JP2001199889A - Collunarium comprising annulated pyridazine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a collunarium exhibiting excellent prophylactic and therapeutic effect upon allergic rhinitis or the like. SOLUTION: This collunarium comprises a compound represented by formula (I) [wherein Ar1 and Ar2 are an aromatic group and may be combined with adjacent carbon into a condensed ring group; B ring is a nitrogen-containing heterocycle; X and Y are each a direct bond, O, S(O)p (wherein p is 0 to 2), NR4 (wherein R4 is H or a lower alkyl) or a bivalent normal lower hydrocarbon group allowed to have one to three intervening hetero atoms; A is N or CR7 (wherein R7 is H, a halogen atom, a hydrocarbon group, an acyl group or hydroxyl group allowed to have a substituent; R1, R2 and R3 are each H, a halogen atom, a hydrocarbon group, an acyl group or hydroxyl group allowed to have a substituent; R8 is) II], or its salt or prodrug.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a nasal drop which is useful as a prophylactic / therapeutic agent for allergic rhinitis and the like.

[0002]

2. Description of the Related Art In WO98 / 49167, the formula

Embedded image [Wherein, Ar ¹ and Ar ² each represent an aromatic group which may have a substituent, and Ar ¹ and Ar ² may form a condensed ring group together with adjacent carbon atoms; Represents a nitrogen-containing heterocyclic ring which may have a substituent, and X and Y
Are the same or different and are each a bond, an oxygen atom, S
(O) p (p represents an integer of 0 to 2), NR ⁴ (R ⁴
Represents a hydrogen atom or a lower alkyl group) or a divalent linear lower hydrocarbon group which may have a substituent and may have 1 to 3 heteroatoms, and A represents a nitrogen atom Or CR ⁷ (R ⁷ represents a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxy group which may have a substituent),
R ¹ , R ² and R ³ are the same or different and each represent a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxy group which may have a substituent, R ⁸ represents a hydrogen atom, a hydroxy group or a carboxyl group which may be substituted with a lower alkyl group. A compound or a salt thereof is an antihistamine and / or an eosinophil chemotaxis inhibitor, an antiallergic agent, asthma, allergic conjunctivitis, allergic rhinitis, chronic urticaria or atopic dermatitis. It is described as being useful as an agent and the like. As specific examples of dosage forms, tablets (including sugar-coated tablets and film-coated tablets), pills, capsules (including microcapsules), granules, fine granules, powders, syrups, emulsions, suspensions, Injections, inhalants, ointments are disclosed.

[0003]

It has been desired to develop a preparation in which the above compound or a salt thereof can exert a therapeutic effect on allergic rhinitis and the like.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, [1,
2,4] triazolo [1,5-b] pyridazine or imidazo [1,2-b] pyridazine from the 6-position of the skeleton having a substituted piperidine or piperazine via a spacer via a spacer, which has a large chemical structural feature.

Embedded image [Wherein, Ar ¹ and Ar ² each represent an aromatic group which may have a substituent, and Ar ¹ and Ar ² may form a condensed ring group together with adjacent carbon atoms; Represents a nitrogen-containing heterocyclic ring which may have a substituent, and X and Y
Are the same or different and are each a bond, an oxygen atom, S
(O) p (p represents an integer of 0 to 2), NR ⁴ (R ⁴
Represents a hydrogen atom or a lower alkyl group) or a divalent linear lower hydrocarbon group which may have a substituent and may have 1 to 3 heteroatoms, and A represents a nitrogen atom Or CR ⁷ (R ⁷ represents a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxy group which may have a substituent),
R ¹ , R ² and R ³ are the same or different and each represent a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxy group which may have a substituent, R ⁸ represents a hydrogen atom, a hydroxy group or a carboxyl group which may be substituted with a lower alkyl group. However, the nitrogen-containing heterocyclic ring represented by the ring B is represented by the formula

Embedded image (Wherein n represents 0 or 1). It has been found that, by using the compound represented by the formula (1) or a salt thereof or a prodrug thereof as a nasal drop, an excellent therapeutic effect can be unexpectedly effectively exerted on allergic rhinitis. The present inventors have further studied based on these findings, and as a result, have completed the present invention.

[0005] That is, the present invention provides the following [1]

Embedded image [Wherein, Ar ¹ and Ar ² each represent an aromatic group which may have a substituent, and Ar ¹ and Ar ² may form a condensed ring group together with adjacent carbon atoms; Represents a nitrogen-containing heterocyclic ring which may have a substituent, and X and Y
Are the same or different and are each a bond, an oxygen atom, S
(O) p (p represents an integer of 0 to 2), NR ⁴ (R ⁴
Represents a hydrogen atom or a lower alkyl group) or a divalent linear lower hydrocarbon group which may have a substituent and may have 1 to 3 heteroatoms, and A represents a nitrogen atom Or CR ⁷ (R ⁷ represents a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxy group which may have a substituent),
R ¹ , R ² and R ³ are the same or different and each represent a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxy group which may have a substituent, R ⁸ represents a hydrogen atom, a hydroxy group or a carboxyl group which may be substituted with a lower alkyl group. However, the nitrogen-containing heterocyclic ring represented by the ring B is represented by the formula

Embedded image (Wherein n represents 0 or 1). [2] an anti-histamine and / or an eosinophil chemotactic inhibitor [1], which comprises a compound represented by the formula: or a salt thereof or a prodrug thereof.
[3] The agent according to [1], which is an antiallergic agent, [4] The agent according to [1], which is a prophylactic / therapeutic agent for allergic rhinitis, [5] 2- [ 6- [3- [4-
(Diphenylmethoxy) piperidino] propylamino]
Imidazo [1,2-b] pyridazin-2-yl] -2-
The agent according to item [1], comprising methylpropionic acid or a salt thereof, [6] 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] ] The agent according to [5], wherein the pyridazin-2-yl] -2-methylpropionic acid is a dihydrate.
[7] Formula for mammals

Embedded image [Wherein, Ar ¹ and Ar ² each represent an aromatic group which may have a substituent, and Ar ¹ and Ar ² may form a condensed ring group together with adjacent carbon atoms; Represents a nitrogen-containing heterocyclic ring which may have a substituent, and X and Y
Are the same or different and are each a bond, an oxygen atom, S
(O) p (p represents an integer of 0 to 2), NR ⁴ (R ⁴
Represents a hydrogen atom or a lower alkyl group) or a divalent linear lower hydrocarbon group which may have a substituent and may have 1 to 3 heteroatoms, and A represents a nitrogen atom Or CR ⁷ (R ⁷ represents a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxy group which may have a substituent),
R ¹ , R ² and R ³ are the same or different and each represent a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxy group which may have a substituent, R ⁸ represents a hydrogen atom, a hydroxy group or a carboxyl group which may be substituted with a lower alkyl group. However, the nitrogen-containing heterocyclic ring represented by the ring B is represented by the formula

Embedded image (Wherein n represents 0 or 1). A method for preventing or treating allergic rhinitis, which comprises administering an effective amount of a nasal drop comprising the compound represented by the formula (I) or a salt thereof or a prodrug thereof; and [8] a nasal drop. Formula for manufacturing

Embedded image [Wherein, Ar ¹ and Ar ² each represent an aromatic group which may have a substituent, and Ar ¹ and Ar ² may form a condensed ring group together with adjacent carbon atoms; Represents a nitrogen-containing heterocyclic ring which may have a substituent, and X and Y
Are the same or different and are each a bond, an oxygen atom, S
(O) p (p represents an integer of 0 to 2), NR ⁴ (R ⁴
Represents a hydrogen atom or a lower alkyl group) or a divalent linear lower hydrocarbon group which may have a substituent and may have 1 to 3 heteroatoms, and A represents a nitrogen atom Or CR ⁷ (R ⁷ represents a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxy group which may have a substituent),
R ¹ , R ² and R ³ are the same or different and each represent a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxy group which may have a substituent, R ⁸ represents a hydrogen atom, a hydroxy group or a carboxyl group which may be substituted with a lower alkyl group. However, the nitrogen-containing heterocyclic ring represented by the ring B is represented by the formula

Embedded image (Wherein n represents 0 or 1). ] Or a salt thereof or a prodrug thereof.

Further, the present invention provides:

[9] Ar ¹ and Ar ² are (i) a halogen atom, (ii) C _1-6 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C _1-6 Alkyl, (vi) optionally halogenated C _2-6 alkenyl, (vii) optionally halogenated C _2-6 alkynyl, (viii) C _3-6 cycloalkyl, (ix) 1-3 halogen atoms, mono- - or di -C _1-6 alkylamino or C _1-6 alkoxy - optionally having a carbonyl C _1-6 alkoxy, optionally (x) halogenated C _{1- 6} alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C _1-6 alkylamino, (xiv) di-C _1-6 alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi) C _1-6 alkyl - carbonyl, (xvii) carboxyl, (xvii
i) C _1-6 alkoxy-carbonyl, (xix) carbamoyl, (xx) thiocarbamoyl, (xxi) mono-C _1-6 alkyl-carbamoyl, (xxii) di-C _1-6 alkyl-carbamoyl, (xxiii) C _6-10 aryl-carbamoyl, (xxiv) sulfo, (xxv) C _1-6 alkylsulfonyl, (xxvi) C _6-10 aryl, (xxvii) C _6-10 aryloxy and (xxviii) C _7-16 aralkyl A 6- to 14-membered monocyclic or condensed polycyclic aromatic hydrocarbon group (for example, a C _6-14 aryl group) which may be substituted with a group selected from the group consisting of oxy, a nitrogen atom other than a carbon atom A 5- to 8-membered monocyclic group containing 1 to 4 kinds of one or two hetero atoms selected from a sulfur atom and an oxygen atom or a fused aromatic heterocyclic group thereof, or the above 6 to 14-membered monocyclic group Or condensed polycyclic aromatic hydrocarbon And a 5- to 8-membered monocyclic group containing 1 to 4 one or two hetero atoms selected from nitrogen, sulfur and oxygen atoms other than the above carbon atoms or a fused aromatic heterocyclic group thereof Represents a monovalent group formed by removing any hydrogen atom from the formed ring, wherein Ar ¹ and Ar ² are (i) a halogen atom,
(Ii) C _1-6 alkylenedioxy, (iii) nitro, (i
v) cyano, (v) optionally halogenated C _1-6 alkyl, (vi) optionally halogenated C _2-6 alkenyl, (vii) optionally halogenated C _2-6 Alkynyl, (viii) C _3-6 cycloalkyl, (ix) one to three halogen atoms, mono- or di-C _1-6 alkylamino or C _1-6 alkoxy-carbonyl optionally having C _1-6 alkoxy-carbonyl. _1-6 alkoxy, (x) optionally halogenated C _1-6 alkylthio, (xi) hydroxy, (x
ii) amino, (xiii) mono-C _1-6 alkylamino, (x
iv) di-C _1-6 alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi) C _1-6 alkyl-carbonyl, (xvi
i) carboxyl, (xviii) C _1-6 alkoxy-carbonyl, (xix) carbamoyl, (xx) thiocarbamoyl, (xxi) mono-C _1-6 alkyl-carbamoyl, (xx
ii) di-C _1-6 alkyl-carbamoyl, (xxiii) C
_6-10 aryl-carbamoyl, (xxiv) sulfo, (xx
v) C _1-6 alkylsulfonyl, (xxvi) C _6-10 aryl, (xxvii) C _6-10 aryloxy, (xxviii) C
_{7-16 a} formula optionally substituted with a group selected from the group consisting of aralkyloxy and (xxix) oxo,

Embedded image[Wherein, R⁸Is a hydrogen atom, C_1-6Substituted with alkyl
Represents a hydroxy group or a carboxyl group which may be present]
May form a condensed ring group represented by
(I) a halogen atom, (ii) C_1-6Alkylenedioxy,
(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_1-6Alkylamino or C_1-6Alkoxy-ka
C optionally having rubonyl_1-6Alkoxy, (x) c
C which may be formed into a log_1-6Alkylthio, (xi)
Hydroxy, (xii) amino, (xiii) mono-C_1-6Al
Killamino, (xiv) di-C_1-6Alkylamino, (xv)
5- or 6-membered cyclic amino, (xvi) C_1-6Alkyl-cal
Bonyl, (xvii) carboxyl, (xviii) C_1-6Arco
Xy-carbonyl, (xix) carbamoyl, (xx) thio
Carbamoyl, (xxi) mono-C_1-6Alkyl-carbamo
Il, (xxii) Di-C_1-6Alkyl-carbamoyl, (x
xiii) C_6-10Aryl-carbamoyl, (xxiv) sul
E, (xxv) C_1-6Alkylsulfonyl, (xxvi) C_6-10
Aryl, (xxvii) C_6-10Aryloxy, (xxvii
i) C_7-16From aralkyloxy and (xxix) oxo
May be substituted with a group selected from the group consisting of
Each contains one nitrogen atom, and further contains a nitrogen atom, an oxygen atom
And 1 to 3 hetero atoms selected from sulfur atoms
Represents a 3- to 13-membered nitrogen-containing heterocyclic ring which may contain
X and Y are the same or different,
Hand, oxygen atom, S (O) p (p is an integer of 0 to 2)
NR)^Four(R^FourIs a hydrogen atom or a linear or
Branched C_1-6Alkyl group) or (i) halo
Gen atom, (ii) C_1-6Alkylenedioxy, (iii) d
Toro, (iv) cyano, (v) halogenated
C_1-6Alkyl, (vi) optionally halogenated
C_2-6Alkenyl, (vii) optionally halogenated
C_2-6Alkynyl, (viii) C_3-6Cycloalkyl, (i
x) 1 to 3 halogen atoms, mono- or di-C
_1-6Alkylamino or C_1-6Alkoxy-carboni
C which may have_1-6Alkoxy, (x) halogen
C which may be_1-6Alkylthio, (xi) hydro
Xy, (xii) amino, (xiii) mono-C_1-6Alkyria
Mino, (xiv) di-C_1-6Alkylamino, not (xv) 5
6-membered cyclic amino, (xvi) C_1-6Alkyl-carboni
(Xvii) carboxyl, (xviii) C_1-6Alkoxy
-Carbonyl, (xix) carbamoyl, (xx) thiocar
Bamoyl, (xxi) Mono-C_1-6Alkyl-carbamoy
Le, (xxii) di-C_1-6Alkyl-carbamoyl, (xxi
ii) C_6-10Aryl-carbamoyl, (xxiv) sulfo,
(Xxv) C_1-6Alkylsulfonyl, (xxvi) C_6-10Ants
, (Xxvii) C_6-10Aryloxy, (xxviii) C
_7-16Group consisting of aralkyloxy and (xxix) oxo
May have a substituent selected from the group consisting of an oxygen atom and
Through 1 to 3 heteroatoms selected from
Optionally a divalent linear C_1-6Represents a hydrocarbon group,
A is a nitrogen atom or CR⁷[R⁷Is (1) a hydrogen atom,
(2) halogen atom, (3) (i) halogen atom, (i
i) C_1-6Alkylenedioxy, (iii) nitro, (iv)
Cyano, (v) optionally halogenated C_1-6Archi
(Vi) optionally halogenated C_2-6Alkene
(Vii) optionally halogenated C _2-6Alkini
Le, (viii) C_3-6Cycloalkyl, (ix) 1-3
Halogen atoms, mono- or di-C_1-6Alkyria
Mino or C_1-6Having alkoxy-carbonyl
May be C_1-6Alkoxy, (x) halogenated
Good C_1-6Alkylthio, (xi) hydroxy, (xii)
Amino, (xiii) mono-C_1-6Alkylamino, (xiv)
Di-C_1-6Alkylamino, (xv) 5- or 6-membered cyclic a
Mino, (xvi) C_1-6Alkyl-carbonyl, (xvii)
Ruboxil, (xviii) C_1-6Alkoxy-carbonyl,
(Xix) carbamoyl, (xx) thiocarbamoyl, (xx
i) Mono-C_1-6Alkyl-carbamoyl, (xxii) di-
C_1-6Alkyl-carbamoyl, (xxiii) C_6-10Ally
Le-carbamoyl, (xxiv) sulfo, (xxv) C_1-6Al
Killsulfonyl, (xxvi) C_6-10Aryl, (xxvii)
C_6-10Aryloxy, (xxviii) C_7-16Aralquilo
A group selected from the group consisting of xy and (xxix) oxo
Optionally substituted C_1-6Alkyl group, C_2-6Alkene
Le group, C_2-6Alkynyl group, C_3-6Cycloalkyl group, C
_3-6A cycloalkyl group and one to three C_1-6Alkoxy
A group condensed with an optionally substituted benzene ring, C
_6-14Aryl group or C_7-16Aralkyl group, (4)-
(C = O) -R⁹, -SO_Two-R⁹, -SO-R⁹,-(C
= O) NR^TenR⁹,-(C = O) OR⁹,-(C = S)
OR⁹Or-(C = S) NR^TenR⁹(R⁹Is (a) water
Element atom, (b) (i) halogen atom, (ii) C_1-6Al
Killenedioxy, (iii) nitro, (iv) cyano, (v)
Optionally halogenated C_1-6Alkyl, (vi) ha
C which may be formed into a log_2-6Alkenyl, (vii) ha
C which may be formed into a log_2-6Alkynyl, (viii)
C_3-6Cycloalkyl, (ix) one to three halogens
Atom, mono- or di-C_1-6Alkylamino or
C_1-6C optionally having alkoxy-carbonyl_1-6
Alkoxy, (x) optionally halogenated C_1-6A
Ruquilthio, (xi) hydroxy, (xii) amino, (xii
i) Mono-C_1-6Alkylamino, (xiv) di-C_1-6Al
Killamino, (xv) 5- or 6-membered cyclic amino, (xvi)
C_1-6Alkyl-carbonyl, (xvii) carboxyl,
(Xviii) C_1-6Alkoxy-carbonyl, (xix) cal
Bamoyl, (xx) thiocarbamoyl, (xxi) mono-C
_1-6Alkyl-carbamoyl, (xxii) di-C_1-6Archi
Le-carbamoyl, (xxiii) C_6-10Aryl-carba
Moyle, (xxiv) sulfo, (xxv) C_1-6Alkylsulfo
Nil, (xxvi) C_6-10Aryl, (xxvii) C_6-10Ants
Oxy, (xxviii) C_7-16Aralkyloxy and
(Xxix) substituted with a group selected from the group consisting of oxo
May be C_1-6Alkyl group, C_2-6Alkenyl group, C
_2-6Alkynyl group, C_3-6Cycloalkyl group, C_3-6Shiku
A loalkyl group and one to three C_1-6Has an alkoxy group
A group condensed with an optionally substituted benzene ring, C_6-14Ants
Or C_7-16An aralkyl group or (c) -O
R¹¹(R¹¹Is a hydrogen atom, or (i) a halogen atom,
(Ii) C_1-6Alkylenedioxy, (iii) nitro, (i
v) cyano, (v) optionally halogenated C_1-6A
Alkyl, (vi) optionally halogenated C_2-6Al
Kenyl, (vii) optionally halogenated C_2-6Al
Quinyl, (viii) C_3-6No cycloalkyl, (ix) 1
Three halogen atoms, mono- or di-C_1-6Archi
Lumino or C_1-6Having an alkoxy-carbonyl
May be C_1-6Alkoxy, (x) halogenated
May be C_1-6Alkylthio, (xi) hydroxy, (x
ii) amino, (xiii) mono-C_1-6Alkylamino, (x
iv) Di-C_1-6Alkylamino, (xv) 5- or 6-membered ring
Amino, (xvi) C_1-6Alkyl-carbonyl, (xvi
i) carboxyl, (xviii) C_1-6Alkoxy-carbo
Nil, (xix) carbamoyl, (xx) thiocarbamoy
, (Xxi) Mono-C_1-6Alkyl-carbamoyl, (xx
ii) Di-C_1-6Alkyl-carbamoyl, (xxiii) C
_6-10Aryl-carbamoyl, (xxiv) sulfo, (xx
v) C_1-6Alkylsulfonyl, (xxvi) C_6-10Ally
Le, (xxvii) C_6-10Aryloxy, (xxviii) C
_7-16Group 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_3-6Shi
Chloroalkyl group, C_3-6Cycloalkyl group and 1 to 3
C_1-6Benzene ring optionally having an alkoxy group
A group condensed with_6-14Aryl group or C_7-16Ara
Rk).^TenIs a hydrogen atom
Or C_1-6An acyl group represented by an alkyl group),
Or (5) -OR¹²(R¹²Is a hydrogen atom, or (i)
A halogen atom, (ii) C_1-6Alkylenedioxy, (ii
i) nitro, (iv) cyano, (v) halogenated
Good C_1-6Alkyl, (vi) even if halogenated
Good C_2-6Alkenyl, (vii) even when halogenated
Good C_2-6Alkynyl, (viii) C_3-6Cycloalkyl,
(Ix) 1 to 3 halogen atoms, mono- or di-
C_1-6Alkylamino or C_1-6Alkoxy-carbo
C optionally having nyl_1-6Alkoxy, (x) halogen
C which may be_1-6Alkylthio, (xi) hydride
Roxy, (xii) amino, (xiii) mono-C_1-6Alkyl
Amino, (xiv) di-C_1-6Alkylamino, (xv) 5
6-membered cyclic amino, (xvi) C_1-6Alkyl-carboni
(Xvii) carboxyl, (xviii) C_1-6Alkoxy
-Carbonyl, (xix) carbamoyl, (xx) thiocar
Bamoyl, (xxi) Mono-C_1-6Alkyl-carbamoy
Le, (xxii) di-C_1-6Alkyl-carbamoyl, (xxi
ii) C_6-10Aryl-carbamoyl, (xxiv) sulfo,
(Xxv) C_1-6Alkylsulfonyl, (xxvi) C_6-10Ants
, (Xxvii) C_6-10Aryloxy, (xxviii) C
_7-16Group 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_3-6Shi
Chloroalkyl group, C_3-6Cycloalkyl group and 1 to 3
C_1-6Benzene ring optionally having an alkoxy group
A group condensed with_6-14Aryl group or C_7-16Ara
And a group represented by the following formula:¹,
R^TwoAnd R^ThreeAre (1) hydrogen atom, (2) halogen
Atom, (3) (i) halogen atom, (ii) C_1-6Archi
Rangeoxy, (iii) nitro, (iv) cyano, (v)
C which may be formed into a log_1-6Alkyl, (vi) halo
C which may be genated_2-6Alkenyl, (vii) halo
C which may be genated_2-6Alkynyl, (viii) C
_3-6Cycloalkyl, (ix) one to three halogen atoms
Child, mono- or di-C_1-6Alkylamino or C
_1-6C optionally having alkoxy-carbonyl_1-6A
Lucoxy, (x) optionally halogenated C_1-6Al
Kirthio, (xi) hydroxy, (xii) amino, (xii
i) Mono-C_1-6Alkylamino, (xiv) di-C_1-6Al
Killamino, (xv) 5- or 6-membered cyclic amino, (xvi)
C_1-6Alkyl-carbonyl, (xvii) carboxyl,
(Xviii) C_1-6Alkoxy-carbonyl, (xix) cal
Bamoyl, (xx) thiocarbamoyl, (xxi) mono-C
_1-6Alkyl-carbamoyl, (xxii) di-C_1-6Archi
Le-carbamoyl, (xxiii) C_6-10Aryl-carba
Moyle, (xxiv) sulfo, (xxv) C_1-6Alkylsulfoni
Le, (xxvi) C_6-10Aryl, (xxvii) C_6-10Ally
Luoxy, (xxviii) C_7-16Aralkyloxy and
(Xxix) substituted with a group selected from the group consisting of oxo
May be C_1-6Alkyl group, C_2-6Alkenyl group, C
_2-6Alkynyl group, C_3-6Cycloalkyl group, C_3-6Shiku
A loalkyl group and one to three C_1-6Has an alkoxy group
A group condensed with an optionally substituted benzene ring, C_6-14Ants
Or C_7-16An aralkyl group, (4)-(C =
O) -R¹³, -SO_Two-R¹³, -SO-R¹³,-(C =
O) NR¹⁴R¹³,-(C = O) OR¹³,-(C = S)
OR¹³Or-(C = S) NR¹⁴R¹³(R¹³Is (a)
Hydrogen atom, (b) (i) halogen atom, (ii) C_1-6A
Lucylenedioxy, (iii) nitro, (iv) cyano,
(V) C which may be halogenated_1-6Alkyl, (v
i) C which may be halogenated_2-6Alkenyl, (vi
i) C which may be halogenated_2-6Alkynyl, (vi
ii) C_3-6Cycloalkyl, (ix) one to three halo
Gen atom, mono- or di-C_1-6If alkylamino
Kuha C_1-6May have an alkoxy-carbonyl
C_1-6Alkoxy, (x) optionally halogenated C
_1-6Alkylthio, (xi) hydroxy, (xii) amino,
(Xiii) Mono-C_1-6Alkylamino, (xiv) di-C
_1-6Alkylamino, (xv) 5- to 6-membered cyclic amino,
(Xvi) C_1-6Alkyl-carbonyl, (xvii) carboxy
Syl, (xviii) C_1-6Alkoxy-carbonyl, (xi
x) carbamoyl, (xx) thiocarbamoyl, (xxi)
No-C_1-6Alkyl-carbamoyl, (xxii) di-C_1-6
Alkyl-carbamoyl, (xxiii) C_6-10Aryl-
Carbamoyl, (xxiv) sulfo, (xxv) C_1-6Alkyl
Sulfonyl, (xxvi) C_6-10Aryl, (xxvii) C
_6-10Aryloxy, (xxviii) C_7-16Aralkyl
And a group selected from the group consisting of (xxix) oxo
C which may be replaced_1-6Alkyl group, C_2-6Alkenyl
Group, C_2-6Alkynyl group, C_3-6Cycloalkyl group, C
_3-6A cycloalkyl group and one to three C_1-6Alkoxy
A group condensed with an optionally substituted benzene ring, C
_6-14Aryl group or C_7-16An aralkyl group, or
(C) -OR^Fifteen(R^FifteenIs a hydrogen atom, or (i) halogen
Atom, (ii) C_1-6Alkylenedioxy, (iii) nitro
B, (iv) cyano, (v) optionally halogenated
C_1-6Alkyl, (vi) optionally halogenated C
_2-6Alkenyl, (vii) optionally halogenated 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
C which may have_1-6Alkoxy, (x) halogenated
C that may be_1-6Alkylthio, (xi) hydroxy
(Xii) amino, (xiii) mono-C_1-6Alkylam
No, (xiv) di-C_1-6Alkylamino, (xv) 5 or
6-membered cyclic amino, (xvi) C_1-6Alkyl-carbonyl,
(Xvii) carboxyl, (xviii) C_1-6Alkoxy-ka
Rubonyl, (xix) carbamoyl, (xx) thiocarbamo
Il, (xxi) Mono-C_1-6Alkyl-carbamoyl,
(Xxii) Di-C_1-6Alkyl-carbamoyl, (xxiii)
C_6-10Aryl-carbamoyl, (xxiv) sulfo, (xx
v) C_1-6Alkylsulfonyl, (xxvi) C_6-10Ally
Le, (xxvii) C_6-10Aryloxy, (xxviii) C
_7-16Group 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_3-6Shi
Chloroalkyl group, C_3-6Cycloalkyl group and 1 to 3
C_1-6Benzene ring optionally having an alkoxy group
A group condensed with_6-14Aryl group or C_7-16Ara
Rk).¹⁴Is a hydrogen atom
Or C_1-6An acyl group represented by an alkyl group),
Or (5) -OR¹⁶(R¹⁶Is a hydrogen atom, or (i)
A halogen atom, (ii) C_1-6Alkylenedioxy, (ii
i) nitro, (iv) cyano, (v) halogenated
Good C_1-6Alkyl, (vi) even if halogenated
Good C_2-6Alkenyl, (vii) even when halogenated
Good C_2-6Alkynyl, (viii) C_3-6Cycloalkyl,
(Ix) 1 to 3 halogen atoms, mono- or di-
C_1-6Alkylamino or C_1-6Alkoxy-carbo
C optionally having nyl_1-6Alkoxy, (x) halogen
C which may be_1-6Alkylthio, (xi) hydride
Roxy, (xii) amino, (xiii) mono-C_1-6Alkyl
Amino, (xiv) di-C_1-6Alkylamino, (xv) 5
6-membered cyclic amino, (xvi) C_1-6Alkyl-carboni
(Xvii) carboxyl, (xviii) C_1-6Alkoxy
-Carbonyl, (xix) carbamoyl, (xx) thiocar
Bamoyl, (xxi) Mono-C_1-6Alkyl-carbamoy
Le, (xxii) di-C_1-6Alkyl-carbamoyl, (xxi
ii) C_6-10Aryl-carbamoyl, (xxiv) sulfo,
(Xxv) C_1-6Alkylsulfonyl, (xxvi) C_6-10Ants
, (Xxvii) C_6-10Aryloxy, (xxviii) C
_7-16Group 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_3-6Shi
Chloroalkyl group, C_3-6Cycloalkyl group and 1 to 3
C_1-6Benzene ring optionally having an alkoxy group
A group condensed with_6-14Aryl group or C_7-16Ara
Rk).⁸Is hydrogen field
Child, C_1-6Hydroxy optionally substituted with alkyl
The agent according to item [1], which represents a group or a carboxyl group,

