JPH08198878A - Triazolopyridazine derivative its production, intermediate and agent - Google Patents

Abstract

PURPOSE: To obtain a triazolopyridazine derivative useful as a preventive or curing agent or an antiasthmatic of allergic rhinitis or atopic dermatitis. CONSTITUTION: This derivative is expressed by formula I (R<2> is H, a halogen or a 1-6C alkyl; R<2> is a polycarbon alkyl or a cycloalkyl; X is O or S(O); P is 0 or 2; Y is a cycloalkylene or a cycloalkylidene, etc.; m and n are each 0-4; R<5> and R<6> are each H, an alkyl or a cycloalkyl, etc.), e.g. 6-(2,2-dimethyl-3- sulfamoyl-1-propoxy)-7-ethyl[1,2,4]triazolo[1,5-b]pyridazine. The derivative of the formula I is obtained by reacting a compound expressed by formula II with a compound expressed by formula III (Z<1> and Z<2> are groups simultaneously reacting and removing together). This derivative has a not-substituted 8-position of [1,2,4]triazolo[1,5-b] pyridazine skeleton and has a polycarbon alkyl group at 7-position as a structural characteristic and has excellent an antiallergic activity and a suppressing activity for a chemical wandering of acidocyte, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel triazolopyridazine derivative having excellent anti-allergic action, anti-inflammatory action, anti-PAF (platelet activating factor) action, eosinophil chemoattractant action and the like, and the production thereof. Laws and agents.

[0002]

2. Description of the Related Art Today, many compounds having a triazolopyridazine skeleton have been synthesized as drugs for various kinds of diseases, and USP 3,915,968 describes
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 the nitrogen atom represent a heterocyclic group selected from pyrrolidine, piperidine, piperazine or morpholine. ] The compound or its salt represented by
In 136 and 182, the formula

[Chemical 9] [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,
At least one of R and R ² is a group other than a hydrogen atom, and when R is phenyl, R ¹ is morpholino and R ²
Is lower alkyl. ] The compound represented by the formula or a salt thereof is disclosed in JP-A-62-292784.

[Chemical 10] It is disclosed that the compound represented by or a salt thereof is useful as a bronchodilator for reducing bronchospasm.

Furthermore, EP 562439 describes the formula

[Chemical 11] [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 each 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 represents an integer of 0 to 2), Y Is an expression

[Chemical 12] (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 And 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. Optionally an aryl group, or R ⁶ and R ⁷ together with an adjacent nitrogen atom may form a nitrogen-containing heterocyclic group which may have a substituent, m is an integer of 0 to 4, and n is An integer of 0 to 4 is shown. ] As one of the compounds represented by

[Chemical 13] It is disclosed that these compounds have anti-asthma action, anti-PAF action, anti-inflammatory action and anti-allergic action.

[0004]

SUMMARY OF THE INVENTION It is desired to develop new compounds that are more satisfactory in terms of action and effect, sustainability, safety, etc., as compared with conventional anti-asthma agents, anti-allergic agents and the like.

[0005]

[Means for Solving the Problems] As a result of various studies, the present inventors have found that [1,2,4] triazolo [1,5-
b] A general formula having a large chemical structure in that the 8-position of the pyridazine skeleton is unsubstituted and has a polycarbon alkyl group at the 7-position.

Embedded image [Wherein R ¹ is a hydrogen atom, a halogen atom or a lower alkyl group which may have a substituent, and R ² is a polycarbon alkyl group which may have a substituent or 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).

[Chemical 15] (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 which may have a substituent or a substituent A cycloalkylidene group, 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. A nitrogen-containing heterocyclic group which may have a substituent may be formed together with the nitrogen atom, and m and n each represent an integer of 0 to 4. ] The novel [1,2,4] triazolo [1,5-b] pyridazine compound represented by the following formula or a salt thereof was produced for the first time, and the compound had an unexpectedly superior anti-oxidation activity based on its unique chemical structure. Allergic action, anti-inflammatory action, anti-PA
F action, eosinophil chemotaxis inhibitory action and excellent durability,
It is safe and can be used as an effective anti-asthma drug because it suppresses bronchospasm and bronchoconstriction, and as a preventive and therapeutic agent for allergic rhinitis and atopic dermatitis based on its eosinophil chemotaxis inhibitory effect. It has been found that the above can also be used, and the present invention has been completed based on these. That is, the present invention provides (1) compound [I] or a salt thereof,

(2) The compound described in (1) above, wherein R ¹ is a hydrogen atom or a C _1-6 alkyl group, (3) The above (1) wherein the polycarbon alkyl group is a lower alkyl group having 2 or more carbon atoms. 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), (6)
R ⁵ and R ⁶ are each a hydrogen atom or a C _1-6 alkyl group, wherein (7) R ¹ is a hydrogen atom, R ² is a C _2-6 alkyl group, X is an oxygen atom, Y is

[Chemical 17] (R ^3b and R ^4b each represent a C _1-6 alkyl group), R ⁵ and R ⁶ represent a hydrogen atom or a C _1-6 alkyl group, and m and n each represent 1 or 2 (1).
(8) R ² is a branched C _3-6 alkyl group, (9) R ⁵ and R ⁶ are hydrogen atoms, and m and n are 1 (8) The compound, (10) the C _3-6 alkyl group is an isopropyl group, (11) 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, as described in (1) above,

