JP2003252797A - Acid-containing preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an acid-containing preparation having a high absorbability via the digestive tract and an excellent stability. <P>SOLUTION: The preparation contains (1) a compound having an antiallergic, antihistamine, anti-inflammatory, anti-PAF and/or eosinophil chemotaxis inhibitory effects (in particular, a basic or bipolar compound having an antiallergic, antihistamine, anti-inflammatory, anti-PAF (platelet aggregating factor) and/or eosinophil chemotaxis inhibitory effects) and (2) an acidic compound. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an acid-blended preparation and a method for producing the same.

[0002]

2. Description of the Related Art Some physiologically active substances have large fluctuations in gastrointestinal absorption. These physiologically active substances with large fluctuations in oral absorption show that intravenous injections,
In many cases, the dosage form must be changed to an intramuscular injection. However, injectables are not always suitable dosage forms for physiologically active substances that require repeated administration or long-term administration, from the viewpoint of ease of use.

[0003]

The present invention deals with in vivo factors among the above-mentioned changes in gastrointestinal absorptivity, in particular, intra-individual fluctuations in gastric pH, and variations caused by intra-individual fluctuations. It is intended to provide a preparation of a physiologically active substance (a compound having an anti-allergic action, an antihistamine action, an anti-inflammatory action, an anti-PAF action and / or an eosinophil chemotaxis inhibitory action) which is hardly affected by changes in internal pH. . That is, the present invention provides a preparation comprising a physiologically active substance having solubility dependent on pH and an acidic compound for the purpose of assisting dissolution of the physiologically active substance.

[0004]

[Means for Solving the Problems] The inventors of the present invention have conducted extensive studies to solve the above-mentioned problems, and have studied physiologically active substances which are basic compounds or bipolar compounds, particularly antiallergic action, antihistamine action, As a result of further studies, it was found that a formulation comprising an acid compound and a compound having an anti-inflammatory action, an anti-PAF action and / or an eosinophil chemoattractant inhibiting action is excellent in absorption and stability. It came to completion.

That is, the present invention relates to [1] a preparation comprising a compound having an antiallergic action, an antihistamine action, an antiinflammatory action, an anti-PAF action and / or an eosinophil chemoattractant action and an acidic compound, 2) The preparation according to the above [1], wherein the compound having an antiallergic action, an antihistamine action, an antiinflammatory action, an anti-PAF action and / or an eosinophil chemotaxis inhibitory action is a basic compound, [3] an antiallergic action A preparation having the above-mentioned [1], wherein the compound having an antihistamine action, an anti-inflammatory action, an anti-PAF action and / or an eosinophil chemotaxis inhibitory action is a bipolar compound, [4] an antiallergic action, an antihistamine action, Anti-inflammatory effect, anti-PA
The preparation according to the above [1], wherein the solubility of the compound having an F action and / or an eosinophil chemotaxis inhibitory action at pH 3 or less is 10 times or more the solubility at pH 5 to 8; [5]
Anti-allergic action, anti-histamine action, anti-inflammatory action, anti-
A compound having a PAF action and / or an eosinophil chemotaxis inhibitory action has the formula

[Chemical 2] [In the formula, Ar¹And Ar²Each has a substituent
Good aromatic group, Ar ¹And Ar²Is adjacent to a carbon atom
May have a condensed ring group, and the B ring has a substituent.
Optionally represents a nitrogen-containing heterocycle, X and Y are respectively
Identical or different, bond, oxygen atom, S (O)_p(P is 0
Indicates the integer of 2), NR^Four(R^FourIs a hydrogen atom or a lower atom
Alkyl group) or may have a substituent,
Divalent straight chain low optionally having 1 to 3 terror atoms
Indicates a primary hydrocarbon group, A is a nitrogen atom or CR⁷(R⁷Is hydrogen
Atoms, halogen atoms, hydrocarbons that may have a substituent
Elementary group, acyl group or optionally substituted hydro group
Xy group), R¹, R²And R³Are the same
Or differently having a hydrogen atom, a halogen atom, a substituent
Optionally having a hydrocarbon group, an acyl group or a substituent
R is an optional hydroxy group⁸Is a hydrogen atom, lower
A hydroxy group which may be substituted with an alkyl group or
Indicates a carboxyl group. ] A compound represented by
Compound (I)) or its salt
[1] The preparation described in [1], [6] Antiallergic action, antihis
Tamine action, anti-inflammatory action, anti-PAF action and / or favorable
Compounds having an inhibitory effect on chemotactic migration of 2-acids are known as 2- [6- [3- [4- (di
(Phenylmethoxy) piperidino] propylamino] imida
Zo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid
Chill, 2- [6- [3- [4- (diphenylmethoxy) piperidino] pre
Ropyramino] imidazo [1,2-b] pyridazin-2-yl] -2-
Methylpropionic acid or its salt, N- [6- [3- [4- (Diphene
Nylmethoxy) piperidino] propylamino] imidazo [1,
2-b] pyridazine-2-carbonyl] glycine ethyl ester
Or its salt, 2- [6- [3- [4- (diphenylmethoxy) pipet
Lysino] propylamino] -3-methylimidazo [1,2-b] pyri
Dazin-2-yl] -2-methylpropionate ethyl or its
Salt of 2- [6- [3- [4- (diphenylmethoxy) piperidino] p
Ropyramino] imidazo [1,2-b] pyridazin-2-yl] -2-
Manufactured according to the above [1], which is methylpropionic acid dihydrate.
[7] The agent according to [1] above, wherein the acidic compound is a solid
Agent, [8] 50% or more of the constituent particles of acidic compound are not 50 μm
The preparation according to [1] above, which is a particle of 1.5 mm,

[9] The preparation according to the above [1], wherein 50% or more of the constituent particles of the acidic compound are particles of 150 μm to 1.0 mm, [10] Among the constituent particles of the acidic compound, particles of 50 μm or less are 20% or less of the whole. [1] The preparation according to [1] above, [11] The preparation according to [1] above wherein the acidic compound is a carboxylic acid, a sulfonic acid, an acidic polysaccharide and an acidic amino acid, [12] above [1] wherein the acidic compound is a carboxylic acid. [13] The preparation described in [12] above, wherein the carboxylic acid is fumaric acid, adipic acid, malic acid, acetic acid, tartaric acid, succinic acid or citric acid.
4] The preparation according to the above [12], wherein the carboxylic acid is tartaric acid, succinic acid or citric acid, [15] The preparation according to the above [12], wherein the carboxylic acid is citric acid, [16] an antiallergic action, an antihistamine action. , Compounds having anti-inflammatory action, anti-PAF action and / or eosinophil chemotaxis inhibitory action
The formulation of the above-mentioned [1] containing 0.1 to 10 parts by weight of an acidic compound, [17] the formulation of the above-mentioned [1] which is a tablet, [18] antiallergic action, antihistamine action, [1] wherein the granules containing a compound having an inflammatory action, an anti-PAF action and / or an eosinophil chemotaxis suppressing action and a granule containing an acidic compound are blended
[19] Granules containing a compound having an antiallergic action, an antihistamine action, an anti-inflammatory action, an anti-PAF action and / or an eosinophil chemoattractant action described in [19].
To 1.5 mm particles of 50% or more, and the granules containing an acidic compound contain 50 μm to 1.5 mm particles of 50% or more, [18] the preparation, [20] antiallergic action, antihistamine action, Granules containing a compound having an inflammatory action, an anti-PAF action and / or an eosinophil chemoattractant inhibiting action contain 50% or more of particles of 150 μm to 1.0 mm, and a granule containing an acidic compound of 150 μm to 1.0 mm. To 50%
The preparation according to [18] above, [21] the preparation according to [1], which is a multilayer tablet, [22] the preparation according to [17] or [21], which is a coated preparation, [23], and further talc. Or / and a compound having the above-mentioned [1], which has magnesium stearate and [24] an anti-allergic action, an antihistamine action, an anti-inflammatory action, an anti-PAF action and / or an eosinophil chemotaxis inhibitory action. The present invention relates to the method for producing the preparation according to the above [1], which comprises blending the contained granules with the granules containing an acidic compound.

The "anti-allergic action," used in the present invention,
Examples of the “compound having an antihistamine action, an anti-inflammatory action, an anti-PAF action and / or an eosinophil chemotaxis inhibitory action” include non-peptidic compounds having a molecular weight of 1000 or less, preferably 900 or less, more preferably 800 or less . The "compound having an antiallergic action, an antihistamine action, an antiinflammatory action, an anti-PAF action and / or an eosinophil chemotaxis inhibitory action" used in the present invention is a basic compound or a bipolar compound. It is preferably used.
In the present specification, the “basic compound” and the “ambipolar compound” refer to a compound that is water-soluble under acidic conditions and poorly water-soluble under neutral conditions. Here, "poorly water-soluble" means
For example, the solubility of a compound in water at 25 ° C is 1000
Less than ppm (10 mg / mL) (preferably less than 10 ppm (0.1 mg / mL))
It means that. The solubility can be measured by a conventional method. Further, the “basic compound” and the “ambipolar compound” can be defined by the value of pKa (logarithm of the reciprocal of acid dissociation constant) in the partial structure of the compound. That is, the "basic compound" is a compound having a partial structure showing a pKa of 7.5 or more, preferably 8.5.
It means a compound having a partial structure showing the above pKa. Further, the "ambipolar compound", a compound having a partial structure showing a pKa of 7.5 or more and a partial structure showing a pKa of 6.5 or less, preferably a partial structure showing a pKa of 8.5 or more and
A compound having a partial structure showing a pKa of 5.5 or less. In the present specification, preferred "basic compound" and "ambipolar compound" mean that the solubility at pH 3 or less is pH 5 to 8
That is 10 times or more the solubility in, preferably pH
Solubility below 3 is less than that of pH 5 to 8
0 times or more, more preferably, the solubility at pH 3 or less is 100 times or more of the solubility at pH 5 to 8, particularly preferably, the solubility at pH 3 or less, p
It is more than 1000 times the solubility in H5 to H8.

As used in the present invention, "anti-allergic action,
Compounds that have antihistamine action, anti-inflammatory action, anti-PAF (platelet activating factor) action, and eosinophil chemotaxis inhibitory action "
As, for example, diphenhydramine, clemastine fumarate, dimenhydrinate, chlorpheniramine maleate, triprrolidine hydrochloride, promethazine hydrochloride, alimemazine tartrate, isothipendyl hydrochloride, homochlorcyclidine hydrochloride, hydroxyzine, cyproheptadine hydrochloride,
Mequitazine, terfenadine, epinastine hydrochloride, astemizole, ebastine, cetirizine hydrochloride, sodium cromoglycate, tranilast, ketotifen fumarate, azelastine hydrochloride, oxatomide, anlexanox, repirinast, ibudilast, pemirolast, tazanolast, ozagrasto hydrochloride, ozagraztolate, tosilate, tosilate, tosilate. Examples include emedastine, pranlukast hydrate, the compound (I) or a salt thereof, and the like. Among them, the compound (I) or a salt thereof and the like are preferable.

In the above formula, Ar¹And Ar²Has a substituent
Optionally aromatic group ", Ar ¹And Ar²Is adjacent charcoal
A condensed ring group may be formed together with the elementary atom. Ar¹And
And Ar²As the "aromatic group" represented by, for example, Monocyclic or condensed polycyclic aromatic hydrocarbon group, twisted
Physically, phenyl, tolyl, xylyl, biphenyl,
1-naphthyl, 2-naphthyl, 2-indenyl, 1-anthri
Le, 2-anthryl, 9-anthryl, 1-phenanthryl,
2-phenanthryl, 3-phenanthryl, 4-phenanthryl
Or C such as 9-phenanthryl_6-14Aryl group, etc.
(Preferably phenyl, tolyl, xylyl, biphenyl
Especially 1-naphthyl or 2-naphthyl, particularly preferably
6- to 14-membered monocyclic or fused polycycles such as phenyl
Formula aromatic hydrocarbon group or the like, or In addition to carbon atoms, nitrogen, sulfur and oxygen atoms
Preferably 1 or 2 heteroatoms selected from
Above (eg 1 to 4, preferably 1 to 3)
Containing monocyclic groups (preferably 5 to 8 members) or condensed groups thereof
Aromatic heterocyclic groups, more specifically thiophene, benzo
[b] thiophene, benzo [b] furan, benzimidazo
Le, benzoxazole, benzothiazole, benzii
Sothiazole, naphtho [2,3-b] thiophene, Chianthre
, Furan, isoindolizine, oxanthrene, fe
Noxatiin, pyrrole, imidazole, triazo
Le, thiazole, oxazole, pyrazole, pyridi
, Pyrazine, pyrimidine, pyridazine, indole,
Isoindole, 1H-indazole, purine, 4H-quinoli
Gin, isoquinoline, quinoline, phthalazine, naphthiri
Gin, quinoxaline, quinazoline, cinnoline, carba
Sol, β-carboline, phenanthridine, acridi
Phenazine, isothiazole, phenothiazine, a
Soxazole, furazan, phenoxazine or iso
Aromatic heterocycles such as chroman (preferably pyridine,
More preferably pyridine, such as thiophene or furan
Etc.), or These rings (preferably the above-mentioned monocyclic heterocycle) are
1 or more (preferably 1 or 2, more preferably
Preferably 1) aromatic ring (for example, aromatic carbonization described above)
Formed by condensation with hydrogen groups, etc., preferably benzene rings etc.
A monovalent group formed by removing any hydrogen atom from the
Which is used. Ar¹And Ar²Represented by "has a substituent
Examples of the “aromatic group” of the “aromatic group which may be
For example, a phenyl group or the like is preferable.

Examples of the “substituent” of the aromatic group represented by Ar ¹ and Ar ² include (i) a halogen atom (eg, fluorine, chlorine, bromine, iodine), (ii) a lower alkylenedioxy group. (For example, a C _1-3 alkylenedioxy group such as methylenedioxy and ethylenedioxy), (iii) nitro group, (iv) cyano group, (v) optionally halogenated lower alkyl group, ( vi) optionally halogenated substituted lower alkenyl group, (vii) optionally halogenated substituted lower alkynyl group, (viii) lower cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, C _3, such as cyclohexyl _{- 6} cycloalkyl group), (ix) optionally substituted lower alkoxy group, (x) optionally halogenated lower alkylthio group, (xi) hydroxy group, (xii) amino group, (xiii) mono -Lower alkyl Mino groups (eg, mono-C such as methylamino, ethylamino, propylamino, isopropylamino, butylamino)
_1-6 alkylamino group), (xiv) di-lower alkylamino group (for example, di-C _1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino), (xv) 5 Or a 6-membered cyclic amino group (eg, morpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl, etc.), (xvi) lower alkyl-carbonyl group (eg, C _1-6 alkyl-carbonyl such as acetyl, propionyl, etc. Group), (xvii) carboxyl group, (xv
iii) lower alkoxy-carbonyl group (for example, C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (xix) carbamoyl group, (xx) thiocarbamoyl, (xxi) mono -Lower alkyl-carbamoyl group (eg, mono-C _1-6 alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyl etc.), (xxii) di-
Lower alkyl-carbamoyl group (eg, di-C _1-6 alkylcarbamoyl group such as dimethylcarbamoyl, diethylcarbamoyl, etc.), (xxiii) aryl-carbamoyl (eg, C _6-10 aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.) Etc.), (xxiv)
Sulfo group, (xxv) lower alkylsulfonyl group (for example,
Methylsulfonyl, etc. C _{1 -6} alkylsulfonyl group such as ethylsulfonyl), (xxvi) aryl groups (e.g., phenyl, C _6-10 aryl groups such as naphthyl), (xxvi
i) aryloxy groups (eg, C _6-10 aryloxy groups such as phenoxy and naphthyloxy), (xxviii) aralkyloxy groups (eg, C such as benzyloxy)
_7-16 aralkyloxy group etc.) and the like are used.

