JP2003137785A - Jnk activation inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a JNK (c-Jun N-terminal kinase) activation inhibitor. SOLUTION: This c-Jun N terminal kinase activation inhibitor contains a compound expressed by formula (A) [Ar<a> and Ar<b> are each a (substituted) aromatic group; Ar<a> and Ar<b> may form a condensed ring together with adjacent carbon atoms; B<a> ring is a (substituted) N-containing heterocyclic group; X<a> and Y<a> are each independently (1) a bond, (2) oxygen atom, (3) S(O)p ((p) is an integer of 0-2), (4) NR<d> (R<d> is H or a lower alkyl) or (5) a (substituted) bivalent straight-chain lower hydrocarbon group optionally containing 1-3 hetero- atoms; A<a> ring is a (substituted) 5-membered ring; R<a> and R<b> are each independently (1) hydrogen atom, (2) a halogen atom, (3) a (substituted) hydrocarbon group, (4) an acyl or (5) a (substituted) hydroxy group; and R<c> is (1) hydrogen atom, (2) a hydroxy group which may be substituted with a lower alkyl group or (3) carboxy group], or its salt or prodrug.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an excellent c-Jun N-terminal kinase (N-Terminal kinase, hereinafter abbreviated as JNK).
The present invention relates to activation inhibitors, TNF (tumor necrosis factor) -α inhibitors, and the like.

[0002]

2. Description of the Related Art JNK is a member of mitogen Activated Protain kinase (MAPK) which mediates an information transduction system that transmits stimuli from the outside into the nucleus. JNK phosphorylates the N-terminal of c-Jun, a transcriptional regulator of AP-1, resulting in AP-1
It is known to increase transcriptional activity of downstream genes (Embo Journal (EMBO J.), 15, 2760-2770 (1996),
Biochemica Et Biophysica Actor (Bioch
emica et Biophysica Acta), 1333, F85 (1997)). In other words, JNK activation inhibitors are thought to suppress the expression of inflammatory and immune factors dependent on AP-1, and may be therapeutic agents for inflammatory diseases such as rheumatoid arthritis and neurodegenerative diseases ( Molecular Cell Biology (Mol. Ce
ll. Biol.) 1997, 17, 6274, Journal of Neuroscience (J. Neurosci.), 1998, 18, 104). In addition, c-Jun is involved in cardiomyocyte apoptosis during ischemia / reperfusion.
It has been reported that JNK may be a therapeutic drug for cardiovascular diseases such as myocardial infarction and heart failure (Circ. Res., 82, 166 (1998)). Oxindole derivatives are reported in WO 00/64 as having such JNK inhibitory action.
872, uracil derivatives are described in WO 00/75118, respectively. Further, TNF-α is considered to play an important role in various diseases, for example, in rheumatoid arthritis, which is an inflammatory disease, the production of TNF-α is enhanced,
This is believed to result in the destruction of joint tissue.

On the other hand, a compound having a condensed pyridazine skeleton is described in USP 3,915,968 and is represented by the formula:

[Chemical 11] [Wherein, R and R ³ are each a hydrogen atom or a lower alkyl (at least one of R and R ³ is a lower alkyl), and R ¹ and R ^{2 are}
Represents a heterocyclic group selected from pyrrolidine, piperidine, piperazine or morpholine together with a nitrogen atom. ] USP 4,136,182 is a compound represented by the formula:

[Chemical 12] [In the formula, R represents a hydrogen atom, phenyl or lower alkylcarbonylamino, R ¹ represents morpholino or piperidino, and R ² represents a hydrogen atom or lower alkyl. However, R
At least one of R ² and R ² is a group other than a hydrogen atom, and when R is phenyl, R ¹ is morpholino and R ² is lower alkyl. ] Or a salt thereof is disclosed as a bronchodilator for reducing bronchospasm.

Further, Japanese Patent Laid-Open No. 6-279447 discloses a formula

[Chemical 13] [Wherein, R ¹ is a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom, R ² and R ³ are each a hydrogen atom or a lower alkyl which may have a substituent, or R ² And R ³ may form a 5- to 7-membered ring with adjacent -C = C-, X is an oxygen atom or S (O) _p (p is an integer of 0 to 2), and Y is a formula.

[Chemical 14] (R ⁴ and R ⁵ each represent a hydrogen atom or a lower alkyl group which may have a substituent) or a 3- to 7-membered homocyclic ring or a heterocyclic group which may have a substituent A divalent group derived from a ring, R ⁶ and R ⁷ each have a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted group. Optionally an aryl group, or R ⁶ and R ⁷ together with the adjacent nitrogen atom may form a nitrogen-containing heterocyclic group which may have a substituent, and m is an integer of 0 to 4 and n Is 0
Is an integer of 4 to 4. ] The compound or its salt represented by these, or one of the synthetic examples

[Chemical 15] Compounds represented by are exemplified and disclosed to have anti-asthma action, anti-PAF action, anti-inflammatory action, and anti-allergic action.

Further, in Japanese Patent Laid-Open No. 6-279446, the formula

[Chemical 16] [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom, and R ² and R ³ each represent a hydrogen atom or a lower alkyl group which may have a substituent. (Provided that one of R ² and R ³ is a hydrogen atom, the other is a lower alkyl group which may have a substituent), R ² and R ³ are 5 or 5 with adjacent -C = C-. A 7-membered ring may be formed, X is an oxygen atom or S (O) _p (p is an integer of 0 to 2), and Y is a formula.

[Chemical 17] (R ⁴ and R ⁵ each represent a hydrogen atom or a lower alkyl group which may have a substituent) or a 3- to 7-membered homocyclic ring or a heterocyclic group which may have a substituent A divalent group derived from a ring, R ⁶ and R ⁷ each have a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted group. Represents an optionally substituted aryl group, R ⁶ and R ⁷ may form a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen atom, m is an integer of 0 to 4, n represents an integer of 0 to 4. ] Or a salt thereof is described, and these compounds have anti-allergic action, anti-inflammatory action and anti-PAF action (platelet activating factor)
It is disclosed that it has an action and is effectively used as an anti-asthma agent by suppressing bronchospasm and bronchoconstriction.

EP 128536 also describes the formula

[Chemical 18] The antibacterial compound represented by
formula

[Chemical 19] Antibacterial compounds represented by, for example, are described.

[0007]

[Problems to be Solved by the Invention] JNK exhibits various physiological actions by phosphorylation of c-Jun. As a preventive and therapeutic drug for ischemia, etc., development of a JNK activation inhibitor that is more satisfactory in terms of action effect, sustainability, safety and the like is desired. In addition, TNF- has excellent properties as a medicine, such as excellent preventive and therapeutic effects for inflammatory diseases and no side effects.
There is a strong demand for the development of α inhibitors.

[0008]

The inventors of the present invention have conducted various studies in order to solve the above-mentioned problems, and as a result, have found that the condensed pyridazine ring has a nitrogen-containing heterocycle through a spacer in terms of chemical structure. Expressions with great characteristics of

[Chemical 20] [In the formula, Ar^aAnd Ar^bEach has a substituent
Good aromatic group, Ar ^aAnd Ar^bIs adjacent to a carbon atom
A condensed ring group may be formed on B^aRing has substituents
A nitrogen-containing heterocycle which may be present, X^aAnd Y^aIs that
Same or different (1) bond, (2) oxygen atom, (3) S
(O)_p(P is an integer from 0 to 2), (4) NR ^d(R^dIs water
(Representing an elementary atom or a lower alkyl group) or (5) substituent
Optionally having 1 to 3 heteroatoms
A divalent linear lower hydrocarbon group which may be present is represented by A^aThe ring is
Represents a 5-membered ring which may have a substituent, R^aAnd R^bIs
The same or different (1) hydrogen atom, (2) halogen
Atom, (3) a hydrocarbon group which may have a substituent, (4)
Sil group or (5) hydroxy which may have a substituent
Represents a group, R^cIs substituted with (1) hydrogen atom, (2) lower alkyl group
Optionally hydroxyl group or (3) carboxyl
Indicates a group. ] The compound or its salt represented by
Prodrugs, especially [1,2,4] triazolo [1,5-b] pyrida
Gin and imidazo [1,2-b] pyridazine
Chemical structure where nitrogen-containing heterocycle is present
Expression with the above major characteristics

[Chemical 21] [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 (1) bond, (2) oxygen atom, (3) S (O)_p
(P is an integer from 0 to 2), (4) NR^Four(R^FourIs hydrogen
Child or lower alkyl group) or (5)
Optionally via one to three heteroatoms
Is a divalent straight-chain lower hydrocarbon group, where A is a nitrogen source
Child or CR⁷(R⁷Is a hydrogen atom, a halogen atom, a substituent
A hydrocarbon group, an acyl group or a substituent which may have
Represents a hydroxy group which may have), R¹, R²
And R³Are the same or different and each is a hydrogen atom or halo.
A gen atom, a hydrocarbon group which may have a substituent, an acyl group
Group or a hydroxy group which may have a substituent is shown.
Then R⁸Is a hydrogen atom or a lower alkyl group
Shows a good hydroxy or carboxyl group. ] In the table
Compound or salt thereof or prodrug thereof
However, unexpectedly excellent JNK activation inhibitory effect and TNF-α
It has an inhibitory effect and the agent containing it is stable.
It has excellent properties as a pharmaceutical product,
For the first time,
The present invention has been completed based on these findings.

That is, the present invention is [1] formula

[Chemical formula 22] [In the formula, Ar^aAnd Ar^bEach has a substituent
Good aromatic group, Ar ^aAnd Ar^bIs adjacent to a carbon atom
A condensed ring group may be formed on B^aRing has substituents
A nitrogen-containing heterocycle which may be present, X^aAnd Y^aIs that
Same or different (1) bond, (2) oxygen atom, (3) S
(O)_p(P is an integer from 0 to 2), (4) NR ^d(R^dIs water
(Representing an elementary atom or a lower alkyl group) or (5) substituent
Optionally having 1 to 3 heteroatoms
A divalent linear lower hydrocarbon group which may be present is represented by A^aThe ring is
Represents a 5-membered ring which may have a substituent, R^aAnd R^bIs
The same or different (1) hydrogen atom, (2) halogen
Atom, (3) a hydrocarbon group which may have a substituent, (4)
Sil group or (5) hydroxy which may have a substituent
Represents a group, R^cIs substituted with (1) hydrogen atom, (2) lower alkyl group
Optionally hydroxyl group or (3) carboxyl
Indicates a group. ] The compound or its salt represented by
C-Jun N-terminal kinase activity containing a prodrug of
Sexual inhibitor; [2] formula

[Chemical formula 23] [In the formula, Ar^aAnd Ar^bEach has a substituent
Good aromatic group, Ar ^aAnd Ar^bIs adjacent to a carbon atom
A condensed ring group may be formed on B^aRing has substituents
A nitrogen-containing heterocycle which may be present, X^aAnd Y^aIs that
Same or different (1) bond, (2) oxygen atom, (3) S
(O)_p(P is an integer from 0 to 2), (4) NR ^d(R^dIs water
(Representing an elementary atom or a lower alkyl group) or (5) substituent
Optionally having 1 to 3 heteroatoms
A divalent linear lower hydrocarbon group which may be present is represented by A^aThe ring is
Represents a 5-membered ring which may have a substituent, R^aAnd R^bIs
The same or different (1) hydrogen atom, (2) halogen
Atom, (3) a hydrocarbon group which may have a substituent, (4)
Sil group or (5) hydroxy which may have a substituent
Represents a group, R^cIs substituted with (1) hydrogen atom, (2) lower alkyl group
Optionally hydroxyl group or (3) carboxyl
Indicates a group. ] The compound or its salt represented by
A TNF-α inhibitor comprising a prodrug of [3] Expression

[Chemical formula 24] [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 (1) bond, (2) oxygen atom, (3) S (O)_p
(p is an integer from 0 to 2), (4) NR^Four(R^FourIs a hydrogen atom
Or a lower alkyl group) or (5) having a substituent
Or optionally through 1 to 3 heteroatoms
Indicates a divalent straight chain lower hydrocarbon group, A is (1) nitrogen atom or
Or (2) CR⁷(R⁷Has a hydrogen atom, a halogen atom, or a substituent
Optionally having a hydrocarbon group, an acyl group or a substituent.
Represents a hydroxy group which may be¹, R²Oh
And R³Are the same or different (1) hydrogen atom, (2)
Halogen atom, (3) hydrocarbon which may have a substituent
Group, (4) acyl group, or (5) optionally substituted substituent
Indicates a droxy group, R⁸Is (1) hydrogen atom, (2) lower alkyl
An optionally substituted hydroxy group or (3) carbox
A boxyl group is shown. ] The compound or its salt represented by
Alternatively, the c-Jun N-terminal fragment containing the prodrug thereof can be used.
An inhibitor of nase activation; [4] Expression

[Chemical 25] [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 (1) bond, (2) oxygen atom, (3) S (O)_p
(p is an integer from 0 to 2), (4) NR^Four(R^FourIs a hydrogen atom
Or a lower alkyl group) or (5) having a substituent
Or optionally through 1 to 3 heteroatoms
Indicates a divalent straight chain lower hydrocarbon group, A is (1) nitrogen atom or
Or (2) CR⁷(R⁷Has a hydrogen atom, a halogen atom, or a substituent
Optionally having a hydrocarbon group, an acyl group or a substituent.
Represents a hydroxy group which may be¹, R²Oh
And R³Are the same or different (1) hydrogen atom, (2)
Halogen atom, (3) hydrocarbon which may have a substituent
Group, (4) acyl group, or (5) optionally substituted substituent
Indicates a droxy group, R⁸Is (1) hydrogen atom, (2) lower alkyl
An optionally substituted hydroxy group or (3) carbox
A boxyl group is shown. ] The compound or its salt represented by
Or a TNF-α inhibitor containing the prodrug thereof; [5] Ar¹And Ar²Is (i) halogen atom, (ii) C_1-6Al
Xylene, (iii) nitro, (iv) cyano, (v) halogen
C, which may be_1-6Alkyl, (vi) halogenated
May be C_2-6Alkenyl, (vii) halogenated
May be C_2-6Alkynyl, (viii) C_3-6Cycloalk
(Ix) 1 to 3 halogen atoms, mono- or di-
C_1-6Alkylamino or C_1-6Alkoxy-Carbonii
C which may have_1-6Alkoxy, (x) halogenated
May be C_1-6Alkylthio, (xi) hydroxy,
(xii) amino, (xiii) mono-C_1-6Alkylamino, (xiv)
The-C_{1 -6}Alkylamino, (xv) 5- or 6-membered cyclic amino
No, (xvi) C_1-6Alkyl-carbonyl, (xvii) carboxy
Le, (xviii) C_1-6Alkoxy-carbonyl, (xix) carba
Moyl, (xx) thiocarbamoyl, (xxi) mono-C_1-6Archi
Le-carbamoyl, (xxii) di-C_1-6Alkyl-carbamoy
Le, (xxiii) C_6-10Aryl-carbamoyl, (xxiv) sul
E, (xxv) C_1-6Alkylsulfonyl, (xxvi) C_6-10Ally
Le, (xxvii) C_6-10Aryloxy and (xxviii) C_7-16
Substituted with a group selected from the group consisting of aralkyloxy
May be (1) C_6-14Aromatic hydrocarbon group or (2) carbon
Other than atom, selected from nitrogen atom, sulfur atom and oxygen atom
5- to 8-membered aromatic ring containing 1 to 4 heteroatoms
An aromatic heterocyclic group, or (3) the aromatic heterocyclic group and C_6-14Aromatic
From a ring formed by condensation with a hydrocarbon ring to any hydrogen source
Ar represents a monovalent group formed by removing the child, Ar¹And Ar²Are adjacent
Along with carbon atom, (i) halogen atom, (ii) C_1-6Arche
Ndioxy, (iii) nitro, (iv) cyano, (v) halogenated
May be C_1-6Alkyl, (vi) halogenated
May be C_2-6Alkenyl, (vii) halogenated
May be C_2-6Alkynyl, (viii) C_3-6Cycloalkyl,
(ix) 1 to 3 halogen atoms, mono- or di-C_1-6
Alkylamino or C_1-6Alkoxy-carbonyl
You may have C_1-6Alkoxy, (x) halogenated
May be C_1-6Alkylthio, (xi) hydroxy, (xi
i) amino, (xiii) mono-C_1-6Alkylamino, (xiv) di-C
_1-6Alkylamino, (xv) 5- or 6-membered cyclic amino, (xv
I c_{1- 6}Alkyl-carbonyl, (xvii) carboxyl, (xv
iii) C_1-6Alkoxy-carbonyl, (xix) carbamoyl,
(xx) thiocarbamoyl, (xxi) mono-C_1-6Alkyl-cal
Bamoi, (xxii) di-C_1-6Alkyl-carbamoyl, (xxi
ii) C_6-10Aryl-carbamoyl, (xxiv) sulfo, (xxv)
C_1-6Alkylsulfonyl, (xxvi) C_6-10Aryl, (xxvi
I c_6-10Aryloxy, (xxviii) C_7-16Aralkyl Oki
Substituted with a group selected from the group consisting of Si and (xxix) oxo
An expression that may be

