JPH05271233A - Condensed pyridazine derivative, its use and production - Google Patents

Abstract

PURPOSE:To obtain a new condensed pyridazine derivative, having excellent antiallergic, antiinflammatory and anti-platelet activating factor (anti-PAF) actions and useful as an antiasthmatic agent, excellent in persistence, safety, etc., and capable of effectively suppressing bronchospasm and bronchoconstriction. CONSTITUTION:The objective compound of formula I (X is CH or N; R<1> to R<5> are H or lower alkyl which may have a substituent group or further R<1> is halogen; R<2> and R<3>, together with the adjacent C=C, form a 5-to 7-membered ring or R<4> and R<5>, together with the adjacent C, form a 3-to 7-membered homo- or heterocyclic ring; A is amino which nay have a substituent group; m and n are integers of 1-4) or its salt, e.g. 6-(3,3-dimethyl-5-sulfamoyl-1-pentyl) imidazo[1,2-b]pyridazine. This compound can be produced by reacting a compound of formula II or its salt with a compound of formula III or its salt (Y and Z are mutually reactive and releasable group; A' is amino which may be protected) or reacting a compound of formula IV (W is halogen) or its salt with a compound of the formula H-A or its salt.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel imidazopyridazine and triazolopyridazine derivative or a salt thereof, a method for producing the same and an agent. The imidazopyridazine and triazolopyridazine derivatives or salts thereof of the present invention have antiallergic action, antiinflammatory action and anti-PAF (platelet activating factor) action, and as an anti-asthma agent by suppressing bronchospasm and bronchoconstriction. It is useful.

[0002]

It has been disclosed in EP-A-185346 that imidazo [1,2-b] pyridazine compounds exhibit antithrombotic and cardiovascular effects, in particular cardiotonic effects. In EP-A-381132, an imidazo [1,2-b] pyridazine compound represented by the following general formula [VI] has anti-allergic, anti-inflammatory and anti-PAF effects and is useful as an anti-asthma agent. It is disclosed that there is.

[Chemical 8] [Wherein, X ¹ is an oxygen atom or S (O) n (n is 0 to 2)
Is an integer). ] Further, EP-A-440119,
EP-A-444549 also has similar disclosures regarding imidazopyridazines, but they all differ from the instant compounds in that the side chains are attached via an atom other than a carbon atom.

[0003]

However, many kinds of anti-asthma agents are commercially available today, but they are not sufficient in terms of therapeutic effect, sustainability, safety, etc. There is a problem in that. Therefore, there is a demand for the development of a novel compound that has a more excellent anti-PAF action than conventional compounds and is more satisfactory as an anti-asthma agent that suppresses bronchospasm and bronchoconstriction.

[0004]

Means for Solving the Problems As a result of intensive investigations by the present inventors on fused pyridazine compounds, the above-mentioned known compounds were found to have imidazo [1] groups whose side chains are not via a heteroatom but via a carbon atom. [2,2-b] Pyridazine ring has a different chemical structure from the viewpoint of being synthesized, and succeeded in synthesizing a novel fused pyridazine compound. Action,
It was found that the anti-asthma agent has an anti-inflammatory action, an anti-PAF action, excellent durability and safety, and effectively suppresses bronchospasm and bronchoconstriction, and the present invention is completed based on these. Came to. That is, the present invention provides the formula (1)

[Chemical 9] [Wherein X is a methine group or a nitrogen atom, R ¹ is a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom, and R ² and R ³ each have a hydrogen atom or a substituent. A lower alkyl group which may be substituted or a 5- to 7-membered ring together with adjacent -C = C-, and R ⁴ and R ⁵ are each a hydrogen atom or a lower alkyl group which may have a substituent. Alternatively, together with a carbon atom adjacent to each other, a 3- to 7-membered homo- or heterocycle, A is an optionally substituted amino group, and m and n are each an integer of 1 to 4. ] The compound or its salt represented by these,
(2) The lower alkyl group which may have a substituent represented by R ¹ , R ² , R ³ , R ⁴ or R ⁵ is hydroxy, amino, carboxy, nitro, mono- or di-C _1- 1 to 4 selected from ₆ alkylamino, C _1-6 alkoxy, C _1-6 alkylcarbonyloxy and halogen atom
Linear or branched C optionally having 1 substituent
The compound of the above (1) which is a _1-6 alkyl group, (3) R ² and R ³ are taken together and are shown together with -C = C-
A compound of the above (1) wherein the to 7-membered ring is a 5- to 7-membered cyclic hydrocarbon or heterocycle, (4) 3 to 7-membered R ⁴ and R ^{5 taken} together are adjacent carbon atoms Wherein the homolog or heterocycle of is a 3- to 7-membered cyclic hydrocarbon or heterocycle, (5) an optionally substituted amino group represented by A

[Chemical 10] [In the formula, R ⁶ and R ⁷ are each a hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or an aryl which may have a substituent. A group or a nitrogen-containing heterocyclic group which may have a substituent together with a nitrogen atom adjacent to each other is shown. ]
The compound of the above (1) represented by the formula (6), (6) the lower alkyl group which may have a substituent is hydroxy, amino, carboxy, nitro, mono- or di-C _1-6 alkylamino, C _{1 -6} alkoxy, C _1-6 alkylcarbonyloxy and a compound of the above (5) which is a C _1-6 alkyl group optionally having 1 to 4 substituents selected from halogen atoms, (7) substitution A cycloalkyl group which may have a group includes hydroxy, amino, carboxy, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 alkylcarbonyloxy and a halogen atom. The compound of the above (5), which is a C _3-6 cycloalkyl group _optionally having 1 to 4 substituents, and (8) the aryl group optionally having substituents,
C _1-6 alkyl, amino, acetamide, hydroxy, carboxy, nitro, C _1-6 alkoxy, C _1-6 alkylcarbonyloxy and C optionally having 1 to 5 substituents selected from halogen atoms The compound of the above (5) which is a _6-14 aryl group, and (9) the nitrogen-containing heterocyclic group which may have a substituent which R ⁶ and R ⁷ together represent with the adjacent nitrogen atom, i) a C _1-6 alkyl group, (ii)
Amino optionally having 1 or 2 substituents selected from C _1-6 alkyl, C _1-6 acyl and 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxy,
(V) nitro, (vi) C _1-6 alkoxy and (vii) a 3- to 13-membered nitrogen-containing heterocyclic group optionally having 1 to 5 substituents selected from the above-mentioned (5 (10) The compound of (1), wherein R ¹ is a hydrogen atom or a C _1-3 alkyl group, (11) R ² and R ³
Wherein each is a hydrogen atom or a C _1-3 alkyl group, or together forms a cyclohexene or benzene together with the adjacent —C═C—, (12) R ⁴ and R ⁵ Are each selected from (i) hydrogen atom or (ii) hydroxy, amino, carboxy, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 alkylcarbonyloxy and halogen atom. A C _1-3 alkyl group which may have 1 to 4 substituents, or (iii) together with the adjacent carbon atom has the formula

[Chemical 11] Forming the compound of (1), (13) R ² ,
The compound of (1) above, wherein R ³ , R ⁴ and R ⁵ are each a hydrogen atom or a C _1-3 alkyl group, (14) The above (1) wherein R ² and R ³ are each a C _1-3 alkyl group Compound of
(15) R ² and R ³ are adjacent to each other together -C = C-
(16) R ⁴ and R ⁵ are both C _1-3 together with cyclohexene or benzene to form cyclohexene or benzene.
The compound of the above (1) which is an alkyl group, (17) R ⁴ and R ⁵ are taken together to form a compound having an adjacent carbon atom.