[10] Ar ¹ and Ar ² are each derived from (1) a phenyl group optionally substituted with a halogen atom or C _1-6 alkyl, or (2) a nitrogen atom, a sulfur atom and an oxygen atom other than a carbon atom. A selected 5- to 8-membered aromatic heterocyclic group containing 1 to 4 heteroatoms, wherein ring B is

Embedded image [Wherein, Z represents a nitrogen atom or a methine group, and Z ¹ and Z ² represent 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, respectively. X is a bond, an oxygen atom or NH, and Y is (i) a C _1-6 alkylene group, (ii)-(CH ₂ ) p ¹ O-, (iii)-( ^{_{NH-, CH 2) p 1 (}} iv) - (S-, CH 2) p 1 (v) - (CH 2) q 1 CH (OH) (CH 2) q 2 O-, (vi) - (CH ^{_{2) q 1 CH (OH)}} (CH 2) q 2 NH
-, (viI) - (CH 2) q 1 CH (OH) (CH 2) q 2 S
-, (viiI) - (CH 2) p 1 CONH-, (iX) -COO (CH 2) p 1 O-, (x) -COO (CH 2) p 1 NH-, (xi) -COO (CH ^{_{2) p 1 S-, (xii}} ) - (O-, CH 2) q 1 O (CH 2) q 2 (xiii) - (CH 2) q 1 O (CH 2) q 2 NH- or (xiv) ^{_{- (CH 2) q 1 O}} (CH 2) q 2 S- (p 1 is 1
And q ¹ and q ² each represent an integer of 1 to 3), wherein A is a nitrogen atom or CR ⁷ ′
(R ⁷ ′ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group,
C _1-6 alkoxy - by showing a carbonyl group or a carboxyl group), R ¹ is (1) hydrogen atom, (2) (i) carboxyl, (ii) C _1-6 alkoxy - carbonyl, (ii
i) hydroxy or (iv) a 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) a carboxyl group, (7) carboxyl or C _1-6 alkoxy - carbamoyl which may have a C _1-6 alkyl optionally substituted with carbonyl Group, or (8) C
C which may be substituted by _1-6 alkoxy-carbonyl
_{A 3-6} cycloalkyl group, wherein R ² is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy-carbonyl group or a carboxyl group, R ³ is a hydrogen atom, and R ⁸ is a hydrogen atom or a hydroxy group; A certain agent according to item [1], [11] wherein Ar ¹ and Ar ² are phenyl groups, and ring B is a group represented by the formula

Embedded image Wherein Z ′ represents a methine group, Z ¹ ′ and Z ² ′ represent a methylene group or an ethylene group, wherein X is a bond or an oxygen atom, and Y is — (CH ₂ ) P ¹ NH-
(P ¹ represents an integer of ¹ to 6), wherein A is C
R ⁷ ″ (R ⁷ ″ represents a hydrogen atom or a C _1-6 alkyl group), wherein R ¹ is substituted by (1) hydrogen atom, (2) carboxyl or C _1-6 alkoxy-carbonyl. also a C _1-6 alkyl group (particularly, isopropyl) or (3) C _1-6 alkoxy - that may have a C _1-6 alkyl optionally substituted with carbonyl carbamoyl group, R ² Is a hydrogen atom, R ³ is a hydrogen atom, and R ⁸ is a hydrogen atom. [12] The agent according to [ ¹ ], wherein Ar ¹ and Ar ² each may have a substituent. The agent according to [1], which is a hydrogen group; [13] the agent according to [ ¹ ], wherein Ar ¹ and Ar ² are each a phenyl group which may have a substituent; [14] Ar ¹ And A
r ² is (1) a phenyl group optionally substituted with a halogen atom or C _1-6 alkyl, or (2) 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom other than a carbon atom The agent according to item [1], which is a 5- to 8-membered aromatic heterocyclic group containing

[15] ring B is a compound of the formula

Embedded image [In the formula, Z represents a nitrogen atom or a methine group, and Z ¹ and Z ² represent 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, respectively. The agent according to item [1], which is a ring represented by the following formula:
[16] The agent of [15], wherein Z ¹ and Z ² are each a linear C _1-2 alkylene group, [17] The agent of [1], wherein X is a bond, an oxygen atom or NH. Agent
[18] X is a bond or agent of the [1], wherein an oxygen atom, [19] Y is the formula _{- (CH 2) m-Y} 1 - (C
H ₂ ) n—Y ² — wherein Y ¹ and Y ² are the same or different and are each a bond, an oxygen atom, S (O) p (p is an integer of 0 to 2), NR ⁴ (R ⁴ represents a hydrogen atom or a lower alkyl group), a carbonyl group, a carbonyloxy group or a formula

Embedded image (Wherein R ⁵ and R ⁶ are the same or different and each represents a hydroxy group or a C _1-4 alkyl group), and m and n each represent an integer of 0 to 4 (provided that wherein the sum of m and n is 6 or less)], wherein [20] Y is (i) a C _1-6 alkylene group, (ii)-(CH ₂ ^{) p 1 O-, (iii)} - (CH 2) p 1 NH-, (iv) - (CH 2) p 1 S-, (v) - (CH 2) q 1 CH (OH) (CH 2) ^{q 2 O-, (vi) -} (CH 2) q 1 CH (OH) (CH 2) q 2 NH
—, (Vii) — (CH ₂ ) q ¹ CH (OH) (CH ₂ ) q ² S
-, (viii) - (CH 2) p 1 CONH-, (ix) -COO (CH 2) p 1 O-, (x) -COO (CH 2) p 1 NH-, (xi) -COO (CH ^{_{2) p 1 S-, (xii}} ) - (O-, CH 2) q 1 O (CH 2) q 2 (xiii) - (CH 2) q 1 O (CH 2) q 2 NH- or (xiv) ^{_{- (CH 2) q 1 O}} (CH 2) q 2 S- (p 1 is 1
6 represents an integer of 6, and q ¹ and q ² each represent an integer of 1 to 3).
1] R ¹ , R ² , R ³ and R ⁷ are the same or different and are (1) hydrogen atom, (2) carboxyl group or C
_A C _1-6 alkyl group which may be substituted with a _1-6 alkoxy-carbonyl group, (3) a C _1-6 alkoxy group, (4) a C
The agent according to item [1], wherein the agent is _1-6 alkoxy-carbonyl group or (5) carboxyl group, [22] R ¹ is (1)
A hydrogen atom, (2) (i) carboxyl, (ii) C _1-6 alkoxy-carbonyl, (iii) hydroxy or (i)
v) a C _1-6 alkyl group optionally substituted with a group selected from the group consisting of carbamoyl optionally having a mono- or di-C _1-6 alkyl, (3) a C _6-14 aryl group,
(4) C _1-6 alkoxy group, (5) C _1-6 alkoxy-carbonyl group, (6) carboxyl group, (7) C _1- optionally substituted by carboxyl or C _1-6 alkoxy-carbonyl. The agent according to [1], which is a carbamoyl group optionally having ₆ alkyl, or (8) a C _3-6 cycloalkyl group optionally substituted with C _1-6 alkoxy-carbonyl, [23] ] R ² is a hydrogen atom, C _1-6 alkyl, C _1-6 alkoxy - Part [1 a carbonyl group or a carboxyl group], wherein the agent, [24] the R ³ is a hydrogen atom [1] [25] The agent according to [1], wherein R ⁷ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy-carbonyl group or a carboxyl group.
The agent according to item [1], wherein [26] R ⁸ is a hydrogen atom or a hydroxy group; the agent according to item [1], wherein [27] A is a nitrogen atom; [29] A agent according to [1], wherein 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 CH, the compound according to item [1], wherein the compound [30] is 2- [6- [3-
[4- (Diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl]
The agent according to item [1], which is ethyl-2-methylpropionate or a salt thereof, wherein the compound [31] is 2- [6- [3-
[4- (Diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl]
-2-methylpropionic acid or a salt thereof [1]
The agent according to item 8, wherein the compound [32] is N- [6- [3- [4-
(Diphenylmethoxy) piperidino] propylamino]
Imidazo [1,2-b] pyridazine-2-carbonyl]
The agent according to [1], which is glycine ethyl or a salt thereof, wherein the compound [33] is 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -3-methylimidazo [1,2] -B] pyridazin-2-yl]-
The agent according to item [1], which is ethyl 2-methylpropionate or a salt thereof, wherein the compound [34] is 2- [6- [3-
The agent according to [1], which is ethyl [4- (diphenylmethylamino) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate or a salt thereof, [35] The compound is 2- [6-
Item [1], which is [3- [4- (diphenylmethoxy) piperidino] propylamino] -3-methylimidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid or a salt thereof. Agent

[36] The compound represented by the formula

Embedded image Wherein R represents a hydrogen atom or an ethyl group, or a hydrate or a succinate or citrate of the compound (I ''). , [3
7] The compound is 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2
-B] ethyl pyridazin-2-yl] -2-methylpropionate disuccinate, wherein the agent according to item [1] and the compound [38] are 2- [6- [3- [4- (diphenyl) Methoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate ethyl citrate is provided. Further, when the compound (I) or a salt thereof contains an asymmetric carbon in the structure, both the optically active form and the racemic form are included in the scope of the present invention, and these compounds or the salts thereof may be hydrated or anhydrous. It may be either of the objects.

In the above formula, Ar ¹ and Ar ² represent “optionally substituted aromatic groups”, and Ar ¹ and Ar ² may form a condensed ring group together with adjacent carbon atoms. Good.
As the “aromatic group” represented by Ar ¹ and Ar ² , for example, a monocyclic or condensed polycyclic aromatic hydrocarbon group, more specifically, phenyl, tolyl, xylyl, biphenyl,
C _6-14 aryl such as 1-naphthyl, 2-naphthyl, 2-indenyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl Groups (preferably phenyl, tolyl, xylyl, biphenyl, 1-naphthyl or 2-naphthyl, and particularly preferably phenyl)
A 4-membered monocyclic or condensed polycyclic aromatic hydrocarbon group or the like, or preferably one or two heteroatoms selected from nitrogen, sulfur and oxygen other than carbon
Or more (for example, 1 to 4, preferably 1 to 3
A monocyclic group (preferably 5 to 8 members) or a fused aromatic heterocyclic group thereof, 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-carboline, phenanthridine, acridine, phenazine, isothiazole,
Aromatic heterocycles such as phenothiazine, isoxazole, furazane, phenoxazine or isochroman (preferably pyridine, thiophene or furan, more preferably pyridine, etc.), or these rings (preferably the above-mentioned monocyclic heterocycle) ) Is condensed with one or more (preferably one or two, more preferably one) aromatic rings (for example, the above-mentioned aromatic hydrocarbon groups, preferably benzene rings, etc.) For example, in addition to the above 6 to 14 membered monocyclic or condensed polycyclic aromatic hydrocarbon group and the above carbon atoms, preferably one or two hetero atoms selected from nitrogen, sulfur and oxygen atoms A ring formed by condensing a monocyclic group containing one or more atoms or a condensed aromatic heterocyclic group thereof by removing any hydrogen atom; A monovalent group or the like is used. As the “aromatic group” of the “aromatic group optionally having substituent (s)” represented by Ar ¹ and Ar ² , for example, a phenyl group is preferable.

The "substituent" of the aromatic group represented by Ar ¹ and Ar ² includes, for example, (i) a halogen atom (eg, fluorine, chlorine, bromine, iodine), (ii) a lower alkylenedioxy group ( For example, a C _1-3 alkylenedioxy group such as methylenedioxy, ethylenedioxy, etc.), (i
ii) a nitro group, (iv) a cyano group, (v) an optionally halogenated lower alkyl group, (vi) an optionally halogenated lower alkenyl group, (vii) an optionally halogenated lower Alkynyl group, (viii) lower cycloalkyl group (for example, C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (ix) optionally substituted lower alkoxy group, (x) halogen An optionally substituted lower alkylthio group, (xi) a hydroxyl group, (xii) an 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, di-C _1-6 alkylamino groups such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), (xv) 5- to 6-membered cyclic amino groups (eg, morpholino, piperazin-1-yl, piperidino, (Xvi) a lower alkyl-carbonyl group (for example, C _1-6 such as acetyl, propionyl, etc.)
(Xvii) carboxyl group, (xviii) lower alkoxy-carbonyl group (for example, C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (xix A) carbamoyl group, (xx) thiocarbamoyl, (xxi) a mono-lower alkyl-carbamoyl group (e.g., methylcarbamoyl,
Etc. carbamoyl group), (xxii) di - - mono -C _1-6 alkyl, such as ethylcarbamoyl lower alkyl - carbamoyl group (e.g., dimethylcarbamoyl, and di -C _1-6 alkylcarbamoyl group such as diethylcarbamoyl), ( xxiii) aryl-carbamoyl (e.g., C-phenylcarbamoyl, naphthylcarbamoyl, etc.
_6-10 aryl-carbamoyl, etc.), (xxiv) sulfo group, (xxv) lower alkylsulfonyl group (eg, C _1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, etc.), (xxvi) aryl group (eg, A C _6-10 aryl group such as phenyl and naphthyl), (xx
vii) aryloxy groups (for example, C _6-10 aryloxy groups such as phenoxy, naphthyloxy, etc.), (xxvi
ii) An aralkyloxy group (for example, a C _7-16 aralkyloxy group such as benzyloxy) is used.

The above-mentioned "optionally lower alkyl group" includes, for example, a lower alkyl group which may have 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine and iodine). For example, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and other C _1-6 alkyl groups) and the like. 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-trifluoro Pentyl, 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, for example, 1 to 3
Lower alkenyl groups (for example, vinyl, propenyl, isopropenyl, 2-butene-1-) which may have two halogen atoms (for example, fluorine, chlorine, bromine and iodine)
C _2-6 alkenyl groups such as yl, 4-penten-1-yl, 5-hexen-1-yl, etc.) and 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) Lower alkynyl group (for example, 2
-Butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl and the like _C2-6 alkynyl group) and the like. 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 Mono- or di-C _1-6 alkylamino groups such as dimethylamino, ethylamino and dimethylamino) or lower alkoxy-carbonyl groups (eg C _1-6 alkoxy-carbonyl groups such as methoxycarbonyl, ethoxycarbonyl and the like) ) May have a lower alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,
and C _1-6 alkoxy groups such as tert-butoxy. Examples of the “optionally halogenated lower alkylthio group” include, for example, a lower alkylthio group optionally having 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) (for example, methylthio group). ,
Ethylthio, n-propylthio, isopropylthio, n-
Butylthio, isobutylthio, sec-butylthio, tert-
And C _1-6 alkylthio groups such as butylthio). 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 ¹ and Ar ² form a condensed ring group together with adjacent carbon atoms include, for example,

Embedded image [Wherein, R ⁸ is as defined above. And the like. Ar ¹ and Ar ² are the same or different and are each preferably an aromatic hydrocarbon group which may have a substituent (eg, a C _6-14 aromatic hydrocarbon group), and preferably have a substituent. A phenyl group which may be present is more preferred. More specifically, each of Ar ¹ and Ar ² is (1) a phenyl group optionally substituted with a halogen atom or C _1-6 alkyl, or (2)
A 5- to 8-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to the carbon atom is preferred.

In the above formula, the ring B represents a “nitrogen-containing heterocycle optionally having substituent (s)”. However, the nitrogen-containing heterocyclic ring represented by the ring B is represented by the formula

Embedded image (Wherein n represents 0 or 1). The “nitrogen-containing heterocycle” represented by ring B includes, for example, one nitrogen atom, and further includes, for example, one to three heteroatoms selected from a nitrogen atom, an oxygen atom, a sulfur atom, and the like. A 3- to 13-membered nitrogen-containing heterocyclic ring which may be used is used. In the above formula, it is preferable to form a divalent group in which one hydrogen atom has been removed from each of the nitrogen atom and the other atoms in the ring B. Specifically, for example,

Embedded image 3 to 9 members (more preferably 3 to 6 members)
And the like are preferred. Examples of the substituent of the nitrogen-containing heterocyclic ring represented by Ring B include, for example, the “substituent” of the “aromatic group which may have a substituent” represented by the above Ar ¹ and Ar ² , An oxo group or the like is used.

Preferred specific examples of the ring B include, for example,
formula

Embedded image [In the formula, Z represents a nitrogen atom or a methine group, and Z ¹ and Z ² represent 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, respectively. Show. And the like represented by the following formula: The "C
_{As the `` 1-6} alkyl group '', for example, methyl, ethyl,
A linear or branched C _1-6 alkyl group such as propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl is used. As the "linear C _1-4 alkylene group", for example, shown as methylene, ethylene, propylene, a linear C _1-4 alkylene group represented by butylene. As the “linear C _1-4 alkylene group optionally substituted with a hydroxy group, oxo group or C _1-6 alkyl group” represented by Z ¹ and Z ² , an unsubstituted linear C _1-4 alkyl group is preferable. _1-4 alkylene groups and the like are used, and unsubstituted linear C _1-2 alkylene groups are particularly preferred. More preferably, ring B is piperidine, piperazine, or the like.

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

The “divalent straight-chain lower hydrocarbon group optionally having 1 to 3 heteroatoms” represented by X and Y is the same or different as a lower (C _1-6 ) hydrocarbon. Hydrogen atoms bonded to the carbon atoms
A group which can be removed, for example, a group which may contain a hetero atom selected from an oxygen atom, a sulfur atom and the like in a hydrocarbon chain. Specific examples of the “divalent linear lower hydrocarbon group” include (i) a C _1-6 alkylene group (eg, —CH ₂ —, — (CH ₂ ) ₂ —, — (CH ₂ ) ₃ — , − (CH ₂ )
_{4 -, - (CH 2)} 5 -, - (CH 2) 6 - , etc.), (ii) C _2-6
Alkenylene group (e.g., -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 (e.g., -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. As the “substituent” of the “divalent linear lower hydrocarbon group optionally having 1 to 3 hetero atoms” represented by X and Y,
For example, in addition to the “substituent” of the “aromatic group which may have a substituent” represented by the above Ar ¹ and Ar ² , an oxo group and the like are used. preferable.

X represents a bond, an oxygen atom or NH
Is particularly preferable, and a bond or an oxygen atom is particularly preferable. Y is preferably, for example, a group represented by the formula — (CH ₂ ) m—Y ¹ — (CH ₂ ) n—Y ² — wherein Y ¹ and Y ² are the same or different and each has a bond, an oxygen atom, S (O P) (p has the same meaning as described above), NR ⁴ (R ⁴ has the same meaning as described above), carbonyl group, carbonyloxy group or formula

Embedded image (Wherein R ⁵ and R ⁶ are the same or different and each represents a hydroxy group or a C _1-4 alkyl group), and m and n each represent an integer of 0 to 4 (provided that they are each an integer of 0 to 4). , M and n are 6 or less)]]. “C _1-4 represented by R ⁵ and R ⁶
As the “alkyl group”, for example, a linear or branched C _1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like are used.

Examples of Y include (i) a C _1-6 alkylene group, (ii)-(CH ₂ ) p ¹ O-, (iii)-(CH ₂ ) p ¹ NH-, and (iv)-( ^{_{CH 2) p 1 S-, (}} v) - (CH 2) q 1 CH (OH) (CH 2) q 2 O-, (vi) - (CH 2) q 1 CH (OH) (CH 2) q ² NH
—, (Vii) — (CH ₂ ) q ¹ CH (OH) (CH ₂ ) q ² S
-, (viii) - (CH 2) p 1 CONH-, (ix) -COO (CH 2) p 1 O-, (x) -COO (CH 2) p 1 NH-, (xi) -COO (CH ^{_{2) p 1 S-, (xii}} ) - (O-, CH 2) q 1 O (CH 2) q 2 (xiii) - (CH 2) q 1 O (CH 2) q 2 NH- or (xiv) ^{_{- (CH 2) q 1 O}} (CH 2) q 2 S- (p 1 is 1
6 represents an integer, and q ¹ and q ² each represent an integer of 1 to 3). Among these, 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
Represents a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxy group which may have a substituent. ). The “halogen atom” represented by R ⁷ includes 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, and examples thereof include an alkyl group, an alkenyl group, an alkynyl group, and a cycloalkyl group. And a chain or cyclic hydrocarbon group such as an aryl group or an aralkyl group. Among them, a chain (linear or branched) or cyclic hydrocarbon group having 1 to 16 carbon atoms is preferable, and a) an alkyl group [preferably a lower alkyl group (eg, methyl, ethyl, propyl, Isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and other C _1-6 alkyl groups)], b) alkenyl groups [preferably lower alkenyl groups (eg, vinyl, allyl, isopropenyl, A C _2-6 alkenyl group such as butenyl, isobutenyl, sec-butenyl, etc.), c) an alkynyl group [preferably a lower alkynyl group (eg, a C _2-6 alkynyl group such as propargyl, ethynyl, butynyl, 1-hexynyl and the like); D) cycloalkyl group [preferably lower cycloalkyl groups (eg, cyclopropyl, cyclobutyl Le, cyclopentyl, 1 to 3 lower alkoxy groups (e.g.,
A C _1-6 alkoxy group such as methoxy, etc.) and a C _3-6 cycloalkyl group such as cyclohexyl which may be condensed with a benzene ring which may have a), e) an aryl group (for example, phenyl, Tolyl, xylyl, biphenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3
A C _6-14 aryl group such as -phenanthryl, 4-phenanthryl or 9-phenanthryl, preferably a phenyl group), f) an aralkyl group [preferably a lower aralkyl group (for example, benzyl, phenethyl, diphenylmethyl, 1-
Naphthylmethyl, 2-naphthylmethyl, 2-phenylethyl, 2-diphenylethyl, 1-phenylpropyl,
And a C _7-16 aralkyl group such as 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl and 5-phenylpentyl, and more preferably a benzyl group)]. “Substituent” of “hydrocarbon group” represented by R ⁷
For example, an oxo group and the like are used in addition to the “substituent” of the “aromatic group which may have a substituent” represented by the above Ar ¹ and Ar ² .

The "acyl group" represented by R ⁷ includes, for example,-(C = O) -R ⁹ , -SO ₂ -R ⁹ , -SO-
R ⁹ , — (C ＝ O) NR ¹⁰ R ⁹ , — (C ＝ O) O—R ⁹ ,
- (C = S) O- R 9, - (C = S) NR 10 R 9, (R 9
Represents a hydrogen atom, a hydrocarbon group which may have a substituent or a hydroxy group which may have a substituent, and R ¹⁰
Represents a hydrogen atom or a lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Preferred are C _1-6 alkyl groups such as sec-butyl, tert-butyl, pentyl and hexyl, and particularly preferred are C _1-3 alkyl groups such as methyl, ethyl, propyl and isopropyl. ). ). Among preferably, - (C = O) -R 9, -SO 2 -R 9, -SO-R 9,
^{- (C = O) NR 10} R 9, - (C = O) a O-R ^9,
— (C ＝ O) —R ⁹ is more preferred. The “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,
Examples thereof include a linear (linear or branched) or cyclic hydrocarbon group such as an aryl group and an aralkyl group. Specifically, indicated above for R ⁷ "hydrocarbon group" and the like, among others including the 16 chain or cyclic hydrocarbon group having 1 to carbon atoms are preferred, especially lower (C _{1- 6} ) Alkyl groups are preferred. Examples of the “substituent” that the “hydrocarbon group” represented by R ⁹ may have include, for example, the above Ar ¹
In addition to the “substituent” of the “aromatic group which may have a substituent” represented by Ar ² and Ar ² , an oxo group and the like are used. As the "optionally substituted hydroxy group" represented by R ^9, for example, those similar to the "optionally substituted hydroxy group" represented by R ⁷ to be described later Used. Examples of the “optionally substituted hydroxy group” represented by R ⁷ include, for example, the above “substituted hydroxy group” in place of the hydrogen atom of (1) the hydroxy group or (2) the hydroxy group. Hydrocarbon group "
And a hydroxy group having one. The R ^7,
(1) a hydrogen atom, (2) a C _1-6 alkyl group optionally substituted by a carboxyl group or a C _1-6 alkoxy-carboxyl, (3) a C _1-6 alkoxy group, (4) a C _1-6 An alkoxy-carbonyl group or (5) a carboxyl group is preferred, and a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy-carbonyl group or a carboxyl group is particularly preferred. A represents a nitrogen atom or CR ⁷ ′
(R ⁷ ′ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group,
C _1-6 alkoxy-carbonyl group or carboxyl group) is preferable, and among them, a nitrogen atom, CH or C
Preferably -CH _3, are preferred, especially nitrogen atom or CH.