(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 described in (1) above, (14) 6-
(2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine or a salt thereof, the compound according to (1), ) 6- (2,2-Diethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine or a salt thereof, as described in (1) above. , (1
6) 6- (2,2-dimethyl-3-sulfamoyl-1
-Propoxy) -7-isobutyl [1,2,4] triazolo [1,5-b] pyridazine or a salt thereof, (17) 6- (2,2-dimethyl-3-) Sulfamoyl-1-propoxy) -7-tert-
The compound according to (1) above, 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,

(19) General formula

Embedded image Or a salt thereof and a general formula

[Chemical 19] Or a salt thereof, wherein Z ¹ and Z ² are groups that react with each other to leave, and other symbols have the same meanings as described in (1) above. ] The method for producing the compound according to the above (1), characterized by reacting with

Embedded image [In the formula, W is a leaving group, and other symbols have the same meanings as described in (1) above. ] The compound or its salt represented by these, (2
1) A pharmaceutical composition comprising the compound according to 1) above, 2)
2) An anti-PAF agent containing the compound according to (1) above, (2
3) an eosinophil chemoattractant containing the compound described in (1), (24) an anti-asthma drug containing the compound described in (1),
(25) An anti-allergic agent containing the compound according to (1), (26) a prophylactic / therapeutic agent for allergic rhinitis containing the compound according to (1), and (27) atopic skin containing the compound according to (1). The present invention relates to a preventive and therapeutic agent for inflammation. Further, when the 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.

The term "lower alkyl group" used in the present specification 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” used in the present specification means, for example, a C _3-6 cycloalkyl group. Examples of the C _3-6 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term "polycarbon alkyl group" used in the present specification indicates, for example, an alkyl group having 2 or more carbon atoms. Preferably, a straight-chain or branched C _2-6 alkyl group (eg, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.) is commonly used, and particularly, a branched alkyl group. Groups (eg isopropyl, isobutyl, tert-butyl etc.) are preferred. Examples of the substituent which the above-mentioned "lower alkyl group", "cycloalkyl group" and "polycarbon alkyl group" may have include, for example, hydroxy group, amino group, carboxyl group, nitro group,
Mono- or di-lower alkylamino group (for example, mono- or di-C _1-6 alkylamino group such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), lower alkoxy group (for example, methoxy, C _1-6 alkoxy groups such as ethoxy, propoxy and hexyloxy), lower alkylcarbonyloxy groups (eg C _1-6 alkylcarbonyloxy groups such as acetoxy and ethylcarbonyloxy) and halogen atoms (eg fluorine, 1 to 4 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.

The term "cycloalkylene group" used in the present specification means, for example, a divalent group obtained by removing two hydrogen atoms bonded to two different carbon atoms of a 3- to 7-membered cycloalkane. It means a group. As used herein, the term "cycloalkylidene group" refers to, for example, 2 bonded to one carbon atom of a 3- to 7-membered cycloalkane.
It means a divalent group obtained by removing one hydrogen atom. Specifically, for example

[Chemical 21] Are used, and preferably,

[Chemical formula 22] Is used in general. The term “nitrogen-containing heterocyclic group” used in the present specification includes, for example, one nitrogen atom in addition to carbon atom, and further includes, for example, 1 to 3 nitrogen atom, oxygen atom, sulfur atom and the like. And a group in which a hydrogen atom bonded to a nitrogen atom of a 3- to 13-membered nitrogen-containing heterocycle optionally containing a hetero atom is removed. Specifically, for example

[Chemical formula 23] A 3- to 9-membered nitrogen-containing heterocyclic group such as is commonly used.

Examples of the substituent which the above "cycloalkylene group", "cycloalkylidene group" and "nitrogen-containing heterocyclic group" may have include a lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, tert-butyl, pentyl, hexyl and other C _1-6 alkyl groups), amino group, mono- or di-lower alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino, etc. mono) _-Or di-C _1-6 alkylamino group, etc., hydroxyl group, carboxyl group, nitro group, lower alkoxy group (eg, C such as methoxy, ethoxy, propoxy, etc.)
_1-6 alkoxy group) and halogen atom (for example,
1 selected from fluorine, chlorine, bromine, iodine, etc.)
Or 3 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 represented by R ¹ and the lower alkyl group which may have a substituent, the same ones as the halogen atom and the lower alkyl group which may have a substituent are used. R ¹ is preferably, for example, a hydrogen atom or a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.), and particularly a hydrogen atom is widely used. In the above formula, R ² represents a polycarbon alkyl group which may have a substituent or a cycloalkyl group which may have a substituent. Here, as the polycarbon alkyl group which may have a substituent and the cycloalkyl group which may have a substituent, which are represented by R ² , the polycarbon which may have a substituent described above. The same groups as the alkyl group and the cycloalkyl group which may have a substituent are used. R ² is preferably, for example, a branched C _3-6 alkyl group (eg, isopropyl, isobutyl, tert-butyl, etc.), and particularly, isopropyl group, tert-butyl group, etc. are widely used, and, for example, isopropyl group is most preferable. preferable. In the above formula, X represents an oxygen atom or S (O) p (p represents an integer of 0 to 2). As X, for example, an oxygen atom or S is preferable, and an oxygen atom is generally used.
In the above formula, Y is (i)