The above-mentioned "optionally halogenated lower alkyl
Examples of the “alkyl group” include, for example, 1 to 3 halogen atoms.
Have offspring (eg, fluorine, chlorine, bromine, iodine)
Optionally lower alkyl groups (eg methyl, ethyl,
Ropil, isopropyl, butyl, isobutyl, sec-butyl
C such as ruthel, tert-butyl, pentyl, hexyl_1-6Al
(Eg, a kill group), and specific examples include methyl groups.
, Fluoromethyl, chloromethyl, difluoromethy
, Trichloromethyl, trifluoromethyl, ethyl,
2-bromoethyl, 2,2,2-trifluoroethyl, propyi
Le, 3,3,3-trifluoropropyl, isopropyl, buty
, 4,4,4-trifluorobutyl, isobutyl, sec-butyl
Ru, tert-butyl, pentyl, isopentyl, neopen
Chill, 5,5,5-trifluoropentyl, hexyl, 6,6,6-
Trifluorohexyl or the like is used. Above "Halogen
Optionally lower alkenyl groups "and" halo "
As the “generally-lowered lower alkynyl group”,
For example, 1 to 3 halogen atoms (for example, fluorine,
Lower alkeny optionally having chlorine, bromine, iodine)
Group (for example, vinyl, propenyl, isopropenyl,
2-buten-1-yl, 4-penten-1-yl, 5-hexene-1-
C such as IL_2-6Alkenyl group) and 1 to 3
Halogen atom (eg, fluorine, chlorine, bromine, iodine)
A lower alkynyl group which may have (for example, 2-butyl
N-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl
Which C_2-6Alkynyl group etc.) is used. the above
As the “optionally substituted lower alkoxy group”,
For example, 1 to 3 halogen atoms (eg, fluorine, salt
Elementary, bromine, iodine), mono- or di-lower alkylami
Group (eg, methylamino, dimethylamino, ethyl
Mono- or di-C such as amino, diethylamino_1-6Al
(Eg, a kylamino group) or lower alkoxy-carbonyl
Groups (eg methoxycarbonyl, ethoxycarbonyl
Such as C _1-6Have an alkoxy-carbonyl group, etc.)
Optionally lower alkoxy groups (eg methoxy, ethoxy)
Ci, propoxy, isopropoxy, n-butoxy, isobu
C such as toxy, sec-butoxy, tert-butoxy_1-6Al
Coxy group etc.) and the like are used. Above "halogenated
Examples of the "optionally lower alkylthio group" include
For example, 1 to 3 halogen atoms (eg fluorine, chlorine, odor
Lower alkylthio group which may have hydrogen, iodine)
(For example, methylthio, ethylthio, n-propylthio,
Isopropylthio, n-butylthio, isobutylthio, se
C such as c-butylthio, tert-butylthio_1-6Alkylchi
Groups, etc., and specific examples include methyl group
O, difluoromethylthio, trifluoromethylthio,
Ethylthio, propylthio, isopropylthio, butyl
Thio, 4,4,4-trifluorobutylthio, pentylthio,
Hexylthio and the like are used.

Specific examples of the case where Ar ¹ and Ar ² form a condensed ring group together with adjacent carbon atoms include, for example,

[Chemical 3] [In the formula, R ⁸ has the same meaning as described above. ] A condensed ring group represented by, for example, is used. As Ar ¹ and Ar ² , the same or different, preferably an aromatic hydrocarbon group which may have a substituent (eg, C _6-14 aromatic hydrocarbon group) is preferable, and it has a substituent. A phenyl group which may be present is more preferable. More specifically, each of Ar ¹ and Ar ² is (1) a phenyl group which may be substituted with a halogen atom or C _1-6 alkyl, or (2) a nitrogen atom other than a carbon atom, a sulfur atom and oxygen. A 5- to 8-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from atoms is preferable.

In the above formula, ring B represents "a nitrogen-containing heterocycle which may have a substituent". The "nitrogen-containing heterocycle" represented by ring B includes, for example, one nitrogen atom, and further includes, for example, 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom, a sulfur atom and the like. Can be 3 to 1
A 3-membered nitrogen-containing heterocycle is used. In the above formula, it is preferable to form a divalent group by removing one hydrogen atom from each of the nitrogen atom and other atom of ring B. Specifically, for example

[Chemical 4] 3 to 9-membered (more preferably 3 to 6-membered) nitrogen-containing heterocyclic groups such as Examples of the substituent of the nitrogen-containing heterocycle represented by ring B include, for example, "substituent" of "aromatic group which may have a substituent" represented by Ar ¹ and Ar ² above, An oxo group or the like is used.

Specific examples of preferred ring B include, for example,
formula

[Chemical 5] [Wherein Z represents a nitrogen atom or a methine group, and Z ¹ and Z
Each of ² represents a linear C _1-4 alkylene group which may be substituted with a hydroxy group, an oxo group or a C _1-6 alkyl group. ] The ring etc. represented by] are used. Examples of the “C _1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
A linear or branched C _1-6 alkyl group such as tert-butyl, pentyl, hexyl and the like are used. The "linear
As the “C _1-4 alkylene group”, for example, a linear C _1-4 alkylene group represented by methylene, ethylene, propylene or butylene is shown. The "linear C _1-4 alkylene group optionally substituted by a hydroxy group, an oxo group or a C _1-6 alkyl group" represented by Z ¹ and Z ² is preferably an unsubstituted linear C _{A 1-4} alkylene group or the like is used, and an unsubstituted linear C _1-2 alkylene group is particularly preferable. More preferably, as ring B, piperidine, piperazine and the like are used.

In the above formula, X and Y are the same or different and each is (1) a bond, (2) an oxygen atom, (3) S (O) _p (p represents an integer of 0 to 2), (4) ) NR ⁴ (R ⁴ represents a hydrogen atom or a lower alkyl group) or (5) a divalent linear lower group which may have a substituent and may have 1 to 3 hetero atoms. Indicates a hydrocarbon group. The lower alkyl group represented by R ⁴ , for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
A linear or branched C _1-6 alkyl group such as butyl, pentyl, hexyl and the like are used.

“Heteroatoms 1 to 3 represented by X and Y
And a divalent straight-chain lower hydrocarbon group which may be interposed
Then, lower (C_1-6) Hydrocarbon identical or different charcoal
Removes one hydrogen atom (two in total) that is bonded to an elementary atom
Groups formed by, for example, oxygen atom, NR^{Four '}(R^{Four '}Is
A hydrogen atom or a lower alkyl group is shown. ), Sulfur atom
Containing a heteroatom selected from
Represents a group. R^{Four '}As a lower alkyl group represented by
Is, for example, methyl, ethyl, propyl, isopropyl
, Butyl, isobutyl, sec-butyl, tert-butyl,
Linear or branched C such as pentyl and hexyl_1-6A
A rutile group or the like is used. "Divalent straight-chain lower hydrocarbon
Specifically, (i) C_1-6Alkylene group (eg
For example, -CH₂-,-(CH₂)₂-,-(CH₂)₃-,-(CH₂)_Four-,-(CH₂) _Five-,
 -(CH₂)₆-Etc.), (ii) C_2-6Alkenylene groups (eg,
-CH = CH-, -CH = CH-CH₂-, -CH₂-CH = CH-CH₂-,-(CH₂)₂-CH =
CH-CH₂-,-(CH₂)₂-CH = CH- (CH₂)₂-,-(CH₂)₃-CH = CH-CH₂-
 Etc.), (iii) C_2-6Alkynylene group (for example, -C≡C-,
-C≡C-CH₂-, -CH₂-C≡C-CH₂-,-(CH₂)₂-C≡C-CH₂-,-(C
H₂)₂-C≡C- (CH₂)₂-,-(CH₂)₃-C≡C-CH₂-Etc)
Used. “Heteroatoms 1 to 3 represented by X and Y
Of a divalent straight-chain lower hydrocarbon group which may be through
Examples of the “substituent” include the above Ar¹And Ar²Represented by
"Substitution of" aromatic group which may have a substituent (s) "
In addition to "group", oxo group and the like are used, but especially hydro group
Xy or oxo groups are preferred.

As X, a bond, an oxygen atom or NH is preferable, and a bond or an oxygen atom is particularly preferable.
As Y, preferably, for example, the formula-(CH ₂ ) _m -Y ^1- (CH ₂ ) _n -Y ^2- [In the formula, Y ¹ and Y ² are the same or different and each is a bond, an oxygen atom, S (O ) _p (p is as defined above), NR ^4
' (R ^{4 '} is as defined above), carbonyl group, carbonyloxy group or formula

[Chemical 6] (In the formula, R ⁵ and R ⁶ are the same or different and each represents a hydroxy group or a C _1-4 alkyl group.), M and n each represent an integer of 0 to 4 (provided that , The sum of m and n is 6 or less)] or the like. Examples of the “C _1-4 alkyl group” represented by R ⁵ and R ⁶ include linear or branched groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. C _1-4 alkyl group and the like are used.

Examples of Y include (i) C _1-6 alkylene group, (ii)-(CH ₂ ) _p1 O-, (iii)-(CH ₂ ) _p1 NH-, (iv)-(CH ₂ ) _p1
S-, (v)-(CH ₂ ) _q1 CH (OH) (CH ₂ ) _q2 O-, (vi)-(CH ₂ ) _q1 CH (OH)
_{(CH 2) q 2 NH -} , (vii) - (CH 2) q1 CH (OH) (CH 2) q2 S -, (viii) -
_{(CH 2) p1 CONH -,} (ix) -COO (CH 2) p1 O -, (x) -COO (CH 2) p1 NH
-, (xi) -COO (CH 2) p1 S -, (xii) - (CH 2) q1 O (CH 2) q2 O -, (xi
ii)-(CH ₂ ) _q1 O (CH ₂ ) _q2 NH- or (xiv)-(CH ₂ ) _q1 O (CH ₂ ) _q2 S
-(P1 is an integer from 1 to 6, q1 and q2 are 1
To 3) are preferred. Among them, as Y, for example, a bond,-(CH ₂ ) _2- O-,-(C
H ₂ ) ₃ -O-,-(CH ₂ ) ₄ -O-,-(CH ₂ ) ₆ -O-,-(CH ₂ ) ₂ -NH-,-(CH
₂ ) ₃ -NH-,-(CH ₂ ) ₄ -NH-,-(CH ₂ ) ₃ -S-, -CH ₂ -CH (OH) -CH _2-
O-,-(CH ₂ ) ₂ -CO-NH-, -CH ₂ -CO-NH-, -CO-O- (CH ₂ ) ₂ -O-,
-CO-O- (CH ₂ ) ₃ -O-,-(CH ₂ ) ₆ -NH-,-(CH ₂ ) ₆ -S-,-(CH ₂ ) _{2-
-O- O- (CH 2) 2,} - (CH 2) 2 -O- (CH 2) 2 -S- and the like are preferable.

In the above formula, A is a nitrogen atom or CR ⁷ (R ⁷ is a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxy which may have a substituent). Group is shown). Examples of the “halogen atom” represented by R ⁷ include fluorine, chlorine, bromine and iodine. Examples of the “hydrocarbon group” represented by R ⁷ include a group obtained by removing one hydrogen atom from a hydrocarbon compound,
Examples thereof include alkyl groups, alkenyl groups,
Examples thereof include chain or cyclic hydrocarbon groups such as alkynyl group, cycloalkyl group, aryl group and aralkyl group.
Of these, a linear (branched or branched) or cyclic hydrocarbon group having 1 to 16 carbon atoms is preferable, and a) an alkyl group [preferably a lower alkyl group (for example,
C _1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.)], b) alkenyl groups [preferably lower alkenyl groups (eg vinyl , C _2-6 alkenyl groups such as allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl etc.)], c) alkynyl groups [preferably lower alkynyl groups (eg propargyl, ethynyl, butynyl, 1-hexynyl etc. C _2-6 alkynyl group etc.)], d) cycloalkyl group [preferably lower cycloalkyl group (eg cyclopropyl, cyclobutyl, cyclopentyl, 1 to 3 lower alkoxy groups (eg C _1- , such as methoxy, etc. ₆ C, such as alkoxy group) may cyclohexyl optionally condensed with benzene ring which may have a like _3-6 cycloalkyl group)], e) an aryl group (eg, phenyl, tolyl, xylyl,
Biphenyl, 1-naphthyl, 2-naphthyl, 2-indenyl,
C _6-14 aryl group such as 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl, preferably phenyl group), f) aralkyl Group [preferably a lower aralkyl group (eg, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-phenylethyl, 2-
C _7-16 aralkyl groups such as diphenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc., more preferably benzyl group)] and the like are preferable. Examples of the “substituent” of the “hydrocarbon group” represented by R ⁷ include, for example, the above.
In addition to the “substituent” of the “aromatic group which may have a substituent” represented by Ar ¹ and Ar ² , an oxo group and the like are used.

Examples of the "acyl group" represented by R ⁷ include-(C = O) -R ⁹ , -SO ₂ -R ⁹ , -SO-R ⁹ , and-(C = O) NR ¹⁰ R. ⁹ ,-(C =
O) OR ⁹ ,-(C = S) OR ⁹ ,-(C = S) NR ¹⁰ R ⁹ , (R ⁹ is a hydrogen atom,
A hydrocarbon group which may have a substituent or a hydroxy group which may have a substituent, R ¹⁰ represents a hydrogen atom or a lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -Butyl, tert-
A C _1-6 alkyl group such as butyl, pentyl, hexyl and the like, particularly a C _1-3 alkyl group such as methyl, ethyl, propyl, isopropyl and the like are preferable. ) Is shown. ) And so on. Of these, preferably-(C = O) -R ⁹ , -SO _2-
R ⁹ , -SO-R ⁹ ,-(C = O) NR ¹⁰ R ⁹ ,-(C = O) OR ⁹ , and-(C = O)
-R ⁹ is more preferred. The "hydrocarbon group" represented by R ⁹ is
A group in which one hydrogen atom has been removed from a hydrocarbon compound is shown, and examples thereof include chain-like (straight or linear) groups such as alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups and aralkyl groups. Branched) or cyclic hydrocarbon groups. Specifically, examples thereof include the “hydrocarbon group” represented by R ⁷ above, and among them, a chain or cyclic hydrocarbon group having 1 to 16 carbon atoms is preferable, and particularly lower (C _{1- 6} ) Alkyl groups are preferred. Examples of the “substituent” that the “hydrocarbon group” represented by R ⁹ may have include, for example, the “optionally substituted aromatic group” represented by Ar ¹ and Ar ² above. In addition to the "substituent" of, an oxo group and the like are used. Examples of the “hydroxy group optionally having a substituent” represented by R ⁹ include, for example, R ⁷ described later.
“A hydroxy group which may have a substituent”
The same thing as is used. Examples of the “hydroxy group optionally having a substituent” represented by R ⁷ include, for example,
In place of the hydrogen atom of (1) hydroxy group or (2) hydroxy group, for example, a hydroxy group having one of the above-mentioned "hydrocarbon group optionally having substituent (s)" and the like is shown. R ⁷ includes (1) hydrogen atom, (2) halogen atom, (3) carboxyl group or C _1-6 alkoxy-carboxyl-substituted C _1-6 alkyl group, (4) C _{1- 6} alkoxy group, (5) C
_{A 1-6} alkoxy-carbonyl group or a (6) carboxyl group is preferable, and a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy-carbonyl group or a carboxyl group is particularly preferable. A is a nitrogen atom or CR ^{7 '}
(R ^{7 '} is hydrogen atom, halogen atom, C _1-6 alkyl group, C
_1-6 alkoxy-carbonyl group or carboxyl group) is preferable, and among them, a nitrogen atom, CH or C—CH ₃ is preferable, and a nitrogen atom or CH is particularly preferable.

