N-dimethylaminopyridine can be exemplified. The benzylamine derivative represented by the general formula [III], which is a raw material, may be used in excess as a hydrogen halide removing agent, and the yield may be improved.

As the reaction temperature, a range from usually 10 ° C. to the boiling point of the solvent used in the reaction can be adopted.

The molar ratio of the raw materials can be set arbitrarily.
I] 4,5-dihalo-3 (2H) -pyridazinone derivative of 1), usually 1 to 10 moles, preferably 1.2 to 5 moles.
It is sufficient to use about twice the molar amount.

The 4,5-dihalo-3 (2) of the general formula [II]
The H) -pyridazinone derivative can be produced, for example, by utilizing or applying the following known production method or a known organic reaction. That is, the method described in Documents (a) and (b) is used for the case where the substituent Y ^{1 at} the 6-position is a hydrogen atom, and the method described in Document (c) for the case where the substituent Y ¹ is a halogen atom, a nitro group, an amino group or an alkoxy group. Can be respectively produced by the method described in (1).

Ω of the general formula [III] in the reaction formula (1)
The -aminoalkyleneoxy- or ω-aminocarbonylalkyleneoxy-substituted benzylamine derivative or a salt thereof can be obtained by utilizing or applying the method described in the literature (a), for example, by the method of the following reaction schemes (A) to (E). Can be manufactured.

[0125]

Embedded image

Wherein hal represents a leaving group such as a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and R represents a hydrogen atom, a hydroxyl group, a C _1-4 alkyl group. Or a C _1-4 alkoxy group.
R ² , R ³ , R ⁴ , R ⁵ , Y ² , A and B are the same as described above. )

[0127]

Embedded image

(Wherein T represents an amino-protecting group such as a benzyloxycarbonyl group, a t-butoxycarbonyl group, a formyl group, an acetyl group, a benzoyl group, a methoxycarbonyl group, an ethoxycarbonyl group; R ² , R ³ , R ⁴ , R ⁵ ,
Y ² , A, B, R and hal are the same as above. )

[0129]

Embedded image

(In the formula, R ⁹ represents a hydrogen atom or a lower alkyl group, and R ² , R ³ , R ⁴ , R ⁵ , Y ² , A, T and hal are the same as described above.)

[0131]

Embedded image

(Wherein R ¹⁰ represents a hydrogen atom or a C _1-4 alkyl group, and hal ′ represents a eliminable substituent in the same range as hal described in the section of the above reaction scheme (A). In the combination, it represents the same substituent as hal or a substituent having a low leaving property, and R ² , R ³ , R ⁴ , R ⁵ , Y ² , A, T and hal are the same as described above.)

[0133]

Embedded image

(In the formula, D represents a C _1-4 alkylene chain.
R ² , R ³ , R ⁴ , R ⁵ , Y ² and hal are the same as described above. )

The reaction scheme (A) uses a hydroxycarbonyl derivative [IX] as a starting material, first reacting a compound represented by the general formula [VIII] at a phenol site,
After introducing the corresponding alkoxy side chain, the carbonyl site is reductively converted to an amino group, whereas the reaction scheme (B) is a production method in which this conversion order in (A) is reversed. . Reaction scheme (C) is (B)
Using an N-protected-hydroxybenzylamine derivative [X], which is an intermediate of the production route of the above, as a starting material, the side chain is extended stepwise to this phenol site to give an ω-aminocarbonylalkyleneoxybenzylamine derivative [IIIa]
And [IIIa] to produce a corresponding reductant [IIIb] relating to this amide binding site. Reaction scheme (D) is a method for producing an ω-aminoalkyleneoxybenzylamine derivative [IIIc] containing a branched methylene chain in which B is substituted with a lower alkyl group, among the benzylamine derivatives represented by the general formula [III]. It is. The reaction scheme (E) is a method for producing a compound [IIId] in which A is a methylene chain having a hydroxyl group among benzylamine derivatives represented by the general formula [III].

Using commercially available raw materials or starting materials derived therefrom, the methods (A) to (E) can be appropriately selected. In the reaction of the hydroxycarbonyl derivative [IX] and [VIII] in the scheme (A), widely used alkylation conditions for phenols can be widely used, and usually, sodium carbonate, potassium carbonate,
Using an inorganic base such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, etc., ketone solvents (acetone, methyl ethyl ketone, diethyl ketone, etc.), amide solvents (formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc.), alcohol solvents (methanol,
This reaction proceeds relatively quickly by heating at about 40 ° C. to 150 ° C. in ethanol, n-propanol, etc.), water or a mixture thereof.

The subsequent conversion of a carbonyl group (formyl group or ketone group) to an aminomethyl group is carried out by using RNH ₂
Can be achieved by subjecting various amines represented by to a condensation reaction to obtain an imino compound, and then reducing the imino compound. In this method, the imino compound may be produced in the reaction system without isolation, and the next reduction reaction may be continuously performed. In some cases, the imino compound is advantageous in terms of yield or economy. In many cases, it gives good results.

Here, among the benzylamine derivatives represented by the general formula [III], when producing primary amines in which R ² is a hydrogen atom, ammonia, hydroxylamine, O-alkylhydroxylamine is used as RNH _2. This is achieved by using amines such as described above and reducing the imines obtained therefrom.

As these reduction conditions, a hydrogenation reaction using Raney nickel, palladium carbon or the like as a catalyst is widely used. Here, when an imine compound with O-alkylhydroxylamine is used, sodium trifluoroacetoxyborohydride [Na
BH ₃ (OCOCF ₃ )] or sodium bis-methoxyethoxyaluminum hydride [NaAlH ₂ (OCH ₂ CH ₂ OCH ₃ ) ₂ ]. (Chemical
and Pharmaceutical Bulletin, Volume 26, pages 2897-2898,
1978).

Among the benzylamine derivatives represented by the general formula [III], compounds containing a halogen atom or a benzyl group which is relatively unstable under the conditions of hydrogenation and reduction in Y ² and R ⁴ and R ⁵ are produced. In some cases, the latter method using a metal hydride may be more advantageous. Further, among the benzylamine derivatives represented by the general formula (III), when producing a secondary amine in which R ² is a C _1-4 alkyl group, the primary amine represented by R ² NH ₂ corresponding to RNH ₂ In the reduction of the imine derivative obtained by this condensation reaction using an alkylamine, in addition to the reducing agent described in the above-mentioned method for producing a primary amine, borohydride is the most widely and preferably used reducing agent. A milder metal hydride reducing agent such as sodium or sodium cyanoborohydride (NaCNBH ₃ ) can be added.

The reaction scheme (B) is a production route for obtaining the benzylamine represented by the general formula [III] by reversing the order of the reaction steps in the reaction scheme (A). The reaction conditions for the conversion of and the alkylation reaction of the phenol moiety can be in accordance with the production method described in the scheme (A). In this route, a step of introducing a protecting group for a benzylamino nitrogen atom is required in the course of the production process, and the protecting group represented by the general formula T used herein includes a benzyloxycarbonyl group and a t-butoxycarbonyl group. Protecting groups for amino groups which are usually used in peptide synthesis, such as, formyl group, acetyl group, benzoyl group, methoxycarbonyl group and ethoxycarbonyl group can be widely used. If the selection of these various protective groups is not particularly strict constraints, the substituents Y ^2, B, depending on the type of R ⁴ and R ^5, which must be appropriately selected protecting group and the deprotection conditions used occurs There is also. For example, benzylamine [III]
In producing a compound containing a halogen atom, a benzyl group or the like in Y ² or R ⁴ and R ⁵ in a high yield, the deprotection reaction proceeds efficiently even by a method other than the catalytic hydrogenation method. It may be necessary to select substituents and reaction conditions. In the case of producing a benzylamine in which B in the general formula [III] is a carbonyl chain, a benzyloxycarbonyl group or a t-butoxycarbonyl group, which easily deprotects under non-hydrolysis conditions, is preferably used. Often used. As the conditions for the introduction and deprotection of the above-mentioned various protecting groups, reaction conditions which are usually adopted may be set, and there is no particular problem.

The reaction scheme (C) uses a hydroxybenzylamine [X] protected with a protecting group T as a starting material, elongates the ether side chain in a stepwise manner, and proceeds from the benzylamine represented by the general formula [III]. In this method, B is a carbonyl chain [IIIa] and this carbonyl site is reduced to produce a linear methylene chain [IIIb]. In the amide bond formation reaction at the ether side chain site, when R ⁹ is a hydrogen atom,
A dehydration condensation method generally used in peptide synthesis can be widely employed. When amines having relatively high nucleophilicity are used, an ester in which R ⁹ is a lower alkyl group can be used.In this case, conditions for heating in an inert solvent are usually set. Can be. Further, examples of the reducing agent used for producing the benzylamine represented by the general formula [IIIb] include a metal hydride reducing agent such as lithium aluminum hydride. The alkylation and deprotection of the phenol moiety in the other steps are described in the above schemes (A) and (B).
The same reaction conditions as those of the corresponding reactions may be set.

The reaction scheme (D) is an aminoalkyleneoxybenzylamine having a methylene chain in which the α-carbon of the amino group at the terminal of the phenol side chain represented by the general formula [IIIc] is a linear or lower alkyl group. A method for producing a derivative is provided. In the step of introducing an amino group portion, reaction conditions generally used for a general substitution reaction of an alkylamine with an alkyl halide can be employed.

In the reaction scheme (E), a hydroxyl group is introduced into the phenol side chain represented by the general formula [IIId]. An epoxy group is introduced into the phenol side chain by reaction with various epoxyalkyl halide compounds. And a method for producing a compound [IIId] by reaction with various amines.

[0145]

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(Wherein R ¹ ′ represents a C _1-4 alkyl group;
al represents a chlorine atom, a bromine atom or an iodine atom, R ² ,
R ³ , R ⁴ , R ⁵ , X, Y ¹ , Y ² , A and B are the same as described above. )

In the reaction formula (2), the compound of the general formula [Ia] in which the 2-position of pyridazinone is a hydrogen atom among the compounds of the present invention of the general formula [I] is a halogeno compound represented by the general formula R ¹ '-hal. This is a method for producing a 2-substituted pyridazinone of the general formula [Ib] which is a compound of the present invention by reacting with a derivative.

The present invention generally relates to an inorganic base such as potassium carbonate, sodium carbonate, lithium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate and lithium hydroxide; an organic base such as triethylamine and tri-n-propylamine; and sodium hydride. Metal hydrides such as n-butyllithium and organometallic compounds can be used.

As the reaction solvent, when an inorganic or 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, when metal hydrides are used, usually ether solvents are preferably used.