[Chemical formula 24] (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 which may have a substituent or a substituent Also represents a cycloalkylidene group. Here, the lower alkyl group which may have a substituent represented by R ³ and R ⁴ and the cycloalkylene group or cycloalkylidene group which may have a substituent represented by Y are the above-mentioned substituents. The same 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
For example, the expression

[Chemical 25] (R ^3a and R ^4a each represent a hydrogen atom or a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, etc.) and the like. More preferred are, for example:

[Chemical formula 26] (R ^3b and R ^4b are each C such as methyl and ethyl.
_{1-4 is} an alkyl group) is commonly used. It is also preferable that Y is a cycloalkylene group or a cycloalkylidene group, and among them, a cycloalkylidene group is preferable, and for example,

[Chemical 27] Are commonly used, especially

[Chemical 28] Are 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 with the adjacent nitrogen atom. Optionally substituted lower alkyl group represented by R ⁵ and R ⁶ , cycloalkyl group optionally substituted, R
Examples of the nitrogen-containing heterocyclic group which may have a substituent formed by ⁵ and R ⁶ together with the adjacent nitrogen atom include a lower alkyl group which may have the above-mentioned substituent and a substituent. The same as the optionally substituted cycloalkyl group 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.) and the like are preferable, and especially a hydrogen atom and the like are widely used. In the above formula, m represents an integer of 0 to 4. As m,
An integer of 1 to 4 is preferable, and when 1 or 2, it is generally 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 generally used. Above all, m
Most preferably, both n and 1 are 1.

The compound [I] or a salt thereof includes, for example, R ¹ is a hydrogen atom, R ² is a C _2-6 alkyl group, X is an oxygen atom, and Y is a formula.

[Chemical 29] (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 each 1 or 2, 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. As the salt of the compound [I] of the present invention, for example, a salt with an inorganic acid (for example, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid), or an organic acid (for example, acetic acid, formic acid, propionic acid, fumaric acid, A salt with maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) or the like is used, and a physiologically acceptable acid addition salt is particularly preferable. Further, when the compound [I] of the present invention has an acidic group such as —COOH as a substituent, the compound [I] is an inorganic base (for example, alkali metal such as sodium, potassium, calcium, magnesium or alkaline earth or alkaline earth). A salt may be formed with a group 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] or salt thereof of the present invention has the general formula (A):

Embedded image Or a salt thereof and a general formula

[Chemical 31] [The symbols in the formulas have the same meanings as described above. ] It can be obtained by reacting with a compound represented by the above or a salt thereof. Examples of the leaving group represented by Z ¹ include a halogen atom (eg, chlorine, bromine, iodine), a C _6-10 arylsulfonyloxy group (eg, benzenesulfonyloxy, p-tolylsulfonyloxy), C _1-4. An alkylsulfonyloxy group (eg, methanesulfonyloxy) or the like is used. Examples of the group capable of leaving by reacting with Z ¹ represented by Z ^2, if X is an oxygen atom or a sulfur atom, for example a hydrogen atom or example 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 its salt is used in an amount of usually 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of the compound [II] or its salt. This reaction is usually condensed in the presence of a base, and examples of the base include 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 is conducted with alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, nitriles such as acetonitrile,
It 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

Embedded image [The symbols in the formulas have the same meanings as described above. ] Or a salt thereof represented by the general formula

[Chemical 33] [The symbols in the formulas have the same meanings as described above. ] It can be obtained by reacting with a compound represented by the above or a salt thereof. In this reaction, compound [IV] or a salt thereof 1
The compound [V] or a salt thereof is used in an amount of usually 1 to 5 mol, preferably 1 to 2 mol, per mol. This reaction is usually condensed in the presence of a base, and examples of the base include 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 and carbonates such as sodium carbonate and potassium carbonate are used. In addition, this reaction is performed using 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. It can also be carried out in an inert solvent such as sulfoxides such as dimethyl sulfoxide. The reaction temperature is generally 10 to 200 ° C., preferably 50 to 1
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 has the general formula (C):

Embedded image [In the formula, W is a leaving group, and other symbols have the same meanings as described above. ] Or a salt thereof represented by the general formula

Embedded image [The symbols in the formulas have the same meanings as described above. ] It can be obtained by reacting with a compound represented by the 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 (eg, methanesulfonyloxy)
Etc. are used, and among them, a halogen atom (eg, chlorine, bromine, iodine) and the like are preferable. In this reaction,
The compound [VI] or the compound [VI] per mol of the salt
I] or a salt thereof is used usually in an amount of 1 to 5 mol, preferably 1 to 2 mol. This reaction is usually performed with methanol,
Alcohols such as ethanol, ethers such as dioxane and tetrahydrofuran, benzene, toluene,
It can be carried out 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,
It is preferably -10 to 50 ° C. Reaction is usually 3
It is 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 in the case of a free form, or into a free form or another salt according to a conventional method when forming a salt. The thus obtained compound [I] or a salt thereof,
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 compound [I] or a salt thereof is an optically active substance, d can be obtained by a conventional optical resolution means.
It can be separated into one body and one body. Next, starting compounds [II] and [II] used for the production of compound [I] or a salt thereof
The production method of 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), or organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid). acid,
Tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) and the like salts are used. Furthermore, these compounds have --COO as a substituent.
When it has an acidic group such as H, an inorganic base (for example,
It may form a salt with an alkali metal such as sodium, potassium, calcium, magnesium, etc., such as an alkaline metal, ammonia) or an organic base (eg, a tri-C _1-3 alkylamine such as triethylamine).

