JP2949473B2 - Triazolopyridazine derivative its production, intermediate and agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel triazolopyridazine derivative having excellent antiallergic action, antiinflammatory action, anti-PAF (platelet activating factor) action, eosinophil chemotaxis inhibitory action and the like, and its production. Laws and agents.

[0002]

2. Description of the Related Art At present, many compounds having a triazolopyridazine skeleton have been synthesized as drugs against various diseases, and US Pat. No. 3,915,968 discloses that
formula

Embedded image Wherein each R and R ³ is a hydrogen atom or a lower alkyl (at least one is lower alkyl of R and R ^3), R ¹
And R ² together with a nitrogen atom represent a heterocyclic group selected from pyrrolidine, piperidine, piperazine or morpholine. Or a salt thereof, USP 4,
In 136 and 182, the formula

Embedded image [In the formula, R represents a hydrogen atom, phenyl or lower alkylcarbonylamino, R ¹ represents morpholino or piperidino, and R ² represents a hydrogen atom or lower alkyl. However,
When at least one of R and R ² is a group other than a hydrogen atom, and R is phenyl, R ¹ is morpholino and R ²
Is lower alkyl. Or a salt thereof, and JP-A-62-292784 discloses a compound represented by the formula

Embedded image It has been disclosed that the compound represented by or a salt thereof is useful as a bronchodilator for reducing bronchospasm.

[0003] Further, EP562439 includes a formula

Embedded image [Wherein, R ¹ is a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom, R ² and R ³ are a hydrogen atom or a lower alkyl group which may have a substituent, or R ² and R ³ may form a 5- to 7-membered ring together with adjacent —C ＝ C—, X is an oxygen atom or S (O) p (p is an integer of 0 to 2), Y Is the expression

Embedded image (R ⁴ and R ⁵ each represent a hydrogen atom or a lower alkyl group which may have a substituent) or a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent R ⁶ and R ⁷ each have a hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent or a substituent, May be an aryl group, or R ⁶ and R ⁷ may form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom, m is an integer of 0 to 4, and n is Indicates an integer of 0 to 4. Or a salt thereof, and one of synthetic examples

Embedded image It is disclosed that the compound has an anti-asthmatic action, an anti-PAF action, an anti-inflammatory action, and an anti-allergic action.

[0004]

There is a need for the development of new compounds that are more satisfactory in terms of effect, sustainability, safety and the like than conventional anti-asthmatics, anti-allergics and the like.

[0005]

Means for Solving the Problems The present inventors have conducted various studies and found that [1,2,4] triazolo [1,5-
b] a general formula having a major chemical structural feature in which the 8-position of the pyridazine skeleton is unsubstituted and has a polycarbon alkyl group at the 7-position.

Embedded image [In the formula, R ¹ is a hydrogen atom, a halogen atom or a lower alkyl group which may have a substituent, and R ² has a polycarbon alkyl group or a substituent which may have a substituent. A cycloalkyl group, X is an oxygen atom or S (O) p (p is an integer of 0 to 2), and Y is (i)

Embedded image (R ³ and R ⁴ each represent a hydrogen atom or a lower alkyl group which may have a substituent) or (ii) a cycloalkylene group or a substituent which may have a substituent R ⁵ and R ⁶ are each a hydrogen atom, a lower alkyl group which may have a substituent or a cycloalkyl group which may have a substituent, or R ⁵ and R ⁶ are adjacent to each other. May form a nitrogen-containing heterocyclic group which may have a substituent together with the nitrogen atom to be formed, and m and n each represent an integer of 0 to 4. The first production of a novel [1,2,4] triazolo [1,5-b] pyridazine compound or a salt thereof represented by the following formula: Allergic, anti-inflammatory, anti-PA
F action, eosinophil chemotaxis inhibitory action and excellent persistence,
Shows safety and suppresses bronchospasm and bronchoconstriction.It is used as an effective anti-asthmatic agent.Also, it is used as a prophylactic and therapeutic agent for allergic rhinitis and atopic dermatitis based on eosinophil chemotaxis. Have been found to be used, and based on these, the present invention has been completed. That is, the present invention relates to (1) Compound [I] or a salt thereof,

(2) The compound according to the above (1), wherein R ¹ is a hydrogen atom or a C _1-6 alkyl group, and (3) the above (1), wherein the polycarbon alkyl group is a lower alkyl group having 2 or more carbon atoms. (4) The compound according to (3), wherein the lower alkyl group is a branched C _3-6 alkyl group.
(5) Y is

Embedded image (R ^3a and R ^4a each represent a hydrogen atom or a C _1-6 alkyl group).
R ⁵ and R ⁶ are each a hydrogen atom or a C _1-6 alkyl group, the compound according to the above (1), (7) R ¹ is a hydrogen atom, R ² is a C _2-6 alkyl group, X is an oxygen atom, Y is

Embedded image Wherein R ^3b and R ^4b each represent a C _1-6 alkyl group, R ⁵ and R ^{6 each} represent a hydrogen atom or a C _1-6 alkyl group, and m and n each represent 1 or 2.
(8) The compound according to (7), wherein R ² is a branched C _3-6 alkyl group, (9) the compound according to (7), wherein R ⁵ and R ⁶ are hydrogen atoms, and m and n are 1. The compound according to (8), (10) the compound according to (8), wherein the C _3-6 alkyl group is an isopropyl group, and (11) the compound according to (11), wherein the C _3-6 alkyl group is t.
The compound according to the above (8), which is an ert-butyl group, (1
2) 6- (2,2-dimethyl-3-sulfamoyl-1)
-Propoxy) -7-ethyl [1,2,4] triazolo [1,5-b] pyridazine or a salt thereof, the compound according to the above (1),

(13) 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-n-propyl [1,2,4] triazolo [1,5-b] pyridazine or a salt thereof The compound of the above (1), (14) 6-
The compound according to the above (1), which is (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine or a salt thereof, (15) ) The compound according to the above (1), which is 6- (2,2-diethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine or a salt thereof. , (1
6) 6- (2,2-dimethyl-3-sulfamoyl-1)
-Propoxy) -7-isobutyl [1,2,4] triazolo [1,5-b] pyridazine or a salt thereof according to the above (1), (17) 6- (2,2-dimethyl-3-) Sulfamoyl-1-propoxy) -7-tert-
The compound according to the above (1), which is butyl [1,2,4] triazolo [1,5-b] pyridazine or a salt thereof, (1)
8) 6- (2,2-diethyl-3-sulfamoyl-1)
-Propoxy) -7-tert-butyl [1,2,4] triazolo [1,5-b] pyridazine or a salt thereof, the compound according to the above (1),

(19) General formula

Embedded image Or a salt thereof and a general formula

Embedded image Or a salt thereof [wherein, Z ¹ and Z ² are groups which react and leave together, and other symbols are as defined in the above (1). And (20) a method for producing the compound according to the above (1),

Embedded image [Wherein, W is a leaving group, and other symbols are as defined in the above (1). Or a salt thereof, (2)
1) a pharmaceutical composition comprising the compound of the above (1), (2)
2) an anti-PAF agent comprising the compound of (1),
3) an eosinophil chemotaxis inhibitor comprising the compound of (1), (24) an anti-asthmatic agent comprising the compound of (1),
(25) An antiallergic agent containing the compound according to (1), (26) a preventive or therapeutic agent for allergic rhinitis containing the compound according to (1), and (27) an atopic skin containing the compound according to (1). It relates to an agent for preventing and treating inflammation. Further, when compound [I] or a salt thereof contains an asymmetric carbon in the structure, an optically active compound and a racemic mixture are also included in the scope of the present invention.

