JPH11315024A - Agent for bronchial tube - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject agent which exhibits an antiasthmatic effect or the like of a triazolopyridazine derivative by specifically acting its inherent effects on the bronchial tube by the minimum quantity by local administration. SOLUTION: This agent contains a compound shown by formula I R<1> is H or the like; R<2> and R<3> are each H, a (substituted) lower alkyl or the like; X is O or the like; Y is a group shown by formula II [R<4> and R<5> are each H or a (substituted) lower alkyl] or the like; R<6> and R<7> are each H, a (substituted) lower alkyl or the like; and (m) is 0 to 4 and (n) is 0 to 4}, e.g. a triazolopyridazine derivative such as 6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)-7- isopropyl [1,2,4] triazolo [1,5-b] pyridazine, preferably at around 0.01 to 99.9 wt.% on the whole agent. The above derivative has various excellent functions, e.g. antiallergic, anti-inflammatory, anti-PAF(platelet activating factor) and eosinophilic chemotactic preventive functions, and also a function of humectation prevention of acidocyte at local allergy or inflammatory reactions.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-
The present invention relates to a bronchoactive agent containing a triazolopyridazine derivative such as isopropyl [1,2,4] triazolo [1,5-b] pyridazine.

[0002]

[Prior Art] General formula

Embedded image [Wherein, R ¹ represents a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom, and R ² and R ³
Represents a hydrogen atom, a lower alkyl group which may have a substituent or a cycloalkyl group which may have a substituent, and R ² and R ³ represent 5 to 7 together with the adjacent -C = C-. X may be an oxygen atom or S
(O) p (p represents an integer of 0 to 2), and Y is a formula

Embedded image (R ⁴ and R ⁵ each represent a hydrogen atom or a lower alkyl group which may have a substituent) or a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent A divalent group derived from R ⁶ and R ⁷
Represents 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,
⁶ and R ⁷ may form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom, m represents an integer of 0 to 4, and n represents an integer of 0 to 4 . A triazolopyridazine derivative represented by the following formula:
It is a compound useful as an agent F, an antiallergic agent, an eosinophil chemotaxis inhibitor, a prophylactic / therapeutic agent for allergic rhinitis, and a prophylactic / therapeutic agent for atopic dermatitis (JP-A-06-279449 and JP-A-08-198878). Gazette).

[0003]

Further, there has been a demand for the development of a preparation which can exert the action of the above triazolopyridazine derivative [I] locally.

[0004]

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that 6- (2,2
-Dimethyl-3-sulfamoyl-1-propoxy)-
7-isopropyl [1,2,4] triazolo [1,5-
b) By using pyridazine or a salt thereof as an inhalant or the like, it has been found that the action of the derivative can be exerted locally on the bronchi, and further, based on these findings, a study has been carried out. It was completed.

That is, the present invention provides (1) a general formula

Embedded image [Wherein, R ¹ represents a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom, and R ² and R ³
Represents a hydrogen atom, a lower alkyl group which may have a substituent or a cycloalkyl group which may have a substituent, and R ² and R ³ represent 5 to 7 together with the adjacent -C = C-. X may be an oxygen atom or S
(O) p (p represents an integer of 0 to 2), and Y is a formula

Embedded image (R ⁴ and R ⁵ each represent a hydrogen atom or a lower alkyl group which may have a substituent) or a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent A divalent group derived from R ⁶ and R ⁷
Represents 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,
⁶ and R ⁷ may form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom, m represents an integer of 0 to 4, and n represents an integer of 0 to 4 . (2) R ¹ is (i) a hydrogen atom, (ii) hydroxy,
Amino, carboxyl, nitro, mono- or di-C
_1-6 alkylamino, C _1-6 alkoxy, C _1-6 alkylcarbonyloxy and C _1-6 alkyl group or may have a substituent group selected from the group consisting of halogen atoms (iii) a halogen atom , R ² and R ³ are each (i) a hydrogen atom, (ii) hydroxy, amino, carboxyl, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 alkylcarbonyloxy And a C _1-6 alkyl group which may have a substituent selected from the group consisting of a halogen atom and (iii) hydroxy, amino, carboxyl, nitro, mono- or di-
C _1-6 alkylamino, C _1-6 alkoxy, shows a C _1-6 alkylcarbonyloxy and optionally C _3-6 cycloalkyl group optionally having a substituent selected from the group consisting of halogen atom, R ² And R ³ together with the adjacent -C = C-
Hydroxy, amino, mono - or di -C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 alkyl - which may have a substituent selected from the group consisting of carbonyloxy and halogen atoms C _{1 -6} alkyl, C _1-6 selected alkyl, C _1-6 acyl or a 5 to substituted 7-membered cyclic amino, amino, hydroxy, carboxyl, nitro, a group consisting of C _1-6 alkoxy and halogen May have a substituent,
It may form a 5- to 7-membered ring which may contain 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms, and X represents an oxygen atom or S (O) p (P represents an integer of 0 to 2), and Y
Is the equation (a)