The reaction temperature can be usually in the range from 0 ° C. to the boiling point of the solvent when using an inorganic base or an organic base, and is usually −78 when using a metal hydride or an organometallic compound. C. to 60.degree. C. can be employed. Although the molar ratio of the raw materials can be set arbitrarily, it is sufficient to use the reactive derivative represented by the general formula R ¹ ′ -hal in a molar amount of 1 to 5 times the compound of the general formula [Ia].

The method for isolating and purifying the desired product includes recrystallization,
Various methods known in organic synthesis such as various kinds of chromatography using silica gel and distillation can be adopted.

[0152]

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(Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁹ , X,
Y ¹ , Y ² and A are the same as above. )

The reaction formula (3) is based on the general formula [V] of 5- (ω-
(Carboxyalkyleneoxy) benzylamino derivative or 5- (ω-alkoxycarbonylalkyleneoxy)
This is a method for producing a corresponding amide derivative of the general formula [Ic] by subjecting a benzylamino derivative to a condensation reaction by dehydration or dealcoholation with an amine compound represented by the general formula [VI].

As the condensation method in the case where R ⁹ is a hydrogen atom, the condensation method generally known in peptide synthesis can be widely used, and examples thereof include an acid chloride method and a mixed acid anhydride method.
A condensation method using a condensing agent such as di-cyclohexylcarbodiimide, carbonyldiimidazole, or N-hydroxysuccinimide can be widely used, and a general formula [VI]
The condensation method can be appropriately selected depending on the reactivity of the amines. As the reaction conditions, conditions that are usually used can be set and there is no problem.

In the reaction with amines having a high nucleophilicity among the amines represented by the general formula [VI], the condensation reaction can be carried out by using an ester in which R ⁹ is an alkyl group. Progresses. In this case, the solvent is not particularly limited as long as it does not participate in the reaction, and most solvents can be used. In many cases, the reaction can be performed without a solvent.
The reaction temperature can be set in the range from room temperature to 200 ° C., but is usually carried out in the range of 50 to 150 ° C.

[0157]

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(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X, Y ¹ ,
Y ² , A, B and hal are the same as above. )

The reaction formula (4) is a method for producing the compound [I] of the present invention by reacting the compound represented by the general formula [VII] with a halogeno derivative represented by the general formula [VIII]. The present invention is generally an inorganic base such as potassium carbonate, sodium carbonate, lithium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydroxide, triethylamine, tri-
An organic base such as n-propylamine can be used.

Examples of the reaction solvent include ketone solvents (acetone, methyl ethyl ketone, diethyl ketone, etc.), amide solvents (formamide, N, N-dimethylformamide, N, N-dimethylacetamide, etc.), and alcohol solvents (methanol, ethanol, etc.). ), Water and the like and a mixed solvent thereof are suitably used.

As the reaction temperature, a range from usually 0 ° C. to the boiling point of the solvent can be adopted.

[0162]

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(Wherein R¹, R^Two, R^Three, R^Four, R^Five, R^Ten, X, Y
¹, Y^Two, A and hal are the same as above. R ⁷Is a hydrogen atom or C
_1-4Shows an alkyl group. )

In the reaction formula (5), a compound represented by the general formula [IX] prepared by a method according to the reaction formula (4) is converted to a compound represented by the general formula [V
This is a method for producing an amine derivative represented by the general formula [Id], which is a compound of the present invention, by reacting with an amine compound represented by the formula [I]. This reaction can be performed by a method similar to the method described in the reaction formula (4).

[0165]

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(Wherein R ² ′ represents a C _1-4 alkyl group;
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X, Y ¹ , Y ² , A, B and hal are the same as described above. )

In the reaction formula (6), the compound of the present invention represented by the general formula [I] wherein R ² is a hydrogen atom is represented by the general formula R ² '-hal in the presence of a base. This is a method for producing a compound of the present invention in which R ² is a C _1-4 alkyl group by reacting the compound with an alkyl halide represented by the following formula:

As the organic solvent to be used, amide solvents such as dimethylformamide, ether solvents such as tetrahydrofuran ethyl ether, and aprotic organic solvents such as hydrocarbon solvents such as n-hexane, benzene and toluene are usually used. , As a base, sodium hydride,
n-butyllithium, lithium diisopropylamide,
Good results are often obtained with metal hydrides such as sodium amide.

Regarding the reaction temperature, the reaction with a base is -78.
The reaction with the alkyl halide in the range of -10 ° C is -15 to
A range of 70 ° C. can often be set.

[0170]

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(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X, Y ¹ ,
Y ² , A, B and hal are the same as above. )

The reaction formula (7) is a compound represented by the general formula [XI]:
By reacting a 3 (2H) -pyridazinone having a -NHR ² group at the ^2- position with a benzyl halide derivative represented by the general formula [XII] in the presence of a base. is there. The reaction conditions can be in accordance with the conditions shown in the reaction formula (6).

The 3 (2H) -pyridazinone derivative of the general formula [I] of the present invention and, if possible, a pharmaceutically acceptable salt thereof may be administered in the form of an injection (subcutaneous, intravenous, intramuscular, intraperitoneal). Internal injection), parenteral administration with ointments, suppositories, aerosols and the like, or oral administration with tablets, capsules, granules, pills, syrups, solutions, emulsions, suspensions and the like.

The above-mentioned pharmaceutical composition containing the compound of the present invention contains the compound of the present invention in an amount of about 0.5% by weight of the total composition.
It contains 1-99.5%, preferably about 0.5-95%.

In addition to the compound of the present invention or a composition containing the compound of the present invention, other pharmaceutically active compounds can be included.

The compounds of the present invention are formulated for administration by conventional pharmaceutical means. That is, tablets, capsules, granules, and pills for oral administration include excipients such as sucrose, lactose, glucose, starch, and mannitol; binders such as syrup, acacia, gelatin, sorbit, tragacanth, methylcellulose, Polyvinylpyrrolidone; disintegrants such as starch, carboxymethylcellulose or its calcium salt, microcrystalline cellulose, polyethylene glycol; lubricants such as talc, magnesium or calcium stearate, silica; lubricants such as sodium laurate, glycerol and the like It is prepared by

Injectable solutions, solutions, emulsions, suspensions, syrups and aerosols are solvents for the active ingredient such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol, polyethylene glycol; Agents such as sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene ether of hydrogenated castor oil, lecithin; suspending agents such as sodium carboxymethylcellulose, cellulose derivatives such as methylcellulose, tragacanth, Natural rubbers such as gum arabic; prepared using preservatives, for example, esters of parahydroxybenzoic acid, benzalkonium chloride, sorbate and the like.

Suppositories include, for example, polyethylene glycol,
It is prepared using lanolin, coconut oil and the like.

[0179]

【Example】

[0180]Examples (Reference Examples, Synthesis Examples, Formulation Examples, Tests
Example) Hereinafter, the present invention will be described with reference to Examples (Reference Examples, Synthesis Examples, Preparations).
Examples and test examples), but the present invention
The present invention is not limited to the embodiments.

In the reference examples, the synthesis examples and “NM” in Table II,
The symbols “R” and “MS” represent “nuclear magnetic resonance spectrum” and “mass spectrum”, respectively. Unless otherwise specified, nuclear magnetic resonance spectra were measured in deuterated chloroform. "MS" in Table II describes only the parent peak or a representative fragment peak.

Reference Example 1 N-benzyloxycarbonyl-3-hydroxy-4-
Methoxybenzylamine

[0183]

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A mixture of 150 g of isovanillin, 93.2 g of sodium hydroxide, 99 g of hydroxylamine sulfate, 600 ml of ethanol and 1500 ml of water was stirred while stirring.
After heating and refluxing for 0 minutes, the mixture was cooled to 40 ° C., 93.2 g of sodium hydroxide was added, and 180 g of Raney alloy was further added.
Was added over 30 minutes and stirred for 1 hour. The insoluble matter was separated by filtration and washed with 100 ml of ethanol and 200 ml of water. The filtrate and the washing solution were combined, and sodium hydroxide was added.
6 g was added, and 186 g of benzyloxycarbonyl chloride was added dropwise under ice cooling, followed by stirring for 4 hours. Hydrochloric acid was added to the reaction mixture until the pH reached 1 to 2, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off. The obtained residue was crystallized from diethyl ether to give 95.11 g of the title compound as white crystals.

NMR δ: 7.34 (s, 5H), 6.79 (s, 3H), 5.
78 (s, 1H), 5.12 (brs, 2H), 4.25 (d, 2H), 3.84 (s, 3H). MS (m / e): 287 (M ⁺ ), 196, 152, 137, 91 (100 %).

Reference Example 2 t-butyloxycarbonyl-3-hydroxy-4-methoxybenzylamine

[0187]

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A mixture of 150 g of isovanillin, 91 g of sodium hydroxide, 89 g of hydroxylamine sulfate, 500 ml of ethanol and 1300 ml of water was heated under reflux for 1 hour with stirring, cooled to 40 ° C., 91 g of sodium hydroxide was added, and 150 g of Raney alloy was further added. The inside temperature 3
The mixture was gradually added between 0 and 50 degrees and stirred for 1 hour. The insoluble matter was filtered off, 150 ml of ethanol and 1
Washed with 50 ml. The filtrate and washing solution were combined, neutralized with concentrated hydrochloric acid until the pH reached 8 while cooling, and acetonitrile 1 was added.
l, 215 g of di-t-butyl dicarbonate was added dropwise at room temperature over 1 hour, and the mixture was stirred overnight. After the reaction solution was concentrated under reduced pressure, dilute hydrochloric acid was added to dissolve insolubles, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off. The obtained residue is subjected to silica gel column chromatography (ethyl acetate: benzene =
1: 5) to give 126 g of the title compound as an oil.

NMR δ: 6.54-6.85 (m, 3H), 6.14-6.47
(bs, 1H), 4.92-5.34 (m, 1H), 4.09 (d, 2H), 3.25 (s, 3
H), 1.44 (s, 9H). MS (m / e): 153 (M ⁺ -100), 137 (100%).

Reference Example 3 N-benzyloxycarbonyl-3-ethoxycarbonylmethyloxy-4-methoxybenzylamine

[0191]

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A mixture of 20 g of N-benzyloxycarbonyl-3-hydroxy-4-methoxybenzylamine, 17.43 g of ethyl bromoacetate, 14.43 g of potassium carbonate and 200 ml of 2-butanone was heated to reflux overnight with stirring. After cooling to room temperature, the inorganic substances are separated by filtration, and the filtrate is distilled off under reduced pressure. The resulting residue was extracted with chloroform,
The organic layer was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off. The obtained residue was crystallized from diethyl ether / n-hexane to give 1 as white crystals.
7.83 g of the title compound were obtained.