[Chemical formula 26] [In the formula, R⁸Is a hydrogen atom, C_1-6Substituted with alkyl
Represents a hydroxy group or a carboxyl group]
It may form a condensed ring group represented by B ring is (i)
Rogen atom, (ii) C_1-6Alkylenedioxy, (iii) nit
B, (iv) cyano, (v) optionally halogenated C_1-6
Alkyl, (vi) optionally halogenated C_2-6Arche
Nil, (vii) optionally halogenated C_2-6Alkini
Le, (viii) C_3-6Cycloalkyl, (ix) 1 to 3 ha
Rogen atom, mono- or di-C _1-6Alkylamino
Is C_1-6Alkoxy-C optionally having carbonyl_1-6
Alkoxy, (x) optionally halogenated C_1-6Al
Kirthio, (xi) hydroxy, (xii) amino, (xiii) mono-
C_1-6Alkylamino, (xiv) di-C_1-6Alkylamino, (x
v) 5- or 6-membered cyclic amino, (xvi) C_1-6Alkyl-carbo
Nil, (xvii) carboxyl, (xviii) C_1-6Alkoxy-mosquito
Lubonyl, (xix) carbamoyl, (xx) thiocarbamoy
Le, (xxi) Mono-C_1-6Alkyl-carbamoyl, (xxii) di-
C_1-6Alkyl-carbamoyl, (xxiii) C_6-10Aryl-mosquito
Lubamoyl, (xxiv) sulfo, (xxv) C_{1- 6}Alkyl sulfo
Nil, (xxvi) C_6-10Aryl, (xxvii) C_6-10Ario
Kish, (xxviii) C_7-16Aralkyloxy and (xxix) o
May be substituted with groups selected from the group consisting of xoxo
Containing at least one nitrogen atom, and
1 to 3 selected from child, oxygen atom and sulfur atom
3 to 13-membered nitrogen-containing, which may contain hetero atoms of
Represents a heterocyclic ring, where X and Y are the same or different
, (1) bond, (2) oxygen atom, (3) S (O)_p(P is 0 or
2), (4) NR^Four(R^FourIs a hydrogen atom or straight chain
Or branched C_1-6Alkyl group) or (5) (i)
Rogen atom, (ii) C_1-6Alkylenedioxy, (iii) nit
B, (iv) cyano, (v) optionally halogenated C_1-6
Alkyl, (vi) optionally halogenated C_2-6Arche
Nil, (vii) optionally halogenated C_2-6Alkini
Le, (viii) C_3-6Cycloalkyl, (ix) 1 to 3 ha
Rogen atom, mono- or di-C_1-6Alkylamino
Is C_1-6Alkoxy-C optionally having carbonyl_1-6
Alkoxy, (x) optionally halogenated C_{1- 6}Al
Kirthio, (xi) hydroxy, (xii) amino, (xiii) mono-
C_1-6Alkylamino, (xiv) di-C_1-6Alkylamino, (x
v) 5- or 6-membered cyclic amino, (xvi) C_1-6Alkyl-carbo
Nil, (xvii) carboxyl, (xviii) C_1-6Alkoxy-mosquito
Lubonyl, (xix) carbamoyl, (xx) thiocarbamoy
Le, (xxi) Mono-C_1-6Alkyl-carbamoyl, (xxii) di-
C_1-6Alkyl-carbamoyl, (xxiii) C_6-10Aryl-
Carbamoyl, (xxiv) sulfo, (xxv) C_1-6Alkylsul
Honil, (xxvi) C_6-10Aryl, (xxvii) C_6-10Aryl
Oxy, (xxviii) C_7-16Aralkyloxy and (xxix)
May have a substituent selected from the group consisting of oxo
Black, oxygen atom, NR^{Four '}(R ^{Four '}Is a hydrogen atom or straight chain
Or branched C_1-6Alkyl group) and sulfur atom
May be through 1 to 3 heteroatoms selected from
A divalent straight chain C_{1 -6}A hydrocarbon group, where A is the nitrogen atom
Or CR⁷[R⁷Is (1) hydrogen atom, (2) halogen atom, (3) (i)
Halogen atom, (ii) C_1-6Alkylenedioxy, (iii)
Toro, (iv) cyano, (v) optionally halogenated C
_1-6Alkyl, (vi) optionally halogenated C_2-6A
Lucenyl, (vii) optionally halogenated C_2-6Al
Quinyl, (viii) C_3-6Cycloalkyl, (ix) 1 to 3
Halogen atom, mono- or di-C_1-6Alkylamino also
Or C_1-6Alkoxy-C optionally having carbonyl
_1-6Alkoxy, (x) optionally halogenated C_1-6A
Ruquilthio, (xi) hydroxy, (xii) amino, (xiii) mo
No-C_1-6Alkylamino, (xiv) di-C_1-6Alkylami
No, (xv) 5- or 6-membered cyclic amino, (xvi) C_1-6Alkyl-
Carbonyl, (xvii) carboxyl, (xviii) C_{1- 6}Arco
Xy-carbonyl, (xix) carbamoyl, (xx) thiocal
Bamoi, (xxi) Mono-C_1-6Alkyl-carbamoyl, (xx
ii) Ji-C_1-6Alkyl-carbamoyl, (xxiii) C_6-10Ants
-Carbamoyl, (xxiv) sulfo, (xxv) C_1-6Alkyl
Sulfonyl, (xxvi) C_6-10Aryl, (xxvii) C_6-10Ants
Oxy, (xxviii) C_7-16Aralkyloxy and (xxi
x) substituted with a group selected from the group consisting of oxo
Good c_1-6Alkyl group, C_2-6Alkenyl group, C_2-6Alkini
Lu group, C_3-6Cycloalkyl group, C_3-6With cycloalkyl groups
1 to 3 Cs_1-6A group which may have an alkoxy group
A group condensed with an benzene ring, C_6-14Aryl group or C
_7-16Aralkyl group, (4)-(C = O) -R⁹, -SO₂-R⁹, −SO-R⁹,
-(C = O) NR^TenR⁹,-(C = O) O-R⁹,-(C = S) O-R⁹Or- (C = S) NR
^TenR⁹(R⁹Is (a) hydrogen atom, (b) (i) halogen atom, (ii) C
_1-6Alkylenedioxy, (iii) nitro, (iv) cyano,
(v) C which may be halogenated_1-6Alkyl, (vi)
C, which may be rogenized_2-6Alkenyl, (vii) halo
C that may be genated_2-6Alkynyl, (viii) C_3-6Shi
Chloroalkyl, (ix) 1 to 3 halogen atoms, mono
-Or the -C_1-6Alkylamino or C_1-6Alkoxy
-C which may have carbonyl_1-6Alkoxy, (x)
C, which may be rogenized_1-6Alkylthio, (xi) hydr
Roxy, (xii) amino, (xiii) mono-C_1-6Alkylami
No, (xiv) di-C_1-6Alkylamino, (xv) 5- or 6-membered ring
Amino, (xvi) C_1-6Alkyl-carbonyl, (xvii) calc
Boxil, (xviii) C_1-6Alkoxy-carbonyl, (xix)
Carbamoyl, (xx) thiocarbamoyl, (xxi) mono-C_1-6
Alkyl-carbamoyl, (xxii) di-C_1-6Alkyl-cal
Bamoi, (xxiii) C_6-10Aryl-carbamoyl, (xxi
v) sulfo, (xxv) C_1-6Alkylsulfonyl, (xxvi) C_6-10
Aryl, (xxvii) C_6-10Aryloxy, (xxviii) C
_7-16A group consisting of aralkyloxy and (xxix) oxo
C optionally substituted with a group selected from_1-6Alkyl group,
C_2-6Alkenyl group, C_2-6Alkynyl group, C_3-6Cycloal
Kill group, C_3-6Cycloalkyl group and 1 to 3 C_1-6A
Condensed with a benzene ring that may have a lucoxy group
Base, C_6-14Aryl group or C_7-16Aralkyl group, also
Is (c) -OR¹¹(R¹¹Is a hydrogen atom, or (i) a halogen atom,
(ii) C_1-6Alkylenedioxy, (iii) nitro, (iv) sia
No, (v) optionally halogenated C_1-6Alkyl, (v
i) C which may be halogenated_2-6Alkenyl, (vi
i) C which may be halogenated_2-6Alkynyl, (vii
I c_3-6Cycloalkyl, (ix) 1 to 3 halogens
Atom, mono- or di-C_1-6Alkylamino or C
_1-6Alkoxy-C optionally having carbonyl_1-6Al
Coxy, (x) optionally halogenated C_1-6Archi
Ruthio, (xi) hydroxy, (xii) amino, (xiii) mono-C
_1-6Alkylamino, (xiv) di-C_1-6Alkylamino, (x
v) 5- or 6-membered cyclic amino, (xvi) C_1-6Alkyl-carbo
Nil, (xvii) carboxyl, (xviii) C_1-6Alkoxy-mosquito
Lubonyl, (xix) carbamoyl, (xx) thiocarbamoy
Le, (xxi) Mono-C_1-6Alkyl-carbamoyl, (xxii) di-
C_1-6Alkyl-carbamoyl, (xxiii) C_6-10Aryl-mosquito
Lubamoyl, (xxiv) sulfo, (xxv) C_1-6Alkyl sulfo
Nil, (xxvi) C_6-10Aryl, (xxvii) C_6-10Ario
Kish, (xxviii) C_7-16Aralkyloxy and (xxix) oki
C optionally substituted with a group selected from the group consisting of
_1-6Alkyl group, C_2-6Alkenyl group, C_2-6Alkynyl
Base, C_3-6Cycloalkyl group, C_3-6Cycloalkyl group and 1
To 3 Cs_1-6Benzo which may have an alkoxy group
A group fused with a zen ring, C_6-14Aryl group or C_7-16
R represents an aralkyl group)^TenIs hydrogen
Atom or C_1-6Acyl represented by (indicating an alkyl group)
Group, or (5) -OR¹²(R¹²Is a hydrogen atom, or (i) a halogen
Atom, (ii) C_1-6Alkylenedioxy, (iii) nitro,
(iv) cyano, (v) optionally halogenated C_1-6Al
Kill, (vi) optionally halogenated C_2-6Archeni
, (Vii) optionally halogenated C_2-6Alkini
Le, (viii) C_3-6Cycloalkyl, (ix) 1 to 3 ha
Rogen atom, mono- or di-C _1-6Alkylamino
Is C_1-6Alkoxy-C optionally having carbonyl_1-6
Alkoxy, (x) optionally halogenated C_1-6Al
Kirthio, (xi) hydroxy, (xii) amino, (xiii) mono-
C_1-6Alkylamino, (xiv) di-C_1-6Alkylamino, (x
v) 5- or 6-membered cyclic amino, (xvi) C_1-6Alkyl-carbo
Nil, (xvii) carboxyl, (xviii) C_1-6Alkoxy-mosquito
Lubonyl, (xix) carbamoyl, (xx) thiocarbamoy
Le, (xxi) Mono-C_1-6Alkyl-carbamoyl, (xxii) di-
C_1-6Alkyl-carbamoyl, (xxiii) C_6-10Aryl-mosquito
Lubamoyl, (xxiv) sulfo, (xxv) C_{1- 6}Alkyl sulfo
Nil, (xxvi) C_6-10Aryl, (xxvii) C_6-10Ario
Kish, (xxviii) C_7-16Aralkyloxy and (xxix) oki
C optionally substituted with a group selected from the group consisting of
_1-6Alkyl group, C_2-6Alkenyl group, C_2-6Alkynyl
Base, C_{3 -6}Cycloalkyl group, C_3-6Cycloalkyl group and 1
To 3 Cs_1-6May have an alkoxy group
A group condensed with a benzene ring, C_6-14Aryl group or C
_7-16Represents a group represented by (which represents an aralkyl group)
Then R¹, R²And R³Are (1) hydrogen atom and (2) halogen
Atom, (3) (i) halogen atom, (ii) C_1-6Alkylene geo
Xy, (iii) nitro, (iv) cyano, (v) halogenated
May be C_1-6Alkyl, (vi) even if halogenated
Good c_2-6Alkenyl, (vii) may be halogenated
I C_2-6Alkynyl, (viii) C_3-6Cycloalkyl, (ix) 1
To 3 halogen atoms, mono- or di-C_1-6Archi
Lumino or C_1-6Having an alkoxy-carbonyl
May be C_1-6Alkoxy, (x) halogenated
Moyo C_1-6Alkylthio, (xi) hydroxy, (xii) ami
No, (xiii) Mono-C_1-6Alkylamino, (xiv) di-C_1-6A
Rukylamino, (xv) 5- or 6-membered cyclic amino, (xvi) C
_1-6Alkyl-carbonyl, (xvii) carboxyl, (xvii
I c_1-6Alkoxy-carbonyl, (xix) carbamoyl, (x
(x) thiocarbamoyl, (xxi) mono-C_1-6Alkyl-carb
Moyle, (xxii) di-C_1-6Alkyl-carbamoyl, (xxii
I c_6-10Aryl-carbamoyl, (xxiv) sulfo, (xxv) C
_1-6Alkylsulfonyl, (xxvi) C_6-10Aryl, (xxvi
I c_6-10Aryloxy, (xxviii) C_7-16Aralkyl Oki
Substituted with a group selected from the group consisting of Si and (xxix) oxo
May be C_{1 -6}Alkyl group, C_2-6Alkenyl group,
C_2-6Alkynyl group, C_3-6Cycloalkyl group, C_3-6Cyclo
Alkyl group and 1 to 3 C_1-6Having an alkoxy group
C, a group condensed with an benzene ring that may be present_6-14Aryl
Group or C_7-16Aralkyl group, (4)-(C = O) -R¹³, -SO₂-R
¹³, -SO-R¹³,-(C = O) NR¹⁴R¹³,-(C = O) O-R¹³,-(C = S) O-R
¹³Or- (C = S) NR¹⁴R¹³(R¹³Is (a) hydrogen atom, (b) (i)
Rogen atom, (ii) C_1-6Alkylenedioxy, (iii) nit
B, (iv) cyano, (v) optionally halogenated C_1-6
Alkyl, (vi) optionally halogenated C_2-6Arche
Nil, (vii) optionally halogenated C_2-6Alkini
Le, (viii) C_3-6Cycloalkyl, (ix) 1 to 3 ha
Rogen atom, mono- or di-C_1-6Alkylamino
Is C_1-6Alkoxy-C optionally having carbonyl_1-6
Alkoxy, (x) optionally halogenated C_1-6Al
Kirthio, (xi) hydroxy, (xii) amino, (xiii) mono-
C_1-6Alkylamino, (xiv) di-C_1-6Alkylamino, (x
v) 5- or 6-membered cyclic amino, (xvi) C_{1- 6}Alkyl-carbo
Nil, (xvii) carboxyl, (xviii) C_1-6Alkoxy-mosquito
Lubonyl, (xix) carbamoyl, (xx) thiocarbamoy
Le, (xxi) Mono-C_1-6Alkyl-carbamoyl, (xxii) di-
C_1-6Alkyl-carbamoyl, (xxiii) C_6-10Aryl-mosquito
Lubamoyl, (xxiv) sulfo, (xxv) C_1-6Alkyl sulfo
Nil, (xxvi) C_6-10Aryl, (xxvii) C_6-10Ario
Kish, (xxviii) C_7-16Aralkyloxy and (xxix) oki
C optionally substituted with a group selected from the group consisting of
_1-6Alkyl group, C_2-6Alkenyl group, C_2-6Alkynyl
Base, C_3-6Cycloalkyl group, C_3-6Cycloalkyl group and 1
To 3 Cs_1-6Benzo which may have an alkoxy group
A group fused with a zen ring, C_6-14Aryl group or C_7-16
Aralkyl group or (c) -OR¹⁵(R¹⁵Is a hydrogen atom,
Is (i) halogen atom, (ii) C_1-6Alkylenedioxy, (ii
i) nitro, (iv) cyano, (v) may be halogenated
I C_1-6Alkyl, (vi) optionally halogenated C_2-6
Alkenyl, (vii) optionally halogenated C_2-6A
Lucinyl, (viii) C_3-6Cycloalkyl, (ix) 1 to 3
Halogen atoms, mono- or di-C_1-6Alkylamino
Or C_1-6May have an alkoxy-carbonyl
I C_1-6Alkoxy, (x) optionally halogenated C
_1-6Alkylthio, (xi) hydroxy, (xii) amino, (xii
i) Mono-C_1-6Alkylamino, (xiv) di-C_1-6Alkyla
Mino, (xv) 5- or 6-membered cyclic amino, (xvi) C_1-6Archi
Le-carbonyl, (xvii) carboxyl, (xviii) C_1-6Al
Coxy-carbonyl, (xix) carbamoyl, (xx) thiocal
Bamoi, (xxi) Mono-C_1-6Alkyl-carbamoyl, (xx
ii) Ji-C_1-6Alkyl-carbamoyl, (xxiii) C_6-10Ants
-Carbamoyl, (xxiv) sulfo, (xxv) C_1-6Alkyl
Sulfonyl, (xxvi) C_6-10Aryl, (xxvii) C_6-10Ants
Oxy, (xxviii) C_7-16Aralkyloxy and (xx
ix) substituted with a group selected from the group consisting of oxo,
Moyo C_1-6Alkyl group, C_2-6Alkenyl group, C_2-6Archi
Nyl group, C_3-6Cycloalkyl group, C_3-6Cycloalkyl group
And 1 to 3 Cs_1-6May have an alkoxy group
A group condensed with a benzene ring, C_6-14Aryl group or C
_7-16R represents an aralkyl group)¹⁴Is
Hydrogen atom or C_1-6(Representing an alkyl group)
Group or (5) -OR¹⁶(R¹⁶Is a hydrogen atom or (i) halo
Gen atom, (ii) C_1-6Alkylenedioxy, (iii) nit
B, (iv) cyano, (v) optionally halogenated C_1-6
Alkyl, (vi) optionally halogenated C_2-6Arche
Nil, (vii) optionally halogenated C_2-6Alkini
Le, (viii) C_3-6Cycloalkyl, (ix) 1 to 3 ha
Rogen atom, mono- or di-C_1-6Alkylamino
Is C_1-6Alkoxy-C optionally having carbonyl_1-6
Alkoxy, (x) optionally halogenated C_1-6Al
Kirthio, (xi) hydroxy, (xii) amino, (xiii) mono-
C_1-6Alkylamino, (xiv) di-C_1-6Alkylamino, (x
v) 5- or 6-membered cyclic amino, (xvi) C_1-6Alkyl-carbo
Nil, (xvii) carboxyl, (xviii) C_1-6Alkoxy-mosquito
Lubonyl, (xix) carbamoyl, (xx) thiocarbamoy
Le, (xxi) Mono-C_1-6Alkyl-carbamoyl, (xxii) di-
C_1-6Alkyl-carbamoyl, (xxiii) C_6-10Aryl-mosquito
Lubamoyl, (xxiv) sulfo, (xxv) C_1-6Alkyl sulfo
Nil, (xxvi) C_6-10Aryl, (xxvii) C_6-10Ario
Kish, (xxviii) C_7-16Aralkyloxy and (xxix) o
May be substituted with groups selected from the group consisting of xoxo
C_1-6Alkyl group, C_2-6Alkenyl group, C_2-6Alkynyl
Base, C_{3 -6}Cycloalkyl group, C_3-6Cycloalkyl group and 1
To 3 Cs_1-6Benzo which may have an alkoxy group
A group fused with a zen ring, C_6-14Aryl group or C_7-16
R represents an aralkyl group)⁸Is hydrogen
Child, C_1-6Hydroxy optionally substituted with alkyl
[3] showing a group or a carboxyl group, or
The agent described in [4]; [6] Ar¹And Ar²Is a phenyl group and B ring is a formula

[Chemical 27] [Wherein Z ′ represents a methine group, Z ^{1 ′} and Z ^{2 ′} represent a methylene group or an ethylene group], X is a bond or an oxygen atom, and Y is — (CH ₂ ) _p1 A group represented by NH- (p1 is an integer of 1 to 6), A is CR ^{7 ''} (R ^{7 ''} is a hydrogen atom or a C _1-6 alkyl group), and R ¹ is (1) Hydrogen atom, (2) carboxyl or C _1-6 alkoxy-carbonyl optionally substituted C _1-6 alkyl group or (3) C _1-6 alkoxy-carbonyl optionally substituted C _1-6 A carbamoyl group which may have alkyl, an agent according to the above [3] or [4], wherein R ² is a hydrogen atom, R ³ is a hydrogen atom, and R ⁸ is a hydrogen atom; [7] The compound is 2- [ 6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazine-2-
[8] The compound is 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino], which is [2] -methylpropionic acid or a salt thereof; Imidazo [1,2-b] pyridazine-2-
[3] or [4] above, which is yl] -2-methylpropionic acid dihydrate;

[9] The above-mentioned [1] which is a preventive / therapeutic agent for c-Jun-related diseases
[10] The agent according to [1] above, which is a preventive / therapeutic agent for c-Jun N-terminal kinase-related diseases; [11] Acute pancreatitis, chronic pancreatitis, adult respiratory distress syndrome, scleroderma, deep skin Lupus erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, myasthenia gravis, multiple myeloma, acute myeloblastic leukemia, chronic sarcoma, Chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, wasting disease, Huntington's disease, diseases associated with ischemia / reperfusion in stroke, myocardial ischemia, ischemic heart disease, renal ischemia, neovascular glaucoma, infantile blood vessels The agent according to [1] above, which is a prophylactic / therapeutic agent for tumors, blood vessel growth, cardiac hypertrophy, abnormal immune response, fever, cell aging, or apoptosis-related diseases; [12] The above-mentioned [1], which is an agent for improving nasal congestion. Agent; [13] Formula for mammals

[Chemical 28] [In the formula, Ar^aAnd Ar^bEach has a substituent
Good aromatic group, Ar ^aAnd Ar^bIs adjacent to a carbon atom
A condensed ring group may be formed on B^aRing has substituents
A nitrogen-containing heterocycle which may be present, X^aAnd Y^aIs that
Same or different (1) bond, (2) oxygen atom, (3) S
(O)_p(P is an integer from 0 to 2), (4) NR ^d(R^dIs water
(Representing an elementary atom or a lower alkyl group) or (5) substituent
Optionally having 1 to 3 heteroatoms
A divalent linear lower hydrocarbon group which may be present is represented by A^aThe ring is
Represents a 5-membered ring which may have a substituent, R^aAnd R^bIs
The same or different (1) hydrogen atom, (2) halogen
Atom, (3) a hydrocarbon group which may have a substituent, (4)
Sil group or (5) hydroxy which may have a substituent
Represents a group, R^cIs substituted with (1) hydrogen atom, (2) lower alkyl group
Optionally hydroxyl group or (3) carboxyl
Indicates a group. ] The compound or its salt represented by
C- characterized by administering an effective amount of a prodrug of
Jun N-terminal kinase activation inhibition method; [14] For mammals, the formula

[Chemical 29] [In the formula, Ar^aAnd Ar^bEach has a substituent
Good aromatic group, Ar ^aAnd Ar^bIs adjacent to a carbon atom
A condensed ring group may be formed on B^aRing has substituents
A nitrogen-containing heterocycle which may be present, X^aAnd Y^aIs that
Same or different (1) bond, (2) oxygen atom, (3) S
(O)_p(P is an integer from 0 to 2), (4) NR ^d(R^dIs water
(Representing an elementary atom or a lower alkyl group) or (5) substituent
Optionally having 1 to 3 heteroatoms
A divalent linear lower hydrocarbon group which may be present is represented by A^aThe ring is
Represents a 5-membered ring which may have a substituent, R^aAnd R^bIs
The same or different (1) hydrogen atom, (2) halogen
Atom, (3) a hydrocarbon group which may have a substituent, (4)
Sil group or (5) hydroxy which may have a substituent
Represents a group, R^cIs substituted with (1) hydrogen atom, (2) lower alkyl group
Optionally hydroxyl group or (3) carboxyl
Indicates a group. ] The compound or its salt represented by
Acute characterized by administering an effective amount of a prodrug of
Pancreatitis, chronic pancreatitis, adult respiratory distress syndrome, scleroderma, deep-seated
Lupus erythematosus, chronic thyroiditis, Graves disease, autoimmune
Gastritis, autoimmune neutropenia, thrombocytopenia, severe muscle
Asthenia, multiple myeloma, acute myeloblastic leukemia, chronic meat
Tumor, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, wasting
Ischemia / reperfusion in sexually transmitted diseases, Huntington's disease, and stroke
Diseases, myocardial ischemia, ischemic heart disease, renal ischemia, blood vessels
Neonatal glaucoma, infantile hemangiomas, blood vessel proliferation, cardiac hypertrophy, abnormal immunity
Of epidemiological response, fever, cell senescence or apoptosis related diseases
Prevention / treatment method and nasal congestion improvement method; [15] Production of c-Jun N-terminal kinase activation inhibitor
Formula for building

[Chemical 30] [In the formula, Ar^aAnd Ar^bEach has a substituent
Good aromatic group, Ar ^aAnd Ar^bIs adjacent to a carbon atom
A condensed ring group may be formed on B^aRing has substituents
A nitrogen-containing heterocycle which may be present, X^aAnd Y^aIs that
Same or different (1) bond, (2) oxygen atom, (3) S
(O)_p(P is an integer from 0 to 2), (4) NR ^d(R^dIs water
(Representing an elementary atom or a lower alkyl group) or (5) substituent
Optionally having 1 to 3 heteroatoms
A divalent linear lower hydrocarbon group which may be present is represented by A^aThe ring is
Represents a 5-membered ring which may have a substituent, R^aAnd R^bIs
The same or different (1) hydrogen atom, (2) halogen
Atom, (3) a hydrocarbon group which may have a substituent, (4)
Sil group or (5) hydroxy which may have a substituent
Represents a group, R^cIs substituted with (1) hydrogen atom, (2) lower alkyl group
Optionally hydroxyl group or (3) carboxyl
Indicates a group. ] The compound or its salt represented by
Use of prodrugs of [16] Acute pancreatitis, chronic pancreatitis, adult respiratory distress syndrome, strong
Dermatosis, deep-seated lupus erythematosus, chronic thyroiditis, Graves
Disease, autoimmune gastritis, autoimmune neutropenia, platelets
, Myasthenia gravis, multiple myeloma, acute myeloblast
Leukemia, chronic sarcoma, chronic myelogenous leukemia, metastatic melanoma, tumor
In positive sarcoma, wasting disease, Huntington's disease, stroke
Diseases associated with ischemia / reperfusion, myocardial ischemia, ischemic heart disease
Patient, renal ischemia, neovascular glaucoma, infantile hemangiomas, vascular increase
Breeding, cardiac hypertrophy, abnormal immune response, fever, cellular senescence or apo
Manufacture of preventive / therapeutic agents for tosis related diseases and nasal congestion improving agent
Formula for building

[Chemical 31] [In the formula, Ar^aAnd Ar^bEach has a substituent
Good aromatic group, Ar ^aAnd Ar^bIs adjacent to a carbon atom
A condensed ring group may be formed on B^aRing has substituents
A nitrogen-containing heterocycle which may be present, X^aAnd Y^aIs that
Same or different (1) bond, (2) oxygen atom, (3) S
(O)_p(P is an integer from 0 to 2), (4) NR ^d(R^dIs water
(Representing an elementary atom or a lower alkyl group) or (5) substituent
Optionally having 1 to 3 heteroatoms
A divalent linear lower hydrocarbon group which may be present is represented by A^aThe ring is
Represents a 5-membered ring which may have a substituent, R^aAnd R^bIs
The same or different (1) hydrogen atom, (2) halogen
Atom, (3) a hydrocarbon group which may have a substituent, (4)
Sil group or (5) hydroxy which may have a substituent
Represents a group, R^cIs substituted with (1) hydrogen atom, (2) lower alkyl group
Optionally hydroxyl group or (3) carboxyl
Indicates a group. ] The compound or its salt represented by
Use of prodrugs of [17] (1) Antihistamine action and / or eosinophil acid
Inhibition of chemotactic chemotaxis and (2) c-Jun N-terminal kinase activity
A compound or a prodrug thereof having an inhibitory action on
A c-Jun N-terminal kinase activation inhibitor comprising: [18] (1) Antihistamine action and / or eosinate
Inhibition of chemotactic chemotaxis and (2) c-Jun N-terminal kinase activity
A compound or a prodrug thereof having an inhibitory action on
A TNF-α inhibitor comprising: [19] (1) Antihistamine action and / or eosinate
Inhibition of chemotactic chemotaxis and (2) c-Jun N-terminal kinase activity
A compound or a prodrug thereof having an inhibitory action on
Containing acute pancreatitis, chronic pancreatitis, adult respiratory distress symptoms
Flock, scleroderma, deep erythematous lupus, chronic thyroiditis, gray
Buss disease, autoimmune gastritis, autoimmune neutropenia, blood
Parenchyma, myasthenia gravis, multiple myeloma, acute myeloblast
Spherical leukemia, chronic sarcoma, chronic myelogenous leukemia, metastatic melanoma
Tumor, Kaposi's sarcoma, wasting disease, Huntington's disease, stroke
Associated with ischemia / reperfusion, myocardial ischemia, ischemic
Heart disease, renal ischemia, neovascular glaucoma, infantile hemangiomas, blood vessels
Proliferation, cardiac hypertrophy, abnormal immune response, fever, cell aging or
Prophylactic / therapeutic agent for porosis-related diseases and nasal congestion improving agent; [20] (1) Antihistamine action and / or eosinophil acid
Inhibition of chemotactic chemotaxis and (2) c-Jun N-terminal kinase activity
Which has an inhibitory effect on oxidization and (3) an inhibitory effect on TNF-α
Pancreatitis, which contains a compound or its prodrug
Pancreatitis, adult respiratory distress syndrome, scleroderma, deep erythematous wolf
Acne, chronic thyroiditis, Graves disease, autoimmune gastritis, autologous
Autoimmune neutropenia, thrombocytopenia, myasthenia gravis,
Multiple myeloma, acute myeloblastic leukemia, chronic sarcoma, chronic
Myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, wasting disease,
Huntington's disease, a disease associated with ischemia / reperfusion in stroke
Patient, myocardial ischemia, ischemic heart disease, renal ischemia, neovascularization within the glaucoma
Disorders, infantile hemangiomas, blood vessel proliferation, cardiac hypertrophy, abnormal immune response,
Prevention and cure of fever, cell aging or diseases related to apoptosis
Remedies and nasal congestion improving agents; [21] On mammals, (1) antihistamine action and
And / or eosinophil chemotaxis inhibitory effect and (2) c-Jun N
A compound having the activity of inhibiting terminal kinase activation or its
C- characterized by administering an effective amount of a prodrug of
Jun N-terminal kinase activation inhibition method; [22] For mammals (1) antihistamine action and
And / or eosinophil chemotaxis inhibitory effect and (2) c-Jun N
A compound having the activity of inhibiting terminal kinase activation or its
Is characterized by administering an effective amount of a prodrug of
Pancreatitis, chronic pancreatitis, adult respiratory distress syndrome, scleroderma, deep-seated
Lupus erythematosus, chronic thyroiditis, Graves' disease, autoimmunity
Gastritis, autoimmune neutropenia, thrombocytopenia, severe
Myasthenia gravis, multiple myeloma, acute myeloblastic leukemia, chronic
Sarcoma, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, disappearance
Ischemia / relapse in attrition, Huntington's disease, and stroke
Diseases associated with flow, myocardial ischemia, ischemic heart disease, renal ischemia, blood
Neovascular glaucoma, infantile hemangiomas, blood vessel proliferation, cardiac hypertrophy, abnormalities
Immune response, fever, cell aging or apoptosis related diseases
Prevention and treatment methods and nasal congestion improvement methods; [23] Production of c-Jun N-terminal kinase activation inhibitor
(1) antihistamine action and / or eosinophils for
Chemical migration inhibition and (2) c-Jun N-terminal kinase activation
Use of a compound having an inhibitory action or a prodrug thereof
for; [24] Acute pancreatitis, chronic pancreatitis, adult respiratory distress syndrome, strong
Dermatosis, deep-seated lupus erythematosus, chronic thyroiditis, Graves
Disease, autoimmune gastritis, autoimmune neutropenia, platelets
, Myasthenia gravis, multiple myeloma, acute myeloblast
Leukemia, chronic sarcoma, chronic myelogenous leukemia, metastatic melanoma, tumor
In positive sarcoma, wasting disease, Huntington's disease, stroke
Diseases associated with ischemia / reperfusion, myocardial ischemia, ischemic heart disease
Patient, renal ischemia, neovascular glaucoma, infantile hemangiomas, vascular increase
Breeding, cardiac hypertrophy, abnormal immune response, fever, cellular senescence or apo
Manufacture of preventive / therapeutic agents for tosis related diseases and nasal congestion improving agent
(1) antihistamine action and / or for producing
Eosinophil chemotaxis inhibitory effect and (2) c-Jun N-terminal kinase
A compound having an activation inhibitory effect or its prodrug
Use of [25] Antihistamine and c-Jun N-terminal kinase activation
In combination with inhibitors or (and) TNF-α inhibitors
Medicines; [26] Antihistamine and c-Jun N-terminal kinase activation
In combination with inhibitors or (and) TNF-α inhibitors
A drug for anti-allergy; [27] Antihistamine and c-Jun N-terminal kinase activation
Chronic urticaria, atopic skin in combination with inhibitors
Dermatitis, allergic rhinitis, allergic conjunctivitis, hypersensitivity
Pneumonitis, eczema, herpetic dermatitis, psoriasis, eosinophilic pneumonia (PI
E syndrome), chronic obstructive pulmonary disease (COPD) or asthma
Medicine for prevention / treatment and improvement of nasal congestion; [28] An effective amount of an antihistamine for mammals
Combined with an effective amount of c-Jun N-terminal kinase activation inhibitor
Prevention and cure of allergies characterized by combined administration
Treatment method; [29] Effective dose of antihistamine to mammal
Combined with an effective amount of c-Jun N-terminal kinase activation inhibitor
Chronic urticaria and atopy characterized by combined administration
Dermatitis, allergic rhinitis, allergic conjunctivitis, hypersensitivity
Aggressive pneumonitis, eczema, herpetic dermatitis, psoriasis, eosinophilic pneumonia
(PIE syndrome), chronic obstructive pulmonary disease (COPD) or asthma
Prevention and treatment methods and nasal congestion improvement methods; [30] Anti-hista for producing a drug for anti-allergy
Use of a mining agent with a c-Jun N-terminal kinase activation inhibitor; [31] Chronic urticaria, atopic dermatitis, allergic
Rhinitis, allergic conjunctivitis, hypersensitivity pneumonitis, eczema, herpes
Dermatitis, psoriasis, eosinophilic pneumonia (PIE syndrome), chronic closure
Drugs for the prevention and treatment of obstructive pulmonary disease (COPD) or asthma
Antihistamine and c-
Use with Jun N-terminal kinase activation inhibitors, etc.