In the above formula, R ¹ , R ² and R ³ are the same or different and each has a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an acyl group or a substituent. Represents a good hydroxy group. Examples of the “halogen atom” represented by R ¹ , R ² and R ³ include fluorine, chlorine, bromine and iodine. Examples of the "hydrocarbon group which may have a substituent" represented by R ¹ , R ² and R ³ include, for example, the "hydrocarbon group which may have a substituent" represented by R ^7. Group "and the like are used. As the “acyl group” represented by R ¹ , R ² and R ³ , for example, the “acyl group” represented by the above R ⁷ and the like can be used. Examples of the "optionally substituted hydroxy group" represented by R ¹ , R ² and R ³ include, for example, the "optionally substituted hydroxy group" represented by R ⁷ above. Are used. R ¹ , R ² and R ³
Are the same or different (1) hydrogen atom,
(2) a carboxyl group or a C _1-6 alkoxy-carbonyl optionally substituted C _1-6 alkyl group, (3) a C _1-6 alkoxy group, (4) a C _1-6 alkoxy-carbonyl group, ( 5) Carboxyl group or (6) C _6-14 aryl group (particularly phenyl) is preferable, (1) hydrogen atom, (2) carboxyl group or C _1-6
Alkoxy - optionally substituted with a carbonyl C _1-6 alkyl group, (3) C _1-6 alkoxy group, (4) C _1-6 alkoxy -
A carbonyl group or a (5) carboxyl group is more preferred. Further, as R ¹ , (1) hydrogen atom, (2) (i) carboxyl, (ii) C _1-6 alkoxy-carbonyl, (iii) hydroxy or (iv) mono- or di-C _1-6 alkyl is used. A C _1-6 alkyl group which may be substituted with a group selected from the group consisting of carbamoyl which may have, (3) C _6-14 aryl group, (4) C _1-6 alkoxy group, (5 ) C _1-6 alkoxy-carbonyl group, (6) carboxyl group, (7) carboxyl or
C _1-6 C optionally substituted with alkoxy-carbonyl
_A carbamoyl group optionally having _1-6 alkyl or
(8) A C _3-6 cycloalkyl group optionally substituted with C _1-6 alkoxy-carbonyl and the like are also preferable. For R ² ,
A hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy-carbonyl group, a carboxyl group and the like are also preferable. R ³ is preferably a hydrogen atom.

In the above formula, R ⁸ represents a hydrogen atom, a hydroxy group which may be substituted with a lower alkyl group, or a carboxyl group. In the above formula, examples of the “lower alkyl group” of the “hydroxy group optionally substituted with a lower alkyl group” represented by R ⁸ include, for example, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl, ter
Examples thereof include C _1-6 alkyl groups such as t-butyl, pentyl and hexyl. R ⁸ is preferably a hydrogen atom or a hydroxy group, and particularly preferably a hydrogen atom.

The compound (I) of the present invention includes Ar ¹ and Ar.
² are each (1) a phenyl group optionally substituted with a halogen atom or C _1-6 alkyl or (2) a carbon atom other than a nitrogen atom, 1 to 4 heteroatoms selected from a sulfur atom and an oxygen atom. 5- to 8-membered aromatic heterocyclic groups, including ring B

[Chemical 7] [In the formula, Z represents a nitrogen atom or a methine group, and¹And Z
²Are hydroxy, oxo or C_1-6Archi
Linear C optionally substituted by_1-4Alkylene group
[Shown], X is a bond, oxygen atom or NH, Y
Is (i) C_1-6Alkylene group, (ii)-(CH₂)_p1O-, (iii)-(CH₂)
_p1NH-, (iv)-(CH₂)_p1S-, (v)-(CH₂)_q1CH (OH) (CH₂)_q2O
-, (Vi)-(CH₂)_q1CH (OH) (CH₂)_q2NH-, (vii)-(CH₂)_q1CH (O
H) (CH₂)_q2S-, (viii)-(CH₂)_p1CONH-, (ix) -COO (CH₂)_p1O
-, (X) -COO (CH₂)_p1NH-, (xi) -COO (CH₂)_p1S-, (xii)-(C
H₂)_q1O (CH₂)_q2O-, (xiii)-(CH₂)_q1O (CH₂)_q2NH-or (x
iv)-(CH ₂)_q1O (CH₂)_q2S- (p1 is an integer from 1 to 6 and q
1 and q2 each represent an integer of 1 to 3)
Group, A is a nitrogen atom or CR^{7 '}(R^{7 '}Is a hydrogen atom, halogen
Atom, C_1-6Alkyl group, C_1-6Alkoxy-carbonyl
Group or carboxyl group), R¹Is (1) hydrogen atom,
(2) (i) Carboxyl, (ii) C_1-6Alkoxy-Carbonii
, (Iii) hydroxy or (iv) mono or di-C_1-6A
From the group consisting of carbamoyl optionally having rukyi
C optionally substituted with a group of choice_1-6An alkyl group,
(3) C_6-14Aryl group, (4) C_1-6Alkoxy group, (5) C_1-6A
Lucoxy-carbonyl group, (6) carboxyl group, (7) cal
Boxil or C_1-6Alkoxy-carbonyl substituted
May be C_1-6Carba which may have alkyl
Moyl group or (8) C_1-6Alkoxy-carbonyl substituted
May be C_3-6Cycloalkyl group, R²Is a hydrogen atom,
C_1-6Alkyl group, C_1-6An alkoxy-carbonyl group or
Carboxyl group, R³Is a hydrogen atom, R⁸Is a hydrogen atom or
Compounds that are droxy groups are preferred.

Particularly, Ar ¹ and Ar ² are phenyl groups, and B ring is a formula.

[Chemical 8] [Wherein Z ′ represents a methine group, Z ^{1 ′} and Z ^{2 ′} represent a methylene group or an ethylene group (preferably an ethylene group)], X represents a bond, an oxygen atom or NH. (Preferably a bond or an oxygen atom), Y is-(CH ₂ ) _p1 NH-
(P1 is an integer of 1 to 6), A is CR ^{7 ''}
(R ^{7 ''} represents a hydrogen atom or a C _1-6 alkyl group), R ¹ is
(1) hydrogen atom, (2) carboxyl or C _1-6 alkoxy-
C _1-6 alkyl group optionally substituted with carbonyl or (3) C _1-6 alkoxy-carbamoyl group optionally having C _1-6 alkyl optionally substituted with carbonyl, R ²
Is preferably a hydrogen atom, R ³ is a hydrogen atom, and R ⁸ is a hydrogen atom.

More specifically, (1) 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,
Ethyl 2-b] pyridazin-2-yl] -2-methylpropionate or salts thereof (especially difumarate, disuccinate, citrate, etc.), (2) 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid or a salt thereof (especially dihydrate),
(3) N- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazine-2-carbonyl]
Glycine ethyl or a salt thereof, (4) 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -3-methylimidazo [1,2-b] pyridazin-2-yl] -2- Ethyl methyl propionate or its salt (particularly dihydrochloride), (5) 2- [6- [3- [4- (diphenylmethylamino) piperidino]
Propylamino] imidazo [1,2-b] pyridazin-2-yl] -2
-Ethyl methylpropionate or its salt, (6) 2- [6- [3-
[4- (diphenylmethoxy) piperidino] propylamino]-
3-Methylimidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid or its salt, and (7) N- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino ] -3-Methylimidazo [1,2-b] pyridazine-2-carbonyl] glycine or a salt thereof is preferable.

Also, the formula

[Chemical 9] [A 'ring is a formula

[Chemical 10] (R ^21a is a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxy group having a substituent, R ^21b is a hydrogen atom, a halogen atom, or a substituent A good hydrocarbon group, an acyl group or a hydroxy group which may have a substituent).
Ar ¹¹ and Ar ¹² may each have an aromatic group which may have a substituent, Ar ¹¹ and Ar ¹² may form a condensed ring group together with the adjacent carbon atom, and B ′ ring may have a substituent. Optionally a nitrogen-containing heterocycle, X ′ and Y ′ are the same or different and each is a bond, an oxygen atom, S (O) _q (q is an integer of 0 to 2), NR ²⁴ (R ²⁴ is Hydrogen atom or lower alkyl group) or may have a substituent, hetero atom
1 to 3 divalent linear lower hydrocarbon groups which may be interposed, R ²² and R ²³ are the same or different and each is a hydrogen atom, a halogen atom, or a hydrocarbon group which may have a substituent. , An acyl group or a hydroxy group which may have a substituent, R ²⁷ represents a hydrogen atom, a hydroxy group which may be substituted by lower alkyl, or a carboxyl group. ]
The compound represented by or a salt thereof has excellent anti-allergic action, anti-histamine action, anti-inflammatory action, anti-PAF (platelet activating factor) action, eosinophil chemotaxis inhibitory action, etc. Alternatively, it can be used in the same manner as the salt or the prodrug thereof.

In the above formula (II), a compound (IIa) in which the A ′ ring represents the type (a) and a compound (II) in which the A ′ ring represents the type (b) will be described below. Notated as IIb).

[Chemical 11]

[Chemical 12]

In the above formula (II), Ar ¹¹ and Ar ¹² represent “an aromatic group which may have a substituent”, and Ar ¹¹ and Ar ¹² together with an adjacent carbon atom form a condensed ring group. May be.
Examples of the “aromatic group” represented by Ar ¹¹ and Ar ¹² include, for example, monocyclic or condensed polycyclic aromatic hydrocarbon groups, more specifically phenyl, tolyl, xylyl, biphenyl, 1-
Naphthyl, 2-naphthyl, 2-indenyl, 1-anthryl,
_C6-14 aryl group such as 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl (preferably phenyl, tolyl, xylyl, biphenyl,
1-naphthyl, 2-naphthyl, etc., particularly preferably phenyl, etc.) 6 to 14 membered monocyclic or condensed polycyclic aromatic hydrocarbon group, etc., or selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom Preferably, a monocyclic group (preferably 5 to 8 members) containing one or more (eg, 1 to 4 and preferably 1 to 3) heteroatoms or a condensed aromatic heterocycle thereof. Group, more specifically, thiophene, benzo [b] thiophene, benzo [b] furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene, thianthrene, furan, iso Indolizine, oxanthrene,
Phenoxathiin, pyrrole, imidazole, triazole, thiazole, oxazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole,
Isoindole, 1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, isothiazole, phenothiazine, isoxazole, flazan. , An aromatic heterocycle such as phenoxazine or isochroman (preferably pyridine,
Thiophene, furan, etc., more preferably pyridine, etc., or one or more (preferably 1 or 1 or more) of these rings (preferably the above-mentioned monocyclic heterocycles).
Two, more preferably one) monovalent monovalent ring formed by removing any hydrogen atom from a ring formed by condensation with two or more aromatic rings (for example, the above-mentioned aromatic hydrocarbon group, preferably benzene ring, etc.) A group or the like is used. As the “aromatic group” of the “aromatic group which may have a substituent” represented by Ar ¹¹ and Ar ¹² , for example, phenyl and the like are preferable.

Examples of the “substituent” of the aromatic group represented by Ar ¹¹ and Ar ¹² include (i) a halogen atom (eg, fluorine, chlorine, bromine, iodine), (ii) a lower alkylenedioxy group ( For example, methylenedioxy, a C _1-3 alkylenedioxy group such as ethylenedioxy), (iii) nitro group, (iv) cyano group, (v) optionally halogenated lower alkyl group, (vi ) optionally halogenated substituted lower alkenyl group, (vii) optionally halogenated substituted lower alkynyl group, (viii) lower cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, C _{3 -6} of cyclohexyl Cycloalkyl group etc.), (ix) optionally substituted lower alkoxy group, (x) optionally halogenated lower alkylthio group, (xi) hydroxy group, (xii) amino group, (xiii) mono- Lower alkyl Amino group (e.g., methylamino, ethylamino, propylamino, isopropyl amino, mono -C such butylamino
_1-6 alkylamino group), (xiv) di-lower alkylamino group (eg, dimethylamino, diethylamino,
Di-C _1-6 alkylamino groups such as dipropylamino, dibutylamino, etc.), (xv) 5- or 6-membered cyclic amino groups (eg, morpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl, etc.) , (Xvi) lower alkyl-carbonyl group (eg C such as acetyl, propionyl, etc.
_1-6 alkyl-carbonyl group, etc.), (xvii) carboxyl group, (xviii) lower alkoxy-carbonyl group (for example, C _1-6 alkoxy-, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
Carbonyl group), (xix) carbamoyl group or thiocarbamoyl group, (xx) mono-lower alkyl-carbamoyl group (eg, mono-C _1-6 alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyl) or mono- Lower alkyl-thiocarbamoyl group (eg, mono-C _1-6 alkyl-thiocarbamoyl group such as methylthiocarbamoyl, ethylthiocarbamoyl etc.), (xxi)
Di-lower alkyl-carbamoyl group (eg, di-C _1-6 alkylcarbamoyl group such as dimethylcarbamoyl, diethylcarbamoyl, etc.) or di-lower alkyl-thiocarbamoyl group (eg, dimethylthiocarbamoyl,
Di-C _1-6 alkylthiocarbamoyl group such as diethylthiocarbamoyl), (xxii) aryl-carbamoyl (eg C _6-10 aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl) or aryl-thiocarbamoyl (eg, C _6-10 aryl-thiocarbamoyl such as phenylthiocarbamoyl and naphthylthiocarbamoyl), (xxiii) sulfo group, (xxiv)
Lower alkylsulfonyl group (for example, C _1-6 alkylsulfonyl group such as methylsulfonyl and ethylsulfonyl), (xxv) aryl group (for example, C _6-10 aryl group such as phenyl and naphthyl), (xxvi) aryl Oxy groups (eg C such as phenoxy, naphthyloxy, etc.
_6-10 aryloxy group etc.), (xxvii) aralkyloxy group (eg C _7-16 aralkyloxy group such as benzyloxy), (xxviii) alkyl-carbonyloxy group (eg methylcarbonyloxy, ethylcarbonyloxy) , propyl carbonyloxy, butylcarbonyloxy, isobutyl carbonyloxy, C _1-6 alkyl, such as tert- butyl carbonyloxy - carbonyl group), (xxix) alkyl - carbonyloxy - alkoxy - carbonyl group (e.g., methyl carbonyloxy Such as methoxycarbonyl, methylcarbonyloxyethoxycarbonyl, ethylcarbonyloxymethoxycarbonyl, ethylcarbonyloxyethoxycarbonyl, etc.
C _1-6 alkyl-carbonyloxy-C _1-6 alkoxy-carbonyl group) and the like are used.