Embedded image (R ⁴ and R ⁵ each represent (i) a hydrogen atom or (ii)
Hydroxy, amino, carboxyl, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy, C
_A C _1-6 alkyl group which may have a substituent selected from the group consisting of _1-6 alkylcarbonyloxy and a halogen atom), or (b) hydroxy, amino, mono- or di- -C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 alkyl - carbonyloxy and C _1-6 alkyl optionally having a substituent selected from the group consisting of halogen atom, C _1-6 Alkyl, C
Amino, hydroxy, carboxyl, which may be substituted with _1-6 acyl or 5- to 7-membered cyclic amino,
A nitrogen atom other than a 3- to 7-membered cyclic hydrocarbon or carbon atom which may have a substituent selected from the group consisting of nitro, C _1-6 alkoxy and halogen atom,
A divalent group derived from a 3- to 7-membered heterocyclic ring containing 1 to 4 hetero atoms selected from the group consisting of an oxygen atom and a sulfur atom, wherein R ⁶ and R ⁷ are each (i) a hydrogen atom (Ii) having a substituent selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 alkylcarbonyloxy and a halogen atom. An optionally substituted C _1-6 alkyl group, (iii) hydroxy, amino, carboxyl, nitro, mono- or di-C _1-6
A C _3-6 cycloalkyl group optionally having a substituent selected from the group consisting of alkylamino, C _1-6 alkoxy, C _1-6 alkylcarbonyloxy and halogen atom, or (iv) hydroxy, amino, mono -Or di-C
C- ₆ which may have a substituent selected from the group consisting of _1-6 alkylamino, C1-6 alkoxy and halogen atom
Amino, acetamido, hydroxy, carboxyl, nitro, C-substituted or substituted with _1-6 alkyl, C _1-6 alkyl or 5- to 7-membered cyclic amino
_A C _6-14 aryl group which may have a substituent selected from the group consisting of _1-6 alkoxy, C _1-6 alkylcarbonyloxy and a halogen atom, wherein R ⁶ and R ⁷ together with an adjacent nitrogen atom Hydroxy, amino, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy, C _1-6
C _1-6 alkyl, C _1-6 alkyl, C _1-6 acyl or 5 to 7 which may have a substituent selected from the group consisting of alkyl-carbonyloxy and halogen atoms
One nitrogen atom which may have a substituent selected from the group consisting of amino, hydroxy, carboxyl, nitro, C _1-6 alkoxy and a halogen atom which may be substituted with a membered cyclic amino, 1 to 4 selected from nitrogen, oxygen and sulfur atoms
May form a group in which one hydrogen atom has been removed from the ring of the 3- to 13-membered nitrogen-containing heterocyclic ring which may contain 3 hetero atoms, m is an integer of 0 to 4, and n is 0 (3) R ¹ is a hydrogen atom or a C _1-3 alkyl group, R ² is a hydrogen atom or a C _1-3 alkyl group, and R ³ is hydrogen. An atom or a C _1-6 alkyl group, X represents an oxygen atom, and Y represents a formula

Embedded image [Wherein R ⁴ ′ and R ⁵ ′ each represent (i) a hydrogen atom or (ii) hydroxy, amino, carboxyl, nitro,
C _1-3 optionally having 1 to 4 substituents selected from mono- or di-C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 alkyl-carbonyloxy or halogen atoms. Shows an alkyl group. A group represented by R ⁶
And ( ⁷⁾ wherein R and R ⁷ each represent a hydrogen atom or a C _1-3 alkyl group, and m and n each represent 1;
The agent according to (1), wherein the compound is 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine, (5) anti-asthmatics, chronic obstructive pulmonary disease (COP)
D) The agent according to (1), which is a prophylactic / therapeutic agent, a hypersensitivity pneumonitis prophylactic / therapeutic agent or an eosinophilic pneumonia prophylactic / therapeutic agent, and (6) a bronchial-acting inhalant (1). Item is provided.

Further, the present invention relates to (7) an agent according to (1), which is a broncho-aerosol, (8) 6- (2,
2-dimethyl-3-sulfamoyl-1-propoxy)
-7-isopropyl [1,2,4] triazolo [1,5-
b] an inhalant containing pyridazine or a salt thereof and a propellant (eg, an inhalant for bronchial application), (9) 6- (2,
2-dimethyl-3-sulfamoyl-1-propoxy)
-7-isopropyl [1,2,4] triazolo [1,5-
b] an aerosol containing pyridazine or a salt thereof and a propellant (eg, an aerosol applied to bronchi), (1)
0) For the whole preparation, the general formula

Embedded image [Wherein, R ¹ represents a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom, and R ² and R ³
Represents a hydrogen atom, a lower alkyl group which may have a substituent or a cycloalkyl group which may have a substituent, and R ² and R ³ represent 5 to 7 together with the adjacent -C = C-. X may be an oxygen atom or S
(O) p (p represents an integer of 0 to 2), and Y is a formula

Embedded image (R ⁴ and R ⁵ each represent a hydrogen atom or a lower alkyl group which may have a substituent) or a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent A divalent group derived from R ⁶ and R ⁷
Represents 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,
⁶ and R ⁷ may form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom, m represents an integer of 0 to 4, and n represents an integer of 0 to 4 . An inhalant containing about 0.01 to 99.9% by weight of a compound represented by the formula (I) or a salt thereof and about 0.1 to 99% by weight of an inhalant additive (eg, an inhalant for bronchial application);

(11) (10) wherein the compound is 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine ), The agent according to item (12), a powder inhalant,
The agent according to (10), which is a capsule-shaped inhalant, a suspension for inhalation or a solution for inhalation, (13) the agent according to (10), which is an aerosol, and (14) an additive for an inhalant. The agent according to (10), which is a propellant, and (15) an antiasthmatic agent, a prophylactic / therapeutic agent for chronic obstructive pulmonary disease (COPD), a prophylactic / therapeutic agent for irritable pneumonitis or a prophylactic / eosinophilic pneumonia. The agent according to (10), which is a therapeutic agent, is provided. When the triazolopyridazine derivative [I] or a salt thereof used in the preparation of the present invention contains an asymmetric carbon in the structure, an optically active compound and a racemic mixture are also included in the scope of the triazolopyridazine derivative [I].