[Chemical 12] The compound of (1), which forms the compound (18) A, wherein (18) A is an amino group optionally substituted with one or two C _1-3 alkyl groups, (19) A Wherein (1) is an amino group, (20) the compound of (1) wherein R ¹ is a hydrogen atom, (21) the compound of (1) wherein both R ² and R ³ are hydrogen atoms, (22) The compound of the above (1), wherein R ⁴ and R ⁵ are both hydrogen atoms, (2
3) The compound of the above (1) in which m and n are each 1 or 2, (24) the compound of the above (1) in which m and n are both 2, (25) the above (1) in which X is a methine group The compound of (1), wherein (26) X is a nitrogen atom,
(27) X is a methine group, R ¹ is a hydrogen atom, R ² , R ³ and R ⁴
And R ⁵ are each a hydrogen atom or a C _1-3 alkyl group,
A is an amino group, m and n are each an integer of 1 to 3, and (28) X is a methine group, R ¹
And R ² are both hydrogen atoms, and R ³ , R ⁴ and R ⁵ are C
_1-3 alkyl group, A is amino group, compound of the above (1) wherein m and n are both 2, (29) X is nitrogen atom, R ¹ is hydrogen atom, R ² , R ³ , R ⁴ and R The compound of the above (1), wherein ⁵ is a hydrogen atom or a C _1-3 alkyl group, A is an amino group, and m and n are both 2. (30) The compound of (1), which is a hydrochloride salt, (31) 6- (3,3-dimethyl-
5-sulfamoyl-1-pentyl) imidazo [1,2
-B] The compound of the above (1) which is pyridazine, (32)
The compound of (1) above, which is 6- (3,3-dimethyl-5-sulfamoyl-1-pentyl) -7-methylimidazo [1,2-b] pyridazine, (33) 6- (3,3-
Dimethyl-5-sulfamoyl-1-pentyl) imidazo [1,2-b] pyridazine hydrochloride, the compound of (1) above, (34) 6- (3,3-dimethyl-5-sulfamoyl-1-pentyl). -7-Methylimidazo [1,
2-b] the compound of (1) which is pyridazine hydrochloride,
Equation (35)

[Chemical 13] Or a salt thereof and a formula

[Chemical 14] Or a salt thereof, wherein Y and Z are groups capable of reacting with each other and leaving, A'is an amino group which may be protected, and other symbols have the same meanings as defined in the above (1). Indicates. ] The method for producing the compound of the above (1), characterized by reacting with

[Chemical 15] [In the formula, W represents a halogen atom, and other symbols have the same meanings as in the above (1). ] The compound or its salt represented by these, and formula HA [V] [In formula, A shows the same meaning as said (1). ] The method of manufacturing the compound of said (1) characterized by reacting with the compound represented by these, or its salt, (37) The anti-asthma agent characterized by containing the compound of said (1), ( 38) An anti-PAF agent containing the compound of the above (1). 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.

The term "lower alkyl" used in the present specification means, for example, a linear or branched C _1-6 alkyl group. As a C _1-6 alkyl group, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl or n-
Hexyl or the like is used. The "lower alkyl" may have a substituent, for example, hydroxy, amino, carboxyl, nitro, mono- or di-lower alkylamino (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino). Such as mono- or di-C _1-6 alkylamino), lower alkoxy (eg, methoxy, ethoxy, propoxy,
C _1-6 alkoxy such as hexyloxy), lower alkylcarbonyloxy (eg C _1-6 alkyl-carbonyloxy such as acetoxy, ethylcarbonyloxy) or a halogen atom (eg fluorine, chlorine, bromine, iodine etc.) ) And the like are used.

R ² and R ³ together form "adjacent --C
The term "5- to 7-membered ring represented by ═C-" means a 5- to 7-membered cyclic hydrocarbon consisting of only carbon atoms, or 1 to 4 selected from a nitrogen atom, an oxygen atom, a sulfur atom and the like in addition to the carbon atom. May contain 4 heteroatoms 5
To 7-membered heterocycle and the like. Specifically, in particular, C _5-7 cycloalkene such as cyclopentene, cyclohexene and cycloheptene, a 5- to 7-membered cyclic hydrocarbon such as benzene, and a nitrogen-containing nitrogen atom composed of a carbon atom and a nitrogen atom such as pyrrole, pyridine and piperidine. Heterocycles are often used.

The term "3- to 7-membered homocyclic ring represented by R ⁴ and R ⁵ together with adjacent carbon atoms" means, for example, a 3- to 7-membered cyclic hydrocarbon consisting of only carbon atoms. .. Specifically, for example, C _3-7 cycloalkane such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, for example, cyclopropene, cyclobutene, cyclopentene, cyclohexene,
C _3-7 cycloalkene such as cycloheptene, or
Benzene is often used. Therefore, the formula

[Chemical 16] Examples of the 3- to 7-membered homocyclic group represented by

[Chemical 17] Are used, especially

[Chemical 18] Is often used.

"A 3- to 7-membered heterocyclic ring represented by R ⁴ and R ⁵ together with adjacent carbon atoms" means, for example, a carbon atom, a nitrogen atom, an oxygen atom, a sulfur atom or the like. To optionally containing 4 heteroatoms 3
To 7-membered heterocycle and the like. Specifically, for example, oxetane, tetrahydrofuran, tetrahydropyran, pyrrole, azetidine, pyrrolidine, piperidine,
Piperazine, tetrahydrothiophene, homopiperidine, morpholine, furan, pyridine or the like is used. Therefore, the formula

[Chemical 19] Examples of the 3- to 7-membered heterocyclic group represented by

[Chemical 20] Etc. are used.

The "3- to 7-membered homocycle represented by adjacent carbon atoms" and "3- to 7-membered heterocycle represented by adjacent carbon atoms" represented by R ⁴ and R ⁵ may have a substituent. Often, such a substituent includes, for example, a lower alkyl optionally having a substituent (eg, C _1-6 alkyl such as methyl, ethyl, propyl, etc.), an amino optionally having a substituent. , Hydroxy, carboxy, nitro, lower alkoxy (eg, methoxy, ethoxy,
1 to 5 selected from C _1-6 alkoxy such as propoxy) and a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) are used. Here, the substituent which lower alkyl may have is, for example, hydroxy, amino, mono- or di-lower alkylamino (for example, monoamino such as methylamino, ethylamino, propylamino, dimethylamino and diethylamino).
Or di-C _1-6 alkylamino etc.), lower alkoxy (eg C _1-6 alkoxy such as methoxy, ethoxy, propoxy, hexyloxy etc.), lower alkylcarbonyloxy (eg C such as acetyl, ethylcarbonyloxy etc. _6alkyl - carbonyloxy, etc.) and a halogen atom (e.g., fluorine, chlorine, bromine, four to 1 selected from such iodine) are used. As the substituent which the amino group may have,
For example, C _1-6 alkyl (eg, methyl, ethyl, propyl, etc.), acyl (eg, C _1-6 acyl such as formyl, acetyl, propionyl, butyryl), and 5- to 7-membered cyclic amino (eg, pyrrolidino, morpholino). , Piperidino, piperazino, etc.) or the like.

The term "optionally substituted amino group" refers, for example, to the formula

[Chemical 21] [In the formula, R ⁶ and R ⁷ are each a hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or an aryl which may have a substituent. A group or a nitrogen-containing heterocyclic group which may have a substituent together with a nitrogen atom adjacent to each other is shown. ] The group etc. which are represented by these are shown. The term “cycloalkyl group” 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 “aryl group” means, for example, a C _6-14 aryl group. Examples of the C _6-14 aryl group include phenyl and naphthyl. As the substituent that the “cycloalkyl group” may have, those similar to the above-mentioned “substituent that the lower alkyl group may have” are used. The number of substituents is preferably 1 to 4.

The substituent that the "aryl group" may have is, for example, lower alkyl which may have a substituent, amino which may have a substituent, acetamide,
Hydroxy, carboxy, nitro, lower alkoxy (eg, C _1-6 alkoxy such as methoxy, ethoxy, propoxy, etc.), lower alkylcarbonyloxy (eg, C _1-6 such as acetoxy, ethylcarbonyloxy, etc.)
1 to 5 selected from an alkylcarbonyloxy group) and a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) are used. Here, the substituent which lower alkyl may have is, for example, hydroxy, amino, mono- or di-lower alkylamino (for example, monoamino such as methylamino, ethylamino, propylamino, dimethylamino and diethylamino). Or di-C _1-6 alkylamino etc.), lower alkoxy (eg C _1-6 alkoxy such as methoxy, ethoxy, propoxy, hexyloxy etc.) or halogen atom (eg fluorine, chlorine, bromine, iodine etc.), etc. 1 to 4 selected from are used. Examples of the substituent that the amino group may have include C _1-6 alkyl (eg, methyl, ethyl, propyl, etc.) and 5
1 to 7-membered cyclic amino (eg, pyrrolidino, morpholino, piperidino, piperazino, etc.) and the like 1
Or two are used. As the term “halogen atom”, for example, fluorine, chlorine, bromine, iodine and the like are used.