NMR δ: 7.33 (s, 5H), 6.85 (s, 3H), 5.
12 (s, 2H), 4.63 (s, 2H), 4.26 (d, 2H), 4.25 (q, 2H),
3.84 (s, 3H), 1.26 (t, 3H). MS (m / e): 373 (M ⁺ ), 282, 239 (100%), 210, 164, 136,
91.

The following compounds were synthesized using a similar method. N-benzyloxycarbonyl-3-ethoxycarbonylpropoxy-4-methoxybenzylamine NMR δ: 7.25-7.55 (m, 5H), 6.72-7.06 (m, 3H), 5.14
(s, 2H), 3.71-4.52 (m, 10H), 1.90-2.80 (m, 4H), 1.24
(t, 3H). N-benzyloxycarbonyl-3-ethoxycarbonylpentyloxy-4-methoxybenzylamine

Reference Example 4 N-benzyloxycarbonyl-3-carboxymethyloxy-4-methoxybenzylamine

[0196]

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A mixture of 23.56 g of N-benzyloxycarbonyl-3-ethoxycarbonylmethyloxy-4-methoxybenzylamine, 7.29 g of sodium hydroxide, 300 ml of methanol and 30 ml of water was added at 60 ° C. for 1 hour.
Stirred for hours. Hydrochloric acid was added to the reaction solution for neutralization, and the solvent was distilled off under reduced pressure. Dilute hydrochloric acid was added to the obtained residue, and the mixture was extracted with chloroform. The extract layer was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off. The obtained residue was crystallized from diethyl ether / n-hexane to obtain 21.55 g of the title compound as white crystals.

NMR δ: 7.34 (s, 5H), 6.85 (s, 3H), 5.
13 (s, 3H), 4.62 (s, 2H), 4.25 (d, 2H), 3.83 (s, 3H). MS (m / e): 345 (M ⁺ ), 254, 210 (100%), 91 .

The following compounds were synthesized using a similar method. N-benzyloxycarbonyl-3-carboxypropyloxy-4-methoxybenzylamine N-benzyloxycarbonyl-3-carboxypentyloxy-4-methoxybenzylamine

Reference Example 5 N-benzyloxycarbonyl-3- (2,3-epoxypropyloxy) -4-methoxybenzylamine

[0201]

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A mixture of 2 g of N-benzyloxycarbonyl-3-hydroxy-4-methoxybenzylamine, 20 ml of dimethylformamide, 1.4 g of potassium carbonate and 1.4 g of epibromohydrin was stirred at 60 ° C. overnight. After evaporating the solvent under reduced pressure, the solvent was distilled off under reduced pressure and the residue was extracted with ethyl acetate.The obtained organic layer was washed successively with an aqueous potassium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to give the title compound as an oil. 2.6 g were obtained.

NMR δ: 7.32 (s, 5H), 6.81 (s, 3H), 5.
0-5.5 (m, 3H), 3.9-4.6 (m, 7H), 3.8 (s, 3H). MS (m / e): 343 (M ⁺ ), 252, 208, 91 (100%).

Reference Example 6 N-benzyloxycarbonyl-3- (4-methylpiperazin-1-yl) -carbonylmethoxy-4-methoxybenzylamine

[0205]

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N-benzyloxycarbonyl-3-carboxymethyloxy-4-methoxybenzylamine 5
g, 1.67 g of triethylamine and 40 ml of tetrahydrofuran were ice-cooled, and 1.79 g of ethyl chloroformate dissolved in 10 ml of tetrahydrofuran was added dropwise thereto. The mixture was stirred for 2 hours and then dissolved in 10 ml of tetrahydrofuran in the reaction solution. Methyl piperazine 1.
65 g was added, and the mixture was stirred at room temperature for 4.5 hours. The precipitate was separated by filtration, the filtrate was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. The extract was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off. The obtained residue was crystallized from ethyl acetate / diethyl ether / n-hexane to give 3.53 g of the title compound as white crystals.

NMR δ: 7.25 (s, 5H), 6.78 (s, 3H), 5.
03 (s, 3H), 4.62 (s, 2H), 4.23 (d, 2H), 3.78 (s, 3H),
3.57-3.72 (m, 4H), 2.11-2.60 (m, 7H). MS (m / e): 427 (M ⁺ ), 292, 235, 141, 91 (100%).

The following compounds were synthesized using a similar method. N-benzyloxycarbonyl-3- [4- (3-pyridylmethyl) -piperazin-1-yl] carbonylmethoxy-4-methoxybenzylamine MS (m / e): 504 (M ⁺ ), 92 (100%) N-benzyloxycarbonyl-3- (4-benzylpiperazin-1-yl) -carbonylmethoxy-4-methoxybenzylamine NMR δ: 7.15-7.43 (m, 10H), 6.7-6.92 (m, 3H), 4.85
-5.24 (m, 3H), 4.62 (s, 2H), 4.22 (d, 2H), 3.4-3.96 (m,
9H), 2.25-2.7 (m, 4H). N-benzyloxycarbonyl-3- [4- (4-fluorobenzyl) -piperazin-1-yl] -carbonylmethoxy-4-methoxybenzylamine NMR δ: 6.60-7.50 (m, 12H), 5.0-5.5 (m, 3H), 4.62
(s, 2H), 4.22 (d, 2H), 3.22-3.95 (m, 9H), 2.2-2.7 (m,
4H). N-Benzyloxycarbonyl-3- [4- (3-pyridylmethyl) -piperazin-1-yl] -carbonylpropoxy-4-methoxybenzylamine MS (m / e): 532 (M ⁺ ), 92 (100%). N-benzyloxycarbonyl-3- (4-benzylpiperazin-1-yl) -carbonylpropoxy-4-methoxybenzylamine NMR δ: 7.0-7.40 (m, 10H), 6.60-6.90) m, 3H ), 5.50
-5.51 (m, 3H), 3.22-4.37 (m, 13H), 2.0-2.68 (m, 8H). N-benzyloxycarbonyl-3- (4-benzylpiperazin-1-yl) -carbonylpentyloxy-4
-Methoxybenzylamine NMR δ: 7.0-7.35 (m, 10H), 6.60-6.80 (m, 3H), 5.0-
5.50 (m, 3H), 3.20-4.32 (m, 13H), 1.1-2.48 (m, 12H).

Reference Example 7 N-benzyloxycarbonyl-3-[{4- (4-fluorobenzyl) -piperazin-1-yl} -β-hydroxypropyloxy] -4-methoxybenzylamine

[0210]

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N-benzyloxycarbonyl-2,3-
A mixture of 2.4 g of epoxypropyloxy-4-methoxybenzylamine, 30 ml of ethanol and 1.4 g of 4-fluorobenzyl-piperazine was heated to reflux overnight with stirring. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and extracted with chloroform. The organic layer was washed with an aqueous potassium carbonate solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 19: 1) to obtain 2.6 g of the title compound. NMR δ: 6.75-7.42 (m, 12H), 5.0-5.5 (m, 3H), 4.26
(d, 2H), 3.82-4.10 (m, 2H), 3.77 (s, 3H), 3.20-3.60
(m, 3H), 2.20-2.85 (m, 10H). MS (m / e): 537 (M ⁺ ), 207 (100%), 109.

The following compounds were synthesized using a similar method. N-benzyloxycarbonyl-3-[{4- (2-quinolylmethyl) piperazin-1-yl} -β-hydroxypropyloxy] -4-methoxybenzylamine NMR δ: 7.03-8.12 (m, 11H), 6.60-6.87 (m, 3H), 5.3
0-5.70 (m, 1H), 5.05 (s, 2H), 3.22-4.37 (m, 11H), 2.22
-2.80 (m, 10H). N-benzyloxycarbonyl-3-[{4- (4-aminobenzyl) -piperazin-1-yl} -β-hydroxypropyloxy] -4-methoxybenzylamine NMR δ: 6.45 7.41 (m, 12H), 5.40-6.78 (m, 1H), 5.0
4 (s, 2H), 3.50-4.38 (m, 11H), 3.30 (s, 2H), 2.10-2.80
(m, 8H).

Reference Example 8 3- (4-methylpiperazin-1-yl) -carbonylmethoxy-4-methoxybenzylamine

[0214]

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N-benzyloxycarbonyl-3- (4
A mixture of 3.26 g of -methylpiperazin-1-yl) -carbonylmethoxy-4-methoxybenzylamine, 0.5 g of 5% palladium carbon and 70 ml of ethanol was stirred at 60 ° C for 6 hours in a hydrogen atmosphere and further overnight at room temperature. After filtering off the palladium carbon, the filtrate was distilled off under reduced pressure.
2.45 g of the title compound were obtained as a light brown oil.

NMR δ: 6.88 (s, 3H), 4.74 (s, 2H), 3.
50-4.10 (m, 9H), 2.29-2.58 (m, 7H). MS (m / e): 293 (M ⁺ ), 152, 99, 70 (100%).

The following compounds were synthesized using the same method. 3- [4- (3-pyridylmethyl) -piperazine-1-
Yl] carbonylmethoxy-4-methoxybenzylamine MS (m / e): 370 (M ⁺ ), 92 (100%). 3- (4-benzylpiperazin-1-yl) -carbonylmethoxy-4-methoxybenzylamine MS (m / e): 369 (M ⁺ ), 91 (100%). 3- [4- (4-Fluorobenzyl) -piperazine-1.
-Yl] carbonylmethoxy-4-methoxybenzylamine MS (m / e): 387 (M ⁺ ), 109 (100%). 3- [4- (3-pyridylmethyl) -piperazine-1-
Yl] carbonylpropoxy-4-methoxybenzylamine MS (m / e): 398 (M ⁺ ), 92 (100%). 3- (4-methylpiperazin-1-yl) -carbonylpropoxy-4-methoxybenzylamine MS (m / e): 321 (M ⁺ ), 99 (100%). 3- (4-benzylpiperazin-1-yl) -carbonylpropoxy-4-methoxybenzylamine MS (m / e): 397 (M ⁺ ), 91 (100%). 3- [4- (4-fluorobenzyl) -piperazine-1
-Yl) -1-oxo-2-methylethyloxy] -4
-Methoxybenzylamine MS (m / e): 401 (M ⁺ ), 109 (100%). 3- (4-benzylpiperazin-1-yl) -carbonylpentyloxy-4-methoxybenzylamine MS (m / e ): 425 (M ⁺ ), 91 (100%).