As used herein, the term "lower alkyl group" means, for example, a linear or branched C _1-6 alkyl group. As the C _1-6 alkyl group,
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like are used. The term “cycloalkyl group” as used herein means, for example, a C _3-6 cycloalkyl group. As the C _3-6 cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like are used. As used herein, the term “polycarbonalkyl group” refers to, for example, an alkyl group having 2 or more carbon atoms. Preferably, a linear or branched C _2-6 alkyl group (for example, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.) and the like are widely used. Groups (e.g., isopropyl, isobutyl, tert-butyl, etc.) are preferred. Examples of the substituent which the “lower alkyl group”, “cycloalkyl group” and “polycarbon alkyl group” may have include, for example, a hydroxy group, an amino group, a carboxyl group, a nitro group,
Mono - or di - lower alkylamino group (e.g., methylamino, ethylamino, propylamino, dimethylamino, mono diethylamino - like or di -C _1-6 alkylamino group), lower alkoxy (e.g., methoxy, C _1-6 alkoxy groups such as ethoxy, propoxy, hexyloxy, etc.), lower alkylcarbonyloxy groups (eg, C _1-6 alkylcarbonyloxy groups such as acetoxy, ethylcarbonyloxy, etc.) and halogen atoms (eg, fluorine, One to four selected from chlorine, bromine, iodine, etc.) are used. As the term "halogen atom" used in the present specification, for example, fluorine, chlorine, bromine, iodine and the like are used.

As used herein, the term "cycloalkylene group" refers to a divalent radical obtained by removing two hydrogen atoms bonded to two different carbon atoms of a 3- to 7-membered cycloalkane, for example. Group, etc. As used herein, “cycloalkylidene group” refers to a group attached to one carbon atom of, for example, a 3- to 7-membered cycloalkane.
And a divalent group obtained by removing two hydrogen atoms. Specifically, for example,

Embedded image Etc. are used, and preferably,

Embedded image Are commonly used. As used herein, the term “nitrogen-containing heterocyclic group” includes, for example, one nitrogen atom in addition to a carbon atom, and further includes, for example, one to three nitrogen atoms, oxygen atoms, sulfur atoms, and the like. And a group obtained by removing a hydrogen atom bonded to a nitrogen atom of a 3- to 13-membered nitrogen-containing heterocyclic ring which may contain a hetero atom. Specifically, for example,

Embedded image A 3- to 9-membered nitrogen-containing heterocyclic group such as is commonly used.

Examples of the substituent which the "cycloalkylene group", "cycloalkylidene group" and "nitrogen-containing heterocyclic group" may have include, for example, lower alkyl groups (for example, methyl, ethyl, propyl, isopropyl, A C _1-6 alkyl group such as butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.), an amino group, a mono- or di-lower alkylamino group (for example, a monoalkyl such as methylamino, ethylamino, dimethylamino, diethylamino, etc.) — Or di-C _1-6 alkylamino group, etc., hydroxyl group, carboxyl group, nitro group, lower alkoxy group (for example, methoxy, ethoxy, propoxy, etc.
_1-6 alkoxy group) and a halogen atom (for example,
1 selected from fluorine, chlorine, bromine, iodine, etc.)
Or three are used.

In the above formula, R ¹ represents a hydrogen atom, a halogen atom or a lower alkyl group which may have a substituent. Here, as the halogen atom and the lower alkyl group which may have a substituent represented by R ¹ , the same as the above-mentioned halogen atom and the lower alkyl group which may have a substituent are used. As R ¹ , for example, a hydrogen atom or a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.) is preferable, and a hydrogen atom is particularly widely used. In the above formula, R ² represents a polycarbonalkyl group which may have a substituent or a cycloalkyl group which may have a substituent. Here, examples of the optionally substituted polycarbon alkyl group represented by R ² and the optionally substituted cycloalkyl group include the above-mentioned optionally substituted polycarbon. The same ones as the alkyl group and the cycloalkyl group which may have a substituent are used. As R ² , for example, a branched C _3-6 alkyl group (eg, isopropyl, isobutyl, tert-butyl, etc.) is preferable, and particularly, an isopropyl group, a tert-butyl group, etc. are widely used. preferable. In the above formula, X represents an oxygen atom or S (O) p (p represents an integer of 0 to 2). X is preferably, for example, an oxygen atom or S, and particularly an oxygen atom is generally used.
In the above formula, Y is (i)

Embedded image (R ³ and R ⁴ each represent a hydrogen atom or a lower alkyl group which may have a substituent) or (ii) a cycloalkylene group or a substituent which may have a substituent Represents a good cycloalkylidene group. Here, as the optionally substituted lower alkyl group represented by R ³ and R ⁴ , the optionally substituted cycloalkylene group or cycloalkylidene group represented by Y, the above-mentioned substituted The same thing as the lower alkyl group which may have a group, the cycloalkylene group which may have a substituent, or the cycloalkylidene group is used. Y
Is, for example, the formula

Embedded image (R ^3a and R ^4a each represent a hydrogen atom or a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, etc.). More preferably, for example,

Embedded image (R ^3b and R ^4b are each a C, such as methyl, ethyl, etc.
_1-4 alkyl group) is widely used. It is also preferable that Y is a cycloalkylene group or a cycloalkylidene group, and among them, a cycloalkylidene group is preferable.

Embedded image Are commonly used, especially

Embedded image Is most preferred.

In the above formula, R ⁵ and R ⁶ are each a hydrogen atom, a lower alkyl group which may have a substituent or a cycloalkyl group which may have a substituent, or R ⁵ and R ⁶ are A nitrogen-containing heterocyclic group which may have a substituent may be formed together with an adjacent nitrogen atom. A lower alkyl group which may have a substituent represented by R ⁵ and R ⁶ , a cycloalkyl group which may have a substituent,
Examples of the nitrogen-containing heterocyclic group which may have a substituent formed by ⁵ and R ⁶ together with an adjacent nitrogen atom include the above-mentioned lower alkyl group which may have a substituent and a substituent. The same as the cycloalkyl group which may be substituted and the substituted heterocyclic group which may have a substituent are used. As R ⁵ and R ⁶ , for example, a hydrogen atom, C _1-3 alkyl (eg, methyl, ethyl, propyl, isopropyl, etc.) are preferable, and a hydrogen atom and the like are particularly widely used. In the above formula, m represents an integer of 0 to 4. As m,
An integer of 1 to 4 is preferred, and particularly when it is 1 or 2, it is widely used. In the above formula, n represents an integer of 0 to 4. n is preferably an integer of 1 to 4,
Especially when it is 1 or 2, it is widely used. Above all, m
Most preferably, n and n are both 1.

As the compound [I] or a salt thereof, R ¹ is a hydrogen atom, R ² is a C _2-6 alkyl group, X is an oxygen atom, and Y is a compound of the formula

Embedded image (R ^3b and R ^4b each represent a C _1-6 alkyl group), R ⁵ and R ⁶ are preferably a hydrogen atom or a C _1-6 alkyl group, and m and n are preferably 1 or 2, respectively. For example, 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-ethyl [1,2,
4] triazolo [1,5-b] pyridazine or a salt thereof, 6- (2,2-dimethyl-3-sulfamoyl-1)
-Propoxy) -7-n-propyl [1,2,4] triazolo [1,5-b] pyridazine or a salt thereof, 6- (2,
2-dimethyl-3-sulfamoyl-1-propoxy)
-7-isopropyl [1,2,4] triazolo [1,5-
b] pyridazine or a salt thereof, 6- (2,2-diethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine or a salt thereof, 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-isobutyl [1,2,
4] triazolo [1,5-b] pyridazine or a salt thereof, 6- (2,2-dimethyl-3-sulfamoyl-1)
-Propoxy) -7-tert-butyl [1,2,4] triazolo [1,5-b] pyridazine or a salt thereof or 6-
(2,2-Dimethyl-3-sulfamoyl-1-propoxy) -7-tert-butyl [1,2,4] triazolo [1,5-b] pyridazine or a salt thereof is more preferable. Examples of the salt of the compound [I] of the present invention include salts with inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid) and organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid, Maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) and the like are used, and physiologically acceptable acid addition salts are particularly preferable. Further, when the compound [I] of the present invention has an acidic group such as -COOH as a substituent, the compound [I] may be an inorganic base (for example, an alkali metal such as sodium, potassium, calcium, or magnesium or an alkaline earth). A salt may be formed with a similar metal, ammonia, etc.) or an organic base (eg, tri-C _1-3 alkylamine such as triethylamine).