The starting compound [II] or a salt thereof can be obtained, for example, from Journal of Organic Chemistry (J. Or
g. Chem.) Vol. 39, page 2143 (1987) or a method analogous thereto or the like. The raw material compound [III] or a salt thereof and the compound [V] or a salt thereof are, for example, Chemisch Berichte (Chem. Ber.).
91, 2130 (1958), Journal of Organic Chemistry (J. Org. Chem.) 52.
Vol., 2162 (1987), JP-A-3-2232
87 or the like or a method similar thereto or the like. 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 is, for example, (1) Compound [I
I] or its salt and formula

Embedded image [The symbols in the formulas have the same meanings as described above. ] Or a compound represented by the formula [2]

Embedded image [The symbols in the formulas have the same meanings as described above. ] It can synthesize by making it react with the compound represented by these, etc.
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 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 used in an amount of usually 1 to 5 mol, preferably 1 to 2 mol, per mol. This reaction can be carried out in the same manner as 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 may be formed by the raw material compound is not particularly limited as long as the object is achieved, and for example, the same salt as that formed by the compound [I] may be used.

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

The protecting group for the hydroxyl group may be, for example, C _1-6 alkyl _optionally having a substituent (eg,
Methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, etc.), phenyl, C _7-10 aralkyl (eg, benzyl), formyl, C _1-6 alkyl-carbonyl (eg, acetyl, Ethylcarbonyl, etc.), phenyloxycarbonyl, benzoyl, C
_7-10 aralkyl-carbonyl (eg, benzylcarbonyl, etc.), pyranyl, furanyl, silyl and the like are used. As these substituents, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl (eg, methyl, ethyl, n-propyl, etc.),
Phenyl, C _7-10 aralkyl (eg, 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 protective group, a method known per se or a method analogous thereto can be used, and examples thereof include acid, 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
It has excellent anti-allergic, anti-inflammatory, anti-PAF (platelet activating factor) and eosinophil chemoattractant action and low toxicity (acute toxicity: LD ₅₀ > 2g / kg)
Therefore, it can be used as a safe anti-asthma agent for mammals (for example, humans, mice, dogs, rats, cows, etc.). Furthermore, the compound [I] or a salt thereof suppresses eosinophil chemotaxis and suppresses infiltration of eosinophils locally in allergic reaction and inflammatory reaction. Therefore, it is useful as a therapeutic agent for diseases associated with eosinophil infiltration. That is, showing eosinophilia in the mammal, for example, urticaria, atopic dermatitis, allergic rhinitis, allergic diseases such as hypersensitivity pneumonitis, eczema, herpes dermatitis, skin diseases such as psoriasis, It can be used for treating or preventing respiratory diseases such as eosinophilic pneumonia (PIE syndrome). The administration route may be oral or parenteral. Further, the preparation used in the present invention may contain a pharmaceutical ingredient other than the compound [I] or a salt thereof as an active ingredient. Such pharmaceutically active ingredients include, for example, anti-asthma 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, tosufloxacin 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 in an appropriate blending 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, the method described in the Japanese Pharmacopoeia). In the preparation of the present invention, the content of the compound [I] or a salt thereof varies depending on the form of the preparation, but is usually 0.01 to 10 based on the whole preparation.
It is 0% by weight, preferably 0.1 to 50% by weight, and more preferably 0.5 to 20% by weight.

Specifically, the method for producing tablets is as follows: a pharmaceutical product as it is, an excipient, a binder, a disintegrating agent or other suitable additives are uniformly mixed and granulated by a suitable method. After that, add a lubricant etc. and press-mold, or directly press-mold the drug as it is, or mix it evenly with excipients, binders, disintegrants or other appropriate additives. It is also possible to manufacture by granulation or by pre-manufactured granules as they are, or by adding appropriate additives and mixing uniformly, and then compression molding. In addition, a colorant, a flavoring agent and the like can be added to the present agent, if necessary. Furthermore, this agent can be coated with a suitable coating agent. The method for producing injections is to make a fixed amount of a fixed amount of a drug by dissolving, suspending or emulsifying it in water for injection in the case of an aqueous solvent, physiological saline, Ringer's solution, etc. Alternatively, it can be manufactured by taking a certain amount of a drug and sealing it in a container for injection. As the oral pharmaceutical carrier, substances commonly used in the pharmaceutical field such as starch, mannitol, crystalline cellulose, sodium carboxymethyl cellulose and the like can be used. As an injection carrier,
For example, distilled water, physiological saline, glucose solution, infusion solution and the like are used. In addition, additives generally used in preparations can be added as appropriate. The dosage of these preparations varies depending on the age, body weight, symptoms, administration route, number of administrations, etc., but is converted to the active ingredient (compound [I] or a salt thereof) per day for adult asthma patients. Usually 0.1 to 100 mg / kg, preferably 1 to 50 mg / kg
It is advisable to administer kg, more preferably 1 to 10 mg / kg, orally in 1 or 2 divided doses per day.