The above-mentioned "optionally halogenated lower alkyl
Examples of the “alkyl group” include, for example, 1 to 3 halogen atoms.
Have offspring (eg, fluorine, chlorine, bromine, iodine)
Optionally lower alkyl groups (eg methyl, ethyl,
Ropil, isopropyl, butyl, isobutyl, sec-butyl
C such as ruthel, tert-butyl, pentyl, hexyl_1-6Al
(Eg, a kill group), and specific examples include methyl groups.
Chloromethyl, difluoromethyl, trichloromethyl
, Trifluoromethyl, ethyl, 2-bromoethyl, 2,
2,2-trifluoroethyl, propyl, 3,3,3-trifluor
Rpropyl, isopropyl, butyl, 4,4,4-trifluor
Butyl, isobutyl, sec-butyl, tert-butyl,
Nyl, isopentyl, neopentyl, 5,5,5-triflu
Oropentyl, hexyl, 6,6,6-trifluorohexyl
Are used. The above "may be halogenated
"Lower alkenyl group" and "may be halogenated"
“Lower alkynyl group” includes, for example, 1 to 3
Halogen atom (eg, fluorine, chlorine, bromine, iodine)
A lower alkenyl group which may have (for example, vinyl
Ru, propenyl, isopropenyl, 2-buten-1-yl, 4
C such as -penten-1-yl, 5-hexen-1-yl_2-6Al
Alkenyl group) and 1 to 3 halogen atoms (eg.
, Fluorine, chlorine, bromine, iodine)
Lower alkynyl groups (eg 2-butyn-1-yl, 4-pen
C such as tin-1-yl, 5-hexyn-1-yl_2-6Alkynyl
Groups, etc. are used. Above "may be replaced
“Lower alkoxy group” includes, for example, 1 to 3
Halogen atom (eg, fluorine, chlorine, bromine, iodine), mo
No- or di-lower alkylamino groups (eg methyl
Mino, dimethylamino, ethylamino, diethylamino
Such as Mono- or Di-C_1-6Alkylamino group, etc.)
Is a lower alkoxy-carbonyl group (eg
Lubonyl, C such as ethoxycarbonyl _1-6Alkoxy-
A lower alkoxy which may have a carbonyl group)
Groups (eg methoxy, ethoxy, propoxy, isop
Ropoxy, n-butoxy, isobutoxy, sec-butoxy,
C such as tert-butoxy_1-6Such as an alkoxy group)
Can be The above “optionally halogenated lower alkyl
Examples of the “alkylthio group” include 1 to 3 halogens.
Having atoms (eg, fluorine, chlorine, bromine, iodine)
A lower alkylthio group (eg, methylthio, ethyl
Ruthio, n-propylthio, isopropylthio, n-butyl
Thio, isobutylthio, sec-butylthio, tert-butyl
C such as Thio_1-6Alkylthio group etc.)
Specific examples include methylthio, difluoromethylthio,
Trifluoromethylthio, ethylthio, propylthio,
Isopropylthio, butylthio, 4,4,4-trifluorobu
Cylthio, pentylthio, hexylthio, etc. are used
It

Specific examples of the case where Ar ¹¹ and Ar ¹² form a condensed ring group together with adjacent carbon atoms include, for example,

[Chemical 13] [In the formula, R ²⁷ has the same meaning as described above. ] A condensed ring group represented by, for example, is used. As Ar ¹¹ and Ar ¹² ,
Each is the same or different, and an aromatic hydrocarbon group which may have a substituent (eg, C _6-14 aromatic hydrocarbon group) is preferable, and a benzene ring which may have a substituent is more preferable. . More specifically, as Ar ¹¹ and Ar ¹² ,
Respectively (1) a phenyl group which may be substituted with a halogen atom or C _1-6 alkyl, or (2) a carbon atom, other than 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom 5 A 8- to 8-membered aromatic heterocyclic group and the like are preferable.

In the above formula (II), the B ′ ring represents “a nitrogen-containing heterocycle which may have a substituent”.

The "nitrogen-containing heterocycle" represented by ring B'includes, for example, one nitrogen atom, and further contains 1 to 3 heterocycles selected from nitrogen atom, oxygen atom, sulfur atom and the like. A 3- to 13-membered nitrogen-containing heterocycle which may contain an atom is used. In the above formula (II), B '
1 hydrogen atom from each of the ring nitrogen and other atoms
It is preferable to form divalent groups that are individually removed.
Specifically, for example

[Chemical 14] 3 to 9-membered (more preferably 3 to 6-membered) nitrogen-containing heterocyclic groups such as As the substituent of the nitrogen-containing heterocycle represented by ring B ', for example, the Ar ¹¹ and Ar ^{1 2}
In addition to the “substituent” of the “aromatic group which may have a substituent” represented by, an oxo group and the like are used.

Preferred specific examples of the B'ring include, for example, formulas

[Chemical 15] [Wherein Z is a nitrogen atom or a methine group, Z ¹¹ and Z ¹²
Each represents a linear C _1-4 alkylene group which may be substituted with a hydroxy group, an oxo group or a C _1-6 alkyl group. ] The ring etc. represented by] are used. Examples of the “C _1-6 alkyl group” include methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl, tert
-A linear or branched C _1-6 alkyl group such as butyl, pentyl and hexyl is used. The "linear C _1-4
As the “alkylene group”, for example, a linear C _1-4 alkylene group represented by methylene, ethylene, propylene or butylene is shown. Z ¹¹ and Z is represented by ¹² is preferably a "hydroxy group, an oxo group or a C _1-6 alkyl is linear C _1-4 alkylene group may be substituted with a group", an unsubstituted straight chain C _{A 1-4} alkylene group or the like is used, and an unsubstituted linear C _1-2 alkylene group is particularly preferable. More preferably, piperidine, piperazine or the like is used as the B ′ ring.

In the above formula (II), X'and Y'are the same.
One or differently (1) bond, (2) oxygen atom, (3) S (O)
_q(Q is an integer from 0 to 2), (4) NR^{twenty four}(R^{twenty four}Is hydrogen
Represents a child or a lower alkyl group. ) Or (5) substituent
May have 1 to 3 heteroatoms
Is a divalent straight-chain lower hydrocarbon group. R^{twenty four}Represented by
Examples of lower alkyl groups include methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec-bu
Linear such as tyl, tert-butyl, pentyl, hexyl
Or branched C_1-6An alkyl group or the like is used. X ’
And represented by Y ', "through 1 to 3 heteroatoms
The divalent straight-chain lower hydrocarbon group which may be mentioned is a low
Grade (C_1-6) Bonding to the same or different carbon atoms of a hydrocarbon
A group formed by removing one hydrogen atom each (2 in total)
Yes, for example, oxygen atom, NR^{twenty four '}(R^{twenty four '}Is a hydrogen atom
Or lower alkyl group. ) And sulfur atom etc.
May contain selected heteroatoms in the hydrocarbon chain
Indicates a group. R^{twenty four '}The lower alkyl group represented by
For example, methyl, ethyl, propyl, isopropyl, bromo
Chill, isobutyl, sec-butyl, tert-butyl, pliers
Straight-chain or branched C such as le, hexyl_1-6Alkyl
A group or the like is used. "Divalent linear lower hydrocarbon group"
Specifically, (i) C_1-6An alkylene group (eg, -CH
₂-,-(CH₂)₂-,-(CH₂)₃-,-(CH₂)_Four-,-(CH₂) _Five-,-(CH₂)
₆-Etc.), (ii) C_2-6Alkenylene group (for example, -CH = CH
-, -CH = CH-CH₂-, -CH₂-CH = CH-CH₂-,-(CH₂)₂-CH = CH-CH₂
-,-(CH₂)₂-CH = CH- (CH₂)₂-,-(CH₂)₃-CH = CH-CH₂-
DO), (iii) C_2-6Alkynylene group (for example, -C≡C-, -C
≡ C-CH₂-, -CH₂-C≡C-CH₂-,-(CH₂)₂-C≡C-CH₂-,-(C
H₂)₂-C≡C- (CH₂)₂-,-(CH₂)₃-C≡C-CH₂-Etc)
Used.

Examples of the "substituent" of the "divalent linear lower hydrocarbon group optionally having 1 to 3 heteroatoms" represented by X'and Y'include, for example, Ar ¹¹ and Ar ¹²
In addition to the "substituent" of the "aromatic group which may have a substituent" represented by, an oxo group and the like are used.
Hydroxy or oxo groups are preferred. As X ′, a bond, an oxygen atom or NH is preferable, and a bond or an oxygen atom is particularly preferable. Preferred as Y ', for example, the formula ^{_{- (CH 2) s -Y 11}} - (CH 2) t -Y 12 - [ wherein, Y ¹¹ and Y ¹² identical or different bond respectively, an oxygen atom, S ( O) _q (q has the same meaning as above), NR
^{24 '} (R ^{24 '} is as defined above), carbonyl group, carbonyloxy group or formula

[Chemical 16] (In the formula, R ²⁵ and R ²⁶ are the same or different and each represents a hydroxy group or a C _1-4 alkyl group.), S and t each represent an integer of 0 to 4 (provided that , The sum of s and t is 6 or less)] or the like.

R^{twenty five}And R²⁶Represented by "C_1-4Alkyl
Examples of the “group” include methyl, ethyl, propyl,
Sopropyl, butyl, isobutyl, sec-butyl, tert-
Linear or branched C such as butyl_1-4Alkyl group, etc.
Is used. Examples of Y ′ include (i) C_1-6Arche
Group, (ii)-(CH₂)_p2O-, (iii)-(CH₂)_{p 2}NH-, (iv)-(CH₂)
_p2S-, (v)-(CH₂)_q3CH (OH) (CH₂)_q4O-, (vi)-(CH₂)_q3CH (O
H) (CH₂)_q4NH-, (vii)-(CH₂)_q3CH (OH) (CH₂)_q4S-, (viii)
-(CH₂)_p2CONH-, (ix) -COO (CH₂) _p2O-, (x) -COO (CH₂)_p2NH
-, (Xi) -COO (CH₂)_p2S-, (xii)-(CH₂)_q3O (CH₂)_q4O-, (xi
ii)-(CH₂)_q3O (CH₂)_q4NH- or (xiv)-(CH₂)_q3O (CH₂)_q4S
-(P2 is an integer from 1 to 6, q3 and q4 are 1
To 3) are preferred. Inside
However, as Y ′, for example, a bond,-(CH₂)₂-O-,-(C
H₂)₃-O-,-(CH₂)_Four-O-,-(CH₂)₆-O-,-(CH₂)₂-NH-,-(CH
₂)₃-NH-,-(CH₂)_Four-NH-,-(CH₂)₃-S-, -CH₂-CH (OH) -CH₂-
O-,-(CH₂)₂-CO-NH-, -CH₂-CO-NH-, -CO-O- (CH₂)₂-O-,
-CO-O- (CH₂)₃-O-,-(CH₂)₆-NH-,-(CH₂)₆-S-,-(CH₂)₂-
O- (CH₂)₂-O-,-(CH₂)₂-O- (CH₂)₂-S- and the like are preferable.

In the case of compound (IIa), Y'is
Formula ^{_{- (CH 2) s -Y 13}} - (CH 2) t -Y 14 - [ wherein, Y ¹³ is a bond or -CH (OH) - a, Y ¹⁴ represents an oxygen atom, S or NH, s And t each represent an integer of 0 to 4 (provided that the sum of s and t is 6 or less). ] The group represented by the group represented by Particularly, as s and t, an integer of 1 to 3 is preferable, and 3 is particularly preferable.
Further, when Y ¹³ is —CH (OH) —, 1 is preferable as s and t. On the other hand, in the case of compound (IIb), examples of _{Y ', - (CH 2)} w -Y 15 - [ wherein an integer of w is not 1 6, Y ¹⁵ represents an oxygen atom or NH
Is also preferable. Particularly, w is preferably an integer of 1 to 3, and 3 is particularly preferable.

In the above formula (II), R ^21a represents a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxy group having a substituent. R ^21b represents a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxy group which may have a substituent. R ²² and R ²³ are the same or different and each represents a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxy group which may have a substituent. Examples of the “halogen atom” represented by R ^21a , R ^21b , R ²² and R ²³ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

"Hydrocarbon group" of "hydrocarbon group optionally having substituent (s)" represented by R ^21a , R ^21b , R ²² and R ²³
As, for example, represents a group obtained by removing one hydrogen atom from a hydrocarbon compound, and examples thereof include, for example, a chain form such as an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, and an aralkyl group. Examples thereof include cyclic hydrocarbon groups. Of these, a linear (branched or branched) or cyclic hydrocarbon group having 1 to 16 carbon atoms is preferable, and a) an alkyl group [preferably a lower alkyl group (for example,
C _1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.)], b) alkenyl groups [preferably lower alkenyl groups (eg vinyl , C _2-6 alkenyl groups such as allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl etc.)], c) alkynyl groups [preferably lower alkynyl groups (eg propargyl, ethynyl, butynyl, 1-hexynyl etc. C _2-6 alkynyl group etc.)], d) cycloalkyl group [preferably lower cycloalkyl group (eg cyclopropyl, cyclobutyl, cyclopentyl, 1 to 3 lower alkoxy groups (eg C _1- , such as methoxy, etc. ₆ C, such as alkoxy group) may cyclohexyl optionally condensed with benzene ring which may have a like _3-6 cycloalkyl group)], e) an aryl group (eg, phenyl, tolyl, xylyl,
Biphenyl, 1-naphthyl, 2-naphthyl, 2-indenyl,
C _6-14 aryl group such as 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl, preferably phenyl group), f) aralkyl Group [preferably a lower aralkyl group (eg, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-phenylethyl, 2-
Diphenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 5-
C _7-16 aralkyl group such as phenylpentyl, and more preferably benzyl group)] and the like are preferable. Examples of the “substituent” of the “hydrocarbon group” include, in addition to the “substituent” of the “optionally substituted aromatic group” represented by Ar ¹¹ and Ar ¹² above, oxo. A group or the like is used. Among the above, the hydrocarbon group is preferably an alkyl group such as a C _1-6 alkyl group, and the substituent of the hydrocarbon group is, for example, cyano, carboxyl, C _1-6 alkoxy-carbonyl, carbamoyl. (Or thiocarbamoyl) and the like are preferable.