Next, a method for producing the compound [I] of the present invention or a salt thereof will be described. The compound [I] of the present invention or a salt thereof is represented by the following general formula (A):

Embedded image Or a salt thereof and a general formula

Embedded image [The symbols in the formula are as defined above. Or a salt thereof. The leaving group represented by Z ¹ includes, for example, a halogen atom (eg, chlorine, bromine, iodine), a C _6-10 arylsulfonyloxy group (eg, benzenesulfonyloxy, p-tolylsulfonyloxy), C _1-4 An alkylsulfonyloxy group (for example, methanesulfonyloxy) and the like are used. When X is an oxygen atom or a sulfur atom, the group capable of reacting with and leaving Z ¹ represented by Z ² includes, for example, a hydrogen atom or sodium,
An alkali metal such as potassium is used, and X is -S
O- or -SO ₂ - if it is, for example sodium, an alkali metal such as potassium is used. In this reaction, the compound [III] or a salt thereof is used in an amount of usually 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of the compound [II] or a salt thereof. This reaction is usually carried out in the presence of a base, such as alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal alkoxides such as sodium methoxide and sodium ethoxide, and water. Alkali metal hydroxides such as sodium oxide and potassium hydroxide,
Carbonates such as sodium carbonate and potassium carbonate are used. In addition, this reaction involves alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile;
The reaction can also be carried out in an inert solvent such as amides such as dimethylformamide and dimethylacetamide, and sulfoxides such as dimethylsulfoxide. The reaction temperature is
Usually 10 to 200 ° C., preferably 50 to 100
° C. The reaction time is generally 30 minutes to 24 hours, preferably 1 to 6 hours.

The compound [I] of the present invention or a salt thereof is represented by the following general formula (B):

Embedded image [The symbols in the formula are as defined above. A compound represented by the general formula

Embedded image [The symbols in the formula are as defined above. Or a salt thereof. In this reaction, compound [IV] or a salt thereof 1
The compound [V] or a salt thereof is generally used in an amount of 1 to 5 mol, preferably 1 to 2 mol, per mol. This reaction is usually carried out in the presence of a base, such as an alkali metal hydride such as sodium hydride or potassium hydride, an alkali metal alkoxide such as sodium methoxide or sodium ethoxide, or water. Alkali metal hydroxides such as sodium oxide and potassium hydroxide, and carbonates such as sodium carbonate and potassium carbonate are used. Further, the reaction is carried out in alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, nitriles such as acetonitrile, and amides such as dimethylformamide and dimethylacetamide. And an inert solvent such as sulfoxides such as dimethyl sulfoxide. The reaction temperature is generally 10 to 200 ° C, preferably 50 to 1 ° C.
50 ° C. The reaction time is generally 30 minutes to 24 hours, preferably 1 to 10 hours.

Further, the compound [I] or a salt thereof is represented by the general formula (C):

Embedded image [Wherein, W is a leaving group, and other symbols are as defined above. A compound represented by the general formula

Embedded image [The symbols in the formula are as defined above. Or a salt thereof. Examples of the leaving group represented by W include a halogen atom (eg, chlorine, bromine, iodine), a C _6-10 arylsulfonyloxy group (eg, benzenesulfonyloxy, p-tolylsulfonyloxy), C _1-4. Alkylsulfonyloxy group (for example, methanesulfonyloxy)
And the like, and among them, a halogen atom (eg, chlorine, bromine, iodine) and the like are preferable. In this reaction,
Compound [VI] or compound [VI per 1 mol of a salt thereof
I] or a salt thereof is generally used in an amount of 1 to 5 mol, preferably 1 to 2 mol. This reaction is usually carried out with methanol,
Alcohols such as ethanol, ethers such as dioxane and tetrahydrofuran, benzene, toluene,
The reaction can be performed in an inert solvent such as aromatic hydrocarbons such as xylene, nitriles such as acetonitrile, amides such as dimethylformamide and dimethylacetamide, and sulfoxides such as dimethylsulfoxide.

The reaction temperature is usually -20 to 100 ° C,
Preferably it is −10 to 50 ° C. The reaction is usually 3
0 minutes to 5 hours, preferably 1 to 3 hours.
The compound [I] thus obtained can be converted into a salt according to a conventional method when it is in a free form, and can be converted into a free form or another salt according to a conventional method when a salt is formed. Compound (I) or a salt thereof thus obtained is
Known means, such as solvent extraction, liquid conversion, phase transfer, salting out,
It can be isolated and purified by crystallization, recrystallization, chromatography and the like. When the compound [I] or a salt thereof is an optically active compound, d is obtained by ordinary optical resolution means.
Body, l-body. Next, starting compounds [II], [II
The method for producing [I], [IV], [V], [VI] and [VII] or salts thereof will be described. Examples of salts of these compounds include salts with inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid) and organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid) acid,
Salts with tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) and the like are used. In addition, these compounds may have -COO as a substituent.
When having an acidic group such as H, an inorganic base (for example,
It may form a salt with an alkali metal or alkaline earth metal such as sodium, potassium, calcium and magnesium, ammonia) or an organic base (for example, tri-C _1-3 alkylamine such as triethylamine).

The starting compound [II] or a salt thereof can be prepared, for example, by the method described in Journal of Organic Chemistry (J. Or
g. Chem.) 39, 2143 (1987) or a method analogous thereto. The raw material compound [III] or a salt thereof and the compound [V] or a salt thereof can be obtained, for example, by using Chem. Ber.
91, 2130 (1958), Journal of Organic Chemistry (J. Org. Chem.) 52
Vol., P. 2162 (1987), JP-A-3-2232
87 and the like or a method analogous thereto. The starting compound [IV] or a salt thereof can be produced, for example, by the method described in JP-A-3-223287 or a method analogous thereto. The starting compound [VI] or a salt thereof can be produced, for example, by using the compound [1]
I] or its salt and formula

Embedded image [The symbols in the formula are as defined above. Or (2) compound (IV) or a salt thereof with a compound of the formula

Embedded image [The symbols in the formula are as defined above. And the like.
In the reaction (1), the compound [VIII] is used in an amount of usually 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of the compound [II] or a salt thereof. This reaction can be carried out in the same manner as in the above-mentioned reaction between compound [II] or a salt thereof and compound [III] or a salt thereof. In the reaction (2), the compound [IV] or a salt thereof 1
The compound [IX] is generally used in an amount of 1 to 5 mol, preferably 1 to 2 mol, per mol. This reaction can be carried out in the same manner as in the above-mentioned reaction between compound [IV] or a salt thereof and compound [V] or a salt thereof. The starting compound [VII] or a salt thereof, the starting compound [VIII] and the starting compound [IX] can be produced by a method known per se or a method analogous thereto. The salt that the starting compound may form is not particularly limited as long as the object is achieved, and for example, the same salts as the salts that the compound [I] may form can be used.