In the above formula, R ¹ , R ² and R ³ are the same or different and each have a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a substituent. Shows a good hydroxy group. ).
The "halogen atom" represented by R ¹ , R ² and R ³ includes fluorine, chlorine, bromine and iodine. R ¹ ,
Examples of the “optionally substituted hydrocarbon group” represented by R ² and R ³ include, for example, the “optionally substituted hydrocarbon group” represented by R ⁷ Is used. As the “acyl group” represented by R ¹ , R ² and R ³ , for example, the “acyl group” represented by R ⁷ is used. As the “optionally substituted hydroxy group” represented by R ¹ , R ² and R ³ , for example, the “optionally substituted hydroxy group” represented by the above R ⁷ Are used. As R ¹ , R ² and R ³ ,
(1) a hydrogen atom, (2) a C _1-6 alkyl group optionally substituted by a carboxyl group or C _1-6 alkoxy-carbonyl, (3) a C _1-6 alkoxy group, (4) ) C _1-6 alkoxy-carbonyl group, (5)
A carboxyl group or (6) C _6-14 aryl group (especially phenyl) is preferred, (1) a hydrogen atom, (2) a carboxyl group or a C _1-6 alkoxy - C _1-6 alkyl optionally substituted with carbonyl A group, (3) a C _1-6 alkoxy group, (4) a C _1-6 alkoxy-carbonyl group or (5)
Carboxyl groups are more preferred. Also, as R ¹ ,
(1) hydrogen atom, (2) (i) carboxyl, (ii) C
_1-6 alkoxy - carbonyl, (iii) hydroxy or (iv) may be substituted with a group selected from the group consisting of mono- or carbamoyl which may have a di -C _1-6 alkyl C _1-6 Alkyl group, (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 A carbamoyl group optionally having C _1-6 alkyl which may be substituted with alkoxy-carbonyl, or (8) a C _3-6 cycloalkyl group optionally substituted with C _1-6 alkoxy-carbonyl Are also preferred. 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 represents a hydrogen atom or a hydroxy group which may be substituted by a lower alkyl group. In the above formula, as the “lower alkyl group” of the “hydroxy group optionally substituted with a lower alkyl group” represented by R ⁸ ,
For example, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like can be mentioned. R ⁸ is preferably a hydrogen atom or a hydroxy group, and particularly preferably a hydrogen atom.

In the compound (I) of the present invention, Ar ¹ and Ar ² each represent (1) a halogen atom or C _1-6
A phenyl group which may be substituted with alkyl or (2) a 5- to 8-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms, Ring B is a formula

Embedded image [Wherein, Z represents a nitrogen atom or a methine group, and Z ¹ and Z ² represent 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, respectively. X is a bond, an oxygen atom or NH, and Y is (i) a C _1-6 alkylene group, (ii)-(CH ₂ ) p ¹ O-, (iii)-( ^{_{NH-, CH 2) p 1 (}} iv) - (S-, CH 2) p 1 (v) - (CH 2) q 1 CH (OH) (CH 2) q 2 O-, (vi) - (CH ^{_{2) q 1 CH (OH)}} (CH 2) q 2 NH
—, (Vii) — (CH ₂ ) q ¹ CH (OH) (CH ₂ ) q ² S
-, (viii) - (CH 2) p 1 CONH-, (ix) -COO (CH 2) p 1 O-, (x) -COO (CH 2) p 1 NH-, (xi) -COO (CH ^{_{2) p 1 S-, (xii}} ) - (O-, CH 2) q 1 O (CH 2) q 2 (xiii) - (CH 2) q 1 O (CH 2) q 2 NH- or (xiv) ^{_{- (CH 2) q 1 O}} (CH 2) q 2 S- (p 1 is 1
And q ¹ and q ² each represent an integer of 1 to 3), wherein A is a nitrogen atom or CR ⁷ ′
(R ⁷ ′ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group,
C _1-6 alkoxy - by showing a carbonyl group or a carbonyl group), R ¹ is (1) hydrogen atom, (2) (i) carboxyl, (ii) C _1-6 alkoxy - carbonyl, (iii)
Hydroxy or (iv) a 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) a carboxyl group, (7) carboxyl or C _1-6 alkoxy - carbamoyl which may have a C _1-6 alkyl optionally substituted with carbonyl Group, or (8) C
C which may be substituted by _1-6 alkoxy-carbonyl
_{A 3-6} cycloalkyl group, wherein R ² is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy-carbonyl group or a carboxyl group, R ³ is a hydrogen atom, and R ⁸ is a hydrogen atom or a hydroxyl group; Certain compounds are preferred.

In particular, Ar ¹ and Ar ² are phenyl groups,
Ring B is a formula

Embedded image [Wherein, Z ′ represents a methine group, Z ¹ ′ and Z ² ′ represent a methylene group or an ethylene group (preferably an ethylene group)], wherein X is a bond, an oxygen atom or N
H (preferably a bond or an oxygen atom), and Y is-
(CH ₂ ) p ¹ NH- (p ¹ is an integer of ¹ to 6), wherein A is CR ⁷ ″ (R ⁷ ″ is a hydrogen atom or C
In _1-6 an alkyl group), R ¹ is (1) hydrogen atom,
(2) carboxyl or C _1-6 alkoxy - C _1-6 alkyl group or optionally substituted with carbonyl (3) C _1-6 alkoxy - have a C _1-6 alkyl optionally substituted with carbonyl Compounds in which R ² is a hydrogen atom, R ³ is a hydrogen atom, and R ⁸ is a hydrogen atom, which are optional carbamoyl groups are preferred.

More specifically, the compounds prepared in Reference Examples B1 to B138 described below are used, and among them, 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo Ethyl [1,2-b] pyridazin-2-yl] -2-methylpropionate or a salt thereof (particularly difumarate, disuccinate, citrate, etc.), 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid or a salt thereof (particularly dihydrate), N- [6- [ 3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazine-2-carbonyl] glycineethyl or a salt thereof, 2- [6- [3- [4- (diffe Nylmethoxy) piperidino] propylamino] -3-methylimidazo [1,
Ethyl 2-b] pyridazin-2-yl] -2-methylpropionate or a salt thereof (particularly dihydrochloride), 2- [6- [3- [4- (diphenylmethylamino)]
Piperidino] propylamino] imidazo [1,2-b]
Ethyl pyridazin-2-yl] -2-methylpropionate or a salt thereof, 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -3-methylimidazo [1,
2-b] pyridazin-2-yl] -2-methylpropionic acid or a salt thereof, and N- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -3-methylimidazo [1,
2-b] pyridazine-2-carbonyl] glycine or a salt thereof is preferred.

The prodrug of the above-mentioned compound (I) or a salt thereof (hereinafter abbreviated as compound (I) of the present invention) can be prepared by reacting the compound of the present invention ( Compounds which are converted into I), that is, compounds which are enzymatically oxidized, reduced, hydrolyzed, etc. to be converted into the compound (I) of the present invention, gastric acid, etc., are hydrolyzed, etc. to the compound (I) of the present invention. It may be a compound that changes. As the prodrug of the compound (I) of the present invention, a compound in which the amino group of the compound (I) of the present invention is acylated, alkylated or phosphorylated (eg, the amino group of the compound (I) of the present invention is eicosanoyl , Alanylation, pentylaminocarbonylation, (5-methyl-2-
Oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.); Compounds in which hydroxyl groups are acylated, alkylated, phosphorylated, and borated (eg, the hydroxyl group of compound (I) of the present invention is acetylated,
Palmitoylated, propanoylated, pivaloylated, succinylated, fumalylated, alanylated, dimethylaminomethylcarbonylated compounds, etc.); compounds in which the carboxyl group of compound (I) of the present invention is esterified or amidated (eg, The carboxyl group of the compound (I) of the present invention is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, ethoxycarbonyloxyethyl-esterified, phthalidyl-esterified , (5
-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound, etc.). These compounds can be produced from compound (I) of the present invention by a method known per se. The prodrug of the compound (I) of the present invention is described in "Development of Pharmaceuticals", Hirokawa Shoten 1990, Vol.
Compounds of the present invention may be converted under physiological conditions, as described on pages 63 to 198.

Next, a method for producing the compound (I) or a salt thereof will be described. The compound (I) or a salt thereof is represented by the formula (A)

Embedded image [Wherein, Q ¹ represents a leaving group, and other symbols have the same meanings as described above. And a salt thereof and a compound represented by the formula

Embedded image [Wherein Q ² represents a leaving group, and other symbols have the same meanings as described above. And a salt thereof, or a salt thereof.

As the leaving group represented by Q ¹ , for example, an alkali metal such as sodium or potassium is used. Further, Q ¹ may be a hydrogen atom. Examples of the leaving group represented by Q ² include a halogen atom (eg, chlorine, bromine, iodine, etc.), a C _6-10 arylsulfonyloxy group (eg, benzenesulfonyloxy, p-tolylsulfonyloxy, etc.), _1-4 alkyl-sulfonyloxy groups (for example, methanesulfonyloxy and the like) and the like are used.

In this reaction, the compound (II ') or a salt thereof is used usually in an amount of about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of the compound (III') or a salt thereof. This reaction is usually carried out in the presence of a base, for example, sodium hydride,
Alkali metal hydrides such as potassium hydride; alkali metal alkoxides such as sodium methoxide and sodium ethoxide; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; Used. further,
This reaction includes alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, nitriles such as acetonitrile, N, N-dimethylformamide, N, N- The reaction can also be performed in an inert solvent such as amides such as dimethylacetamide and sulfoxides such as dimethylsulfoxide. The reaction temperature is usually about 10 to about 200 ° C, preferably about 50 to about 100 ° C. The reaction time is generally about 30 minutes to about 24 hours, preferably about 1 to about 6 hours.

Compound (I) or a salt thereof is represented by (B)
formula

Embedded image [Wherein the symbols have the same meanings as described above. And a salt thereof and a compound represented by the formula

Embedded image [Wherein the symbols have the same meanings as described above. And a salt thereof, or a salt thereof.

In this reaction, the compound (IV) or a salt thereof is used usually in an amount of about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of the compound (III ′) or a salt thereof. This reaction is usually carried out in the presence of a base, and the base may be, for example, an alkali metal hydride such as sodium hydride or potassium hydride, an alkali metal alkoxide such as sodium methoxide or sodium ethoxide, or water. Alkali metal hydroxides such as sodium oxide and potassium hydroxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate are used. Further, the reaction is carried out in alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; N, N-dimethylformamide; The reaction can also be carried out in an inert solvent such as amides such as N-dimethylacetamide and sulfoxides such as dimethylsulfoxide. The reaction temperature is generally about 10 to about 200 ° C, preferably about 50 to about 10 ° C.
0 ° C. The reaction time is generally about 30 minutes to about 24 hours, preferably about 1 to about 6 hours.

The compound (I) or a salt thereof is represented by the formula (C)
formula

Embedded image [Wherein the symbols have the same meanings as described above. And a salt thereof and a compound represented by the formula

Embedded image [Wherein the symbols have the same meanings as described above. And a salt thereof, or a salt thereof.

In this reaction, the compound (V) or a salt thereof is used usually in an amount of about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of the compound (VI ') or a salt thereof. This reaction is usually carried out in the presence of a base, and examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal alkoxides such as sodium methoxide and sodium ethoxide, and the like. Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate are used. In addition, this reaction involves alcohols such as methanol and ethanol,
Ethers such as dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene;
The reaction can also be performed in an inert solvent such as nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. The reaction temperature is usually about 10 to about 200 ° C, preferably about 50 to about 1 ° C.
00 ° C. The reaction time is generally about 30 minutes to about 24 minutes.
Hours, preferably from about 1 to about 6 hours.

Compound (I) or a salt thereof is (D)
formula

Embedded image [Wherein the symbols have the same meanings as described above. And a salt thereof and a compound represented by the formula

Embedded image [Wherein the symbols have the same meanings as described above. And a salt thereof, or a salt thereof.

In this reaction, about 1 to about 5 mol, preferably about 1 to about 2 mol, of compound (VII) or a salt thereof is used per 1 mol of compound (VI) or a salt thereof. This reaction is usually carried out in the presence of a base, and examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal alkoxides such as sodium methoxide and sodium ethoxide, and the like. Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate are used. In addition, this reaction involves alcohols such as methanol and ethanol,
Ethers such as dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene;
The reaction can also be performed in an inert solvent such as nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. The reaction temperature is usually about 10 to about 200 ° C, preferably about 50 to about 1 ° C.
00 ° C. The reaction time is generally about 30 minutes to about 24 minutes.
Hours, preferably from about 1 to about 6 hours.

Further, the compound (I) or a salt thereof is
Equation (E)

Embedded image [Wherein the symbols have the same meanings as described above. And a salt thereof and a compound represented by the formula

Embedded image [Wherein the symbols have the same meanings as described above. And a salt thereof, or a salt thereof.

In this reaction, the compound (VII) or a salt thereof is generally used in an amount of about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of the compound (VIII) or a salt thereof. Further, the reaction is carried out in alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; N, N-dimethylformamide; The reaction can also be carried out in an inert solvent such as amides such as N-dimethylacetamide and sulfoxides such as dimethylsulfoxide. The reaction temperature is usually about 10 to about 200 ° C, preferably about 50 to about 100 ° C. The reaction time is generally about 30 minutes to about 24 hours, preferably about 1 to about 6 hours. The thus-obtained compound of the present invention can be converted into a salt according to a conventional method when it is in a free form, and can be converted into a free form or another salt according to a conventional method when a salt is formed. The compound of the present invention or a salt thereof thus obtained can be isolated and purified by a known means, for example, solvent extraction, liquid conversion, phase transfer, salting out, crystallization, recrystallization, chromatography and the like. When the compound of the present invention or a salt thereof contains an optical isomer, it can be resolved into R-form and S-form by a usual optical resolution means.

Examples of the salt of compound (I) include salts with inorganic salts (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, etc.) and organic acids (eg, acetic acid, formic acid, propionic acid, For example, salts with fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid and the like are used. Further, when the compound (I) has an acidic group such as a carboxylic acid as a substituent, an inorganic base (eg, an alkali metal or an alkaline earth metal such as sodium, potassium, calcium, and magnesium, or ammonia) Or an organic base (for example, tri-
(C _1-3 alkylamine).

Next, the starting compound (II) of the compound of the present invention
Or (VIII) or a method for producing the salt thereof. As the salts of these starting compounds, those similar to the salts of compound (I) are used. Starting compounds (II) and (IV)
Or their salts are described, for example, in Journal of Medicinal Chemistry (J. Med. Chem.) 32
, P. 583 (1989) or a method analogous thereto. The starting compound (III) or a salt thereof is described in, for example, Journal of Organic Chemistry (J. Org. Chem.) 39, 214.
It can be synthesized by the method described on page 3 (1974) or a method analogous thereto. The starting compound (V) or a salt thereof can be synthesized, for example, by the method described in JP-A-62-2739 or a method analogous thereto. Starting compounds (VI) and (VIII) or salts thereof can be synthesized, for example, by the method described in JP-A-3-223287 or a method analogous thereto. The starting compound (VII) or a salt thereof is described, for example, in Journal of Medicinal Chemistry (J. Med. Chem.) 38, 247.
It can be synthesized by the method described on page 2 (1995) or a method analogous thereto. These starting compounds or salts thereof thus obtained can be obtained by known means, for example, solvent extraction,
It can be isolated and purified by liquid conversion, phase transfer, salt transfer, salting out, crystallization, recrystallization, chromatography, etc., but it may be used as a raw material in the next step as it is without isolation as a reaction mixture. .

In each of the reactions of the present invention and each of the reactions for synthesizing the starting material, when the starting compound has an amino group, a carboxyl group or a hydroxyl group as a substituent, these groups are generally used in peptide chemistry and the like. Such a protective group may be introduced, and the target compound can be obtained by removing the protective group as necessary after the reaction. Examples of the amino-protecting group include formyl, an optionally substituted C _1-6 alkylcarbonyl (eg, acetyl, ethylcarbonyl, etc.), phenylcarbonyl, C _1-6 alkyl-oxycarbonyl ( For example, methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl, C _7-10
Aralkyl-carbonyl (eg, benzylcarbonyl), trityl, phthaloyl, N, N-dimethylaminomethylene and the like are used. As these substituents, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), nitro group and the like are used. The number of substituents is about 1 to 3. As a carboxyl protecting group,
For example, it may have a substituent, C _1-6 alkyl (e.g., methyl, ethyl, n- propyl, i- propyl, n- butyl, tert- butyl, etc.), phenyl, trityl or silyl and using Can be As these substituents, a halogen atom (for example, fluorine, chlorine, bromine,
Iodine), formyl, C _1-6 alkyl-carbonyl (eg, acetyl, ethylcarbonyl, butylcarbonyl, etc.), nitro group and the like, and the number of substituents is 1
Or about three. Examples of the protecting group for the hydroxyl group include, for example, C _1-6 alkyl (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl and the like) which may have a substituent. Phenyl, C
_7-10 aralkyl (such as benzyl), formyl,
C _1-6 alkyl-carbonyl (eg, acetyl, ethylcarbonyl, etc.), phenyloxycarbonyl, benzoyl, C _7-10 aralkyl-carbonyl (eg, benzylcarbonyl, etc.), pyranyl, furanyl, silyl and the like are used. These substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.),
C _1-6 alkyl (eg, methyl, ethyl, n-propyl, etc.), phenyl, C _7-10 aralkyl (eg, benzyl, etc.), nitro group and the like are used, and the number of substituents is 1
Or about four. As a method for removing the protecting group, a method known per se or a method analogous thereto is used. Examples thereof include an acid, a base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, and tetrabutylammonium fluoride. And a method of treating with palladium acetate or the like.

The compound (I) or a salt thereof or a prodrug thereof has excellent antiallergic action, antihistamine action, antiinflammatory action, anti-PAF (platelet activating factor) action, eosinophil chemotaxis inhibitory action and the like. Mammals (eg, humans, mice, dogs, rats, cows, etc.) because of their low toxicity (acute toxicity: LD ₅₀ > 2 g / kg)
Can be used as a safe anti-allergic agent. Further, the compound (I) or a salt thereof or a prodrug thereof has an antihistamine effect and an eosinophil chemotaxis inhibitory effect, and allergic disease, inflammatory disease, skin disease, respiratory disease and the like in the mammal. Can be used for treatment or prevention. The compound (I) or a salt thereof or a prodrug thereof can suppress nasal resistance increase, sneezing, nasal secretion, itching of the eyes, and inflammation of the eyes, and particularly, allergic and inflammatory diseases of the nose and eyes. Useful for the treatment or prevention of Allergic diseases include allergic skin diseases (eg, eczema, eczema / dermatitis,
Contact dermatitis, pruritus, dry dermatitis, chronic urticaria, acute urticaria, prurigo, atopic dermatitis, etc.), allergic rhinitis, allergic conjunctivitis, irritable pneumonitis and the like. Skin diseases include allergic diseases such as atopic dermatitis, eczema, eczema / dermatitis, contact dermatitis, pruritus, dry dermatitis, chronic urticaria, acute urticaria, prurigo, herpetic dermatitis and psoriasis. Inflammatory skin diseases. Respiratory diseases include asthma, eosinophilic pneumonia (PIE syndrome), chronic obstructive pulmonary disease (COPD) and the like. Allergic and inflammatory diseases of the nose include allergic rhinitis,
Upper respiratory irritability, hay fever, and the like. Allergic and inflammatory diseases of the eye include conjunctivitis (eg, allergic conjunctivitis, giant papillary conjunctivitis, contact blepharoconjunctivitis, etc.),
Spring catarrh, hay fever and the like. Among the above-mentioned diseases, compound (I) or a salt thereof or a prodrug thereof is useful for conjunctivitis (eg, allergic conjunctivitis, giant papillary conjunctivitis, contact blepharoconjunctivitis, etc.), spring catarrh, allergic rhinitis, pollinosis and the like. It is useful as an agent for preventing and treating allergic and inflammatory diseases of the nose and eyes. Further, the compound (I), a salt thereof, or a prodrug thereof has reduced central transferability as compared with a conventional fused pyridazine compound. The route of administration of these prophylactic / therapeutic agents is oral,
It may be either parenteral.

The preparation used in the present invention may contain, as an active ingredient, other pharmaceutical ingredients other than the compound (I) or a salt thereof or a prodrug thereof. Such pharmaceutically active ingredients include, for example, anti-asthmatics (for example,
Theophylline, procaterol, ketotifen, azelastine, seratrodast, etc.), antiallergic agents (eg, ketotifen, terfenadine, azelastine, epinastine, etc.), anti-inflammatory agents (eg, diclofenac sodium, ibuprofen, indomethacin, etc.),
Antibacterial agents (eg, cefixime, cefdinir, ofloxacin, tosfloxacin, etc.), antifungal agents (eg,
Fluconazole, itraconazole and the like). These components are not particularly limited as long as the object of the present invention is achieved, and can be used at an appropriate mixing ratio. Specific examples of the dosage form include, for example, nasal drops, eye drops, aerosols, eye ointments, plasters, suppositories, troches, cataplasms, liniments, sustained-release preparations, sustained-release preparations, and the like. . In particular, nasal drops are used for the prevention and treatment of allergic rhinitis and hay fever. It is suitable. These preparations are prepared according to a conventional method using additives generally used for pharmaceutical preparations. For example, eye drops can be manufactured according to the method described in the general rules of preparations of the Japanese Pharmacopoeia.

The additives used in the nasal drops and eye drops of the present invention include, for example, buffers, stabilizers, thickeners, suspending agents, preservatives (preservatives), isotonic agents , A solubilizing agent, a pH adjusting agent, a cooling agent and the like. Examples of the buffer include sodium hydrogen phosphate, sodium dihydrogen phosphate, crystalline sodium dihydrogen phosphate, boric acid, borax, sodium carbonate, sodium L-glutamate or a combination thereof, a weak acid, a weak base or a salt thereof. A combination of these is used. As the stabilizer, for example, sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, Rongalit, thioglycerol, thioglycolic acid, thiolactic acid, cysteine, glutathione, thioacetic acid,
Sulfur compounds such as methionine, thiosorbitol, thioglucose and thiourea; inorganic acids and salts thereof such as boric acid, borax, phosphoric acid, metaphosphoric acid, sodium carbonate and sodium hydrogen carbonate; formic acid, oxalic acid, tartaric acid and citric acid , Edetic acid, and other organic acids and salts thereof (eg, sodium edetate); acetamide, diethylacetamide,
Acid amides such as nicotinamide, urea and barbital;
Urea derivatives; polyhydric alcohols such as glycol, propylene glycol, glycerin, polyethylene glycol, glucose, and ascorbic acid; sugars; phenols such as phenol, thymol, quinone, coumarone, and isocoumarone; , Casein, edestin and the like; amino acids; proteins and the like. Examples of the thickener or suspending agent include polyhydric alcohols such as glycerin and macrogol; sugars such as sorbitol, mannitol and sucrose; celluloses such as methylcellulose, carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinyl alcohol; Synthetic polymers such as polyvinylpyrrolidone and carboxyvinyl polymer; chondroitin sulfate and the like are used. As preservatives (preservatives), for example, paraoxybenzoic acid esters such as propyl paraoxybenzoate and butyl paraoxybenzoate; parabens such as methylparaben, ethylparaben, propylparaben, and butylparaben; benzalkonium chloride; benzethonium chloride Chlorhexidine gluconate; inverted soaps such as cetylpyridium chloride; alcohol derivatives such as chlorobutanol, phenylethyl alcohol and benzyl alcohol; organic acids such as sodium dehydroacetate, sorbic acid and sodium sorbate and salts thereof; Chloromethoxyphenol,
Phenols such as parachlorometacresol; organic mercury agents such as thimerosal, phenolmercuric nitrate, phenylmercuric borate, phenylmercuric acetate, and nitromezole; polymyxin B sulfate; As the tonicity agent, for example, sodium chloride, calcium chloride, potassium chloride, concentrated glycerin, propylene glycol, mannitol, sucrose and the like are used. As a solubilizing agent, for example, polyvinylpyrrolidone K30, macrogol 40
00, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like are used. As the pH adjuster, for example, sodium hydroxide or the like is used. As the cooling agent, for example, 1-menthol, dl-camphor and the like are used. The nasal drops of the present invention can be produced as a solution or suspension using the above-mentioned components and by a known method, for example, using a production machine. It can also be used as a powder formulation by triturating with an appropriate excipient such as lactose. Specifically, the above-mentioned components are uniformly dissolved and suspended, or the powder formulation is used for commonly used nasal drops such as an animal pressure type (mechanical pump), a pressure type (aerosol), a squeeze type, and an inhalation type. By filling the administration device, it can be supplied as a product. In the preparation of the present invention, the content of compound (I) or a salt thereof or a prodrug thereof varies depending on the form of the preparation, but is usually about 0.001 to about 30% by weight, preferably about 0 to about 30% by weight, based on the whole preparation. 0.01 to about 10% by weight, more preferably about 0.1 to about 10% by weight.
It is about 05 to about 2% by weight. The dosage of these preparations varies depending on age, body weight, symptoms, administration route, number of administrations and the like. For example, for an adult patient with allergic rhinitis, the active ingredient (compound (I) or its salt or Usually, about 0.00
1 to about 30 mg / human, preferably about 0.01 to about 10 mg / human, more preferably about 0.05 to about 2 mg / human.
mg / human should be instilled once or twice a day. For an adult patient with allergic conjunctivitis, the amount is usually about 0.001 to about 30 m / day in terms of the active ingredient (compound (I) or a salt thereof or a prodrug thereof) per day.
g / human, preferably about 0.01 to about 10 mg / human, more preferably about 0.05 to about 2 mg / human.
It is recommended to apply it once or twice a day.

[0045]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail by reference examples, examples and experimental examples, but the present invention is not limited to these examples. The detection of the fraction containing the target substance in the reference example was performed by TLC (Thin Layer Chromatography).
atography, thin layer chromatography). In the TLC observation, the 60F ₂₅₄ Merck (Merck) manufactured as a TLC plate, U as the detection method
A V detector was employed. The powder X-ray diffraction analysis was measured as follows. RINT 1100 (Science)
The sample was placed in a quartz (0 scattering) sample holder for XRPD pattern measurement. A powder diffractometer equipped with a Cu X-ray tube source, a first beam monochromator and a position detector (PSD) was used. 1. Incident beam ^. Parallelized using a divergence slit. The X-ray tube source was set at 40 KV and 40 mA, and the sample was irradiated with CuK _α1 radiation. XRPD data at 3-35θ
6.000 ^. / Min. 10 most prominent peaks
An X-ray peak reaching 30% or more was displayed as 0%.