Synthesis Example 1 4-chloro-5- [3- (4-methylpiperazine-1-
Yl) -carbonylmethoxy-4-methoxybenzylamino] -3 (2H) -pyridazinone

[0219]

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3- (4-methylpiperazin-1-yl)
A mixture of 1.16 g of -carbonylmethoxy-4-methoxybenzylamine, 0.5 g of 4,5-dichloro-3 (2H) -pyridazinone, 0.46 g of triethylamine, 10 ml of ethanol and 10 ml of water was heated to reflux overnight with stirring. The solvent was distilled off under reduced pressure, an aqueous potassium carbonate solution was poured into the obtained residue, and the mixture was extracted with chloroform. The extract was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off. After the obtained residue was purified by silica gel column chromatography, it was crystallized from chloroform / diethyl ether to obtain 0.61 g of the title compound as white crystals.

NMR δ: 12.66 (br.s, 1H), 7.44 (s, 1
H), 6.78 (s, 3H), 5.43 (t, 1H), 4.68 (s, 2H), 4.39 (d,
2H), 3.77 (s, 3H), 3.30-3.70 (m, 4H), 2.0-2.60 (m, 7
H). MS (m / e): 421 (M ⁺ ), 386, 140, 99, 70 (100%).

Reference Example 9 4-chloro-5- (3-carboxymethyloxy-4-
Methoxybenzylamino) -3 (2H) -pyridazinone

[0223]

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4-Chloro-5- [3- (4-methylpiperazin-1-yl) -carbonylmethoxy-4-methoxybenzylamino] -3 (2H) -pyridazinone 0.3
g, potassium hydroxide 2.0 g, ethanol 10 ml and water 2 ml was heated and refluxed overnight with stirring. After neutralizing the reaction solution with an aqueous hydrochloric acid solution, the solvent was distilled off under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. The extract was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off to obtain 212 mg of the title compound as a white solid. MS (m / e): 281 (M ⁺ -CHCO ₂ H), 246, 209, 159, 145 (100
%), 116.

Synthesis Example 2 4-chloro-5- [3- (3-pyridylmethylaminocarbonylmethoxy) -4-methoxybenzylamino]-
3 (2H) -pyridazinone

[0226]

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4-Chloro-5- (3-carboxymethyloxy-4-methoxybenzylamino) -3 (2H)-
A mixture of 200 mg of pyridazinone, 65 mg of triethylamine and 10 ml of N, N-dimethylformamide was ice-cooled, 88 mg of isobutyl chlorocarbonate was added, and the mixture was stirred at the same temperature for 1 hour.
g was added and stirred at room temperature overnight. The solvent is distilled off under reduced pressure,
Water was poured into the obtained residue and extracted with chloroform. The extract was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluent; chloroform / methanol = 9/1) to give white. Title compound 12 as a solid
9 mg were obtained.

NMR δ: 8.35-8.58 (m, 2H), 7.81-8.33
(m, 1H), 7.72 (s, 1H), 7.45-7.60 (m, 2H), 6.88 (s, 3
H), 6.40-6.80 (m, 1H), 4.31-4.62 (m, 6H), 3.75 (s, 3
H) MS (m / e): 429 (M ⁺ ), 394, 298, 137, 121, 107, 92 (10
0%)

Reference Example 10 N-benzyloxycarbonyl-3- (3-chloropropoxy) -4-methoxybenzylamine

[0230]

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N-benzyloxycarbonyl-3-hydroxy-4-methoxybenzylamine 20 g, potassium carbonate 14.43 g, bromochloropropane 16.44 g
And a mixture of 200 ml of 2-butanone were heated under reflux with stirring for 16 hours. After cooling to room temperature, the inorganic substances are filtered off,
The filtrate was evaporated under reduced pressure, and the obtained residue was extracted with chloroform. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and evaporated. The obtained residue was crystallized from diethyl ether / n-hexane to obtain 23.19 g of the title compound as white crystals.

NMR δ: 7.21 (s, 5H), 6.71 (s, 3H), 5.
04 (s, 3H), 4.20 (d, 2H), 4.02 (t, 2H), 3.75 (s, 3H),
3.67 (t, 2H), 1.94-2.47 (m, 2H). MS (m / e): 363 (M ⁺ ), 316, 273 (100%), 228, 152, 137,
125, 91.

The following compounds were synthesized using a similar method. N-benzyloxycarbonyl-3- (2-chloroethoxy) -4-methoxybenzylamine N-benzyloxycarbonyl-3- (2-diethylaminoethoxy) -4-methoxybenzylamine

Reference Example 11 N-benzyloxycarbonyl-3- [3- (4-formylpiperazin-1-yl) propoxy] -4-methoxybenzylamine

[0235]

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N-benzyloxycarbonyl-3- (3
-Chloropropoxy) -4-methoxybenzylamine 2
3.1 g, 8.7 g of N-formylpiperazine, 13.16 g of potassium carbonate, 0.95 g of sodium iodide and 300 ml of N, N-dimethylformamide in 8
Stirred at 0 ° C. for 16 hours. After cooling to room temperature, the inorganic substance was filtered off, the filtrate was distilled off under reduced pressure, the obtained residue was extracted with chloroform, and the organic layer was washed with water and saturated saline,
After drying over sodium sulfate, the solvent was distilled off to obtain 30.67 g of the title compound as a slightly brown oil.

NMR δ: 7.97 (s, 1H), 7.32 (s, 5H), 6.
81 (s, 3H), 5.36 (brt, 1H), 5.11 (s, 2H), 4.26 (d, 2H),
4.02 (t, 2H), 3.81 (s, 3H), 3.12-3.66 (m, 4H), 1.78-
2.78 (m, 8H). MS (m / e): 441 (M ⁺ ), 383, 306, 155 (100%), 128, 91.

The following compounds were synthesized using the same method. N-benzyloxycarbonyl-3- (3-diethylaminopropoxy) -4-methoxybenzylamine N-benzyloxycarbonyl-3- [2- (4-benzylpiperazin-1-yl) -ethoxy] -4-methoxybenzylamine N-benzyloxycarbonyl-3- [2- {4- (4
-Chlorobenzyl) -piperazin-1-yl} -ethoxy] -4-methoxybenzylamine N-benzyloxycarbonyl-3- [2- {4- (4
-Fluorobenzyl) piperazin-1-yl} -ethoxy] -4-methoxybenzylamine N-benzyloxycarbonyl-3- [3- (4-benzylpiperazin-1-yl) -propoxy] -4-methoxybenzylamine N -Benzyloxycarbonyl-3- [3- (4-methylpiperazin-1-yl) -propoxy] -4-methoxybenzylamine

Reference Example 12 3- [3- (4-Formylpiperazin-1-yl) -propoxy] -4-methoxybenzylamine

[0240]

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N-benzyloxycarbonyl-3- [3
A mixture of-(4-formylpiperazin-1-yl) -propoxy] -4-methoxybenzylamine (30.4 g, 5% palladium on carbon (3.1 g) and ethanol (300 ml) was stirred at 60 ° C for 9 hours under a hydrogen atmosphere. After filtering off the palladium carbon, the filtrate was distilled off under reduced pressure to obtain 17.99 g of the title compound as a slightly brown oil.

NMR δ: 8.03 (s, 1H), 6.86 (s, 3H), 4.
11 (t, 2H), 3.84 (s, 3H), 3.25-3.71 (m, 4H), 2.30-2.8
2 (m, 4H), 1.82-2.30 (m, 4H). MS (m / e): 307 (M ⁺ ), 292, 246, 171, 155, 125, 99 (10
0%).

The following compounds were synthesized using a similar method. 3- (2-diethylaminoethoxy) -4-methoxybenzylamine 3- (3-diethylaminopropoxy) -4-methoxybenzylamine 3- [2- (4-benzylpiperazin) -1-yl]-
Ethoxy-4-methoxybenzylpiperazine 3- [2- {4- (4-chlorobenzyl) -piperazin-1-yl} -ethoxy] -4-methoxybenzylamine 3- [2- {4- (4-fluorobenzyl) ) -Piperazin-1-yl} -ethoxy] -4-methoxybenzylamine 3- [3- (4-benzylpiperazin-1-yl) -propoxy] -4-methoxybenzylamine 3- [3- (4-methyl Piperazin-1-yl) -propoxy] -4-methoxybenzylamine

Synthesis Example 3 4-Chloro-5- [3- {3- (4-formylpiperazin-1-yl) -propoxy} -4-methoxybenzylamino] -3 (2H) -pyridazinone (Compound No. 5)
0)

[0245]

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3- [3- (4-formylpiperazine-1)
-Yl) -propoxy] -4-methoxybenzylamine (11.58 g), 4,5-dichloro-3 (2H) -pyridazinone (5.0 g), triethylamine (4.6 g), n-propanol (50 ml) and water (50 ml).
Heated to reflux for an hour. The solvent was distilled off under reduced pressure, an aqueous potassium carbonate solution was poured into the obtained residue, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated saline, dried over sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel chromatography to obtain 6.21 g of the title compound as a pale yellowish white solid.

NMR δ: 12.49 (br.s, 1H), 8.06 (s, 1
H), 7.65 (s, 1H), 6.88 (s, 3H), 5.37 (t, 1H), 4.51 (d,
2H), 4.08 (t, 2H), 3.87 (s, 3H), 3.19-3.74 (m, 4H),
2.30-2.84 (m, 6H), 1.76-2.30 (m, 2H).

Synthesis Example 4 4-chloro-5- [3- {3- (4-ethylpiperazin-1-yl) -propoxy} -4-methoxybenzylamino] -3 (2H) -pyridazinone

[0249]

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4-Chloro-5- [3- {3- (4-formylpiperazin-1-yl) -propoxy} -4-methoxybenzylamino] -3 (2H) -pyridazinone
After refluxing a mixture of 0 g, potassium hydroxide 0.62 g, ethanol 7 ml and water 7 ml under stirring for 3.5 hours, potassium carbonate 0.32 g and ethyl bromide 570 mg
Was added and stirred at 60 ° C. for 4 hours. The solvent is distilled off under reduced pressure,
Water was poured into the obtained residue and extracted with chloroform. The extract was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain 0.50 g of the title compound as a slightly brown solid.

NMR δ: 7.65 (s, 1H), 6.89 (s, 3H), 5.
41 (collapsed, 1H), 4.50 (d, 2H), 4.08 (t, 2H), 3.87
(s, 3H), 1.73-3.10 (m, 14H), 1.08 (t, 3H). MS (m / e): 435 (M ⁺ ), 365, 343, 206, 127 (100%), 99.