[0008] 6- (2,2-) used in the preparation of the present invention
Dimethyl-3-sulfamoyl-1-propoxy) -7
-Isopropyl [1,2,4] triazolo [1,5-b]
The triazolopyridazine derivatives [I] including pyridazine are known compounds described in JP-A-06-279449 or JP-A-08-198878. In the above formula, the “lower alkyl” represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ or R ⁷ includes, for example, methyl, ethyl, n-propyl, i-propyl, n
-Butyl, i-butyl, tert-butyl, n-pentyl,
A linear or branched C _1-6 alkyl group such as n-hexyl is used. As the “cycloalkyl group” represented by R ² , R ³ , R ⁶ or R ⁷ , for example, a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like are used. R ⁶
Alternatively, as the “aryl group” represented by R ⁷ , for example, a C _6-14 aryl group such as phenyl and naphthyl is used. Examples of the substituent which the “lower alkyl” and “cycloalkyl group” may have include, for example, hydroxy, amino, carboxyl, nitro, mono- or di-lower alkylamino (for example, methylamino, ethylamino, Mono- or di-C _1-6 alkylamino such as propylamino, dimethylamino, diethylamino and the like, lower alkoxy (eg methoxy, ethoxy,
C _1-6 alkoxy such as propoxy, hexyloxy, etc., lower alkylcarbonyloxy (eg, C _1-6 alkylcarbonyloxy such as acetoxy, ethylcarbonyloxy, etc.) and halogen atom (fluorine, chlorine, bromine, iodine, etc.) One to four selected from the above are used. Examples of the substituent which the “aryl group” may have include, for example, lower alkyl which may have a substituent, amino which may have a substituent, acetamido, hydroxy, carboxyl, nitro, Lower alkoxy (eg, C _1-6 alkoxy such as methoxy, ethoxy, propoxy, etc.), lower alkyl-carbonyloxy (eg, C _1-6 alkylcarbonyloxy such as acetoxy, ethylcarbonyloxy, etc.) and halogen atoms (fluorine, Chlorine, bromine, iodine, etc.) are used. Here, lower alkyl (for example, C, such as methyl, ethyl, n-propyl, etc.)
_1-6 alkyl group) may have a substituent
For example, hydroxy, amino, mono- or di-lower alkylamino (eg, methylamino, ethylamino,
Mono- or di-C _1-6 alkylamino such as propylamino, dimethylamino, diethylamino and the like; lower alkoxy (eg C _1-6 alkoxy such as methoxy, ethoxy, propoxy and hexyloxy) and halogen atom (fluorine) , Chlorine, bromine, iodine, etc.)
One to four selected from the above are used. Examples of the substituent which the amino group may have include, for example, C _1-6 alkyl (eg, methyl, ethyl, propyl, etc.) and 5- to 7-membered cyclic amino (eg, pyrrolidino, morpholino, piperidino, piperazino, etc.) One or two selected from the above are used. As the “halogen atom” represented by R ¹ , for example, fluorine, chlorine, bromine, iodine and the like are used.

The 5- to 7-membered ring formed by R ² and R ³ together with the adjacent —C ＝ C— is, for example, one selected from a nitrogen atom, an oxygen atom, a sulfur atom and the like in addition to a carbon atom. A 5- to 7-membered ring which may contain from 4 to 4 heteroatoms is used. Specifically, C such as cyclopentene, cyclohexene, cycloheptene, etc.
5- to 7-membered cyclic hydrocarbons such as _5-7 cycloalkene and benzene, and 5- or 6-membered nitrogen-containing heterocycles composed of a carbon atom and a nitrogen atom (eg, pyrrole, pyridine, piperidine, etc.) are frequently used. Examples of the “3- to 7-membered homocyclic ring” of the “divalent group derived from a 3- to 7-membered homocyclic ring” represented by Y include, for example, a 3- to 7-membered cyclic hydrocarbon consisting only of carbon atoms. Used. Specifically, for example, C _3-7 cycloalkane such as cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane, and C _3-7 cycloalkane such as cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, etc.
_3-7 Cycloalkene, benzene, etc. are frequently used. The divalent group derived from the “3- to 7-membered homocyclic ring” is
It means a divalent group obtained by removing two hydrogen atoms from one carbon atom or one hydrogen atom from two different carbon atoms in the aforementioned 3- to 7-membered cyclic hydrocarbon. Specifically, for example,

[0010]

Embedded image Etc. are used, and preferably

Embedded image Etc., more preferably

Embedded image Are often used.

The term "3- to 7-membered heterocyclic ring" of the "divalent group derived from a 3- to 7-membered heterocyclic ring" for Y includes, for example, other than a carbon atom, for example, a nitrogen atom, an oxygen atom, A 3- to 7-membered heterocyclic ring containing 1 to 4 hetero atoms selected from a sulfur atom or the like is used. Specifically, for example, oxetane, tetrahydrofuran, tetrahydropyran, pyrrole, azetidine, pyrrolidine, piperidine, piperazine, tetrahydrothiophene, homopiperidine, morpholine and the like are used. The divalent group derived from the “3- to 7-membered heterocycle” is
The same carbon atom in the aforementioned 3 to 7 membered heterocyclic ring as 2
Hydrogen atom or a divalent group obtained by removing one hydrogen atom from each of two different atoms. Specifically, for example,

Embedded image Are used.