[0046]

EXAMPLES Reference Example B1 Preparation of 6- [3- [4- (diphenylmethyl) -1-piperazinyl] propoxy] [1,2,4] triazolo [1,5-b] pyridazine dihydrochloride 4- ( (Diphenylmethyl) -1-piperazinepropanol 466m
g was dissolved in 10 ml of dry tetrahydrofuran, 173 mg of sodium tert-butoxide was added, and the mixture was heated under reflux for 30 minutes. After cooling, 268 mg of 6-chloro [1,2,4] triazolo [1,5-b] pyridazine was added, and the mixture was heated under reflux 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, and eluted with ethyl acetate: methanol (10: 1). The desired fraction was collected, dissolved in 10 ml of ethyl acetate, and 0.7 ml of a 4N solution of hydrogen chloride in ethyl acetate was added. The obtained crystal was recrystallized from 95% aqueous ethanol to obtain 413 mg of the title compound. Melting point: 251-253 ° C. Elemental analysis: C ₂₅ H ₃₀ N ₆ OCl ₂ Calculated (%): C, 59.88; H, 6.03; N, 16.76 Actual (%): C, 59.76; H, 6 .
09; N, 16.80

Reference Example B2 Preparation of 6- [3- [4- (diphenylmethoxy) piperidino] propoxy] [1,2,4] triazolo [1,5-b] pyridazine fumarate 4- (diphenylmethoxy)- 1-piperidinepropanol 39
0 mg was dissolved in 10 ml of dry tetrahydrofuran, 127 mg of sodium tert-butoxide was added, and the mixture was heated under reflux for 30 minutes. After cooling, 215 mg of 6-chloro [1,2,4] triazolo [1,5-b] pyridazine was added, and the mixture was heated under reflux 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, and eluted with ethyl acetate: methanol: triethylamine (95: 5: 1). The desired fraction was collected, dissolved in 10 ml of ethanol, crystallized by adding 93 mg of fumaric acid, and recrystallized from ethanol to obtain 218 mg of the title compound. Mp 157-159 ° C. Elemental analysis: Calculated as _{C 30 H 33 N 5 O 6} (%): C, 64.39; H, 5.94; N, 12.51 Found (%): C, 64.16; H, 5.71; N , 12.32

Reference Example B3 Preparation of 6- [3- [4- (diphenylmethyl) -1-piperazinyl] propoxy] -7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine dihydrochloride 4- (diphenylmethyl) -1-piperazinepropanol 466m
g was dissolved in 10 ml of dry tetrahydrofuran, 173 mg of sodium tert-butoxide was added, and the mixture was heated under reflux for 30 minutes. After cooling, 6-chloro-7-isopropyl [1,2,4] triazolo
295 mg of [1,5-b] pyridazine was added, and the mixture was heated under reflux 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,
Elution was performed with ethyl acetate: methanol (10: 1). Collect the desired fractions, dissolve in 10 ml of ethanol, and add
After l was added and the mixture was concentrated under reduced pressure, the resulting crystals were recrystallized from ethyl acetate to obtain 582 mg of the title compound. Melting point 177 ° C Elemental analysis: C ₂₈ H ₃₆ N ₆ OCl ₂ Calculated (%): C, 59.89; H, 6.82; N, 14.97 Found (%): C, 59.47; H, 6.89; N, 14.45

Reference Example B4 6- [3- [4- (diphenylmethoxy) piperidino] propoxy]
-7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine
Preparation of fumarate salt 4- (diphenylmethoxy) -1-piperidinepropanol 48
8 mg was dissolved in 10 ml of dry tetrahydrofuran, 173 mg of sodium tert-butoxide was added, and the mixture was heated under reflux for 30 minutes. After cooling, 295 mg of 6-chloro-7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine was added, and the mixture was heated under reflux 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, and ethyl acetate: methanol: triethylamine (95: 5: 1).
Eluted. Collect the desired fractions and add ethanol 10
The crystals were crystallized by adding 98 mg of fumaric acid, and recrystallized from ethanol to obtain 385 mg of the title compound. Mp 163-165 ° C. Elemental analysis: Calculated as _{C 33 H 39 N 5 O 6} (%): C, 65.87; H, 6.53; N, 11.64 Found (%): C, 65.77; H, 6.46; N , 11.71

Reference Example B5 Preparation of 6- [3- [4- (diphenylmethyl) -1-piperazinyl] propylamino] [1,2,4] triazolo [1,5-b] pyridazine Step A: 6- ( Production of 3-hydroxypropylamino) [1,2,4] triazolo [1,5-b] pyridazine 6-chloro [1,2,4] triazolo [1,5-b] pyridazine 928 mg
Was dissolved in 10 ml of ethanol, 1.23 g of 3-amino-1-propanol was added, and the mixture was heated under reflux for 20 hours. After cooling, concentrate under reduced pressure to half volume, wash the obtained crystals with ethanol,
Drying afforded 835 mg of the title compound. Melting point 193-194 ° C Elemental analysis: Calculated as C ₈ H ₁₁ N ₅ O (%): C, 49.73; H, 5.74; N, 36.25 Found (%): C, 49.70; H, 5.53; N, 36.28 Step B: 450 mg of 6- (3-hydroxypropylamino) [1,2,4] triazolo [1,5-b] pyridazine is added to tetrahydrofuran 15
The suspension was added to N-ethyldiisopropylamine (582 mg) and methanesulfonyl chloride (533 mg) and stirred at room temperature for 1 hour. Ice water and salt were 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 dissolved in 10 ml of N, N-dimethylformamide, and 1- (diphenylmethyl) piperazine
504 mg, sodium iodide 298 mg, potassium carbonate 276 mg
And stirred at 60 ° C for 2 hours. After cooling, add ice water,
The mixture was extracted with ethyl acetate, and the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and ethyl acetate: methanol:
Elution with triethylamine (90: 10: 1). The desired fraction was collected and concentrated, and the obtained crystals were washed with ethyl ether and dried to obtain 281 mg of the title compound. Mp 139-140 ° C. Elemental _{analysis: C 25 H 29 N 7 ·} 0.5H 2 O Calculated (%): C, 68.78; H, 6.93; N, 22.46 Found (%): C, 68.72; H, 6.86; N, 22.16

Reference Example B6 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, and 388 mg of N-ethyldiisopropylamine and 344 mg of methanesulfonyl chloride were added.
Stir for hours. Ice water and salt were 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 dissolved in 5 ml of N, N-dimethylformamide, and 352 mg of 4- (diphenylmethoxy) piperidine, 208 mg of sodium iodide, potassium carbonate
193 mg was 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,
Elution was performed with ethyl acetate: methanol: triethylamine (90: 10: 1). The desired fractions are collected and concentrated, and the resulting crystals are washed with ethyl ether and dried to give the title compound 2
09 mg were obtained. Melting point 136-138 ° C Elemental analysis: Calculated as C ₂₆ H ₃₀ N ₆ O (%): C, 70.56; H, 6.83; N, 18.99 Found (%): C, 70.43; H, 6.83; N, 19.04

Reference Example B7 Preparation of 6- [3- [4- (diphenylmethyl) -1-piperazinyl] propylthio] [1,2,4] triazolo [1,5-b] pyridazine Step A: 6- (3 -Bromopropylthio) [1,2,4] triazolo
Production of [1,5-b] pyridazine Methyl 3-mercaptopropionate (3.9 ml)
The mixture was dissolved in 40 ml, and 15 ml of a 2N methanol solution of sodium methoxide and 1.55 g of 6-chloro [1,2,4] triazolo [1,5-b] pyridazine were added, and the mixture was heated under reflux for 1 hour. After cooling, the mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the precipitated crystals were collected, washed with ethyl acetate, suspended in 40 ml of tetrahydrofuran, added with 3.06 ml of 1,3-dibromopropane, and heated under reflux for 2 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. Concentrate under reduced pressure, and add ethyl acetate-hexane to the residue.
(1: 1) was added, and the precipitated crystals were collected and dried to obtain 1.97 g of the title compound. 133-135 ° C Elemental analysis: Calculated as C ₈ H ₉ N ₄ SBr (%): C, 35.18; H, 3.32; N, 20.51 Found (%): C, 35.11; H, 3.13; N, 20.43 Step B: 6- (3-bromopropylthio) [1,2,4] triazolo
Dissolve 546 mg of [1,5-b] pyridazine and 505 mg of 1- (diphenylmethyl) piperazine in 15 ml of acetonitrile, and add 373 mg of sodium iodide and 277 mg of potassium carbonate to give 5
Stir at 0-60 ° C for 15 hours. 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, and eluted with ethyl acetate: methanol (95: 5). The desired fractions are collected and concentrated, and the obtained crystals are washed with ethyl ether and dried to give the title compound 507.
mg was obtained. Melting point: 128-130 ° C Elemental analysis: Calculated as C ₂₅ H ₂₈ N ₆ S (%): C, 67.54; H, 6.35; N, 18.90 Found (%): C, 67.25; H, 6.29; N, 18.78

Reference Example B8 Preparation of 6- [3- [4- (diphenylmethoxy) piperidino] propylthio] [1,2,4] triazolo [1,5-b] pyridazine fumarate 6- (3-bromopropyl Thio) [1,2,4] triazolo [1,5-b] pyridazine (546 mg) and 4- (diphenylmethoxy) piperidine (535 mg) are dissolved in acetonitrile (15 ml), and sodium iodide (373 mg) and potassium carbonate (277 mg) are added.
Stir at 15 ° C for 15 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, and eluted with ethyl acetate: methanol: triethylamine (95: 5: 1). Collect and concentrate the desired fractions, dissolve in 20 ml of ethanol and 159 mg of fumaric acid
added. The precipitated crystals were collected, washed with ethyl ether, and dried to obtain 435 mg of the title compound. Mp 185-187 ° C. Elemental _{analysis: C 30 H 33 N 5 O} 5 S · 0.5H 2 O Calculated (%): C, 61.63; H, 5.86; N, 11.98 Found (%): C, 61.98 ; H, 5.83; N, 11.95

Reference Example B9 Preparation of 6- [3- [4- (diphenylmethyl) -1-piperazinyl] propylthio] -7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine Step A: 6- (3-chloropropylthio) -7-isopropyl [1,
Production of 2,4] triazolo [1,5-b] pyridazine Methyl 3-mercaptopropionate (3.9 ml) in methanol
The mixture was dissolved in 40 ml, and 15 ml of a 2N sodium methoxide methanol solution and 1.97 g of 6-chloro-7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine were added, and the mixture was heated under reflux for 40 minutes. After cooling, the mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the precipitated crystals were collected, washed with ethyl acetate, suspended in 40 ml of tetrahydrofuran, added with 2 ml of 1-bromo-3-chloropropane, and heated under reflux for 2 hours. After cooling, add ice water, extract with ethyl acetate, wash the extract with saturated saline,
Dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with hexane: ethyl acetate (2: 3). The desired fraction was collected and concentrated, and the precipitated crystals were filtered and dried to obtain 2.39 g of the title compound. Melting point 82-83 ° C Elemental analysis: Calculated as C ₁₁ H ₁₅ N ₄ SCl (%): C, 48.79; H, 5.58; N, 20.69 Found (%): C, 48.79; H, 5.53; N, 20.87 Step B: 6- (3-chloropropylthio) -7-isopropyl [1,
2,4] Triazolo [1,5-b] pyridazine (542 mg) and 1- (diphenylmethyl) piperazine (555 mg) were mixed with acetonitrile 15
Dissolve in 4 ml of sodium iodide 447mg, potassium carbonate 2
77 mg was added and the mixture was heated under reflux for 20 hours. After cooling, add ice water, extract with ethyl acetate, wash the extract with saturated saline,
Dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected and concentrated, and the obtained crystal was recrystallized from ethyl acetate: ethyl ether (1: 1) and dried to obtain 607 mg of the title compound. Mp 137-139 ° C. Elemental analysis: C ₂₈ H ₃₄ N ₆ Calculated S (%): C, 69.10 ; H, 7.04; N, 17.27 Found (%): C, 69.04; H, 7.06; N, 17.33

Reference Example B10 Preparation of 6- [3- [4- (diphenylmethoxy) piperidino] propylthio] -7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine fumarate 6- ( Dissolve 542 mg of 3-chloropropylthio) -7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine and 535 mg of 4- (diphenylmethoxy) piperidine in 15 ml of acetonitrile, 447 mg of sodium iodide, potassium carbonate 277 mg was added and the mixture was heated under reflux for 15 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, and ethyl acetate: methanol (95: 5)
Eluted. The desired fraction was collected and concentrated, the residue was dissolved in 20 ml of ethanol, and 196 mg of fumaric acid was added. The precipitated crystals were collected, washed with ethanol and dried to obtain 780 mg of the title compound. Mp 164-165 ° C. Elemental _{analysis: C 33 H 39 N 5 O} 5 Calculated S (%): C, 64.16 ; H, 6.36; N, 11.34 Found (%): C, 64.45; H, 6.49; N, 11.67

Reference Example B11 Preparation of 6- [4- (diphenylmethoxy) piperidino] [1,2,4] triazolo [1,5-b] pyridazine 1.12 g of 4- (diphenylmethoxy) piperidine and 6-chloro [1 558 mg of 2,2,4] triazolo [1,5-b] pyridazine was dissolved in 25 ml of 1-butanol, 700 mg of N-ethyldiisopropylamine was added, and the mixture was heated under reflux for 17 hours. After cooling, the mixture was concentrated under reduced pressure, ice water was added to the residue, 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 hexane: ethyl acetate (1: 3). The desired fraction was collected and recrystallized from ethanol to give 757 mg of the title compound. 137-139 ° C Elemental analysis: Calculated as C ₂₃ H ₂₃ N ₅ O (%): C, 71.67; H, 6.01; N, 18.17 Found (%): C, 71.75; H, 5.90; N, 18.34

Reference Example B12 Preparation of 6- [4- [4- (diphenylmethoxy) piperidino] butylamino] [1,2,4] triazolo [1,5-b] pyridazine 4- (diphenylmethoxy) -1- Piperidine butanamine 1.
83 g with 6-chloro [1,2,4] triazolo [1,5-b] pyridazine 5
57 mg was dissolved in 30 ml of 1-butanol, 931 mg of N-ethyldiisopropylamine was added, and the mixture was heated under reflux for 14 hours.
After cooling, the mixture was concentrated under reduced pressure, ice water was added to the residue, 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: triethylamine (45: 5: 1). The desired fraction was collected and concentrated, and the precipitated crystals were collected, washed with ethyl ether, and dried to give 149 mg of the title compound. Melting point 102-104 ° C Elemental analysis: Calculated as C ₂₇ H ₃₂ N ₆ O (%): C, 71.03; H, 7.06; N, 18.41 Found (%): C, 70.78; H, 6.77; N, 18.40

Reference Example B13 Preparation of 6- [2- [4- (diphenylmethoxy) piperidino] ethylamino] [1,2,4] triazolo [1,5-b] pyridazine Step A: 6- (2-hydroxy Production of ethylamino) [1,2,4] triazolo [1,5-b] pyridazine 2.01 g of 2-aminoethanol and 2.03 g of 6-chloro [1,2,4] triazolo [1,5-b] pyridazine It was dissolved in 22 ml of ethanol and heated under reflux for 20 hours. After cooling, the mixture was concentrated under reduced pressure, and the precipitated crystals were collected and dried to obtain 1.48 g of the title compound. Melting point 219-221 ° C Elemental analysis: Calculated as C ₇ H ₉ N ₅ O (%): C, 46.92; H, 5.06; N, 39.09 Found (%): C, 46.67; H, 5.00; N, 38.93 Step B: 1.25 g of 6- (2-hydroxyethylamino) [1,2,4] triazolo [1,5-b] pyridazine in 40 ml of tetrahydrofuran
And 1.81 g of N-ethyldiisopropylamine and 1.60 g of methanesulfonyl chloride were added, and the mixture was stirred at room temperature for 45 minutes. Ice water was added, sodium chloride was added to saturate the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The residue was dissolved in N, N-dimethylformamide (21 ml), and 4- (diphenylmethoxy) piperidine (1.79 g), sodium iodide (1.00 g) and potassium carbonate (927 mg) were added. Was. Ice water was added, and the mixture was extracted with ethyl ether. The extract was washed with saturated saline and dried over magnesium sulfate. Concentrate under reduced pressure, collect the precipitated crystals, wash with ethyl ether, and dry to give 1.13 g of the title compound.
I got Melting point 152-154 ° C Elemental analysis: Calculated as C ₂₅ H ₂₈ N ₆ O (%): C, 70.07; H, 6.59; N, 19.61 Found (%): C, 69.66; H, 6.40; N, 20.03

Reference Example B14 6- [2- [4- (diphenylmethoxy) piperidino] ethoxy]
Preparation of [1,2,4] triazolo [1,5-b] pyridazine fumarate 4- (diphenylmethoxy) -1-piperidineethanol 774m
g was dissolved in 20 ml of dry tetrahydrofuran, 263 mg of sodium tert-butoxide was added, and the mixture was heated under reflux for 30 minutes. After cooling, 385 mg of 6-chloro [1,2,4] triazolo [1,5-b] pyridazine was added, and the mixture was refluxed for 6 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, and eluted with ethyl acetate: methanol (10: 1). The desired fractions are collected, dissolved in 10 ml of ethanol, crystallized by adding 216 mg of fumaric acid, and recrystallized from ethanol to give the title compound.
mg was obtained. Melting point: 176-177 ° C Elemental analysis: Calculated as C ₂₉ H ₃₁ N ₅ O ₆・ H ₂ O (%): C, 61.80; H, 5.90; N, 12.43 Found (%): C, 61.72; H , 5.65; N, 12.03

Reference Example B15 Preparation of 7-tert-butyl-6- [2- [4- (diphenylmethoxy) piperidino] ethoxy] [1,2,4] triazolo [1,5-b] pyridazine 4- (diphenyl (Methoxy) -1-piperidineethanol 740m
g was dissolved in 18 ml of dry tetrahydrofuran, 251 mg of sodium tert-butoxide was added, and the mixture was heated under reflux for 25 minutes. After cooling, 7-tert-butyl-6-chloro [1,2,4] triazolo
[1,5-b] pyridazine (501 mg) was added, and the mixture was heated under reflux for 2 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,
Eluted with ethyl acetate. The desired fraction was collected and recrystallized from ethyl acetate to obtain 380 mg of the title compound. Melting point: 133-135 ° C Elemental analysis: C ₂₉ H ₃₅ N ₅ O ₂ Calculated (%): C, 71.73; H, 7.26; N, 14.42 Found (%): C, 71.47; H, 7 .0
6; N, 14.19

Reference Example B16 1- [4- (diphenylmethoxy) piperidino] -3-([1,
Production of 2,4] triazolo [1,5-b] pyridazin-6-yloxy) -2-propanol Step A: 6- (2-oxiranylmethoxy) [1,2,4] triazolo
Preparation of [1,5-b] pyridazine 0.13 ml of glycidol and 6-chloro [1,2,4] triazolo
[1,5-b] pyridazine 309 mg in N, N-dimethylformamide
Suspend in 5 ml and at room temperature 60% oily sodium hydride 80m
g and stirred for 3 hours. Brine was added, 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. The desired fraction was collected and dried to give 170 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 2.7-2.9 (1H, m), 2.9-3.1 (1H, m), 3.
3-3.4 (1H, m), 4.1-4.4 (1H, m), 4.7-4.9 (1H, m), 7.11 (1H, d,
J = 9Hz), 8.02 (1H, d, J = 9Hz), 8.34 (1H, s). Step B: 6- (2-oxiranylmethoxy) [1,2,4] triazolo
[1,5-b] pyridazine 171mg and 4- (diphenylmethoxy)
Suspension of 238 mg of piperidine in 8 ml of ethanol and 60 ° C
And stirred for 5 hours. After concentrating under reduced pressure, ethyl acetate was added to the residue, and the precipitated crystals were collected, washed with ethyl ether and dried to obtain 327 mg of the title compound. 133-135 ° C Elemental analysis: C ₂₆ H ₂₉ N ₅ O ₃ Calculated (%): C, 67.96; H, 6.36; N, 15.24 Found (%): C, 67.84; H, 6.13; N , 15.34

Reference Example B17 1- [4- (diphenylmethyl) -1-piperazinyl] -3-([1,2,4]
Preparation of triazolo [1,5-b] pyridazin-6-yloxy) -2-propanol dihydrochloride 6- (2-oxiranylmethoxy) [1,2,4] triazolo [1,5-b]
485 mg of pyridazine and 764 mg of 1- (diphenylmethyl) piperazine were suspended in 30 ml of ethanol and stirred at 60 ° C. for 15 hours. After concentrating under reduced pressure, ethyl acetate was added to the residue, and the precipitated crystals were collected and washed with ethyl ether. The obtained crystals were dissolved in 20 ml of ethyl acetate, and 5 ml of a 4N ethyl acetate solution of hydrogen chloride was added, followed by concentration under reduced pressure. The precipitated crystals were recrystallized from ethanol to obtain 392 mg of the title compound. Melting point 242 ° C (decomp.) Elemental analysis: Calculated as C ₂₅ H ₃₀ N ₆ O ₂ Cl ₂・ H ₂ O (%): C, 56.08; H, 6.02; N, 15.69 Actual (%): C , 56.44; H, 6.03; N, 15.84

Reference Example B18 3- [4- (Diphenylmethoxy) piperidino] -N-([1,2,4] triazolo [1,5-b] pyridazin-6-yl) propionamide
Step A: 3-chloro-N-([1,2,4] triazolo [1,5-b] pyridazin-6-yl) propionamide 6-amino [1,2,4] triazolo [1,5 -b] Pyridazine 0.80g
Was dissolved in 7 ml of N, N-dimethylacetamide, and
Add 0.68 ml of -chloropropionyl chloride and add
Stir for hours. The reaction solution was poured into ice water, extracted with ethyl acetate-tetrahydrofuran (1: 1), and the extract was washed with saturated saline and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and ethyl ether was added to the residue.
Drying yielded 0.875 g of the title compound. ¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.99 (2H, t, J = 7Hz), 3.91 (2H,
t, J = 7Hz), 8.36, 8.43 (1H, d, J = 10Hz each), 8.57 (1H, s), 1
1.37 (1H, s). Step B: 339 mg of 3-chloro-N-([1,2,4] triazolo [1,5-b] pyridazin-6-yl) propionamide and 4- (diphenylmethoxy) piperidine 401 mg of acetonitrile 15 ml
Sodium iodide 447mg, potassium carbonate 249
mg was added and the mixture was stirred at room temperature for 15 hours. Ice water was added to the reaction solution, 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 and eluted with ethyl acetate-methanol (85:15). The desired fraction was collected and concentrated, and the obtained crystals were recrystallized from ethanol and dried to obtain 495 mg of the title compound. Melting point 176-177 ° C Elemental analysis: C ₂₆ H ₂₈ N ₆ O ₂ Calculated (%): C, 68.40; H, 6.18; N, 18.41 Found (%): C, 68.20; H, 6.00; N , 18.36

Reference Example B19 3- [4- (diphenylmethyl) -1-piperazinyl] -N-([1,2,4]
Preparation of triazolo [1,5-b] pyridazin-6-yl) propionamide 3-chloro-N-([1,2,4] triazolo [1,5-b] pyridazin-6-
Yl) propionamide 339mg and 1- (diphenylmethyl)
Dissolve 379 mg of piperazine in 15 ml of acetonitrile,
447 mg of sodium iodide and 249 mg of potassium carbonate were added, and the mixture was stirred at room temperature for 15 hours, and further heated under reflux for 8 hours. After cooling, ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. After concentrating under reduced pressure, the resulting crystals were recrystallized from ethanol and dried to obtain 408 mg of the title compound. Melting point 176-177 ° C Elemental analysis: Calculated as C ₂₅ H ₂₇ N ₇ O (%): C, 66.65; H, 6.26; N, 21.76 Found (%): C, 66.36; H, 6.16; N, 21.95

Reference Example B20 6- [3- [4- (Diphenylmethoxy) piperidino] propylamino] -2-methyl [1,2,4] triazolo [1,5-b] pyridazine
Preparation of 655 mg of 6-chloro-2-methyl [1,2,4] triazolo [1,5-b] pyridazine and 1.26 g of 4- (diphenylmethoxy) -1-piperidinepropanamine in 20 ml of 1-butanol N-
1.94 ml of ethyldiisopropylamine was added, and the mixture was heated under reflux for 22 hours. Ice water and sodium hydrogen carbonate were 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, and eluted with ethyl acetate: methanol: triethylamine (50: 5: 1). The desired fraction was collected and concentrated, and the obtained crystals were washed with hexane and dried to give 547 mg of the title compound. Melting point: 119-120 ° C Elemental analysis: Calculated as C ₂₇ H ₃₂ N ₆ O (%): C, 71.03; H, 7.06; N, 18.41 Found (%): C, 70.91; H, 6.95; N, 18.18

Reference Example B21 6- [3- [4- (diphenylmethoxy) piperidino] propoxy]
Preparation of 2-methyl [1,2,4] triazolo [1,5-b] pyridazine 4- (diphenylmethoxy) -1-piperidinepropanol 74
Dissolve 3 mg in 17 ml of dry tetrahydrofuran, add 241 mg of sodium tert-butoxide and heat to 60 ° C.
Stir for 30 minutes. After cooling, 6-chloro-2-methyl [1,2,4]
384 mg of triazolo [1,5-b] pyridazine was added, and the mixture was heated under reflux for 21 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, and ethyl acetate: methanol: triethylamine.
(50: 5: 1). The crystals obtained by collecting the desired fractions were washed with diethyl ether and dried to obtain 700 mg of the title compound. Melting point: 134-136 ° C Elemental analysis: Calculated as C ₂₇ H ₃₁ N ₅ O ₂ (%): C, 70.87; H, 6.83; N, 15.31 Found (%): C, 70.67; H, 6.94; N , 15.34

Reference Example B22 6- [4- [4- (diphenylmethoxy) piperidino] butoxy]
Preparation of [1,2,4] triazolo [1,5-b] pyridazine fumarate 4- (diphenylmethoxy) -1-piperidinebutanol 2.04
g was dissolved in 60 ml of dry tetrahydrofuran, 480 mg of 60% oily sodium hydride was added, and the mixture was heated under reflux for 70 minutes. After cooling, add 927 mg of 6-chloro [1,2,4] triazolo [1,5-b] pyridazine and 30 ml of N, N-dimethylformamide
The mixture was refluxed for 18 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, and eluted with ethyl acetate: methanol: triethylamine (50: 5: 1). The oily substance obtained by collecting the desired fractions is dissolved in ethanol and fumaric acid 80mg
Was added, and the mixture was concentrated under reduced pressure, recrystallized from methanol, and dried to obtain 266 mg of the title compound. Melting point 159-161 ° C Elemental analysis: Calculated for C ₃₁ H ₃₅ N ₅ O ₆ (%): C, 64.91; H, 6.15; N, 12.21 Found (%): C, 64.72; H, 6.10; N , 12.06