[0024]

BEST MODE FOR CARRYING OUT THE INVENTION In the following, examples, reference examples,
The present invention is made more concrete by formulation examples and experimental examples, but the present invention is not limited thereto. The detection of the fraction containing the target substance in the examples was carried out by TLC (Thin L
ayer 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 3,2.5-dichloropyridazine 22.5 g, silver nitrate 12.7
g, propionic acid 16.3 g, water 250 ml suspension solution was heated to an internal temperature of 50 ° C., concentrated sulfuric acid 49.3 g was added to water 250 ml.
The diluted solution was added. Raise the internal temperature to 60 ℃, 20
Add 2 g of a solution of 93 g of ammonium persulfate in 0 ml of water.
It was dripped in 0 minutes. The mixture was reacted at an internal temperature of 70-75 ° C for 30 minutes, and 25% aqueous ammonia was added under ice cooling to obtain a pH of 7.0.
And The reaction solution was extracted with ethyl ether, 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 = 7Hz), 2.78 (2H, q,
J = 7Hz), 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 title compound 1 was reacted with 4 g in the same manner as in Reference Example 1.
2.7 g was obtained. NMR (CDCl ₃ ) δ: 1.10 (3H, t, J = 7Hz), 1.5-1.9 (2
H, m), 2.72 (2H, t, J = 7Hz), 7.37 (1H, s)

Reference Example 3 Preparation of 3,6-dichloro-4-isobutylpyridazine 22.3 g of 3,6-dichloropyridazine and isovaleric acid 1
The reaction was performed 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 = 7Hz), 1.8-2.2 (1
H, m), 2.60 (2H, d, J = 7Hz), 7.38 (1H, s) Reference Example 4 Preparation of 3,6-dichloro-4-n-hexylpyridazine 3,6-dichloropyridazine 11.7 g and n -Using 23.0 g of heptanoic acid, the reaction was carried out in the same manner as in Reference Example 1 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 Preparation of 4-cyclopentyl-3,6-dichloropyridazine 22.4 g of 3,6-dichloropyridazine and cyclopentanecarboxylic acid 25 The reaction was performed 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 3,6-dichloro-4-ethylpyridazine 13.5 g, 2
150 ml of 5% aqueous ammonia and 10 ml of ethanol were put into a sealed stainless steel reaction tube and stirred at 130 to 140 ° C. for 22 hours. After cooling and concentrating, 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 = 7Hz), 2.54
(2H, q, J = 7Hz), 6.48 (2H, s), 6.73 (1H, s) Reference Example 7 Preparation 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 = 7Hz), 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 3,6-dichloro-4-isopropylpyridazine 21.7
g, 170 ml of 25% aqueous ammonia, and 10 ml of ethanol were reacted in the same manner as in Reference Example 6 to give 11.1 g of the title compound.
I got Melting point 164-165 ° C NMR (CDCl ₃ ) δ: 1.26 (6H, d, J = 7Hz), 3.16 (1H,
m), 4.89 (2H, br.s), 6.65 (1H, s) Reference Example 9 Preparation of 3-amino-6-chloro-5-isobutylpyridazine 13.5 g of 3,6-dichloro-4-isobutylpyridazine
And 180 ml of 25% aqueous ammonia and 5 ml of ethanol were reacted in the same manner as in Reference Example 6 to obtain 7.3 g of the title compound. Melting point 122-123 ° C NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 7Hz), 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-t-butyl-6-chloropyridazine 4-t-butyl-3,6-dichloropyridazine 31.1
g, 150 ml of 25% aqueous ammonia, and 15 ml of ethanol were reacted in the same manner as in Reference Example 6 to give the title compound 20.8.
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 Method for producing 3-amino-6-chloro-5-n-hexylpyridazine 3,6-dichloro-4-n-hexylpyridazine 14.4
g, 25% ammonia water 150 ml, ethanol 150 ml
Was reacted in the same manner as in Reference Example 6 to give the title compound 6.2.
g was obtained. Melting point 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 Preparation of 3-amino-6-chloro-5-cyclopentylpyridazine 4-Cyclopentyl-3,6-dichloropyridazine 28.
7g, 210% ammonia water 210ml, ethanol 70ml
Was reacted in the same manner as in Reference Example 6 to give the title compound 15.
5 g was 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 formamido 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 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: methanol = 10: 1.
The desired fractions were collected, concentrated and the residue was dissolved in 40 ml of methanol to give 1.8 g of hydroxylamine hydrochloride.
Was added and the mixture was stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration to give the title compound (4.40 g). 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-
Preparation of yl) formamidoxime 3-amino-6-chloro-5-n-propylpyridazine (6.8 g) was reacted in the same manner as in Reference Example 13 to obtain 4.7 g of the title compound. NMR (d ₆ -DMSO) δ: 0.95 (3H, t, J = 7Hz), 1.5-
1.8 (2H, m), 2.57 (2H, t, J = 7Hz), 7.36 (1H, s), 7.91 (1H,
d, J = 10Hz), 9.65 (1H, d, J = 10Hz), 10.40 (1H, s) Reference Example 15 N- (6-chloro-5-isopropylpyridazine-3-
Preparation of yl) formamido oxime 3-amino-6-chloro-5-isopropylpyridazine (8.6 g) was reacted in the same manner as in Reference Example 13 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) formamido oxime In the same manner as in Reference Example 13 using 7.0 g of 3-amino-6-chloro-5-isobutylpyridazine. The reaction was carried out to obtain 4.9 g of the title compound. Melting point 155-158 ° C. Elemental analysis value: calculated as C ₉ H ₁₃ N ₄ OCl.H ₂ O (%): C, 43.82; H, 6.13; N, 22.
71 Found (%): C, 43.23; H, 6.21; N, 23.
00 Reference Example 17 Preparation of N- (5-t-butyl-6-chloropyridazin-3-yl) formamide oxime 3-Amino-5-t-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 value: Calculated as C ₉ H ₁₃ N ₄ OCl (%): 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-
Production of yl) formamido oxime 6.0 g of 3-amino-6-chloro-5-n-hexylpyridazine was reacted in the same manner as in Reference Example 13 to obtain 5.7 g of the title compound. Melting point 131-133 ° C. Elemental analysis value: C ₁₁ H ₁₇ N ₄ OCl Calculated value (%): 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
-Yl) Production of formamido oxime The reaction was performed 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)
Formamide oxime (4.02 g) and polyphosphoric acid (25 g) 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 concentration under reduced pressure, hexane was added to the residue and the precipitated crystal was 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 Preparation of 6-chloro-7-n-propyl [1,2,4] triazolo [1,5-b] pyridazine N- (6-chloro-5-n-propylpyridazine-3-
Il) formamide oxime 4.7 g and polyphosphoric acid 23
The reaction was performed in the same manner as in Reference Example 20 using g to obtain 3.1 g of the title compound. Melting point 61-62 ° C Elemental analysis value: 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-
The reaction was carried out in the same manner as in Reference Example 20 using 20.04 g of (yl) formamide oxime and 97 g of polyphosphoric acid to obtain 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 Preparation of 6-chloro-7-isobutyl [1,2,4] triazolo [1,5-b] pyridazine N- (6-chloro-5-isobutylpyridazin-3-yl) formamide oxime 4.6 g And polyphosphoric acid 22g
Was reacted in the same manner as in Reference Example 20 to give the title compound 2.
2 g was obtained. Melting point 60-62 ° C. Elemental analysis value: calculated as C ₉ H ₁₁ ClN ₄ (%): C, 51.31; H, 5.26; N, 26.
60 Actual value (%): C, 51.33; H, 5.05; N,
26.71