The thus obtained starting compounds or salts thereof can be isolated and purified by known means such as solvent extraction, liquid conversion, phase transfer, salting out, crystallization, recrystallization, chromatography and the like. May be used as a raw material in the next step as it is as a reaction mixture without isolation. In each of the reactions of the present invention and each of the reactions for synthesizing the starting material, when the starting compound has an amino group, a carboxyl group, or a hydroxyl group as a substituent, such a group is generally used in peptide chemistry or the like. The target compound may be obtained by removing the protecting group as needed after the reaction, if necessary. Examples of the amino-protecting group include, for example,
Formyl, optionally substituted C _1-6 alkylcarbonyl (eg, acetyl, ethylcarbonyl, etc.), phenylcarbonyl, C _1-6 alkyl-oxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), For example, phenyloxycarbonyl, C _7-10 aralkyl-carbonyl (eg, benzylcarbonyl), trityl, phthaloyl, N, N-dimethylaminomethylene and the like are used. As these substituents, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), nitro group and the like are used. The number of substituents is about 1 to 3. Examples of the carboxyl-protecting group include, for example, optionally substituted C _1-6 alkyl (for example, methyl, ethyl, n-propyl, i-propyl, n
-Butyl, tert-butyl and the like), phenyl, trityl or silyl and the like. As these substituents, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), formyl, C _1-6 alkyl-carbonyl (eg, acetyl, ethylcarbonyl, butylcarbonyl, etc.), a nitro group and the like are used. And the number of substituents is about 1 to 3.

Examples of the hydroxyl-protecting group include, for example, C _1-6 alkyl which may have a substituent (for example,
Methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, etc.), phenyl, C _7-10 aralkyl (eg, benzyl etc.), formyl, C _1-6 alkyl-carbonyl (eg, acetyl, Ethylcarbonyl), phenyloxycarbonyl, benzoyl, C
_7-10 aralkyl-carbonyl (such as benzylcarbonyl), pyranyl, furanyl or silyl and the like are used. These substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl (eg, methyl, ethyl, n-propyl, etc.),
Phenyl, C _7-10 aralkyl (for example, benzyl etc.), nitro group and the like are used, and the number of substituents is about 1 to 4. As a method for removing the protecting group, a method known per se or a method analogous thereto is used.For example, an acid, a base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate,
A method of treating with tetrabutylammonium fluoride, palladium acetate or the like is used.

The compound [I] of the present invention or a salt thereof is
Has excellent antiallergic, anti-inflammatory, anti-PAF (platelet activating factor) and eosinophil chemotaxis inhibitory effects and low toxicity (acute toxicity: LD ₅₀ > 2 g / kg)
Therefore, it can be used as a safe anti-asthmatic agent for mammals (eg, human, mouse, dog, rat, cow, etc.). Furthermore, the compound [I] or a salt thereof suppresses eosinophil chemotaxis, and suppresses infiltration of eosinophils at local sites of allergic reaction and inflammatory reaction. Therefore, it is useful as a therapeutic agent for diseases involving eosinophil infiltration. That is, showing eosinophilia in the mammal, for example, urticaria, atopic dermatitis, allergic rhinitis, allergic diseases such as irritable pneumonitis, eczema, herpetic dermatitis, skin diseases such as psoriasis, It can be used for treatment or prevention of respiratory diseases such as eosinophilic pneumonia (PIE syndrome). The administration route may be oral or parenteral. The preparation used in the present invention may contain other active ingredients other than the compound [I] or a salt thereof as an active ingredient. Such pharmaceutically active ingredients include, for example, anti-asthmatic agents (eg, theophylline, procaterol, ketotifen, azelastine, seratrodast, etc.), anti-allergic agents (eg, ketotifen, terfenadine, azelastine, epinastine, etc.), anti-inflammatory agents (eg, diclofenac sodium, Ibuprofen, indomethacin, etc.), antibacterial agents (eg, cefixime, cefdinir, ofloxacin, tosfloxacin, etc.), antifungal agents (eg, fluconazole, itraconazole, etc.) and the like.
These components are not particularly limited as long as the object of the present invention is achieved, and can be used at an appropriate mixing ratio. Specific examples of dosage forms include tablets (including sugar-coated tablets and film-coated tablets), pills, capsules (including microcapsules), granules, fine granules, powders, syrups, emulsions, suspensions, Injections, inhalants, ointments and the like are used.
These preparations are prepared according to a conventional method (for example, a method described in Japanese Pharmacopoeia). In the preparation of the present invention, the content of compound [I] or a salt thereof varies depending on the form of the preparation.
It is about 0% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight.

Specifically, a tablet is produced by adding the excipients, binders, disintegrants or other suitable additives and mixing the drug as it is and mixing the granules in an appropriate manner with granules. After that, add lubricants and compression-mold, or directly compress-mold the drug as it is, or mix evenly with excipients, binders, disintegrants or other appropriate additives. Alternatively, the granules can be produced by compressing and molding the granules prepared beforehand as they are, or after adding an appropriate additive thereto and mixing them uniformly. In addition, the present agent can contain a coloring agent, a flavoring agent, and the like as needed. Further, the agent can be coated with an appropriate coating agent. In the method of manufacturing an injection, a certain amount of a drug is dissolved, suspended or emulsified in a vegetable oil or the like in the case of an aqueous solvent, water for injection, physiological saline, Ringer's solution, etc. in the case of an aqueous solvent, or a non-aqueous solvent, to a certain amount. Alternatively, a predetermined amount of a drug can be taken and sealed in a container for injection. As the carrier for oral preparations, for example, substances commonly used in the field of preparations such as starch, mannitol, crystalline cellulose and sodium carboxymethylcellulose are used. As an injection carrier,
For example, distilled water, physiological saline, glucose solution, infusion agent and the like are used. In addition, additives generally used in preparations can be appropriately added. The dosage of these preparations varies depending on age, body weight, symptoms, route of administration, number of administrations, etc. For example, for adult asthma patients, it is converted to the active ingredient (compound [I] or its salt) per day. 0.1 to 100 mg / kg, preferably 1 to 50 mg / kg
It is preferable to orally administer 1 kg, more preferably 1 to 10 mg / kg, once or twice a day.

[0024]

BEST MODE FOR CARRYING OUT THE INVENTION In the following, examples, reference examples,
The present invention will be more specifically described with reference to formulation examples and experimental examples, but the present invention is not limited thereto. The detection of the fraction containing the target substance in Examples was carried out by TLC (Thin L
ayer Chromatography (thin layer chromatography). In the TLC observation, the 60F ₂₅₄ Merck (Merck) manufactured as a TLC plate, was used a UV detector as a detection method.

[0025]

【Example】

Reference Example 1 Production of 3,6-dichloro-4-ethylpyridazine 22.5 g of 3,6-dichloropyridazine, 12.7 of silver nitrate
and a suspension of 16.3 g of propionic acid in 250 ml of water was heated to an internal temperature of 50 ° C., and 49.3 g of concentrated sulfuric acid was added to 250 ml of water.
The diluted solution was added. Raise the internal temperature to 60 ° C,
A solution of 93 g of ammonium persulfate in 0 ml of water was added to 2
It was dropped in 0 minutes. The reaction was carried out at an internal temperature of 70-75 ° C. for 30 minutes, and 25% aqueous ammonia was added under ice cooling to pH 7.0.
And The reaction solution was extracted with ethyl ether, and the extract was washed with water and dried over magnesium sulfate. Concentrate under reduced pressure,
The residue was purified by silica gel column chromatography to obtain 13.5 g of the title compound. NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7 Hz), 2.78 (2H, q,
J = 7 Hz), 7.39 (1H, s) Reference Example 2 Production of 3,6-dichloro-4-n-propylpyridazine 16.6 g of 3,6-dichloropyridazine and n-butyric acid 14.
The reaction was carried out in the same manner as in Reference Example 1 using 4 g of the title compound 1
2.7 g were obtained. NMR (CDCl ₃ ) δ: 1.10 (3H, t, J = 7 Hz), 1.5-1.9 (2
H, m), 2.72 (2H, t, J = 7Hz), 7.37 (1H, s)