Examples of the “acyl group” represented by R ^21a , R ^21b , R ²² and R ²³ include, for example, the formula — (C═O) —R ²⁸ , —SO ₂ —R ²⁸ ,
-SO-R ²⁸ ,-(C = O) NR ²⁸ R ²⁹ ,-(C = O) OR ²⁸ ,-(C = S) OR ²⁸ or-(C = S) NR ²⁸ R ²⁹ (R ²⁸ is hydrogen An atom, a hydrocarbon group which may have a substituent or a hydroxy group which may have a substituent, R ²⁹ represents a hydrogen atom or a lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl) , Sec-butyl, tert-butyl, pentyl, hexyl and other C _1-6 alkyl groups, especially methyl,
C _1-3 alkyl groups such as ethyl, propyl and isopropyl are preferable). ) And the like are used. Among them, the formula-(C = O) -R ²⁸ , -SO ₂ -R ²⁸ , -SO-
The group represented by R ²⁸ ,-(C = O) NR ²⁸ R ²⁹ or-(C = O) OR ²⁸ is preferable, and the group represented by the formula-(C = O) -R ²⁸ is particularly preferable. The "optionally substituted hydrocarbon group" represented by R ²⁸ is the same as the optionally substituted hydrocarbon group represented by R ^21a , R ^21b , R ²² and R ²³ described above. What is used. Of these, the hydrocarbon group represented by R ^28, for example, preferably an alkyl group such as C _1-6 alkyl group, examples of the substituent include a carboxyl, C _1-6 alkoxy - carbonyl is preferable. R ²⁹ is preferably a hydrogen atom or the like.

The “hydroxy group having a substituent” represented by R ^21a is, for example, a hydroxy group having one hydrocarbon group which may have a substituent instead of the hydrogen atom of the hydroxy group. Indicates. R ^21b , R ²² , R ²³
Examples of the “optionally substituted hydroxy group” represented by R ²⁸ and R ²⁸ include, for example, (1) a hydroxy group or (2) a hydroxy group having a substituent in place of the hydrogen atom of the hydroxy group. Is a hydroxy group having one hydrocarbon group or the like. As the hydrocarbon group which may have a substituent which the hydroxy group has, R ^21a , R ^21b described above,
The same as the optionally substituted hydrocarbon group represented by R ²² , R ²³ and R ²⁸ is used. Compound (IIa)
In the acyl groups represented by R ^21a , R ^21b , R ²² and R ²³ described above, (1) a carboxyl group, (2) C _1-6
Alkoxy-carbonyl group, (3) carboxyl or C
_A carbamoyl group (or a thiocarbamoyl group) optionally substituted with a C _1-6 alkyl group which may have _1-6 alkoxy-carbonyl is preferable. Among the above, as R ^21a , (1) hydrogen atom, (2) carboxyl group,
(3) C _{1- 6} alkoxy - carbonyl group, (4) (i) cyano, (ii)
Carboxyl, (iii) C _1-6 alkoxy-carbonyl and
(iv) C _1-6 alkyl group which may be substituted with a group selected from the group consisting of carbamoyl (or thiocarbamoyl) or (5) C which may have carboxyl or C _1-6 alkoxy-carbonyl _A carbamoyl group (or a thiocarbamoyl group) which may be substituted with a _1-6 alkyl group is preferable.

In the compound (IIb), when R ^21b represents a hydrogen atom, the oxo group of the triazolo [4,3-b] pyridazine ring may be enolized.

[Chemical 17] The partial structural formula represented by

[Chemical 18] Either of may be shown.

Among the above, R ^21b is (1) hydrogen atom, or (2) (i) carboxyl, (ii) C _1-6 alkoxy.
-Carbonyl, (iii) C _1-6 alkyl-carbonyloxy and (iv) C _1-6 alkyl-carbonyloxy-C _1-6 alkoxy-carbonyl optionally substituted with a group selected from C _{1 A -6} alkyl group and the like are preferable. Formula (II) above
In, R ²² and R ²³ are preferably hydrogen atoms. In the above formula (II), R ²⁷ represents a hydrogen atom, a hydroxy group which may be substituted with a lower alkyl group, or a carboxyl group. Examples of the “lower alkyl group” of the “hydroxy group optionally substituted with a lower alkyl group” represented by R ²⁷ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl. ,
A C _1-6 alkyl group such as pentyl and hexyl is used. R ²⁷ is preferably a hydrogen atom or a hydroxy group, and particularly preferably a hydrogen atom.

The following compounds are preferred as the compound (II) of the present invention. [Compound (II) -I] R ^21a is (1) hydrogen atom, (2) carboxyl group, (3) C _1-6 alkoxy-carbonyl group, (4) (i) cyano,
(ii) Carboxyl, (iii) C _1-6 alkoxy-carbonyl and (iv) C _1-6 alkyl group optionally substituted with a group selected from the group consisting of carbamoyl or (5) carboxyl or C _1-6 A carbamoyl group optionally substituted with an C _1-6 alkyl group which may have an alkoxy-carbonyl, R ^21b is (1) a hydrogen atom, or (2) (i) carboxyl, (ii) C _1- May be substituted with a group selected from the group consisting of ₆ alkoxy-carbonyl, (iii) C _1-6 alkyl-carbonyloxy and (iv) C _1-6 alkyl-carbonyloxy-C _1-6 alkoxy-carbonyl C _1-6 alkyl group, R ²²
And R ²³ is a hydrogen atom, R ²⁷ is a hydrogen atom or a hydroxy group (particularly a hydrogen atom), Ar ¹¹ and Ar ¹² are each a phenyl group which may be substituted, and a B ′ ring is

[Chemical 19] X 'is a bond or an oxygen atom, Y' has the formula ^{_{- (CH 2) s -Y 13}} - (CH 2) t -Y 14 - [ wherein, Y ¹³ is a bond or -CH (OH) -, Y ¹⁴ is an oxygen atom,
S or NH, s and t each represent an integer of 0 to 6 (provided that the sum of s and t is 6 or less). ] The compound (II) which is a group represented by the group represented by.

[Compound (II) -II] (1) 6- [6- [4- (diphenylmethoxy) piperidino] hexyloxy] [1,2,4] triazolo [4,3-b] pyridazine or a salt thereof . (2) 6- [6- [4- (diphenylmethoxy) piperidino] hexylamino] [1,2,4] triazolo [4,3-b] pyridazine or a salt thereof. (3) 3-tert-butyl-6- [3- [4- (diphenylmethoxy) piperidino] propoxy] [1,2,4] triazolo [4,3
-b] pyridazine or a salt thereof. (4) 6- [3- [4- (diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [4,3-b] pyridazine-3-carboxylic acid or a salt thereof. (5) 6
-[3- [4- (Diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one or a salt thereof. (6) 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -3-oxo- [1,2,4] triazolo
Ethyl [4,3-b] pyridazin-2 (3H) -yl] -2-methylpropionate or a salt thereof. (7) 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -3-oxo- [1,2,4] triazolo [4,3-b] pyridazine-2 (3H)- Il] -2-methylpropionic acid or a salt thereof. (8) 2- [6- [3- [4- (Diphenylmethoxy) piperidino] propylamino] -3-oxo- [1,2,4] triazolo [4,3-b] pyridazine-2 (3H)- [Il] -2-methylpropionate pivaloyloxymethyl or a salt thereof. (9) 2- [6
-[3- [4- (Diphenylmethoxy) piperidino] propoxy]-
3-oxo- [1,2,4] triazolo [4,3-b] pyridazine-2 (3H)-
[Il] -2-methylpropionate pivaloyloxymethyl or a salt thereof.

The following compounds are preferred as the compound (IIa) of the present invention. [Compound (IIa) -I] Ar ¹¹ and Ar ¹² are each a phenyl group which may be substituted, and a B ′ ring is

[Chemical 20] X 'is a bond or an oxygen atom, Y' has the formula ^{_{- (CH 2) s -Y 13}} - (CH 2) t -Y 14 - [ wherein, Y ¹³ is a bond or -CH (OH) -, Y ¹⁴ is an oxygen atom,
S or NH, s and t each represent an integer of 0 to 4 (provided that the sum of s and t is 6 or less). ] A group represented by the group represented by, R ^21a is (1) a hydrogen atom, (2) a carboxyl group,
(3) C _1-6 alkoxy-carbonyl group, (4) (i) cyano, (ii)
Carboxyl, (iii) C _1-6 alkoxy-carbonyl and
(iv) C _1-6 alkyl group which may be substituted with a group selected from the group consisting of carbamoyl (or thiocarbamoyl) or (5) C which may have carboxyl or C _1-6 alkoxy-carbonyl A compound in which a carbamoyl group (or a thiocarbamoyl group) optionally substituted with _1-6 alkyl group, R ²² , R ²³ and R ^{27 each} represent a hydrogen atom (II
a).

[Compound (IIa) -II] (1) 6- [6- [4- (diphenylmethoxy) piperidino] hexyloxy] [1,2,4] triazolo [4,3-b] pyridazine or a salt thereof . (2) 6- [6- [4- (diphenylmethoxy) piperidino] hexylamino] [1,2,4] triazolo [4,3-b] pyridazine or a salt thereof. (3) 3-tert-butyl-6- [3- [4- (diphenylmethoxy) piperidino] propoxy] [1,2,4] triazolo [4,3
-b] pyridazine or a salt thereof. (4) 6- [3- [4- (diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [4,3-b] pyridazine-3-carboxylic acid or a salt thereof.

The following compounds are preferred as the compound (IIb) of the present invention. [Compound (IIb) -I] Ar ¹¹ and Ar ¹² are each a phenyl group which may be substituted, and a B ′ ring is

[Chemical 21] X 'is an oxygen atom, Y' has the formula ^{_{- (CH 2) w -Y 15}} - [ wherein, w is 1 to 6 integer, Y ¹⁵ represents an oxygen atom or NH] groups represented by, R ^{2 1b} is (1) hydrogen atom or (2) (i)
Carboxyl, (ii) C _1-6 alkoxy-carbonyl, (iii)
C _1-6 alkyl-carbonyloxy and (iv) C _1-6 alkyl-carbonyloxy-C _1-6 alkoxy-carbonyl which may be substituted with a group selected from the group consisting of C _1-6 alkyl group, R Compounds in which ²² , R ²³ and R ²⁷ represent a hydrogen atom (II
b).

[Compound (IIb) -II] (1) 6- [3- [4- (diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [4,3-b] pyridazine-3 ( 2H) -one or salt thereof. (2) 2- [6- [3- [4- (diphenylmethoxy)
Ethyl piperidino] propylamino] -3-oxo- [1,2,4] triazolo [4,3-b] pyridazin-2 (3H) -yl] -2-methylpropionate or a salt thereof. (3) 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -3-oxo- [1,2,4]
Triazolo [4,3-b] pyridazin-2 (3H) -yl] -2-methylpropionic acid or a salt thereof. (4) 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -3-oxo- [1,2,
[4] Triazolo [4,3-b] pyridazin-2 (3H) -yl] -2-methyl pivaloyloxymethyl propionate or a salt thereof.
(5) 2- [6- [3- [4- (Diphenylmethoxy) piperidino] propoxy] -3-oxo- [1,2,4] triazolo [4,3-b] pyridazin-2 (3H) -yl ] -2-Methylpropionate pivaloyloxymethyl or a salt thereof.

The compound (I) or a salt thereof can be prepared by a method known per se, for example, the methods described in JP 2000-191663 A, JP 2000-191664 A, JP 2000-198735 A and WO 00/23450. Or it can manufacture by the method according to these. The compound (II) or a salt thereof can be produced by a method known per se, for example, the method described in JP 2000-178277 A and WO 00/20417 or a method analogous thereto.

The salt of compound (I) or (II) is, for example, a salt with an inorganic salt (for example, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, etc.) or an organic acid (for example, acetic acid, formic acid,
Propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, etc.) and the like are used. Furthermore, when the compound (I) or (II) has an acidic group such as carboxylic acid as a substituent, an inorganic base (for example, alkali metal or alkaline earth metal such as sodium, potassium, calcium, magnesium, etc., Alternatively, a salt with ammonia) or an organic base (eg, tri-C _1-3 alkylamine such as triethylamine) may be formed.

The "acidic compound" used in the present invention may be either solid or liquid at room temperature (15 to 25 ° C), but it is preferable to use a solid acidic compound. . Further, in order to enhance chemical stability and dissolution property, it is preferable that 50% or more of the constituent particles of the acidic compound are particles of 50 μm to 1.5 mm. Among them, it is preferable that the constituent particles of the acidic compound are particles of 150 μm to 1.0 mm. Since the acidic compound has a better effect as the content of fine particles is smaller, a preferable example is one in which particles of 50 μm or less in the constituent particles of the acidic compound account for 20% or less of the whole. Examples of acidic compounds include carboxylic acids, sulfonic acids, acidic polysaccharides and acidic amino acids, which may be hydrates or anhydrides. For example, acetic acid, lactic acid, fumaric acid,
Tartaric acid, succinic acid, citric acid (especially citric acid (anhydrous)), oxalic acid, malonic acid, maleic acid, dl-malic acid, stearic acid, carboxylic acids such as adipic acid, sulfonic acids such as aminoethyl sulfonic acid, Examples thereof include acidic polysaccharides such as alginic acid, glutamic acid, acidic amino acids such as aspartic acid, glycine hydrochloride, salts of amino acids such as aspartic acid hydrochloride and glutamic acid and mineral acids, etc., and one or more of them should be used. You can

Among the acidic compounds, carboxylic acid is preferable, and fumaric acid, adipic acid, malic acid, acetic acid, tartaric acid,
Preferred is succinic acid or citric acid. Above all, tartaric acid, which is a solid carboxylic acid at room temperature (15 to 25 ° C),
Succinic acid or citric acid is preferable, and citric acid is particularly preferable.

The acid-containing preparation of the present invention contains a compound having an anti-allergic action, an antihistamine action, an anti-inflammatory action, an anti-PAF action and / or an eosinophil chemotaxis inhibitory action and an acidic compound. The amount of the acidic compound used in the acid mixture preparation of the present invention is about 0.01 per 1 part by weight of a compound having an antiallergic action, an antihistamine action, an antiinflammatory action, an anti-PAF action and / or an eosinophil chemotaxis inhibitory action. To 100 parts by weight, preferably about 0.1 to 10 parts by weight, more preferably 0.5 to 2 parts by weight. The acidic compound in the acid-containing preparation of the present invention is added for the purpose of locally lowering the pH in the portion where the preparation is present in the stomach, and is added for the purpose of assisting the dissolution of the physiologically active substance. Can be used in small amounts.

The acid-containing preparation of the present invention further comprises conventional excipients, disintegrants, binders, lubricants, colorants, etc.
It may contain a fragrance, a light-shielding agent, and the like.

Examples of the "excipient" include lactose, starch, sucrose, mannitol, crystalline cellulose, light anhydrous silicic acid, magnesium carbonate, calcium carbonate, calcium phosphate, calcium sulfate, aluminum silicate, aluminum metasilicate and the like. Is mentioned. Examples of the "disintegrant" include carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch sodium, starch, low-substituted hydroxypropylcellulose, crosslinked insoluble polyvinylpyrrolidone, and the like. Examples of the "binder" include hydroxypropyl cellulose, pregelatinized starch, sucrose, gelatin, gum arabic powder, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, crystalline cellulose,
Examples include dextrin and pullulan.