In the above formula (A), Ar ^a and Ar ^b represent “an aromatic group which may have a substituent”, and Ar ^a and Ar ^b together with an adjacent carbon atom form a condensed ring group. May be. Ar ^a
Examples of the "optionally substituted aromatic group" represented by Ar ^b and Ar ^b include, for example, "an optionally substituted aromatic group represented by Ar ¹ and Ar ² described below. And the like. When Ar ^a and Ar ^b form a condensed ring group with adjacent carbon atoms, for example, the same as the case where Ar ¹ and Ar ² described later form a condensed ring group with adjacent carbon atoms can be mentioned.

In the above formula (A), ring B ^a represents a “nitrogen-containing heterocycle which may have a substituent”. Examples of the “nitrogen-containing heterocyclic ring which may have a substituent” represented by B ^a ring include
The same thing as the "nitrogen-containing heterocycle which may have a substituent" represented by ring B is mentioned.

In the above formula (A), X ^a and Y ^a 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 ^d (R ^d represents a hydrogen atom or a lower alkyl group) or (5) may have a substituent, and has 1 to 3 hetero atoms. It represents a divalent linear lower hydrocarbon group which may be interposed. Examples of the lower alkyl group represented by R ^d include linear or branched C _1- , such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl. ₆ Alkyl groups are used. The “divalent straight-chain lower hydrocarbon group optionally having 1 to 3 heteroatoms” represented by X ^a and Y ^a is described below.
Examples thereof include the same as the "divalent linear lower hydrocarbon group optionally having 1 to 3 heteroatoms" represented by X and Y.

In the above formula (A), ring A ^a represents a “5-membered ring which may have a substituent”. Examples of the “5-membered ring optionally having substituent (s)” represented by ring A ^a include compounds represented by the formula:

[Chemical 32] And a ring represented by (including a resonance structure when a resonance structure is present). These rings may have a substituent at a substitutable position, and as the substituent,
(1) hydrogen atom, (2) halogen atom (for example, fluorine, chlorine, bromine, iodine), (3) hydrocarbon group optionally having a substituent, (4) acyl group, (5) substituent Examples thereof include a hydroxy group which may have and a (6) oxo group. The "hydrocarbon group optionally having substituent (s)", "acyl group" and "hydroxy group optionally having substituent (s)"
Examples of the same as the "hydrocarbon group which may have a substituent", "acyl group" and "hydroxy group which may have a substituent" represented by R ¹ described later. To be

In the formula (A), R ^a and R ^b are the same or different and each represents (1) a hydrogen atom, (2) a halogen atom (for example, fluorine, chlorine, bromine, iodine) and (3) a substituent. A hydrocarbon group which may have, (4) an acyl group or (5) a hydroxy group which may have a substituent is shown. “A hydrocarbon group which may have a substituent” represented by R ^a and R ^b ,
The "acyl group" and "hydroxy group optionally having substituents" include R ¹ , R ² and R ³ described later "hydrocarbon group optionally having substituents", "Acyl group" and "hydroxy group optionally having substituent (s)"
The same thing as is mentioned.

In the above formula (A), R ^c is (1) a hydrogen atom, (2) a hydroxy group which may be substituted with a lower alkyl group, or
(3) Indicates a carboxyl group. ^Examples of the "hydroxy group optionally substituted with a lower alkyl group" represented by R ^c include
Examples thereof include the same ones as the “hydroxy group optionally substituted with lower alkyl group” represented by R ⁸ described later.

Formula (A)

[Chemical 33] [In the formula, each symbol has the same meaning as described above. ] As the compound represented by the formula or a salt thereof, specifically, the compound represented by the formula (I)

[Chemical 34] [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 (1) bond, (2) oxygen atom, (3) S (O)_p
(P is an integer from 0 to 2), (4) NR^Four(R^FourIs hydrogen
Child or lower alkyl group) or (5)
Optionally via one to three heteroatoms
Is a divalent straight chain lower hydrocarbon group, A is (1) nitrogen
Atom or (2) CR⁷(R⁷Is hydrogen atom, halogen atom, substitution
Optionally substituted hydrocarbon group, acyl group or substituted
Represents a hydroxy group which may have a group),
R¹, R²And R³Are the same or different (1) hydrogen
Atom, (2) halogen atom, (3) may have a substituent
Having a hydrocarbon group, (4) acyl group or (5) substituent
Shows a good hydroxy group, R⁸Is (1) hydrogen atom, (2) lower
A hydroxy group which may be substituted with an alkyl group or
(3) Indicates a carboxyl group. ] The compound represented by
Is its salt and formula (II)

[Chemical 35] [A 'ring is a formula

[Chemical 36] (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, and R ^21b is a hydrogen atom, a halogen atom, or a substituent. Represents a hydrocarbon group, an acyl group or a hydroxy group which may have a substituent), and Ar ¹¹ and Ar ¹² each represent an aromatic group which may have a substituent. Shown, Ar ¹¹ and Ar ¹² may form a condensed ring group with the adjacent carbon atom, B'ring represents a nitrogen-containing heterocycle which may have a substituent, X'and Y '
Are the same or different (1) bond, (2) oxygen atom, (3) S (O) _q (q is an integer of 0 to 2), (4) NR ²⁴
(R ²⁴ represents a hydrogen atom or a lower alkyl group) or
(5) optionally having a substituent, hetero atom 1 to 3
R ²² and R ²³ are the same or different and each has (1) a hydrogen atom, (2) a halogen atom, and (3) a substituent. Optionally a hydrocarbon group, (4) an acyl group or (5) represents a hydroxy group which may have a substituent, R ²⁷ is (1) a hydrogen atom, (2)
It represents a hydroxy group which may be substituted with lower alkyl or a (3) carboxyl group. ] The compound or its salt represented by these is mentioned. The compounds represented by formula (I) and formula (II) or salts thereof will be described in detail below.

In the above formula (I), Ar ¹ and Ar ² represent “an aromatic group which may have a substituent”, and Ar ¹ and Ar ² together with an adjacent carbon atom form a condensed ring group. May be. Ar ¹
As the "aromatic group" represented by Ar ² and, for example,
(1) Monocyclic or condensed polycyclic aromatic hydrocarbon group, more specifically, phenyl, tolyl, xylyl, biphenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 1-anthryl, 2-anthryl , C _6-14 aryl group such as 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl (preferably phenyl, tolyl, xylyl, biphenyl, 1-naphthyl or 2 -Naphthyl etc., particularly preferably phenyl etc.) 6 to 14 membered monocyclic or condensed polycyclic aromatic hydrocarbon group, or (2) preferably selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom Is a monocyclic group (preferably 5 to 8 members) containing at least one (1 to 4), preferably 1 to 3 heteroatoms of 1 or 2 kinds, or The condensed aromatic heterocyclic group, more specifically, thiophene, benzo [b] thiophene, benzo [b] furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene , Thianthrene, furan, isoindolizine, xanthrene, 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
An aromatic heterocycle such as carboline, phenanthridine, acridine, phenazine, isothiazole, phenothiazine, isoxazole, furazan, phenoxazine or isochroman (preferably pyridine, thiophene or furan, more preferably pyridine), or One or more (preferably 1 or 2) of these rings (preferably the above-mentioned monocyclic heterocycle),
More preferably, it can be formed by removing any hydrogen atom from a ring formed by condensation with one aromatic ring (for example, the aromatic hydrocarbon group described above, preferably a benzene ring etc.) 1.
A valent group or the like is used. As the “aromatic group” of the “aromatic group which may have a substituent” represented by Ar ¹ and Ar ² , for example, a phenyl group and the like are 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, C _1-6 alkylenedioxy group such as methylenedioxy and ethylenedioxy, preferably C _1-3 alkylenedioxy group), (iii) nitro group, (iv) cyano group, (v) halogenated Optionally a lower alkyl group,
(vi) an optionally halogenated lower alkenyl group, (v
ii) an optionally halogenated lower alkynyl group, (vi
ii) a lower cycloalkyl group (for example, cyclopropyl,
Such as cyclobutyl, cyclopentyl, cyclohexyl
C _3-6 cycloalkyl group), (ix) optionally substituted lower alkoxy group, (x) optionally halogenated lower alkylthio group, (xi) hydroxy group, (xii) amino group, ( xiii) mono-lower alkylamino group (for example, mono-C _1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), (xiv) di-lower alkylamino group (for example, ,
Dimethylamino, diethylamino, dipropylamino,
Di-C _1-6 alkylamino group such as dibutylamino), (xv) 5- or 6-membered cyclic amino group (eg, morpholino, piperazin-1-yl, piperidino, pyrrolidine-1-)
And the like), (xvi) lower alkyl-carbonyl group (eg, C _1-6 alkyl-carbonyl group such as acetyl and propionyl), (xvii) carboxyl group, (xviii) lower alkoxy-carbonyl group (eg, methoxycarbonyl) , C _1-6 alkoxy-carbonyl groups such as ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl), (xix) carbamoyl group, (xx) thiocarbamoyl,
(xxi) mono-lower alkyl-carbamoyl group (for example, mono-C such as methylcarbamoyl and ethylcarbamoyl)
_1-6 alkyl-carbamoyl group), (xxii) di-lower alkyl-carbamoyl group (for example, di-C _1-6 alkylcarbamoyl group such as dimethylcarbamoyl, diethylcarbamoyl, etc.), (xxiii) aryl-carbamoyl (eg, , C _6-10 aryl-carbamoyl such as phenylcarbamoyl and naphthylcarbamoyl), (xxiv) sulfo group, (xxv) lower alkylsulfonyl group (for example, C _1-6 alkylsulfonyl group such as methylsulfonyl and ethylsulfonyl) , (Xxvi) aryl groups (for example, C _6-10 aryl groups such as phenyl and naphthyl), (xxvii) aryloxy groups (for example, C _6-10 aryloxy groups such as phenoxy and naphthyloxy), (xxviii ) An aralkyloxy group (for example, a C _7-16 aralkyloxy group such as benzyloxy) is used.

The above-mentioned "optionally halogenated lower alkyl group" is, for example, a lower alkyl group optionally having 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) ( For example, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, C _1-6 alkyl groups such as hexyl) and the like, and specific examples include methyl, fluoromethyl, chloromethyl, difluoromethyl, Trichloromethyl, trifluoromethyl, ethyl,
2-bromoethyl, 2,2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, Pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-
Trifluorohexyl or the like is used. As the above-mentioned "optionally halogenated lower alkenyl group" and "optionally halogenated lower alkynyl group",
For example, a lower alkenyl group optionally having 1 to 3 halogen atoms (eg fluorine, chlorine, bromine, iodine) (eg vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4- Penten-1-yl, 5-hexene
A C _2-6 alkenyl group such as 1-yl) and a lower alkynyl group optionally having 1 to 3 halogen atoms (eg fluorine, chlorine, bromine, iodine) (eg,
2-butyn-1-yl, 4-pentyn-1-yl, 5-hex-1-
C _2-6 alkynyl group such as yl) and the like are used.
Examples of the "optionally substituted lower alkoxy group" include 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine), mono- or di-lower alkylamino groups (eg, methylamino). , Dimethylamino,
Mono- or di-C such as ethylamino, dimethylamino
_1-6 alkylamino group etc.) or a lower alkoxy-carbonyl group (eg C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl etc.) which may have a lower alkoxy group (eg methoxy,
Ethoxy, propoxy, isopropoxy, n-butoxy,
C such as isobutoxy, sec-butoxy, tert-butoxy
_1-6 alkoxy group etc.) and the like are used. Examples of the “optionally halogenated lower alkylthio group” include a lower alkylthio group optionally having 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) (eg, methylthio). C _1-6 such as, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, etc.
Alkylthio group etc.), and specific examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio, etc. .

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

[Chemical 37] [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 (I), 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 nitrogen atom, oxygen atom, sulfur atom and the like. An optionally used 3- to 13-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 the other atom of ring B. Specifically, for example

[Chemical 38] Such as 3 to 9 members (more preferably 3 to 6 members)
And a nitrogen-containing heterocyclic group are preferred. Examples of the substituent of the nitrogen-containing heterocycle represented by ring B include Ar ¹ and Ar ² described above.
In addition to the “substituent” of the “aromatic group which may have a substituent” represented by, an oxo group and the like are used.

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

[Chemical Formula 39] [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 (I), X and Y are the same or different and each is (1) a bond, (2) an oxygen atom, (3) S (O) _p (p is an integer of 0 to 2) , (4) NR ⁴ (R ⁴ represents a hydrogen atom or a lower alkyl group) or (5) a divalent straight chain which may have a substituent and may have 1 to 3 hetero atoms. A lower chain hydrocarbon group is shown. Examples of the lower alkyl group represented by R ⁴ include linear or branched C _1- , such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl. ₆ Alkyl groups are used.

“Heteroatoms 1 to 1” represented by X and Y
A divalent linear lower hydrocarbon group which may be intervened by three "
As a lower grade (C_1-6) Hydrocarbon same or different
Take one hydrogen atom that bonds to a carbon atom (two in total)
A group that can be removed, for example, an oxygen atom, NR^{Four '}(R^Four
'Represents a hydrogen atom or a lower alkyl group) and sulfur
Contains a heteroatom selected from atoms in the hydrocarbon chain
The group which may be shown is shown. R^{Four '}A lower alkyl group represented by
Are, for example, methyl, ethyl, propyl, isop
Ropil, butyl, isobutyl, sec-butyl, tert-butyl
Straight-chain or branched C such as le, pentyl and hexyl
_1-6An alkyl group or the like is used. "Bivalent linear lower
Specifically, as a “hydrocarbon group”, (i) C_1-6Alkylene group
(For example, -CH₂-,-(CH₂)₂-,-(CH₂)₃-,-(CH₂)_Four-,-(C
H₂) _Five-,-(CH₂)₆-Etc), (ii) C_2-6Alkenylene group (eg
For example, -CH = CH-, -CH = CH-CH₂-, -CH₂-CH = CH-CH₂-,-(C
H₂)₂-CH = CH-CH₂-,-(CH₂)₂-CH = CH- (CH₂)₂-,-(CH₂)₃-CH
= CH-CH₂-Etc), (iii) C_2-6Alkynylene groups (eg-
C≡C-, -C≡C-CH₂-, -CH₂-C≡C-CH₂-,-(CH₂)₂-C≡C-CH
₂-,-(CH₂)₂-C≡C- (CH₂)₂-,-(CH₂)₃-C≡C-CH₂-Such)
Are used. “Hetero atom 1 represented by X and Y
To 3 divalent straight chain lower hydrocarbons
Examples of the “substituent” of the “primitive group” include the aforementioned Ar¹And A
r²Of the "aromatic group which may have a substituent" represented by
In addition to “substituent”, oxo group and the like are used, but in particular,
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.
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 40] (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 methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
A linear or branched C _1-4 alkyl group such as butyl is used.

Examples of Y include (i) C _1-6 alkylene group, (ii)-(CH ₂ ) _p1 O-, (iii)-(CH ₂ ) _p1 NH-, (iv)-(C
H ₂ ) _p1 S-, (v)-(CH ₂ ) _q1 CH (OH) (CH ₂ ) _q2 O-, (vi)-(CH ₂ ).
_q1 CH (OH) (CH ₂ ) _{q2 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 -,} (xiii) - (CH 2) q1 O (CH 2) q2 NH- or (xiv) -
(CH ₂ ) _q1 O (CH ₂ ) _q2 S- (p1 represents an integer of 1 to 6, q1
And q2 each represent an integer of 1 to 3). Among them, as Y, for example, a bond,-(CH ₂ ) ₂ -O-,-(CH 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- (CH ₂ ) ₂ -O-,-(CH ₂ ) ₂ -O- (CH ₂ ) _2-
S- and the like are preferred.

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. The “hydrocarbon group” represented by R ⁷ is, for example, 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 alkoxy group, etc.) may cyclohexyl optionally condensed with benzene ring which may have a etc. C _3-6 cycloalkyl group)], e) an aryl group (e.g., 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 A group [preferably a lower aralkyl group (eg, benzyl,
Phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-
C _7-16 aralkyl groups such as naphthylmethyl, 2-phenylethyl, 2-diphenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, and the like, more preferably Benzyl group)] and the like are preferable. The “substituent” of the “hydrocarbon group” represented by R ⁷ includes, for example, Ar ¹ and Ar ² described above.
In addition to the “substituent” of the “optionally substituted aromatic group” represented by, an oxo group (excluding the case where a hydrocarbon group and an oxo group form an acyl group) and the like are used. To be

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 has a hydrogen atom, an optionally substituted hydrocarbon group or a substituent. Optionally a hydroxy group, R ¹⁰ is a hydrogen atom or a lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
C _1-6 alkyl groups such as tert-butyl, pentyl, hexyl and the like, particularly C _1-3 alkyl groups such as methyl, ethyl, propyl and isopropyl 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. "Hydrocarbon group" represented by R ⁹
Represents a group obtained by removing one hydrogen atom from a hydrocarbon compound, and examples thereof include an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group,
Examples thereof include chain (linear or branched) or cyclic hydrocarbon groups such as aralkyl groups. Specifically, R ⁷
The "hydrocarbon group" and the like are exemplified. Among them, a chain or cyclic hydrocarbon group having 1 to 16 carbon atoms is preferable, and a lower (C _1-6 ) alkyl group is particularly preferable.
Examples of the “substituent” which the “hydrocarbon group” represented by R ⁹ may have include, for example, the “aromatic group which may have a substituent” 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,
The same ones as the “hydroxy group optionally having substituent (s)” represented by R ⁷ described later are used. Examples of the “hydroxy group optionally having a substituent” represented by R ⁷ include
For example, instead 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 _1-6 alkoxy-carbonyl group or (6) carboxyl group is preferable, particularly a hydrogen atom, a halogen atom,
A C _1-6 alkyl group, a C _1-6 alkoxy-carbonyl group or a carboxyl group is preferred. As A, a nitrogen atom or CR ^{7 '} (R ^{7 '} represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy-carbonyl group or a 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 formula (I), R ¹ , R ² and R ³ are the same or different and each is (1) a hydrogen atom, (2) a halogen atom,
(3) A hydrocarbon group which may have a substituent, (4) an acyl group or (5) a hydroxy group which may have a substituent. Examples of the “halogen atom” represented by R ¹ , R ² and R ³ include fluorine, chlorine, bromine and iodine. R ¹ , R ²
As the "hydrocarbon group which may have a substituent" represented by R ³ and, for example, the "hydrocarbon group which may have a substituent" represented by R ⁷ and the like are used. To be R ¹ ,
Examples of the “acyl group” represented by R ² and R ³ include
The “acyl group” represented by R ⁷ is used. R ¹ ,
As the “optionally substituted hydroxy group” represented by R ² and R ³ , for example, the “optionally substituted hydroxy group” represented by R ⁷ is used. To be R ¹ , R ² and R ³ are the same or different (1) a hydrogen atom, (2) a carboxyl group or a C _1-6 alkoxy-carbonyl optionally substituted C _1-6 alkyl group, ( 3) C _1-6 alkoxy group, (4) C _1-6 alkoxy-carbonyl group, (5) carboxyl group or (6) C _6-14 aryl group (especially phenyl) is preferable, (1) hydrogen atom, ( 2) carboxyl group or a C _1-6 alkoxy - optionally substituted with a carbonyl C _1-6 alkyl group, (3) C _1-6 alkoxy group,
More preferred is (4) C _1-6 alkoxy-carbonyl group or (5) carboxyl group. R ¹ is (1) hydrogen atom, (2) (i) carboxyl, (ii) C _1-6 alkoxy-carbonyl, (iii) hydroxy or (iv) mono- or di-C _1-6
A C _1-6 alkyl group which may be substituted with a group selected from the group consisting of carbamoyl which may have alkyl,
(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 alkoxy-carbonyl group preferred such good C _3-6 cycloalkyl group optionally substituted by a carbonyl - in the optionally substituted C _1-6 carbamoyl group which may have an alkyl, or (8) C _1-6 alkoxy . R ² is also preferably a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy-carbonyl group or a carboxyl group. R ³ is preferably a hydrogen atom.

In the above formula, R ⁸ is (1) a hydrogen atom, (2) a hydroxy group optionally substituted with a lower alkyl group, or (3)
Indicates a carboxyl group. In the above formula, the “lower alkyl group” of the “hydroxy group optionally substituted with a lower alkyl group” represented by R ⁸ includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s
C such as ec-butyl, tert-butyl, pentyl, hexyl
_Examples include _1-6 alkyl groups. R ⁸ is preferably a hydrogen atom or a hydroxy group, and particularly preferably a hydrogen atom.