The "nitrogen-containing heterocyclic group" represented by R ⁶ and R ⁷ together with the adjacent nitrogen atom includes, for example, one nitrogen atom in addition to the carbon atom, and further includes, for example, a nitrogen atom and an oxygen atom. , A 3- to 13-membered nitrogen-containing heterocyclic ring which may contain 1 to 3 heteroatoms selected from sulfur atom, etc., and one of the hydrogen atoms bonded to the nitrogen atom in the ring is removed Means a possible group. Specifically, for example,

[Chemical formula 22] A 3- to 9-membered nitrogen-containing heterocyclic group such as is commonly used.
Examples of the substituent that the "nitrogen-containing heterocyclic group" may have include "a 3- to 7-membered homocyclic ring shown with adjacent carbon atoms" for R ⁴ and R ⁵ and an adjacent carbon atom. The same substituents as those which may be possessed by the “3- to 7-membered heterocycle” shown together with are used. The number of substituents is preferably 1 to 4.

In the above formula, R ¹ represents a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom. R ¹ is, for example, a hydrogen atom or C _1-3 alkyl (eg, methyl, ethyl, n-propyl, etc.)
And the like are preferable, and hydrogen atom is particularly frequently used. R ² and R ³ each represent a hydrogen atom or a lower alkyl group which may have a substituent, and R ² and R ³ together form a 5- to 7-membered ring together with adjacent —C═C—. You may. Examples of R ² and R ³ include a hydrogen atom and C _1-3 alkyl (eg, methyl, ethyl, n-propyl, etc.)
And the like are preferable, and particularly, a hydrogen atom and the like are frequently used. It is also preferable that R ² and R ³ form a 5- to 7-membered homocyclic ring together with adjacent —C═C—. In particular, cyclohexene, benzene and the like are preferably formed.

R ⁴ and R ⁵ each represent a hydrogen atom or a lower alkyl group which may have a substituent, and R ⁴
And R ⁵ may be taken together to form a 5- to 7-membered ring with the adjacent —C═C—. R ⁴ and R ⁵ are preferably a hydrogen atom or a C _1-3 alkyl group (eg, methyl, ethyl, n-propyl, etc.). It is also preferred that R ⁴ and R ⁵ together form a 3- to 7-membered homocyclic or heterocyclic ring with the adjacent carbon atom,
Expression

[Chemical formula 23] And especially

[Chemical formula 24] It is often used to indicate such as.

R ⁶ and R ⁷ are each a hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or an aryl group which may have a substituent. Or R ⁶ and R ⁷ may together form a nitrogen-containing heterocyclic group which may have a substituent with an adjacent nitrogen atom. As R ⁶ and R ⁷ , for example, a hydrogen atom, C _1-3 alkyl (eg, methyl, ethyl, n-propyl, etc.) and the like are preferable, and particularly a hydrogen atom and the like are frequently used. That is, A which is an optionally substituted amino group is

[Chemical 25] Is more preferable, and further, an unsubstituted amino group in which R ⁶ and R ⁷ are each a hydrogen atom or a hydrogen atom or a C _1-3 alkyl group (for example, methyl, ethyl, n-
More preferred is an amino group substituted with propyl, etc.).
Most preferably, it is an unsubstituted amino group. m is 1
Is an integer of 4 to 4. As m, 1 and 2 are preferable, and 2 is particularly often used. n represents an integer of 1 to 4, and as n, 1 and 2 are preferable, and 2 and the like are often used. Especially, the case where both m and n are 2 is the most preferable.

Further, examples of preferred compound [I] include
The following compounds or salts thereof may be mentioned. 1) 6- (3,3-diethyl-5-sulfamoyl-
1-pentyl) imidazo [1,2-b] pyridazine 2) 6- (3,3-diethyl-5-sulfamoyl-
1-pentyl) -7-methylimidazo [1,2-b] pyridazine 3) 6- (3,3-pentamethylene-5-sulfamoyl-1-pentyl) imidazo [1,2-b] pyridazine 4) 6- (3,3-Pentamethylene-5-sulfamoyl-1-pentyl) -7-methylimidazo [1,2-
b] pyridazine 5) 6- (3,3-tetramethylene-5-sulfamoyl-1-pentyl) imidazo [1,2-b] pyridazine 6) 6- (3,3-tetramethylene-5-sulfamoyl-1- Pentyl) -7-methylimidazo [1,2-
b] pyridazine 7) 6- (3,3-trimethylene-5-sulfamoyl-1-pentyl) imidazo [1,2-b] pyridazine 8) 6- (3,3-trimethylene-5-sulfamoyl-1-pentyl) -7-Methylimidazo [1,2-
b] Pyridazine As the salt of the compound [I] of the present invention, a pharmaceutically or physiologically acceptable acid addition salt is particularly preferable. Examples of such salts 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). , Tartaric acid, lactic acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, p-tolylsulfonic acid, benzenesulfonic acid) and the like.

Next, a method for producing the compound [I] of the present invention or a salt thereof will be described. A) The compound [I] of the present invention or a salt thereof is a compound [I]
It can be obtained by reacting I] or a salt thereof with a compound [III] or a salt thereof. Y and Z represent groups capable of leaving each other by reacting with each other. Specifically, as the group represented by Z, for example, halogen (eg, chlorine, bromine, iodine), C _6-10 arylsulfonyloxy (eg, benzenesulfonyloxy, p-tolylsulfonyloxy), C _1-4 Alkylsulfonyloxy (eg, methanesulfonyloxy, trifluoromethanesulfonyloxy, etc.) and the like are used. The group represented by Y is a halogeno metal, and the halogen is (for example, chlorine, bromine, iodine, etc.), and iodine is preferably used. Further, as the metal (for example, zinc, magnesium, etc.), zinc or the like is preferably used. This reaction is preferably condensed in the presence of a palladium catalyst, and the palladium catalyst is a catalyst that can be used in a palladium catalyst-cross coupling reaction [Accounts.
Accounts of Chemical Res
earch), 12 , 146-151 (1979); ibid, 1
5 , 340-348 (1982); Angewand Chemie Int. Ed. Engl. 25 , 508-
524 (1986) and the like], and examples thereof include a palladium-tertiary phosphine complex, a palladium salt, or a combination of a palladium complex and a third phosphine. Palladium-tertiary phosphine complex means 0
Means a complex of trivalent or divalent palladium with a tertiary phosphine such as trialkylphosphine or triarylphosphine, for example tetrakis (triphenylphosphine)
Palladium, bis (triphenylphosphine) palladium bromide, bis (triphenylphosphine) palladium chloride, acetoxybis (triphenylphosphine) palladium, benzylchlorobis (triphenylphosphine)
Palladium, tetrakis (tributylphosphine) palladium, bis (trimethylphosphine) palladium chloride, bis (triethylphosphine) palladium chloride, bis (tripropylphosphine) palladium chloride, bis (tributylphosphine) palladium chloride, etc. can be used, and are preferably used. For example, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium bromide, bis (triphenylphosphine) palladium chloride, acetoxybis (triphenylphosphine) palladium, etc. can be used.

The palladium salt means a salt formed from a divalent palladium ion and an acid residue, and for example, palladium chloride, palladium bromide, palladium acetate, palladium nitrate, palladium sulfate, etc. can be used. Palladium chloride, palladium bromide and palladium acetate can be preferably used. The palladium complex means the above palladium-tertiary phosphine complex, and also means other zero-valent or divalent palladium complex. Examples of such a complex include bis (phenylethylamine) palladium chloride and bis (phenyl chloride) chloride. Examples thereof include benzonitrile) palladium, bis (benzonitrile) palladium bromide, and bis (acetonitrile) palladium chloride. Preferable examples include bis (benzonitrile) palladium chloride and bis (acetonitrile) palladium chloride. Examples of the third phosphine include triphenylphosphine,
Tributylphosphine, tripropylphosphine, triethylphosphine, trimethylphosphine and the like can be used, and preferably triphenylphosphine and the like can be used.

This reaction is preferably carried out in a solvent. Examples of such a solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran and dioxane, dimethylformamide and dimethylacetamide. And amides such as dimethyl sulfoxide, nitriles such as acetonitrile, and the like. Reaction temperature is 0 to 2
The reaction time is 30 minutes to 24 hours, preferably 1 to 3 hours at 00 ° C., preferably 10 to 100 ° C., and the reaction is advantageously carried out under a stream of nitrogen or argon. The reaction product can be isolated and purified by a known means such as solvent extraction, liquid conversion, phase transfer, salting out, crystallization, recrystallization, chromatography and the like. In this reaction, when A ′ is an amino group in the general formula [III], it is preferable to protect the amino group, and as the protecting group, a protecting group generally used in the field of peptide chemistry and the like can be used. Amide-type protecting groups, eg formyl, acetyl, benzoyl, etc .; eg te
Carbamate-forming protecting groups such as rt-butoxycarbonyl and benzyloxycarbonyl; imino-type protecting groups such as dimethylaminomethylene, benzylidene, p-methoxybenzylidene and diphenylmethylene are used. Preferred protecting groups include, for example, formyl, acetyl or dimethylaminomethylene. When the product obtained in the above reaction has a protecting group, the protecting group can be removed according to a conventional method, for example, protection by deprotection operation such as hydrolysis with acid or base or catalytic reduction. The group can be removed.