Reference Example 3 Production of 3,6-dichloro-4-isobutylpyridazine 22.3 g of 3,6-dichloropyridazine and isovaleric acid 1
The reaction was carried out in the same manner as in Reference Example 1 using 9.9 g to obtain 15.0 g of the title compound. NMR (CDCl ₃ ) δ: 1.06 (6H, d, J = 7 Hz), 1.8-2.2 (1
H, m), 2.60 (2H, d, J = 7 Hz), 7.38 (1H, s) Reference Example 4 Production of 3,6-dichloro-4-n-hexylpyridazine 11.7 g of 3,6-dichloropyridazine and n The reaction was carried out in the same manner as in Reference Example 1 using 23.0 g of -heptanoic acid to obtain 14.4 g of the title compound. NMR (CDCl ₃ ) δ: 0.84-0.97 (3H, m), 1.22-1.48 (8
H, m), 1.57-1.76 (2H, m), 7.37 (1H, s) Reference Example 5 Production of 4-cyclopentyl-3,6-dichloropyridazine 22.4 g of 3,6-dichloropyridazine and cyclopentanecarboxylic acid 25 The reaction was carried out in the same manner as in Reference Example 1 using 0.1 g to obtain 28.7 g of the title compound. NMR (CDCl ₃ ) δ: 1.4-2.3 (8H, m), 3.30 (1H, m),
7.38 (1H, s)

Reference Example 6 Preparation of 3-amino-6-chloro-5-ethylpyridazine 13.5 g of 3,6-dichloro-4-ethylpyridazine 1
150 ml of 5% aqueous ammonia and 10 ml of ethanol were placed in a sealed stainless steel reaction tube and stirred at 130 to 140 ° C. for 22 hours. After cooling and concentration, water was added to the residue, and the precipitated crystals were collected by filtration, washed with water and ethyl ether, and dried to obtain 6.96 g of the title compound. NMR (d ₆ -DMSO) δ: 1.16 (3H, t, J = 7 Hz), 2.54
(2H, q, J = 7Hz), 6.48 (2H, s), 6.73 (1H, s) Reference Example 7 Production of 3-amino-6-chloro-5-n-propylpyridazine 3,6-dichloro-5 n-propylpyridazine 12.7
g, 150 ml of 25% aqueous ammonia and 5 ml of ethanol were reacted in the same manner as in Reference Example 6 to obtain 6.8 g of the title compound. NMR (CDCl ₃ ) δ: 1.0 (3H, t, J = 7 Hz), 1.57-1.76 (2
H, m), 2.59 (2H, t, J = 7Hz), 4.80 (2H, br.s), 6.60 (1H, s)

Reference Example 8 Preparation of 3-amino-6-chloro-5-isopropylpyridazine 2,6-dichloro-4-isopropylpyridazine 21.7
g, 170 ml of 25% aqueous ammonia and 10 ml of ethanol, and reacted in the same manner as in Reference Example 6. 11.1 g of the title compound
I got Melting point 164-165 ° C NMR (CDCl ₃ ) δ: 1.26 (6H, d, J = 7 Hz), 3.16 (1H,
m), 4.89 (2H, br.s), 6.65 (1H, s) Reference Example 9 Production of 3-amino-6-chloro-5-isobutylpyridazine 15.0 g of 3,6-dichloro-4-isobutylpyridazine
And 180 ml of 25% aqueous ammonia and 5 ml of ethanol in the same manner as in Reference Example 6 to obtain 7.3 g of the title compound. 122-123 ° C. NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 7 Hz), 1.8-2.2 (1
H, m), 2.48 (2H, d, J = 7Hz), 4.88 (2H, br.s), 6.38 (1H, s)

Reference Example 10 Preparation of 3-amino-5-tert-butyl-6-chloropyridazine 4-tert-butyl-3,6-dichloropyridazine 31.1
g, 150 ml of 25% aqueous ammonia and 15 ml of ethanol and reacted in the same manner as in Reference Example 6 to give 20.8 of the title compound.
g was obtained. Melting point 185-188 ° C NMR (CDCl ₃ ) δ: 1.44 (9H, s), 4.88 (2H, br.s),
6.74 (1H, s) Reference Example 11 Production of 3-amino-6-chloro-5-n-hexylpyridazine 3,6-dichloro-4-n-hexylpyridazine 14.4
g, 25% ammonia water 150ml, ethanol 150ml
And reacted in the same manner as in Reference Example 6 to give the title compound 6.2
g was obtained. 97-98 ° C NMR (CDCl ₃ ) δ: 0.84-1.02 (3H, m), 1.20-1.48 (8
H, m), 1.54-1.71 (2H, m), 4.97 (2H, br.s), 6.62 (1H, s)

Reference Example 12 Method for producing 3-amino-6-chloro-5-cyclopentylpyridazine 4-cyclopentyl-3,6-dichloropyridazine 28.
7 g, 210 ml of 25% ammonia water, 70 ml of ethanol
And reacted in the same manner as in Reference Example 6 to give the title compound 15.
5 g were obtained. NMR (CDCl ₃ ) δ: 1.4-2.3 (8H, m), 3.20 (1H, m),
4.84 (2H, br.s), 6.65 (1H, s) Reference Example 13 N- (6-chloro-5-ethylpyridazin-3-yl)
Preparation of formamide oxime 3-amino-6-chloro-5-ethylpyridazine 4.6
g was suspended in 58 ml of toluene, 6.2 ml of dimethylformamide dimethyl acetal was added, and the mixture was refluxed for 2 hours. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate: methanol = 10: 1.
The desired fraction was collected and concentrated, the residue was dissolved in 40 ml of methanol, and 1.8 g of hydroxylamine hydrochloride was obtained.
And stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration to obtain 4.40 g of the title compound. Mp 175-178 ° C. Elemental analysis: C ₇ H ₉ N ₄ Calculated OCl (%): C, 41.91 ; H, 4.52; N, 27.
93 Found (%): C, 41.73; H, 4.65; N, 27.
69

Reference Example 14 N- (6-Chloro-5-n-propylpyridazine-3-
Il) Preparation of formamide oxime The reaction was carried out in the same manner as in Reference Example 13 using 6.8 g of 3-amino-6-chloro-5-n-propylpyridazine to obtain 4.7 g of the title compound. NMR (d ₆ -DMSO) δ: 0.95 (3H, t, J = 7 Hz), 1.5-
1.8 (2H, m), 2.57 (2H, t, J = 7Hz), 7.36 (1H, s), 7.91 (1H,
d, J = 10 Hz), 9.65 (1 H, d, J = 10 Hz), 10.40 (1 H, s) Reference Example 15 N- (6-chloro-5-isopropylpyridazine-3-
Il) Preparation of formamide oxime The reaction was carried out in the same manner as in Reference Example 13 using 8.6 g of 3-amino-6-chloro-5-isopropylpyridazine to obtain 10.6 g of the title compound. Mp 170-171 ° C. Elemental analysis: C ₈ H ₁₁ N ₄ Calculated OCl (%): C, 44.76 ; H, 5.17; N, 26.
10 Found (%): C, 46.62; H, 5.02; N, 26.
01

Reference Example 16 Preparation of N- (6-chloro-5-isobutylpyridazin-3-yl) formamide oxime In the same manner as in Reference Example 13 except that 7.0 g of 3-amino-6-chloro-5-isobutylpyridazine was used. The reaction was performed to obtain 4.9 g of the title compound. Melting point 155-158 ° C Elemental analysis: C ₉ H ₁₃ N ₄ OCl.H ₂ O Calculated (%): C, 43.82; H, 6.13; N, 22.
71 Found (%): C, 43.23; H, 6.21; N, 23.
Reference Example 17 Production of N- (5-tert-butyl-6-chloropyridazin-3-yl) formamide oxime 3-amino-5-tert-butyl-6-chloropyridazine 1
The reaction was carried out in the same manner as in Reference Example 13 using 1.1 g to obtain 12.0 g of the title compound. Melting point 221-224 ° C Elemental analysis: C ₉ H ₁₃ N ₄ OCl Calculated (%): C, 47.27; H, 5.73; N, 24.
50 found (%): C, 47.10; H, 5.48; N, 24.
68