The compound represented by the formula (I) (hereinafter sometimes abbreviated as the compound (I) of the present invention) includes Ar ¹ and
Ar ² is selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to (1) a halogen atom or a phenyl group optionally substituted by C _1-6 alkyl, or (2) a carbon atom, 1
A 5- to 8-membered aromatic heterocyclic group containing 4 to 4 heteroatoms, wherein B ring is

[Chemical 41] [Wherein Z represents a nitrogen atom or a methine group, and Z ¹ and Z
² represents a hydroxy group, an oxo group or a linear C _1-4 alkylene group which may be substituted with a C _1-6 alkyl group], and X is a bond, an oxygen atom or NH
And Y is an (i) C _1-6 alkylene group, (ii)-(CH ₂ ) _p1 O-, (ii
i)-(CH ₂ ) _p1 NH-, (iv)-(CH ₂ ) _p1 S-, (v)-(CH ₂ ) _q1 CH (O
H) (CH ₂ ) _q2 O-, (vi)-(CH ₂ ) _q1 CH (OH) (CH ₂ ) _{q2 NH-} , (vii)
-(CH ₂ ) _q1 CH (OH) (CH ₂ ) _q2 S-, (viii)-(CH ₂ ) _p1 CONH-, (i
x) -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 -, (xiii) - (CH 2) q1
O (CH ₂ ) _q2 NH- or (xiv)-(CH ₂ ) _q1 O (CH ₂ ) _q2 S- (p1 is 1
To q6, q1 and q2 each represent an integer of 1 to 3), wherein A is a nitrogen atom or C
R ^{7 '} (R ^7'is a hydrogen atom, a halogen atom, a C _1-6 alkyl group,
C _1-6 alkoxy-carbonyl group or carbonyl group), and R ¹ is (1) hydrogen atom, (2) (i) carboxyl, (ii) C
_1-6 alkoxy-carbonyl, (iii) hydroxy or (i
v) C _1-6 alkyl group optionally substituted with a group selected from the group consisting of carbamoyl optionally having mono- or di-C _1-6 alkyl, (3) C _6-14 aryl group, (4) C _1-6
Alkoxy group, (5) C _1-6 alkoxy-carbonyl group, (6)
Substituted with a carbonyl - carboxyl group, (7) carboxyl or C _1-6 alkoxy - optionally substituted C _1-6 carbamoyl group which may have an alkyl carbonyl or (8) C _1-6 alkoxy, _Optionally substituted C _3-6 cycloalkyl group, R ² is hydrogen atom, C _1-6 alkyl group, C _1-6
An alkoxy-carbonyl or carboxyl group, R ³
Is preferably a hydrogen atom and R ⁸ is a hydrogen atom or a hydroxy group.

In particular, Ar ¹ and Ar ² are phenyl groups and the B ring is of the formula

[Chemical 42] [Wherein Z ′ represents a methine group, Z ^{1 ′} and Z ^{2 ′} represent a methylene group or an ethylene group (preferably an ethylene group)], and X represents a bond, an oxygen atom or NH
(Preferably a bond or an oxygen atom) and Y is-(CH ₂ ).
_p1 NH- (p1 represents an integer of 1 to 6), A is CR ^{7 ''} (R ^{7 ''} is a hydrogen atom or a C _1-6 alkyl group), and R ¹ is (1) hydrogen atom, (2) carboxyl or C
_1-6 Alkoxy-carbonyl optionally substituted C _1-6
Alkyl group or (3) carbamoyl group optionally having C _1-6 alkoxy-carbonyl optionally substituted C _1-6 alkyl, R ² is a hydrogen atom, R ³ is a hydrogen atom, A compound in which R ⁸ is a hydrogen atom is suitable.

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] pyridazine-
2-yl] -2-methylpropionic acid or its salt (particularly dihydrate), (3) N- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2] -b] pyridazine-2-carbonyl] glycine ethyl or its salt, (4) 2- [6- [3- [4
-(Diphenylmethoxy) piperidino] propylamino] -3-
Methylimidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate ethyl or its salt (particularly dihydrochloride), (5) 2
Ethyl-[6- [3- [4- (diphenylmethylamino) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-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 suitable.

In addition, the formula (II)

[Chemical 43] [A 'ring is a formula

[Chemical 44] (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, and R ^21b is a hydrogen atom, a halogen atom, or a substituent. Represents a hydrocarbon group, an acyl group or a hydroxy group which may have a substituent), and Ar ¹¹ and Ar ¹² each represent an aromatic group which may have a substituent. Shown, Ar ¹¹ and Ar ¹² may form a condensed ring group with the adjacent carbon atom, B'ring represents a nitrogen-containing heterocycle which may have a substituent, X'and Y '
Are the same or different (1) bond, (2) oxygen atom, (3) S (O) _q (q is an integer of 0 to 2), (4) NR ²⁴
(R ²⁴ represents a hydrogen atom or a lower alkyl group) or
(5) optionally having a substituent, hetero atom 1 to 3
R ²² and R ²³ are the same or different and each has (1) a hydrogen atom, (2) a halogen atom, and (3) a substituent. Optionally a hydrocarbon group, (4) an acyl group or (5) represents a hydroxy group which may have a substituent, R ²⁷ is (1) a hydrogen atom, (2)
It represents a hydroxy group which may be substituted with lower alkyl or a (3) carboxyl group. A compound represented by the formula (I) is included in the compound (A),
I) or its salt or its prodrug is also excellent in JN
Compound with K activation inhibitory action and TNF-α inhibitory action
It can be used similarly to (I) or a salt thereof or a prodrug thereof.

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

[Chemical formula 45]

[Chemical formula 46]

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 (1) a monocyclic or condensed polycyclic aromatic hydrocarbon group,
More specifically, phenyl, tolyl, xylyl, biphenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4 A C _6-14 aryl group such as -phenanthryl or 9-phenanthryl (preferably phenyl, tolyl, xylyl, biphenyl, 1-naphthyl or 2-naphthyl, particularly preferably phenyl) 6 to 14 membered monocyclic Alternatively, a condensed polycyclic aromatic hydrocarbon group or the like, or (1) one or more hetero atom (s) selected from nitrogen atom (s), sulfur atom (s) and oxygen atom (s) in addition to carbon atom (s) (for example, 1 to 1 A monocyclic group (preferably 5 to 8 members) containing four, preferably 1 to 3) or a condensed aromatic heterocyclic group thereof, more specifically, thio. E down, benzo [b]
Thiophene, benzo [b] furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene, thianthrene, furan, isoindolizine, xanthrene, phenoxathine, 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 or the like, more preferably pyridine or the like, or one or more (preferably 1 or 2 and more preferably 1) aroma of these rings (preferably the above-mentioned monocyclic heterocycle) A monovalent group obtained by removing an arbitrary hydrogen atom from a ring formed by condensation with a ring (for example, the aromatic hydrocarbon group described above, preferably a benzene ring, etc.) 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, di-C _1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), (xv) 5 To 6-membered cyclic amino groups (eg, morpholino, piperazin-1-yl, piperidino,
Pyrrolidin-1-yl), (xvi) lower alkyl-carbonyl group (for example, C _1-6 alkyl-carbonyl group such as acetyl and propionyl), (xvii) carboxyl group,
(xviii) lower alkoxy-carbonyl group (for example, C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (xix) carbamoyl group, (xx) thiocarbamoyl group, (xxi ) Mono-lower alkyl-carbamoyl groups (eg, mono-C _1-6 alkyl-carbamoyl groups such as methylcarbamoyl, ethylcarbamoyl, etc.) or mono-lower alkyl-thiocarbamoyl groups (eg, methylthiocarbamoyl, ethylthiocarbamoyl, etc.) mono
-C _1-6 alkyl-thiocarbamoyl group), (xxii) di-
Lower alkyl-carbamoyl group (eg, di-C _1-6 alkylcarbamoyl group such as dimethylcarbamoyl, diethylcarbamoyl) or di-lower alkyl-thiocarbamoyl group (eg, di-C such as dimethylthiocarbamoyl, diethylthiocarbamoyl) _1-6 alkylthiocarbamoyl group), (xxiii) aryl-carbamoyl (eg, C _6-10 aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl) or aryl-thiocarbamoyl (eg, phenylthiocarbamoyl, naphthylthiocarbamoyl, etc.) C _6-10 aryl-thiocarbamoyl, etc.), (xxiv) sulfo group, (xxv) lower alkylsulfonyl group (for example, methylsulfonyl,
C _1-6 alkylsulfonyl group such as ethylsulfonyl), (xxvi) aryl group (eg C _6-10 aryl group such as phenyl and naphthyl), (xxvii) aryloxy group (eg phenoxy, naphthyloxy etc.) C _6-10
Aryloxy group), (xxviii) aralkyloxy group (eg, C _7-16 aralkyloxy group such as benzyloxy, etc.) and the like are used.

The above-mentioned "optionally halogenated lower alkyl group" is, for example, a lower alkyl group optionally having 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) ( For example, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, C _1-6 alkyl groups such as hexyl) and the like, and specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, Trifluoromethyl, ethyl, 2-bromoethyl, 2,
2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-Trifluoropentyl, hexyl, 6,6,6-trifluorohexyl and the like are used. Examples of the “optionally halogenated lower alkenyl group” and “optionally halogenated lower alkynyl group” include 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine). A lower alkenyl group which may have (for example, C _2-6 such as vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl)
An alkenyl group) and a lower alkynyl group optionally having 1 to 3 halogen atoms (eg fluorine, chlorine, bromine, iodine) (eg 2-butyn-1-yl, 4
-Pentin-1-yl, 5-hexyn-1-yl and the like C _2-6 alkynyl group) and the like are used. Examples of the “optionally substituted lower alkoxy group” include 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine), mono- or di-lower alkylamino groups (eg,
Mono- or di-C _1-6 alkylamino groups such as methylamino, dimethylamino, ethylamino, dimethylamino etc. or lower alkoxy-carbonyl groups (eg C _1-6 alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl etc.) Group, etc.) which may have a lower alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-
Butoxy, tert-butoxy and other C _1-6 alkoxy groups, etc.) and the like are used. Examples of the “optionally halogenated lower alkylthio group” include a lower alkylthio group optionally having 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) (eg,
(C _1-6 alkylthio groups such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio etc.)
And the like, specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,
4,4-trifluorobutylthio, pentylthio, hexylthio and the like are used.

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

[Chemical 47] [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 ,
Aromatic hydrocarbon groups which may be the same or different and may have a substituent (eg, C _6-14 aromatic hydrocarbon group) are preferable, and phenyl groups which may have a substituent are more preferable. . More specifically, as Ar ¹¹ and Ar ¹² ,
In addition to (1) a phenyl group which may be substituted with a halogen atom or C _1-6 alkyl or (2) a carbon atom, 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom are included 5 A 8- to 8-membered aromatic heterocyclic group is 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 1 to 3 selected from, for example, nitrogen atom, oxygen atom, sulfur atom and the like.
For example, a 3- to 13-membered nitrogen-containing heterocyclic ring which may contain one hetero atom is used. In the formula (II),
It is preferable to form a divalent group by removing one hydrogen atom from each of the nitrogen atom and other atom of the B ′ ring. Specifically, for example

[Chemical 48] Such as 3 to 9 members (more preferably 3 to 6 members)
And a nitrogen-containing heterocyclic group are preferred. Examples of the substituent of the nitrogen-containing heterocycle represented by the B ′ ring include Ar ¹¹ and
"Aromatic group which may have a substituent" represented by Ar ^{1 2}
In addition to the same as the "substituent" of, an oxo group and the like are used.

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

[Chemical 49] [In the formula, Z "represents a nitrogen atom or a methine group, and Z ¹¹ and Z ¹² are each 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. such rings represented by the indicating.] is used. the "C _1-6
As the `` alkyl group '', for example, a linear or branched C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl is used. To be Examples of the "linear C _1-4 alkylene group" include methylene,
Linear C represented by ethylene, propylene and butylene
_{1-4 represents an} alkylene group. As the “linear C _1-4 alkylene group which may be substituted with a hydroxy group, an oxo group or a C _1-6 alkyl group” represented by Z ¹¹ and Z ¹² , an unsubstituted linear C is preferable. _1-4 alkylene group etc. are used,
In particular, an unsubstituted straight chain C _1-2 alkylene group is 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 or different and each is (1) a bond, (2) an oxygen atom, (3) S (O).
_q (q represents an integer of 0 to 2), (4) NR ²⁴ (R ²⁴ represents a hydrogen atom or a lower alkyl group) or (5) may have a substituent, and the hetero atom 1 to It represents a divalent straight-chain lower hydrocarbon group which may be linked through three. As the lower alkyl group represented by R ²⁴ , for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
A linear or branched C _1-6 alkyl group such as sec-butyl, tert-butyl, pentyl and hexyl is used. The “divalent linear lower hydrocarbon group optionally having 1 to 3 heteroatoms” represented by X ′ and Y ′ is the same or different from a lower (C _1-6 ) hydrocarbon. A group formed by removing one hydrogen atom (two in total) bonded to a carbon atom, such as an oxygen atom, NR ^{24 '} (R ^{24 '}
Represents a hydrogen atom or a lower alkyl group) and a hetero atom selected from a sulfur atom and the like and represents a group optionally containing in the hydrocarbon chain. The lower alkyl group represented by R ^{24 '} is, for example, a straight chain or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. C
_{A 1-6} alkyl group or the like is used. Specific examples of the “divalent linear lower hydrocarbon group” include (i) a C _1-6 alkylene group (for example, —CH ₂ —, — (CH ₂ ) ₂ —, — (CH ₂ ) ₃ — ,-(CH ₂ ) ₄ -,-(C
H ₂ ) ₅ -,-(CH ₂ ) _6-, etc.), (ii) C _2-6 alkenylene group (for example, -CH = CH-, -CH = CH-CH _2- , -CH ₂ -CH = CH -CH ₂ -,-(CH ₂ )
₂ -CH = CH-CH ₂ -,-(CH ₂ ) ₂ -CH = CH- (CH ₂ ) ₂ -,-(CH ₂ ) ₃ -CH = CH
-CH _2-, etc., (iii) C _2-6 alkynylene group (for example, -C
≡ C-, -C ≡ C-CH _2- , -CH ₂ -C ≡ C-CH ₂ -,-(CH ₂ ) ₂ -C ≡ C-CH ₂
-,-(CH ₂ ) ₂ -C≡C- (CH ₂ ) ₂ -,-(CH ₂ ) ₃ -C≡C-CH _2- ) and the like are used.

The "substituent" of the "divalent straight-chain lower hydrocarbon group optionally having 1 to 3 heteroatoms" represented by X'and Y'includes, for example, Ar ¹¹ and Ar
^In addition to the "substituent" of the "aromatic group which may have a substituent" represented by ¹² , an oxo group or the like is 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 50] (Wherein R ²⁵ and R ²⁶ are the same or different and each represents a hydroxy group or a C _1-4 alkyl group), and 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.

Examples of the “C _1-4 alkyl group” represented by R ²⁵ and R ²⁶ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
A linear or branched C _1-4 alkyl group such as butyl is used. Examples of _Y'include (i) C _1-6 alkylene group, (ii)-(CH ₂ ) _p2 O-, (iii)-(CH ₂ ) _p2 NH-, (iv)-
_{(CH 2) p2 S -,} (v) - (CH 2) q3 CH (OH) (CH 2) q4 O -, (vi) - (C
_{H 2) q3 CH (OH)} (CH 2) q4 NH -, (vii) - (CH 2) q3 CH (OH) (CH 2) q4
S-, (viii)-(CH ₂ ) _p2 CONH-, (ix) -COO (CH ₂ ) _p2 O-, (x)
-COO (CH ₂ ) _p2 NH-, (xi) -COO (CH ₂ ) _p2 S-, (xii)-(CH ₂ ) _{q3
O (CH 2) q4 O -} , (xiii) - (CH 2) q3 O (CH 2) q4 NH- or (xiv)
-(CH ₂ ) _q3 O (CH ₂ ) _q4 S- (p2 represents an integer of 1 to 6, q3
And q4 each represent an integer of 1 to 3). Among them, Y'is, for example, a bond,-(CH ₂ ) ₂ -O-,-(CH 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-N
_{H-, -CO-O- (CH 2} ) 2 -O-, -CO-O- (CH 2) 3 -O-, - (CH 2) 6 -NH-,
-(CH ₂ ) ₆ -S-,-(CH ₂ ) ₂ -O- (CH ₂ ) ₂ -O-,-(CH ₂ ) ₂ -O- (CH ₂ ) 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. 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 - in the Formula, an integer of w is not 1 6, Y ¹⁵ represents an oxygen atom or
A group represented by [indicating NH] and the like are also preferable. In particular, w is preferably an integer of 1 to 3, and 3 is particularly preferable.

In the formula (II), R ^21a is (1) a hydrogen atom, (2) a halogen atom, (3) a hydrocarbon group which may have a substituent, (4) an acyl group or (5). A hydroxy group having a substituent is shown. In the formula (II), R ^21b is (1) a hydrogen atom, (2) a halogen atom, (3) a hydrocarbon group which may have a substituent, (4)
The hydroxy group which may have an acyl group or a (5) substituent is shown. R ²² and R ²³ are the same or different (1) a hydrogen atom, (2) a halogen atom, (3) a hydrocarbon group which may have a substituent, (4) an acyl group or (5) a substituent. Represents a hydroxy group which may have. R ^21a , R ^21b , R
Examples of the “halogen atom” represented by 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
Is, for example, a group obtained by removing one hydrogen atom from a hydrocarbon compound, and examples thereof include 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, 1 to 16 carbon atoms
A chain (straight or branched) or cyclic hydrocarbon group 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 alkoxy group, etc.) may cyclohexyl optionally condensed with benzene ring which may have a etc. C _3-6 cycloalkyl group)], e) an aryl group (e.g., 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 A group [preferably a lower aralkyl group (eg, benzyl,
Phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-
C _7-16 aralkyl groups such as naphthylmethyl, 2-phenylethyl, 2-diphenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, and the like, more preferably Benzyl group)] and the like are preferable. Examples of the “substituent” of the “hydrocarbon group” are the same as the “substituent” of the “aromatic group which may have a substituent” represented by Ar ¹¹ and Ar ¹² above. 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.

R^21a, R^21b, R^{twenty two}And R^{twenty three}Represented by
Examples of the “silyl group” include, for example, the formula — (C═O) —R²⁸, -S
O₂-R²⁸, -SO-R²⁸,-(C = O) NR²⁸R²⁹,-(C = O) O-R²⁸,-(C =
S) O-R ²⁸Or- (C = S) NR²⁸R²⁹(R²⁸Is a hydrogen atom, a substituent
Optionally having a hydrocarbon group or a substituent
R is an optional hydroxy group²⁹Is a hydrogen atom or low
Secondary alkyl groups (eg methyl, ethyl, propyl, a
Sopropyl, butyl, isobutyl, sec-butyl, tert
-C such as butyl, pentyl, hexyl_1-6Alkyl group
, Especially methyl, ethyl, propyl, isopropyl, etc.
C_1-3Alkyl groups and the like are preferable). )
Groups are used. Among them, the formula- (C = O) -R²⁸, -S
O₂-R²⁸, -SO-R²⁸,-(C = O) NR²⁸R²⁹Or- (C = O) O-R²⁸so
Preferred are the groups represented, especially the formula-(C = O) -R²⁸Represented by
Groups are preferred. R²⁸Indicated by "even if replaced
Examples of the “good hydrocarbon group” include R described above.^21a, R^21b, R^{twenty two}
And R^{twenty three}Hydrocarbon which may have a substituent represented by
The same thing as the base is used. Above all, R²⁸Indicated by
Examples of the hydrocarbon group to be used include C_{1- 6}Alkyl group, etc.
Is preferred, and the substituent thereof is, for example,
For example, carboxyl, C_1-6Alkoxy-carbonyl etc.
preferable. R²⁹Is 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 “hydroxy group optionally having substituent (s)” represented by R ²⁸ and R ²⁸ include, for example, in place of the hydrogen atom of (1) hydroxy group or (2) hydroxy group,
A hydroxy group having one hydrocarbon group which may have a substituent is shown. Examples of the hydrocarbon group which may have a substituent which the hydroxy group may have include R ^21a and R described above.
^{The same as the optionally} substituted hydrocarbon group represented by ^21b , R ²² , R ²³ and R ²⁸ is used. Compound (I
In Ia), among 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 _1-6 alkoxy-carbonyl optionally having C _1-6
A carbamoyl group (or a thiocarbamoyl group) which may be substituted with an alkyl group is preferable. Among the above, as the R ^21a, (1) a 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 thiocarbamoyl) or (5) carboxyl Or C _1-6 alkoxy-
A carbamoyl group (or a thiocarbamoyl group) which may be substituted with a C _1-6 alkyl group which may have carbonyl 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 51] The partial structural formula represented by

[Chemical 52] 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)
In, R ²² and R ²³ are preferably hydrogen atoms. In the 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 53] 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) -, and Compound (II) which is a group represented by Y ¹⁴ is an oxygen atom, S or NH, s and t are each an integer of 0 to 6 (provided that the sum of s and t is 6 or less)].

[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 [4,3-b] pyridazin-2 (3H) -yl ] -2-Methylpropionate ethyl or a salt thereof. (7) 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. (8) 2- [6- [3- [4- (Diphenylmethoxy) piperidino] propylamino] -3-oxo [1,2,4] triazolo [4,3-b] pyridazin-2 (3H) -yl ] -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) -yl] -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 54] The, 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 represents an oxygen atom, S or NH, and 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 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) carbamoyl (or thiocarbamoyl)
C _{1-6 optionally} substituted with groups selected from the group consisting of
Alkyl group or (5) carboxyl or C _1-6 alkoxy-carbamoyl group (or thiocarbamoyl group) optionally substituted by C _1-6 alkyl group optionally having carbonyl, R ²² , R ²³ and Compound (IIa) in which R ²⁷ represents a hydrogen atom.

[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 (IIb) 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 55] X 'is an oxygen atom, Y' has the formula ^{_{- (CH 2) w -Y 15}} - in the Formula, an integer of w is not 1 6, Y ¹⁵ represents an oxygen atom or
[Representing NH], R ^21b is (1) a 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 the group consisting of
A compound (IIb) in which a C _1-6 alkyl group, R ²² , R ²³ and R ²⁷ represent a hydrogen atom.

[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) piperidino] propylamino] -3-oxo [1,2,4] triazolo [4,3-b] pyridazin-2 (3H) -yl ] -2-Methylpropionate ethyl 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-Methylpropionate pivaloyloxymethyl or a salt thereof. (5) 2- [6- [3- [4- (diphenylmethoxy) piperidino] propoxy] -3-oxo [1,2,4] triazolo [4,3-b] pyridazine
-2 (3H) -yl] -2-methylpropionate pivaloyloxymethyl or a salt thereof.

The above-mentioned compound (A), (I) or (II) or a salt thereof (hereinafter, compound (A), (I) or (I
The abbreviated I)) is a compound of the present invention by a reaction with an enzyme or gastric acid under physiological conditions in vivo.
(A), a compound that is converted to (I) or (II), that is, a compound of the present invention that undergoes enzymatic oxidation, reduction, hydrolysis, etc.
(A), (I) or a compound that changes to (II), the compound of the present invention by hydrolysis or the like caused by gastric acid (A), (I) or (I
It may be a compound that changes to I). Compounds of the invention
(A), as a prodrug of (I) or (II), the compound of the present invention (A), (I) or (II) amino group is acylated, alkylated, phosphorylated compound (e.g., Compounds of the invention
The amino group of (A), (I) or (II) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2
-Oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation,
Pivaloyloxymethylated, tert-butylated compounds, etc.); Compounds (A), (I) or (II) of the present invention in which the hydroxyl group is acylated, alkylated, phosphorylated or borated ( For example, the compound of the present invention (A), (I) or (II) having a hydroxyl group acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, etc. );
Compound of the present invention (A), (I) or (II) carboxyl group is esterified, amidated compound (e.g., the compound of the present invention (A), (I) or (II) carboxyl group is ethyl Esterification, phenylesterification, carboxymethylesterification, dimethylaminomethylesterification, pivaloyloxymethylesterification, ethoxycarbonyloxyethylesterification, phthalidylesterification, (5-methyl-2-oxo-1,3 -Dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds, etc.) and the like. These compounds are compounds (A) of the present invention by a method known per se,
It can be produced from (I) or (II). Further, the prodrug of the compound (A), (I) or (II) of the present invention can be obtained by Hirokawa Shoten 1990 "Development of Pharmaceuticals" Volume 7 Molecular Design 16
It may be the compound (A), (I) or (II) of the present invention which is changed under physiological conditions as described on pages 3 to 198.