B) Further, the compound [I] or a salt thereof is
It can be obtained by reacting compound [IV] or a salt thereof with compound [V] or a salt thereof. This reaction is
It is preferably carried out in alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, halogenated hydrocarbons such as dichloromethane, chloroform, and an inert solvent such as acetonitrile and dimethyl sulfoxide. The reaction temperature is generally -20 to 100 ° C, preferably -10 to 50 ° C. The reaction time is generally 30 minutes to 5 hours, preferably 1 to 3 hours. The reaction product can be isolated and purified by a known means such as solvent extraction, liquid conversion, phase transfer, salting out, crystallization, recrystallization, chromatography and the like. A) or B) above
When the compound [I] obtained by the method of 1) is free, it can be converted into a salt according to a conventional method if desired, and when the compound [I] is obtained in the form of a salt, a free compound according to a conventional method Or can be converted to other salts.

The salts of the starting compounds [II], [III], [IV] and [V] used for producing the compound [I] or a salt thereof are as described in the above compound [I]. I can give you some salt. And such raw material compounds [II], [II
I], [IV], [V] or a salt thereof can be produced by a known method or a method analogous thereto, or a method described in Reference Examples described below or a method analogous thereto. Furthermore, the compound [I] of the present invention or a pharmaceutically or physiologically acceptable salt thereof has excellent anti-PAF properties.
It has a (platelet activating factor) action and can be used as a safe anti-asthma agent for mammals (human, mouse, dog, rat, cow, etc.). Specifically, when it is used as an anti-asthma agent for humans, its dose varies depending on the age, body weight, symptoms, administration route, number of administrations, etc., but is 0.1 to 100 mg / kg per day, preferably 1 to 50 mg
/ Kg, more preferably 5 to 50 mg / kg, is preferably administered in 2 to 3 divided doses per day. The route of administration may be oral or parenteral. Compound of this invention [I]
Alternatively, the salt thereof may be used as the bulk powder, but it is usually administered in the form prepared with a carrier for formulation. Specific examples thereof include tablets, capsules, granules, fine granules, powders, syrups, injections and inhalants. These preparations are prepared according to a conventional method. 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 the carrier for injection, distilled water, physiological saline, glucose solution, infusion solution and the like are used. Other additives commonly used in pharmaceutical preparations can be added as appropriate.

[0029]

[Examples] "Room temperature" in the following Reference Examples and Examples is 1
Indicates 5 to 25 ° C. Reference Example 1 Production of 3-aminosulfonyl-1-iodopropane 3-aminosulfonyl-1-chloropropane 10.76
g was dissolved in 150 ml of acetone, and sodium iodide 2 was added.
0.46 g was added and the mixture was heated under reflux for 15 hours. After concentration under reduced pressure, the residue was dissolved in water and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate, the solvent was distilled off, and the obtained crystals were collected by filtration to give the title compound (15.0)
6 g was obtained. NMR (d ₆ -DMSO) δ: 2.0-2.3 (2H, m), 3.06 (2H, t,
J = 8Hz), 3.37 (2H, t, J = 8Hz), 6.89 (2H, s).

Reference Example 2 Production of 4-aminosulfonyl-1-iodobutane In the same manner as in Reference Example 1, except that 4-aminosulfonyl-1-chlorobutane was used instead of 3-aminosulfonyl-1-chloropropane in Reference Example 1. The title compound was prepared. NMR (CDCl ₃ ) δ: 1.8-2.2 (4H, m),
3.0-3.3 (4H, m), 4.68 (2H,
s).

Reference Example 3 Preparation of 5-bromo-3,3-dimethylpentane-1-thiocyanate 1,5-dibromo-3,3-dimethylpentane 17.3 g
Was dissolved in 100 ml of dimethylformamide, 6.84 g of potassium thiocyanate was added, and the mixture was stirred at 80 ° C. for 2 hours.
After cooling, 400 ml of ice water was added, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography and eluted with hexane: ethyl acetate (19: 1) to obtain 7.81 g of the title compound. NMR (CDCl ₃ ) δ: 0.97 (6H, s), 1.7-2.0 (4H, m),
2.8-3.0 (2H, m), 3.3-3.5 (2H, m).

Reference Example 4 Preparation of 5-aminosulfonyl-3,3-dimethyl-1-bromopentane 4.0 g of 5-bromo-3,3-dimethylpentane-1-thiocyanate was dissolved in 30 ml of acetic acid and 30 ml of water and iced. Chlorine gas was bubbled through for 75 minutes while stirring under cold conditions. Then, the mixture was stirred at room temperature for 30 minutes, 100 ml of ice water was added, and the mixture was extracted with dichloromethane. The extract was washed with water and dried over magnesium sulfate. The solvent was distilled off, the residue was dissolved in 50 ml of dichloromethane, and ammonia gas was bubbled in for 45 minutes while stirring with ice cooling. Then stir at room temperature for 30 minutes,
The precipitated insoluble matter was removed by filtration, the filtrate was concentrated and subjected to silica gel column chromatography, and eluted with dichloromethane: methanol (40: 1) to obtain 3.36 g of the title compound. NMR (CDCl ₃ ) δ: 0.97 (6H, s), 1.7-2.0 (4H, m),
3.0-3.2 (2H, m), 3.3-3.5 (2H, m), 4.65 (2H, s).

Reference Example 5 Preparation of 5-aminosulfonyl-3,3-dimethyl-1-iodopentane 5.41 g of 5-aminosulfonyl-3,3-dimethyl-1-bromopentane was dissolved in 80 ml of acetone and sodium iodide was added. 7.85 g was added and the mixture was heated under reflux for 3 hours. After concentration under reduced pressure, the residue was dissolved in water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, the solvent was distilled off, and the obtained crystals were collected by filtration to obtain 6.2 g of the title compound. NMR (CDCl ₃ ) δ: 0.94 (6H, s), 1.7-2.0 (4H, m),
3.0-3.2 (4H, m), 4.66 (2H, s).

Reference Example 6 Preparation of 5- (N, N-dimethylaminomethylene) aminosulfonyl-3,3-dimethyl-1-iodopentane 6.3 g of 5-aminosulfonyl-3,3-dimethyl-1-iodopentane Was dissolved in 50 ml of benzene, and N, N-dimethylformamide dimethylacetal was added to the solution.
1 ml (23.4 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture is concentrated and the residue is treated with 150 g of silica gel.
Was subjected to column chromatography by using an eluent of ethyl acetate-hexane (4: 1, v / v) to obtain 7.24 g of the title compound as colorless crystals. Mp: 105-106 ° C. Elemental _{analysis: C 10 H 21 N 2 O} 2 SI Calculated (%): C, 33.34; H, 5.88; N, 7.78 Found (%): C, 33.57; H, 5.79 N, 8.09 ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.91 (6H, s), 1.
65-1.78 (2H, m), 1.84-1.98 (2H, m), 2.91-3.03 (2H, m),
3.05 (3H, s), 3.14 (3H, s), 3.06-3.19 (2H, m), 8.05 (1H,
s).

Reference Example 7 1-Cyano-5- (N, N-dimethylaminomethylene)
Production of aminosulfonyl-3,3-dimethylpentane 7.20 g (20.0 mmol) of the iodo derivative obtained in Reference Example 6,
A mixture of 1.95 g (30 mmol) of potassium cyanide, 0.26 g (1.0 mmol) of 18-crown-6 and 100 ml of dimethyl sulfoxide was stirred at 90 ° C. for 5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate.
The extract was washed with water, dried (MgSO _4), and evaporated.
The residue was subjected to column chromatography using 100 g of silica gel, ethyl acetate-chloroform (5: 1,
From the elution part of v / v), 4.23 g (82%) of the title compound was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 0.94 (6H, s), 1.57-1.80 (4H, m),
2.32 (2H, t, J = 7.6Hz), 2.91-3.04 (2H, m), 3.05 (3H, s),
3.15 (3H, s), 8.05 (1H, s).