Reference Example 24 Preparation of 7-t-butyl-6-chloro [1,2,4] triazolo [1,5-b] pyridazine N- (5-t-butyl-6-chloropyridazin-3-yl ) Formamide oxime 8.0g and polyphosphoric acid 38g
Was 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 value: Calculated value as C ₉ H ₁₁ ClN ₄ (%): C, 51.31; H, 5.26; N, 26.
60 Found (%): C, 51.15; H, 5.15; N, 26.
66 Reference Example 25 Preparation of 6-chloro-7-n-hexyl [1,2,4] triazolo [1,5-b] pyridazine N- (6-chloro-5-n-hexylpyridazine-3-
Ill) formamide oxime 5.5 g and polyphosphoric acid 22
Using g, the reaction was carried out 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 value: Calculated as C ₁₁ H ₁₅ ClN ₄ (%): 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 7.76 g and polyphosphoric acid 40 g were reacted 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 value: calculated as C ₁₀ H ₁₁ ClN ₄ (%): 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-
Ile) Production 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 fractions were collected and concentrated, the residue was dissolved in 25 ml of methanol, 1.37 g of hydroxylamine hydrochloride was added, and the mixture was stirred at room temperature for 1 hr. The precipitated crystals were collected by filtration to obtain 3.42 g of the title compound. Melting point 175-178 ° C Elemental analysis value: Calculated value as C ₉ H ₁₃ N ₄ OCl (%): 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] Preparation of triazolo [1,5-b] pyridazine N- (6-chloro-5-isopropylpyridazine-3-
Yl) acetamide oxime 1.7 g and polyphosphoric acid 10
g was 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. The mixture was concentrated under reduced pressure, hexane was added to the residue, and the precipitated crystals were collected by filtration to give the title compound (1.06 g). Melting point 58-60 ° C. Elemental analysis value: Calculated value as C ₉ H ₁₁ N ₄ Cl (%): 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.
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 saturated 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 fractions were collected and the obtained crystals were recrystallized from acetone-H ₂ O to give 0.787 g of the title compound. 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 2,2-dimethylpropane-1-sulfonamide and 6-chloro-7-n-propyl [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 0.77.
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 Sodium 0.336 g was suspended in 30 ml of tetrahydrofuran to give 3-hydroxy-2,2.
-Dimethylpropane-1-sulfonamide 0.669 g
Was added and the mixture was heated to reflux 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 saturated 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:
Elute at 1. The desired fractions were collected, and the obtained 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 0.5 of 6-chloro-7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine.
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 2,2-dimethylpropane-1-sulfonamide and 6-chloro-7-isobutyl [1,2,4] triazolo [1,5-b] pyridazine 1.0
g 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. Melting point 168-170 ° C. Elemental analysis value: Calculated as C ₁₄ H ₂₃ N ₅ O ₃ 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 give the title compound 1.5.
g was obtained. Melting point 150-151 ° C Elemental analysis value: C ₁₆ H ₂₇ N ₅ O ₃ S Calculated value (%): 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 1.01 g of dimethylpropan-1-sulfonamide and 6-chloro-7-cyclopentyl [1,2,4] triazolo [1,5-b] pyridazine 1.
The title compound 1. was reacted in the same manner as in Example 1 using 27 g.
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 60% oily sodium hydride (168 mg) in tetrahydrofuran (25 ml). Suspended 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 pH 5 to saturate the salt, and the mixture was extracted with tetrahydrofuran. The extract was washed with saturated brine 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. Melting point 190-191 ° C Elemental analysis value: Calculated value as C ₁₁ H ₁₇ N ₅ O ₃ 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] Preparation of triazolo [1,5-b] pyridazine 60%
252 mg of oily sodium hydride and tetrahydrofuran 3
The mixture was suspended 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, add ice water and add 5N hydrochloric acid to adjust the pH to 5 to saturate the salt,
Extract with ethyl acetate-tetrahydrofuran (2: 1),
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 dichloromethane: ethyl acetate: methanol = 1.
Elute at 0: 10: 1. The desired fractions were 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% oiliness Sodium hydride (380 mg) was suspended in tetrahydrofuran (30 ml), and 3-hydroxy-2,2-diethylpropane-1-sulfonamide (980 mg) was added to give 1
Heated to reflux for hours. After cooling, 7-t-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 bring the pH to pH 4 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 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 value: Calculated value as C ₁₆ H ₂₇ N ₅ O ₃ S (%): 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 the compound [I] of the present invention or a salt thereof are shown below. [Effect on Platelet Activating Factor (PAF) -Induced Guinea Pig Airway Stenosis Response] Male (Hartley) Hartley guinea pigs (body weight: about 500 g) were used. PAF 1 μg / kg
The airway stenosis response of guinea pigs by intravenous administration was measured according to the Konchett-Roessler method. Urethane from guinea pig (1.5 g / kg, IV)
Under anesthesia, the patient was fixed in a dorsal position, tracheotomized, and connected to a ventilator via a cannula. Also, the side branch of the tracheal cannula was connected to a transducer (type 7020, manufactured by Ugobasile). The insufflation rate was 3 to 7 ml, the insufflation rate was 70 times / min, the load pressure on the lung was 10 cmH ₂ O, and the overflowing air amount was passed through the transducer to the rectigraph (Recte-Hori).
-8s, manufactured by Nihon Denki Sanei). PA dissolved in physiological saline after treatment with galamine (1 mg / kg, IV)
F 1 μg / kg was administered via the jugular cannula, and the resulting airway stenosis response was recorded for 15 minutes. The drug is 3 mg / kg
And 1 mg / kg were suspended in 5% gum arabic solution and orally administered 1 hour before the administration of PAF. The results are shown in [Table 1].