The compound (I) or a salt thereof of the present invention can be prepared by a method known per se, for example, JP-A-2000-191663 and JP-A-2000-
191664, JP 2000-198735 and WO 00/2345
It can be manufactured by the method described in Publication 0 or a method analogous thereto. Further, the compound (II) of the present invention or a salt thereof,
A method known per se, for example, JP 2000-178277 A and W
It can be produced by the method described in O00 / 20417 or a method analogous thereto.

The salt of the compound (A), (I) or (II) of the present invention 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,
Salts with 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.) are used. Furthermore, when the compound (A), (I) or (II) has an acidic group such as a carboxylic acid as a substituent, an inorganic base (for example, alkali metal or alkaline earth such as sodium, potassium, calcium or magnesium) is used. Salts with metals such as ammonia or with organic bases (eg, tri-C _1-3 alkylamines such as triethylamine) may be formed.

The compound (A), (I) or (II) of the present invention or a salt thereof or a prodrug thereof (hereinafter sometimes abbreviated as the present compound) has an excellent JNK activation inhibitory action, Further, since it has low toxicity and few side effects, it is useful as a safe drug, for example, a drug having an inhibitory effect on JNK activation.

The JNK activation inhibitor of the present invention containing the present compound can be administered to mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.) Shows excellent JNK activation inhibitory effect,
Due to its excellent (oral) absorption and (metabolism) stability, JN
K-related diseases and c-Jun-related diseases, such as acute pancreatitis, chronic pancreatitis, adult respiratory distress syndrome, scleroderma, deep erythematous lupus,
Chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, myasthenia gravis, multiple myeloma, acute myeloblastic leukemia, chronic sarcoma, chronic myelogenous leukemia, Metastatic melanoma, Kaposi's sarcoma, wasting disease, Huntington's disease, diseases associated with ischemia / reperfusion in stroke,
Myocardial ischemia, ischemic heart disease, renal ischemia, neovascular glaucoma,
It can be used as a prophylactic / therapeutic agent for infantile hemangiomas, blood vessel proliferation, cardiac hypertrophy, abnormal immune response, fever, cell aging, apoptosis-related diseases and the like.

Further, since the present compound has an excellent TNF-α inhibitory action, has low toxicity and has few side effects,
It is also useful as a safe drug, for example, a drug having a TNF-α inhibitory action.

The TNF-α inhibitor of the present invention containing the present compound can be administered to mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.) Shows excellent TNF-α inhibitory effect (oral)
Since it has excellent absorbability, (metabolism) stability, etc., it can be used as a prophylactic / therapeutic agent for diseases associated with TNF-α.
Here, the disease in which TNF-α is involved (induced by TNF-α) is a disease that develops due to the presence of TNF-α and is treated through the suppressive effect of TNF-α. Examples of such diseases include inflammatory diseases [eg, retinopathy, nephropathy, neuropathy,
Diabetic complications such as macrovascular disorder; arthritis such as rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, gouty arthritis, and periosteitis; low back pain; gout; inflammation after surgery / trauma; remission of swelling; neuralgia; Pharyngitis; cystitis; pneumonia; atopic dermatitis; inflammatory bowel disease such as Crohn's disease and ulcerative colitis; meningitis; inflammatory eye disease; pneumonia, silicosis, pulmonary sarcoidosis,
Inflammatory lung diseases such as pulmonary tuberculosis], cardiovascular diseases (eg, angina, myocardial infarction, congestive heart failure, generalized intravascular coagulation syndrome, etc.), diabetic nephropathy, asthma, allergic disease, chronic obstruction Lung disease, systemic lupus erythematosus, Crohn's disease, autoimmune hemolytic anemia, psoriasis, neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, AIDS encephalopathy, etc.), central nervous system disorders (eg. , Cerebrovascular accidents such as cerebral hemorrhage and cerebral infarction, head trauma, spinal cord injury, cerebral edema, multiple sclerosis, etc.), toxemia (eg, sepsis, septic shock,
Endotoxic shock, gram-negative sepsis, toxin shock syndrome, etc.), Addison's disease, Creutzfeldt-Jakob disease, viral infection (eg, viral infections such as cytomegalovirus, influenza virus, herpes virus), rejection at the time of transplantation Examples include suppression of reaction and dialysis hypotension.

This compound inhibits JNK activation and TNF-
An eosinophil infiltration inhibitory action can be brought about based on the α inhibitory action, and based on this action, the compound of the present invention can also be used as a nasal congestion improving agent. Furthermore, among the present compounds, in addition to the JNK activation inhibitory action and TNF-α inhibitory action,
A compound having both an antihistamine action and / or an eosinophil chemotaxis inhibitory action is preferable for the purpose of the present invention. Thus, in addition to JNK activation inhibitory action, TNF-α inhibition, compounds that may have antihistamine action and / or eosinophil chemotaxis inhibitory action have low toxicity and side effects. Therefore, it is useful as a safe drug, for example, a JNK activation inhibitor, an antihistamine, an eosinophil chemotaxis inhibitor, an antiallergic agent, and the like. In addition to JNK activation inhibitory action and TNF-α inhibition, a pharmaceutical composition of the present invention comprising a compound having antihistamine action and / or eosinophil chemotaxis inhibitory action, Animals (eg mouse, rat, hamster, rabbit,
Cats, dogs, cows, sheep, monkeys, humans, etc.)
Excellent JNK activation inhibitory action, antihistamine action, eosinophil chemotaxis inhibitory action, antiallergic action, (oral)
Due to its excellent absorbability and (metabolism) stability, for example, chronic urticaria, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, hypersensitivity pneumonitis, eczema, herpes dermatitis, psoriasis, eosinophilic Pneumonia (PIE syndrome), chronic obstructive pulmonary disease (C
OPD) or asthma and contact dermatitis, pruritus, dry dermatitis, acute urticaria, prurigo and the like, and a nasal obstruction improving agent.

The preparation of the present invention containing the present compound can be prepared by mixing the present compound as it is or with a pharmacologically acceptable carrier according to a method known per se generally used in the production method of pharmaceutical preparations. For example, tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), solutions, injections, suppositories,
Oral or parenteral (eg,
(Topical, rectal, intravenous administration, etc.) can be safely administered. The content of the present compound in the preparation of the present invention is about
It is 0.01 to about 100% by weight, preferably about 0.1 to about 50% by weight, more preferably about 0.5 to about 20% by weight. The dose varies depending on the administration subject, administration route, disease, symptom, etc., but as a c-Jun-related disease preventive / therapeutic agent,
For example, for a patient (body weight of about 60 kg), the daily dose of the active ingredient [the present compound] is about 0.01 to about 30 mg / kg body weight, preferably about 0.1 to about 20 mg / kg body weight, more preferably about 1 to about 20 mg / kg. The kg body weight may be orally administered in 1 to several times a day. Examples of the pharmacologically acceptable carrier that may be used in the production of the formulation of the present invention include various organic or inorganic carrier substances that are commonly used as formulation materials, for example, an excipient in a solid formulation, a lubricant, Examples thereof include binders and disintegrants, or solvents for liquid preparations, solubilizing agents, suspending agents, isotonic agents, buffering agents, soothing agents, and the like.
Further, if necessary, conventional additives such as antiseptics, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be appropriately used in appropriate amounts. Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like. As a lubricant,
Examples thereof include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like. Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like. As a solvent,
For example, water for injection, alcohol, propylene glycol,
Macrogol, sesame oil, corn oil, olive oil and the like can be mentioned. Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. As the suspending agent, for example, stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid,
Surfactants such as lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc. Can be mentioned. Examples of the isotonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D
-Mannitol etc. are mentioned. Examples of the buffer include phosphate buffer, acetate buffer, carbonate buffer, citrate buffer, and the like. Examples of soothing agents include benzyl alcohol and the like. Examples of the preservative include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Examples of the antioxidant include sulfite, ascorbic acid, α-tocopherol and the like.

Furthermore, this compound can be used as an antiallergic drug in combination with an antihistamine agent other than this compound. Examples of the antihistamines include chlorpheniramine maleate, diphenhydramine hydrochloride, dimenhydrinate, cyproheptadine hydrochloride, promethazine hydrochloride, alimemazine tartrate, clemastine fumarate, hydroxyzine pamoate, homochlorcyclidine hydrochloride, terfenadine and mequitazine.

The present compound can be used in combination with drugs other than the present compound. Examples of the drug that can be used in combination with the present compound include immunomodulators (immunosuppressants), steroid drugs and the like. Examples of the immunomodulator (immunosuppressive drug) include 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid. Acid ethyl ester (JP-A-7-118266), methotrexate, cyclophosphamide, MX-6
8, Atiprimodo dihydrochloride, BMS-18866
7, CKD-461, rimexolone, cyclosporine, tacrolimus, gusperimus, azathioprine, antilymph serum,
Examples include dry sulfonated immunoglobulin, erythropoietin, colony stimulating factor, interleukin, interferon and the like. Steroids include dexamethasone, hexestrol, methimazole, betamethasone,
Examples include triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone, beclomethasone propionate, and estriol.

By combining the present compound and the concomitant drug, (1) the dose can be reduced as compared with the case where the present compound or the concomitant drug is administered alone.
(2) A drug to be used in combination with the present compound can be selected according to the patient's condition (mildness, seriousness, etc.), and (3) Treatment period is selected by selecting a combination drug with a different mechanism of action from the present compound. (4) The therapeutic effect can be sustained by selecting a concomitant drug having a different mechanism of action from that of the compound. (5) Combining the compound with a concomitant drug Thereby, an excellent effect such as a synergistic effect can be obtained. In particular, when the concomitant compound is a steroid drug, it is possible to use a steroid drug in a weaker class than when the steroid drug is used alone. Hereinafter, the combined use of the present compound and a concomitant drug is referred to as a "combination agent of the present invention". In using the concomitant drug of the present invention, the administration time of the present compound and the concomitant drug is not limited, and the present compound or a pharmaceutical composition thereof and the concomitant drug or a pharmaceutical composition thereof are simultaneously administered to an administration subject. The dose may be administered at different times. The dose of the concomitant drug may be in accordance with the dose clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like. The administration form of the concomitant drug of the present invention is not particularly limited as long as the present compound and the concomitant drug are combined at the time of administration. Examples of such a dosage form include (1) administration of a single preparation obtained by simultaneously formulating the present compound and a concomitant drug, and (2) preparation of the present compound and a concomitant drug separately. Simultaneous administration of two types of preparations by the same administration route, (3) Administration of two types of preparations obtained by separately formulating the present compound and a concomitant drug at the same administration route with a time lag, (4) Simultaneous administration of two kinds of preparations obtained by separately formulating the present compound and a concomitant drug through different administration routes, (5) Different two preparations obtained by separately preparing the present compound and concomitant drug Administration with a time lag in the administration route (for example, administration of the present compound; concomitant drug in order or administration in reverse order) and the like can be mentioned.

The combination agent of the present invention has low toxicity, and for example,
According to a method known per se, the present compound or (and) the concomitant drug is mixed with a pharmacologically acceptable carrier to give a pharmaceutical composition such as tablets (including sugar-coated tablets and film-coated tablets), powders, granules and capsules. It can be safely administered orally or parenterally (eg, topical, rectal, intravenous administration, etc.) as an agent, (including soft capsules), solution, injection, suppository, sustained release agent and the like. The injection can be administered intravenously, intramuscularly, subcutaneously or intra-organly, or directly to the lesion. Examples of the pharmacologically acceptable carrier that may be used in the production of the concomitant drug of the present invention include various organic or inorganic carrier substances conventionally used as a formulation material, for example, an excipient in a solid formulation, a lubricant. , Binders and disintegrants, or solvents for liquid preparations, solubilizers, suspending agents, isotonic agents, buffering agents, soothing agents and the like.
Further, if necessary, conventional additives such as antiseptics, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be appropriately used in appropriate amounts.

Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like. As a lubricant,
Examples thereof include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like. Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like. As a solvent,
For example, water for injection, alcohol, propylene glycol,
Macrogol, sesame oil, corn oil, olive oil and the like can be mentioned. Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. As the suspending agent, for example, stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid,
Surfactants such as lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc. Can be mentioned. Examples of the isotonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D
-Mannitol etc. are mentioned. Examples of the buffer include phosphate buffer, acetate buffer, carbonate buffer, citrate buffer, and the like. Examples of soothing agents include benzyl alcohol and the like. Examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Examples of the antioxidant include sulfite, ascorbic acid, α-tocopherol and the like.

The compounding ratio of the present compound and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like. For example, the content of the present compound in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5% to the whole preparation.
Or about 20% by weight. The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about 0.5 to 20% by weight relative to the whole preparation.
It is about% by weight. The content of additives such as a carrier in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 1 to the whole preparation.
It is about 0 to 90% by weight. Also, when the compound and the concomitant drug are separately formulated, the same content may be used.

These preparations are prepared by a conventional method (for example, the method described in the Japanese Pharmacopoeia). Specifically, the method for producing tablets is as follows: a pharmaceutical product as it is, an excipient, a binder, a disintegrating agent or other appropriate additives are uniformly mixed and granulated by a suitable method, Made by adding a lubricant, etc. and compression molding, or by directly compressing the drug as it is, or by uniformly mixing it with excipients, binders, disintegrating agents or other suitable additives. Alternatively, the granules may be produced by pre-manufacturing the granules as they are, or by adding appropriate additives and mixing them uniformly, followed by compression molding. In addition, a colorant, a flavoring agent and the like can be added to the present agent, if necessary. Furthermore, this agent can be coated with a suitable coating agent. The method for producing injections is to make a fixed amount of a fixed amount of a drug by dissolving, suspending or emulsifying it in water for injection in the case of an aqueous solvent, physiological saline, Ringer's solution, etc. Alternatively, it can be manufactured by taking a certain amount of a drug and sealing it in a container for injection. As the oral pharmaceutical carrier, substances commonly used in the pharmaceutical field such as starch, mannitol, crystalline cellulose, sodium carboxymethyl cellulose and the like can be used. As the carrier for injection, for example, distilled water, physiological saline, glucose solution, infusion solution and the like are used. In addition, additives generally used in preparations can be added as appropriate.

The dose of the concomitant drug of the present invention varies depending on the kind, age, body weight, symptom, dosage form, administration method, administration period and the like of the present compound. For example, asthmatic patients (adults, body weight about 60).
Generally, about 0.1 to about 100 mg / kg, preferably about 1 to 10 mg / day of this compound and the concomitant drug per person, respectively.
About 50 mg / kg, more preferably about 1 to about 10 mg / kg, is orally administered once a day in divided doses. Of course, since the dose varies depending on various conditions as described above, a dose smaller than the above dose may be sufficient in some cases, or a dose exceeding the range may be required in some cases. The concomitant drug can be set in any amount as long as the side effects are not a problem and the object of the present invention can be achieved. The daily dose as a concomitant drug varies depending on the degree of symptoms, age of the subject, sex, weight, sensitivity difference, timing of administration, interval, properties of pharmaceutical preparation, preparation, type, type of active ingredient, etc. Not limited.

When the concomitant drug of the present invention is administered, it may be administered at the same time, but after the concomitant drug is administered first,
The compound may be administered, or the compound may be administered first,
Thereafter, the concomitant drug may be administered. When administered at a time lag, the time lag varies depending on the active ingredient to be administered, the dosage form, and the method of administration. Ten
The method includes administering the present compound within minutes to 1 day, more preferably within 15 minutes to 1 hour. When the present compound is administered first, a method of administering the concomitant drug within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after the administration of the present compound can be mentioned. .

[0077]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples and Experimental Examples, but the present invention is not limited thereto. In the reference example, the TLC (Thin Layer Chromatog
Raphy, thin layer chromatography). In TLC observation, Merck (Me
rck) 60F ₂₅₄ was used as a UV detector.

Reference Example 1 Preparation of 6- [3- [4- (diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [1,5-b] pyridazine 6- (3-hydroxypropylamino) [1,2,4] triazolo [1,
290 mg of 5-b] pyridazine was suspended in 10 mL of tetrahydrofuran, 388 mg of N-ethyldiisopropylamine and 344 mg of methanesulfonyl chloride were added, and the mixture was stirred at room temperature for 1 hr. Ice water and sodium chloride were added, the mixture was extracted with ethyl acetate, the extract was washed with saturated brine and dried over magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in N, N-dimethylformamide (5 mL). 4- (diphenylmethoxy) piperidine 352 m
g, 208 mg of sodium iodide and 193 mg of potassium carbonate were added, and the mixture was stirred at room temperature for 15 hours and at 60 ° C for 3 hours. After cooling, ice water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, ethyl acetate:
Elution with methanol: triethylamine (90: 10: 1). The desired fractions were collected and concentrated, and the obtained crystals were washed with ethyl ether and dried to give the title compound (209 mg). Melting point 136-138 ℃ Elemental analysis value: Calculated value as C ₂₆ H ₃₀ N ₆ O (%): C, 70.56; H, 6.83; N, 18.99 Measured value (%): C, 70.43; H, 6.83; N, 19.04

Reference Example 2 Ethyl 2-fumaric acid 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate Preparation of salt 4- (diphenylmethoxy) -1-piperidinepropanamine
190 g of 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate (1.76 g) with 4.2 g
Stirred for 3.5 hours. 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. This gave 2.30 g of the title compound. Melting point 126-128 ℃ Elemental analysis value: C ₄₁ H ₄₉ N ₅ O ₁₁ Calculated value (%): C, 62.50; H, 6.27; N, 8.89 Measured value (%): C, 62.28; H, 6.15; N , 8.97

Reference Example 3 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 ℃ Elemental analysis value: Calculated value 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 4 Preparation of N- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazine-2-carbonyl] glycine ethyl ester dihydrochloride N- [6- [3- [4- (Diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazine-2-carbonyl] glycine ethyl ester 0.628 g in tetrahydrofuran 10
This was dissolved in mL, 1.5 mL of 4N hydrogen chloride ethyl acetate solution was added, and the mixture was concentrated under reduced pressure. 10 mL of methanol was added to the residue and the mixture was concentrated under reduced pressure. The obtained crystals were collected and washed with ethyl acetate to obtain 0.658 g of the title compound. Melting point 205 ℃ Elemental analysis value: Calculated value as C ₃₂ H ₄₀ N ₆ O ₄ Cl ₂ (%): C, 59.72; H, 6.26; N, 13.06 Actual value (%): C, 59.74; H, 6.41; N , 12.63

Reference Example 5 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, concentrate under reduced pressure, and dissolve in 5 mL of ethyl acetate.
0.96 mL of N 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: C ₃₄ H ₄₅ N ₅ O ₃ Cl ₂ · 1.5H ₂ O calculated value (%): C, 60.98; H, 7.22; N, 10.46 Actual value (%): C, 60.70; H , 6.95; N, 10.34

Reference Example 6 Preparation of ethyl 2- [6- [3- [4- (diphenylmethylamino) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate 4- (diphenylmethylamino) -1-piperidinepropanamine 3.12g and 2- (6-chloroimidazo [1,2-b] pyridazine
2-yl) -2-methylpropionate ethyl 1.72 g and 180
Stir at ℃ for 3 hours. 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, concentrate under reduced pressure, and concentrate the residue in ethyl ether-hexane.
(1: 3) was added to crystallize, collected by filtration, washed with hexane and dried to obtain 1.83 g of the title compound. Melting point 115-117 ℃ Elemental analysis value: Calculated value as C ₃₃ H ₄₂ N ₆ O ₂ (%): C, 71.45; H, 7.63; N, 15.15 Measured value (%): C, 71.40; H, 7.70; N , 14.94

Reference Example 7 Ethyl 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate Disuccinic acid Preparation of salt 2- [6- [3- [4- (diphenylmethoxy) synthesized in Reference Example 2
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. Melting point 98-101 ℃ (decomposition) Elemental analysis value: C ₄₁ H ₅₃ N ₅ O ₁₁・ 1 / 3CH ₃ CO ₂ C ₂ H ₅
Calculated as (%): C, 61.92; H, 6.83; N, 8.53 Measured value (%): C, 61.54; H, 6.83; N, 8.50

Reference Example 8 Ethyl 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate citrate Preparation of (1: 1) ethyl 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate 1.667g Was dissolved in 8 mL of ethanol, 0.631 g of citric acid monohydrate was added, and the mixture was heated to dissolve, and 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. To this crystal was added 30 mL of methanol, 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 value: Calculated value as C ₃₉ H ₄₉ N ₅ O ₁₀ (%): C, 62.64; H, 6.60; N, 9.36 Actual value (%): C, 62.50; H, 6.56; N, 9.43

Reference Example 9 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid dihydrate Process for producing 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 dimethyl sulfoxide, and heated in an oil bath (bath temperature of 165-170 ° C) while stirring with 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 60
It was dissolved in 0 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%. The crude title compound 353 obtained here.
1240 mL of ethanol was added to 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 10 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -3-methylimidazo [1,2-b] pyridazin-2-yl]-
Preparation of 2-methylpropionic acid 4- (diphenylmethoxy) -1-piperidinepropanamine
17.0 g and ethyl 2- (6-chloro-3-methylimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate 7.39 g
Dissolve it in 25 mL of N-methyl-2-pyrrolidinone, and at 160 ° C for 8.
Stir for 5 hours. After cooling, the aqueous layer was added, and 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 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -3-methylimidazo [1,2-b] pyridazin-2-yl]- 10.4 g of ethyl 2-methylpropionate was obtained as an oil. 10.4 g of this oil was added to 100 mL of ethanol.
The mixture was dissolved in water, 18.3 mL of 5N sodium hydroxide aqueous solution was added, and the mixture was heated under reflux for 2 hours. After cooling, concentrate under reduced pressure, dilute the residue with water, wash with diisopropyl ether, and add 5N to the aqueous layer.
The pH was adjusted to 5 by adding hydrochloric acid. The precipitated crystals were collected by filtration, recrystallized from methanol-water (10: 1) and dried to give 4.09 g of the title compound. Melting point 219-220 ℃ Elemental analysis value: Calculated value as C ₃₂ H ₃₉ N ₅ O ₃ (%): C, 70.95; H, 7.26; N, 12.93 Measured value (%): C, 70.85; H, 7.00; N , 13.20

Reference Example 11 Preparation of 6- [6- [4- (diphenylmethoxy) piperidino] hexyloxy] [1,2,4] triazolo [4,3-b] pyridazine fumarate 4- (diphenylmethoxy) -1-piperidine hexanol 82
Dissolve 5 mg in 13 mL of tetrahydrofuran, add 108 mg of sodium hydride (60% in oil), heat to reflux for 1.5 hours, cool, and then cool 6-chloro [1,2,4] triazolo [4,3-b ] 347 mg of pyridazine was added, and the mixture was heated under reflux for 2 hours. After cooling
Water was added and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and extracted with ethyl acetate.
-Eluted with methanol-triethylamine (50: 5: 1).
Collect the desired fractions and concentrate under reduced pressure to give a residue 940
mg was dissolved in ethanol, 225 mg of fumaric acid in ethanol was added, and the mixture was concentrated under reduced pressure. Ethanol residue
-Crystallized from ethyl acetate (1: 5), washed with ethyl acetate,
After drying, 939 mg of the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.30-1.55 (4H, m), 1.65-
1.85 (4H, m), 1.85-2.20 (4H, m), 2.80-3.35 (5H,
m), 3.73 (1H, brs), 4.27 (2H, t, J = 6.4 Hz), 5.44
(1H, s), 6.76 (2H, s), 6.78 (1H, d, J = 9.6 Hz),
7.25-7.35 (10H, m), 7.94 (1H, d, J = 9.8 Hz), 8.87
(1H, s). Melting point 144-146 ° C Elemental analysis: Calculated as C ₃₃ H ₃₉ N ₅ O ₆ (%): C, 65.87; H, 6.53; N, 11.64 Measured value (%): C, 65.81 ; H, 6.48; N, 10.87