Reference Example 8 Preparation of methyl 4,4-dimethyl-6-sulfamoylhexanoate 1-cyano-5- (N, N-dimethylaminomethylene)
Aminosulfonyl-3,3-dimethylpentane 3.6 g
And a mixture of 30 ml of concentrated hydrochloric acid at 110 to 115 ° C for 11
Stir the time. The reaction mixture was concentrated to dryness, the obtained carboxylic acid was dissolved in 50 ml of methanol, and 0.3 ml of concentrated sulfuric acid was added.
Was added and the mixture was refluxed for 6 hours. The mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was dried over magnesium sulfate, the solvent was evaporated, and the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (2: 1) to give 2.95 g of the title compound. NMR (CDCl ₃ ) δ: 0.93 (6H, s), 1.54-1.85 (4H, m),
2.30 (3H, t, J = 8.0Hz), 3.10 (2H, dt, J = 8.0Hz), 3.68 (3H,
s), 4.89 (2H, br s).

Reference Example 9 Preparation of 6- (N, N-dimethylaminomethylene) aminosulfonyl-3,3-dimethylhexanol (1) A suspension of 0.79 g of lithium aluminum hydride in 100 ml of tetrahydrofuran was stirred under ice cooling. ,
A solution of 3.30 g of the methyl ester compound obtained in Reference Example 8 in 20 ml of tetrahydrofuran was added dropwise. After dropping, 4 at the same temperature
After stirring for 0 minutes, water was added little by little to the reaction mixture, and 2
Acidified with N hydrochloric acid. The organic layer is separated, washed with water and dried (M
After gSO ₄ ), the solvent was distilled off to obtain 3.08 g of an oily substance.
This product was used in the next reaction without further purification. (2) The oil obtained in the above (1) was dissolved in 50 ml of toluene, and 1.85 ml of N, N-dimethylformamide dimethyl acetal was added thereto, and the mixture was stirred at 80 ° C for 1 hr.
The reaction mixture was concentrated, the residue was subjected to column chromatography using 80 g of silica gel, and the title compound 3.15 was eluted from the elution part of chloroform-methanol (20: 1).
g was obtained as an oil. IR (Neat): 3480, 1630 cm ^-1 .NMR (CDCl ₃ ) δ: 0.90 (6H, s), 1.20-1.33 (2H, m),
1.46-1.78 (4H, m), 1.61 (1H, s), 2.98 (2H, dt, J = 6.4Hz),
3.05 (3H, s), 3.14 (3H, s), 3.62 (2H, t, J = 6.4Hz), 8.04 (1
H, s).

Reference Example 10 Preparation of 6- (N, N-dimethylaminomethylene) aminosulfonyl-1-iodo-3,3-dimethylhexane 3.10 g of the alcohol derivative obtained in Reference Example 9 was dissolved in 50 ml of dichloromethane and iced. While stirring under cooling, 2.76 ml of trifluoromethanesulfonic anhydride was added dropwise. After stirring for 30 minutes under ice cooling, 1.98 ml of 2,6-lutidine was added, and the mixture was stirred for another 30 minutes. Water was added to the reaction mixture,
It was extracted with dichloromethane. The extract was washed with potassium hydrogensulfate solution and then with saturated saline solution, and dried (MgS
O ₄₎ after, to give an oil and the solvent was distilled off. This product was used in the next reaction without further purification. The obtained oily substance was dissolved in 50 ml of acetone, and 5.26 g of sodium iodide was added thereto, and the mixture was heated under reflux for 2 hours while stirring. After cooling, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), and evaporated. The residue was subjected to column chromatography using 80 g of silica gel, eluted with ethyl acetate-hexane (3: 1), and crystallized from isopropyl ether to give 3.14 g of the title compound.
Obtained. Melting point: 67-68 ° C. Elemental analysis value: Calculated as C ₁₁ H ₂₃ IN ₂ O ₃ S (%): C, 35.30; H, 6.19; N, 7.48 Actual value (%): C, 35.64; H, 6.20 N, 7.72 NMR (CDCl ₃ ) δ: 0.90 (6H, s), 1.
23-1.36 (2H, m), 1.60-1.90
(4H, m), 2.93-3.21 (4H, m),
3.05 (3H, s), 3.14 (3H, s),
8.05 (1H, s).

Example 1 Preparation of 6- (3-sulfamoylylpropyl) imidazo [1,2-b] pyridazine 3-aminosulfonyl-1-iodopropane 1.25 g
Was suspended in 10 ml of toluene, 0.731 ml of dimethylformamide dimethyl acetal was added, and the mixture was stirred for 30 minutes. After concentration under reduced pressure, the residue was dissolved in 10 ml of toluene and 1 ml of dimethylacetamide, 0.491 g of copper-activated zinc was added in a nitrogen atmosphere, and the mixture was stirred at 80 ° C. for 2 hours. After cooling to room temperature, 6-chloroimidazo [1,
2-b] Pyridazine (0.615 g) and bis (triphenylphosphine) palladium (II) chloride (56 mg) were added, and the mixture was stirred at 80 ° C. for 1.5 hours in a nitrogen atmosphere. After cooling, ice water 10m
l and 10 ml of 1N hydrochloric acid are added, and the aqueous layer is separated. Deuterium oxide was added to the aqueous layer to adjust the pH to 6, and the mixture was extracted with ethyl acetate-tetrahydrofuran (1: 1). The extract was dried over magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography, dichloromethane: ethyl acetate: methanol =
It was eluted at 10: 10: 4. Collect and concentrate the relevant fractions,
0.72 g of the obtained residue was dissolved in 25 ml of 5N hydrochloric acid, and 2
The mixture was heated under reflux for 0 minutes. After cooling, the mixture was concentrated under reduced pressure, and the residue was adjusted to pH 6 with sodium bicarbonate water, saturated with sodium chloride and then extracted with ethyl acetate: tetrahydrofuran (1: 2).
The extract was dried over magnesium sulfate, the solvent was evaporated, and the residue was subjected to silica gel column chromatography and eluted with a 5% (v / v) methanol-dichloromethane solution. The relevant fractions were concentrated to obtain 0.302 g of the title compound. Melting point: 210-213 ° C. Elemental analysis value: Calculated as C ₉ H ₁₂ N ₄ O ₂ S (%): C, 44.99; H, 5.03; N, 23.32 Measured value (%): C, 44.72; H, 5.12 N, 22.91 NMR (d ₆ -DMSO) δ: 2.0-2.3 (2H, m), 2.9-3.2 (4
H, m), 6.80 (2H, s), 7.18,8.05 (each 1H, d, J = 9Hz), 7.7
2,8.21 (each 1H, s).

Example 2 Preparation of 6- (4-sulfamoyl-1-butyl) imidazo [1,2-b] pyridazine In place of 3-aminosulfonyl-1-iodopropane of Example 1, 4-aminosulfonyl-1 The title compound was prepared in a similar manner to Example 1 using iodobutane. Melting point: 167-175 ° C. Elemental analysis value: Calculated as C ₁₀ H ₁₄ N ₄ O ₂ S (%): C, 47.23; H, 5.55; N, 22.03 Actual value (%): C, 47.01; H, 5.40 N, 22.15 NMR (d ₆ -DMSO) δ: 1.6-2.0 (4H, m), 2.7-3.1 (4
H, m), 6.75 (2H, s), 7.25,8.11 (each 1H, d, J = 10Hz), 7.7
2,8.23 (each 1H, d, J = 1Hz).