[Table 1] Comparative compound: Compound of Example 3 of EP 562439 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 it has a better anti-PAF action than the compound having a methyl group at the 7-position of the triazolopyridazine skeleton.

Experimental Example 2 1) Preparation of guinea pig eosinophils Male Hartley guinea pigs (body weight 300 g) were intraperitoneally administered with 2 ml of horse serum (Whittaker Bioproducts) once a week for 8 consecutive weeks. 48 hours after the last administration
After injecting 5 ml into the abdominal cavity, the collected solution was centrifuged at 400 × g for 5 minutes. The precipitate is Percoll solution (specific gravity d = 1.
07) Suspended in 5 ml, discontinuous layer of specific gravity of Percoll (specific gravity d =
1.112, 5 ml; d = 1.095, 10 ml; d = 1.0
90, 10 ml; d = 1.085, 5 ml)
It was centrifuged at 00 × g for 25 minutes (18 ° C.). Specific gravity d = 1.
The cell layer formed at the interface between 112 and d = 1.0095 was collected. Erythrocytes mixed in the separated cell sediment were removed by hypotonic treatment (suspension in water for 30 seconds). 10 mM Hep
Wash with Hans solution (Hanks-Hepes) containing es (Dojindo) three times, and suspend in Hanks-Hepes solution (Hanks-Hepes-HSA) containing 2% human serum albumin (Wako Pure Chemical Industries). It was adjusted to 56 × 10 ⁶ cells / ml. The purity of eosinophils is 90% and its viability is 98%.
That was all. 2) Measurement method for chemotaxis reaction inhibition LTB ₄ (final concentration 10 ⁻⁸ M, Cascade Biochemical L) suspended in Hanks-Hepes-HSA solution in a 24-well culture dish in the lower chamber.
td.) 600 μl was added, and the mixture was kept at 37 ° C. for 30 minutes in a carbon dioxide gas incubator. In addition, eosinophil suspension 200μ that was incubated in a constant temperature bath at 37 ° C for 15 minutes
L (5 × 10 ⁶ cells / ml) is placed in a 24-well culture dish as the upper chamber
Chemotaxicell (Polycarbonate membrane, pore size
3 μm, thickness 10 μm), and then added to the upper chamber. After reacting for 2 hours in a carbon dioxide incubator, chemot
The axicell was removed, and 60 μl of a 2% (W / V) EDTA physiological saline solution was added to the lower chamber liquid. After ice-cooling, the number of cells that had migrated into the lower chamber fluid was calculated using a hemocytometer (Coulter Counter).
(Product name)). The drug was dissolved in dimethylformamide (DMF) and added to both the lower chamber and the upper chamber so that the final concentration was 10 ⁻⁵ M.