Reference Example 12 6- [6- [4- (diphenylmethoxy) piperidino] hexylamino] [1,2,4] triazolo [4,3-b] pyridazine production process A: 6- (6-hydroxy Hexylamino) [1,2,4] triazolo [4,3-b] pyridazine preparation 6-chloro [1,2,4] triazolo [4,3 in 35 mL of ethanol.
-b] Pyridazine 3.55 g is suspended and 6-aminohexanol is suspended.
6.73 g was added and the mixture was heated under reflux for 16 hours. After cooling, the mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, ethyl acetate-methanol-triethylamine (5
It was eluted at 0: 5: 1). The target fractions were collected and concentrated under reduced pressure, and the precipitated crystals were washed with diethyl ether and dried to give 5.67 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.38-1.80 (8H, m), 3.11
(1H, q, J = 6.4 Hz), 3.37 (2H, q, J = 6.4 Hz), 3.67
(2H, t, J = 6.1 Hz), 5.12 (1H, brs), 6.61 (1H, d,
J = 9.8 Hz), 7.78 (1H, d, J = 10.0 Hz), 8.74 (1H,
s). Step B: Preparation of 6- [6- (methanesulfonyloxy) hexylamino] [1,2,4] triazolo [4,3-b] pyridazine 6- (6-hydroxyhexylamino) [1,2 , 4] Triazolo [4,
3.26 g of 3-b] Pyridazine was suspended in 60 mL of tetrahydrofuran, 3.59 g of N-ethyldiisopropylamine and 3.17 g of methanesulfonyl chloride were added, and the mixture was stirred at room temperature for 4 hours. Brine was added, the mixture was extracted with ethyl acetate-tetrahydrofuran (1: 1) 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). The desired fractions were collected and concentrated under reduced pressure, and the precipitated crystals were washed with diethyl ether and dried to give the title compound (3.24 g). Melting point 103-105 ° C Elemental analysis: Calculated as C ₁₂ H ₁₉ N ₅ O ₃ S ・ 0.3H ₂ O (%): C, 45.21; H, 6.20; N, 21.97 Measured value (%): C, 45.15 ; H, 6.24; N, 21.60 Step C: 6- [6- (Methanesulfonyloxy) hexylamino] [1,2,4] triazolo [4,3-b] pyridazine 810 mg in N, N
-Dissolved in 15 mL of dimethylformamide, 4- (diphenylmethoxy) piperidine 829 mg, potassium carbonate 428 m
g and 515 mg of potassium iodide were added, and the mixture was stirred at 60 ° C. for 4 hours. After cooling, brine was added, the mixture was extracted with ethyl acetate and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and extracted with ethyl acetate.
-Eluted with methanol-triethylamine (50: 5: 1).
Collect the target fractions and concentrate under reduced pressure.The residue was crystallized from ethanol-ethyl acetate (1: 5), washed with diethyl ether, recrystallized in the same manner, and dried to give 599 mg of the title compound. It was Melting point 124-127 ℃ Elemental analysis value: Calculated value as C ₂₉ H ₃₆ N ₆ O ・ 0.5H ₂ O (%): C, 70.56; H, 7.55; N, 17.02 Actual value (%): C, 70.68; H , 7.29; N, 17.38

Reference Example 13 Preparation of 3-tert-butyl-6- [3- [4- (diphenylmethoxy) piperidino] propoxy] [1,2,4] triazolo [4,3-b] pyridazine 4- (diphenyl Methoxy) -1-piperidine propanol 99
1 mg was dissolved in tetrahydrofuran 20 mL, tert-butoxy sodium 322 mg was added, and the mixture was stirred at an external temperature of 60 ° C. for 2 hours. After cooling, 642 mg of 3-tert-butyl-6-chloro [1,2,4] triazolo [4,3-b] pyridazine was added, and the mixture was heated under reflux for 2 hours. After cooling, brine was added and the mixture was extracted with ethyl acetate 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 target fractions, concentrate under reduced pressure, and dissolve 1.26 g of the residue in 3 mL of pyridine.
L was added and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, ethyl acetate-methanol-triethylamine (50:
Elute at 5: 1). Collect the desired fractions, concentrate under reduced pressure, and concentrate the residue in ethyl acetate-diethyl ether (1: 1).
It was further crystallized, washed with diethyl ether, and dried to obtain 500 mg of the title compound. Melting point 125-127 ℃ Elemental analysis value: Calculated value as C ₃₀ H ₃₇ N ₅ O ₂ (%): C, 72.12; H, 7.46; N, 14.02 Measured value (%): C, 71.93; H, 7.47; N , 14.18

Reference Example 14 Preparation of ethyl 6- [3- [4- (diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [4,3-b] pyridazine-3-carboxylate 4- ( Diphenylmethoxy) -1-piperidinepropanamine
5.15 g and 3.6 g of ethyl 6-chloro [1,2,4] triazolo [4,3-b] pyridazine-3-carboxylate were dissolved in 70 mL of N, N-dimethylformamide, and 5.48 mL of N-ethyldiisopropylamine. Was added and the mixture was heated with stirring at an external temperature of 70 ° C. for 4 hours. After cooling, cold saline was added to the reaction solution, extracted with tetrahydrofuran, and dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and ethyl acetate-methanol-triethylamine (50: 5:
It was eluted in 1). The target fractions were collected and concentrated under reduced pressure. Half of the precipitated crystals were recrystallized from ethanol-ethyl acetate (1: 1), filtered, collected and dried to give 2.13 g of the title compound. Melting point 129-133 ℃ Elemental analysis value: Calculated value as C ₂₉ H ₃₄ N ₆ O ₃・ 0.3H ₂ O (%): C, 66.98; H, 6.71; N, 16.16 Measured value (%): C, 67.09; H, 6.88; N, 16.02

Reference Example 15 Preparation of 6- [3- [4- (diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [4,3-b] pyridazine-3-carboxylic acid 6- [3 Ethyl 1- [4- (diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [4,3-b] pyridazine-3-carboxylate was dissolved in 8 mL of ethanol, and 1 N sodium hydroxide was added. 8 mL of an aqueous solution was added, and the mixture was heated under reflux for 3 hours. After cooling, ethanol was distilled off and washed with ethyl acetate,
The pH was adjusted to 5 by adding 1 N hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and ethyl acetate and dried to give the title compound 1.1.
Got 9 g. Mp 102-104 ° C. Elemental _{analysis: C 27 H 30 N 6 O} 3 · 2H 2 O Calculated (%): C, 62.05; H, 6.56; N, 16.00 Found (%): C, 61.82; H , 6.40; N, 16.06

Reference Example 16 Preparation of 6- [3- [4- (diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one 6- Chloro [1,2,4] triazolo [4,3-b] pyridazine-3 (2H)-
0.512 g of ON-ON was dissolved in 15 mL of n-butanol, and 0.88 g of 4- (diphenylmethoxy) -1-piperidinepropanamine was added.
N-Ethyldiisopropylamine (1.04 mL) was added, and the mixture was heated under reflux in an oil bath for 5 hr. After cooling, n-butanol was distilled off under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the residue, and 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 (85: 15: 1). The desired fractions were collected and concentrated, and the obtained crystals were filtered, washed with ethyl ether and dried to give 0.35 g of the title compound. Melting point 156-170 ° C Elemental analysis: C ₂₆ H ₃₀ N ₆ O ₂・ 2H ₂ O calculated (%): C, 65.52; H, 6.72; N, 17.64 Measured value (%): C, 65.78; H , 6.71; N, 17.52

Reference Example 17 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -3-oxo [1,2,4] triazolo [4,3-b] pyridazine
Preparation of -2 (3H) -yl] -2-methylpropionate ethyl hydrochloride 6- [3- [4- (diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [4,3-b ] Pyridazine-3 (2H) -one
0.606 g was suspended in 3 mL of N, N-dimethylformamide, 0.063 g of 60% oily sodium hydride was added, and the mixture was stirred at room temperature for 1 hr. Ethyl 2-bromoisobutyrate 0.253 mL
Was added and the mixture was stirred in an oil bath (bath temperature 80 ° C.) for 17 hours. After cooling, 0.063 g of 60% oily sodium hydride and 0.253 mL of ethyl 2-bromoisobutyrate were added, and an oil bath (bath temperature 80
Stir for 3 hours in (° C). After cooling, ice water was added to the reaction solution, which was extracted with ethyl acetate, and the extract was washed with saturated saline,
It was 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 (90: 10: 1). The desired fractions were collected and concentrated to give 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -3-oxo [1,2,
0.38 g of ethyl 4] triazolo [4,3-b] pyridazin-2 (3H) -yl] -2-methylpropionate was obtained as an oil. This oil was dissolved in 5 mL of ethyl acetate, 0.5 mL of a 4N solution of hydrogen chloride in ethyl acetate was added and concentrated, and the residue was triturated with ethyl ether, filtered, collected and dried to give 0.342 g of the title compound. It was Melting point 162 ℃ Elemental analysis value: Calculated value as C ₃₂ H ₄₀ N ₆ O ₄ .HCl ・ (C ₂ H ₅ ) ₂ O (%): C, 61.83; H, 7.35; N, 12.02 Measured value (%): C, 62.16; H, 7.02; N, 12.15

Reference Example 18 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -3-oxo [1,2,4] triazolo [4,3-b] pyridazine
Preparation of -2 (3H) -yl] -2-methylpropionic acid 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -3-oxo [1,2,4] triazolo [4 , 3-b] Pyridazine
Ethyl -2 (3H) -2-yl] -2-methylpropionate (0.50 g) was dissolved in ethanol (3 mL), 1N aqueous sodium hydroxide solution (2.2 mL) was added, and the mixture was stirred at room temperature for 24 hr. Ethanol is distilled off under reduced pressure, the residue is diluted with water and washed with ethyl acetate. To the aqueous layer was added 1N hydrochloric acid (2.2 mL), saturated with sodium chloride, extracted with ethyl acetate-tetrahydrofuran (2: 1), the extract was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, ethyl acetate was added to the residue to make a powder, which was collected by filtration, washed with ethyl acetate and dried to obtain 0.203 g of the title compound. Melting point 181-185 ° C Elemental analysis: Calculated as C ₃₀ H ₃₆ N ₆ O ₄・ 2.5H ₂ O (%): C, 61.10; H, 7.01; N, 14.25 Measured value (%): C, 61.31; H, 7.02; N, 13.91

Reference Example 19 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -3-oxo [1,2,4] triazolo [4,3-b] pyridazine
Preparation of pivaloyloxymethyl-2- (3H) -yl] -2-methylpropionate 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -3-oxo [1,2, 4] Triazolo [4,3-b] pyridazine
Ethyl -2 (3H) -yl] -2-methylpropionate 0.750g was dissolved in ethanol 5mL and 1N sodium hydroxide aqueous solution was added.
3.28 mL was added and the mixture was stirred at room temperature for 24 hours. Ethanol was distilled off under reduced pressure, the residue was diluted with water, washed with ethyl acetate, 3.28 mL of 1N hydrochloric acid was added to the aqueous layer, extracted with ethyl acetate-tetrahydrofuran (1: 1), and the extract was saturated brine. It was washed with and dried over magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in 5 mL of N, N-dimethylformamide, 0.273 g of potassium carbonate and 0.285 mL of chloromethyl pivalate were added, and the mixture was stirred at room temperature for 15 hours. Add ice water to the reaction mixture,
It 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 eluted with ethyl acetate: methanol: triethylamine (185: 15: 2). Fractions of interest were collected and concentrated, ethyl ether was added to the residue for crystallization, filtered, collected and dried to give the title compound 0.524.
got g. Melting point 162 ℃ Elemental analysis value: Calculated value as C ₃₆ H ₄₆ N ₆ O ₆ (%): C, 65.63; H, 7.04; N, 12.76 Actual value (%): C, 65.52; H, 6.80; N, 12.86

Reference Example 20 2- [6- [3- [4- (diphenylmethoxy) piperidino] propoxy] -3-oxo [1,2,4] triazolo [4,3-b] pyridazine-2 (3H)- 2- [6- [3- [4- (Diphenylmethoxy) piperidino] propoxy] -3-oxo [1,2,4] triazolo []-[2-]-methylpropionic acid pivaloyloxymethyl fumarate 4,3-b] Pyridazine-2 (3
H) -yl] -2-methylpropionate (0.750 g) was dissolved in ethanol (6 mL) and 1N sodium hydroxide aqueous solution was added (3.9 m).
L was added and the mixture was stirred at room temperature for 40 hours. Ethanol was distilled off under reduced pressure, the residue was diluted with water, washed with ethyl acetate, 3.9 mL of 1N hydrochloric acid was added to the aqueous layer, extracted with ethyl acetate-tetrahydrofuran (1: 1), and the extract was saturated brine. It was washed with and dried over magnesium sulfate. Concentrate under reduced pressure and remove the residue with N, N
-Dissolved in 5 mL of dimethylformamide, potassium carbonate 0.3
24 g and 0.339 mL of chloromethyl pivalate were added, and the mixture was stirred at room temperature for 18 hours. Ice water was added to the reaction solution 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 eluted with ethyl acetate: methanol (95: 5). Collect the desired fractions, concentrate, and concentrate on 2- [6- [3- [4
-(Diphenylmethoxy) piperidino] propoxy] -3-oxo [1,2,4] triazolo [4,3-b] pyridazin-2 (3H) -yl] -2
-0.50 g of pivaloyloxymethyl methylpropionate was obtained as an oil. 0.50 g of this oily substance was added to 5 m of ethyl acetate.
A solution of 87 mg of fumaric acid in 3 mL of methanol was added, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue for crystallization, which was collected by filtration and dried to obtain 0.463 g of the title compound. Melting point 160-162 ℃ Elemental analysis value: Calculated value as C ₄₀ H ₄₉ N ₅ O ₁₁・ 0.5H ₂ 0 (%): C, 61.21; H, 6.42; N, 8.92 Measured value (%): C, 61.37; H, 6.50; N, 8.88

[0098]

Examples Example 1 (1) Compound of Reference Example 1 10.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Gelatin 3.0 mg (5) Magnesium stearate 2.0 mg Reference Example A mixture of 10.0 mg of the compound obtained in 1 above, 60.0 mg of lactose, and 35.0 mg of corn starch was added to 0.03 m of a 10% aqueous gelatin solution.
L (3.0 mg as gelatin) was granulated through a 1 mm mesh sieve, dried at 40 ° C. and sieved again. 2.0 mg of magnesium stearate was thus obtained.
Mixed with and compressed. The obtained central tablets were coated with sugar coating with a suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were polished with beeswax to obtain coated tablets.

Example 2 (1) Compound of Reference Example 1 10.0 mg (2) Lactose 70.0 mg (3) Corn Starch 50.0 mg (4) Soluble Starch 7.0 mg (5) Magnesium Stearate 3.0 mg Reference Example The compound (10.0 mg) obtained in Example 1 and magnesium stearate (3.0 mg) were granulated with 0.07 mL of an aqueous solution of soluble starch (7.0 mg as soluble starch) and then dried to give lactose 7
Mixed with 0.0 mg and 50.0 mg corn starch. The mixture was compressed to give tablets.

Example 3 (1) Compound of Reference Example 1 5.0 mg (2) Salt 20.0 mg (3) Distilled water 5.0 mg of the compound obtained in Reference Example 1 and 20.0 mg of salt were prepared in distilled water. Was dissolved in water and water was added to make the total volume 2.0 mL. The solution was filtered and filled under aseptic conditions into 2 mL ampoules. The ampoule was sterilized and then sealed to obtain a solution for injection.

Example 4 (1) Compound of Reference Example 9 10.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Gelatin 3.0 mg (5) Magnesium stearate 2.0 mg Reference Example 9 A mixture of 10.0 mg of the compound obtained in 1. with lactose 60.0 mg and corn starch 35.0 mg was added to a 10% gelatin aqueous solution 0.03 m.
L (3.0 mg as gelatin) is passed through a 1 mm mesh sieve to granulate, then dried at 40 ° C and sieved again. The granules thus obtained are mixed with 2.0 mg of magnesium stearate and compressed. The resulting core tablets are sugar-coated with a suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets are polished with beeswax to obtain coated tablets.

Example 5 (1) Compound of Reference Example 9 10.0 mg (2) Lactose 70.0 mg (3) Corn Starch 50.0 mg (4) Soluble Starch 7.0 mg (5) Magnesium Stearate 3.0 mg Reference Example The compound (10.0 mg) obtained in Example 9 and magnesium stearate (3.0 mg) were granulated with 0.07 mL of an aqueous solution of soluble starch (7.0 mg as soluble starch) and dried to give lactose.
Mix with 0.0 mg and 50.0 mg cornstarch. The mixture is compressed to give tablets.

Example 6 (1) Compound of Reference Example 10 10.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Gelatin 3.0 mg (5) Magnesium stearate 2.0 mg Reference Example 10 A mixture of the compound (10.0 mg) obtained above, lactose (60.0 mg) and corn starch (35.0 mg) in 10% gelatin aqueous solution 0.0
Using 3 mL (3.0 mg as gelatin), pass through a 1 mm mesh sieve to granulate, dry at 40 ° C, and sieve again. Magnesium stearate 2.0 mg
Mix with and compress. The resulting core tablets are sugar-coated with a suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets are polished with beeswax to obtain coated tablets.

Example 7 (1) Compound of Reference Example 10 10.0 mg (2) Lactose 70.0 mg (3) Corn Starch 50.0 mg (4) Soluble Starch 7.0 mg (5) Magnesium Stearate 3.0 mg Reference Example 10.0 mg of the compound obtained in 10 and 3.0 mg of magnesium stearate are granulated with 0.07 mL of an aqueous solution of soluble starch (7.0 mg as soluble starch), dried and mixed with 70.0 mg of lactose and 50.0 mg of corn starch. The mixture is compressed to give tablets.

Example 8 1500 g of the compound described in Reference Example 9, 2025 g of lactose and 556.5 g of corn starch were uniformly mixed in a fluidized bed granulation dryer (FD-5S, Powrex Co., Ltd.), and then the mixture was put in the machine. An aqueous solution in which 126 g of hydroxypropyl cellulose was dissolved was sprayed for granulation, and then dried in a fluidized bed granulation dryer.
The obtained granules were crushed by a power mill with a punching screen having a diameter of 1.5 mm to obtain a sized powder. Take 3927 g of this sized powder and add it to croscarmellose sodium.
210g and 63g magnesium stearate are added and mixed with a tumbler mixer to give granules for tableting. The granules were tabletted with a tableting machine using a frame having a diameter of 6.5 mm to a weight of 300 mg to give plain tablets. The obtained uncoated tablets were hydroxypropylmethylcellulose 2910 (TC-
5) and Macrogol 6000 were dissolved, and a liquid in which titanium oxide and iron sesquioxide were dispersed was sprayed to obtain about 13500 tablets, a film tablet of the following formulation containing 100 mg per tablet. Tablet formulation: Composition Compounding amount (mg) (1) Compound described in Reference Example 9 100.0 (2) Lactose 135.0 (3) Corn starch 37.1 (4) Croscarmellose sodium 15.0 (5) Hydroxypropyl cellulose 8.4 (6) Magnesium stearate 4.5 Total (naked tablet) 300.0 Film tablet formulation: (1) Naked tablet 300.0 (film component) (2) Hydroxypropyl methylcellulose 2910 7.485 ( 3) Macrogol 6000 1.5 (4) Titanium oxide 1.0 (5) Iron sesquioxide 0.015 Total 310.0

Example 9 According to the method described in Example 8, about 13,500 film tablets having the following formulation containing 25 mg of the compound described in Reference Example 9 per tablet were obtained. Tablet formulation: Composition Composition amount (mg) (1) Compound described in Reference Example 9 25.0 (2) Lactose 210.0 (3) Corn starch 37.1 (4) Croscarmellose sodium 15.0 (5) Hydroxypropyl cellulose 8.4 (6) Magnesium stearate 4.5 Total (naked tablet) 300.0 Film tablet formulation: (1) Naked tablet 300.0 (film component) (2) Hydroxypropyl methylcellulose 2910 7.485 ( 3) Macrogol 6000 1.5 (4) Titanium oxide 1.0 (5) Iron sesquioxide 0.015 Total 310.0

Example 10 According to the method described in Example 8, about 13500 film tablets of the following formulation containing 5 mg each of the compound described in Reference Example 9 were obtained. Tablet formulation: Composition Composition amount (mg) (1) Compound described in Reference Example 9 5.0 (2) Lactose 230.0 (3) Corn starch 37.1 (4) Croscarmellose sodium 15.0 (5) Hydroxypropyl cellulose 8.4 (6) Magnesium stearate 4.5 Total (naked tablet) 300.0 Film tablet formulation: (1) Naked tablet 300.0 (film component) (2) Hydroxypropyl methylcellulose 2910 7.485 ( 3) Macrogol 6000 1.5 (4) Titanium oxide 1.0 (5) Iron sesquioxide 0.015 Total 310.0

Example 11 According to the method described in Example 8, about 13,500 film tablets having the following formulation containing 1 mg of the compound described in Reference Example 9 per tablet were obtained. Tablet formulation: Composition Compound amount (mg) (1) Compound described in Reference Example 9 1.0 (2) Lactose 234.0 (3) Corn starch 37.1 (4) Croscarmellose sodium 15.0 (5) Hydroxypropyl cellulose 8.4 (6) Magnesium stearate 4.5 Total (naked tablet) 300.0 Film tablet formulation: (1) Naked tablet 300.0 (film component) (2) Hydroxypropyl methylcellulose 2910 7.485 ( 3) Macrogol 6000 1.5 (4) Titanium oxide 1.0 (5) Iron sesquioxide 0.015 Total 310.0

Example 12 White petrolatum 40 g Cetanol 10 g Sarah beeswax 5 g Sorbitan sesquioleate 5 g Lauromoclogold 0.5 g Methyl paraoxybenzoate 0.1 g Propyl paraoxybenzoate 0.1 g Purified water qs Station consisting of the above composition The water absorption ointment (100 g) was preheated to 70 ° C., and 1 g of the compound of Reference Example 9 was added to methanol in the solution.
The solution dissolved by heating to 20 mL was added. The mixture was heated and mixed at the same temperature for 10 minutes, residual methanol was removed, and the mixture was cooled to room temperature to obtain a water-absorbing ointment.

Experimental Example 1 TNF-α in tissues after antigen stimulation in IgE passively sensitized mice
Inhibitory effect on the increase in the amount BALB / c female mice were intravenously administered with 0.25 mL of a 20-fold diluted anti-DNP monoclonal antibody, and systemically passively sensitized. The next day, 0.15% dinitrofluorobenzene solution (DNFB, acetone-olive oil 4: 1) was applied to both left and right auricles of the mouse.
10 μL each was diluted with the mixed solution) to induce a skin reaction. 8 hours after applying DNFB, cut the left and right auricles, and 400 μL of PBS
The mixture was homogenized using a polytron in the inside, and the supernatant after centrifugation (15,000 rpm, 15 minutes, 4 ° C.) was used as a sample. The amount of TNF-α was measured using a commercially available ELISA kit.
In addition, the amount of protein in the sample was measured, and the amount of TNF-α was converted per mg protein. As a preliminary study, the auricle was collected at regular intervals of antigen application and the time course of TNF-α level was observed.
The drug was orally administered 1 hour before the application of DNFB. Results: The amount of TNF-α in the ear tissue was increased 4 hours after application of the antigen, and reached the maximum 8 hours after application (FIG. 1). The amount of TNF-α in the control group 8 hours after antigen application was 3.34 ± 0.3
It was 1 pg / mg protein. The compound of Reference Example 9 (hereinafter,
Abbreviated as Compound A) (0.1-10 mg / kg, po) is TNF-α
The increase in the amount was suppressed in a dose-dependent manner, and the effect of 1 mg / kg or more was significant (Fig. 2).