Reference Example B23 Production of 2- [4- (diphenylmethoxy) piperidino] -N-([1,2,4] triazolo [1,5-b] pyridazin-6-yl) acetamide Step A: 2- Preparation of bromo-N-([1,2,4] triazolo [1,5-b] pyridazin-6-yl) acetamide 1.32 g of 6-amino [1,2,4] triazolo [1,5-b] pyridazine
Was dissolved in 12 ml of N, N-dimethylacetamide, and 1.02 ml of bromoacetyl bromide was added thereto under ice cooling, followed by stirring at room temperature for 30 minutes. The reaction solution was poured into ice water, and the precipitated crystals were washed with water and ethyl acetate, and dried to obtain 2.37 g of the title compound. Melting point 210 ° C (decomp.) Elemental analysis: Calculated as C ₇ H ₆ N ₅ OBr (%): C, 32.83; H, 2.36; N, 27.35 Found (%): C, 33.04; H, 2.50; N, 26.84 Step B: 605 mg of 2-bromo-N-([1,2,4] triazolo [1,5-b] pyridazin-6-yl) acetamide and 632 mg of 4- (diphenylmethoxy) piperidine in 20 ml of acetonitrile The mixture was dissolved, 391 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 3 hours. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate.
The mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration, recrystallized from ethanol, and dried to give 769 mg of the title compound. Melting point 158-160 ° C Elemental analysis: Calculated as C ₂₆ H ₂₆ N ₆ O ₂ (%): C, 67.86; H, 5.92; N, 18.99 Found (%): C, 67.59; H, 5.91; N , 18.76

Reference Example B24 2- [4- (diphenylmethyl) -1-piperazinyl] -N-([1,2,4]
Preparation of triazolo [1,5-b] pyridazin-6-yl) acetamide 2-bromo-N-([1,2,4] triazolo [1,5-b] pyridazine-6-
636 mg of yl) acetamide and 627 mg of 1- (diphenylmethyl) piperazine were dissolved in 20 ml of acetonitrile, 411 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 2 hours. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and the precipitated crystals were collected by filtration, recrystallized from methanol, and dried to obtain 525 mg of the title compound. Melting point 203-204 ° C Elemental analysis: Calculated as C ₂₄ H ₂₅ N ₇ O (%): C, 67.43; H, 5.89; N, 22.93 Found (%): C, 67.22; H, 5.87; N, 22.97

Reference Example B25 6- [2- [4- (Diphenylmethoxy) piperidinocarbonyloxy] ethoxy] [1,2,4] triazolo [1,5-b] pyridazine
Step A: Production of 2-([1,2,4] triazolo [1,5-b] pyridazin-6-yloxy) ethanol Suspension of 510 mg of 60% oily sodium hydride in 70 ml of N, N-dimethylformamide Then, 3.83 g of 2- (tert-butyldiphenylsilyloxy) ethanol was added, and the mixture was stirred at room temperature for 1 hour. 1.98 g of 6-chloro [1,2,4] triazolo [1,5-b] pyridazine was added and stirred at room temperature for 5 hours. The reaction solution was poured into ice water and extracted with ethyl ether. The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in 40 ml of tetrahydrofuran, 2.02 g of tetra-n-butylammonium fluoride trihydrate was added, and the mixture was stirred at room temperature for 10 minutes. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and ethyl acetate: hexane (1: 1).
Eluted in 1). The desired fraction was collected and concentrated to obtain 0.875 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 4.06 (2H, t, J = 5 Hz), 4.5-4.7 (2H,
m), 7.10, 8.01 (each 1H, d, J = 10Hz), 8.34 (1H, s). Step B: 2-([1,2,4] triazolo [1,5-b] pyridazin-6-yloxy ) Ethanol 275mg in tetrahydrofuran 12ml
, And 544 mg of N, N'-carbonyldiimidazole was added thereto, followed by stirring at room temperature for 3 hours. 900 mg of 4- (diphenylmethoxy) piperidine and 0.53 ml of N-ethyldiisopropylamine were added thereto, and the mixture was further stirred at room temperature for 13 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate. The desired fraction was collected and concentrated to give 490 mg of the title compound. Melting point 75-76 ° C Elemental analysis: C ₂₆ H ₂₇ N ₅ O ₄ Calculated (%): C, 65.95; H, 5.75; N, 14.79 Found (%): C, 65.88; H, 5.84; N , 14.88

Reference Example B26 Preparation of 6- [2- [4- (diphenylmethyl) -1-piperazinylcarbonyloxy] ethoxy] [1,2,4] triazolo [1,5-b] pyridazine 2- ( 450 mg of [1,2,4] triazolo [1,5-b] pyridazin-6-yloxy) ethanol was dissolved in 20 ml of tetrahydrofuran, 649 mg of N, N'-carbonyldiimidazole was added, and the mixture was stirred at room temperature for 3 hours. There 1- (diphenylmethyl)
1.07 g of piperazine and N-ethyldiisopropylamine 0.
73 ml was added and the mixture was stirred at 60 ° C. for 17 hours. The reaction solution was concentrated under reduced pressure, ice water was added to the residue, 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: hexane (1: 1). The desired fraction was collected and concentrated, and the resulting crystals were recrystallized from ethyl acetate to give 464 mg of the title compound. Melting point 157-159 ° C Elemental analysis: Calculated as C ₂₅ H ₂₆ N ₆ O ₃・ 0.5H ₂ O (%): C, 64.23; H, 5.82; N, 17.98 Actual (%): C, 64.32; H, 5.50; N, 17.56

Reference Example B27 Preparation of 6- [3- [4- (diphenylmethoxy) piperidinocarbonyloxy] propoxy] [1,2,4] triazolo [1,5-b] pyridazine Step A: 1- [ Preparation of 3- (tert-butyldiphenylsilyloxy) propoxycarbonyl] -4- (diphenylmethoxy) piperidine 3- (tert-butyldiphenylsilyloxy) propanol
2.12 g was dissolved in tetrahydrofuran (20 ml), N, N'-carbonyldiimidazole (1.20 g) was added, and the mixture was stirred at room temperature for 20 minutes. 1.98 g of 4- (diphenylmethoxy) piperidine and 1.28 ml of N-ethyldiisopropylamine were added thereto, and the mixture was stirred at room temperature for 23 hours. The reaction solution was concentrated under reduced pressure, ice water was added to the residue, 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: hexane (1:10). The desired fraction was collected and concentrated to give 3.95 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.04 (9H, s), 1.50-1.90 (6H, m),
3.05-3.25 (2H, m), 3.50-3.80 (5H, m), 4.21 (2H, t, J = 7H
z), 5.51 (1H, s), 7.2-7.8 (20H, m). Step B: Preparation of 3- [4- (diphenylmethoxy) piperidinocarbonyloxy] -1-propanol 1- [3- (tert -Butyldiphenylsilyloxy) propoxycarbonyl] -4- (diphenylmethoxy) piperidine 1.9
5 g was dissolved in 15 ml of tetrahydrofuran, 2.02 g of tetra-n-butylammonium fluoride trihydrate was added, and the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected and concentrated to obtain 1.33 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.5-2.0 (6H, m), 3.1-3.4 (2H, m),
3.5-3.9 (5H, m), 4.26 (2H, t, J = 6Hz), 5.52 (1H, s), 7.1-
7.5 (10H, m). Step C: Dissolve 1.33 g of 3- [4- (diphenylmethoxy) piperidinocarbonyloxy] -1-propanol in 30 ml of tetrahydrofuran and 339 mg of sodium tert-butoxide
And stirred at 60 ° C. for 1.5 hours. After cooling, 6-chloro
Add 496 mg of [1,2,4] triazolo [1,5-b] pyridazine and add 2
Heated to reflux for an hour. 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. The desired fraction was collected and concentrated to obtain 0.730 g of the title compound. Mp 119-120 ° C. Elemental analysis: Calculated as _{C 27 H 29 N 5 O 4} (%): C, 66.51; H, 6.00; N, 14.36 Found (%): C, 66.65; H, 5.78; N , 14.64

Reference Example B28 Process for producing 6- [3- [4- (diphenylmethyl) -1-piperazinylcarbonyloxy] propoxy] [1,2,4] triazolo [1,5-b] pyridazine hydrochloride A: Preparation of 1- [3- (tert-butyldiphenylsilyloxy) propoxycarbonyl] -4- (diphenylmethyl) piperazine 3- (tert-butyldiphenylsilyloxy) propanol
1.71 g was dissolved in 16 ml of tetrahydrofuran, 0.97 g of N, N'-carbonyldiimidazole was added, and the mixture was stirred at room temperature for 20 minutes. There 1- (diphenylmethyl) piperazine
1.51 g and N-ethyldiisopropylamine (1.03 ml) were added, and the mixture was stirred at 60 ° C. for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure, ice water was added to the residue, 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: hexane (1:10). The desired fractions were collected and concentrated to give 2.53 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.03 (9H, s), 1.7-2.0 (2H, m), 2.
2-3.6 (8H, m), 3.71 (2H, t, J = 6Hz), 4.21 (2H, t, J = 6Hz),
4.21 (1H, s), 7.1-7.7 (20H, m). Step B: Preparation of 3- [4- (diphenylmethyl) -1-piperazinylcarbonyloxy] -1-propanol 1- [3- (tert -Butyldiphenylsilyloxy) propoxycarbonyl] -4- (diphenylmethyl) piperazine 2.50 g
Was dissolved in 12 ml of tetrahydrofuran, and 1.46 g of tetra-n-butylammonium fluoride trihydrate was added thereto, followed by stirring at room temperature for 3 hours. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: hexane (1: 1). The desired fraction was collected and concentrated to give 1.51 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.7-2.0 (6H, m), 2.2-3.6 (8H, m),
3.64 (2H, t, J = 6Hz), 4.25 (2H, t, J = 6Hz), 4.24 (1H, s),
7.1-7.5 (10H, m). Step C: Dissolve 1.44 g of 3- [4- (diphenylmethyl) -1-piperazinylcarbonyloxy] -1-propanol in 30 ml of tetrahydrofuran and add sodium tert-butoxide 429.
mg was added and the mixture was stirred at 60 ° C for 0.5 hour. After cooling, 627 mg of 6-chloro [1,2,4] triazolo [1,5-b] pyridazine was added, and the mixture was heated under reflux for 3 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: hexane (3: 1). The desired fractions are collected and concentrated, and the residue is dissolved in 10 ml of ethyl acetate.
32 ml was added and the mixture was concentrated under reduced pressure, and the precipitated crystals were recrystallized from ethanol to obtain 0.450 g of the title compound. Mp 167-169 ° C. Elemental _{analysis: C 26 H 29 N 6 O} 3 Cl · 0.5H 2 O Calculated (%): C, 60.29; H, 5.84; N, 16.22 Found (%): C, 60 .52; H, 5.
96; N, 16.05

Reference Example B29 Preparation of 6- [6- [4- (diphenylmethoxy) piperidino] hexyloxy] [1,2,4] triazolo [1,5-b] pyridazine fumarate 4- (diphenylmethoxy) -1-piperidinehexanol 0.
905 g was dissolved in 15 ml of tetrahydrofuran, 118 mg of 60% oily sodium hydride was added, and the mixture was heated under reflux for 1 hour. After cooling, 6-chloro [1,2,4] triazolo [1,5-b] pyridazine 381
The mixture was heated under reflux for 3 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: triethylamine (50: 5: 1). The desired fractions are collected, concentrated, dissolved in 10 ml of ethyl acetate, and fumaric acid
The residue was recrystallized from ethyl acetate to give 0.979 g of the title compound. Mp 136-138 ° C. Elemental analysis: Calculated as _{C 33 H 39 N 5 O 6} (%): C, 65.87; H, 6.53; N, 11.64 Found (%): C, 65.79; H, 6.54; N , 11.62

Reference Example B30 Production of 6- [6- [4- (diphenylmethyl) -1-piperazinyl] hexyloxy] [1,2,4] triazolo [1,5-b] pyridazine fumarate 4- ( Diphenylmethyl) -1-piperazinehexanol 0.64
0 g was dissolved in tetrahydrofuran (10 ml), 145 mg of 60% oily sodium hydride was added, and the mixture was heated under reflux for 1 hour. After cooling, 6-chloro [1,2,4] triazolo [1,5-b] pyridazine 281
The mixture was heated under reflux for 1.5 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. The desired fraction was collected and concentrated, dissolved in 10 ml of ethyl acetate, and concentrated by adding a solution of 140 mg of fumaric acid in 10 ml of methanol. The residue was recrystallized from ethanol to give 189 mg of the title compound. Mp 149-151 ° C. Elemental _{analysis: C 32 H 38 N 6 O} 5 · 0.5H 2 O Calculated (%): C, 64.52; H, 6.60; N, 14.11 Found (%): C, 64.95; H, 6.64; N, 13.91

Reference Example B31 6- [3- [4- (diphenylmethoxy) piperidino] propoxy]
Preparation of 2-phenyl [1,2,4] triazolo [1,5-b] pyridazine hydrochloride 4- (diphenylmethoxy) -1-piperidinepropanol 48
7 mg was dissolved in 10 ml of dry tetrahydrofuran, 144 mg of sodium tert-butoxide was added, and the mixture was heated under reflux for 40 minutes. After cooling, 6-chloro-2-phenyl [1,2,4] triazolo
[1,5-b] pyridazine (315 mg) was added, and the mixture was heated under reflux for 4 hours. After cooling, ice water was added, and the mixture was extracted with ethyl acetate-tetrahydrofuran (2: 1). The extract was washed with brine and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography.
0: 1). Collect and concentrate the desired fractions,
The residue was dissolved in 10 ml of ethyl acetate, 0.25 ml of a 4N solution of hydrogen chloride in ethyl acetate was added, and the mixture was concentrated under reduced pressure. The precipitated crystals were recrystallized from ethanol to obtain 0.334 g of the title compound. Mp 127-129 ° C. Elemental _{analysis: C 32 H 34 N 5 O} 2 Cl · H 2 O Calculated (%): C, 66.95; H, 6.32; N, 12.20 Found (%): C, 67.01; H, 6.46; N, 12.27

Reference Example B32 Preparation of 6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -2-phenyl [1,2,4] triazolo [1,5-b] pyridazine 6-chloro-2 N-phenyl [1,2,4] triazolo [1,5-b] pyridazine 365 mg and 4- (diphenylmethoxy) -1-piperidinepropanamine 0.513 g are suspended in 1-butanol 8 ml
-Ethyldiisopropylamine (0.54 ml) was added, and the mixture was heated under reflux for 19 hours. Ice water and sodium hydrogen carbonate were 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, and eluted with ethyl acetate: methanol: triethylamine (50: 5: 1). The desired fraction was collected and concentrated, and the obtained crystals were recrystallized from ethyl acetate to give 308 mg of the title compound. Melting point 170-172 ° C Elemental analysis: Calculated as C ₃₂ H ₃₄ N ₆ O ・ 0.5H ₂ O (%): C, 72.84; H, 7.69; N, 15.93 Actual (%): C, 73.08; H , 7.61; N, 16.03

Reference Example B33 2-tert-butyl-6- [3- [4- (diphenylmethoxy) piperidino] propoxy] [1,2,4] triazolo [1,5-b] pyridazine
Production of fumarate salt 4- (diphenylmethoxy) -1-piperidinepropanol 91
1 mg was dissolved in 20 ml of dry tetrahydrofuran, 296 mg of sodium tert-butoxide was added, and the mixture was heated under reflux for 30 minutes. After cooling, 589 mg of 2-tert-butyl-6-chloro [1,2,4] triazolo [1,5-b] pyridazine was added, and the mixture was refluxed for 6 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,
Elution was performed with ethyl acetate: methanol: triethylamine (50: 5: 1). The desired fraction was collected and concentrated, and the residue was dissolved in 10 ml of ethyl acetate, and concentrated by adding a solution of 102 mg of fumaric acid in 10 ml of methanol. The residue was recrystallized from ethyl acetate to give 382 mg of the title compound. Melting point 170-172 ° C Elemental analysis: C ₃₄ H ₄₁ N ₅ O ₆ Calculated (%): C, 66.32; H, 6.71; N, 11.37 Found (%): C, 66.15; H, 6.74; N , 11.28

Reference Example B34 Production of 2-tert-butyl-6- [3- [4- (diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [1,5-b] pyridazine fumarate 276 mg of 2-tert-butyl-6-chloro [1,2,4] triazolo [1,5-b] pyridazine and 0.425 g of 4- (diphenylmethoxy) -1-piperidinepropanamine are suspended in 8 ml of 1-butanol. 0.45 ml of N-ethyldiisopropylamine was added, and the mixture was heated under reflux for 40 hours. Ice water and sodium hydrogen carbonate were 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, and eluted with ethyl acetate: methanol: triethylamine (50: 5: 1). The desired fractions were collected and concentrated.The residue was dissolved in 10 ml of ethyl acetate, and concentrated by adding a solution of 40 mg of fumaric acid in 5 ml of methanol.The residue was triturated with ethyl ether, and collected by filtration to collect 164 mg of the title compound. Obtained. Mp 80 ° C. Elemental _{analysis: C 34 H 42 N 6 O} 5 · H 2 O, 0.5Et 2 O Calculated (%): C, 64.55; H, 7.37; N, 12.55 Found (%): C, 64.79; H, 7.76; N, 12.44

Reference Example B35 Preparation of 6- [6- [4- (diphenylmethoxy) piperidino] hexylamino] [1,2,4] triazolo [1,5-b] pyridazine Step A: 6-[([1 Of 2,2,4] Triazolo [1,5-b] pyridazin-6-yl) amino] -1-hexanol 6-chloro [1,2,4] triazolo [1,5-b] pyridazine 2.03 g
Was dissolved in ethanol (20 ml), 6-amino-1-hexanol (3.85 g) was added, and the mixture was heated under reflux for 19 hours. After cooling, the resulting crystals were collected by filtration, washed with ethanol and dried to give 3.64 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.3-1.8 (8H, m), 3.46 (2H, t, J = 6H
z), 3.67 (2H, q, J = 6Hz), 4.58 (1H, broad s), 6.71, 7.78 (each
1H, d, J = 10Hz), 8.19 (1H, s). Step B: 6-[([1,2,4] triazolo [1,5-b] pyridazin-6-yl) amino] -1-hexanol 1.64 g was suspended in 40 ml of tetrahydrofuran and N-ethyldiisopropylamine 2.2
Add 5g and 2.0g of methanesulfonyl chloride and add 5.5g at room temperature
Stir for hours. Ice water and sodium chloride were added, and the mixture was extracted with ethyl acetate-tetrahydrofuran (2: 1). The extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in 14 ml of acetonitrile, 743 mg of 4- (diphenylmethoxy) piperidine, 457 mg of potassium iodide and 380 mg of potassium carbonate were added, and the mixture was stirred at 50 ° C. for 16 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, and eluted with ethyl acetate: methanol: triethylamine (50: 5: 1). The desired fraction was collected and concentrated, and the obtained crystals were recrystallized from ethyl acetate-ethyl ether (1: 1) to obtain 597 mg of the title compound. Melting point 97-98 ° C Elemental analysis: C ₂₉ H ₃₆ N ₆ O Calculated (%): C, 71.87; H, 7.49; N, 17.34 Found (%): C, 71.77; H, 7.37; N, 17.36

Reference Example B36 Production of methyl 6- [3- [4- (diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [1,5-b] pyridazine-2-carboxylate 6-chloro 0.92 g of methyl [1,2,4] triazolo [1,5-b] pyridazine-2-carboxylate and 1.40 g of 4- (diphenylmethoxy) -1-piperidinepropanamine are suspended in 20 ml of N, N-dimethylformamide. N-ethyldiisopropylamine
1.49 ml was added and the mixture was heated and refluxed at 80 ° C. for 15 hours. After cooling, ice water and sodium chloride were added, and the mixture was extracted with ethyl acetate-tetrahydrofuran (1: 2). The extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol: triethylamine (50: 5: 1). The desired fraction was collected and concentrated, and the residue was recrystallized from ethanol-ethyl acetate (1: 2) to give 639 mg of the title compound. Melting point 93-96 ° C Elemental analysis: Calculated as C ₂₈ H ₃₂ N ₆ O ₃・ 0.5H ₂ O (%): C, 65.99; H, 6.53; N, 16.49 Actual (%): C, 65.69; H, 6.28; N, 16.58

Reference Example B37 Preparation of 6- [6- [4- (diphenylmethyl) -1-piperazinyl] hexylamino] [1,2,4] triazolo [1,5-b] pyridazine 6- (6-hydroxy Hexylamino) [1,2,4] triazolo [1,
1.64 g of 5-b] pyridazine was suspended in 40 ml of tetrahydrofuran, 2.25 g of N-ethyldiisopropylamine and 2.0 g of methanesulfonyl chloride were added, and the mixture was stirred at room temperature for 1 hour. Ice water and salt were 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 N, N-dimethylformamide 13 ml
And 694 mg of 1- (diphenylmethyl) piperazine, 456 mg of potassium iodide and 379 mg of potassium carbonate were added thereto, and the mixture was stirred at room temperature for 2 hours and at 60 ° C. for 4 hours. After cooling, add ice water,
The mixture was extracted with ethyl acetate, and the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and ethyl acetate: methanol:
Elution was performed with triethylamine (50: 5: 1). The desired fraction was collected and concentrated, and the obtained crystal was recrystallized from ethyl acetate and dried to obtain 702 mg of the title compound. Melting point 130-132 ° C Elemental analysis: C ₂₈ H ₂₅ N ₇ Calculated (%): C, 71.61; H, 7.51; N, 20.88 Found (%): C, 71.39; H, 7.39; N, 21.04

Reference Example B38 6- [3- [4- (diphenylmethoxy) piperidino] propoxy]
Preparation of imidazo [1,2-b] pyridazine fumarate Dissolve 159 mg of sodium tert-butoxide in 15 ml of N, N-dimethylformamide and prepare 4- (diphenylmethoxy)-
Add 489 mg of 1-piperidinepropanol, and add
Stir for a minute. After cooling, 253 mg of 6-chloroimidazo [1,2-b] pyridazine was added, and the mixture was stirred at 80 to 90 ° 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. The mixture was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and ethyl acetate: methanol: triethylamine (90:
10: 1). Collect the desired fractions, dissolve in 10 ml of ethyl acetate, and add 93 mg of fumaric acid to 10 ml of methanol.
The precipitated crystals were collected by filtration, washed with ethyl acetate, dried and dried to give the title compound 288.
mg was obtained. Melting point 155-157 ° C Elemental analysis: Calculated as C ₃₁ H ₃₄ N ₄ O ₆・ H ₂ O (%): C, 64.57; H, 6.29; N, 9.72 Actual (%): C, 64.24; H , 5.98; N, 9.28

Reference Example B39 Preparation of 6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazine fumarate [2: 3] 4- (diphenylmethoxy) -1 -Piperidinepropanamine
325mg and 6-chloroimidazo [1,2-b] pyridazine 184mg
And stirred at 180 ° C. for 1 hour. After cooling, add overlay water,
The mixture was extracted with ethyl acetate, and the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and ethyl acetate: methanol:
Elution with triethylamine (90: 10: 1). The desired fractions are collected and dissolved in 10 ml of ethyl acetate, and fumaric acid 193
A solution of mg in 10 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 to obtain 246 mg of the title compound. Mp 137-139 ° C. Elemental _{analysis: C 33 H 37 N 5 O} 7 · 0.5H 2 O Calculated (%): C, 63.45; H, 6.13; N, 11.21 Found (%): C, 63.66; H, 6.00; N, 11.12

Reference Example B40 Ethyl 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate Difumaric acid Production of salt 4- (diphenylmethoxy) -1-piperidinepropanamine
4.2 g and 1.76 g of ethyl 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate at 190-200 ° C
For 3.5 hours. After cooling, 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, and eluted with ethyl acetate: methanol: triethylamine (100: 5: 1). The desired fraction was collected, dissolved in 16 ml of ethyl acetate, concentrated by adding a solution of 867 mg of fumaric acid in 16 ml of methanol, concentrated by adding acetone 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 ° C Elemental analysis: Calculated for C ₄₁ H ₄₉ N ₅ O ₁₁ (%): C, 62.50; H, 6.27; N, 8.89 Found (%): C, 62.28; H, 6.15; N , 8.97

Reference Example B41 6- [3- [4- (diphenylmethoxy) piperidino] propoxy]
Preparation of 2-methoxyimidazo [1,2-b] pyridazine 4- (diphenylmethoxy) -1-piperidinepropanol 75
Dissolve 8mg in N, N-dimethylformamide 40ml and 60%
102 mg of oily sodium hydride was added, and the mixture was stirred at 60 ° C for 40 minutes. After cooling, 6-chloro-2-methoxyimidazo [1,2
-b] pyridazine (428 mg) was added and the mixture was stirred at 100 ° C for 2.5 hours. After cooling, add ice water and sodium chloride, add ethyl acetate
-Extracted with tetrahydrofuran (1: 2), the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol: triethylamine (50: 5: 1). The desired fraction was collected and the precipitated crystals were recrystallized from ethanol to give 499 mg of the title compound. 133-135 ° C Elemental analysis: Calculated as C ₂₈ H ₃₂ N ₄ O ₃ (%): C, 71.16; H, 6.83; N, 11.86 Found (%): C, 71.23; H, 6.83; N , 11.94

Reference Example B42 Preparation of 6- [3- [4- (diphenylmethyl) -1-piperazinyl] propoxy] -2-methoxyimidazo [1,2-b] pyridazine 4- (diphenylmethyl) -1-piperazine Propanol 251m
g was dissolved in N, N-dimethylformamide (14 ml), 60% oily sodium hydride (36 mg) was added, and the mixture was stirred at 60 ° C. for 30 minutes. After cooling, 6-chloro-2-methoxyimidazo [1,2-
b] Pyridazine (149 mg) was added and the mixture was stirred at 90 ° C for 4.5 hours. After cooling, add ice water and sodium chloride, and add ethyl acetate
The mixture was extracted with tetrahydrofuran (1: 2), and the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected and the precipitated crystals were recrystallized from ethyl acetate to give 99 mg of the title compound. Mp 144-146 ° C. Elemental _{analysis: C 27 H 31 N 5 O} 2 Calculated (%): C, 70.87; H, 6.83; N, 15.31 Found (%): C, 70.79; H, 6.82; N , 15.39