Reference Example 18 N- (6-chloro-5-n-hexylpyridazine-3-
Il) Production of formamide oxime The reaction was carried out in the same manner as in Reference Example 13 using 6.0 g of 3-amino-6-chloro-5-n-hexylpyridazine to obtain 5.7 g of the title compound. Mp 131-133 ° C. Elemental analysis: C ₁₁ H ₁₇ N ₄ Calculated OCl (%): C, 51.46 ; H, 6.67; N, 21.
82 Found (%): C, 51.15; H, 6.87; N, 21.
59 Reference Example 19 N- (6-Chloro-5-cyclopentylpyridazine-3)
Preparation of -yl) formamide oxime The reaction was carried out in the same manner as in Reference Example 13 using 8.9 g of 3-amino-6-chloro-5-cyclopentylpyridazine to obtain 8.05 g of the title compound. Mp 207-208 ° C. Elemental analysis: C ₁₀ H ₁₃ N ₄ Calculated OCl (%): C, 49.90 ; H, 5.44; N, 23.
28 Found (%): C, 49.85; H, 5.60; N, 23.
31

Reference Example 20 6-chloro-7-ethyl [1,2,4] triazolo [1,
5-b] Preparation of pyridazine N- (6-chloro-5-ethylpyridazin-3-yl)
4.02 g of formamide oxime and 25 g of polyphosphoric acid were kneaded and reacted in an oil bath at 110 to 115 ° C. for 1 hour. After cooling, ice water was added, and the mixture was extracted with dichloromethane. The extract was washed with water and dried over magnesium sulfate. After concentrating under reduced pressure, hexane was added to the residue, and the precipitated crystals were collected by filtration to obtain 2.33 g of the title compound. Mp 84-85 ° C. Elemental analysis: Calculated as _{C 7 H 7 ClN 4 (%} ): C, 46.04; H, 3.86; N, 30.
68 Found (%): C, 46.00; H, 3.79; N, 30.
59 Reference Example 21 Production of 6-chloro-7-n-propyl [1,2,4] triazolo [1,5-b] pyridazine N- (6-chloro-5-n-propylpyridazine-3-
Il) 4.7 g formamide oxime and 23 polyphosphoric acid
The reaction was carried out in the same manner as in Reference Example 20 using g, to give 3.1 g of the title compound. Mp 61-62 ° C. Elemental analysis: Calculated as _{C 8 H 9 ClN 4 (%} ): C, 48.87; H, 4.61; N, 28.
49 found (%): C, 48.87; H, 4.55; N, 28.
55

Reference Example 22 Preparation of 6-chloro-7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine N- (6-chloro-5-isopropylpyridazine-3-
Il) Formamide oxime was reacted with 20.04 g of polyphosphoric acid in the same manner as in Reference Example 20 to give 12.7 g of the title compound. Mp 53-54 ° C. Elemental analysis: Calculated as _{C 8 H 9 ClN 4 (%} ): C, 48.87; H, 4.61; N, 28.
49 found (%): C, 48.85; H, 4.55; N, 28.
48 Reference Example 23 Production of 6-chloro-7-isobutyl [1,2,4] triazolo [1,5-b] pyridazine 4.6 g of N- (6-chloro-5-isobutylpyridazin-3-yl) formamide oxime And polyphosphoric acid 22g
And reacted in the same manner as in Reference Example 20 to give the title compound 2.
2 g were obtained. Melting point 60-62 ° C Elemental analysis: C ₉ H ₁₁ ClN ₄ Calculated (%): C, 51.31; H, 5.26; N, 26.
60 Found (%): C, 51.33; H, 5.05; N,
26.71

Reference Example 24 Preparation of 7-tert-butyl-6-chloro [1,2,4] triazolo [1,5-b] pyridazine N- (5-tert-butyl-6-chloropyridazin-3-yl ) 8.0 g of formamide oxime and 38 g of polyphosphoric acid
And reacted in the same manner as in Reference Example 20 to give the title compound 5.
13 g were obtained. Melting point: 110-112 ° C Elemental analysis: C ₉ H ₁₁ ClN ₄ Calculated (%): C, 51.31; H, 5.26; N, 26.
60 Found (%): C, 51.15; H, 5.15; N, 26.
66 Reference Example 25 Production of 6-chloro-7-n-hexyl [1,2,4] triazolo [1,5-b] pyridazine N- (6-chloro-5-n-hexylpyridazine-3-
Ill) 5.5 g formamide oxime and 22 polyphosphoric acid
g and reacted in the same manner as in Reference Example 20 to obtain 2.2 g of the title compound. Melting point 52-53 ° C Elemental analysis: C ₁₁ H ₁₅ ClN ₄ Calculated (%): C, 55.35; H, 6.33; N, 23.
47 Found (%): C, 55.25; H, 6.12; N, 23.
52

Reference Example 26 Preparation of 6-chloro-7-cyclopentyl [1,2,4] triazolo [1,5-b] pyridazine N- (6-chloro-5-cyclopentylpyridazine-3)
-Yl) Formamide oxime was reacted with 7.76 g of polyphosphoric acid in the same manner as in Reference Example 20 to obtain 5.51 g of the title compound. Melting point 57-59 ° C Elemental analysis: C ₁₀ H ₁₁ ClN ₄ Calculated (%): C, 53.94; H, 4.98; N, 25.
16 Found (%): C, 53.88; H, 4.97; N, 25.
07 Reference Example 27 N- (6-chloro-5-isopropylpyridazine-3-
I) Preparation of acetamide oxime 3.44 g of 3-amino-6-chloro-5-isopropylpyridazine was suspended in 40 ml of toluene, 4.44 g of dimethylacetamide methyl acetal was added, and the mixture was heated under reflux for 2 hours. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected and concentrated, the residue was dissolved in 25 ml of methanol, and 1.37 g of hydroxylamine hydrochloride was added, followed by stirring at room temperature for 1 hour. The precipitated crystals were collected by filtration to give 3.42 g of the title compound. Melting point 175-178 ° C Elemental analysis: C ₉ H ₁₃ N ₄ OCl Calculated (%): C, 47.27; H, 5.73; N, 24.
50 Found (%): C, 47.21; H, 5.81; N, 24.
twenty one

Reference Example 28 6-chloro-7-isopropyl-2-methyl [1,2,
4] Production of triazolo [1,5-b] pyridazine N- (6-chloro-5-isopropylpyridazine-3-
Il) 1.7 g of acetamide oxime and 10 polyphosphoric acid
g were kneaded well at room temperature and reacted in an oil bath at 110-115 ° C for 1 hour. After cooling, ice water was added, and the mixture was extracted with dichloromethane. The extract was washed with water and dried over magnesium sulfate. After concentrating under reduced pressure, hexane was added to the residue, and the precipitated crystals were collected by filtration to obtain 1.06 g of the title compound. Melting point 58-60 ° C Elemental analysis: C ₉ H ₁₁ N ₄ Cl Calculated (%): C, 51.31; H, 5.26; N, 26.
60 actual value (%): C, 51.24; H, 5.11; N,
26.53