The "nitrogen-containing heterocyclic group" formed by R ⁶ and R ⁷ together with an adjacent nitrogen atom includes, for example, one nitrogen atom and carbon atom, and further includes, for example, nitrogen atom, oxygen atom, sulfur atom and the like. And a group obtained by removing one hydrogen atom from a nitrogen atom in a ring such as a 3- to 13-membered nitrogen-containing heterocyclic ring which may contain 1 to 3 heteroatoms selected from the group consisting of: Specifically, for example,

Embedded image And a 3- to 9-membered nitrogen-containing heterocyclic group.

The "3 to 7-membered homocyclic ring", "3 to 7
Examples of the substituent which the "membered heterocyclic ring" and the "nitrogen-containing heterocyclic group" may have include, for example, lower alkyl optionally having substituents, amino optionally having substituents, , Carboxyl, nitro, lower alkoxy (eg,
One to five members selected from C _1-6 alkoxy such as methoxy, ethoxy, propoxy, etc.) and halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) are used. Here, the substituent which the lower alkyl (for example, C _1-6 alkyl group such as methyl, ethyl, n-propyl and the like) may have is, for example, hydroxy, amino, mono- or di-lower alkylamino (Eg, mono- or di-C _1-6 such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.)
Alkylamino, etc., lower alkoxy (for example, methoxy, ethoxy, propoxy, hexyloxy, etc.
_C1-6 alkoxy, etc.), lower alkylcarbonyloxy (e.g., C _1-6 alkyl, such as acetyloxy, ethyl carbonyloxy - selected from such carbonyloxy, etc.) and a halogen atom (fluorine, chlorine, bromine, iodine, etc.) One to four are used. Examples of the substituent which the amino group may have include, for example, C _1-6 alkyl (for example, methyl, ethyl, propyl and the like), acyl (for example, C _1-6 acyl such as formyl, acetyl, propionyl and butyryl) And 5- to 7-membered cyclic aminos (eg, pyrrolidino, morpholino, piperidino,
One or two selected from piperazino and the like are used.

As R ¹ , for example, a hydrogen atom or C
_1-3 alkyl (for example, methyl, ethyl, n-propyl and the like) and the like are preferable, and particularly a hydrogen atom is frequently used. R ²
For example, a hydrogen atom, C _1-3 alkyl (for example, methyl, ethyl, n-propyl and the like) are preferable, and a hydrogen atom and the like are particularly used. As R ³ , for example, a hydrogen atom, a C _1-6 alkyl group and the like are preferable, and particularly, a branched C _3-6 alkyl group (for example, i-propyl and the like) is frequently used. -C = C where R ² and R ³ are adjacent
It is also preferable to form a 5- to 7-membered cyclic hydrocarbon together with-, particularly to form cyclohexene, benzene and the like. X is, for example, an oxygen atom or S
And the like are preferred, and oxygen atoms and the like are particularly frequently used. As Y, for example,

Embedded image [Wherein R ⁴ ′ and R ⁵ ′ each represent (i) a hydrogen atom or (ii) hydroxy, amino, carboxyl, nitro,
C _1-3 optionally having 1 to 4 substituents selected from mono- or di-C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 alkyl-carbonyloxy or halogen atoms. Shows an alkyl group. And the like are preferred.

As the “C _1-3 alkyl group” represented by R ⁴ ′ and R ⁵ ′, for example, methyl, ethyl, n-propyl, i-propyl and the like are used, and methyl and ethyl are particularly preferred. is there. Further, it is also preferable that Y is a divalent group derived from a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent, for example,

Embedded image Etc., more preferably

Embedded image Are often used, especially

Embedded image Is the most frequently used.

As R ⁶ and R ⁷ , for example, a hydrogen atom, C _1-3 alkyl (eg, methyl, ethyl, n-propyl and the like) are preferable, and a hydrogen atom and the like are particularly used. m is preferably an integer of 1 to 4, more preferably an integer of 1 to 3, especially 1 or the like.
n is preferably an integer of 1 to 4, particularly 1 or the like. Above all, it is most preferable that both m and n are 1. The triazolopyridazine derivative [I] used in the preparation of the present invention is specifically described in
-279947 and JP-A-08-198878.
All the compounds prepared in the examples of the publication are preferred, but in particular 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [1,2
4] Triazolo [1,5-b] pyridazine or a salt thereof is preferred. The above triazolopyridazine derivative (I)
As the salts of, especially preferred are physiologically acceptable acid addition salts. 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) Acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) and the like are used. Furthermore, when the triazolopyridazine derivative [I] has an acidic group such as -COOH as a substituent, the triazolopyridazine derivative [I] may be an inorganic base (for example, an alkali base such as sodium, potassium, calcium, or magnesium). Salts may be formed with metals or alkaline earth metals, ammonia, etc.) or organic bases, such as tri-C _1-3 alkylamines such as triethylamine. The above triazolopyridazine derivative [I] or a salt thereof is disclosed in JP-A-06-2.
It can be produced based on the description in JP-A-79447 or JP-A-08-198878, particularly the description in the examples of the publication.