The following compounds were synthesized using a similar method. 4-chloro-5- [3- {3- (4- (4-fluorobenzyl) -piperazin-1-yl) -propoxy} -4
-Methoxybenzylamino] -3 (2H) -pyridazinone MS (m / e): 515 (M ⁺ ), 109 (100%).

Synthesis Example 5 2-ethyl-4-chloro-5- [3- {2- (4- (4
-Fluorobenzyl) -piperazin-1-yl) -ethoxy {-4-methoxybenzylamino] -3 (2H)-
Pyridazinone

[0254]

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4-Chloro-5- [3- {2- (4- (4
-Fluorobenzyl) -piperazin-1-yl) -ethoxy {-4-methoxybenzylamino] -3 (2H)-
A mixture of 500 mg of pyridazinone, 130 mg of ethyl bromide, 190 mg of potassium carbonate and 10 ml of 2-butanone was heated to reflux for 5 hours while stirring. After inorganic substances were filtered off, the solvent was distilled off under reduced pressure, water was poured into the obtained residue, and the mixture was extracted with chloroform. The extract was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluent; chloroform / methanol = 19/1),
429 mg of the title compound was obtained as a colorless and transparent candy.

NMR δ: 7.47 (s, 1H), 7.00 to 7.31 (m,
4H), 6.88 (s, 3H), 5.20 (t, 1H), 4.46 (d, 2H), 4.14
(t, 2H), 4.12 (q, 2H), 3.85 (s, 3H), 3.47 (s, 2H), 2.
73 (t, 2H), 2.21-3.05 (m, 10H), 1.32 (t, 3H). MS (m / e): 574 (M ⁺ ), 493, 273, 221, 192 (100%), 164,
111, 84.

Reference Example 13 1-chloroacetyl-4- (2-quinolylmethyl) -piperazine

[0258]

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N-quinolylmethylpiperazine 600 m
g, a solution of 20 ml of anhydrous tetrahydrofuran at −60 ° C.
Then, a mixed solution of 330 mg of acetyl chloride and 5 ml of anhydrous tetrahydrofuran was added dropwise over 10 minutes. -60
The mixture was stirred at ℃ for 1 hour, 10 ml of water was added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was distilled off under reduced pressure and extracted with chloroform. The organic layer was washed with an aqueous potassium carbonate solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 750 mg of the title compound as an oil. NMR δ: 7.32-8.20 (m, 6H), 4.01 (s, 2H), 3.20-3.90
(m, 6H), 2.30-2.74 (m, 4H). MS (m / e): 143 (M ⁺ -160).

The following compounds were synthesized using the same method. 1-Chloroacetyl-4- (4-chlorobenzyl) -piperazine MS (m / e): 286 (M ⁺ ), 125 (100%). 1-Chloroacetyl-4- [1- (4-fluorobenzyl) -2-methylbenzimidazole] -piperazine NMR δ: 6.66 to 7.40 (m, 8H), 5.44 (s, 2H), 3.95 (s, 2
H), 3.74 (s, 2H), 3.04-3.60 (m, 4H), 2.24-2.65 (m, 4
H). 1-Chloroacetyl-4-benzylpiperazine MS (m / e): 252 (M ⁺ ), 91 (100%). 1-Chloroacetyl-4-benzylpiperidine MS (m / e): 251 (M ⁺ ), 91 (100%). 1-chloroacetyl-4- (t-butyloxycarbonylaminobenzyl) -piperazine MS (m / e): 368 (M ⁺ ), 150 (100%).

Reference Example 14 Nt-butyloxycarbonyl-3- [4- (2-quinolylmethylpiperazin) -1-yl] -carbonylmethoxy-4-methoxybenzylamine

[0262]

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660 mg of t-butyloxycarbonyl-3-hydroxy-4-methoxybenzylamine, 10 ml of dimethylformamide, 510 mg of potassium carbonate,
A mixture of 750 mg of -chloroacetyl-4- (2-quinolylmethyl) -piperazine was heated at 80 ° C with stirring overnight. After filtering off insolubles, the reaction solution was distilled off under reduced pressure and extracted with chloroform. After washing with an aqueous potassium carbonate solution, the mixture was purified by silica gel column chromatography (ethyl acetate: methanol = 19: 1), and 1.2 g of the title compound was obtained as an oil.
I got NMR δ: 7.32-8.03 (m, 6H), 6.63-6.93 (m, 3H), 5.15
-5.50 (m, 1H), 4.64 (s, 2H), 4.16 (d, 2H), 3.38-3.93
(m, 9H), 2.30-2.73 (m, 4H), 1.43 (s, 9H). MS (m / e): 520 (M ⁺ ), 144 (100%).

The following compounds were synthesized using a similar method. Nt-butyloxycarbonyl-3- [4- (4-chlorobenzyl) -piperazin-1-yl] -carbonylmethoxy-4-methoxybenzylamine MS (m / e): 503 (M ⁺ ), 125 ( 100%). Nt-butyloxycarbonyl-3- [4- {1-
(4-Fluorobenzyl) -2-methylbenzimidazol {-piperazin-1-yl] -carbonylmethoxy-4-methoxybenzylamine NMR δ: 6.10-7.35 (m, 11H), 5.45 (s, 2H), 4.80-5.1
7 (m, 1H), 4.10 (s, 2H), 4.15 (d, 2H), 3.76 (s, 3H), 3.
70 (s, 12H), 3.26-3.65 (m, 4H), 2.27-2.65 (m, 4H). Nt-butyloxycarbonyl-3- (4-benzylpiperidin-1-yl) -carbonylmethoxy-4 -Methoxybenzylamine MS (m / e): 468 (M ⁺ ), 91 (100%). Nt-butyloxycarbonyl-3- (4-t-butyloxycarbonylaminobenzylpiperazin-1-yl)- Carbonylmethoxy-4-methoxybenzylamine MS (m / e): 585 (M ⁺ ), 150 (100%).

Reference Example 15 3- [4- (2-quinolylmethyl) -piperazine-1-
Yl] -carbonylmethoxy-4-methoxybenzylamine

[0266]

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T-butyloxycarbonyl-3- [4-
(2-quinolylmethyl) -piperazin-1-yl] -carbonylmethoxy-4-methoxybenzylamine 1.3
g, chloroform 15 ml and trifluoroacetic acid 2.8.
g mixture was stirred at room temperature day and night. 50 ml of chloroform and 50 ml of 0.5N hydrochloric acid were added to the reaction solution, and back-extraction was performed. The aqueous layer was adjusted to pH 12 with an aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was washed with an aqueous potassium carbonate solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 850 mg of the title compound as an oil. NMR δ: 7.39-8.20 (m, 6H), 6.72-7.0 (m, 3H), 4.7
(s, 2H), 3.40-4.00 (m, 11H), 2.32-2.70 (m, 4H), 2.05
(br. s, 2H). MS (m / e): 420 (M ⁺ ), 143 (100%).

The following compounds were synthesized using the same method. 3- [4- (4-chlorobenzyl) -piperazine-1-
Yl] -carbonylmethoxy-4-methoxybenzylamine MS (m / e): 403 (M ⁺ ), 125 (100%). 3- [3- {4- (4-fluorobenzyl) -piperazin-1-yl {-2,2-dimethylpropoxy] -4-
Methoxybenzylamine MS (m / e): 429 (M ⁺ ), 109 (100%). 3- (4-benzyl-piperidin-1-yl) -carbonylmethoxy-4-methoxybenzylamine MS (m / e) : 368 (M ⁺ ), 91 (100%). 3- [4- {1- (4-fluorobenzyl) -2-benzimidazolylmethyl} -piperazin-1-yl] -carbonylmethoxy-4-methoxybenzylamine MS (m / e): 517 (M ⁺ ), 109 (100%).

Synthesis Example 6 4-Chloro-5- [3- {4- (2-quinolylmethyl)
-Piperazin-1-yl} -carbonylmethoxy-4-
Methoxybenzylamino] -6-ethoxy-3 (2)-
Pyridazinone

[0270]

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3- [4- (2-quinolylmethyl) -piperazin-1-yl] -carbonylmethoxy-4-methoxybenzylamine 2.4 g, 4,5-dichloro-6-ethoxy-3 (2H) -pyridazinone 1 g 580 mg of triethylamine, 10 ml of propanol and 10 ml of water
The mixture was heated to reflux overnight with stirring. The solvent was distilled off under reduced pressure, and extracted with chloroform. The organic layer was washed with an aqueous potassium carbonate solution, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 6: 1 → chloroform: methanol = 12: 1), and crystallized from diethyl ether to give 1.5 g of the title compound as white crystals. Obtained. NMR δ: 7.40-8.28 (m, 6H), 6.72-7.05 (m, 3H), 4.62
-5.40 (m, 5H), 3.48-4.50 (m, 11H), 2.32-2.70 (m, 4H),
1.31 (t, 3H). MS (m / e): 592 (M ⁺ ), 143 (100%).

Reference Example 16 1-Formyl-4- (4-aminobenzyl) -piperazine

[0273]

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While cooling a mixture of 9 g of 1-formyl-4- (4-nitrobenzyl) -piperazine, 180 ml of methanol and 14.6 g of nickel chloride hexahydrate in an ice bath, 4.6 g of sodium borohydride was slowly added. added. The mixture was stirred at 0 ° C. for 30 minutes, and further stirred at room temperature for 30 minutes.
Stirred for minutes. The reaction solution was distilled off under reduced pressure, and the residue was dissolved by adding 200 ml of 10% hydrochloric acid.
After adjusting to H10, the mixture was extracted with ethyl acetate. After washing with a saturated saline solution, the solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from diethyl ether to give 8.0 g of the title compound as white crystals. NMR δ: 7.82 (s, 1H), 6.97 (d, 2H), 6.47 (d, 2H),
3.01-3.91 (m, 8H), 2.11-2.48 (m, 4H). MS (m / e): 263 (M ⁺ ), 218 (100%).

Reference Example 17 1-Formyl-4- (4-t-butyloxycarbonylaminobenzyl) -piperazine

[0276]

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A mixture of 4 g of 1-formyl-4-aminobenzylpiperazine, 50 ml of toluene and 4.8 g of di-t-butyl dicarbonate was heated under reflux for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 9: 1), and crystallized from diethyl ether to obtain 5.1 g of the title compound as white crystals. NMR δ: 7.87 (s, 1H), 6.97-7.42 (m, 5H), 3.15-3.65
(m, 6H), 2.15-2.57 (m, 4H), 1.45 (s, 9H). MS (m / e): 319 (M ⁺ ), 106 (100%).