Examples of the "lubricant" include stearic acid, calcium stearate, magnesium stearate, talc, colloidal silica and the like. Examples of the “colorant” include yellow ferric oxide, ferric oxide, and the like. The "fragrance" may be either synthetic or natural, and examples thereof include lemon flavor, lime flavor, orange flavor, strawberry flavor, menthol and the like. Examples of the “light-shielding agent” include titanium oxide, talc, calcium carbonate, magnesium carbonate and the like.

The content of the excipient in the acid-blended preparation of the present invention is
Although not particularly limited as long as the object of the present invention is achieved, for example, about 1 to 99.9% by weight, preferably about 20 to 90% by weight.
%, Etc. The content of the disintegrant in the acid-blended preparation of the present invention is not particularly limited as long as the object of the present invention is achieved, but is, for example, about 0.05 to 50% by weight, preferably about 0.2 to 20% by weight. The content of the binder in the acid-blended preparation of the present invention is not particularly limited as long as the object of the present invention is achieved, but is, for example, 0.05 to 50% by weight, preferably about 0.2 to 20% by weight. The content of the lubricant in the acid-blended preparation of the present invention is not particularly limited as long as the object of the present invention is achieved, but is, for example, about 0.1 to 10% by weight, preferably about 0.
For example, 3 to 3% by weight. The content of the colorant in the acid-containing preparation of the present invention is not particularly limited as long as the object of the present invention is achieved, but is, for example, about 0.001 to 10% by weight, preferably about 0.001 to 1% by weight. The content of the perfume in the acid-containing preparation of the present invention is not particularly limited as long as the object of the present invention is achieved, but is, for example, about 0.001 to 10% by weight, preferably about 0.001 to 1% by weight. The content of the light-shielding agent in the acid-containing preparation of the present invention is not particularly limited as long as the object of the present invention is achieved, but for example, about 0.02 to 20% by weight,
It is preferably about 0.05 to 5% by weight.

Preferred specific examples of the acid-containing preparation of the present invention include (1) compound (I) or (II) or a salt thereof, an acid-containing preparation containing tartaric acid, and (2) compound
(I) or (II) or a salt thereof, an acid-containing preparation containing tartaric acid, lactose and corn starch, (3) compound (I)
Or (II) or a salt thereof, an acid-containing preparation containing tartaric acid, lactose, corn starch, hydroxypropyl cellulose and crystalline cellulose, (4) compound (I) or (I
I) or salts thereof, tartaric acid, lactose, corn starch, hydroxypropyl cellulose, crystalline cellulose,
An acid-containing preparation containing croscarmellose sodium and magnesium stearate, (5) compound (I) or (I
(I) or a salt thereof, an acid-containing preparation containing succinic acid, (6) compound (I) or (II) or a salt thereof, an acid-containing preparation containing succinic acid, lactose and corn starch, (7) compound ( I) or (II) or a salt thereof, succinic acid, lactose, corn starch, an acid-containing preparation containing hydroxypropyl cellulose and crystalline cellulose,
(8) Compound (I) or (II) or a salt thereof, succinic acid, lactose, corn starch, hydroxypropyl cellulose, crystalline cellulose, croscarmellose sodium and magnesium stearate containing an acid formulation, (9) compound ( I) or (II) or a salt thereof, an acid-containing preparation containing citric acid (anhydrous), (10) Compound (I) or (II) or a salt thereof, citric acid (anhydrous), lactose and corn starch (11) compound (I) or (II) or a salt thereof, citric acid (anhydrous), lactose, corn starch, hydroxypropyl cellulose, and an acid mixed preparation containing crystalline cellulose, (1)
2) Compound (I) or (II) or a salt thereof, citric acid (anhydrous), lactose, corn starch, hydroxypropyl cellulose, crystalline cellulose, croscarmellose sodium and an acid-containing preparation containing magnesium stearate and the like. .. In addition, a preparation in which talc is contained in these acid-containing preparations is also mentioned as a preferable example.

The acid-blended preparation of the present invention is produced, for example, by the following method. A compound having an anti-allergic action, an antihistamine action, an anti-inflammatory action, an anti-PAF action and / or an eosinophil chemotaxis inhibitory action (hereinafter sometimes abbreviated as a physiologically active substance) is mixed with a binder to form a mixture. Granules are prepared by granulating (bioactive substance granules). Similarly, granules are prepared by mixing an acidic compound and a binder and granulating (acidic compound granules). Mixing and granulation are performed using a commonly used granulator. At this time, a mixture (premix) obtained by previously mixing the excipient and / or the disintegrant with the physiologically active substance or the acidic compound and the binder may be mixed and granulated. Mixing and granulating a physiologically active substance or acidic compound with a binder,
Preferably it is carried out at about 0 to 100 ° C. The content of binder used in the granules is about 0.1 to 50% by weight. The content of excipients and disintegrants in the granules is about 1 each
To 99.9% by weight and about 0.1 to 50% by weight. The resulting granules contain 50% or more of particles of 50 μm to 1.5 mm (preferably 50% or more of particles of 150 μm to 1.0 mm). For the purpose of removing water, the obtained granules may be dried at about 10 to 80 ° C for about 0.01 to 72 hours. Further, the prepared granules may be sized. For the sizing, a commercially available sizing machine such as a power mill is usually used. Granules after sizing are approximately 50 μm
50% or more (preferably 150 μm or
50% or more of 1.0 mm particles). The physiologically active substance granules thus prepared and the acidic compound granules may be usually used by mixing (mixed granules) or separately. When mixed and used, the physiologically active substance granules and the acidic compound granules are 10 μm
It is preferable to use particles containing 50% or more of 2.0 to 2.0 mm particles. More preferably, particles comprising 50 μm to 1.5 mm or more 50% or more, particularly preferably 150 μm to 1.0 mm.
50% or more of the particles are included. To these, a disintegrant such as croscarmellose sodium and a lubricant such as magnesium stearate may be added. Alternatively, the acidic compound powder may be used as it is without using the acidic compound granules. A commercially available mixer such as a tumbler mixer is usually used for mixing these. The amount of disintegrant used and the content of lubricant are slightly higher than those used in the usual formulation, each about 0.1 to 50% by weight.
And about 0.1 to 10% by weight. The mixed granules thus obtained may be used as they are as granules, but usually they are made into a dosage form such as a pill, a tablet, a capsule or the like. It is preferably formed into a tablet such as a round tablet or an oval tablet, more preferably an oval tablet. A commercially available molding machine such as a tablet machine is used for molding. The tableting pressure for tableting is usually about 1 to 25 kN. Round tablets are usually about 5 to 20 mm in diameter and about 1 to 10 mm thick. Oval type tablets usually have a major axis of about 7 to 20 mm, a minor axis of about 5 to 15 mm, and a thickness of about 1 to 10 mm. In order to make the tablet obtained above into a coated preparation, it may be further subjected to film coating. A pan coating device or the like is usually used for the film coating operation. Examples of the film-coated tablet include those obtained by film-coating a circular tablet and those obtained by film-coating an oval tablet, and preferably those obtained by film-coating an oval tablet. The film coating solution can be prepared by dissolving or suspending a film-coating polymer such as hydroxypropylmethylcellulose in a solvent such as water. It is preferable that a colorant or a light-shielding agent is further added to the film coating liquid. Product (tablet) temperature when spraying film coating solution is about 10
It is preferable to control the temperature to 100 ° C. About 30
It is more preferable to control the temperature to 80 ° C,
It is more preferable to control the temperature to 40 to 60 ° C. In addition, when the physiologically active substance granules and the acidic compound granules are not mixed and used separately, a layer of the physiologically active substance granules and the acidic compound granules such as a separately packaged granule in which the physiologically active substance granules and the acidic compound granules are separately packaged. Examples thereof include a multi-layer tablet or a double-layer tablet. Furthermore, in formulating the physiologically active substance in the present invention, solid dispersion formulations, oily formulations and the like are also included as examples of formulations.

The acid-containing preparation of the present invention is excellent in absorbability and stability, and is also excellent in elution of physiologically active substances.

Since the acid-containing preparation of the present invention has low toxicity, it can be administered to mammals (eg, human, mouse, dog, rat,
It can be used as a safe drug for cattle etc.).
The acid-containing preparation of the present invention contains a compound having an antiallergic action, an antihistamine action, an antiinflammatory action, an anti-PAF (platelet activating factor) action, an eosinophil chemotaxis inhibitory action, etc. Use for treatment or prevention of allergic skin diseases such as eczema / dermatitis, contact dermatitis, pruritus, dry dermatitis, acute urticaria, prurigo and inflammatory skin diseases such as atopic dermatitis in animals You can Further, it is also useful as a preventive / therapeutic agent for nasal resistance increase, sneezing, nasal discharge, hay fever, upper respiratory tract hypersensitivity and a nasal obstruction improving agent. The dosage of the acid-containing preparation of the present invention varies depending on the type and content of the physiologically active substance, the dosage form, the duration of the physiologically active substance release, the target disease, the target animal, and the like. ) Or a salt thereof, for an adult patient (body weight 60 kg), it is usually converted to an effective ingredient (compound (I) or a salt thereof) of about 0.1 to about 100 mg / kg, preferably about 1 to About 50mg
/ kg, more preferably about 1 to about 10 mg / kg daily 1 or 2
It is recommended to administer in divided doses orally.

[0063]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples and Evaluation Examples, but these do not limit the present invention. Corn starch, hydroxypropylcellulose (HPC-L), magnesium stearate, tartaric acid, citric acid (anhydrous), crystalline cellulose, light anhydrous silicic acid, polyvinylpyrrolidone, lactose, sterile talc, croscarmellose used in the following examples Sodium (Ac-Di-Sol), Hydroxypropyl methylcellulose, Polyethylene glycol 600
As the 0, red ferric oxide and titanium oxide, the 14th revised Japanese Pharmacopoeia compliant products and the succinic acid special grade reagents were used.

[0064]

Examples Reference Example 1 Ethyl 2-fumarate 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate Preparation of acid salts 4- (diphenylmethoxy) -1-piperidinepropanamine
190-200 of 4.2 g of ethyl 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate
Stir for 3.5 hours at ℃. After cooling, aqueous sodium hydrogen carbonate was added, the mixture was extracted with ethyl acetate, the extract was washed with saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate: methanol: triethylamine (100: 5: 1). The desired fractions were collected and dissolved in 16 mL of ethyl acetate, and a solution of 867 mg of fumaric acid in 16 mL of methanol was added and concentrated.Acetone was added to the residue, and the precipitated crystals were collected by filtration, washed with acetone, and dried. 2.30 g of the title compound
Got Melting point 126-128 ° C Elemental analysis: Calculated as C ₄₁ H ₄₉ N ₅ O ₁₁ (%): C, 62.50; H, 6.27; N, 8.89 Actual value (%): C, 62.28; H, 6.15; N , 8.97 Reference Example 2 2- [6- [3- [4- (Diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate ethyl disuccinate 2- [6- [3- [4- (diphenylmethoxy) synthesized in Reference Example 1
0.278 g of ethyl piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate was dissolved in 1 mL of ethanol, 0.118 g of succinic acid was added and dissolved, and the mixture was concentrated under reduced pressure. Tetrahydrofuran in the residue
0.5 mL was added to dissolve it, and 2 mL of ethyl acetate was added, and the precipitated crystals were collected by filtration, washed with ethyl acetate and dried to obtain 0.382 g of the title compound. Mp 98-101 ° C. (decomposition) Elemental _{analysis: C 41 H 53 N 5 O} 11 · 1 / 3CH 3 CO 2 C 2 H 5 Calculated (%): C, 61.92; H, 6.83; N, 8.53 Found Value (%): C, 61.54; H, 6.83; N, 8.50

Reference Example 3 Ethyl 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate citrate Preparation of (1: 1) 2- [6- [3- [4- (diphenylmethoxy)) synthesized in Reference Example 1
1.667 g of ethyl piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate was dissolved in 8 mL of ethanol, and 0.631 g of citric acid monohydrate was added and dissolved by heating. It was concentrated under reduced pressure. 23 mL of ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration and washed with 12 mL of ethyl acetate. 30 mL of methanol in this crystal
Was added, heated to dissolve, and concentrated under reduced pressure. Ethanol (30 mL) was added to the residue to dissolve it, and the crystals precipitated after standing were collected by filtration, washed with ethanol (10 mL) and dried to obtain 2.01 g of the title compound. Melting point 176 ° C (decomposition) Elemental analysis: Calculated as C ₃₉ H ₄₉ N ₅ O ₁₀ (%): C, 62.64; H, 6.60; N, 9.36 Measured value (%): C, 62.50; H, 6.56; N, 9.43 Reference Example 4 Preparation of 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid 2- Ethyl [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate 468mg was dissolved in ethanol 3mL.
2 mL of a 1N sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 15 hours. Concentrate under reduced pressure, dilute the residue with water, wash with ethyl acetate, add 1N hydrochloric acid to the aqueous layer to adjust pH to 7, and extract with ethyl acetate-tetrahydrofuran (1: 1). Wash the extract with saturated brine and wash with magnesium sulfate. Dried in. Ethyl acetate was added to the residue after concentration under reduced pressure, and the precipitated crystals were collected by filtration, washed with ethyl acetate and dried to give 267 mg of the title compound.
Got It can be recrystallized from acetone. Melting point 205-206 ° C Elemental analysis: Calculated as C ₃₁ H ₃₇ N ₅ O ₃ (%): C, 70.56; H, 7.07; N, 13.27 Actual value (%): C, 70.46; H, 7.06; N , 13.36