The bronchoactive agent of the present invention does not cause the above triazolopyridazine derivative [I] or a salt thereof to act on the whole body, but causes it to act specifically on the bronchi. Further, the preparation of the present invention may act on tissues surrounding the bronchi, and may act on, for example, the trachea, lungs, and the like.
The preparation of the present invention may be any preparation as long as it can exert the local action of the triazolopyridazine derivative [I] or a salt thereof, but is preferably used as an inhalant, for example. For example, when the formulation of the present invention is used as an inhalant, the inhalant additive may be any additive that is generally used in inhalant formulations, for example, a propellant, White sugar, lactose,
Solid excipients such as glucose, mannitol, sorbit,
Liquid excipients such as inert liquids such as propylene glycol, methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyethylene glycol,
Binders such as sucrose, lubricants such as magnesium stearate, light silicic anhydride, talc, sodium lauryl sulfate, flavoring agents such as citric acid, menthol, glycyrrhizin ammonium salt, glycine, orange powder, sodium benzoate, hydrogen bisulfite Sodium, methyl paraben,
Preservatives such as propylparaben, stabilizers such as citric acid and sodium citrate, suspending agents such as methylcellulose, polyvinylpyrrolidone, lecithin, sorbitan trioleate, dispersants such as surfactants, solvents such as water, Isotonic agents such as sodium chloride, pH adjusters such as sulfuric acid and hydrochloric acid, and solubilizing agents such as ethanol are used.

As the propellant, a liquefied gas propellant, a compressed gas or the like is used. As the liquefied gas propellant, for example, a fluorinated hydrocarbon (eg, HCFC22, HCFC-1)
23, HCFC-134a, HCFC142, etc.), liquefied petroleum, dimethyl ether, and the like. As the compressed gas, for example, a soluble gas (eg, carbon dioxide gas, nitrous oxide gas, etc.), an insoluble gas (eg, nitrogen gas, etc.) and the like are used. Further, the preparation of the present invention may contain another pharmaceutical ingredient other than the triazolopyridazine derivative [I] or a salt thereof as an active ingredient. Examples of such pharmaceutically active ingredients include anti-asthmatic agents (eg, theophylline, procaterol, ketotifen, azelastine, seratrodast (bronica), etc.), anti-allergic agents (eg, ketotifen, terfenadine, azelastine, epinastine, etc.), anti-inflammatory Agents (eg, diclofenac sodium, ibuprofen, indomethacin, etc.), antibacterial agents (eg, cefixime, cefdinir, ofloxacin, tosfloxacin, etc.), antifungal agents (eg, fluconazole, itraconazole, etc.)
And the like. These components are not particularly limited as long as the object of the present invention is achieved, and can be used at an appropriate mixing ratio.

In the preparation of the present invention, the content of the triazolopyridazine derivative [I] or a salt thereof depends on the target disease,
Although it varies depending on the age, sex, disease state and the like of the subject patient, it is usually about 0.01 to 99.9% by weight, preferably about 0.1 to 50% by weight, more preferably about 0.1 to 50% by weight based on the whole preparation. It is about 5 to 20% by weight. The content of various additives such as additives for inhalants varies depending on the target disease, the age and sex of the target patient, the symptoms of the disease and the like, but is usually about 0.1 to 99% by weight, preferably about 0.1 to 99% by weight based on the whole preparation. Is about 10
%, More preferably about 50 to 99% by weight, particularly preferably about 70 to 99% by weight. The content of other pharmaceutical ingredients other than the triazolopyridazine derivative [I] or a salt thereof varies depending on the target disease, the age and gender of the target patient, the state of the disease, and the like. ９９99.9% by weight, preferably about 0.1-50% by weight, more preferably about 0.5-20% by weight.
% By weight.

When the preparation of the present invention is used as an inhalant, a powder inhaler, a suspension for inhalation, a solution for inhalation or a capsule inhaler is prepared by a method known per se, and an appropriate inhaler is used at the time of use. Can be applied. Further, the preparation of the present invention can be used as an aerosol. In the case of aerosols, the contents enclosed in the can are completely free from contamination during the period of use, so the inside of the aerosol can is always kept in a pressurized state, and there is no contamination from the outer periphery It has the feature of. Aerosols are usually composed of five components: containers, valves, buttons, contents, and propellants, and are classified into two-phase systems, three-phase systems, and diaphragm systems (double containers). As the container, those specified by the High Pressure Gas Control Law are used, and as the material, metal (eg, tin, aluminum), glass or plastic is used. As metal containers, three-piece side seam cans, two-piece seamless cans,
There are three types of monoblock cans consisting of one piece. Glass containers are excellent in solvent resistance and corrosion resistance and are easy to process, so they are easy to be deformed containers. The valve is the part that most affects the injection characteristics and the sealing performance of the aerosol.
The valve is generally composed of a mountain cup, a stem, a housing, a spring, a dip tube, and a gasket rubber, and a valve with a gas phase hole or a fixed valve is used. In the valve mechanism, when the stem is pressed, the stem hole closed by the gasket rubber, which is a hermetic seal, communicates with the inside of the container, and the contents are released by being released. As the button, a straight button, a break cap button, a button for foaming, a button with a long nozzle, and the like are used. As the contents, the above-mentioned topical agent (inhalant) of the present invention is used. As the propellant, the same propellant as described above is used.

In a two-phase aerosol using a liquefied gas propellant as a propellant, a suspension (stock solution) containing a triazolopyridazine derivative [I] or a salt thereof is mixed with a propellant to form a uniform liquid phase. The interior of the container is composed of a liquid phase and a gas phase in which a propellant is vaporized in an upper space. In this system, fine particles can be obtained due to the vaporization and crushing force when the propellant, which has been liquefied under pressure in the container, is jetted under normal pressure through a valve. In the case of a compressed gas, it is compressed and present in the upper space, and only presses the stock solution. In the three-phase system, the liquid phase forms a two-phase emulsified state, and there are an emulsified system consisting of the two phases and a gas phase in the upper space, and a suspension system consisting of a powder / liquefied gas phase consisting of the gas phase in the upper space. The diaphragm system is a form in which the stock solution is jetted as it is, and the stock solution is filled in the inner container in which the propellant is passed through the valve to the outer container using a double container, and only the stock solution is jetted. When the preparation of the present invention is used as an aerosol, it is preferable to use a powder aerosol.