Reference Example B43 Production of 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid Dissolve 468 mg of ethyl [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate in 3 ml of ethanol.
2 ml of a 1N aqueous sodium hydroxide 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 the pH to 7, extract with ethyl acetate-tetrahydrofuran (1: 1), wash the extract with saturated saline, and add magnesium sulfate. And dried. After concentration under reduced pressure, ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration, washed with ethyl acetate, and dried to give the title compound (267 mg)
I got It can be recrystallized from acetone. Melting point 205-206 ° C Elemental analysis: Calculated as C ₃₁ H ₃₇ N ₅ O ₃ (%): C, 70.56; H, 7.07; N, 13.27 Found (%): C, 70.46; H, 7.06; N , 13.36

Reference Example B44 tert-butyl difumal 2- [6- [3- [4- (diphenylmethoxy) piperidino] propoxy] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate Preparation of acid salt 70 mg of 60% sodium hydride was dissolved in 5 ml of N, N-dimethylformamide, 570 mg of 4- (diphenylmethoxy) -1-piperidinepropanol was added, and the mixture was stirred at room temperature under reduced pressure for 30 minutes. 2- (6-chloroimidazo [1,2-b] pyridazine-2-
520 mg of tert-butyl yl) -2-methylpropionate were added, and the mixture was stirred at room temperature for 8 hours. 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, and eluted with ethyl acetate: methanol: triethylamine (195: 5: 1). The desired fractions were collected, dissolved in 5 ml of ethyl acetate, concentrated by adding a solution of 233 mg of fumaric acid in 10 ml of methanol, and the precipitated crystals were collected by filtration, washed with acetone, dried and dried to give the title compound.
631 mg were obtained. Melting point 162-164 ° C Elemental analysis: Calculated for C ₄₃ H ₅₂ N ₄ O ₁₂ (%): C, 63.22; H, 6.42; N, 6.86 Found (%): C, 62.91; H, 6.36; N , 6.90

Reference Example B45 Preparation of 2- [6- [3- [4- (diphenylmethoxy) piperidino] propoxy] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid Dissolve 818 mg of tert-butyl 6- [3- [4- (diphenylmethoxy) piperidino] propoxy] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate in 8 ml of 1-butanol and add potassium hydroxide 393 mg was added and the mixture was stirred at 90 ° C. for 14 hours. After cooling, 7 ml of 1N hydrochloric acid was added to the aqueous layer, 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, ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration and washed with ethyl acetate.
Drying afforded 465 mg of the title compound. Melting point: 183-185 ° C Elemental analysis: Calculated as C ₃₁ H ₃₆ N ₄ O ₄・ 2.5H ₂ O (%): C, 64.90; H, 7.20; N, 9.77 Actual (%): C, 65.15; H, 6.73; N, 9.52

Reference Example B46 Ethyl 2- [6- [3- [4- (diphenylmethoxy) piperidino] propoxy] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate Difumarate Preparation of 2- [6- [3- [4- (diphenylmethoxy) piperidino] propoxy] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid (529 mg) in N, N-dimethylformamide (3 ml) The solution was added with N-ethyldiisopropylamine (0.207 ml) and ethyl iodide (0.135 ml) and stirred at room temperature for 15 hours. Ice water was added to the reaction solution, 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, and eluted with ethyl acetate: methanol: triethylamine (100: 5: 1). The desired fractions were collected and dissolved in 3 ml of ethyl acetate, and a solution of 153 mg of fumaric acid in 3 ml of methanol was added and concentrated.The precipitated crystals were collected by filtration, washed with ethyl acetate, and dried to obtain 406 mg of the title compound. Was. Melting point 116-122 ° C Elemental analysis: C ₄₁ H ₄₈ N ₄ O ₁₂・ 0.5H ₂ O Calculated (%): C, 61.72; H, 6.19; N, 7.02 Actual (%): C, 61.61; H, 6.11; N, 6.85

Reference Example B47 6- [2- [2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy] ethoxy] -7-methyl [1,2,4] triazolo [1,5-b] pyridazine Production of 60% sodium hydride 260 mg in tetrahydrofuran 20
The mixture was suspended in 1 ml of the reaction mixture, and 1.15 g of 2- [2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy] ethanol was added, followed by heating under reflux for 1 hour. After cooling, 6-chloro-7-methyl [1,2,4] triazolo
[1,5-b] pyridazine (540 mg) was added, and the mixture was heated under reflux 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,
Elution was performed with dichloromethane: ethyl acetate: methanol (10: 10: 1). The desired fraction was collected, and the precipitated crystals were collected by filtration, washed with ethyl ether, and dried to obtain 730 mg of the title compound. Mp 71-72 ° C. Elemental _{analysis: C 27 H 32 N 6 O} 2 Calculated (%): C, 68.62; H, 6.82; N, 17.78 Found (%): C, 68.35; H, 6.71; N , 17.79

Reference Example B48 6- [2- [2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy] ethoxy] [1,2,4] triazolo [1,5-b] pyridazine
Manufacture of dihydrochloride 100% 60% sodium hydride in tetrahydrofuran 20
The suspension was added with 470 mg of 2- [2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy] ethanol and heated under reflux for 1 hour. After cooling, 200 mg of 6-chloro [1,2,4] triazolo [1,5-b] pyridazine was added, and the mixture was heated under reflux for 4.5 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. Concentrate under reduced pressure,
The residue was subjected to silica gel column chromatography, and eluted with dichloromethane: ethyl acetate: methanol (10: 10: 1). Collect the desired fractions, dissolve in 5 ml of ethyl acetate and add 4N
0.83 ml of a hydrogen acetate solution in ethyl acetate was added, and the precipitated crystals were collected by filtration, washed with ethyl ether, and dried to obtain 0.54 g of the title compound. Mp 182-184 ° C. Elemental _{analysis: C 26 H 32 N 6 O} 2 Cl 2 · H 2 O Calculated (%): C, 56.83; H, 6.24; N, 15.29 Found (%): C, 56.98 ; H, 6.10; N, 15.39

Reference Example B49 Preparation of 6- [4- [4- (diphenylmethyl) -1-piperazinyl] butoxy] -7-methyl [1,2,4] triazolo [1,5-b] pyridazine dihydrochloride 240 mg of 60% oily sodium hydride was suspended in 20 ml of tetrahydrofuran, and 0.99 g of 4- (diphenylmethyl) -1-piperazinebutanol was added, followed by heating under reflux for 1 hour. After cooling, 510 mg of 6-chloro-7-methyl [1,2,4] triazolo [1,5-b] pyridazine was added, and the mixture was heated under reflux 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, and eluted with dichloromethane: ethyl acetate: methanol (20: 20: 1). Collect the desired fractions, dissolve in 5 ml of ethyl acetate and add 4N
0.64 ml of an ethyl hydrogen chloride solution was added, and the precipitated crystals were collected by filtration, washed with ethyl ether, and dried to obtain 470 mg of the title compound. Mp 190-192 ° C. Elemental _{analysis: C 27 H 34 N 6 OCl} 2 · 0.5AcOEt · H 2 O Calculated (%): C, 58.88; H, 6.82; N, 14.21 Found (%): C, 59.11; H, 6.82; N, 14.03

Reference Example B50 6- [2- [2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy] ethylthio] [1,2,4] triazolo [1,5-b] pyridazine dihydrochloride Production step A: Production of 6- [2- (2-bromoethoxy) ethylthio] [1,2,4] triazolo [1,5-b] pyridazine Methyl 3-mercaptopropionate 2.8 ml
The mixture was dissolved in 10 ml, and 19.4 ml of a 2N sodium methoxide methanol solution and 1.0 g of 6-chloro [1,2,4] triazolo [1,5-b] pyridazine were added, and the mixture was heated under reflux for 1 hour. After cooling, the mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the precipitated crystals were collected, washed with ethyl acetate, and washed with
And add 1.63 ml of 2-bromoethyl ether
The mixture was refluxed for 2 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, and eluted with dichloromethane: ethyl acetate: methanol (20: 20: 1). The desired fractions were collected to give 0.60 g of the title compound as an oil. ¹ H-NMR (CDCl ₃ ) δ ppm: 3.49 (2H, t, J = 6Hz), 3.55 (2H, t, J
= 6Hz), 3.86 (2H, t, J = 6Hz), 3.90 (2H, t, J = 6Hz), 7.22,
7.93 (1H, d, J = 9Hz each), 8.37 (1H, s). Step B: 6- [2- (2-bromoethoxy) ethylthio] [1,2,4] triazolo [1,5-b] 890 mg of pyridazine and 740 mg of 1- (diphenylmethyl) piperazine in 10 ml of N, N-dimethylformamide
And added 490 mg of potassium carbonate and stirred at room temperature for 24 hours. 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, and eluted with dichloromethane: methanol (10: 1). The desired fractions are collected and concentrated, and the residue is ethyl acetate
After dissolving in 5 ml, 1.64 ml of a 4N solution of hydrogen chloride in ethyl acetate was added, and the precipitated crystals were collected by filtration, washed with ethyl ether, and dried to obtain 1.13 g of the title compound. Melting point 188-189 ° C Elemental analysis: Calculated as C ₂₆ H ₃₂ N ₆ OSCl ₂・ H ₂ O (%): C, 55.22; H, 6.06; N, 14.86 Actual (%): C, 55.49; H , 6.02; N, 15.08

Reference Example B51 6- [6- [4- (Diphenylmethyl) -1-piperazinyl] hexyloxy] -7-methyl [1,2,4] triazolo [1,5-b] pyridazine dihydrochloride Production: 210% of 60% sodium hydride in tetrahydrofuran 15
The resulting mixture was suspended in 0.1 ml, and 0.91 g of 4- (diphenylmethyl) -1-piperazinehexanol was added, followed by heating under reflux for 1 hour. After cooling,
6-Chloro-7-methyl [1,2,4] triazolo [1,5-b] pyridazine (440 mg) was added, and the mixture was heated under reflux for 3 hours. After cooling, add ice water, extract with ethyl acetate, wash the extract with saturated saline,
Dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with dichloromethane: ethyl acetate: methanol (10: 10: 1). The desired fraction was collected, dissolved in 5 ml of ethyl acetate, added with 1.44 ml of a 4N solution of hydrogen chloride in ethyl acetate, and the precipitated crystals were collected by filtration, washed with ethyl ether, and dried to obtain 1.06 g of the title compound. Recrystallized from ethanol. Melting point 170-172 ° C Elemental analysis: C ₂₉ H ₃₈ N ₆ OCl ₂・ 0.5EtOH Calculated (%): C, 62.06; H, 7.11; N, 14.47 Actual (%): C, 61.77; H, 6.94; N, 14.33

Reference Example B52 6- [6- [4- (diphenylmethoxy) piperidino] hexyloxy] -7-methyl [1,2,4] triazolo [1,5-b] pyridazine
Production of hydrochloride 60% sodium hydride 160 mg in tetrahydrofuran 20
The mixture was suspended in 1 ml of the resulting mixture, and 1.24 g of 4- (diphenylmethoxy) -1-piperidinehexanol was added, followed by heating under reflux for 1 hour. After cooling, 570 mg of 6-chloro-7-methyl [1,2,4] triazolo [1,5-b] pyridazine was added, and the mixture was heated under reflux for 1 hour. 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, and eluted with ethyl acetate: methanol (10: 1). The desired fraction was collected, dissolved in 5 ml of ethyl acetate, 0.54 ml of a 4N solution of hydrogen chloride in ethyl acetate was added, and the precipitated crystals were collected by filtration, washed with ethyl ether, and dried to obtain 0.70 g of the title compound. Melting point 208-209 ° C Elemental analysis: Calculated as C ₃₀ H ₃₈ N ₅ O ₂ Cl ・ 0.8H ₂ O (%): C, 65.45; H, 7.25; N, 12.72 Actual (%): C, 65.47 ; H, 7.21; N, 12.60

Reference Example B53 Preparation of 6- [2- [2- [4- (diphenylmethoxy) piperidino] ethoxy] ethoxy] -7-methyl [1,2,4] triazolo [1,5-b] pyridazine 60 % Sodium hydride 190mg in tetrahydrofuran 15
The suspension was added to 1.47 g of 2- [2- [4- (diphenylmethoxy) piperidino] ethoxy] ethanol and heated under reflux for 1 hour. After cooling, 6-chloro-7-methyl [1,2,4] triazolo [1,
660 mg of 5-b] pyridazine was added, and the mixture was heated under reflux 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, and eluted with ethyl acetate: methanol (10: 1). The desired fraction was collected, and the precipitated crystals were collected by filtration, washed with ethyl ether, and dried to obtain 1.23 g of the title compound. Melting point 80-82 ° C Elemental analysis: C ₂₈ H ₃₃ N ₅ O ₃ Calculated (%): C, 68.97; H, 6.82; N, 14.36 Found (%): C, 68.75; H, 6.70; N , 14.57

Reference Example B54 6- [6- [4- (diphenylmethyl) -1-piperazinyl] hexylthio] -7-methyl [1,2,4] triazolo [1,5-b] pyridazine
Production of dihydrochloride Step A: Production of 6- (6-bromohexylthio) -7-methyl [1,2,4] triazolo [1,5-b] pyridazine Methyl 3-mercaptopropionate 5.57 g in methanol
Dissolve in 20 ml, and add 35.6 ml of 2N sodium methoxide methanol solution and 6-chloro-7-methyl [1,2,4] triazolo [1,
2.0 g of 5-b] pyridazine was added, and the mixture was heated under reflux for 1 hour. After cooling, the mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the precipitated crystals were collected, washed with ethyl acetate, suspended in 30 ml of tetrahydrofuran, added with 3.65 ml of 1,6-dibromohexane, and heated under reflux 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, ethyl ether was added to the residue, and the precipitated crystals were collected by filtration to give the title compound.
2.42 g was obtained. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.49-1.54 (4H, m), 1.75-1.95 (4
H, m), 2.40 (3H, s), 3.31 (2H, t, J = 7Hz), 3.43 (2H, t, J = 7H
z), 7.72 (1H, s), 8.30 (1H, s). Step B: 6- (6-bromohexylthio) -7-methyl [1,2,4] triazolo [1,5-b] pyridazine 1.0 g and 1- (diphenylmethyl) piperazine 770 mg in N, N-dimethylformamide 10m
and added 500 mg of potassium carbonate and stirred at room temperature for 18 hours. 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, and eluted with ethyl acetate: methanol (20: 1). The desired fractions are collected and concentrated, and the residue is concentrated in ethyl acetate (5 ml).
The precipitate was collected by filtration, washed with ethyl ether, and dried to give 0.98 g of the title compound. Melting point 180-182 ° C Elemental analysis: Calculated as C ₂₉ H ₃₈ N ₆ SCl ₂・ 0.4H ₂ O (%): C, 59.97; H, 6.73; N, 14.47 Actual (%): C, 60.17; H, 6.55; N, 14.62

Reference Example B55 6- [2- [2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy] ethylthio] -7-methyl [1,2,4] triazolo [1,5-b]
Production of pyridazine dihydrochloride Step A: 6- [2- (2-bromoethoxy) ethylthio] -7-methyl
Production of [1,2,4] triazolo [1,5-b] pyridazine Methyl 3-mercaptopropionate 5.57 g in methanol
Dissolve in 20 ml, and add 35.6 ml of 2N sodium methoxide methanol solution and 6-chloro-7-methyl [1,2,4] triazolo [1,
2.0 g of 5-b] pyridazine was added, and the mixture was heated under reflux for 1 hour. After cooling, the mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue to collect the precipitated crystals.
Was added and the mixture was heated under reflux 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, and dichloromethane: ethyl acetate:
Elution was carried out with methanol (30: 30: 1). The desired fractions were collected to give 2.06 g of the title compound as an oil. ¹ H-NMR (CDCl ₃ ) δ ppm: 2.42 (3H, s), 3.50 (2H, t, J = 6Hz),
3.56 (2H, t, J = 6Hz), 3.86 (2H, t, J = 6Hz), 3.91 (2H, t, J = 6
Hz), 7.74 (1H, s), 8.30 (1H, s). Step B: 6- [2- (2-bromoethoxy) ethylthio] -7-methyl
Dissolve 1.0 g of [1,2,4] triazolo [1,5-b] pyridazine and 790 mg of 1- (diphenylmethyl) piperazine in 10 ml of N, N-dimethylformamide, add 520 mg of potassium carbonate and stir at room temperature for 23 hours. Was. 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, and dichloromethane: ethyl acetate: methanol was added.
(5: 5: 1). The desired fractions were collected and concentrated, the residue was dissolved in 5 ml of ethyl acetate, 1.55 ml of a 4N solution of hydrogen chloride in ethyl acetate was added, and the precipitated crystals were collected by filtration, washed with ethyl ether, dried and dried to give the title compound.
0.85 g was obtained. Recrystallized from ethanol. Mp 198-200 ° C. Elemental _{analysis: C 27 H 34 N 6 OSCl} 2 Calculated (%): C, 57.75; H, 6.10; N, 14.97 Found (%): C, 57.53; H, 6.00; N , 14.93

Reference Example B56 Production of 6- [6- [4- (diphenylmethoxy) piperidino] hexylthio] -7-methyl [1,2,4] triazolo [1,5-b] pyridazine fumarate 6- ( 6-bromohexylthio) -7-methyl [1,2,4] triazolo
1.0 g of [1,5-b] pyridazine and 810 mg of 4- (diphenylmethoxy) piperidine were dissolved in 10 ml of N, N-dimethylformamide, 500 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 24 hours. 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,
Elution was performed with ethyl acetate: methanol (10: 1). The desired fraction was collected and concentrated, the residue was dissolved in ethanol (10 ml), and fumaric acid (290 mg) was added to concentrate. Ethyl ether was added to the residue, and the precipitated crystals were collected by filtration, washed with ethyl ether, and dried to give 1.43 g of the title compound. 137-138 ° C Elemental analysis: Calculated as C ₃₄ H ₄₁ N ₅ O ₅ S ・ 0.5H ₂ O (%): C, 63.73; H, 6.61; N, 10.93 Actual (%): C, 63.97 ; H, 6.44; N, 11.00

Reference Example B57 6- [2- [2- [4- (diphenylmethoxy) piperidino] ethoxy] ethylthio] -7-methyl [1,2,4] triazolo [1,5-b] pyridazine fumarate Preparation of 6- [2- (2-bromoethoxy) ethylthio] -7-methyl [1,2,4]
1.09 g of triazolo [1,5-b] pyridazine and 840 mg of 4- (diphenylmethoxy) piperidine were dissolved in 10 ml of N, N-dimethylformamide, 520 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 23 hours. 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, and dichloromethane: ethyl acetate: methanol was added.
(5: 5: 1). The desired fraction was collected, the residue was dissolved in 10 ml of ethanol, and 200 mg of fumaric acid was added, followed by concentration. Ethyl ether was added to the residue, and the precipitated crystals were collected by filtration, washed with ethyl ether, and dried to give the title compound (0.78 g). Mp 119-122 ° C. Elemental _{analysis: C 32 H 37 N 5 O} 6 S · 0.5H 2 O Calculated (%): C, 61.13; H, 6.09; N, 11.14 Found (%): C, 61.12 ; H, 5.82; N, 11.40

Reference Example B58 6- [2- [2- [4- (diphenylmethoxy) piperidino] ethoxy] ethylthio] [1,2,4] triazolo [1,5-b] pyridazine
Preparation of fumarate salt 1.35 g of 6- [2- (2-bromoethoxy) ethylthio] [1,2,4] triazolo [1,5-b] pyridazine and 4- (diphenylmethoxy)
1.19 g of piperidine was dissolved in 15 ml of N, N-dimethylformamide, 740 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 17 hours. 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,
Elution was performed with ethyl acetate: methanol (10: 1). The desired fraction was collected and concentrated, the residue was dissolved in 10 ml of ethanol, and 360 mg of fumaric acid was added to concentrate. Ethyl ether was added to the residue, and the precipitated crystals were collected by filtration, washed with ethyl ether and dried to give 1.64 g of the title compound. Melting point 110-111 ° C Elemental analysis: C ₃₁ H ₃₅ N ₅ O ₆ S ・ 0.5H ₂ O Calculated (%): C, 60.57; H, 5.90; N, 11.39 Actual (%): C, 60.35 ; H, 5.73; N, 11.16

Reference Example B59 6- [2- [2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy] ethylthio] -7-isopropyl [1,2,4] triazolo
Production of [1,5-b] pyridazine dihydrochloride Step A: Preparation of 6- [2- (2-bromoethoxy) ethylthio] -7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine Production 3-Methyl mercaptopropionate 2.05 g in methanol
The mixture was dissolved in 10 ml, and 7.64 ml of a 2N sodium methoxide methanol solution and 1.0 g of 6-chloro-7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine were added, followed by heating under reflux for 1 hour. After cooling, the mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue.The precipitated crystals were collected, washed with ethyl acetate, suspended in 15 ml of tetrahydrofuran and suspended in 2-bromoethyl ether.
1.28 ml was added and the mixture was heated under reflux for 2 hours. After cooling, add ice water, extract with ethyl acetate, wash the extract with saturated saline,
Dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol (20: 1). The desired fractions were collected to give 0.98 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.35 (6H, s), 3.15-3.30 (1H, m),
3.50 (2H, t, J = 6Hz), 3.55 (2H, t, J = 6Hz), 3.86 (2H, t, J = 6H)
z), 3.91 (2H, t, J = 6Hz), 7.80 (1H, s), 8.31 (1H, s) .Step B: 6- [2- (2-bromoethoxy) ethylthio] -7-isopropyl [1 , 2,4] triazolo [1,5-b] pyridazine 0.98g and 1
720 mg of-(diphenylmethyl) piperazine was dissolved in 10 ml of N, N-dimethylformamide, 470 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 15 hours. 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, and eluted with ethyl acetate: methanol (10: 1). The desired fractions were collected and concentrated, the residue was dissolved in 5 ml of ethyl acetate, 1.45 ml of a 4N solution of hydrogen chloride in ethyl acetate was added, and the precipitated crystals were collected by filtration, washed with ethyl ether, dried and dried to give 1.04 g of the title compound. I got Recrystallized from ethanol. Mp 143-145 ° C. Elemental _{analysis: C 29 H 38 N 6 OSCl} 2 · H 2 O Calculated (%): C, 57.32; H, 6.64; N, 13.83 Found (%): C, 57.20; H , 6.43; N, 13.89

Reference Example B60 6- [2- [2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy] ethylthio] -7-tert-butyl [1,2,4] triazolo [1,
Production of 5-b] pyridazine Step A: 6- [2- (2-bromoethoxy) ethylthio] -7-tert-
Preparation of butyl [1,2,4] triazolo [1,5-b] pyridazine Methyl 3-mercaptopropionate 2.23g in methanol
The mixture was dissolved in 10 ml, and thereto were added 7.2 ml of a 2N sodium methoxide methanol solution and 1.0 g of 6-chloro-7-tert-butyl [1,2,4] triazolo [1,5-b] pyridazine, and the mixture was heated under reflux for 1 hour. After cooling, the mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the precipitated crystals were collected, washed with ethyl acetate, suspended in 20 ml of tetrahydrofuran and suspended in 2-bromoethyl ether
1.19 ml was added and the mixture was heated under reflux for 3 hours. After cooling, add ice water, extract with ethyl acetate, wash the extract with saturated saline,
Dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: hexane (2: 1). The desired fractions were collected to give 1.06 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.56 (9H, s), 3.50 (2H, t, J = 6Hz),
3.58 (2H, t, J = 6Hz), 3.86 (2H, t, J = 6Hz), 3.92 (2H, t, J = 6
Hz), 7.94 (1H, s), 8.32 (1H, s). Step B: 6- [2- (2-bromoethoxy) ethylthio] -7-tert-
Butyl [1,2,4] triazolo [1,5-b] pyridazine 1.06g and 1
740 mg of-(diphenylmethyl) piperazine was dissolved in 10 ml of N, N-dimethylformamide, 480 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 18 hours. 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, and eluted with ethyl acetate: methanol (20: 1). The desired fraction was collected and concentrated, and the precipitated crystals were collected by filtration, washed with ethyl ether, and dried to give the title compound (0.85 g). Mp 106-108 ° C. Elemental analysis: C ₃₀ H ₃₈ N ₆ OS Calculated (%): C, 67.89; H, 7.22; N, 15.83 Found (%): C, 67.65; H, 7.33; N, 15.98

Reference Example B61 6- [2- [2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy] ethoxy] -7-isopropyl [1,2,4] triazolo [1,5
-b] Production of pyridazine 60% sodium hydride 160mg in tetrahydrofuran 20
The suspension was added to 1.20 g of 2- [2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy] ethanol, and heated under reflux for 1 hour. After cooling, 610 mg of 6-chloro-7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine was added, and the mixture was heated under reflux for 1 hour. 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, and eluted with ethyl acetate: methanol (10: 1). The desired fraction was collected, and the precipitated crystals were collected by filtration, washed with ethyl ether, and dried to obtain 790 mg of the title compound. Mp 119-120 ° C. Elemental _{analysis: C 29 H 36 N 6 O} 2 · 0.5H 2 O Calculated (%): C, 68.34; H, 7.32; N, 16.49 Found (%): C, 68. 64; H, 7.3
1; N, 16.54

Reference Example B62 7-tert-butyl-6- [2- [2- [4- (diphenylmethyl)
Preparation of 1-piperazinyl] ethoxy] ethoxy] [1,2,4] triazolo [1,5-b] pyridazine dihydrochloride 150% of 60% sodium hydride in tetrahydrofuran 20
The mixture was suspended in 1.0 ml of 2- [2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy] ethanol and heated under reflux for 1 hour. After cooling, 650 mg of 7-tert-butyl-6-chloro [1,2,4] triazolo [1,5-b] pyridazine was added, and the mixture was heated under reflux for 2 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, and eluted with ethyl acetate: methanol (10: 1). The desired fraction was collected, the residue was dissolved in 5 ml of ethyl acetate, 2.1 ml of a 4N solution of hydrogen chloride in ethyl acetate was added, and the precipitated crystals were collected by filtration, washed with ethyl ether, dried and the precipitated crystals were filtered. The precipitates were collected, washed with ethyl ether and dried to give 1.55 g of the title compound. Mp 150-152 ° C. Elemental _{analysis: C 30 H 40 N 6 O} 2 Cl 2 · 0.5H 2 O Calculated (%): C, 60.39; H, 6.92; N, 14.09 Found (%): C, 60.20; H, 6.64; N, 14.09