Experimental Example 2 Inhibitory Effect on TNF-α Release from Mast Cells by Antigen Stimulation Wistar female rats were treated with anti-DNP-IgE antibody (250-fold dilution) for 2 m.
L was intraperitoneally administered, and 48 hours after that, it was killed by exsanguination, and 20 mL of a physiological solution for mast cells (MCM) was intraperitoneally injected, and the washing solution was collected. Centrifuge at 4 ° C, 50 × g for 7 minutes, wash twice with MCM, add 1 mL of heparin-free MCM, and add 1.25 × 1.
A cell suspension of 0 ⁵ cells / mL was prepared, and CaCl ₂ (final concentration 1 mmol / L) was added thereto. After incubating with Compound A or DMSO (final concentration 0.1%) for 60 minutes at 37 ℃,
-BSA (final concentration 30 ng / mL) was added and further incubated for 2 hours. Then, collect the supernatant and measure the amount of TNF-α.
Stored at -40 ° C. The amount of TNF-α was measured using a commercially available ELISA kit. Results: In passively sensitized rat peritoneal mast cells, 27.46 ± 1.40 μg / 10 ⁶ cells were added 2 hours after the addition of antigen (DNP-BSA).
TNF-α was released. Compound A (10 ⁻⁹ to 10 ⁻⁵ mol / L) suppressed antigen-stimulated TNF-α release in a concentration-dependent manner (FIG. 3).

Experimental Example 3 Effect on intracellular signal transduction system in RBL-2H3 cells Rat basophilic leukemia 2H3 (RBL-2H3) cells (JCRB00
23, Human Science Research Resource Bank) is seeded on a 6-well plate or 60-mm dish (0.5 × 10 ⁶ cel).
ls / mL) and anti-DNP-IgE antibody (1: 2000) at 37 ° C. for 90 minutes, and then washed twice with glucose / PIPES buffer. RBL-2H3 cells at 37 ℃ in the presence of Compound A or DMSO (final concentration 0.1%)
After incubating for 15 minutes, DNP-BSA (final concentration 3 ng /
mL) was added and incubated for another 10 minutes. After that, the cells were washed twice with PBS under ice-cooling, and then western bl
Detach with a scraper in cell extraction buffer for ot analysis or kinase assay, incubate on ice for 15 minutes, then centrifuge (14,500 rpm, 4 ° C, 15 min)
Then, the supernatant was recovered. Western blot analysis: 10% SDS of supernatant total cell extract protein solution
-PAGE separated, anti-PLCγ-1 [pY783] phosphospecific
Antibody, anti-PLCγ antibody, anti-active JNK (pTPpY) antibody, anti-pho
spho-MAPK (ERK1 / 2) (Thr202 / Tyr204) antibody, anti-phospho-
p38 MAPK (Thr180 / Tyr182) antibody, anti-p44 / 42 MAP kinase
The protein and its phosphorylated protein were detected by chemiluminescence method using the antibody and anti-JNK antibody. JNK Kinase Assay: G for total cell extract protein solution (250 μg)
The mixture was incubated with ST-c-Jun (1-89) Sepharose beads (2 μg) at 4 ° C. for 12 hours with gentle stirring, washed, and then replaced with a kinase buffer. Kinase reaction is ATP
(100 μmol) was added and incubated at 30 ° C for 30 min, then separated by 10% SDS-PAGE and anti-p
Using the hospho-c-Jun antibody, phosphorylated GST-c-Jun (1-89) was detected by chemiluminescence method. Results: Antigen-stimulated JNK in passively sensitized RBL-2H3 cells
Activation site-specific phosphorylation of s, PLCγ, ERKs and p38 MAPK was observed 10 min after antigen stimulation. Compound A (10 ^-5
--10 ^-7 mol / L suppressed the specific phosphorylation of JNK (JNK1 and JNK2) in a dose-dependent manner (Fig. 4). However, Compound A did not affect activation site-specific phosphorylation of PLCγ, ERKs and p38 MAPK. In addition, the expression level of any protein was not affected by antigen stimulation or treatment with Compound A (Fig. 4). Furthermore, J in the protein extract obtained from cells treated with compound A using c-Jun (1-89) as a substrate
As a result of examining the NK activity, it was confirmed that the JNK activity was suppressed depending on the concentration of Compound A (10 ^{−5 −10 −7} mol / L) (FIG. 5). From the above results, it was revealed that Compound A selectively suppresses JNK activation among various Cascades activated in an IgE-dependent manner.

[0113]

The compound (A), (I) or (II) of the present invention or a salt thereof has an excellent JNK activation inhibitory action,
It can be used as a prophylactic / therapeutic agent for NK-related diseases.

[Brief description of drawings]

[Fig. 1] Auricular TNF- after DNFB application in passively sensitized mice.
The time course of the α amount is shown (mean ± standard error (n = 10)).

FIG. 2 shows the effect of Compound A on the auricular TNF-α amount 8 hours after DNFB application in passively sensitized mice (mean ± standard error (n = 10), ^** p <0.01 (vs: control group) Dunnett).

FIG. 3 shows the effect of Compound A on the TNF-α release amount after antigen stimulation in passively sensitized rat peritoneal mast cells (mean ± standard error (n = 3)).

FIG. 4: JNK after antigen stimulation in passively sensitized RBL-2H3 cells
3 shows the effect of Compound A on the activation of s, PLC-γ, ERKs and p38MAPK.

FIG. 5: cJ after passive antigen stimulation in passively sensitized RBL-2H3 cells
The effect | action of the compound A with respect to JNK kinase activity which uses un as a substrate is shown.

─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. ⁷ Identification Code FI Theme Coat (Reference) A61P 7/00 A61P 7/00 9/00 9/00 9/10 9/10 11/00 11/00 11 / 06 11/06 13/12 13/12 17/00 17/00 17/06 17/06 19/00 19/00 19/08 19/08 25/14 25/14 27/02 27/02 27/06 27/06 27/16 27/16 35/02 35/02 35/04 35/04 37/02 37/02 37/08 37/08 43/00 111 43/00 111 113 113 C07D 487/04 144 C07D 487 / 04 144 145 145 F-term (reference) 4C050 AA01 BB05 BB06 CC08 EE03 EE04 FF02 FF03 GG03 GG04 HH04 4C084 AA02 AA03 AA20 BA44 CA59 MA02 MA17 MA28 MA35 MA41 MA52 MA63 MA66 NA14 ZA022 ZA332 ZA342 ZA362 ZA392 ZA512 ZA592 ZA662 ZA812 ZA892 ZA942 ZA962 ZB072 ZB132 ZB262 ZB272 ZC062 ZC132 ZC202 4C086 AA01 AA02 CB05 MA01 MA02 MA04 MA17 MA28 MA35 MA41 MA52 MA63 MA66 NA14 ZA02 ZA33 ZA34 ZA36 ZA39 Z A51 ZA59 ZA66 ZA81 ZA89 ZA94 ZA96 ZB07 ZB13 ZB26 ZB27 ZC06 ZC13 ZC20

Claims (31)