The production of an aerosol usually comprises two steps: a step of preparing the contents and a step of filling the contents and the propellant. Preparation of the contents can be carried out using a method known per se, but a method of mixing a triazolopyridazine derivative [I] or a salt thereof and an auxiliary agent with a solvent to form a uniform suspension. A method of kneading a triazolopyridazine derivative [I] or a salt thereof with a surfactant to form a powder, mixing a triazolopyridazine derivative [I] or a salt thereof with a water-soluble additive for an inhalant, A method is used in which the emulsion is heated and then cooled to form an emulsion. The filling of the contents and the propellant usually includes washing of the container, filling of the contents, deaeration of the container, filling of the propellant, and mounting of a valve device. Cooling filling,
Pressure filling, under cup filling, and the like are used. After filling, check the crimp status to see if the valve is properly installed. In addition, a hot water test is performed to check for leakage of the product, and water droplets are removed. Further, in order to confirm the safety of the aerosol agent during storage and use, a flame length test and a time-dependent change test (eg, tests for weight loss, injection characteristics, container corrosion, valve function, internal pressure, etc.) are performed.

When the preparation of the present invention is used, a commercially available inhaler may be used as a device used for application. For example, VENTOLIN (Ventolin Rotacaps) may be used.
ROTACAPS; Glaxo), Spin Heller (registered trademark,
Fujisawa Pharmaceutical Co., Ltd.), INTAL SPINCAPS (Fisons), Atrovent & Verotech Inhalette (ATROVENT AND BER)
OTEC INHALETTEN; Boehringer Ingelheim), Foradil (FORADIL; Ciba), Bent Discs (BENTODISKS; Glaxo), Publyzer (registered trademark, Teijin Limited), Bricanil Tarbhaller (BRIC)
ANYL TURBUHALER; Astra), MIAT INSUFFLATOR and the like.

The triazolopyridazine derivative [I] or a salt thereof used in the preparation of the present invention has excellent antiallergic action, antiinflammatory action, anti-PAF (platelet activating factor) action, eosinophil chemotaxis inhibitory action, It has an action to suppress infiltration of eosinophils in local areas of allergic and inflammatory reactions, and has low toxicity (acute toxicity: LD ₅₀ > 2 g / k)
g). The topical agent of the present invention can cause the triazolopyridazine derivative [I] or a salt thereof to specifically act on the bronchi or surrounding tissues by injection into the mouth, throat and the like. As described above, the local administration of the triazolopyridazine derivative [I] or a salt thereof requires the administration of the minimum effective amount, so that systemic large-scale administration can be avoided. Therefore, even a child can easily and safely take the medicine. In particular, when used as an inhalant or an aerosol, a special local effect can be exhibited. As mentioned above,
The preparations of the present invention can be used in mammals (eg, humans, mice, rats, cats, dogs, sheep, horses, cows, monkeys, etc.), which are safe as anti-asthmatic agents, anti-PAF agents, anti-allergic agents, eosinophils Chemotaxis inhibitors, diseases involving eosinophil infiltration (eg, urticaria, atopic dermatitis, allergic rhinitis,
Prevention of allergic diseases such as hypersensitivity pneumonitis, skin diseases such as eczema, herpetic dermatitis and psoriasis, and respiratory diseases such as eosinophilic pneumonia (PIE syndrome) and chronic obstructive pulmonary disease (COPD). It can be used as a therapeutic agent and the like.
In particular, anti-asthmatics, prevention of chronic obstructive pulmonary disease (COPD)
It is useful as a therapeutic agent, a prophylactic / therapeutic agent for hypersensitivity pneumonitis or a prophylactic / therapeutic agent for eosinophilic pneumonia. The dosage of the preparation of the present invention varies depending on the target disease, age, body weight, symptom, administration route, number of administrations and the like. For example, for an adult, the active ingredient (triazolopyridazine derivative [I] or its derivative per day) Salt) and usually about 0.001 to 10 mg / k
g, preferably about 0.01 to 10 mg / kg, more preferably about 0.1 to 10 mg / kg, particularly preferably about 0.1 to 5 mg / kg, divided into 1 or 2 divided doses per day. Is good. As the administration route, it is usually preferable to inhale directly into the mouth or the like using an inhalation device.

[0025]

Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereto. The detection of the fraction containing the target substance in the reference example was performed by TLC (Thin Layer Chromatography,
It was performed under observation by thin layer chromatography). T
In LC observation, Merck (Me) was used as a TLC plate.
rck) 60F ₂₅₄ was used as a detection method with a UV detector. Silica gel 60 (70-230 mesh) manufactured by Merck was used as silica gel for column chromatography. Abbreviations used in the text have the following meanings. J: coupling constant s: singlet bs: broad singlet t: triplet m: multiplet Hz: hertz d: doublet q: quartet (quartet) NMR: proton nuclear magnetic resonance DMSO: heavy methyl sulfoxide CDCl _3: heavy Kurotohorumu v / v: volume / volume%: weight%

[0026]