Reference Example B63 7-tert-butyl-6- [2- [2- [4- (diphenylmethoxy) piperidino] ethoxy] ethoxy] [1,2,4] triazolo [1,5-b]
Manufacture of pyridazine fumarate 60% sodium hydride 120 mg in tetrahydrofuran 20
The suspension was added to 0.94 g of 2- [2- [4- (diphenylmethoxy) piperidino] ethoxy] ethanol and heated under reflux for 1 hour. After cooling, 530 mg of 7-tert-butyl-6-chloro [1,2,4] triazolo [1,5-b] pyridazine was added, and the mixture was heated under reflux 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,
Elution was performed with ethyl acetate: methanol (10: 1). The desired fraction was collected, and the residue was dissolved in 10 ml of ethanol, and 250 mg of fumaric acid was added, followed by concentration. Ethyl ether was added to the residue, and the precipitated crystals were collected by filtration, washed with ethyl ether, and dried to give 1.17 g of the title compound. Mp 80-82 ° C. Elemental _{analysis: C 35 H 43 N 5 O} 7 · 1.3H 2 O Calculated (%): C, 62.82; H, 6.87; N, 10.46 Found (%): C, 62.89; H, 6.69; N, 10.22

Reference Example B64 Ethyl 2- [6- [5- [4- (diphenylmethoxy) piperidino] pentylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate Difumaric acid Production of salt 4- (diphenylmethoxy) -1-piperidinepentanamine
1.41 g and 0.536 g of ethyl 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate
Stir at 3.5 ° C for 3.5 hours. After cooling, ethyl acetate-tetrahydrofuran (2: 1) was added, and the mixture was washed with an aqueous layer and saturated brine, and dried over sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and ethyl acetate: methanol:
Eluted with triethylamine (185: 15: 2). Collect the desired fractions and dissolve in 5 ml of ethanol, 235m of fumaric acid
g was dissolved in 5 ml of methanol and concentrated. Ethyl ether was added to the residue, and the precipitated powder was collected by filtration, washed with ethyl ether, and dried to obtain 0.629 g of the title compound. Melting point 138 ° C Elemental analysis: C ₄₃ H ₅₃ N ₅ O ₁₁ Calculated (%): C, 63.30; H, 6.55; N, 8.58 Found (%): C, 64.24; H, 6.92; N, 8.42

Reference Example B65 2- [6- [3- [4- (diphenylmethoxy) piperidino] -2-hydroxypropylamino] imidazo [1,2-b] pyridazine-2-
Preparation of ethyl yl] -2-methylpropionate difumarate 0.511 g of 1-amino-3- [4- (diphenylmethoxy) piperidino] -2-propanol and 2- (6-chloroimidazo [1,2-b ] 0.268 g of ethyl pyridazin-2-yl) -2-methylpropionate was stirred at 190-200 ° C for 3 hours. After cooling, ethyl acetate-tetrahydrofuran (2: 1) was added, and the mixture was washed with a layered water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and ethyl acetate:
Elution with methanol: triethylamine (90: 10: 1). Collect the desired fractions, dissolve in 5 ml of ethyl acetate,
A solution of 82 mg of fumaric acid in 5 ml of methanol was added and concentrated. Ethyl ether was added to the residue, and the precipitated powder was collected by filtration, washed with ethyl ether, and dried to obtain 0.223 g of the title compound. Melting point: 145 ° C Elemental analysis: C ₄₁ H ₄₉ N ₅ O ₁₂・ Et ₂ O Calculated (%): C, 61.56; H, 6.77; N, 7.98 Found (%): C, 61.39; H, 6.49 ; N, 7.91

Reference Example B66 2- [6- [3- [4- [bis (4-fluorophenyl) methoxy] piperidino] propylamino] imidazo [1,2-b] pyridazine-2-
Preparation of ethyl yl] -2-methylpropionate difumarate 1.62 g of 4- [bis (4-fluorophenyl) methoxy] -1-piperidinepropanamine and 2- (6-chloroimidazo [1,2-b]
Ethyl (pyridazin-2-yl) -2-methylpropionate 0.80
3 g at 190-200 ° C. for 3 hours. After cooling, layered water and brine were added, extracted with ethyl acetate, and 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 (90: 10: 1). The desired fraction was collected and dissolved in 20 ml of ethyl acetate, and a solution of 301 mg of fumaric acid dissolved in 10 ml of methanol was added thereto and concentrated. Acetone was added to the residue, and the precipitated crystals were collected by filtration, washed with acetone, and dried to obtain 0.966 g of the title compound. Melting point 159-161 ° C Elemental analysis: Calculated as C ₄₁ H ₄₇ N ₅ O ₁₁ F ₂・ 0.5H ₂ O (%): C, 59.13; H, 5.81; N, 8.41 Actual (%): C, 58.94; H, 5.84; N, 8.34

Reference Example B67 Ethyl 6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazine-2-carboxylate
Preparation of difumarate 4- (diphenylmethoxy) -1-piperidinepropanamine
686 mg and 477 mg of ethyl 6-chloroimidazo [1,2-b] pyridazine-2-carboxylate are combined with N, N-dimethylformamide 7
The mixture was dissolved in the same solution and 0.73 ml of N-ethyldiisopropylamine was added, followed by stirring in an oil bath (80 ° C.) for 18.5 hours. After cooling, ice water and common salt were added, and the mixture was extracted with ethyl acetate-tetrahydrofuran (1: 1). The extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol: triethylamine (50: 5: 1). Collect the desired fractions, dissolve in 5 ml of ethyl acetate, add 95 mg of fumaric acid to ethanol
The solution dissolved in 5 ml was added and concentrated. The residue was recrystallized by adding acetone-ethyl ether (1: 2), collected by filtration and washed with ethyl ether to obtain 211 mg of the title compound. Melting point 176-179 ° C Elemental analysis: Calculated as C ₃₈ H ₄₃ N ₅ O ₁₁ (%): C, 61.20; H, 5.81; N, 9.39 Found (%): C, 61.17; H, 5.98; N , 9.80

Reference Example B68 Isopropyl 2-fumarate [2- [6- [3- [4- (diphenylmethoxy) piperidino] propoxy] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate Production of 4- (diphenylmethoxy) -1-piperidinepropanol 8.
Dissolve 10g in N, N-dimethylformamide 60ml, 60%
1.11 g of sodium hydride was added, and the mixture was stirred under reduced pressure at room temperature for 1 hour. Isopropyl 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate under ice-cooling 7.
79 g was added and stirred at the same temperature for 4 hours. Add ice water,
The mixture was extracted with ethyl acetate-tetrahydrofuran (1: 1), and 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. Collect the desired fractions, concentrate under reduced pressure, dissolve the residue in 10 ml of ethanol,
476 mg of fumaric acid was added, and the mixture was concentrated again. The residue was crystallized from ethyl acetate, collected by filtration, washed with ethyl acetate and dried to give 1.05 g of the title compound. Melting point: 145-147 ° C Elemental analysis: Calculated as C ₄₂ H ₅₀ N ₄ O ₁₂ (%): C, 62.83; H, 6.28; N, 6.98 Found (%): C, 62.50; H, 6.10; N , 7.04

Reference Example B69 2- [6- [3- [4- [bis (4-methylphenyl) methoxy] piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methyl Preparation of ethyl dipropionate difumarate 2.11 g of 4- [bis (4-methylphenyl) methoxy] -1-piperidinepropanamine and 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) 0.803 g of ethyl 2-methylpropionate
Was stirred at 190-200 ° C. for 3 hours. After cooling, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol: triethylamine (95: 5: 1). The desired fractions were collected and dissolved in 20 ml of ethyl acetate, and a solution of 358 mg of fumaric acid in 20 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 to give the title compound 0.9
01g was obtained. Melting point 159-161 ° C Elemental analysis: Calculated for C ₄₃ H ₅₃ N ₅ O ₁₁ (%): C, 63.30; H, 6.55; N, 8.56 Found (%): C, 63.29; H, 6.32; N , 8.67

Reference Example B70 Production of N- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazine-2-carbonyl] glycine ethyl ester 4- (diphenylmethoxy) ) -1-Piperidinepropanamine
1.90 g and 1.38 g of N- (6-chloroimidazo [1,2-b] pyridazine-2-carbonyl) glycine ethyl ester in 1-methyl
It was dissolved in 15 ml of 2-pyrrolidone, and 0.841 ml of N-ethyldiisopropylamine was added, followed by stirring in an oil bath (90-100 ° C.) for 24 hours. After cooling, ice water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and ethyl acetate: methanol: triethylamine (95: 5: 1).
Eluted. The desired fraction was collected and recrystallized from ethyl acetate to give 1.28 g of the title compound. Melting point 172-174 ° C Elemental analysis: Calculated as C ₃₂ H ₃₈ N ₆ O ₄・ 0.5H ₂ O (%): C, 66.30; H, 6.78; N, 14.50 Actual (%): C, 66.42; H, 6.68; N, 14.55

Reference Example B71 Production of N- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazine-2-carbonyl] glycine ethyl ester dihydrochloride 0.628 g of [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazine-2-carbonyl] glycine ethyl ester was added to tetrahydrofuran 10
The mixture was dissolved in the residue, and 1.5 ml of a 4N solution of hydrogen chloride in ethyl acetate was added, followed by concentration 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 ° C Elemental analysis: C ₃₂ H ₄₀ N ₆ O ₄ Cl ₂ Calculated (%): C, 59.72; H, 6.26; N, 13.06 Actual (%): C, 59.74; H, 6.41; N , 12.63

Reference Example B72 Production of N- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazine-2-carbonyl] glycine N- [6- [3 Dissolve 0.810 g of-[4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazine-2-carbonyl] glycine ethyl ester in 4 ml of ethanol.
2 ml of a 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 3 hours. Concentrate under reduced pressure, add ice water and 1N hydrochloric acid 2.1m to the residue.
The mixture was extracted with ethyl acetate-tetrahydrofuran (1: 2), and the extract was washed with brine and dried over magnesium sulfate. Concentrate under reduced pressure, pulverize the residue by adding ethyl acetate, collect by filtration, wash with ethyl acetate and wash the title compound 0.1
83 g were obtained. Mp 171 ° C. Elemental _{analysis: C 30 H 34 N 6 O} 4 · 2H calcd _{2 O · AcOEt (%):} C, 61.25; H, 6.95; N, 12.60 Found (%): C, 61.30; H , 6.74; N, 12.45

Reference Example B73 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionamide dihydrochloride Production 4- (diphenylmethoxy) -1-piperidinepropanamine
1.29 g and 0.478 g of 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionamide at 190-200 ° C
And stirred for 70 minutes. After cooling, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol: triethylamine (90: 10: 1). The desired fraction was collected, the residue was dissolved in 10 ml of ethyl acetate, 1.5 ml of a 4N hydrogen chloride acetate solution was added, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the precipitated powder was collected by filtration, washed with ethyl acetate, and dried to obtain 0.823 g of the title compound. Mp 191 ° C. Elemental _{analysis: C 31 H 40 N 6 O} 2 Cl Calculated _{2 · AcOEt (%): C} , 64.11; H, 7.38; N, 12.82 Found (%): C, 63.70; H, 7.27 ; N, 12.34

Reference Example B74 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -N, N, 2-trimethylpropionamide Preparation of dihydrochloride 4- (diphenylmethoxy) -1-piperidinepropanamine
1.04 g and 0.426 g of 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -N, N, 2-trimethylpropionamide
Stir at 90-200 ° C for 60 minutes. After cooling, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol: triethylamine (85: 15: 1). The desired fraction was collected, the residue was dissolved in 10 ml of ethyl acetate, 1.5 ml of a 4N hydrogen chloride acetate solution was added, and the mixture was concentrated under reduced pressure. The residue was recrystallized from acetone to give 0.823 g of the title compound. Mp 183 ° C. Elemental _{analysis: C 33 H 44 N 6 O} 2 Cl 2 · 1.5H 2 O Calculated (%): C, 60.54; H, 7.24; N, 11.84 Found (%): C, 60.48; H, 7.28; N, 11.90

Reference Example B75 Production of 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropanol 4- ( Diphenylmethoxy) -1-piperidinepropanamine
1.29 g and 0.451 g of 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropanol are mixed at 190-200 ° C for 90
Stir for a minute. After cooling, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and ethyl acetate: methanol: triethylamine.
(90: 10: 1). The desired fraction was collected and the residue was recrystallized from ethyl ether to give the title compound 0.465.
g. Mp 105-108 ° C. Elemental _{analysis: C 31 H 39 N 5 O} 2 · 0.5H 2 O Calculated (%): C, 71.24; H, 7.71; N, 13.40 Found (%): C, 71.22; H, 7.87; N, 13.32

Reference Example B76 N- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazine-2-carbonyl] -2,2
Preparation of 4-dimethylglycine ethyl ester dihydrochloride 4- (diphenylmethoxy) -1-piperidinepropanamine
1.23 g and N- (6-chloroimidazo [1,2-b] pyridazine-2-carbonyl) -2,2-dimethylglycine ethyl ester 1.18 g
Was dissolved in 15 ml of N, N-dimethylformamide, and 1.31 ml of N-ethyldiisopropylamine was added.
Stir for hours. After cooling, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol: triethylamine (50: 5: 1). The desired fractions were collected, concentrated under reduced pressure, dissolved in 5 ml of ethyl acetate, added with 0.28 ml of a 4N ethyl acetate solution of hydrogen chloride and concentrated again. Ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration, washed with ethyl ether, and dried to give 284 mg of the title compound. Melting point 194-196 ° C Elemental analysis: Calculated as C ₃₄ H ₄₄ N ₆ O ₄ Cl ₂ (%): C, 60.80; H, 6.60; N, 12.51 Found (%): C, 60.82; H, 6.67 ; N, 12.77

Reference Example B77 Ethyl 2- [6- [3- [4- (diphenylmethyl) piperazino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate trihydrochloride Preparation of 4- (diphenylmethyl) -1-piperazinepropanamine 1.
31 g and 567 mg of ethyl 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate at 185 ° C.
Stir for hours. After cooling, 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, and eluted with ethyl acetate: methanol: triethylamine (50: 5: 1). The desired fractions were collected, concentrated under reduced pressure, dissolved in 5 ml of ethyl acetate, added with 0.80 ml of a 4N solution of hydrogen chloride in ethyl acetate, and concentrated again. Ethanol was added to the residue, and the precipitated crystals were collected by filtration, washed with ethanol-ethyl acetate (1: 3), dried and dried to give the title compound 5
02 mg was obtained. Mp 190-193 ° C. Elemental _{analysis: C 32 H 43 N 6 O} 2 Cl 3 · H 2 O Calculated (%): C, 57.53; H, 6.79; N, 12.58 Found (%): C, 57.27 ; H, 6.52; N, 12.55

Reference Example B78 Production of 2- [6- [4- [4- (diphenylmethoxy) piperidino] butylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid 4- (Diphenylmethoxy) -1-piperidinebutanamine 1.
56 g and 617 mg of ethyl 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate were added at 185 ° C for 3 hours.
Stir for hours. After cooling, 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, and eluted with ethyl acetate: methanol: triethylamine (50: 5: 1). The desired fractions were collected, concentrated under reduced pressure, dissolved in 5 ml of ethanol, and concentrated by adding 0.52 ml of a 4N solution of hydrogen chloride in ethyl acetate. Dissolve the residue in 4 ml of ethanol and add 4 ml of 1N aqueous sodium hydroxide
Was added and the mixture was stirred at room temperature for 4 hours, 1 ml of a 2N aqueous sodium hydroxide solution was added, and the mixture was stirred at 50 ° C for 16 hours. Concentrate under reduced pressure, dilute the residue with water, wash with ethyl acetate, add
The pH was adjusted to 4.5 by adding N hydrochloric acid, and the mixture was extracted with ethyl acetate-tetrahydrofuran (1: 1) .The extract was washed with saturated saline,
Dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was triturated with ethyl acetate, collected by filtration and dried to give 271 mg of the title compound. Amorphous Elemental _{analysis: C 32 H 39 N 5 O} 3 · 2.1H 2 O, calcd 0.5AcOEt (%): C, 65.49 ; H, 7.63; N, 11.23 Found (%): C, 65.23; H, 7.29; N, 11.19

Reference Example B79 Production of 2- [6- [2- [4- (diphenylmethoxy) piperidino] ethylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid Step A : 2- [6- (2-hydroxyethylamino) imidazo [1,2-
Preparation of isopropyl b] pyridazin-2-yl] -2-methylpropionate 130 mg of 2-aminoethanol and isopropyl 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate 300 mg was stirred at 170 ° C. for 4 hours. After cooling, add 260 mg of 2-aminoethanol and
Stir for 45 minutes. After cooling, 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, and eluted with ethyl acetate: methanol (10: 1). The desired fraction was collected, concentrated under reduced pressure, and the precipitated crystals were collected and dried to obtain 145 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.29 (3H, s), 1.32 (3H, s), 1.64 (6
H, s), 3.44 (2H, td, J = 4.6,6.1Hz), 3.88 (2H, t, J = 4.6Hz),
4.96-5.15 (1H, m), 5.43 (1H, t, J = 6.2Hz), 5.72 (1H, d, J = 9.
7Hz), 6.98 (1H, d, J = 9.7Hz), 7.45 (1H, s). Step B: 2- [6-[(2-methanesulfonyloxy) ethylamino] imidazo [1,2-b] pyridazine Preparation of isopropyl 2- [2-yl] -2-methylpropionate Isopropyl 2- [6- (2-hydroxyethylamino) imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate 2.
18 g was suspended in tetrahydrofuran (20 ml), N-ethyldiisopropylamine (2.45 ml) and methanesulfonyl chloride (1.10 ml) were added, and the mixture was stirred at room temperature for 1 hour. Add ice water, extract with ethyl acetate, wash the extract with saturated saline,
Dried over magnesium sulfate. The filtrate was concentrated under reduced pressure and dried to obtain 2.37 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.19 (3H, s), 1.22 (3H, s), 1.63 (6
H, s), 3.40 (3H, s), 3.74 (2H, td, J = 5.1,5.4Hz), 4.48 (2
H, t, J = 5.1Hz), 4.76 (1H, t, J = 5.4Hz), 4.95-5.12 (1H, m),
6.39 (1H, d, J = 9.6Hz), 7.54 (1H, s), 7.62 (1H, d, J = 9.6H
Step C: Production of isopropyl 2- [6- [2- [4- (diphenylmethoxy) piperidino] ethylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate 2 1.13 g of isopropyl- [6- [2- (methanesulfonyloxy) ethylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate in N, N-dimethylformamide (15 ml)
Dissolved in 4- (diphenylmethoxy) piperidine 943m
g, potassium iodide 586 mg and potassium carbonate 488 mg were added, and the mixture was stirred at 60 ° C. for 2 hours. Ice water was added, the mixture was saturated with sodium chloride, extracted with ethyl acetate, and the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol (10: 1). The desired fraction was collected, concentrated under reduced pressure, and dried to obtain 571 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.18 (3H, s), 1.21 (3H, s), 1.60-
1.20 (4H, m), 1.62 (6H, s), 2.10-2.30 (2H, m), 2.59 (2H,
t, J = 5.6Hz), 2.70-2.85 (2H, m), 3.35 (2H, dt, J = 5.3,5.6H
z), 3.35-3.55 (1H, m), 4.90-5.10 (1H, m), 5.05 (1H),
5.53 (1H, s), 6.39 (1H, d, J = 9.4Hz), 7.16-7.39 (10H, m),
7.54 (1H, s), 7.57 (1H, d, J = 9.4Hz). Step D: 2- [6- [2- [4- (diphenylmethoxy) piperidino] ethylamino] imidazo [1,2-b] 565 mg of isopropyl pyridazin-2-yl] -2-methylpropionate in ethanol 4m
Then, 2.04 ml of a 1N aqueous solution of sodium hydroxide was added, and the mixture was heated under reflux for 20 hours. After cooling, the mixture was concentrated under reduced pressure, the residue was diluted with water, and adjusted to pH 5.5 with 1N hydrochloric acid. Ethyl acetate was added, and the precipitated crystals were collected by filtration, washed with water and ethyl acetate, and dried to obtain 443 mg of the title compound. Mp 194-198 ° C. Elemental _{analysis: C 30 H 35 N 5 O} 3 · 2.5H 2 O Calculated (%): C, 64.50; H, 7.22; N, 12.54 Found (%): C, 64.57; H, 7.03; N, 12.58

Reference Example B80 Production of [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] carboxylic acid [6- [3- [4 876 mg of ethyl-(diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] carboxylate was dissolved in 5 ml of ethanol, 1.9 ml of a 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 3 hours.
Concentrate under reduced pressure, dilute the residue with water, wash with ethyl acetate,
The aqueous layer was adjusted to pH 5 by adding 1N hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and ethyl acetate, and dried to obtain 256 mg of the title compound. Melting point 152-155 ° C Elemental analysis: Calculated as C ₂₈ H ₃₁ N ₅ O ₃ 1.5 H ₂ O (%): C, 65.61; H, 6.69; N, 13.66 Actual (%): C, 65.52; H, 6.61; N, 13.61

Reference Example B81 2- [3-chloro-6- [3- [4- (diphenylmethoxy) piperidino] propoxy] imidazo [1,2-b] pyridazin-2-yl] -2-
Preparation of ethyl methyl propionate 0.5 fumarate 4- (diphenylmethoxy) -1-piperidinepropanol 33
Dissolve 4mg in N, N-dimethylformamide 20ml and 60%
Add 45 mg of oily sodium hydride and add
Stir for 35 minutes. Then, 2- [3,6-dichloroimidazo
310 mg of ethyl [1,2-b] pyridazin-2-yl] -2-methylpropionate was added, and the mixture was stirred at 0 ° C for 2 hours. Add ice water, extract with ethyl acetate, wash the extract with saturated saline,
Dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected and the precipitated crystals were dissolved in 5 ml of ethanol, added with 160 mg of fumaric acid and concentrated. The mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue.
The extract was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the residue, which was crystallized and collected by filtration, washed with ethyl ether and dried to give the title compound 1
68 mg were obtained. Melting point 186-188 ° C Elemental analysis: Calculated as C ₃₅ H ₄₁ N ₄ O ₆ Cl ・ 0.5H ₂ O (%): C, 63.87; H, 6.43; N, 8.51 Actual (%): C, 63.33 ; H, 6.34; N, 8.85

Reference Example B82 2- [3-Chloro-6- [3- [4- (diphenylmethyl) -1-piperazinyl] propoxy] imidazo [1,2-b] pyridazin-2-yl]-
Preparation of ethyl 2-methylpropionate dihydrochloride 4- (diphenylmethyl) -1-piperazinepropanol 1.0 g
Was dissolved in 10 ml of N, N-dimethylformamide and 142 mg of 60% oily sodium hydride was added.
Stir for a minute. Add 2- (3,6-dichloroimidazo) to the reaction mixture.
973 mg of ethyl [1,2-b] pyridazin-2-yl) -2-methylpropionate was added, and the mixture was stirred at 0 ° C for 2 hours. Add ice water, extract with ethyl acetate, wash the extract with saturated saline,
Dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with hexane: ethyl acetate: triethylamine (50: 50: 1). The desired fractions were collected and concentrated under reduced pressure.The precipitated crystals were dissolved in 5 ml of ethyl acetate, and 1.01 ml of a 4N solution of hydrogen chloride in ethyl acetate was added.
And then concentrated again. Recrystallized from methanol, collected by filtration, washed with ethyl acetate and dried to give the title compound 4
24 mg were obtained. Mp 203-205 ° C. Elemental _{analysis: C 32 H 40 N 5 O} 3 Cl 3 · H 2 O Calculated (%): C, 57.62; H, 6.35; N, 10.50 Found (%): C, 57.60 ; H, 6.37; N, 10.15

Reference Example B83 2- [3-Chloro-6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid Preparation of ethyl dihydrochloride 4- (diphenylmethoxy) -1-piperidinepropanamine
2.56 g with 2- [3,6-dichloroimidazo [1,2-b] pyridazine-
1.19 g of ethyl 2-yl] -2-methylpropionate at 160 ° C
For 3 hours. After cooling, 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, and eluted with ethyl acetate: methanol: triethylamine (50: 5: 1). Collect the desired fractions, dissolve in 5 ml of ethyl acetate, and add 4N hydrogen chloride in ethyl acetate
0.80 ml was added and concentrated. Ether was added to the residue to give a powder, which was dried to obtain 1.33 g of the title compound. Amorphous elemental analysis: Calculated as C ₃₃ H ₄₂ N ₅ O ₃ Cl ₃ .0.5H ₂ O (%): C, 58.97; H, 6.45; N, 10.42 Actual (%): C, 58.98; H , 6.64; N, 10.42

Reference Example B84 2- [3-chloro-6- [3- [4- (diphenylmethyl) -1-piperazinyl] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2- Preparation of ethyl methyl propionate trihydrochloride 4- (diphenylmethyl) -1-piperazinepropanamine 1.
75 g with 2- [3,6-dichloroimidazo [1,2-b] pyridazine-2-
Yl] -2-methylpropionate (854 mg) at 160 ° C
For 4 hours. After cooling, 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, and eluted with ethyl acetate: methanol (30: 1). The desired fractions are collected, concentrated under reduced pressure, dissolved in 5 ml of ethyl acetate, and 4N hydrogen chloride in ethyl acetate 1.
55 ml was added and the mixture was concentrated again. The precipitated crystals were washed with ethanol-ethyl acetate (1: 3), collected by filtration and dried to give 628 mg of the title compound. Mp 203-205 ° C. Elemental _{analysis: C 32 H 42 N 6 O} 2 Cl 4 · H 2 O Calculated (%): C, 54.71; H, 6.31; N, 11.96 Found (%): C, 54.88 ; H, 6.07; N, 11.97

Reference Example B85 2- [3-chloro-6- [3- [4- (diphenylmethyl) -1-piperazinyl] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2- Preparation of methylpropionic acid 2- [3-chloro-6- [3- [4- (diphenylmethyl) -1-piperazinyl] propylamino] imitadiso [1,2-b] pyridazin-2-yl]-
Dissolve 633mg of ethyl 2-methylpropionate trihydrochloride in 6ml of ethanol and 2.31ml of 2N sodium hydroxide aqueous solution
Was added and the mixture was heated under reflux for 1.5 hours. After cooling, the mixture was concentrated under reduced pressure, the residue was diluted with water, washed with ethyl acetate, and the aqueous layer was adjusted to pH 5 with 1N hydrochloric acid. Methanol was added, and the precipitated crystals were collected by filtration, washed with water-ethyl acetate, and dried to obtain 462 mg of the title compound. Mp 184-186 ° C. Elemental _{analysis: C 30 H 35 N 6 O} 2 Cl · H 2 O Calculated (%): C, 63.76; H, 6.60; N, 14.87 Found (%): C, 63.49; H, 6.52; N, 14.81