Reference Example 18 1- (4-t-butyloxycarbonylaminobenzyl) -piperazine

[0279]

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4 g of 1-formyl-4- (t-butyloxycarbonylaminobenzyl) -piperazine was dissolved in 50 ml of methanol, an aqueous solution of 1.5 g of sodium hydroxide in 10 ml of water was added, and the mixture was heated at 60 ° C. for 5 hours. . The reaction solution was concentrated under reduced pressure and extracted with chloroform.
The organic layer was washed with an aqueous potassium carbonate solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 5: 1), and crystallized from diethyl ether to obtain 3.2 g of the title compound as white crystals. NMR δ: 7.0-7.7 (m, 5H), 3.38 (s, 2H), 2.60-3.12
(m, 4H), 1.90-2.60 (m, 5H), 1.50 (s, 9H). MS (m / e): 291 (M ⁺ ), 206, 106 (100%).

Synthesis Example 7 4-chloro-5- [3- (4- (4-aminobenzyl)
-Piperazin-1-yl) -carbonylmethoxy-4-
Methoxybenzylamino] -6-isopropoxy-3
(2H) -pyridazinone

[0282]

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1.6 g of 3- [4- (4-aminobenzyl) piperazin-1-yl] -carbonylmethoxy-4-methoxybenzylamine, 4,5-dichloro-6-isopropoxy-3 (2H) -pyridazinone A mixture of 770 mg, 460 mg of trimethylamine and 20 ml of methanol was heated to reflux for 2 days with stirring. The solvent was distilled off under reduced pressure, and extracted with chloroform. The organic layer was washed with an aqueous potassium carbonate solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 9: 1 → chloroform: methanol = 15: 1), and then crystallized from diethyl ether to give 1.6 g as white crystals.
The title compound was obtained. NMR δ: 6.55-7.15 (m, 7H), 4.45-5.33 (m, 6H), 3.13
-3.88 (m, 11H), 2.13-2.58 (m, 4H), 1.28 (d, 6H). MS (m / e): 465 (M ⁺ -106), 430, 106 (100%).

Synthesis Example 8 4-chloro-5- [3- {4- (4-N-formylbenzyl) -piperazin-1-yl} -carbonylmethoxy-4-methoxybenzylamino] -6-isopropoxy-3 (2H) -pyridazinone

[0285]

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4-Chloro-5- [3- (4-aminobenzyl) piperazin-1-yl] -carbonylmethoxy-
4-methoxybenzylamino-6-isopropoxy-3
400 mg of (2H) -pyridazinone was added to 3 m of phenyl formate.
and stirred at room temperature overnight. After evaporating the reaction solution under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) and crystallized from diethyl ether to obtain 380 mg of the title compound as white crystals. NMR δ: 11.75 (brs, 1H), 8.2-8.85 (m, 2H), 6.75-
7.62 (m, 7H), 4.58-5.30 (m, 6H), 3.77 (s, 3H), 3.20-
3.75 (m, 6H), 2.05-2.60 (m, 4H), 1.27 (d, 6H). MS (m / e): 464 (M ⁺ -134), 137 (100%).

Synthesis Example 9 4-Chloro-5- [3- {4- (4-N-acetylaminobenzyl) -piperazin-1-yl} -carbonylmethoxy-4-methoxybenzylamino] -6-isopropoxy- 3 (2H) -pyridazinone

[0288]

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4-Chloro-5- [3- (4-aminobenzyl) -piperazin-1-yl] -carbonylmethoxy-4-methoxybenzylamino-6-isopropoxy-
400 mg of 3 (2H) -pyridazinone is added to pyridine 400
The resulting solution was dissolved in acetic acid, and 220 mg of acetic anhydride was added, followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and extracted with chloroform. The organic layer was washed with an aqueous potassium carbonate solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1), and crystallized from diethyl ether to obtain 340 mg of the title compound as white crystals. NMR δ: 11.84 (br s, 1H), 8.24 (br s, 1H), 6.63-7.
52 (m, 8H), 4.52-5.30 (m, 6H), 3.30-3.92 (m, 9H), 2.0
-2.62 (m, 7H), 1.25 (d, 6H) MS (m / e):. 613 (M + + H), 466.

Synthesis Example 10 4-bromo-5- [3- {2- (4- (4-chlorobenzyl) -piperazin-1-yl) -ethoxy} -4-methoxybenzylamino] -3 (2H)- Pyridazinone hydrochloride (Compound No. 7)

[0291]

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4-bromo-5- [3- {2- (4- (4
-Chlorobenzyl) piperazin-1-yl) ethoxy}
4-methoxybenzylamino] -3 (2H) -pyridazinone in a mixture of 440 mg and chloroform 5 ml
0% methanolic hydrochloric acid is added until the pH becomes 2-3, and the mixture is stirred at room temperature for 2 hours. Diethyl ether was added to the reaction solution for crystallization to obtain 465 mg of the title compound as white crystals having a melting point of 176-183 ° C. MS (m / e): 562 (M ⁺ -2HCl), 482, 238, 223 (100%), 203,
125, 91.

Synthesis Example 11 4-bromo-5- [3- {2- (4- (4-chlorobenzyl) -piperazin-1-yl) -ethoxy} -4-methoxybenzylamino] -3 (2H)- Pyridazinone fumarate (Compound No. 8)

[0294]

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4-bromo-5- [3- {2- (4- (4
-Chlorobenzyl) -piperazin-1-yl) -ethoxy {-4-methoxybenzylamino] -3 (2H) -pyridazinone, a mixture of 163 mg of fumaric acid and 4 ml of chloroform were stirred at room temperature for 3 hours. The reaction solution was crystallized by adding diethyl ether, and the melting point was 178-18.
120 mg of the title compound was obtained as white crystals at 5 ° C. MS (m / e): 562 (M ⁺ -(CHCO ₂ H) ₂ ), 482, 237, 223, 125 (1
00%), 91.

Synthesis Example 12 4-bromo-5- [3- {2- (4- (4-chlorobenzyl) -piperazin-1-yl) -ethoxy} -4-methoxybenzylamino] -3 (2H)- Pyridazinone sulfate (Compound No. 9)

[0297]

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4-bromo-5- [3- {2- (4- (4
A mixture of -chlorobenzyl) -piperazin-1-yl) -ethoxy {-4-methoxybenzylamino] -3 (2H) -pyridazinone, 5 ml of methanol, 5 ml of chloroform and 140 mg of sulfuric acid was stirred at room temperature for 3 hours. The reaction solution was evaporated under reduced pressure, and the obtained residue was crystallized from isopropyl ether-diethyl ether to give the title compound 800 as white crystals having a melting point of 158-162 ° C.
mg was obtained. MS (m / e): 482 (M + -Br-H 2 SO 4), 238, 223 (100%), 125.

The compounds synthesized according to the above synthesis examples are shown in Table II.
It was shown to. The structures of the compounds are referred to by the compound numbers shown in Table I. In the rightmost column of the table, the numbers of synthesis examples applied mutatis mutandis are described.

[0300]

[Table 26] Table II 化合物 Compound No. Melting point (℃) MS ( m / e) Synthetic Example No. １1 Solid 424 ( M ⁺ -HCl), 100 (100%) 10 2 Solid 414 (M ⁺ -HCl), 100 (100%) 10 3 193-196 425 (M ⁺ -HCl), 86 (100%) 10 4 170- 180 483 (M ⁺ -2HCl), 91 (100%) 10 5 179 -186 527 (M ⁺ -2HCl), 190 (100%) 10 6 128-135 527 (M ⁺ -Q35), 203 (100%) 11 7 176-183 See Synthesis Example 10 10 8 178-185 See Synthesis Example 11 11 9 158-162 See Synthesis Example 12 12 10 159-163 517 (M ⁺ -2HCl), 125 (100%) 10 11 179-184 _{^{517 (M + -H 2 SO 4}} ), 125 (100%) 12 12 170-173 517 (M + -Q35), 125 (100%) 11 13 180-187 545 (M + -2HCl), 207 (100 %) 10 14 184-188 545 (M ⁺ -Q35), 109 (100%) 11 15 178-185 501 (M ⁺ -2HCl), 221 (100%) 10 16 217-22 1 501 (M ⁺ -Q35), 109 (100%) 11 17 157-162 573 (M ⁺ -2HCl), 221 (100%) 10 18 62-70 438 (M ⁺ -HCl), 86 (100%) 10 19 78-89 428 (M ⁺ -HCl), 86 (100%) 10 20 159 -168 421 (M ⁺ -2HCl), 113 (100%) 10 21 Solid 435 (M ⁺ -2HCl), 127 ( 100%) 10 22 173-177 541 (M ⁺ -2HCl), 91 (100%) 10 ──────────────────────────── ───────

[0301]

[Table 27] 化合物 Compound No. Melting point (° C) MS (m / e) Synthetic Example No. ─────────────────────────────────── 23 175-180 569 (M ⁺ -2HCl), 91 (100%) 10 24 201-205 542 (M ⁺ -2HCl), 91 (100%) 10 25 164-167 531 (M ⁺ -2HCl), 91 (100%) 10 26 Solid 515 (M ⁺ -2HCl), 109 (100%) 10 27 169 -172 543 (M ⁺ -2Q35), 109 (100%) 11 28 163-171 557 (M ⁺ -2Q35), 109 (100%) 11 29 Solid 576 (M ⁺ -2HCl), 125 (100%) 10 30 98-120 565 (M ⁺ -2HCl), 206 (100%) 10 31 143-148 429 (M ⁺ -HCl), 92 (100 %) 10 32 170-180 421 (M ⁺ -HCl), 140 (100%) 10 33 161-178 465 (M ⁺ -HCl), 140 (100%) 10 34 181-188 542 (M ⁺ -2HCl) , 92 (100%) 10 35 182-190 498 (M ⁺ -2HCl), 134 (100%) 10 36 110-116 497 (M ⁺ -Q36), 91 (100%) 11 37 177-180 497 (M ⁺ -HCl), 91 (100% ) 10 38 110-122 541 (M ⁺ -Q36), 91 (100%) 11 39 112-124 515 (M ⁺ -Q36), 109 (100%) 11 40 184-187 515 (M ⁺ -HCl), 109 (100%) 10 41 82-86 543 (M ⁺ -Q36), 234 (100%) 11 42 88-91 557 (M ⁺ -Q35), 522 (100%) 11 43 105-112 559 (M ⁺ -Q36), 109 (100%) 11 44 174-178 559 (M ⁺ -HCl), 109 (100%) 10 45 165-173 526 (M ⁺ -HCl), 92 (100%) 10 ──── ───────────────────────────────