EXAMPLES Reference Example 1 Production of 3-amino-6-chloro-5-isopropylpyridazine 2,6-dichloro-4-isopropylpyridazine 21.7
g, 170 ml of 25% aqueous ammonia and 10 ml of ethanol were placed in a sealed stainless steel reaction tube.
Stir for 2 hours. After cooling, concentrate and add water to the residue,
The precipitated crystals are collected by filtration, washed with water and ethyl ether,
Drying gave 11.1 g of the title compound. Melting point 164-165 ° C NMR (CDCl ₃ ) δ: 1.26 (6H, d, J = 7 Hz), 3.16 (1H,
m), 4.89 (2H, br.s), 6.65 (1H, s) Reference Example 2 N- (6-chloro-5-isopropylpyridazine-3-
Il) Preparation of formamide oxime 8.6 g of 3-amino-6-chloro-5-isopropylpyridazine 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 fraction was collected and concentrated, the residue was dissolved in 40 ml of methanol, 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 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 3 Preparation of 6-chloro-7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine N- (6-chloro-5-isopropylpyridazine-3-
(Il) 20.04 g of formamide oxime and 97 g of polyphosphoric acid were kneaded and reacted in an oil bath at 110-115 ° C for 1 hour. After cooling, ice water was added, and the mixture was extracted with dichloromethane. The extract was washed with water and dried over magnesium sulfate. After concentrating under reduced pressure, hexane was added to the residue, and the precipitated crystals were collected by filtration to obtain 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 4 Production of 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine 60% oily sodium hydride 0 .336 g in 30 ml of tetrahydrofuran to give 3-hydroxy-2,2
0.669 g of dimethylpropane-1-sulfonamide
Was added and the mixture was refluxed for 1 hour. After cooling, 0.748 g of 6-chloro-7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine was added, and the mixture was heated under reflux for 4 hours. After cooling, ice water was added, the pH was adjusted to 6.0 with 1N hydrochloric acid, and the mixture was extracted with tetrahydrofuran-ethyl acetate (1: 1). The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and dichloromethane: ethyl acetate: methanol = 10: 10:
Eluted at 1. The desired fraction was collected and the resulting crystals were recrystallized from acetone-water to give the title compound 1.10
g was obtained. Mp 197-198 ° C. Elemental _{analysis: C 13 H 21 N 5 O} 3 Calculated S (%): C, 47.69 ; H, 6.46; N, 21.
39 found (%): C, 47.84; H, 6.60; N, 21.
33

Reference Example 5 The results of a pharmacological test of the compound of Reference Example 4 are shown. [Effect on Platelet Activating Factor (PAF) -Induced Guinea Pig Airway Constriction Response] Male (Hartley) Hartley guinea pigs (body weight: about 500 g) were used. PAF 1μg / kg
The airway constriction response in guinea pigs due to intravenous administration was measured according to the Konchet-Roessler method. Guinea pig urethane (1.5 g / kg, IV)
After fixation of the dorsal position under anesthesia, a tracheotomy was performed, and the tracheostomy was connected to an artificial respiratory organ via a cannula. The side branch of the tracheal cannula was connected to a transducer (Model 7020, Ugobasile). The volume of air supplied is 3 to 7 ml, the frequency of air supply is 70 times / minute, the load pressure on the lungs is 10 cmH ₂ O, and the amount of air that overflows is measured using a rectograph (Recte-Hori) via a transducer.
-8s, manufactured by Nippon Electric Sanei Co., Ltd.). After treatment with gallamine (1 mg / kg, iv), PA dissolved in physiological saline
F 1 μg / kg was administered via the jugular vein cannula and the evoked airway constriction response was recorded for 15 minutes. The drug is 3mg / kg
And 1 mg / kg were each suspended in 5% gum arabic solution and orally administered 1 hour before PAF administration. The results are shown in [Table 1].

[0029]

[Table 1] From Table 1, it was found that the compound of Reference Example 4 had an effect of suppressing the airway constriction reaction induced by PAF.

Example 1 Suspension for Inhalation (1) Compound of Reference Example 4 20.0 mg (2) HCFC-123 1560.0 mg (3) HCFC-134a 240.0 mg (4) Sorbitan trioleate 20.0 mg or more To give a suspension for inhalation. Use a metering valve that ejects 50 μl each time.

Example 2 Solution for Inhalation (1) 20.0 mg of the compound of Reference Example 4 (2) 100.0 g of purified water is mixed to obtain a solution for inhalation. This inhalation solution is applied using a nebulizer (trade name).

Example 3 Powder Inhalant (1) Compound of Reference Example 4 25.0 g (2) Lactose 250.0 g The above ingredients are mixed to obtain a powder inhalant.

Example 4 Capsule Inhaler (1) 25.0 g of the compound of Reference Example 4 (2) 250.0 g of lactose The above ingredients were mixed, and 2.5 mg of the compound of Reference Example 4 was contained in one capsule. Into 2 capsules
000 capsule inhalations are obtained. This capsule-shaped inhaler is applied using a spin-herler (Fujisawa Pharmaceutical Co., Ltd.) as a small injector.

[0034]

EFFECT OF THE INVENTION The preparation of the present invention can cause the triazolopyridazine derivative [I] to specifically act on the anti-asthmatic effect on the bronchi or surrounding tissues. Therefore,
By local administration, administration of a minimally effective amount is sufficient, so that systemic administration of a large amount of the triazolopyridazine derivative [I] can be avoided.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/00 629 A61K 31/00 629 637 637E 643 643G // C07D 487/04 145 C07D 487/04 145

Claims (6)