Example 1 6- (2,2-Dimethyl-3-sulfamoyl-1-propoxy) -7-ethyl [1,2,4] triazolo [1,
5-b] Preparation of pyridazine 0.42 g of 60% oily sodium hydride was suspended in 25 ml of tetrahydrofuran, 0.836 g of 3-hydroxy-2,2-dimethylpropane-1-sulfonamide was added, and the mixture was heated under reflux for 40 minutes. . After cooling, 6-chloro-7-ethyl [1,2,4] triazolo [1,5-b] pyridazine 0.1.
913 g was added and the mixture was heated under reflux for 2 hours. After cooling, ice water was added, the pH was adjusted to 6.0 with 1N hydrochloric acid, and the mixture was extracted with tetrahydrofuran-ethyl acetate (1: 1). The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with dichloromethane: ethyl acetate: methanol = 10: 10: 1. The desired fraction was collected, the crystals obtained was recrystallized from acetone -H ₂ O to give the title compound 0.787 g. Mp 222-224 ° C. Elemental _{analysis: C 12 H 19 N 5 O} 3 Calculated S (%): C, 45.99 ; H, 6.11; N, 22.
35 found (%): C, 45.87; H, 6.14; N, 22.
33 Example 2 Preparation of 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-n-propyl [1,2,4] triazolo [1,5-b] pyridazine 3-hydroxy-2 0.90 g of 1,2-dimethylpropane-1-sulfonamide and 6-chloro-7-n-propyl [1,2,4] triazolo [1,5-b] pyridazine 1.0
g and reacting in the same manner as in Example 1 to give the title compound 0.77
g was obtained. Mp 196-197 ° C. Elemental _{analysis: C 13 H 21 N 5 O} 3 S · H 2 O Calculated (%): C, 45.20; H, 6.70; N, 20.
27 Found (%): C, 45.68; H, 6.39; N,
20.55

Example 3 Preparation of 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine 60% oily hydrogenation 0.336 g of sodium is suspended in 30 ml of tetrahydrofuran to give 3-hydroxy-2,2.
0.669 g of dimethylpropane-1-sulfonamide
Was added and the mixture was refluxed for 1 hour. After cooling, 0.748 g of 6-chloro-7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine was added, and the mixture was heated under reflux for 4 hours. After cooling, ice water was added, the pH was adjusted to 6.0 with 1N hydrochloric acid, and the mixture was extracted with tetrahydrofuran-ethyl acetate (1: 1). The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and dichloromethane: ethyl acetate: methanol = 10: 10:
Eluted at 1. The desired fraction was collected and the resulting crystals were recrystallized from acetone-water to give the title compound 1.10
g was obtained. Mp 197-198 ° C. Elemental _{analysis: C 13 H 21 N 5 O} 3 Calculated S (%): C, 47.69 ; H, 6.46; N, 21.
39 found (%): C, 47.84; H, 6.60; N, 21.
33 Example 4 Preparation of 6- (2,2-diethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine 3-hydroxy-2,2 0.586 g of -diethylpropane-1-sulfonamide and 6-chloro-7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine 0.5%.
The reaction was carried out in the same manner as in Example 1 using 561 g to obtain 0.967 g of the title compound. Mp 190-192 ° C. Elemental _{analysis: C 15 H 25 N 5 O} 3 Calculated S (%): C, 50.68 ; H, 7.09; N, 19.
70 Found (%): C, 50.90; H, 7.30; N,
19.42

Example 5 Preparation of 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-isobutyl [1,2,4] triazolo [1,5-b] pyridazine 3-hydroxy-2 0.84 g of 1,2-dimethylpropane-1-sulfonamide and 6-chloro-7-isobutyl [1,2,4] triazolo [1,5-b] pyridazine 1.0
g, and reacted in the same manner as in Example 1 to give the title compound 0.63.
g was obtained. Mp 132-135 ° C. Elemental _{analysis: C 14 H 23 N 5 O} 3 S · H 2 O Calculated (%): C, 46.78; H, 6.45; N, 19.
98 Found (%): C, 46.91; H, 6.40; N, 19.
79 Example 6 Preparation of 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-t-butyl [1,2,4] triazolo [1,5-b] pyridazine 3-hydroxy-2 1.0 g of 2,2-dimethylpropane-1-sulfonamide and 7-t-butyl-6-chloro [1,
The same reaction as in Example 1 was carried out using 1.2 g of [2,4] triazolo [1,5-b] pyridazine to obtain 1.13 g of the title compound. Mp 168-170 ° C. Elemental _{analysis: C 14 H 23 N 5 O} 3 Calculated S (%): C, 49.25 ; H, 6.79; N, 20.
51 Found (%): C, 49.12; H, 6.69; N, 20.
81

Example 7 Preparation of 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-n-hexyl [1,2,4] triazolo [1,5-b] pyridazine 3-hydroxy 0.74 g of -2,2-dimethylpropane-1-sulfonamide and 6-chloro-7-n-hexyl [1,2,4] triazolo [1,5-b] pyridazine 1.0
g, and reacted in the same manner as in Example 1 to obtain the title compound 1.5.
g was obtained. Mp 150-151 ° C. Elemental _{analysis: C 16 H 27 N 5 O} 3 Calculated S (%): C, 52.01 ; H, 7.37; N, 18.
95 Found (%): C, 52.00; H, 7.32; N, 19.
15 Example 8 Preparation of 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-cyclopentyl [1,2,4] triazolo [1,5-b] pyridazine 3-hydroxy-2,2 -Dimethylpropane-1-sulfonamide (1.01 g) and 6-chloro-7-cyclopentyl [1,2,4] triazolo [1,5-b] pyridazine 1.
The title compound was reacted in the same manner as in Example 1 using 27 g of the title compound 1.
56 g were obtained. Mp 170-172 ° C. Elemental _{analysis: C 15 H 23 N 5 O} 3 S · 0.5H 2 O Calculated (%): C, 49.71; H, 6.67; N, 19.
32 found (%): C, 49.65; H, 6.69; N, 19.
48

Example 9 Preparation of 7-isopropyl-6- (3-sulfamoyl-1-propoxy) [1,2,4] triazolo [1,5-b] pyridazine 168 mg of 60% oily sodium hydride was added to 25 ml of tetrahydrofuran. 3-hydroxypropane-1-
279 mg of sulfonamide was added, and the mixture was heated under reflux for 40 minutes. After cooling, 394 mg of 6-chloro-7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine was added and the mixture was stirred at room temperature for 20 hours. Ice water was added, 5N hydrochloric acid was added to adjust the pH to 5 to saturate the salt, and the mixture was extracted with tetrahydrofuran. The extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the obtained crystals were washed with ethyl ether and recrystallized from 95% ethanol to obtain 414 mg of the title compound. Mp 190-191 ° C. Elemental _{analysis: C 11 H 17 N 5 O} 3 Calculated S (%): C, 44.14 ; H, 5.72; N, 23.
39 found (%): C, 44.12; H, 5.77; N,
22.92

Example 10 6- (2,2-Dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl-2-methyl [1,2,
4] Production of triazolo [1,5-b] pyridazine 60%
252 mg of oily sodium hydride was added to tetrahydrofuran 3
After suspending in 0 ml, 527 mg of 3-hydroxy-2,2-dimethylpropane-1-sulfonamide was added, and the mixture was heated under reflux for 1 hour. After cooling, 6-chloro-7-isopropyl-2-
Methyl [1,2,4] triazolo [1,5-b] pyridazine (632 mg) was added, and the mixture was heated under reflux for 6 hours. After cooling, ice water was added, 5N hydrochloric acid was added to adjust the pH to 5, and the salt was saturated.
Extract with ethyl acetate-tetrahydrofuran (2: 1),
The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and dichloromethane: ethyl acetate: methanol = 1.
Eluted at 0: 10: 1. The desired fraction was collected, and the obtained crystals were recrystallized from 95% ethanol to obtain 746 mg of the title compound. Mp 196-199 ° C. Elemental _{analysis: C 14 H 23 N 5 O} 3 Calculated S (%): C, 49.25 ; H, 6.79; N, 20.
51 Found (%): C, 49.18; H, 6.76; N, 20.
44