[0302]

[Table 28] ─────────────────────────────────── Compound No. Melting point (° C) MS (m / e) Synthetic example No. ─────────────────────────────────── 46 162-168 449 (M ⁺ -HCl), 169 (100%) 10 47 136-138 525 (M ⁺ -HCl), 91 (100%) 10 48 130 -133 569 (M ⁺ -HCl), 91 (100%) 10 49 130- 135 553 (M ⁺ -HCl), 91 (100%) 10 50 134-135 515 (M ⁺ -44-Q35), 109 (100%) 10 51 133-137 10 52 128-129 529 (M ⁺ -Q35 ), 109 (100%) 10 53 134-135 531 (M ⁺ -2Q35), 207 (100%) 10 54 175-179 497 (M ⁺ -2Q35), 91 (100%) 10 55 195-196 515 ( M ⁺ -2Q35), 109 (100%) 10 56 126-129 557 (M ⁺ -Q35), 109 (100%) 10 57 142-144 543 (M ⁺ -2Q35), 109 (100%) 10 58 121 -125 564 (M ⁺ -2Q35), 109 (100%) 10 59 108 -110 548 (M ⁺ -2Q35), 143 (100%) 10 60 126 -128 646 (M ⁺ -2Q35), 109 (100% ) 10 61 113-117 5 48 (M ⁺ -Q35), 143 (100%) 10 62 98-103 496 (M ⁺ ), 91 (100%) 1 63 112-115 482 (M ⁺ -Q35), 91 (100%) 10 64 166 -171 558 (M ⁺ -1-Q35), 109 (100%) 10 65 162-163 545 (M ⁺ -2 Q35), 109 (100%) 10 66 174 -175 541 (M ⁺ -Q35), 91 ( 100%) 10 67 104-107 592 (M ⁺ -Q36), 143 (100%) 10 68 108 -110 573 (M ⁺ -Q35), 109 (100%) 10 ────────── ─────────────────────────

[0303]

[Table 29] ─────────────────────────────────── Compound No. Melting point (° C) MS (m / e) Synthetic example No. ─────────────────────────────────── 69 98-100 601 (M ⁺ -Q35), 109 (100%) 10 70 184-186 559 (M ⁺ -2Q35), 109 (100%) 10 71 118-119 592 (M ⁺ -2Q35), 143 (100%) 10 72 130- 132 690 (M ⁺ + 1-2Q35), 109 (100%) 10 73 106 -109 691 (M ⁺ + 1-Q35), 109 (100%) 10 74 80-83 540 (M ⁺ ) 6 75 105- 108 526 (M ⁺ -Q35), 91 (100%) 10 76 102 -103 573 (M ⁺ -Q35), 109 (100%) 10 77 94-96 615 (M ⁺ + 1-2Q35), 106 (100 %) 10 78 87-89 465 (M ⁺ -106), 106 (100%) 7 79 118 -121 599 (M ⁺ +1 -Q35), 106 (100%) 10 80 121 -123 613 (M ⁺ + 1-Q35), 106 (100%) 10 ───────────────────────────────────

Formulation Example 1 Tablet Compound No. 39 10 g Lactose 20 g Starch 4 g Starch (for glue) 1 g Magnesium stearate 0.1 g Carboxymethylcellulose calcium 7 g Total amount 42.1 g After mixing the above components by a conventional method, 50 mg per tablet Sugar-coated tablets containing the active ingredient of

Formulation Example 2 After mixing the above ingredients in a conventional manner, the mixture is filled into a gelatin capsule to give a capsule containing 50 mg of the active ingredient in one capsule.

Formulation Example 3 After mixing the above components, a soft capsule is prepared by a conventional method.

Formulation Example 4 The above components are mixed by a conventional method to prepare a 1% ointment.

Formulation Example 5 Aerosol suspension (A) 37 0.25% Isopropyl myristate 0.10% Ethanol 26.40% (B) Mixture of 60% to 40% of 1,2-dichlorotetrafluoroethane and 1-chloropentafluoroethane
73.25% The above composition (A) was mixed, and the resulting mixture was charged into a container equipped with a valve.
Pressurize from the valve nozzle to 2.81 mg / cm ² cage pressure to obtain an aerosol suspension.

Test Example I. Bronchodilation 1. in vitro inhibitory active agent was the test drug against LTD ₄ contracts with tracheal muscle specimen of the test guinea pig was 100% dimethyl sulfoxide (DMSO, Wako Junyaku) dissolved, be diluted. Leukotriene D ₄ (LTD
₄ , Ultrafine) and Isoprotereno (Isoprotereno)
l, Sigma) is diluted with distilled water. Indomethacin (Sigm
a) is dissolved in 100% ethanol (EtOH, Komune Chemical). Aminophylline (AP, Sigma), histamine (histam
ine dihydrochrolide, Wako Pure Chemicals) dissolves in distilled water. The final concentrations of DMSO and ethanol in the bath were each 0.1.
25, 0.1 v / v% or less.

Method 1-1 A 300-450 g guinea pig was killed by exsanguination, the trachea was excised, fat and connective tissue were removed, and the slice was cut into a spiral having a width of about 2 mm so as to contain four smooth muscle tissues. -Divided into three pieces. Specimens were suspended in an 8 ml organ bath containing modified-Tyrode's solution aerated at 37 ° C., 95% O ₂ + 5% CO ₂ and a 1 g load was applied. Muscle relaxation was recorded with a pen recorder (Yokogawa Hokushin Electric, Type 3066) via an isotonic transducer (Nihon Kohden, TD-112S).

The composition of the Modified-Tyrode solution is as follows (mM). NaCl 137, KCl 2.7, CaCl ₂ 1.8, MgCl ₂ 1.0, NaHCO ₃ 2
0, NaH ₂ PO ₄ 0.32, Glucose 11. After resting the sample for 50-60 minutes, Histamine dihydrochrol
After contraction at 100 μM ide and the reaction was constant, it was washed and rested for 20-30 minutes. After incubation for an additional 30 minutes added indomethacin 5μM, LTD ₄ 30 n
M was added and contracted. After a constant response, the test drug was applied cumulatively. Finally, 1 mM aminophylline was added to obtain a maximum relaxation reaction. The results indicate that the aminophylline relaxes by 10
The concentration (EC ₅₀ , μM) for relaxing by 50% was calculated by expressing the relaxation as 0%. In addition, aminophylline was used as a control drug. The results are shown in Table III-1.

[0312]

[Table 30]

Method 1-2 The same measurement method as in method 1-1 was used. Specimen 60-90
After resting for 1 minute, 1 μM of isoproterenol was added to relax. Specimens were washed and repeated at 30-40 minute intervals until a constant relaxation response was obtained, after which the test drug was applied cumulatively and relaxed. Finally, 1 mM aminophylline was added to obtain a maximum relaxation reaction. The results were expressed as a percentage of relaxation when the relaxation of aminophylline was defined as 100%, and the concentration (EC ₅₀ , μM) for relaxing by 50% was determined.
The final concentration of DMSO in the bath was 0.2 v / v%. Aminophylline was used as a control drug. Table II shows the results
Shown in I-2.

[0314]

[Table 31]

[0315] 2. In vivo test Effect of passively sensitized guinea pig on endogenous SRS-A-mediated airway constriction Rabbit anti-egg albumin (EA) serum (Capple) in penile vein of guinea pig (weight 350-450 g)
125 ml was administered for passive sensitization. One to two days after sensitization, airway constriction was induced by endogenous SRS-A that appeared upon antigen administration, and the inhibitory activity against the airway was examined.

The airway constriction was measured using Konzett & Roessler [Archive, Experimental, Path, Pharmacology]
(Arch. Exp. Path. Pharmakol.), 195, 71-7
See page 4, 1940. ] In the modified method. Anesthetized by intraperitoneally administering urethane (1.5 g / kg dose) to sensitized guinea pigs, inserting a cannula into the trachea and fixing it, then using a small animal respirator (manufactured by Shinano Seisakusho) and a differential pressure transducer (Nihon Kohden TP-602T) Connected.

Artificial respiration was performed at 50 strokes / min, 4.5
Perform positive pressure at the rate of ml / stroke, 3
After intravenous injection of various drugs, EA 0.2 mg / kg was administered via the jugular vein to induce airway constriction via endogenous SRS-A, and the amount of air overflow from the bypass was measured by a polygraph ( (Nihon Kohden WI-681C).

At the end of the experiment, the value when the trachea was completely occluded with Kochel was defined as the maximum contraction (100%), and the results were expressed as percentages. Indomethacin (2.0 mg / kg), pyrilamine (2.0 mg / kg) and propranolol (0.1 mg / kg) were administered from the jugular vein 10 minutes, 6 minutes and 5 minutes before the antigen administration. Test compound is 5%
It was suspended in gum arabic and orally administered 2 hours before the administration of the antigen, and the suppression (%) of airway constriction was determined as follows.

Inhibition of airway constriction (%) = {1- (maximum response (%) after administration of test compound / maximum response of control (%)} ×
100 The maximum response of the control in this test was 62 ± 6% (Mean ±
SEM; n = 6), the test was carried out on 5 to 6 cases, and the inhibition rate was represented by the average value of each. Test compound dose 30
The inhibition rate at mg / kg is shown in Table III-3.

[0320]

[Table 32]

II. Antiallergic ³ H- pyrilamine binding test using (histamine H ₁ receptor binding assay) Chang et al. Method [J. Neurochem., 32, 1653 ( 197
9)]. To a suspension of bovine cerebellum and 50 mM phosphate buffer (pH 7.5) was added pyrramine labeled with tritium, and the mixture was allowed to stand at 25 ° C. for 30 minutes. Measure performance.
Percent inhibition against H ₁ receptor in the test compound 10μM concentration was calculated by the following equation. Inhibition rate (%) = {1- (binding amount in the presence of drug−non-specific binding amount) / (total binding amount−non-specific binding amount)} × 100 (Note) The total binding amount is the test compound. ³ H-Pyrylamine binding radioactivity in the absence. The non-specific binding amount is ³ H-pyrylamine binding radioactivity in the presence of triprolidine at 10 μM. The results are shown in Table IV.