Example 3 Preparation of 6- (3,3-dimethyl-5-sulfamoyl-1-pentyl) imidazo [1,2-b] pyridazine 5-aminosulfonyl-3,3-dimethyl-1-iodopentane 2 0.45 g was suspended in 15 ml of toluene, 1.17 ml of dimethylformamide dimethyl acetal was added, and the mixture was stirred at room temperature for 30 minutes. After concentration under reduced pressure, the residue was dissolved in 20 ml of toluene and 2 ml of dimethylacetamide, 0.785 g of copper-activated zinc was added in a nitrogen atmosphere, and the mixture was stirred at 80 ° C. for 1.5 hours. After cooling to room temperature, 6-chloroimidazo [1,2-b] pyridazine 1.2
3 g and 112 mg of bis (triphenylphosphine) palladium (II) chloride were added and the mixture was stirred at 80 ° C. for 1.5 hours in a nitrogen atmosphere. After cooling, 15 ml of ice water and 12 ml of 1N hydrochloric acid were added, the insoluble matter was filtered, and the aqueous layer was separated. Water was added to the aqueous layer to adjust the pH to 6, and the mixture was extracted with ethyl acetate-tetrahydrofuran (3: 1). The extract was dried over magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography and eluted with a 5% (v / v) methanol-dichloromethane solution. The relevant fractions were collected and concentrated, and the resulting residue 1.
56 g was dissolved in 30 ml of 5N hydrochloric acid and heated under reflux for 30 minutes. After cooling, concentrate under reduced pressure, add sodium bicarbonate water to the residue and p.
As H7, ethyl acetate-tetrahydrofuran (3:
Extracted in 1). After drying the extract over magnesium sulfate,
The solvent was distilled off and subjected to silica gel column chromatography, 7%
Elution with (v / v) methanol-dichloromethane. The relevant fractions were concentrated to obtain 0.712 g of the title compound. Melting point: 152 ° C. Elemental analysis value: Calculated as C ₁₃ H ₂₀ N ₄ O ₂ S (%): C, 52.68; H, 6.80; N, 18.90 Measured value (%): C, 52.79; H, 6.98; N , 18.70 NMR (d ₆ -DMSO) δ: 0.96 (6H, s), 1.5-1.9 (4H,
m), 2.7-3.1 (4H, m), 6.78 (2H, s), 7.23,8.07 (each 1H,
d, J = 9Hz), 7.71,8.22 (each 1H, s).

Example 4 Preparation of 6- (3,3-dimethyl-5-sulfamoyl-1-pentyl) -7-methylimidazo [1,2-b] pyridazine 5-Aminosulfonyl-3,3-dimethyl-1 7.90 g of iodopentane was suspended in 60 ml of toluene, 4.19 ml of dimethylformamide dimethyl acetal was added, and the mixture was stirred at room temperature for 30 minutes. After concentration under reduced pressure, the residue was dissolved in 150 ml of toluene and 15 ml of hexamethylphosphoric triamide, 3.93 g of zinc activated by copper was added in a nitrogen atmosphere, and the mixture was stirred at 80 ° C. for 1.5 hours. After cooling to room temperature, 4.02 g of 6-chloro-7-methylimidazo [1,2-b] pyridazine and 0.84 g of bis (triphenylphosphine) palladium (II) chloride were added to the mixture at 80 ° C. in a nitrogen atmosphere. Stir for 2 hours. After cooling, 200 ml of ethyl acetate, 80 ml of water, and 40 ml of 25% aqueous ammonia were added under ice water and the mixture was stirred for 30 minutes. The insoluble matter is filtered off, the aqueous layer is extracted three times with ethyl acetate, washed with brine and dried over magnesium sulfate. The solvent was evaporated, the residue was subjected to silica gel column chromatography, and eluted with dichloromethane: methanol (35: 1). The fractions were collected and concentrated, 3.3 g of the obtained residue was dissolved in 100 ml of 5N hydrochloric acid, and the mixture was heated under reflux for 45 minutes. After cooling, the mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate was added to the residue to adjust the pH to 7, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was distilled off and subjected to silica gel column chromatography,
Elution with dichloromethane: methanol (15: 1).
The relevant fractions were collected and concentrated to give 2.55 g of the title compound. Mp: 170-172 ° C. Elemental _{analysis: C 14 H 22 N 4 O} 2 S Calculated (%): C, 54.17; H, 7.14; N, 18.05 Found (%): C, 53.86; H, 7.11 N, 17.76 NMR (d ₆ -DMSO) δ: 0.96 (6H, s), 1.5-1.9 (4H,
m), 2.6-3.1 (4H, m), 2.37 (3H, s), 6.77 (2H, s), 7.60 (1
H, s), 7.84 (1H, s), 8.11 (1H, s).

Example 5 Preparation of 7,8-Dimethyl-6- (3,3-dimethyl-5-sulfamoyl-1-pentyl) imidazo [1,2-b] pyridazine The 6-chloroimidazo [1 of Example 3 was prepared. , 2-b] Pyridazine instead of 6-chloro-7,8-dimethylimidazo [1,
2-b] Pyridazine was used to produce the title compound in the same manner as in Example 3. Melting point: 160-163 ° C Elemental analysis value: Calculated as C ₁₅ H ₂₄ N ₄ O ₂ S (%): C, 55.53; H, 7.46; N, 17.27 Actual value (%): C, 55.35; H, 7.40 N, 16.98 NMR (d ₆ -DMSO) δ: 0.98 (6H, s), 1.4-1.8 (4H,
m), 2.29 (3H, s), 2.52 (3H, s), 2.7-3.1 (4H, m), 6.77 (2
H, s), 7.59,8.08 (each 1H, d, J = 1Hz).

Example 6 Preparation of 6- (3,3-dimethyl-5-sulfamoyl-1-pentyl) -8-methylimidazo [1,2-b] pyridazine 5-Aminosulfonyl-3,3-dimethyl-1 1.53 g of iodopentane was suspended in 10 ml of toluene, 0.74 ml of dimethylformamide dimethylacetal was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, the residue was dissolved in 13 ml of toluene and 1.3 ml of dimethylacetamide, 0.654 g of zinc activated by copper was added in a nitrogen atmosphere, and the mixture was stirred at 80 ° C. for 2.5 hours. After cooling to room temperature, 6-chloro-8-methylimidazo [1,2-
b] Pyridazine (0.755 g) and bis (triphenylphosphine) palladium (II) chloride (64 mg) were added, and the mixture was stirred at 80 ° C. for 2 hours in a nitrogen atmosphere. After cooling, ethyl acetate 1
0 ml, 10 ml of ice water and 7.5 ml of 25% aqueous ammonia were added and the mixture was stirred at room temperature for 30 minutes. The insoluble matter is filtered, 3 g of food salt is added to the aqueous layer, the mixture is extracted 3 times with ethyl acetate, washed once with brine and dried over magnesium sulfate. The solvent was evaporated, the residue was subjected to silica gel column chromatography, and eluted with dichloromethane: methanol (30: 1). The fractions were collected and concentrated, and 0.802 g of the obtained residue was added to 5N.
It was dissolved in 25 ml of hydrochloric acid and heated under reflux for 1 hour. After cooling, the mixture was concentrated under reduced pressure, and the residue was adjusted to pH 7 with sodium bicarbonate water and extracted with ethyl acetate. After the extract was dried over magnesium sulfate, the solvent was distilled off and subjected to silica gel column chromatography,
Elution with dichloromethane: methanol (15: 1).
The relevant fraction was concentrated to obtain 0.527 g of the title compound. Mp: 136-138 ° C. Elemental _{analysis: C 14 H 22 N 4 O} 2 S Calculated (%): C, 54.17; H, 7.14; N, 18.05 Found (%): C, 54.13; H, 7.25 N, 17.82 NMR (d ₆ -DMSO) δ: 0.96 (6H, s), 1.5-1.8 (4H,
m), 2.53 (3H, s), 2.6-3.1 (4H, m), 6.77 (2H, s), 7.03 (1
H, s), 7.62,8.12 (each 1H, d, J = 1Hz).

Example 7 Preparation of 7,8-dimethyl-6- (3,3-dimethyl-5-sulfamoyl-1-pentyl) [1,2,4] triazolo [1,5-b] pyridazine Example 6 6-chloro-8-methylimidazo [1,2-
The title compound was prepared in the same manner as in Example 6 by using 6-chloro-7,8-dimethyl [1,2,4] triazolo [1,5-b] pyridazine instead of b] pyridazine. Melting point: 90 ° C. Elemental analysis value: Calculated as C ₁₄ H ₂₃ N ₅ O ₂ S.0.4H ₂ O (%): C, 50.55; H, 7.21; N, 21.06 Measured value (%): C, 50.88 H, 7.27; N, 20.86 NMR (d ₆ -DMSO) δ: 0.99 (6H, s), 1.5-1.9 (4H, m), 2.
37 (3H, s), 2.57 (3H, s), 2.7-3.1 (4H, m), 6.77 (2H, s),
8.46 (1H, s).

Example 8 6- (3,3-Dimethyl-5-sulfamoyl-1-pentyl) -7-methyl [1,2,4] triazolo [1,5
-B] Preparation of pyridazine 6-chloro-8-methylimidazo [1,2- of Example 6]
The title compound was prepared in the same manner as in Example 6 except that 6-chloro-7-methyl [1,2,4] triazolo [1,5-b] pyridazine was used instead of b] pyridazine. Mp: 191-193 ° C. Elemental _{analysis: C 14 H 21 N 5 O} 2 S · 0.2H 2 O Calculated (%): C, 49.57; H, 6.85; N, 22.23 Found (%): C , 49.50; H, 6.81; N, 22.18 NMR (d ₆ -DMSO) δ: 0.99 (6H, s), 1.5-1.8 (4H,
m), 2.49 (3H, d, J = 1Hz), 2.7-3.1 (4H, m), 6.77 (2H, s),
8.17 (1H, q, J = 1Hz), 8.50 (1H, s).