Example 11 Preparation of 6- (2,2-diethyl-3-sulfamoyl-1-propoxy) -7-t-butyl [1,2,4] triazolo [1,5-b] pyridazine 60% oil 380 mg of sodium hydride are suspended in 30 ml of tetrahydrofuran, and 980 mg of 3-hydroxy-2,2-diethylpropane-1-sulfonamide is added thereto to give 1
Heated to reflux for an hour. After cooling, 7-tert-butyl-6-chloro [1,2,4] triazolo [1,5-b] pyridazine 1.0
g was added and the mixture was heated under reflux for 3 hours. After cooling, add ice water and add 5N
Hydrochloric acid was added to saturate the salt to pH 4 and extracted with tetrahydrofuran. The extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with dichloromethane: methanol = 30: 1. The desired fractions were collected to give 720 mg of the title compound. Melting point 172-174 ° C Elemental analysis: C ₁₆ H ₂₇ N ₅ O ₃ S Calculated (%): C, 52.01; H, 7.37; N, 18.
95 Found (%): C, 51.86; H, 7.31; N, 18.
90

Experimental Example 1 The results of pharmacological tests of compound [I] of the present invention or a salt thereof are shown. [Effect on Platelet Activating Factor (PAF) -Induced Guinea Pig Airway Constriction Response] Male (Hartley) Hartley guinea pigs (body weight: about 500 g) were used. PAF 1μg / kg
The airway constriction response in guinea pigs due to intravenous administration was measured according to the Konchet-Roessler method. Guinea pig urethane (1.5 g / kg, IV)
After fixation of the dorsal position under anesthesia, a tracheotomy was performed, and the tracheostomy was connected to an artificial respiratory organ via a cannula. The side branch of the tracheal cannula was connected to a transducer (Model 7020, Ugobasile). The volume of air supplied is 3 to 7 ml, the frequency of air supply is 70 times / minute, the load pressure on the lungs is 10 cmH ₂ O, and the amount of air that overflows is measured using a rectograph (Recte-Hori) via a transducer.
-8s, manufactured by Nippon Electric Sanei Co., Ltd.). After treatment with gallamine (1 mg / kg, iv), PA dissolved in physiological saline
F 1 μg / kg was administered via the jugular vein cannula and the evoked airway constriction response was recorded for 15 minutes. The drug is 3mg / kg
And 1 mg / kg were each suspended in 5% gum arabic solution and orally administered 1 hour before PAF administration. The results are shown in [Table 1].

[Table 1] Comparative compound: compound of Example 3 of EP562439 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-methyl [1,2,4] triazolo [1,
5-b] Pyridazine [Table 1] shows that the target compound [I] or a salt thereof is
It can be seen that the compound has a better anti-PAF effect than a compound having a methyl group at the 7-position of the triazolopyridazine skeleton.

Experimental Example 2 1) Preparation of Eosinophils from Guinea Pig 2 ml of horse serum (Whittaker Bioproducts) was intraperitoneally administered to Hartley male guinea pigs (body weight: 300 g) once a week for 8 weeks. 48 hours after the last administration, physiological saline 7
After injecting 5 ml into the peritoneal cavity, the recovered solution was centrifuged at 400 × g for 5 minutes. The precipitate is washed with Percoll solution (specific gravity d = 1.
07) Suspended in 5 ml, and a Percoll specific gravity discontinuous layer (specific gravity d =
1.112, 5 ml; d = 1.095, 10 ml; d = 1.0
90, 10 ml; d = 1.085, 5 ml).
Centrifuged at 00 × g for 25 minutes (18 ° C.). Specific gravity d = 1.
The cell layer formed at the interface of 112 and d = 1.095 was collected. Erythrocytes mixed into the collected cell sediment were removed by hypotonic treatment (suspension in water for 30 seconds). 10 mM Hep
Washed three times with Hanks solution (Hanks-Hepes) containing es (Dojindo Chemical), suspended in Hanks-Hepes solution (Hanks-Hepes-HSA) containing 2% human serum albumin (Wako Pure Chemical Industries), and 5. It was adjusted to 56 × 10 ⁶ cells / ml. The eosinophil purity is 90% and its viability is 98%.
That was all. 2) Chemical migration reaction inhibition assay LTB ₄ suspended in Hanks-Hepes-HSA solution (final concentration 10 ⁻⁸ M, Cascade Biochemical L) was placed in a 24-well culture dish in the lower chamber.
td.) was placed in a carbon dioxide gas incubator and kept at 37 ° C. for 30 minutes. Also, 200 μl of eosinophil suspension incubated in a thermostat at 37 ° C. for 15 minutes.
l (5 × 10 ⁶ cells / ml) in a 24-well culture dish
Chemotaxicell (Polycarbonate membrane, pore size
(3 μm, thickness 10 μm) and then added to the upper chamber. After reacting for 2 hours in carbon dioxide gas incubator, Chemot
The axicell was removed and 60 μl of a 2% (W / V) EDTA physiological saline solution was added to the lower room liquid. After cooling on ice, the number of cells that migrated into the lower chamber solution was counted using a hemocytometer (Coulter Counter).
(Trade name)). The drug was dissolved in dimethylformamide (DMF) and added to both the lower and upper chambers to a final concentration of 10 ^-5 M.

[0048]

(Equation 1) The inhibition rate of the subject (1 × 10 ⁻⁵ M concentration) against the chemotactic reaction by LTB ₄ was determined. The results are shown in [Table 2].

[Table 2] Effect on LTB ₄ -induced chemotactic reaction in guinea pig eosinophils 化合物 Compound inhibition rate (%) ━━━━━━ {Example 1 35 Example 2 24 Example 4 23 Example 5 27 Example 6 38 Example 7 24} ────────── Comparative compound * 12 １２ Comparative compound: same as that used in Experimental Example 1 [Table 2 The target compound [I] or a salt thereof,
It can be seen that the compound has a superior inhibitory effect on eosinophil chemotaxis than a compound having a methyl group at the 7-position of the triazolopyridazine skeleton.

Formulation Example 1 (1) 10.0 mg of the compound of Example 3 (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Gelatin 3.0 mg (5) Magnesium stearate 2.0 mg Example 3 Using a mixture of 10.0 mg of the compound obtained in the above, lactose 60.0 mg and corn starch 35.0 mg in 10% gelatin aqueous solution 0.03 ml (3.0 mg as gelatin),
After granulating through a 1 mm mesh sieve, it was dried at 40 ° C. and sieved again. The granules thus obtained were mixed with 2.0 mg of magnesium stearate and compressed. The resulting core tablets were coated with a sugar coating in aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were polished with beeswax to obtain coated tablets.

Formulation Example 2 (1) 10.0 mg of the compound of Example 3 (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg 10.0 mg of the compound obtained in Step 3 and 3.0 mg of magnesium stearate were added to 0.07 ml of an aqueous solution of soluble starch.
(7.0 mg as soluble starch), dried and mixed with 70.0 mg of lactose and 50.0 mg of corn starch. The mixture was compressed to give tablets. Formulation Example 3 (1) 5.0 mg of the compound of Example 3 (2) 20.0 mg of salt (3) Distilled water The total amount is 2 ml 5.0 mg of the compound obtained in Example 3 and 20.0 mg of salt
Was dissolved in distilled water, and water was added to make a total volume of 2.0 ml.
The solution was filtered and filled under aseptic conditions into 2 ml ampules. The ampoule was sterilized and sealed to obtain a solution for injection.

[0051]

The compound [I] or a salt thereof has an excellent anti-PAF action and an inhibitory action on eosinophil chemotaxis,
It is useful as a prophylactic / therapeutic agent for asthma, allergic rhinitis, atopic dermatitis and the like.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ identification code FI A61K 31/00 637 A61K 31/00 637E 31/50 603 31/50 603 (58) Investigated field (Int. Cl. ⁶ , DB Name) C07D 487/04 A61K 31/50 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] (1) 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [1,2,
4] Triazolo [1,5-b] pyridazine or a salt thereof. [2] a pharmaceutical comprising the compound of [1]; 3. The medicament according to claim 2, which is an anti-PAF agent, an eosinophil chemotaxis inhibitor, an anti-asthmatic agent, an anti-allergic agent, a prophylactic or therapeutic agent for allergic rhinitis or a therapeutic agent for atopic dermatitis.