[Claims] 1. A formula [Chemical 1] [In the formula, Ar^aAnd Ar^bEach has a substituent
Good aromatic group, Ar ^aAnd Ar^bIs adjacent to a carbon atom
A condensed ring group may be formed on B^aRing has substituents
A nitrogen-containing heterocycle which may be present, X^aAnd Y^aIs that
Same or different (1) bond, (2) oxygen atom, (3) S
(O)_p(P is an integer from 0 to 2), (4) NR ^d(R^dIs water
(Representing an elementary atom or a lower alkyl group) or (5) substituent
Optionally having 1 to 3 heteroatoms
A divalent linear lower hydrocarbon group which may be present is represented by A^aThe ring is
Represents a 5-membered ring which may have a substituent, R^aAnd R^bIs
The same or different (1) hydrogen atom, (2) halogen
Atom, (3) a hydrocarbon group which may have a substituent, (4)
Sil group or (5) hydroxy which may have a substituent
Represents a group, R^cIs substituted with (1) hydrogen atom, (2) lower alkyl group
Optionally hydroxyl group or (3) carboxyl
Indicates a group. ] The compound or its salt represented by
C-Jun N-terminal kinase activity containing a prodrug of
Sexual inhibitor. 2. A formula [Chemical 2] [In the formula, Ar^aAnd Ar^bEach has a substituent
Good aromatic group, Ar ^aAnd Ar^bIs adjacent to a carbon atom
A condensed ring group may be formed on B^aRing has substituents
A nitrogen-containing heterocycle which may be present, X^aAnd Y^aIs that
Same or different (1) bond, (2) oxygen atom, (3) S
(O)_p(P is an integer from 0 to 2), (4) NR ^d(R^dIs water
(Representing an elementary atom or a lower alkyl group) or (5) substituent
Optionally having 1 to 3 heteroatoms
A divalent linear lower hydrocarbon group which may be present is represented by A^aThe ring is
Represents a 5-membered ring which may have a substituent, R^aAnd R^bIs
The same or different (1) hydrogen atom, (2) halogen
Atom, (3) a hydrocarbon group which may have a substituent, (4)
Sil group or (5) hydroxy which may have a substituent
Represents a group, R^cIs substituted with (1) hydrogen atom, (2) lower alkyl group
Optionally hydroxyl group or (3) carboxyl
Indicates a group. ] The compound or its salt represented by
A TNF-α inhibitor comprising a prodrug of 3. A formula [Chemical 3] [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 (1) bond, (2) oxygen atom, (3) S (O)_p
(P is an integer from 0 to 2), (4) NR^Four(R^FourIs hydrogen
Child or lower alkyl group) or (5)
Optionally via one to three heteroatoms
Is a divalent straight chain lower hydrocarbon group, A is (1) nitrogen
Atom or (2) CR⁷(R⁷Is hydrogen atom, halogen atom, substitution
Optionally substituted hydrocarbon group, acyl group or substituted
Represents a hydroxy group which may have a group),
R¹, R²And R³Are the same or different (1) hydrogen
Atom, (2) halogen atom, (3) may have a substituent
Having a hydrocarbon group, (4) acyl group or (5) substituent
Shows a good hydroxy group, R⁸Is (1) hydrogen atom, (2) lower
A hydroxy group which may be substituted with an alkyl group or
(3) Indicates a carboxyl group. ] The compound represented by
C-Jun containing its salt or its prodrug
N-terminal kinase activation inhibitor. 4. A formula [Chemical 4] [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 (1) bond, (2) oxygen atom, (3) S (O)_p
(P is an integer from 0 to 2), (4) NR^Four(R^FourIs hydrogen
Child or lower alkyl group) or (5)
Optionally via one to three heteroatoms
Is a divalent straight chain lower hydrocarbon group, A is (1) nitrogen
Atom or (2) CR⁷(R⁷Is hydrogen atom, halogen atom, substitution
Optionally substituted hydrocarbon group, acyl group or substituted
Represents a hydroxy group which may have a group),
R¹, R²And R³Are the same or different (1) hydrogen
Atom, (2) halogen atom, (3) may have a substituent
Having a hydrocarbon group, (4) acyl group or (5) substituent
Shows a good hydroxy group, R⁸Is (1) hydrogen atom, (2) lower
A hydroxy group which may be substituted with an alkyl group or
(3) Indicates a carboxyl group. ] The compound represented by
Is TNF-α containing its salt or its prodrug
Inhibitor. 5. Ar¹And Ar²Is (i) halogen atom, (ii) C
_1-6Alkylenedioxy, (iii) nitro, (iv) cyano,
(v) C which may be halogenated_1-6Alkyl, (vi)
C, which may be rogenized_2-6Alkenyl, (vii) halo
C that may be genated_2-6Alkynyl, (viii) C_3-6Shi
Chloroalkyl, (ix) 1 to 3 halogen atoms, mono
-Or the -C_1-6Alkylamino or C_1-6Alkoxy
-C which may have carbonyl_1-6Alkoxy, (x)
C, which may be rogenized_1-6Alkylthio, (xi) hydr
Roxy, (xii) amino, (xiii) mono-C_1-6Alkylami
No, (xiv) di-C_1-6Alkylamino, (xv) 5- or 6-membered ring
Amino, (xvi) C_1-6Alkyl-carbonyl, (xvii) calc
Boxil, (xviii) C_1-6Alkoxy-carbonyl, (xix)
Carbamoyl, (xx) thiocarbamoyl, (xxi) mono-C_1-6
Alkyl-carbamoyl, (xxii) di-C_1-6Alkyl-cal
Bamoi, (xxiii) C_6-10Aryl-carbamoyl, (xxi
v) sulfo, (xxv) C_1-6Alkylsulfonyl, (xxvi) C_6-10
Aryl, (xxvii) C_{6- Ten}Aryloxy and (xxviii)
C_7-16Based on a group selected from the group consisting of aralkyloxy
May be replaced (1) C_6-14Aromatic hydrocarbon group or
(2) In addition to carbon atom, nitrogen atom, sulfur atom and oxygen atom
5 to containing 1 to 4 heteroatoms selected from
8-membered aromatic heterocyclic group, or (3) the aromatic heterocyclic group and C
_6-14Starts from a ring formed by condensation with an aromatic hydrocarbon ring
A monovalent group formed by removing the intended hydrogen atom, Ar¹And Ar²
Is a halogen atom together with the adjacent carbon atom, (ii) C
_1-6Alkylenedioxy, (iii) nitro, (iv) cyano,
(v) C which may be halogenated_{1 -6}Alkyl, (vi)
C, which may be rogenized_2-6Alkenyl, (vii) halo
C that may be genated_2-6Alkynyl, (viii) C_3-6Shi
Chloroalkyl, (ix) 1 to 3 halogen atoms, mono
-Or the -C_1-6Alkylamino or C_1-6Alkoxy
-C which may have carbonyl_1-6Alkoxy, (x)
C, which may be rogenized_1-6Alkylthio, (xi) hydr
Roxy, (xii) amino, (xiii) mono-C_1-6Alkylami
No, (xiv) di-C_1-6Alkylamino, (xv) 5- or 6-membered ring
Amino, (xvi) C _1-6Alkyl-carbonyl, (xvii) calc
Boxil, (xviii) C_1-6Alkoxy-carbonyl, (xix)
Carbamoyl, (xx) thiocarbamoyl, (xxi) mono-C_1-6
Alkyl-carbamoyl, (xxii) di-C_1-6Alkyl-cal
Bamoi, (xxiii) C_6-10Aryl-carbamoyl, (xxi
v) sulfo, (xxv) C_1-6Alkylsulfonyl, (xxvi) C_6-10
Aryl, (xxvii) C_6-10Aryloxy, (xxviii) C
_7-16A group consisting of aralkyloxy and (xxix) oxo
A formula optionally substituted with a group selected from [Chemical 5] [In the formula, R⁸Is a hydrogen atom, C_1-6Substituted with alkyl
Represents a hydroxy group or a carboxyl group]
It may form a condensed ring group represented by B ring is (i)
Rogen atom, (ii) C_1-6Alkylenedioxy, (iii) nit
B, (iv) cyano, (v) optionally halogenated C_1-6
Alkyl, (vi) optionally halogenated C_2-6Arche
Nil, (vii) optionally halogenated C_2-6Alkini
Le, (viii) C_3-6Cycloalkyl, (ix) 1 to 3 ha
Rogen atom, mono- or di-C _1-6Alkylamino
Is C_1-6Alkoxy-C optionally having carbonyl_1-6
Alkoxy, (x) optionally halogenated C_1-6Al
Kirthio, (xi) hydroxy, (xii) amino, (xiii) mono-
C_1-6Alkylamino, (xiv) di-C_1-6Alkylamino, (x
v) 5- or 6-membered cyclic amino, (xvi) C_1-6Alkyl-carbo
Nil, (xvii) carboxyl, (xviii) C_1-6Alkoxy-mosquito
Lubonyl, (xix) carbamoyl, (xx) thiocarbamoy
Le, (xxi) Mono-C_1-6Alkyl-carbamoyl, (xxii) di-
C_1-6Alkyl-carbamoyl, (xxiii) C_6-10Aryl-mosquito
Lubamoyl, (xxiv) sulfo, (xxv) C_{1- 6}Alkyl sulfo
Nil, (xxvi) C_6-10Aryl, (xxvii) C_6-10Ario
Kish, (xxviii) C_7-16Aralkyloxy and (xxix) o
May be substituted with groups selected from the group consisting of xoxo
Containing at least one nitrogen atom, and
1 to 3 selected from child, oxygen atom and sulfur atom
3 to 13-membered nitrogen-containing, which may contain hetero atoms of
Represents a heterocyclic ring, where X and Y are the same or different
, (1) bond, (2) oxygen atom, (3) S (O)_p(P is 0 or
2), (4) NR^Four(R^FourIs a hydrogen atom or straight chain
Or branched C_1-6Alkyl group) or (5) (i)
Rogen atom, (ii) C_1-6Alkylenedioxy, (iii) nit
B, (iv) cyano, (v) optionally halogenated C_1-6
Alkyl, (vi) optionally halogenated C_2-6Arche
Nil, (vii) optionally halogenated C_2-6Alkini
Le, (viii) C_3-6Cycloalkyl, (ix) 1 to 3 ha
Rogen atom, mono- or di-C_1-6Alkylamino
Is C_1-6Alkoxy-C optionally having carbonyl_1-6
Alkoxy, (x) optionally halogenated C_{1- 6}Al
Kirthio, (xi) hydroxy, (xii) amino, (xiii) mono-
C_1-6Alkylamino, (xiv) di-C_1-6Alkylamino, (x
v) 5- or 6-membered cyclic amino, (xvi) C_1-6Alkyl-carbo
Nil, (xvii) carboxyl, (xviii) C_1-6Alkoxy-mosquito
Lubonyl, (xix) carbamoyl, (xx) thiocarbamoy
Le, (xxi) Mono-C_1-6Alkyl-carbamoyl, (xxii) di-
C_1-6Alkyl-carbamoyl, (xxiii) C_6-10Aryl-
Carbamoyl, (xxiv) sulfo, (xxv) C_1-6Alkylsul
Honil, (xxvi) C_6-10Aryl, (xxvii) C_6-10Aryl
Oxy, (xxviii) C_7-16Aralkyloxy and (xxix)
May have a substituent selected from the group consisting of oxo
Black, oxygen atom, NR^{Four '}(R^{Four '}Is a hydrogen atom or lower alkyl
1 to 3 selected from a sulfur atom) and a sulfur atom
Divalent straight-chain C optionally via one heteroatom_1-6Charcoal
A hydrogen atom group, A is a nitrogen atom or CR⁷[R⁷Is (1) hydrogen
Atom, (2) halogen atom, (3) (i) halogen atom, (ii) C
_1-6Alkylenedioxy, (iii) nitro, (iv) cyano,
(v) C which may be halogenated_1-6Alkyl, (vi)
C, which may be rogenized_2-6Alkenyl, (vii) halo
C that may be genated_2-6Alkynyl, (viii) C_3-6Shi
Chloroalkyl, (ix) 1 to 3 halogen atoms, mono
-Or the -C_1-6Alkylamino or C_1-6Alkoxy
-C which may have carbonyl_1-6Alkoxy, (x)
C, which may be rogenized_1-6Alkylthio, (xi) hydr
Roxy, (xii) amino, (xiii) mono-C_1-6Alkylami
No, (xiv) di-C_1-6Alkylamino, (xv) 5- or 6-membered ring
Amino, (xvi) C_1-6Alkyl-carbonyl, (xvii) calc
Boxil, (xviii) C_1-6Alkoxy-carbonyl, (xix)
Carbamoyl, (xx) thiocarbamoyl, (xxi) mono-C_1-6
Alkyl-carbamoyl, (xxii) di-C_1-6Alkyl-cal
Bamoi, (xxiii) C_6-10Aryl-carbamoyl, (xxi
v) sulfo, (xxv) C_1-6Alkylsulfonyl, (xxvi) C_6-10
Aryl, (xxvii) C_6-10Aryloxy, (xxviii) C
_7-16A group consisting of aralkyloxy and (xxix) oxo
C optionally substituted with a group selected from_{1 -6}Alkyl group,
C_2-6Alkenyl group, C_2-6Alkynyl group, C_3-6Cycloal
Kill group, C_3-6Cycloalkyl group and 1 to 3 C_1-6A
Condensed with a benzene ring that may have a lucoxy group
Base, C_6-14Aryl group or C_7-16Aralkyl group, (4)-
(C = O) -R⁹, -SO₂-R⁹, -SO-R⁹,-(C = O) NR^TenR⁹,-(C = O) O-R
⁹,-(C = S) O-R⁹Or- (C = S) NR^TenR⁹(R⁹Is (a) a hydrogen atom,
(b) (i) halogen atom, (ii) C_1-6Alkylenedioxy, (i
ii) nitro, (iv) cyano, (v) may be halogenated
I C_1-6Alkyl, (vi) optionally halogenated C_2-6
Alkenyl, (vii) optionally halogenated C_2-6A
Lucinyl, (viii) C_3-6Cycloalkyl, (ix) 1 to 3
Halogen atoms, mono- or di-C_1-6Alkylamino
Or C_1-6May have an alkoxy-carbonyl
I C_1-6Alkoxy, (x) optionally halogenated C
_1-6Alkylthio, (xi) hydroxy, (xii) amino, (xii
i) Mono-C_1-6Alkylamino, (xiv) di-C_1-6Alkyla
Mino, (xv) 5- or 6-membered cyclic amino, (xvi) C_1-6Archi
Le-carbonyl, (xvii) carboxyl, (xviii) C_1-6Al
Coxy-carbonyl, (xix) carbamoyl, (xx) thiocal
Bamoi, (xxi) Mono-C_1-6Alkyl-carbamoyl, (xx
ii) Ji-C_1-6Alkyl-carbamoyl, (xxiii) C_6-10Ants
-Carbamoyl, (xxiv) sulfo, (xxv) C_1-6Alkyl
Sulfonyl, (xxvi) C_6-10Aryl, (xxvii) C_6-10Ants
Oxy, (xxviii) C_7-16Aralkyloxy and (xx
ix) substituted with a group selected from the group consisting of oxo,
Moyo C_1-6Alkyl group, C_2-6Alkenyl group, C_2-6Archi
Nyl group, C_3-6Cycloalkyl group, C_3-6Cycloalkyl group
And 1 to 3 Cs_1-6May have an alkoxy group
A group condensed with a benzene ring, C_{6 -14}Aryl group or C
_7-16Aralkyl group or (c) -OR¹¹(R¹¹Is a hydrogen atom,
Or (i) halogen atom, (ii) C_1-6Alkylene Dioki
Si, (iii) nitro, (iv) cyano, (v) halogenated
May be C_1-6Alkyl, (vi) may be halogenated
I C_2-6Alkenyl, (vii) optionally halogenated C
_2-6Alkynyl, (viii) C_3-6Cycloalkyl, (ix) 1
3 halogen atoms, mono- or di-C_{1- 6}Alkyl
Amino or C_1-6Has an alkoxy-carbonyl
May be C_1-6Alkoxy, (x) even if halogenated
Good c_1-6Alkylthio, (xi) hydroxy, (xii) ami
No, (xiii) Mono-C_1-6Alkylamino, (xiv) di-C_1-6A
Rukylamino, (xv) 5- or 6-membered cyclic amino, (xvi) C
_1-6Alkyl-carbonyl, (xvii) carboxyl, (xvii
I c_1-6Alkoxy-carbonyl, (xix) carbamoyl, (x
(x) thiocarbamoyl, (xxi) mono-C_1-6Alkyl-carb
Moyle, (xxii) di-C_1-6Alkyl-carbamoyl, (xxii
I c_6-10Aryl-carbamoyl, (xxiv) sulfo, (xxv) C
_1-6Alkylsulfonyl, (xxvi) C_6-10Aryl, (xxvi
I c_6-10Aryloxy, (xxviii) C_7-16Aralkyl Oki
Substituted with a group selected from the group consisting of Si and (xxix) oxo
May be C_1-6Alkyl group, C_2-6Alkenyl group,
C_2-6Alkynyl group, C_{3 -6}Cycloalkyl group, C_3-6Cyclo
Alkyl group and 1 to 3 C_1-6Having an alkoxy group
C, a group condensed with an benzene ring that may be present_6-14Aryl
Group or C_7-16Represents an aralkyl group)
Shows, R^TenIs a hydrogen atom or C_1-6(Indicating an alkyl group)
The indicated acyl group, or (5) -OR¹²(R¹²Is a hydrogen atom,
Or (i) halogen atom, (ii) C_1-6Alkylene Dioki
Si, (iii) nitro, (iv) cyano, (v) halogenated
May be C_1-6Alkyl, (vi) may be halogenated
I C_2-6Alkenyl, (vii) optionally halogenated C
_2-6Alkynyl, (viii) C_3-6Cycloalkyl, (ix) 1
3 halogen atoms, mono- or di-C_1-6Alkyl
Amino or C_1-6Has an alkoxy-carbonyl
May be C_1-6Alkoxy, (x) even if halogenated
Good c_1-6Alkylthio, (xi) hydroxy, (xii) ami
No, (xiii) Mono-C_1-6Alkylamino, (xiv) di-C_1-6A
Rukylamino, (xv) 5- or 6-membered cyclic amino, (xvi) C
_1-6Alkyl-carbonyl, (xvii) carboxyl, (xvii
I c_1-6Alkoxy-carbonyl, (xix) carbamoyl, (x
(x) thiocarbamoyl, (xxi) mono-C_1-6Alkyl-carb
Moyle, (xxii) di-C_1-6Alkyl-carbamoyl, (xxii
I c_6-10Aryl-carbamoyl, (xxiv) sulfo, (xxv) C
_1-6Alkylsulfonyl, (xxvi) C_6-10Aryl, (xxvi
I c_6-10Aryloxy, (xxviii) C_7-16Aralkyl Oki
Substituted with a group selected from the group consisting of Si and (xxix) oxo
May be C_1-6Alkyl group, C_2-6Alkenyl group,
C_2-6Alkynyl group, C_3-6Cycloalkyl group, C_3-6Cyclo
Alkyl group and 1 to 3 C_1-6Having an alkoxy group
C, a group condensed with an benzene ring that may be present_6-14Aryl
Group or C_7-16Represents an aralkyl group)
Show], R¹, R²And R³Is (1) Hydrogen source
Child, (2) halogen atom, (3) (i) halogen atom, (ii) C_1-6
Alkylenedioxy, (iii) nitro, (iv) cyano, (v) ha
C, which may be rogenized_1-6Alkyl, (vi) halogen
C that may be_2-6Alkenyl, (vii) halogenated
May be C_2-6Alkynyl, (viii) C_3-6Cycloa
Ruquil, (ix) 1 to 3 halogen atoms, mono-also
Is di-C_1-6Alkylamino or C_1-6Alkoxy-Cal
C optionally having bonyl_1-6Alkoxy, (x) halogen
C, which may be_1-6Alkylthio, (xi) hydroxy
Ci, (xii) amino, (xiii) mono-C_1-6Alkylamino, (x
iv) Di-C_1-6Alkylamino, (xv) 5- or 6-membered cyclic amino
No, (xvi) C_1-6Alkyl-carbonyl, (xvii) carboxy
Le, (xviii) C_1-6Alkoxy-carbonyl, (xix) carba
Moyl, (xx) thiocarbamoyl, (xxi) mono-C_1-6Archi
Le-carbamoyl, (xxii) di-C_1-6Alkyl-carbamoy
Le, (xxiii) C_6-10Aryl-carbamoyl, (xxiv) sul
E, (xxv) C_1-6Alkylsulfonyl, (xxvi) C_6-10Ally
Le, (xxvii) C_6-10Aryloxy, (xxviii) C_7-16Ara
Selected from the group consisting of ruxyloxy and (xxix) oxo
C optionally substituted with a group_{1 -6}Alkyl group, C_2-6Al
Kenyl group, C_2-6Alkynyl group, C_3-6Cycloalkyl group,
C_3-6Cycloalkyl group and 1 to 3 C_1-6Alkoxy
A group condensed with a benzene ring which may have a group, C
_6-14Aryl group or C_7-16Aralkyl group, (4)-(C = O)
-R¹³, -SO₂-R¹³, -SO-R¹³,-(C = O) NR¹⁴R¹³,-(C = O) O-R
¹³,-(C = S) O-R¹³Or- (C = S) NR¹⁴R¹³(R¹³Is (a) hydrogen source
Child, (b) (i) halogen atom, (ii) C_1-6Alkylene Dioki
Si, (iii) nitro, (iv) cyano, (v) halogenated
May be C_1-6Alkyl, (vi) may be halogenated
I C_2-6Alkenyl, (vii) optionally halogenated C
_2-6Alkynyl, (viii) C_3-6Cycloalkyl, (ix) 1
3 halogen atoms, mono- or di-C_1-6Alkyl
Amino or C_1-6Has an alkoxy-carbonyl
May be C_1-6Alkoxy, (x) even if halogenated
Good c_1-6Alkylthio, (xi) hydroxy, (xii) ami
No, (xiii) Mono-C_1-6Alkylamino, (xiv) di-C_1-6A
Rukylamino, (xv) 5- or 6-membered cyclic amino, (xvi) C_1-
6Alkyl-carbonyl, (xvii) carboxyl, (xviii) C
_1-6Alkoxy-carbonyl, (xix) carbamoyl, (xx)
Thiocarbamoyl, (xxi) mono-C_1-6Alkyl-carbamo
Ill, (xxii) di-C_1-6Alkyl-carbamoyl, (xxiii) C
_6-10Aryl-carbamoyl, (xxiv) sulfo, (xxv) C_1-6
Alkylsulfonyl, (xxvi) C_6-10Aryl, (xxvii) C
_6-10Aryloxy, (xxviii) C_7-16Aralkyloxy
And a group selected from the group consisting of (xxix) oxo and
May be C_1-6Alkyl group, C_2-6Alkenyl group, C_2-6
Alkynyl group, C_3-6Cycloalkyl group, C_3-6Cycloal
Kill group and 1 to 3 Cs_1-6Has an alkoxy group
A group condensed with a good benzene ring, C_6-14Aryl group too
Or C_7-16Aralkyl group or (c) -OR¹⁵(R¹⁵Is hydrogen
Atom, or (i) halogen atom, (ii) C_1-6Alkylenedi
Oxy, (iii) nitro, (iv) cyano, (v) halogenated
May be C_1-6Alkyl, (vi) halogenated
Moyo C_2-6Alkenyl, (vii) even if halogenated
Good c_2-6Alkynyl, (viii) C_3-6Cycloalkyl, (ix)
1 to 3 halogen atoms, mono- or di-C_1-6Al
Kiramino or C_1-6Having an alkoxy-carbonyl
May be C_1-6Alkoxy, (x) halogenated
May be C_1-6Alkylthio, (xi) hydroxy, (xii) a
Mino, (xiii) Mono-C_1-6Alkylamino, (xiv) di-C_1-6
Alkylamino, (xv) 5- or 6-membered cyclic amino, (xvi) C
_1-6Alkyl-carbonyl, (xvii) carboxyl, (xvii
I c_1-6Alkoxy-carbonyl, (xix) carbamoyl, (x
(x) thiocarbamoyl, (xxi) mono-C_1-6Alkyl-carb
Moyle, (xxii) di-C_1-6Alkyl-carbamoyl, (xxii
I c_6-10Aryl-carbamoyl, (xxiv) sulfo, (xxv) C
_1-6Alkylsulfonyl, (xxvi) C_6-10Aryl, (xxvi
I c_6-10Aryloxy, (xxviii) C_7-16Aralkyl Oki
Substituted with a group selected from the group consisting of Si and (xxix) oxo
May be C_1-6Alkyl group, C_2-6Alkenyl group,
C_2-6Alkynyl group, C_3-6Cycloalkyl group, C_3-6Cyclo
Alkyl group and 1 to 3 C_1-6Having an alkoxy group
C, a group condensed with an benzene ring that may be present_6-14Aryl
Group or C_7-16Represents an aralkyl group)
Shows, R¹⁴Is a hydrogen atom or C_1-6(Indicating an alkyl group)
The indicated acyl group, or (5) -OR¹⁶(R¹⁶Is a hydrogen atom,
Or (i) halogen atom, (ii) C_1-6Alkylene Dioki
Si, (iii) nitro, (iv) cyano, (v) halogenated
May be C_1-6Alkyl, (vi) may be halogenated
I C_2-6Alkenyl, (vii) optionally halogenated C
_2-6Alkynyl, (viii) C_3-6Cycloalkyl, (ix) 1
3 halogen atoms, mono- or di-C_1-6Alkyl
Amino or C_1-6Has an alkoxy-carbonyl
May be C_1-6Alkoxy, (x) even if halogenated
Good c_1-6Alkylthio, (xi) hydroxy, (xii) ami
No, (xiii) Mono-C_1-6Alkylamino, (xiv) di-C_1-6A
Rukylamino, (xv) 5- or 6-membered cyclic amino, (xvi) C
_1-6Alkyl-carbonyl, (xvii) carboxyl, (xvii
I c_1-6Alkoxy-carbonyl, (xix) carbamoyl, (x
(x) thiocarbamoyl, (xxi) mono-C_1-6Alkyl-carb
Moyle, (xxii) di-C_1-6Alkyl-carbamoyl, (xxii
I c_6-10Aryl-carbamoyl, (xxiv) sulfo, (xxv) C
_1-6Alkylsulfonyl, (xxvi) C_6-10Aryl, (xxvi
I c_6-10Aryloxy, (xxviii) C_7-16Aralkyl Oki
Substituted with a group selected from the group consisting of Si and (xxix) oxo
May be C_1-6Alkyl group, C_2-6Alkenyl group, C
_2-6Alkynyl group, C_3-6Cycloalkyl group, C_3-6Cycloa
Rukyl radical and 1 to 3 Cs_1-6Has an alkoxy group
An optionally condensed benzene ring, C,_6-14Aryl group
Or C_7-16Represents an aralkyl group)
Then R⁸Is a hydrogen atom, C_1-6May be substituted with alkyl
A hydroxy group or a carboxyl group,
Or the agent described in 4. 6. Ar ¹ and Ar ² are phenyl groups and B ring is of the formula: [Wherein Z ′ represents a methine group, Z ^{1 ′} and Z ^{2 ′} represent a methylene group or an ethylene group], X is a bond or an oxygen atom, and Y is — (CH ₂ ) _p1 A group represented by NH- (p1 is an integer of 1 to 6), A is CR ^{7 ''} (R ^{7 ''} is a hydrogen atom or a C _1-6 alkyl group), and R ¹ is (1) Hydrogen atom, (2) carboxyl or C _1-6 alkoxy-carbonyl optionally substituted C _1-6 alkyl group or (3) C _1-6 alkoxy-carbonyl optionally substituted C _1-6 The agent according to claim 3 or 4, wherein a carbamoyl group optionally having alkyl, R ² is a hydrogen atom, R ³ is a hydrogen atom, and R ⁸ is a hydrogen atom. 7. The compound is 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid or a salt thereof. The agent according to claim 3 or 4, which is 8. The compound is 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid dihydrate. The agent according to claim 3 or 4, which is a product. 9. The agent according to claim 1, which is a prophylactic / therapeutic agent for c-Jun-related diseases. 10. Prevention of diseases associated with c-Jun N-terminal kinase
The agent according to claim 1, which is a therapeutic agent. 11. Acute pancreatitis, chronic pancreatitis, adult respiratory distress syndrome, scleroderma, deep lupus erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia. Disease, myasthenia gravis, multiple myeloma, acute myeloblastic leukemia, chronic sarcoma, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, wasting disease, Huntington's disease, ischemia / reperfusion in stroke Disease, myocardial ischemia, ischemic heart disease, renal ischemia, neovascular glaucoma, infantile hemangiomas, blood vessel proliferation, cardiac hypertrophy, abnormal immune response, fever, cell aging or apoptosis-related diseases Item 1. The agent according to Item 1. 12. The agent according to claim 1, which is an agent for improving nasal congestion. 13. For mammals, the formula [Chemical 7] [In the formula, Ar^aAnd Ar^bEach has a substituent
Good aromatic group, Ar ^aAnd Ar^bIs adjacent to a carbon atom
A condensed ring group may be formed on B^aRing has substituents
A nitrogen-containing heterocycle which may be present, X^aAnd Y^aIs that
Same or different (1) bond, (2) oxygen atom, (3) S
(O)_p(P is an integer from 0 to 2), (4) NR ^d(R^dIs water
(Representing an elementary atom or a lower alkyl group) or (5) substituent
Optionally having 1 to 3 heteroatoms
A divalent linear lower hydrocarbon group which may be present is represented by A^aThe ring is
Represents a 5-membered ring which may have a substituent, R^aAnd R^bIs
The same or different (1) hydrogen atom, (2) halogen
Atom, (3) a hydrocarbon group which may have a substituent, (4)
Sil group or (5) hydroxy which may have a substituent
Represents a group, R^cIs substituted with (1) hydrogen atom, (2) lower alkyl group
Optionally hydroxyl group or (3) carboxyl
Indicates a group. ] The compound or its salt represented by
C-Ju characterized by administering an effective amount of a prodrug of c-Ju
n N-terminal kinase activation inhibition method. 14. For mammals, the formula [Chemical 8] [In the formula, Ar^aAnd Ar^bEach has a substituent
Good aromatic group, Ar ^aAnd Ar^bIs adjacent to a carbon atom
A condensed ring group may be formed on B^aRing has substituents
A nitrogen-containing heterocycle which may be present, X^aAnd Y^aIs that
Same or different (1) bond, (2) oxygen atom, (3) S
(O)_p(P is an integer from 0 to 2), (4) NR ^d(R^dIs water
(Representing an elementary atom or a lower alkyl group) or (5) substituent
Optionally having 1 to 3 heteroatoms
A divalent linear lower hydrocarbon group which may be present is represented by A^aThe ring is
Represents a 5-membered ring which may have a substituent, R^aAnd R^bIs
The same or different (1) hydrogen atom, (2) halogen
Atom, (3) a hydrocarbon group which may have a substituent, (4)
Sil group or (5) hydroxy which may have a substituent
Represents a group, R^cIs substituted with (1) hydrogen atom, (2) lower alkyl group
Optionally hydroxyl group or (3) carboxyl
Indicates a group. ] The compound or its salt represented by
Acute characterized by administering an effective amount of a prodrug of
Pancreatitis, chronic pancreatitis, adult respiratory distress syndrome, scleroderma, deep-seated
Lupus erythematosus, chronic thyroiditis, Graves disease, autoimmune
Gastritis, autoimmune neutropenia, thrombocytopenia, severe muscle
Asthenia, multiple myeloma, acute myeloblastic leukemia, chronic meat
Tumor, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, wasting
Ischemia / reperfusion in sexually transmitted diseases, Huntington's disease, and stroke
Diseases, myocardial ischemia, ischemic heart disease, renal ischemia, blood vessels
Neonatal glaucoma, infantile hemangiomas, blood vessel proliferation, cardiac hypertrophy, abnormal immunity
Of epidemiological response, fever, cell senescence or apoptosis related diseases
Prevention / treatment method and nasal congestion improvement method. 15. A method for producing a c-Jun N-terminal kinase activation inhibitor
Formula for building [Chemical 9] [In the formula, Ar^aAnd Ar^bEach has a substituent
Good aromatic group, Ar ^aAnd Ar^bIs adjacent to a carbon atom
A condensed ring group may be formed on B^aRing has substituents
A nitrogen-containing heterocycle which may be present, X^aAnd Y^aIs that
Same or different (1) bond, (2) oxygen atom, (3) S
(O)_p(P is an integer from 0 to 2), (4) NR ^d(R^dIs water
(Representing an elementary atom or a lower alkyl group) or (5) substituent
Optionally having 1 to 3 heteroatoms
A divalent linear lower hydrocarbon group which may be present is represented by A^aThe ring is
Represents a 5-membered ring which may have a substituent, R^aAnd R^bIs
The same or different (1) hydrogen atom, (2) halogen
Atom, (3) a hydrocarbon group which may have a substituent, (4)
Sil group or (5) hydroxy which may have a substituent
Represents a group, R^cIs substituted with (1) hydrogen atom, (2) lower alkyl group
Optionally hydroxyl group or (3) carboxyl
Indicates a group. ] The compound or its salt represented by
Use of prodrugs. 16. Acute pancreatitis, chronic pancreatitis, adult respiratory distress syndrome
Flock, scleroderma, deep erythematous lupus, chronic thyroiditis, gray
Buss disease, autoimmune gastritis, autoimmune neutropenia, blood
Parenchyma, myasthenia gravis, multiple myeloma, acute myeloblast
Spherical leukemia, chronic sarcoma, chronic myelogenous leukemia, metastatic melanoma
Tumor, Kaposi's sarcoma, wasting disease, Huntington's disease, stroke
Associated with ischemia / reperfusion, myocardial ischemia, ischemic
Heart disease, renal ischemia, neovascular glaucoma, infantile hemangiomas, blood vessels
Proliferation, cardiac hypertrophy, abnormal immune response, fever, cell aging or
Prophylactic / therapeutic agent for porosis-related diseases and agent for improving nasal congestion
Formula for manufacturing [Chemical 10] [In the formula, Ar^aAnd Ar^bEach has a substituent
Good aromatic group, Ar ^aAnd Ar^bIs adjacent to a carbon atom
A condensed ring group may be formed on B^aRing has substituents
A nitrogen-containing heterocycle which may be present, X^aAnd Y^aIs that
Same or different (1) bond, (2) oxygen atom, (3) S
(O)_p(P is an integer from 0 to 2), (4) NR ^d(R^dIs water
(Representing an elementary atom or a lower alkyl group) or (5) substituent
Optionally having 1 to 3 heteroatoms
A divalent linear lower hydrocarbon group which may be present is represented by A^aThe ring is
Represents a 5-membered ring which may have a substituent, R^aAnd R^bIs
The same or different (1) hydrogen atom, (2) halogen
Atom, (3) a hydrocarbon group which may have a substituent, (4)
Sil group or (5) hydroxy which may have a substituent
Represents a group, R^cIs substituted with (1) hydrogen atom, (2) lower alkyl group
Optionally hydroxyl group or (3) carboxyl
Indicates a group. ] The compound or its salt represented by
Use of prodrugs. 17. A compound comprising a compound having (1) an antihistamine action and / or an eosinophil chemotaxis inhibitory action and (2) a c-Jun N-terminal kinase activation inhibitory action or a prodrug thereof. -Jun N-terminal kinase activation inhibitor. 18. A TNF comprising a compound having (1) an antihistamine action and / or an eosinophil chemotaxis inhibitory action and (2) a c-Jun N-terminal kinase activation inhibitory action, or a prodrug thereof. -alpha inhibitor. 19. Acute comprising a compound having (1) an antihistamine action and / or an eosinophil chemotaxis inhibitory action and (2) a c-Jun N-terminal kinase activation inhibitory action, or a prodrug thereof. Pancreatitis, chronic pancreatitis, adult respiratory distress syndrome, scleroderma, deep erythematous lupus, chronic thyroiditis,
Graves' disease, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, myasthenia gravis, multiple myeloma, acute myeloblastic leukemia, chronic sarcoma, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, wasting disease, Huntington's disease, diseases associated with ischemia / reperfusion in stroke, myocardial ischemia, ischemic heart disease, renal ischemia, neovascular glaucoma, infantile hemangiomas,
A prophylactic / therapeutic agent for vascular proliferation, cardiac hypertrophy, abnormal immune response, fever, cell aging or apoptosis-related diseases and a nasal congestion improving agent. 20. A compound having (1) an antihistamine action and / or an eosinophil chemotaxis inhibitory action, (2) a c-Jun N-terminal kinase activation inhibitory action and (3) a TNF-α inhibitory action. Acute pancreatitis, chronic pancreatitis, adult respiratory distress syndrome, scleroderma, deep erythematosus lupus, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune neutropenia comprising the prodrug , Thrombocytopenia, myasthenia gravis, multiple myeloma, acute myeloblastic leukemia, chronic sarcoma, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, wasting disease, Huntington's disease, ischemia / relapse in stroke Diseases associated with perfusion, myocardial ischemia, ischemic heart disease, renal ischemia, neovascular glaucoma, infantile hemangiomas, vascular proliferation, cardiac hypertrophy, abnormal immune response, fever, cell aging or apoptosis-related diseases And nasal congestion Good agent. 21. An antihistamine action and / or an eosinophil chemotaxis inhibitory action on a mammal, and (2) c- on a mammal.
A method for inhibiting c-Jun N-terminal kinase activation, which comprises administering an effective amount of a compound having an action of inhibiting Jun N-terminal kinase activation or a prodrug thereof. 22. (1) Antihistamine action and / or (2) Inhibition of eosinophil chemotaxis on mammals and (2) c-
Acute pancreatitis, chronic pancreatitis, adult respiratory distress syndrome, scleroderma, deep-seated lupus erythematosus, chronic characterized by administering an effective amount of a compound having a Jun N-terminal kinase activation inhibitory effect or a prodrug thereof Thyroiditis, Graves disease,
Autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, myasthenia gravis, multiple myeloma, acute myeloblastic leukemia, chronic sarcoma, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, Wasting disease, Huntington's disease, diseases associated with ischemia / reperfusion in stroke, myocardial ischemia, ischemic heart disease, renal ischemia, neovascular glaucoma, infantile hemangiomas, blood vessel proliferation, cardiac hypertrophy, abnormal immune response, A method for preventing / treating fever, cell aging or apoptosis-related diseases and a method for improving nasal obstruction. 23. (1) Antihistamine action and / or for producing c-Jun N-terminal kinase activation inhibitor
Use of a compound or a prodrug thereof having an eosinophil chemotaxis inhibitory action and (2) c-Jun N-terminal kinase activation inhibitory action. 24. Acute pancreatitis, chronic pancreatitis, adult respiratory distress syndrome, scleroderma, deep lupus erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia Disease, myasthenia gravis, multiple myeloma, acute myeloblastic leukemia, chronic sarcoma, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, wasting disease, Huntington's disease, and ischemia / reperfusion in stroke Diseases, myocardial ischemia, ischemic heart disease, renal ischemia, neovascular glaucoma, infantile hemangiomas, blood vessel growth, cardiac hypertrophy, abnormal immune response, fever, cell aging or apoptosis-related diseases and prophylactic / therapeutic agents Use of a compound or a prodrug thereof having (1) antihistamine action and / or eosinophil chemotaxis inhibitory action and (2) c-Jun N-terminal kinase activation inhibitory action for producing an improving agent. 25. A medicine comprising a combination of an antihistamine and a c-Jun N-terminal kinase activation inhibitor or / and a TNF-α inhibitor. 26. An antiallergic drug comprising a combination of an antihistamine and a c-Jun N-terminal kinase activation inhibitor or (and) a TNF-α inhibitor. 27. Chronic urticaria, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, which comprises a combination of an antihistamine and a c-Jun N-terminal kinase activation inhibitor.
A drug for the prevention and treatment of hypersensitivity pneumonitis, eczema, herpetic dermatitis, psoriasis, eosinophilic pneumonia (PIE syndrome), chronic obstructive pulmonary disease (COPD) or asthma, and improvement of nasal obstruction. 28. A method for preventing or treating allergy, which comprises administering to a mammal a combination of an effective amount of an antihistamine and an effective amount of a c-Jun N-terminal kinase activation inhibitor. 29. Chronic urticaria, atopic dermatitis, allergy, which is administered to a mammal in combination with an effective amount of an antihistamine and an effective amount of a c-Jun N-terminal kinase activation inhibitor. Of rhinitis, allergic conjunctivitis, hypersensitivity pneumonitis, eczema, herpetic dermatitis, psoriasis, eosinophilic pneumonia (PIE syndrome), chronic obstructive pulmonary disease (COPD) or asthma and improvement of nasal obstruction Method. 30. Use of an antihistamine and a c-Jun N-terminal kinase activation inhibitor for producing an antiallergic drug. 31. Chronic urticaria, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, hypersensitivity pneumonitis, eczema, herpes dermatitis, psoriasis, eosinophilic pneumonia (PIE syndrome), chronic obstructive lung. Use of an antihistamine and a c-Jun N-terminal kinase activation inhibitor for producing a medicament for preventing / treating disease (COPD) or asthma and a medicament for improving nasal congestion.