[0322]

[Table 33]

III. Platelet aggregation inhibitory activity Rabbit platelet aggregation inhibitory activity Nine volumes of blood were collected from an abdominal aorta of a Japanese white male rabbit (body weight 1.8-2.5 kg) using a syringe containing 1 volume of 3.8% sodium citrate. This is 200 × g, 7
After centrifugation at room temperature for minutes, platelet-rich plasma (PRP) was obtained. The residue was further centrifuged at 2,000 × g for 10 minutes to prepare platelet poor plasma (PPP). For the measurement, those diluted to 300,000 / mm ³ with PRP and PPP were used. P for coagulation cell
Put RP and PPP and set the transmittance measurement range to 0% for PRP, P
After the PP was adjusted to 100%, the test drug dissolved in 100% dimethyl sulfoxide (DMSO) was added to PRP (final concentration of DMSO was 0.25%). 37 ° C, 9
After incubation at 00 rpm for 2 minutes, an aggregating agent was added and the aggregation curve was recorded. A concentration that inhibits the aggregation inhibition effect of the test drug by 50% (IC ₅₀ : μ
M). The minimum concentration (5 to 10 μM) showing the maximum aggregation was used as the aggregating agent ADP. In addition, NBS HEMA TRACER 601 was used for platelet aggregation measurement. The results are shown in Table V.

[0324]

[Table 34]

[0325]

As is apparent from the above results, the compounds of the present invention have excellent bronchodilator, antiallergic and platelet aggregation inhibiting effects. Further, the compound of the present invention shows strong pharmacological activity even in oral administration, so bronchial asthma,
Immediate allergic diseases such as allergic rhinitis, urticaria and hay fever, various inflammatory diseases such as rheumatoid arthritis and spondyloarthritis, ischemic diseases such as angina pectoris and myocardial infarction, and diseases such as thrombotic diseases Can be a useful prophylactic and therapeutic agent.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 11/08 A61P 11/08 37/08 37/08 C07D 401/12 C07D 401/12 403/12 403/12 (56) Reference Document JP-A-63-301870 (JP, A) JP-A-62-30769 (JP, A) JP-A-61-267560 (JP, A) International Publication No. 91/16314 (WO, A1) (58) Fields investigated (Int.Cl. ⁷ , DB name) C07D 237/22 A61K 31/50 A61K 31/501 A61K 31/505 A61P 7/02 A61P 11/08 A61P 37/08 C07D 401/12 C07D 403/12 CA (STN) REGISTRY (STN)

Claims (10)

(57) [Claims] 1. A compound of the general formula [I] Wherein R ¹ , R ² and R ³ are each independently a hydrogen atom or
It represents a C _1-4 alkyl group. X represents a chlorine atom or a bromine atom. Y ¹ represents a hydrogen atom, a halogen atom, a nitro group, an amino group, or a C _1-4 alkoxy group. Y ² represents a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-4 alkyl group or a C _1-4 alkoxy group. A represents a C _1-5 alkylene chain which may be substituted with a hydroxyl group. B represents a methylene chain which may be substituted with a carbonyl or C _1-4 alkyl group. R ⁴ and R ⁵
Is a R ⁴ is a hydrogen atom, an alkylene chain of R ⁵ is -Z-Ar (Z is C _1-5, Ar is an aromatic also contain a nitrogen atom 6
Shows a member ring. ) Or R ⁴ and R ⁵ together form C _2-6
To form a cyclic alkylene or with a nitrogen atom {R ⁶ is, C _1-4 alkyl group (the alkyl group, C _1-4 alkyl group, a phenyl group (Y ³ may be substituted with Y ³ represents a hydrogen atom, a halogen atom, C _1-4 An alkyl group, a C _1-4 alkoxy group, an amino group, an N-formyl group or a C _1-4 alkylcarbonylamino group.), (R ⁷ and R ⁸ each represent a hydrogen atom or a benzene ring together with the carbon atom to which each is attached. A, B, C and D
Represents a nitrogen atom or a carbon atom each independently. ) And (Y ³ is the same as above. R ⁹ represents a C _1-4 alkyl group or a C _1-4 alkyl group, a C _1-4 alkoxy group or a benzyl group which may be substituted on a benzene ring with a halogen atom. May be substituted with one or more substituents in the group of substituents. ) Or -COR ¹⁰ (R ¹⁰ represents a hydrogen atom or a C _1-4 alkyl group). 4- represented by｝
Forming a substituted piperazine ring, or {R ¹¹ is, C _1-4 alkyl group (said alkyl group, a phenyl group (Y ³ may be substituted with Y ³ are the same.) And one of the substituent group of the hydroxyl or May be substituted by a substituent). To form a 4-substituted piperidine represented by｝. 3 (2H) -pyridazinone derivatives or salts thereof. 2. The 3 (2H) -pyridazinone derivative or a salt thereof according to claim 1, wherein R ² and R ³ are a hydrogen atom, and Y ¹ is a hydrogen atom, a halogen atom, a nitro group or a C _1-4 alkoxy group. 3. R ⁴ and R ⁵ together with the nitrogen atom to which each is attached [R ¹² is, C _1-4 alkyl group {said alkyl group, C _1-4 alkyl group, a phenyl group which may be substituted with Y ³ (Y ³ is
It represents a hydrogen atom, a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, an amino group, an N-formyl group or a C _1-4 alkylcarbonylamino group. ), (R ⁷ and R ⁸ each represent a hydrogen atom or a benzene ring together with the carbon atom to which each is attached. A, B, C and D
Represents a nitrogen atom or a carbon atom each independently. ) And (Y ³ is the same as above. R ⁹ represents a C _1-4 alkyl group or a C _1-4 alkyl group, a C _1-4 alkoxy group or a benzyl group which may be substituted on a benzene ring with a halogen atom. May be substituted with one or more substituents. ｝ Or -COR ¹⁰ (R ¹⁰ is a hydrogen atom or C
Represents an _1-4 alkyl group. ). To form a 4-substituted piperazine ring represented by the formula: [R ¹¹ is, C _1-4 alkyl group {said alkyl group, Y ³ which may be substituted with a phenyl group (Y ³ are as defined above.) And one of the hydroxyl substituents or more substituent May be substituted by a group. Represents｝. The 3 (2H) -pyridazinone derivative or a salt thereof according to claim 2, which forms a 4-substituted piperidine represented by the following formula: 4. R ⁴ and R ⁵ together with the nitrogen atom to which each is attached [R ¹³ is a methyl group {said methyl group, a phenyl group (Y ³ may be substituted with Y ³ represents a hydrogen atom, a halogen atom,
It represents a C _1-4 alkyl group, a C _1-4 alkoxy group, an amino group, an N-formyl group or a C _1-4 alkylcarbonylamino group. ), Embedded image (R ⁷ and R ⁸ each represent a hydrogen atom or a benzene ring together with the carbon atom to which each is attached. A, B, C and D
Represents a nitrogen atom or a carbon atom each independently. ) And (Y ³ is the same as above. R ⁹ represents a C _1-4 alkyl group or a C _1-4 alkyl group, a C _1-4 alkoxy group or a benzyl group which may be substituted on a benzene ring with a halogen atom. May be substituted with one or more substituents in the group of substituents. Represents — or —COR ¹⁰ (R ¹⁰ represents a hydrogen atom or a C _1-4 alkyl group). 4-
The 3 (2H) according to claim 3, which forms a substituted piperazine ring.
-A pyridazinone derivative or a salt thereof. 5. The 3 (2H) -pyridazinone derivative according to claim 4, wherein Y ² is a halogen atom or a C _1-4 alkoxy group.
Or a salt thereof. 6. R ⁴ and R ⁵ together with a nitrogen atom [R ¹⁴ is (Y ⁴ represents a hydrogen atom, a halogen atom, an amino group, an N-formyl group or a C _1-4 alkylcarbonylamino group.), (R ¹⁵ represents a benzyl group which may be substituted with a halogen atom.) 6. The method according to claim 5, wherein
(2H) -pyridazinone derivatives or salts thereof. 7. A compound of the general formula [II] [In the formula, R ¹ represents a hydrogen atom or a C _1-4 alkyl group. X
Represents a chlorine atom or a bromine atom. Y ¹ represents a hydrogen atom, a halogen atom, a nitro group, an amino group, or a C _1-4 alkoxy group. 4,5-dihalo-3 (2H) -pyridazinone compound represented by the general formula [III]: Wherein R ² and R ³ are each independently a hydrogen atom or C _1-4
Shows an alkyl group. Y ² represents a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-4 alkyl group or a C _1-4 alkoxy group. A
_Represents a C _1-5 alkylene chain which may be substituted with a hydroxyl group. B represents a methylene chain which may be substituted with a carbonyl or C _1-4 alkyl group. R ⁴ and R ⁵ are such that R ⁴ is a hydrogen atom, R ⁵ is —Z—Ar (Z is a C _1-5 alkylene chain, and Ar is an aromatic 6 which may contain a nitrogen atom.
Shows a member ring. ) Or R ⁴ and R ⁵ together form C _2-6
Or together with a nitrogen atom {R ⁶ is, C _1-4 alkyl group (the alkyl group, C _1-4 alkyl group, a phenyl group (Y ³ may be substituted with Y ³ represents a hydrogen atom, a halogen atom, C _1-4 An alkyl group, a C _1-4 alkoxy group, an amino group, an N-formyl group or a C _1-4 alkylcarbonylamino group.), (R ⁷ and R ⁸ each represent a hydrogen atom or a benzene ring together with the carbon atom to which each is attached. A, B, C and D
Represents a nitrogen atom or a carbon atom each independently. ) And (Y ³ is the same as above. R ⁹ represents a C _1-4 alkyl group or a benzyl group which may be substituted on the benzene ring by a C _1-4 alkyl group, a C _1-4 alkoxy group or a halogen atom. May be substituted with one or more substituents in the group of substituents. ) Or -COR ¹⁰ (R ¹⁰ represents a hydrogen atom or a C _1-4 alkyl group). 4- represented by｝
Forming a substituted piperazine ring, or {R ¹¹ is, C _1-4 alkyl group (said alkyl group, a phenyl group (Y ³ may be substituted with Y ³ are the same.) And one of the substituent group of the hydroxyl or May be substituted by a substituent). To form a 4-substituted piperidine represented by｝. 3) wherein the alkoxybenzylamine derivative or a salt thereof is reacted in the presence of a deoxidizing agent if necessary.
-A method for producing a pyridazinone derivative or a salt thereof. 8. A bronchodilator comprising the 3 (2H) -pyridazinone derivative or a salt thereof according to claim 1 as an active ingredient. 9. An antiallergic agent comprising the 3 (2H) -pyridazinone derivative or a salt thereof according to claim 1 as an active ingredient. 10. An antiplatelet agent comprising the 3 (2H) -pyridazinone derivative or a salt thereof according to claim 1 as an active ingredient.