Example 9 Preparation of 6- (3,3-dimethyl-5-sulfamoyl-1-pentyl) [1,2,4] triazolo [1,5-b] pyridazine 6-chloro-8 of Example 6 -Methylimidazo [1,2-
The title compound was prepared in the same manner as in Example 6 using 6-chloro [1,2,4] triazolo [1,5-b] pyridazine instead of b] pyridazine. Melting point: 165-168 ° C Elemental analysis value: Calculated as C ₁₂ H ₁₉ N ₅ O ₂ S (%): C, 48.47; H, 6.44; N, 23.55 Actual value (%): C, 48.82; H, 6.61 N, 23.07 NMR (d ₆ -DMSO) δ: 0.97 (6H, s),
1.5-1.8 (4H, m), 2.7-3.1 (4
H, m), 6.76 (2H, s), 7.65, 8.
36 (each 1H, d, J = 9 Hz), 8.58
(1H, s).

Example 10 7-Methyl-6- (4-sulfamoyl-1-butyl)
Preparation of Imidazo [1,2-b] pyridazine 5-aminosulfonyl-3,3-dimethyl-of Example 6
4-aminosulfonyl-in place of 1-iodopentane
Example 1 using 1-iodobutane and substituting 6-chloro-7-methylimidazo [1,2-b] pyridazine for 6-chloro-8-methylimidazo [1,2-b] pyridazine. The title compound was prepared similarly. Melting point: 166-173 ° C Elemental analysis value: Calculated as C ₁₁ H ₁₆ N ₄ O ₂ S (%): C, 49.24; H, 6.01; N, 20.88 Measured value (%): C, 49.35; H, 6.23 N, 20.62 NMR (d ₆ -DMSO) δ: 1.6-2.0 (4H, m), 2.36 (3H,
s), 2.7-3.2 (4H, m), 6.77 (2H, s), 7.60 (1H, s), 7.84,8.
09 (each 1H, s).

Example 11 Preparation of 6- (3,3-Dimethyl-5-sulfamoyl-1-pentyl) imidazo [1,2-b] pyridazine hydrochloride 6- (3,3-Dimethyl prepared in Example 3 0.637 g of -5-sulfamoyl-1-pentyl) imidazo [1,2-b] pyridazine was dissolved in 30 ml of methanol to give 1
2.4 ml of N hydrochloric acid was added and filtered, and the filtrate was concentrated under reduced pressure. The obtained crystals were collected to give 0.707 g of the title compound. Melting point: 181-185 ° C Elemental analysis value: Calculated as C ₁₃ H ₂₁ ClN ₄ O ₂ S (%): C, 46.91; H, 6.36; N, 16.83 Measured value (%): C, 46.79; H, 6.35 N, 16.63 NMR (d ₆ -DMSO) δ: 0.97 (6H, s),
1.5-1.8 (4H, m), 2.8-3.1 (4
H, m), 6.78 (2H, s), 7.79, 8.
41 (each 1H, d, J = 9 Hz), 8.2
8,8.62 (each 1H, d, J = 2 Hz).

Example 12 Preparation of 6- (3,3-dimethyl-5-sulfamoyl-1-pentyl) -7-methylimidazo [1,2-b] pyridazine hydrochloride 6- (3 prepared in Example 4 0.25 g of 3,3-dimethyl-5-sulfamoyl-1-pentyl) -7-methylimidazo [1,2-b] pyridazine was added to 25 ml of ethanol.
Suspended in, dissolved by adding 1N hydrochloric acid, filtered, and the filtrate was concentrated under reduced pressure. Ethyl ether was added to the residue for crystallization, and the crystals were collected to give 0.267 g of the title compound. Melting point: 193-196 ° C. Elemental analysis value: Calculated as C ₁₄ H ₂₃ ClN ₄ O ₂ S (%): C, 48.48; H, 6.68; N, 16.15 Actual value (%): C, 48.56; H, 6.89 N, 15.88 NMR (d ₆ -DMSO) δ: 0.99 (6H, s), 1.5-1.9 (4H,
m), 2.54 (3H, s), 2.8-3.1 (4H, m), 6.79 (2H, s), 8.23,8.
56 (each 1H, d, J = 2Hz), 8.26 (1H, s).

Example 13 6- (4,4-Dimethyl-6-sulfamoyl-1-hexyl) -7-methylimidazo [1,2-b] pyridazine 6- (N, N-dimethylaminomethylene) aminosulfonyl- 1-iodo-3,3-dimethylhexane 1.30
g was dissolved in a mixed solvent of 20 ml of toluene and 2.0 ml of N, N-dimethylacetamide, 0.72 g of copper-activated zinc was added thereto in a nitrogen atmosphere, and the mixture was vigorously stirred at 90 ° C. for 2 hours. After cooling to room temperature, 6-chloro-7
-Methylimidazo [1,2-b] pyridazine 0.50 g
And 60 mg of bis (triphenylphosphine) palladium (II) chloride were added, and the mixture was stirred at 90 ° C. for 2 hours in a nitrogen atmosphere. After cooling, 28% aqueous ammonia (5 ml) and water (12 ml) were added to the reaction mixture, and the insoluble material was filtered off using Celite. The filtrate was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), and evaporated. The residue was subjected to silica gel column chromatography, and 0.32 g of an oily matter was obtained from the fraction eluted with chloroform-methanol (40: 1). A mixture of the obtained oil and 7 ml of 6N hydrochloric acid was added to 100
Stir at 40 ° C. for 40 minutes. The reaction mixture was concentrated, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate-tetrahydrofuran (3: 1). Wash the extract with water and dry (M
After gSO ₄ ) the solvent was distilled off. The residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (20: 1), and crystallized from ethyl ether to give the title compound (34 mg). Melting point: 141-142 ° C. Elemental analysis value: Calculated as C ₁₅ H ₂₄ N ₄ O ₂ S (%): C, 55.53; H, 7.46; N, 17.27 Actual value (%): C, 55.31; H, 7.66 N, 17.20 NMR (d ₆ -DMSO) δ: 0.89 (6H, s), 1.23-1.39 (2H,
m), 1.53-1.79 (4H, m), 2.35 (3H, s), 2.78 (2H, t, J = 7.0H
z), 2.89-3.04 (2H, m), 6.75 (2H, br s), 7.60 (1H, s), 7.
83 (1H, s), 8.11 (1H, s).

Formulation Example (a) Coated tablet Compound of Example 1 10.0 mg Lactose 60.0 mg Corn starch 35.0 mg Gelatin 3.0 mg Magnesium stearate 2.0 mg Method Method of the compound obtained in Example 1 and lactose and corn starch The mixture was granulated with a 10% aqueous gelatin solution through a 1 mm mesh sieve, dried at 40 ° C. and sieved again. The granules thus obtained were mixed with magnesium stearate and compressed. The obtained central tablets were coated with a sugar coating of sucrose, titanium dioxide, talc and gum arabic in a conventional manner by a conventional method. The coated tablets were polished with beeswax.

[0053] Granulating the compound obtained in Example 1 and magnesium stearate with an aqueous solution of soluble starch, drying the granules,
Mixed with lactose and corn starch. The mixture was compressed into tablets.

C) Injectable solution Compound of Example 1 5.0 mg Salt 20.0 mg Distilled water Total amount 2 ml The compound obtained in Example 1 and the excipient are dissolved in distilled water, and water is added to a predetermined amount. And the concentration. The solution was filtered and filled under aseptic conditions into 2 ml ampoules. The ampoule was sterilized and sealed. The content of the compound of Example 1 in 1 ampoule was 5 mg.