Reference Example 5 Preparation of sodium 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate 2 -[6- [3- [4- (Diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid (528 mg) in methanol (2 mL) To 2
Normal aqueous sodium hydroxide solution (0.47 mL) was added, and the mixture was stirred at room temperature for 5 min. This solution was diluted with 2-propanol and concentrated under reduced pressure. The residue was dissolved in 2-propanol and concentrated under reduced pressure again. 2-Propanol and ethyl ether were added to this residue, and the precipitated powder was collected by filtration to give the title compound (47
4 mg) was obtained. Amorphous elemental analysis value: Calculated value as C ₃₁ H ₃₆ N ₅ O ₃ Na ・ 0.5H ₂ O (%): C, 66.65; H, 6.68; N, 12.54 Actual value (%): C, 66.45; H, 6.54; N, 12.53 Reference Example 6 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid dihydrate Method for producing hydrate (hereinafter abbreviated as compound A) 4- (diphenylmethoxy) -1-piperidinepropanamine
363.6 g (1120 mmol), ethyl 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate 200.0 g
(747 mmol) and 158.4 g (1490 mmol) of sodium carbonate were suspended in 600 mL of dimethylsulfoxide, heated in an oil bath (bath temperature 165-170 ° C.) while passing nitrogen gas, and stirred for 3.5 hours. Cool to room temperature, 2000 mL of ethyl acetate and 2000 mL of water
Was added to separate the layers. The organic layer was washed twice with 1000 mL of water, and the organic layer was concentrated under reduced pressure. 1000m ethanol in the residue
L was added and concentrated under reduced pressure to give crude 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b].
Pyridazin-2-yl] -2-methylpropionate ethyl 588g
Was obtained as an oil. 1400 mL of this oily substance in ethanol
59.8 g (1490 mmol) of sodium hydroxide in water and
It was dissolved in 00 mL and added. The reaction solution was heated to 60 ° C. (internal temperature) and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, 2000 mL of water and 2000 mL of ethyl acetate were added to the residue, and the layers were separated. The aqueous layer was washed twice with 1000 mL of ethyl acetate, and 2000 mL of ethanol was added to the aqueous layer. Add 1N hydrochloric acid (1000 mL) to bring the pH to about 6, and collect the crystals that have precipitated by filtration.
It was washed with 800 mL and 800 mL of ethanol: water (1: 1) and dried to obtain 353.6 g of the crude title compound. HPLC purity area percentage 97.7%, yield 82.0%. Crude title compound obtained here 35
1240 mL of ethanol was added to 3.6 g and the mixture was heated under reflux for 1 hour. The reaction solution was stirred under ice cooling, and the precipitated crystals were collected by filtration, washed with 930 mL of cold ethanol and dried. The obtained crystals were suspended in 2000 mL of water and stirred in a water bath (internal temperature 65-70 ° C) for 1 hour while heating. After cooling to room temperature, the precipitated crystals were collected by filtration, washed with 1000 mL of water, and dried to obtain 276 g of the title compound. Mp 203-205 ° C. (initially softens at 110-120 ° C., again solidified) Elemental _{analysis: C 31 H 37 N 5 O} 3 · 2H 2 O Calculated (%): C, 66.05; H, 7.33; N , 12.42 Actual value (%): C, 66.35; H, 7.29; N, 12.39

Reference Example 7 Preparation of N- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazine-2-carbonyl] glycine ethyl ester 4- (diphenylmethoxy) ) -1-Piperidinepropanamine
1.90 g of N- (6-chloroimidazo [1,2-b] pyridazine-2-carbonyl) glycine ethyl ester and 1.38 g of 1-methyl
-2-Pyrrolidone was dissolved in 15 mL, N-ethyldiisopropylamine (0.841 mL) was added, and the mixture was stirred in an oil bath (90-100 ° C) for 24 hours. After cooling, ice water was added and the mixture was extracted with ethyl acetate. 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 ethyl acetate: methanol: triethylamine
Elution at (95: 5: 1). The desired fractions were collected and recrystallized from ethyl acetate to obtain 1.28 g of the title compound. Melting point 172-174 ° C Elemental analysis: Calculated as C ₃₂ H ₃₈ N ₆ O ₄・ 0.5H ₂ O (%): C, 66.30; H, 6.78; N, 14.50 Measured value (%): C, 66.42; H, 6.68; N, 14.55

Reference Example 8 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -3-methylimidazo [1,2-b] pyridazin-2-yl]-
Preparation of ethyl 2-methylpropionate dihydrochloride 4- (diphenylmethoxy) -1-piperidinepropanamine
2.38 g of 2- (6-chloro-3-methylimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate and 1.03 g of
Stir for 7.5 hours at 160 ° C. After cooling, aqueous sodium hydrogen carbonate was added, the mixture was extracted with ethyl acetate, the extract was washed with saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate: methanol: triethylamine (50: 5: 1). Collect the desired fractions and concentrate under reduced pressure to give 5 mL of ethyl acetate.
The mixture was dissolved in water, 0.96 mL of 4N hydrogen chloride ethyl acetate solution was added, and the mixture was concentrated again. The residue was triturated with ethyl ether, collected by filtration and dried to give 666 mg of the title compound. Amorphous elemental analysis value: Calculated as C ₃₄ H ₄₅ N ₅ O ₃ Cl ₂・ 1.5H ₂ O (%): C, 60.98; H, 7.22; N, 10.46 Measured value (%): C, 60.70; H , 6.95; N, 10.34

Evaluation Example 1 For compound A, p was applied in Britton-Robinson buffer at 20 ° C.
Solubility was measured by the solubility of H1,3,5,7,9,11,13 at each pH. Compound A was added to the solution of each pH and vigorously stirred for 30 seconds every 5 minutes, and the dissolved amount of the physiologically active substance at the time of 30 minutes was measured. Compliant). As shown in FIG. 1, it is understood that the compound A is a bipolar compound which hardly dissolves in an aqueous solution having a neutral pH and has improved solubility on an acidic side or an alkaline side.

Control Example 1 Compound A (412.5 g), lactose (3465) in a fluid bed granulation dryer.
g) and corn starch (612.2 g) are mixed uniformly and then hydroxypropyl cellulose (HPC-
An aqueous solution in which L) (138.6 g) was sprayed was granulated and then dried in the same machine. The obtained granules were crushed and sized using a power mill with a 1.5 mmφ punching screen. Further, 3871 g of this granule was taken, croscarmellose sodium (Ac-Di-Sol) (207 g) and magnesium stearate (62.1 g) were added thereto, and mixed by a tumbler mixer to obtain a mixed granule. 9.5 mmφ of this mixed granule with a tablet machine
Using a pestle, the tablets were tableted to a weight of 300 mg to give plain tablets.

Example 1 Compound A (825 g), lactose (2087) in a fluidized bed granulation dryer.
g) and corn starch (742.5 g) are mixed uniformly and then in-machine hydroxypropyl cellulose (HPC-L)
An aqueous solution in which (148.5 g) was dissolved was sprayed to granulate, and then dried in the same machine. Using the power mill,
Granules of compound A were obtained by crushing with a 1.5 mmφ punching screen. 3181 g of this granule was taken and ground into tartaric acid (690 g), croscarmellose sodium (Ac-Di-So
l) (207 g) and magnesium stearate (62.1
g) was added and mixed with a tumbler mixer to give mixed granules. This granule weighs 300 m with a tableting machine using a 9.5 mmφ punch.
Tablets were pressed into g to give plain tablets.

Example 2 Citric acid (anhydrous) (6100 g), crystalline cellulose (Avicel PH101) (2928 g) and light anhydrous silicic acid (122 g) were uniformly mixed, and then the powder was pulverized. 8850 g of this ground powder
Chicken, crystalline cellulose (Avicel PH302) (2832 g), polyvinylpyrrolidone (PVP-K30) (1708 g), lactose (513
3 g) and magnesium stearate (177 g) were added and mixed in a tumbler mixer. This powder on a tablet machine
Using a 9.5 mmφ punch, the tablets were tableted to a weight of about 300 mg to give plain tablets. The obtained plain tablets were crushed with a power mill using a 1.5 mmφ punching screen to obtain citric acid granules. Separately, compound A (1649 g), lactose (2229 g) and corn starch (612.2 g) were uniformly mixed in a fluid bed granulation dryer, and then hydroxypropyl cellulose (HPC-L) (138.6 g) ) Was dissolved, the mixture was sprayed to granulate, and then dried in the same machine. The obtained granules were crushed and sized using a power mill with a 1.5 mmφ punching screen. Take 3647 g of the granules of Compound A, and add citric acid granules (3530 g) and croscarmellose sodium (Ac-D
i-Sol) (507 g) and magnesium stearate (11
7 g) was added and mixed with a tumbler mixer to give mixed granules. The mixed granules were tableted to a weight of 300 mg with a tableting machine using a 9.5 mmφ punch to give plain tablets.

Example 3 Succinic acid (6100 g), crystalline cellulose (Avicel PH101)
(2928 g) and light anhydrous silicic acid (122 g) were uniformly mixed, and then the powder was pulverized. To this ground powder (8850 g), add crystalline cellulose (Avicel PH302) (2832 g), polyvinylpyrrolidone (PVP-K30) (1708 g), lactose (5133 g) and magnesium stearate (177 g), and mix by tumbling. Mix with a machine to obtain mixed powder. This powder was tableted with a tableting machine using a 9.5 mmφ punch to a weight of about 300 mg to give an uncoated tablet. The obtained plain tablets were crushed with a power mill using a 1.5 mmφ punching screen to obtain succinic acid granules. Separately from this, in a fluidized bed granulation dryer, compound A (1649 g),
Lactose (2229 g) and corn starch (612.2
g) was uniformly mixed, and then an aqueous solution in which hydroxypropyl cellulose (HPC-L) (138.6 g) was dissolved was sprayed and granulated in the machine, and then dried in the same machine. The obtained granulated product was crushed using a power mill with a 1.5 mmφ punching screen to obtain a sized powder. This sized powder (3647 g), acid mixed powder (3530 g), croscarmellose sodium (Ac-Di-So
l) (507 g) and magnesium stearate (117
Add g) and mix with a tumbler mixer to give granules for tableting. The granules are weighed 300 times with a tableting machine using a 9.5 mmφ punch.
Tableted into mg to give a plain tablet.

Table 1 shows the formulations of Control Example 1, Example 1, Example 2 and Example 3 containing Compound A.

[Table 1]

Evaluation Example 2 As confirmation of absorbability, the difference in the absorption rate of Compound A due to the difference in gastric pH was examined using Beagle dogs. As a system with low intragastric pH, histamine (30 μg / k
g, sc) treated. After that, histamine was administered by sc every hour to maintain the gastric pH in the acidic range. Formulation (50 mg / body)
Blood was collected with a heparinized syringe 15 minutes, 30 minutes, 1, 2, 4 and 8 hours after administration, plasma was separated, and the blood concentration was measured. Cimetidine (100 mg / body, twice a day) was orally administered from 2 days before the administration of the preparation as a system having a high gastric pH, and further, 30 minutes before the administration of the preparation, cimetidine (100 mg / kg) was intravenously administered. Formulation (50 mg / body) administration 15 minutes, 30 minutes, 1, 2, 4 and 8
After a lapse of time, blood was collected with a heparin-treated syringe, plasma was separated, and the blood concentration was measured. The results of the absorption evaluation are shown in Table 2. As is clear from the results, even in the case where the formulation of Control Example 1 containing no acidic compound has low absorbability, the formulations of Examples 1, 2 and 3 containing the acidic compound have excellent absorbability,
It was found to be a formulation with little absorption fluctuation.

[Table 2]

Example 4 A formulation was prepared in the formulation system shown in Table 3. That is, for example, in the case of 100 mg tablets, compound A (or diphenhydramine) (1597 g), lactose (2163 g), corn starch (593.6 g), hydroxypropyl prepared by the fluidized bed granulation method (FD-5S, Paulec) Cellulose (HPC-
L) (134.4 g) of compound A (or diphenhydramine) granules and citric acid (anhydrous) (1600 g) made by dry granulation (Collect 12HUK, Kikusui Seisakusho), crystalline cellulose (1152 g), sterile talc ( 192 g), light anhydrous silicic acid (32 g), lactose (1032 g), croscarmellose sodium (Ac-Di-Sol) (240 g), magnesium stearate (96 g) ,
In addition to this, croscarmellose sodium (Ac-Di-So
l) (624 g) and magnesium stearate (144
g) was added to obtain mixed granules. The mixed granules were compressed with a tablet press (Correct 19) using an oval (8.0 × 14.0 mm) punch.
K, Kikusui Seisakusho). A film coating solution consisting of hydroxypropylmethylcellulose (179.7 g), polyethylene glycol 6000 (36 g), titanium oxide (24 g) and red iron sesquioxide (0.32 g) was applied to the obtained tablets using a pan-type coating machine (high coater, Freund). Industry) to obtain film-coated tablets. At this time, the conditions were controlled so that the product temperature was 40 ° C to 50 ° C. Similarly, 12.5 mg tablets, 25 mg tablets,
And 50 mg tablets with Compound A (or diphenhydramine)
It was prepared by adjusting the content of compound A (or diphenhydramine) and lactose in the granules of.

[Table 3]

Evaluation Example 3 25 mg tablet of Compound A prepared in Example 4 and 1 of Compound A
To evaluate the stability of 00 mg tablets, 10 tablets of each formulation were divided into glass bottles and sealed, and the system was conditioned to 60% RH at 25 ° C (relative humidity 60%) and to 75% RH at 40 ° C. System (relative humidity
75%), each stored for 1 month, appearance, content, residual rate,
And the behavior of related substances was observed and measured. Check the light resistance of the xenon lamp 100,000 Lux 1
This was done by confirming the behavior of related substances in the sample directly irradiated on the tablet for 2 hours. Table 4 shows the results of stability evaluation of 25 mg tablets of compound A, and Table 5 shows 100 mg of compound A.
The result about the stability evaluation of a tablet is shown. Table 4 and Table 5
As is clear from the above, no significant property change, decrease in content and remarkable formation of related substances were observed, and the stability was good.

[Table 4]

[Table 5]

Evaluation Example 4 12.5 mg tablets and 100 mg tablets of the compound A produced in Example 4 were divided into 10 glass bottles each, which was sealed at 25 ° C.
System conditioned at 60% RH (60% relative humidity) and 75% RH at 40 ° C
Each was stored for 1 month in a humidity-controlled system (75% relative humidity). In addition, for 100 mg tablets of Compound A, 10 tablets were divided into 10 glass bottles each, and in the opened state, the system was adjusted to 11% RH at 40 ° C (relative humidity 11%) and adjusted to 33% RH at 40 ° C. Each of them was also stored for 1 month in a damp system (relative humidity 33%).
For tablets before storage and tablets after storage, in accordance with the Japanese Pharmacopoeia Dissolution Test 2nd Law of the 14th Edition, 37
The elution behavior was confirmed in an acetate buffer solution (900 mL) at ℃, 50 rpm, pH 3.8 (n = 3). 2 shows the dissolution profile of the 12.5 mg tablet of compound A produced in Example 4, and FIG. 3 shows the dissolution profile of the 100 mg tablet of compound A produced in Example 4.

Example 5 A formulation was prepared in the formulation system shown in Table 6. That is, for example, in the case of 100 mg tablets, compound A (or diphenhydramine) (1597 g), lactose (2163 g), corn starch (593.6 g), hydroxypropyl prepared by the fluidized bed granulation method (FD-5S, Paulec) Cellulose (HPC-
L) (134.4 g) granules of compound A and citric acid (anhydrous) (1600 g), crystalline cellulose (1152 g), sterile talc (192 g), light anhydrous silica made by dry granulation (Collect 12HUK, Kikusui Seisakusho) Acid (32g), lactose (103
2g), croscarmellose sodium (Ac-Di-Sol)
(240 g), citric acid granules consisting of magnesium stearate (96 g) and granules obtained by removing powder of 1000 μm or more and less than 150 μm are mixed, and further mixed with croscarmellose sodium (Ac-Di-Sol) (624 g) and stearin. Magnesium acid (144 g) was added to obtain mixed granules. The mixed granules were tabletted with a tableting machine (Correct 19K, Kikusui Seisakusho) using an oval type (8.0 × 14.0 mm) punch. Hydroxypropylmethyl cellulose (179.
7g), polyethylene glycol 6000 (36g), titanium oxide (24g), and red iron sesquioxide (0.32g) are sprayed with a pan-type coating machine (Hicoater, Freund Sangyo) to form film-coated tablets. Obtained. At this time, the conditions were controlled so that the product temperature was 40 ° C to 50 ° C. Similarly, 12.5mg
Tablets, 25 mg tablets, and 50 mg tablets were prepared by adjusting compound A (or diphenhydramine) and lactose content in granules of compound A (or diphenhydramine).