[Claims] 1. A compound of the general formula [Wherein, R ¹ represents a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom, and R ² and R ³
Represents a hydrogen atom, a lower alkyl group which may have a substituent or a cycloalkyl group which may have a substituent, and R ² and R ³ represent 5 to 7 together with the adjacent -C = C-. X may be an oxygen atom or S
(O) represents p (p represents an integer of 0 to 2), and Y represents a formula (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 A divalent group derived from R ⁶ and R ⁷
Represents 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,
⁶ and R ⁷ may form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom, m represents an integer of 0 to 4, and n represents an integer of 0 to 4 . ] Or a salt thereof. (2) R ¹ is (i) a hydrogen atom, (ii) hydroxy, amino, carboxyl, nitro, mono- or di-
C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 alkylcarbonyloxy and C _1-6 alkyl group or may have a substituent group selected from the group consisting of halogen atoms (iii) a halogen atom Wherein R ² and R ³ are each (i) a hydrogen atom, (ii) hydroxy, amino, carboxyl, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 alkylcarbonyl A C _1-6 alkyl group which may have a substituent selected from the group consisting of oxy and halogen atoms, or (iii) hydroxy, amino, carboxyl, nitro, mono- or di-
C _1-6 alkylamino, C _1-6 alkoxy, shows a C _1-6 alkylcarbonyloxy and optionally C _3-6 cycloalkyl group optionally having a substituent selected from the group consisting of halogen atom, R ² And R ³ together with the adjacent -C = C-
Hydroxy, amino, mono - or di -C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 alkyl - which may have a substituent selected from the group consisting of carbonyloxy and halogen atoms C _{1 -6} alkyl, C _1-6 selected alkyl, C _1-6 acyl or a 5 to substituted 7-membered cyclic amino, amino, hydroxy, carboxyl, nitro, a group consisting of C _1-6 alkoxy and halogen May have a substituent,
It may form a 5- to 7-membered ring which may contain 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms, and X represents an oxygen atom or S (O) p (P represents an integer of 0 to 2), and Y
Is the formula (a) (R ⁴ and R ⁵ each represent (i) a hydrogen atom or (ii)
Hydroxy, amino, carboxyl, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy, C
_A C _1-6 alkyl group which may have a substituent selected from the group consisting of _1-6 alkylcarbonyloxy and a halogen atom), or (b) hydroxy, amino, mono- or di- -C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 alkyl - carbonyloxy and C _1-6 alkyl optionally having a substituent selected from the group consisting of halogen atom, C _1-6 Alkyl, C
Amino, hydroxy, carboxyl, which may be substituted with _1-6 acyl or 5- to 7-membered cyclic amino,
A nitrogen atom other than a 3- to 7-membered cyclic hydrocarbon or carbon atom which may have a substituent selected from the group consisting of nitro, C _1-6 alkoxy and halogen atom,
A divalent group derived from a 3- to 7-membered heterocyclic ring containing 1 to 4 hetero atoms selected from the group consisting of an oxygen atom and a sulfur atom, wherein R ⁶ and R ⁷ are each (i) a hydrogen atom (Ii) having a substituent selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 alkylcarbonyloxy and a halogen atom. An optionally substituted C _1-6 alkyl group, (iii) hydroxy, amino, carboxyl, nitro, mono- or di-C _1-6
A C _3-6 cycloalkyl group optionally having a substituent selected from the group consisting of alkylamino, C _1-6 alkoxy, C _1-6 alkylcarbonyloxy and halogen atom, or (iv) hydroxy, amino, mono -Or di-C
C- ₆ which may have a substituent selected from the group consisting of _1-6 alkylamino, C1-6 alkoxy and halogen atom
Amino, acetamido, hydroxy, carboxyl, nitro, C-substituted or substituted with _1-6 alkyl, C _1-6 alkyl or 5- to 7-membered cyclic amino
_A C _6-14 aryl group which may have a substituent selected from the group consisting of _1-6 alkoxy, C _1-6 alkylcarbonyloxy and a halogen atom, wherein R ⁶ and R ⁷ together with an adjacent nitrogen atom Hydroxy, amino, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy, C _1-6
C _1-6 alkyl, C _1-6 alkyl, C _1-6 acyl or 5 to 7 which may have a substituent selected from the group consisting of alkyl-carbonyloxy and halogen atoms
One nitrogen atom which may have a substituent selected from the group consisting of amino, hydroxy, carboxyl, nitro, C _1-6 alkoxy and a halogen atom which may be substituted with a membered cyclic amino, 1 to 4 selected from nitrogen, oxygen and sulfur atoms
May form a group in which one hydrogen atom is removed from the ring of the 3- to 13-membered nitrogen-containing heterocyclic ring which may contain 3 hetero atoms, m is an integer of 0 to 4, and n is 0 The agent according to claim 1, which represents an integer of from 4 to 4. (3) R ¹ is a hydrogen atom or a C _1-3 alkyl group,
R ² is a hydrogen atom or a C _1-3 alkyl group, R ³ is a hydrogen atom or a C _1-6 alkyl group, X is an oxygen atom, and Y is a compound of the formula [Wherein R ⁴ ′ and R ⁵ ′ each represent (i) a hydrogen atom or (ii) hydroxy, amino, carboxyl, nitro,
C _1-3 optionally having 1 to 4 substituents selected from mono- or di-C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 alkyl-carbonyloxy or halogen atoms. Shows an alkyl group. A group represented by R ⁶
2. The agent according to claim 1, wherein R and R ⁷ each represent a hydrogen atom or a C _1-3 alkyl group, and m and n each represent 1. 4. The compound according to claim 1, wherein the compound is 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine. Agent. 5. An anti-asthmatic, chronic obstructive pulmonary disease (COPD)
The agent according to claim 1, which is a prophylactic / therapeutic agent, a hypersensitivity pneumonitis prophylactic / therapeutic agent or an eosinophilic pneumonia prophylactic / therapeutic agent. 6. The agent according to claim 1, which is a bronchial inhaler.