[0048]

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

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

Formulation Example 1 (1) Compound of Example 3 10.0 mg (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 above in 60.0 mg of lactose and 35.0 mg of corn starch in 0.03 ml of 10% aqueous gelatin solution (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 obtained central tablets were coated with sugar coating with a suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were polished with beeswax to obtain coated tablets.

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

[0051]

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

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display area A61K 31/50 ADA AED

Claims (27)

[Claims] 1. A general formula: [Wherein R ¹ is a hydrogen atom, a halogen atom or a lower alkyl group which may have a substituent, and R ² is a polycarbon alkyl group which may have a substituent or 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) (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 which may have a substituent or a substituent A cycloalkylidene group, 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. A nitrogen-containing heterocyclic group which may have a substituent may be formed together with the nitrogen atom, and m and n each represent an integer of 0 to 4. ] The compound or its salt represented by these. 2. The compound according to claim ¹ , wherein R ¹ is a hydrogen atom or a C _1-6 alkyl group. 3. The compound according to claim 1, wherein the polycarbon alkyl group is a lower alkyl group having 2 or more carbon atoms. 4. The compound according to claim 3, wherein the lower alkyl group is a branched C _3-6 alkyl group. 5. Y is The compound according to claim 1, wherein R ^3a and R ^4a each represent a hydrogen atom or a C _1-6 alkyl group. 6. R ⁵ and R ⁶ are each a hydrogen atom or C
The compound according to claim 1, which is a _1-6 alkyl group. 7. R ¹ is a hydrogen atom, R ² is a C _2-6 alkyl group,
X is an oxygen atom and Y is (R ^3b and R ^4b each represent a C _1-6 alkyl group), R ⁵ and R ⁶ are hydrogen atoms or C _1-6 alkyl groups, and m and n are 1 or 2, respectively. . 8. The compound according to claim 7, wherein R ² is a branched C _3-6 alkyl group. 9. R ⁵ and R ⁶ are hydrogen atoms, and m and n are 1
9. The compound according to claim 8, which is 10. The compound according to claim 8, wherein the C _3-6 alkyl group is an isopropyl group. 11. The compound according to claim 8, wherein the C _3-6 alkyl group is a tert-butyl group. 12. A 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-ethyl [1,2,4] triazolo [1,5-b] pyridazine or a salt thereof. The described compound. 13. 6- (2,2-Dimethyl-3-sulfamoyl-1-propoxy) -7-n-propyl [1,2,
[4] The compound according to claim 1, which is triazolo [1,5-b] pyridazine or a salt thereof. 14. 6- (2,2-Dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [1,2,
[4] The compound according to claim 1, which is triazolo [1,5-b] pyridazine or a salt thereof. 15. 6- (2,2-Diethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [1,2,
[4] The compound according to claim 1, which is triazolo [1,5-b] pyridazine or a salt thereof. 16. 6- (2,2-Dimethyl-3-sulfamoyl-1-propoxy) -7-isobutyl [1,2,
[4] The compound according to claim 1, which is triazolo [1,5-b] pyridazine or a salt thereof. 17. 6- (2,2-Dimethyl-3-sulfamoyl-1-propoxy) -7-tert-butyl [1,2,
[4] The compound according to claim 1, which is triazolo [1,5-b] pyridazine or a salt thereof. 18. 6- (2,2-diethyl-3-sulfamoyl-1-propoxy) -7-tert-butyl [1,2,
[4] The compound according to claim 1, which is triazolo [1,5-b] pyridazine or a salt thereof. 19. A general formula: A compound represented by or a salt thereof and a general formula: Or a salt thereof, wherein Z ¹ and Z ² are groups that react with each other to leave, and other symbols have the same meanings as in claim 1. ] The method for producing the compound according to claim 1, characterized in that 20. A general formula: [In the formula, W is a leaving group, and other symbols have the same meanings as in claim 1. ] The compound or its salt represented by these. 21. A pharmaceutical composition comprising the compound of claim 1. 22. An anti-PAF containing the compound according to claim 1.
Agent. 23. An eosinophil chemoattractant comprising the compound according to claim 1. 24. An anti-asthma agent containing the compound according to claim 1. 25. An anti-allergic agent comprising the compound according to claim 1. 26. A prophylactic / therapeutic agent for allergic rhinitis, which comprises the compound according to claim 1. 27. A prophylactic / therapeutic agent for atopic dermatitis, which comprises the compound according to claim 1.