[Table 6]

Evaluation Example 5 The stability of the preparation prepared in Example 5 was evaluated by a system in which 10 tablets of each tablet were divided into glass bottles and sealed, and the humidity was adjusted to 75% RH at 40 ° C. (75% relative humidity). So, save each one month,
It was conducted by observing and measuring appearance, content, residual rate, and behavior of related substances. Table 7 shows the results for the stability evaluation of the 12.5 mg tablet of compound A produced in Example 5, Table 8 shows the results for the stability evaluation of the 25 mg tablet of compound A produced in Example 5, and Table 9 Table 10 shows the results regarding the stability evaluation of the 50 mg tablet of compound A produced in Example 5 in Table 5.
The result about the stability evaluation of the 100 mg tablet of the compound A manufactured in Example 5 is shown in FIG. As is clear from Tables 7 to 10, no significant property change, decrease in content, and remarkable formation of related substances were observed, and stability was good.

[Table 7]

[Table 8]

[Table 9]

[Table 10]

Evaluation Example 6 12.5 mg tablet and 100 mg tablet of the compound A produced in Example 5 were divided into 10 glass bottles each, and the bottles were sealed at 40 ° C.
It was stored for 1 month in a system whose humidity was adjusted to 75% RH (relative humidity 75%).
For tablets before storage and tablets after storage, in accordance with the Japanese Pharmacopoeia Dissolution Test 2nd Law of the 14th Edition, 37
The elution behavior was confirmed in an acetate buffer solution (900 mL) at ℃, 50 rpm, pH 3.8 (n = 6). FIG. 4 shows the dissolution profile of the 12.5 mg tablet of compound A produced in Example 5, and FIG. 5 shows the dissolution profile of the 100 mg tablet of compound A produced in Example 5. The formulation of Compound A prepared in Example 5 was prepared as in Example 4
It was found that the change in the dissolution profile was smaller than that of the compound A preparation produced in.

Example 6 A formulation was prepared in the formulation system shown in Table 11. That is,
For example, in the case of 50 mg tablets, compound A (or diphenhydramine) (1000 g), lactose (1350 g), corn starch (371.0 g), hydroxypropyl cellulose (prepared by the fluidized bed granulation method (FD-5S, Paulec)) HPC-
L) (84.0 g) of compound A (or diphenhydramine) granules and dry granulation (roller compactor,
Citric acid (anhydrous) made by Alexanderwerk) (1000
g), crystalline cellulose (480 g), sterile talc (120
g), light anhydrous silicic acid (20 g), lactose (645 g), croscarmellose sodium (Ac-Di-Sol) (150 g), magnesium stearate (60 g) and more than 1000 μm from citric acid granules and Mix the granules from which the powder of less than 150 μm has been removed, and further add croscarmellose sodium (Ac-Di-Sol) (390 g), crystalline cellulose (240 g),
Magnesium stearate (60 g) was added to obtain mixed granules. The mixed granules were tabletted with a tableting machine (Correct 19K, Kikusui Seisakusho) using a 9.5 mmφ punch. Hydroxypropylmethyl cellulose (336.825
g), polyethylene glycol 6000 (67.5 g), titanium oxide (45 g), red iron sesquioxide (0.675 g), a film coating solution is sprayed using a pan-type coating machine (high coater, Freund Sangyo) to perform film coating. I got a lock. At this time, the product temperature should be 40 ℃ to 50 ℃
The conditions were controlled so that Similarly, 12.5 m
A g tablet and a 25 mg tablet were prepared by adjusting compound A (or diphenhydramine) and lactose content in granules of compound A (or diphenhydramine).

[Table 11]

Evaluation Example 7 The stability of the preparation produced in Example 6 was evaluated by a system in which 10 tablets of each tablet were divided into glass bottles and sealed, and the humidity was adjusted to 75% RH at 40 ° C. (75% relative humidity). So, save each one month,
It was conducted by observing and measuring appearance, content, residual rate, and behavior of related substances. Table 12 shows the results for the stability evaluation of the 12.5 mg tablet of compound A produced in Example 6, Table 13 shows the results for the stability evaluation of the 25 mg tablet of compound A produced in Example 6, and Table 14 The results of the stability evaluation of the 50 mg tablet of Compound A produced in Example 6 are shown in FIG. As is clear from Tables 12 to 14, no significant property change, decrease in content, and remarkable formation of related substances were observed, and stability was good.

[Table 12]

[Table 13]

[Table 14]

Evaluation Example 8 A 12.5 mg tablet, a 25 mg tablet and a 50 mg tablet of the compound A produced in Example 6 were divided into 10 glass bottles each, and the bottles were sealed, and the system was adjusted to 75% RH at 40 ° C. (relative It was stored at a humidity of 75%) for 1 month. About tablets before storage and tablets after storage,
Acetic acid buffer solution (900 mL) at 37 ° C, 50 rpm, pH 3.8 based on the 2nd method (paddle method) of Japanese Pharmacopoeia dissolution test
The elution behavior was confirmed (n = 6). FIG. 6 shows the dissolution profile of the 12.5 mg tablet of compound A produced in Example 6, FIG.
FIG. 8 shows the dissolution profile of the 25 mg tablet of Compound A produced in Example 6, and FIG. 8 shows the dissolution profile of the 50 mg tablet of Compound A produced in Example 6. The formulation of Compound A produced in Example 6 was found to have less change in the dissolution profile compared with the formulation of Compound A produced in Example 4.

The acid-containing preparation of the present invention remarkably improves the digestive tract absorption of physiologically active substances and has excellent stability.

[Brief description of drawings]

FIG. 1 is a drawing showing a change in solubility of Compound A with respect to pH. The vertical axis represents solubility (mg / mL) and the horizontal axis represents pH.

FIG. 2 is a drawing showing dissolution evaluation results (n = 3, average value ± standard deviation) of a 25 mg tablet of Compound A produced in Example 4. -▲-is a tablet before storage,-◆-is a tablet stored for 1 month in a system controlled to 25 ° C and 60% RH, and-■-is a tablet stored for 1 month in a system controlled to 40 ° C and 75% RH. The solubility of the prepared tablets is shown. The vertical axis represents the dissolution rate (%) and the horizontal axis represents the time (minutes).

FIG. 3 is a drawing showing dissolution evaluation results (n = 3, average value ± standard deviation) of a 100 mg tablet of Compound A produced in Example 4. -▲-is a tablet before storage,-◆-is a tablet stored for 1 month in a system controlled to 25 ° C and 60% RH, and-■-is a tablet stored for 1 month in a system controlled to 40 ° C and 75% RH. The solubility of the tablets stored in -X- was stored for 1 month in a system adjusted to 40 ° C and 11% RH, and the solubility of tablets stored in-○-for 1 month in a system adjusted to 40 ° C and 33% RH. Show. The vertical axis represents the dissolution rate (%) and the horizontal axis represents the time (minutes).

FIG. 4 is a view showing dissolution evaluation results (n = 6, average value ± standard deviation) of a 12.5 mg tablet of Compound A produced in Example 5. -◆-indicates the solubility of the tablet before storage, and- ■-indicates the solubility of the tablet stored for 1 month in a system controlled to 40 ° C and 75% RH. The vertical axis represents the dissolution rate (%) and the horizontal axis represents the time (minutes).

FIG. 5 is a drawing showing dissolution evaluation results (n = 6, average value ± standard deviation) of a 100 mg tablet of Compound A produced in Example 5. -◆-indicates the solubility of the tablet before storage, and- ■-indicates the solubility of the tablet stored for 1 month in a system controlled to 40 ° C and 75% RH. The vertical axis represents the dissolution rate (%) and the horizontal axis represents the time (minutes).

FIG. 6 is a drawing showing dissolution evaluation results (n = 6, average value ± standard deviation) of a 12.5 mg tablet of compound A produced in Example 6. -◆-indicates the solubility of the tablet before storage, and- ■-indicates the solubility of the tablet stored for 1 month in a system controlled to 40 ° C and 75% RH. The vertical axis represents the dissolution rate (%) and the horizontal axis represents the time (minutes).

FIG. 7 is a drawing showing dissolution evaluation results (n = 6, average value) of a 25 mg tablet of Compound A produced in Example 6. -◆-indicates the solubility of the tablet before storage, and- ■-indicates the solubility of the tablet stored for 1 month in a system controlled to 40 ° C and 75% RH. The vertical axis represents the dissolution rate (%) and the horizontal axis represents the time (minutes).

FIG. 8 is a drawing showing the dissolution evaluation results (n = 6, average value) of the 50 mg tablet of compound A produced in Example 6. -◆-indicates the solubility of the tablet before storage, and- ■-indicates the solubility of the tablet stored for 1 month in a system controlled to 40 ° C and 75% RH. The vertical axis represents the dissolution rate (%) and the horizontal axis represents the time (minutes).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 47/18 A61K 47/18 47/20 47/20 47/36 47/36 A61P 29/00 A61P 29 / 00 37/00 37/00 37/08 37/08 F term (reference) 4C076 AA42 CC03 CC07 DD27C DD41Q DD42Q DD43Q DD51Q DD57Q EE37Q FF24 FF63 4C084 AA17 AA27 MA05 NA03 ZB011 ZB111 ZB131 4C086 AA01 AA02 MA35 MA01 MA02 MA52 MA01 ZB13

Claims (24)

[Claims] 1. An antiallergic action, an antihistamine action,
A preparation comprising a compound having an anti-inflammatory action, an anti-PAF action and / or an eosinophil chemotaxis inhibitory action, and an acidic compound. 2. The preparation according to claim 1, wherein the compound having an antiallergic action, an antihistamine action, an antiinflammatory action, an anti-PAF action and / or an eosinophil chemotaxis inhibitory action is a basic compound. 3. The preparation according to claim 1, wherein the compound having an antiallergic action, an antihistamine action, an antiinflammatory action, an anti-PAF action and / or an eosinophil chemotaxis inhibitory action is a bipolar compound. 4. A compound having an anti-allergic action, an antihistamine action, an anti-inflammatory action, an anti-PAF action and / or an eosinophil chemotaxis inhibitory action has a solubility at pH 3 or less that is 10 times or more that at pH 5 to 8. The formulation according to claim 1. 5. Antiallergic action, antihistamine action, anti
Inflammatory, anti-PAF and / or eosinophil chemotaxis
Compounds with production formula [Chemical 1] [In the formula, Ar¹And Ar²Each has a substituent
Good aromatic group, Ar ¹And Ar²Is adjacent to a carbon atom
May have a condensed ring group, and the B ring has a substituent.
Optionally represents a nitrogen-containing heterocycle, X and Y are respectively
Identical or different, bond, oxygen atom, S (O)_p(P is 0
Indicates the integer of 2), NR^Four(R^FourIs a hydrogen atom or a lower atom
Alkyl group) or may have a substituent,
Divalent straight chain low optionally having 1 to 3 terror atoms
Indicates a primary hydrocarbon group, A is a nitrogen atom or CR⁷(R⁷Is hydrogen
Atoms, halogen atoms, hydrocarbons that may have a substituent
Elementary group, acyl group or optionally substituted hydro group
Xy group), R¹, R²And R³Are the same
Or differently having a hydrogen atom, a halogen atom, a substituent
Optionally having a hydrocarbon group, an acyl group or a substituent
R is an optional hydroxy group⁸Is a hydrogen atom, lower
A hydroxy group which may be substituted with an alkyl group or
Indicates a carboxyl group. ] Or a compound represented by
The formulation according to claim 1, which is a salt. 6. A compound having an anti-allergic action, an antihistamine action, an anti-inflammatory action, an anti-PAF action and / or an eosinophil chemoattractant action is 2- [6- [3- [4- (diphenylmethoxy) piperidino]. ] Propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate ethyl or its salt, N- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] Pyridazine-2-carbonyl]
Glycine ethyl ester or its salt, 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -3-methylimidazo [1,2-b] pyridazin-2-yl] -2-methylpropion The preparation according to claim 1, which is ethyl acid or a salt thereof. 7. The preparation according to claim 1, wherein the acidic compound is a solid. 8. The preparation according to claim 1, wherein 50% or more of the constituent particles of the acidic compound are particles of 50 μm to 1.5 mm. 9. 50% or more of the constituent particles of the acidic compound are 150 μm
The formulation according to claim 1, which is particles having a size of from 1.0 to 1.0 mm. 10. The preparation according to claim 1, wherein 50% or less of the constituent particles of the acidic compound account for 20% or less of the whole. 11. An acidic compound is carboxylic acid, sulfonic acid,
The preparation according to claim 1, which is an acidic polysaccharide and an acidic amino acid. 12. The acidic compound is a carboxylic acid.
The described formulation. 13. The preparation according to claim 12, wherein the carboxylic acid is fumaric acid, adipic acid, malic acid, acetic acid, tartaric acid, succinic acid or citric acid. 14. The preparation according to claim 12, wherein the carboxylic acid is tartaric acid, succinic acid or citric acid. 15. The carboxylic acid is citric acid.
The described formulation. 16. An antiallergic action, an antihistamine action,
An acidic compound is added to 1 part by weight of a compound having an anti-inflammatory effect, an anti-PAF effect and / or an eosinophil chemotaxis inhibitory effect.
The formulation according to claim 1, which comprises 0.1 to 10 parts by weight. 17. The preparation according to claim 1, which is a tablet. 18. An antiallergic action, an antihistamine action,
The preparation according to claim 1, which comprises a granule containing a compound having an anti-inflammatory action, an anti-PAF action and / or an eosinophil chemoattractant inhibiting action, and a granule containing an acidic compound. 19. An antiallergic action, an antihistamine action,
Granules containing a compound having an anti-inflammatory action, an anti-PAF action and / or an eosinophil chemotaxis inhibitory action are 50 μm or
2. 50% or more of 1.5 mm particles and 50% or more of 50 μm to 1.5 mm particles containing an acidic compound.
8. The preparation according to 8. 20. Antiallergic action, antihistamine action,
Granules containing a compound having an anti-inflammatory action, an anti-PAF action and / or an eosinophil chemotaxis inhibitory action are 150 μm or
5. 50% or more of 1.0 mm particles and 50% or more of 150 μm to 1.0 mm particles containing an acidic compound.
8. The preparation according to 8. 21. The preparation according to claim 1, which is a multi-layer tablet. 22. The preparation according to claim 17 or 21, which is a coated preparation. 23. The preparation according to claim 1, further comprising talc or / and magnesium stearate. 24. An antiallergic action, an antihistamine action,
The method for producing a preparation according to claim 1, wherein a granule containing a compound having an anti-inflammatory action, an anti-PAF action and / or an eosinophil chemoattractant inhibiting action is mixed with a granule containing an acidic compound.