[0055]

The results of the pharmacological test 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 Guinea Pig (body weight about 5
00g) was used. The airway stenosis response of guinea pigs by intravenous administration of PAF 1 μg / kg was measured according to the Konzet-Roessler method. The guinea pig was fixed to the dorsal position under urethane (1.5 g / kg, intravenous injection) anesthesia, then tracheostomized, and connected to a ventilator via a cannula. In addition, the side branch of the tracheal cannula was connected to a transducer (type 7020, Ugobasile). The insufflation rate is 3 to 7 ml, the insufflation rate is 70 times / min, the load pressure on the lung is 10 cmH ₂ O, and the amount of overflowing air is passed through the transducer to the rectigraph (Recte-Ho).
ri-8s, Sanei Sokki). Galamine (1 mg / kg,
IV) PAF 1 μg / kg dissolved in physiological saline after treatment
Was administered via a jugular cannula, and the airway stenosis reaction that occurred was recorded for 15 minutes. The drug was suspended at 30 mg / kg in 5% gum arabic solution and orally administered 1 hour before administration of PAF. The results are shown in [Table 1].

[Table 1] From this table, it can be seen that the object compound [I] of the present invention or a salt thereof has an excellent inhibitory effect on airway stenosis and is excellent as an anti-asthma agent.

[0056]

The present invention provides a novel compound having excellent properties as an anti-asthma agent.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location // (C07D 487/04 233: 00 237: 00) (C07D 487/04 237: 00 249: 00 )

Claims (38)

[Claims] 1. The formula: [Wherein X is a methine group or a nitrogen atom, R ¹ is a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom, and R ² and R ³ each have a hydrogen atom or a substituent. A lower alkyl group which may be substituted or a 5- to 7-membered ring together with adjacent -C = C-, and R ⁴ and R ⁵ are each a hydrogen atom or a lower alkyl group which may have a substituent. Alternatively, together with a carbon atom adjacent to each other, a 3- to 7-membered homo- or heterocycle, A is an optionally substituted amino group, and m and n are each an integer of 1 to 4. ] The compound or its salt represented by these. 2. A lower alkyl group which may have a substituent represented by R ¹ , R ² , R ³ , R ⁴ or R ⁵ is hydroxy, amino, carboxy, nitro, mono- or di-C.
_1-6 alkylamino, C _1-6 alkoxy, C _1-6 alkylcarbonyloxy and a linear or branched C _1- which may have 1 to 4 substituents selected from a halogen atom. The compound according to claim 1, which is a ₆ alkyl group. 3. R ² and R ³ are adjacent to each other at -C =
The compound according to claim 1, wherein the 5- to 7-membered ring shown together with C- is a 5- to 7-membered cyclic hydrocarbon or heterocycle. 4. A 3- to 7-membered homologous or heterocyclic ring represented by R ⁴ and R ⁵ together with adjacent carbon atoms is a 3- to 7-membered cyclic hydrocarbon or heterocyclic ring. The described compound. 5. An optionally substituted amino group represented by A has the formula: [In the formula, R ⁶ and R ⁷ are each a hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or an aryl which may have a substituent. A group or a nitrogen-containing heterocyclic group which may have a substituent together with a nitrogen atom adjacent to each other is shown. ]
The compound according to claim 1, which is represented by: 6. A lower alkyl group which may have a substituent is hydroxy, amino, carboxy, nitro or mono-.
Or di-C _1-6 alkylamino, C _1-6 alkoxy, C
_1-6 alkylcarbonyloxy and C optionally having 1 to 4 substituents selected from halogen atoms
The compound according to claim 5, which is a _1-6 alkyl group. 7. A cycloalkyl group which may have a substituent is hydroxy, amino, carboxy, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy,
C _1-6 alkylcarbonyloxy and C _optionally having 1 to 4 substituents selected from halogen atoms
The compound according to claim 5, which is a _3-6 cycloalkyl group. 8. An aryl group which may have a substituent,
C _1-6 alkyl, amino, acetamide, hydroxy, carboxy, nitro, C _1-6 alkoxy, C _1-6 alkylcarbonyloxy and C optionally having 1 to 5 substituents selected from halogen atoms The compound according to claim 5, which is a _6-14 aryl group. 9. A nitrogen-containing heterocyclic group which may have a substituent represented by R ⁶ and R ⁷ together with the adjacent nitrogen atom is (i) a C _1-6 alkyl group, (ii) C _1-6 alkyl, C
_1-6 acyl and amino optionally having 1 or 2 substituents selected from 5- to 7-membered cyclic amino, (ii
i) hydroxy, (iv) carboxy, (v) nitro, (v
The compound according to claim 5, which is i) C _1-6 alkoxy and (vii) a 3- to 13-membered nitrogen-containing heterocyclic group optionally having 1 to 5 substituents selected from halogen atoms. 10. The compound according to claim ¹ , wherein R ¹ is a hydrogen atom or a C _1-3 alkyl group. 11. R ² and R ³ are each a hydrogen atom or C.
_1-3 Alkyl groups or adjacent -C together
The compound according to claim 1, which forms cyclohexene or benzene together with = C-. 12. R ⁴ and R ⁵ are each (i) a hydrogen atom or (ii) hydroxy, amino, carboxy, nitro,
C _1-3 alkyl optionally having 1 to 4 substituents selected from mono- or di-C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 alkylcarbonyloxy and a halogen atom. A group, or (iii) together with adjacent carbon atoms have the formula: The compound according to claim 1, which forms 13. The compound according to claim 1, wherein R ² , R ³ , R ⁴ and R ⁵ are each a hydrogen atom or a C _1-3 alkyl group. 14. The compound according to claim 1, wherein R ² and R ³ are each a C _1-3 alkyl group. 15. R ² and R ³ together are adjacent to each other, --C.
The compound according to claim 1, which forms cyclohexene or benzene together with = C-. 16. The compound according to claim 1, wherein R ⁴ and R ⁵ are both C _1-3 alkyl groups. 17. R ⁴ and R ^{5 taken} together with the adjacent carbon atom have the formula: The compound according to claim 1, which forms 18. The compound according to claim 1, wherein A is an amino group which may be substituted with one or two C _1-3 alkyl groups. 19. The compound according to claim 1, wherein A is an amino group. 20. The compound according to claim ¹ , wherein R ¹ is a hydrogen atom. 21. The compound according to claim 1, wherein R ² and R ³ are both hydrogen atoms. 22. The compound according to claim 1, wherein R ⁴ and R ⁵ are both hydrogen atoms. 23. The compound according to claim 1, wherein m and n are 1 or 2, respectively. 24. The compound according to claim 1, wherein m and n are both 2. 25. The compound according to claim 1, wherein X is a methine group. 26. The compound according to claim 1, wherein X is a nitrogen atom. 27. X is a methine group, R ¹ is a hydrogen atom, R ² and R
The compound according to claim 1, wherein ³ , R ⁴ and R ⁵ are each a hydrogen atom or a C _1-3 alkyl group, A is an amino group, and m and n are each an integer of 1 to 3. 28. X is a methine group, R ¹ and R ² are both hydrogen atoms, R ³ , R ⁴ and R ⁵ are each a C _1-3 alkyl group, A is an amino group, and m and n are both 2. The compound according to claim 1. 29. X is a nitrogen atom, R ¹ is a hydrogen atom, R ² and R
The compound according to claim 1, wherein ³ , R ⁴ and R ⁵ are each a hydrogen atom or a C _1-3 alkyl group, A is an amino group, and m and n are both 2. 30. The compound according to claim 1, which is a hydrochloride. 31. The compound according to claim 1, which is 6- (3,3-dimethyl-5-sulfamoyl-1-pentyl) imidazo [1,2-b] pyridazine. 32. 6- (3,3-Dimethyl-5-sulfamoyl-1-pentyl) -7-methylimidazo [1,2]
-B] pyridazine. 33. The compound according to claim 1, which is 6- (3,3-dimethyl-5-sulfamoyl-1-pentyl) imidazo [1,2-b] pyridazine hydrochloride. 34. 6- (3,3-Dimethyl-5-sulfamoyl-1-pentyl) -7-methylimidazo [1,2]
-B] Pyridazine hydrochloride. 35. The formula: A compound represented by the formula or a salt thereof and a compound represented by the formula: Or a salt thereof, wherein Y and Z are groups capable of reacting with each other and leaving, A'is an amino group which may be protected, and other symbols are as defined in claim 1. Indicates. ] It reacts with and, The manufacturing method of the compound of Claim 1 characterized by the above-mentioned. 36. The formula: [In the formula, W is a halogen atom, and other symbols are defined in Claim 1
Indicates the same meaning as described. ] The compound or its salt represented by these, and formula H-A [V] [In formula, A shows the same meaning as Claim 1. ] The compound of Claim 1 or its salt is made to react, The manufacturing method of the compound of Claim 1 characterized by the above-mentioned. 37. An anti-asthma agent comprising the compound according to claim 1. 38. An anti-PAF agent containing the compound according to claim 1.