Reference Example B86 Preparation of 2- [6- [2- [4- (diphenylmethyl) -1-piperazinyl] ethylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid Production Step A: 2- [6- [2- [4- (diphenylmethyl) -1-piperazinyl] ethylamino] imidazo [1,2-b] pyridazin-2-yl]-
Preparation of isopropyl 2-methylpropionate 1.24 g of isopropyl 2- [6- [2- (methanesulfonyloxy) ethylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate was added to N, N-dimethylformamide 15m
l, and 977 mg of 1- (diphenylmethyl) piperazine,
642 mg of potassium iodide and 535 mg of potassium carbonate were added, and the mixture was stirred at room temperature for 1 hour and at 60 ° C. for 1.5 hours. Ice water and salt were 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 and eluted with ethyl acetate. The desired fraction was collected, concentrated under reduced pressure, and dried to obtain 570 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.17 (3H, s), 1.20 (3H, s), 1.62 (6
H, s), 2.36-2.60 (8H, m), 2.63 (2H, t, J = 5.8Hz), 3.37 (2
H, dt, J = 5.6,5.8Hz), 4.24 (1H, s), 4.37 (1H), 4.90-5.10
(1H, m), 6.38 (1H, d, J = 9.6Hz), 7.13-7.44 (10H, m), 7.52
(1H, s), 7.55 (1H, d, J = 9.4Hz). Step B: 2- [6- [2- [4- (diphenylmethyl) -1-piperazinyl] ethylamino] imidazo [1,2- b] pyridazin-2-yl]-
Dissolve 565 mg of isopropyl 2-methylpropionate in 4 ml of ethanol, and add 2.09 ml of 1N aqueous sodium hydroxide solution.
Was added and the mixture was heated under reflux for 19 hours. After cooling, the mixture was concentrated under reduced pressure, and the residue was diluted with water and adjusted to pH 5 with 1N hydrochloric acid. Ethyl acetate was added, and the precipitated crystals were collected by filtration, washed with water and methanol, and N, N-dimethylformamide-ethyl acetate was added.
(5: 1) was added to recrystallize, collected by filtration, washed with ethyl acetate and dried to give 249 mg of the title compound. Melting point 192-194 ° C Elemental analysis: Calculated as C ₂₉ H ₃₄ N ₆ O ₂・ 3.0H ₂ O (%): C, 63.02; H, 7.30; N, 15.21 Actual (%): C, 62.99; H, 6.72; N, 15.01

Reference Example B87 2- [3-chloro-6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid Preparation of ethyl 2- [3-chloro-6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate dihydrochloride Dissolve 653mg in ethanol 6ml and 2N sodium hydroxide aqueous solution 1.
97 ml was added and the mixture was heated under reflux for 2.5 hours. After cooling, concentrate under reduced pressure, dilute the residue with water, wash with ethyl acetate, and add 1N to the aqueous layer.
The pH was adjusted to 4.5 by adding hydrochloric acid. Acetone was added, and the precipitated crystals were collected by filtration, washed with water-acetone (5: 1), and dried to obtain 465 mg of the title compound. Melting point: 133-135 ° C Elemental analysis: Calculated as C ₃₁ H ₃₆ N ₅ O ₃ Cl.H ₂ O (%): C, 64.18; H, 6.60; N, 12.07 Actual (%): C, 64.16 H, 6.64; N, 12.33

Reference Example B88 2- [3-chloro-6- [3- [4- (diphenylmethyl) -1-piperazinyl] propoxy] imidazo [1,2-b] pyridazin-2-yl]-
Preparation of 2-methylpropionic acid 2- [3-chloro-6- [3- [4- (diphenylmethyl) -1-piperazinyl] propoxy] imidazo [1,2-b] pyridazin-2-yl]-
Dissolve 458 mg of ethyl 2-methylpropionate trihydrochloride in 4 ml of 2-propanol, and add 2N aqueous sodium hydroxide solution.
After adding 1.34 ml and stirring at 80 ° C. for 1.5 hours, 0.3 ml of a 2N aqueous sodium hydroxide solution was added, and the mixture was heated under reflux for 2 hours. After cooling, the mixture was concentrated under reduced pressure, the residue was diluted with water, washed with ethyl acetate, the aqueous layer was adjusted to pH 4 with 1N hydrochloric acid, extracted with ethyl acetate, and the extract was dried over sodium sulfate.
Concentrate under reduced pressure, ethyl acetate-ethyl ether-hexane
(2: 5: 1) was added for crystallization, collected by filtration, washed with ethyl ether and dried to give 125 mg of the title compound. Mp 118-121 ° C. Elemental _{analysis: C 30 H 34 N 5 O} 3 Cl · 1.5H 2 O Calculated (%): C, 62.65; H, 6.48; N, 12.18 Found (%): C, 62.95 ; H, 6.47; N, 11.76

Reference Example B89 Preparation of 2- [6- [3- [4- (diphenylmethoxy) piperidino] propoxy] -7-methylimidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid Production 0.16 g of 60% oily sodium hydride and 1.30 g of 4- (diphenylmethoxy) -1-piperidinepropanol were added to 10 ml of N, N-dimethylformamide, and the mixture was stirred at room temperature under reduced pressure for 1 hour. The reaction solution was cooled with ice water, 1.31 g of isopropyl 2- (6-chloro-7-methylimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate was added, and the mixture was added at room temperature.
Stir for 1.5 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 hexane: ethyl acetate (1: 5).
Collect the desired fractions and add 2- [6- [3- [4- (diphenylmethoxy) piperidino] propoxy] -7-methylimidazo
582 mg of isopropyl [1,2-b] pyridazin-2-yl] -2-methylpropionate was obtained as an oil. Dissolve this oil in 4 ml of ethanol, and add 2m of 1N aqueous sodium hydroxide solution.
Add l and heat to reflux for 7 hours. After cooling, the mixture was concentrated under reduced pressure, 2 ml of 1N hydrochloric acid was added to the residue under ice-cooling, and the mixture was extracted with ethyl acetate-tetrahydrofuran (1: 1). The extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was crystallized by adding a small amount of water and ethyl ether,
It was collected by filtration, washed with ethyl ether and dried to give 0.413 g of the title compound. Mp 122 ° C. Elemental _{analysis: C 32 H 38 N 4 O} 4 · 1.5H 2 O Calculated (%): C, 67.47; H, 7.25; N, 9.83 Found (%): C, 67.61; H, 7.13; N, 9.68

Reference Example B90 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -7-methylimidazo [1,2-b] pyridazin-2-yl]-
Preparation of 2-methylpropionic acid dihydrochloride 4- (diphenylmethoxy) -1-piperidinepropanamine
1.40 g and isopropyl 2- (6-chloro-7-methylimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate 0.63
6 g at 190-200 ° C. for 3 hours. After cooling, layered water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol: triethylamine (185: 15: 2). Collect the desired fractions and add 2- [6- [3- [4- (diphenylmethoxy)
Piperidino] propylamino] -7-methylimidazo [1,2-b]
0.737 g of isopropyl [pyridazin-2-yl] -2-methylpropionate was obtained as an oil. Dissolve the oil in 6 ml of ethanol and add 3.15 ml of 1N aqueous sodium hydroxide
Was added and the mixture was refluxed for 7 hours. After cooling, the mixture was concentrated under reduced pressure, and the residue was added with 1.89 ml of 1N hydrochloric acid under ice cooling, and washed with ethyl acetate. 1.89 ml of 1N hydrochloric acid was added to the aqueous layer to saturate the salt, extracted with ethyl acetate-tetrahydrofuran (1: 1), and the extract was washed with saturated saline and dried over magnesium sulfate. Concentrate under reduced pressure, add 1.89 ml of 1N hydrochloric acid to the residue, concentrate to dryness under reduced pressure, crystallize by adding ethyl ether to the residue, collect by filtration, wash with ethyl ether, dry and dry the title compound 0.445. g. Mp 202 ° C. (decomposition) Elemental _{analysis: C 32 H 41 N 5 O} 3 Cl 2 · 0.5H 2 O Calculated (%): C, 61.63; H, 6.79; N, 11.23 Found (%): C , 61.66; H, 6.8
3; N, 11.11

Reference Example B91 Pivaloyloxy 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate Preparation of methyl difumarate Ethyl 2- [6- [3- (4-diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate 1.36 g of salt in ethyl acetate
The suspension was suspended in 20 ml and washed with water, and the ethyl acetate layer was dried over magnesium sulfate. Concentrate under reduced pressure, dissolve the residue in 8 ml of ethanol, and add 1N aqueous sodium hydroxide solution 4.3
Then, the mixture was stirred at room temperature for 40 hours. After concentrating under reduced pressure, 4.3 ml of 1N hydrochloric acid and brine were added to the residue under ice-cooling, and the mixture was extracted with ethyl acetate-tetrahydrofuran (1: 1). The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in 5 ml of N, N-dimethylformamide, 0.374 ml of chloromethyl pivalate and 0.357 g of potassium carbonate were added, and the mixture was stirred at room temperature for 20 hours. Ice water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol: triethylamine (185: 15: 2). The desired fractions were collected and dissolved in 10 ml of ethyl acetate, and a solution of 227 mg of fumaric acid in 5 ml of methanol was added and concentrated. The residue was recrystallized from ethyl acetate to give the title compound.
0.772 g was obtained. Melting point: 164-167 ° C Elemental analysis: Calculated as C ₄₅ H ₅₅ N ₅ O ₁₃ (%): C, 61.84; H, 6.34; N, 8.01 Found (%): C, 61.83; H, 6.30; N , 8.10

Reference Example B92 2- [6- [4- [4- (diphenylmethoxy) piperidino] butyl]
Production of ethyl imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate dihydrochloride Step A: 2- [6- (4-chlorobutyl) imidazo [1,2-b] pyridazine-2 Preparation of ethyl [-yl] -2-methylpropionate Dissolve 5.0 g of 1-chloro-4-iodobutane in 50-5 ml of toluene-N, N-dimethylacetamide and activate zinc with copper
2.24 g was added and the mixture was stirred at 80 ° C. for 3.5 hours under a nitrogen atmosphere. After cooling, 2- (6-chloroimidazo [1,2-b] pyridazine-2-
Ethyl) -2-methylpropionate (3.06 g) and dichlorobis (triphenylphosphine) palladium (II) 160 mg
And stirred at 80 ° C. for 4 hours. After cooling, water and ethyl acetate were added, the insolubles were filtered through celite, the aqueous layer was separated, and the organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with hexane: ethyl acetate (1: 1). Collect the desired fractions, concentrate under reduced pressure, and dry to give the title compound.
1.74 g was obtained. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.23 (3H, t, J = 6.8 Hz), 1.68 (6H,
s), 1.80-2.00 (4H, m), 2.84 (2H, t, J = 7.2Hz), 3.59 (2H, t,
J = 6.0Hz), 4.17 (2H, q, J = 7.1Hz), 6.89 (1H, d, J = 9.5Hz),
7.80 (1H, s), 7.82 (1H, d, J = 9.2Hz). Step B: 2- [6- (4-chlorobutyl) imidazo [1,2-b] pyridazin-2-yl] -2-methyl Dissolve 828 mg of ethyl propionate in 10 ml of acetonitrile and add 4- (diphenylmethoxy)
To the mixture were added 752 mg of piperidine, 552 mg of potassium iodide, and 460 mg of potassium carbonate, and the mixture was stirred at 60 ° C. for 4 hours, and then heated under reflux for 18 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, and ethyl acetate: methanol: triethylamine.
(100: 5: 2). The desired fraction was collected, concentrated under reduced pressure, dissolved in 5 ml of ethyl acetate, added with 1.01 ml of 4N hydrogen chloride in ethyl acetate, and concentrated under reduced pressure. Powdered from ethyl ether, collected by filtration and dried to give 1.18 g of the title compound. Amorphous elemental analysis: calculated as C ₃₄ H ₄₄ N ₄ O ₃ Cl ₂ .H ₂ O (%): C, 63.25; H, 7.18; N, 8.68 Actual (%): C, 63.10; H, 7.4
3; N, 8.64

Reference Example B93 Production of sodium 2- [6- [4- [4- (diphenylmethoxy) piperidino] butyl] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate [6- [4- [4- (diphenylmethoxy) piperidino] butyl]
631 mg of ethyl imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate dihydrochloride was dissolved in 4 ml of ethanol, 5.5 ml of a 1N aqueous sodium hydroxide solution was added, and the mixture was heated under reflux for 3 hours. After cooling, concentrate under reduced pressure and dilute the residue with water.
The pH was adjusted to 5.5 with 1N hydrochloric acid. Crystallize by adding acetone, wash with water-acetone (2: 1), dry and dry the title compound 3
45 mg were obtained. Melting point 177-179 ° C Elemental analysis: Calculated as C ₃₂ H ₃₇ N ₄ O ₃ Na ・ 1.75H ₂ O (%): C, 66.25; H, 7.04; N, 9.66 Actual (%): C, 66.13 ; H, 6.93; N, 9.81

Reference Example B94 Ethyl 2- [6- [4- [4- (diphenylmethyl) -1-piperazinyl] butyl] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate Production 2- [6- (4-chlorobutyl) imidazo [1,2-b] pyridazine-2-
921 mg of ethyl [yl] -2-methylpropionate was dissolved in 10 ml of N, N-dimethylformamide, 789 mg of 1- (diphenylmethyl) piperazine, 433 mg of potassium iodide and 520 mg of potassium carbonate were added, and the mixture was stirred at 60 ° C. for 5 hours. After cooling, ethyl acetate was added, washed with saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: triethylamine (50: 1). The desired fraction was collected, concentrated under reduced pressure, crystallized from ethyl ether-hexane (1: 1), collected by filtration, washed with hexane, and dried to give 554 mg of the title compound. Mp 105-106 ° C. Elemental _{analysis: C 33 H 41 N 5 O} 2 · 0.5H 2 O Calculated (%): C, 72.23; H, 7.71; N, 12.76 Found (%): C, 72.48; H, 7.73; N, 12,95

Reference Example B95 Production of 2- [6- [4- [4- (diphenylmethyl) -1-piperazinyl] butyl] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid Dissolve 482 mg of ethyl 2- [6- [4- [4- (diphenylmethyl) -1-piperazinyl] butyl] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate in 2 ml of ethanol, 1N
1.8 ml of an aqueous sodium hydroxide solution was added, and the mixture was heated under reflux for 1 hour. After cooling, concentrate under reduced pressure, dilute the residue with water, and add 1N
The pH was adjusted to 5 by adding hydrochloric acid. Crystallize by adding ethyl acetate, wash with water-acetone (2: 1), dry and dry the title compound 3
86 mg were obtained. Melting point: 108-110 ° C Elemental analysis: Calculated as C ₃₁ H ₃₇ N ₅ O ₂・ H ₂ O (%): C, 70.30; H, 7.42; N, 13.22 , 7.73; N, 13.32

Reference Example B96 Production of isopropyl 1- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] cyclopentanecarboxylate dihydrochloride 1.67 g of 4- (diphenylmethoxy) -1-piperidinepropanamine
793 mg of isopropyl 1- (6-chloroimidazo [1,2-b] pyridazin-2-yl) cyclopentanecarboxylate at 165 ° C
Stir for 5.5 hours. After cooling, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol: triethylamine (100: 5: 2). The desired fractions were collected, concentrated under reduced pressure, dissolved in 5 ml of ethyl acetate, and concentrated by adding 0.84 ml of 4N hydrogen chloride in ethyl acetate. The residue was triturated with ethyl ether, collected by filtration, washed with ethyl ether and dried to give 999 mg of the title compound. Amorphous Elemental _{analysis: C 36 H 47 N 5 O} 3 Cl 2 · 0.5H 2 O, 0.5Et 2 O Calculated (%): C, 63.85; H, 7.47; N, 9.80 Found (%): C, 63.83; H, 7.54; N, 9.83

Reference Example B97 Preparation of 1- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] cyclopentanecarboxylic acid 1- [6 Dissolve 598 mg of isopropyl- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] cyclopentanecarboxylate in 3 ml of ethanol, and add 2N aqueous sodium hydroxide solution. 2.24m
l was added and heated under reflux for 7 hours. After cooling, the mixture was concentrated under reduced pressure, the residue was diluted with water, washed with ethyl acetate, and adjusted to pH 4.5 with 1N hydrochloric acid. The mixture was saturated with sodium chloride, extracted with ethyl acetate-tetrahydrofuran (1: 2), and the extract was dried over magnesium sulfate. Concentrate under reduced pressure, add ethyl acetate-ethyl ether (1: 1), powder and wash with ethyl ether,
Drying afforded 349 mg of the title compound. Amorphous elemental analysis: Calculated as C ₃₃ H ₃₉ N ₅ O ₃・ 3.0H ₂ O (%): C, 65.22; H, 7.46; N, 11.52 Observed (%): C, 65.19; H, 7.17 ; N, 11.29

Reference Example B98 Production of 1- [6- [3- [4- (diphenylmethoxy) piperidino] propoxy] imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxylic acid Step A: 1- Production of isopropyl [6- [3- [4- (diphenylmethoxy) piperidino] propoxy] imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxylate 1- (diphenylmethoxy) -1-piperidinepropanol 1 .
Dissolve 14g in N, N-dimethylformamide 15ml and 60%
140 mg of oily sodium hydride was added, and the mixture was stirred at room temperature under reduced pressure for 30 minutes. Under ice-cooling, 980 mg of isopropyl 1- (6-chloroimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxylate was added to the reaction solution, and the mixture was stirred at the same temperature for 4 hours. Ice water was added, the mixture was saturated with sodium chloride, extracted with ethyl acetate-tetrahydrofuran (1: 1), and the extract was dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fractions are collected and concentrated under reduced pressure to give the title compound 4
96 mg were obtained. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.25 (3H, s), 1.28 (3H, s), 1.40-2.2
5 (12H, m), 2.43-2.55 (2H, m), 2.70-2.88 (2H, s), 3.36-3.55
(1H, m), 4.33 (2H, t, J = 6.3Hz), 4.98-5.18 (1H, m), 5.52 (1H,
s), 6.58 (1H, d, J = 9.8Hz), 7.15-7.40 (10H, m), 7.64 (1H, d, J
= 9.4Hz), 8.03 (1H, s). Step B: 1- [6- [3- [4- (diphenylmethoxy) piperidino] propoxy] imidazo [1,2-b] pyridazin-2-yl] cyclopropane 490 mg of isopropyl carboxylate in 2 ml of ethanol
And 0.86 ml of a 2N aqueous sodium hydroxide solution was added thereto, followed by heating under reflux for 2 hours. After cooling, the mixture was concentrated under reduced pressure, the residue was diluted with water, and adjusted to pH 5 with 1N hydrochloric acid. Ethyl acetate-
Extracted with tetrahydrofuran (1: 3), the extract was washed with brine and dried over magnesium sulfate. Concentrate under reduced pressure,
Ethyl ether was added, powdered, washed with ethyl ether and dried to obtain 382 mg of the title compound. Amorphous elemental analysis: Calculated as C ₃₁ H ₃₄ N ₄ O ₄・ 2.0H ₂ O (%): C, 66.17; H, 6.81; N, 9.96 Actual (%): C, 66.27; H, 7.00 ; N, 9.75

Reference Example B99 Preparation of isopropyl 1- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxylate dihydrochloride 4- (diphenylmethoxy) -1-piperidinepropanamine
2.72 g and 1.27 g of isopropyl 1- (6-chloroimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxylate
Stir at 165 ° C for 4.5 hours. After cooling, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol: triethylamine (50: 5: 1). Collect the desired fractions, concentrate under reduced pressure, dissolve in 5 ml of ethyl acetate,
0.72 ml of N hydrogen acetate solution in ethyl acetate was added, and the mixture was concentrated again. The residue was crystallized from ethyl acetate-acetone (2: 1), collected by filtration, washed with ethyl acetate and dried to give 714 mg of the title compound. Melting point: 206-208 ° C Elemental analysis: Calculated as C ₃₄ H ₄₃ N ₅ O ₃ Cl ₂・ 0.5H ₂ O (%): C, 62.86; H, 6.83; N, 10.78 Actual (%): C, 63.10; H, 6.88; N, 10.83

Reference Example B100 Preparation of 1- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxylic acid 1- [6 Dissolve 554 mg of-[3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxylate dihydrochloride in 3 ml of ethanol, and add 2N aqueous sodium hydroxide solution 1.73 ml
Was added and the mixture was heated under reflux for 1.5 hours. After cooling, the mixture was concentrated under reduced pressure, the residue was diluted with water, washed with ethyl acetate, and adjusted to pH 5.5 with 1N hydrochloric acid. Acetone was added for crystallization, washed with acetone and dried to obtain 321 mg of the title compound. Mp 115-117 ° C. Elemental _{analysis: C 31 H 35 N 5 O} 3 · H 2 O Calculated (%): C, 68.49; H, 6.86; N, 12.88 Found (%): C, 68.24; H , 6.89; N, 12.93

Reference Example B101 Ethyl 2- [6- [3- [4- (diphenylmethoxy) piperidino] propyl] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate Production Step A: Production of ethyl 2- [6- [3- (tetrahydropyranyl-2-oxy) propyl] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate 2- (3 10.6 g of (-iodopropoxy) tetrahydropyran was dissolved in 106-10.6 ml of toluene-N, N-dimethylacetamide, and 3.87 g of copper-activated zinc was added thereto, followed by stirring at 80 ° C. for 3 hours under a nitrogen atmosphere. After cooling, 5.28 g of ethyl 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate and dichlorobis (triphenylphosphine)
277 mg of palladium (II) was added, and the mixture was stirred at 80 ° C for 14 hours. After cooling, ice water and ethyl acetate were added, the insolubles were filtered through celite, the filtrate was extracted with ethyl acetate, and 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 hexane: ethyl acetate (1: 1). The desired fraction was collected, concentrated under reduced pressure, and dried to obtain 2.64 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.23 (3H, t, J = 7.0 Hz), 1.68 (6H,
s), 1.40-1.95 (6H, m), 1.98-2.15 (2H, m), 2.87-2.96 (2
H, m), 3.40-3.56 (2H, m), 3.75-3.94 (2H, m), 4.17 (2H, q,
J = 7.1Hz), 4.54-4.62 (1H, broad t), 6.91 (1H, d, J = 9.2H
z), 7.79 (1H, s), 7.80 (1H, d, J = 9.0Hz). Step B: 2- [6- (3-hydroxypropyl) imidazo [1,2-b] pyridazin-2-yl] Preparation of ethyl 2-methylpropionate Ethyl 2- [6- [3- (tetrahydropyranyl-2-oxy) propyl] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate 3.67 g was dissolved in 38 ml of ethanol, 2.40 g of p-toluenesulfonic acid monohydrate 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 and extracted with ethyl acetate and tetrahydrofuran. 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. The desired fraction was collected, concentrated under reduced pressure, and dried to obtain 2.05 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.23 (3H, t, J = 7.2 Hz), 1.68 (6H,
s), 1.95-2.10 (2H, m), 2.94 (2H, t, J = 7.5Hz), 3.74 (2H, m
q, J = 7.1Hz), 4.17 (2H, q, J = 7.1Hz), 6.91 (1H, d, J = 9.0Hz),
7.80 (1H, s), 7.82 (1H, d, J = 9.2Hz). Step C: 2- [6- [3- (methanesulfonyloxy) propyl] imidazo [1,2-b] pyridazin-2-yl Production of ethyl] -2-methylpropionate 2.04 g of ethyl 2- [6- (3-hydroxypropyl) imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate is suspended in 40 ml of tetrahydrofuran. Then, under ice-cooling, 2.41 ml of N-ethyldiisopropylamine and 0.83 ml of methanesulfonyl chloride were added, and the mixture was stirred at room temperature for 15 minutes. Ice water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure and dried to obtain 2.78 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.23 (3H, t, J = 7.1 Hz), 1.68 (6H,
s), 2.15-2.35 (2H, m), 2.97 (2H, t, J = 7.5Hz), 3.03 (3H, m
s), 4.17 (2H, q, J = 7.4Hz), 4.34 (2H, t, J = 6.2Hz), 6.89 (1
H, d, J = 9.2Hz), 7.80 (1H, s), 7.84 (1H, d, J = 10Hz). Step D: 2- [6- [3- (methanesulfonyloxy) propyl] imidazo [1, Dissolve 1.32 g of ethyl 2-b] pyridazin-2-yl] -2-methylpropionate in 15 ml of N, N-dimethylformamide and add 1.15 g of 4- (diphenylmethoxy) piperidine, 712 mg of potassium iodide and 593 mg of potassium carbonate. And 6
Stir at 0 ° C for 2 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. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate: methanol: triethylamine (50: 5: 1), the desired fraction was collected and concentrated under reduced pressure, dissolved in 5 ml of ethyl acetate, and dissolved in 4N 1.6 ml of an ethyl hydrogen chloride solution was added, and the mixture was concentrated under reduced pressure. Trituration from ethyl ether, collection by filtration and drying gave 1.55 g of the title compound. Amorphous Elemental _{analysis: C 33 H 42 N 4 O} 3 Cl 2 · 0.5H 2 O Calculated (%): C, 63.66; H, 6.96; N, 9.00 Found (%): C, 63.61; H , 6.94; N, 9.07

Reference Example B102 Production of 2- [6- [3- [4- (diphenylmethoxy) piperidino] propyl] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid Dissolve 905 mg of ethyl 6- [3- [4- (diphenylmethoxy) piperidino] propyl] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate in 6 ml of ethanol and add 1N sodium hydroxide An aqueous solution (5.9 ml) was added, and the mixture was heated under reflux for 2 hours. After cooling, the mixture was concentrated under reduced pressure, the residue was diluted with water, and 1N hydrochloric acid was added to adjust the pH to 4.5. Add acetone,
Crystallize, wash with acetone and dry to give 476 mg of the title compound
I got Melting point 195-205 ° C Elemental analysis: Calculated as C ₃₁ H ₃₆ N ₄ O ₃・ 0.3H ₂ O (%): C, 71.87; H, 7.12; N, 10.81 Actual (%): C, 71.95; H, 6.94; N, 10.73

Reference Example B103 Ethyl 2- [6- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate Preparation of hydrochloride 2- [6- [3- (methanesulfonyloxy) propyl] imidazo
Dissolve 1.41 g of ethyl [1,2-b] pyridazin-2-yl] -2-methylpropionate in 15 ml of N, N-dimethylformamide, 1.16 g of 1- (diphenylmethyl) piperazine, 760 mg of potassium iodide, potassium carbonate Add 633 mg and add
Stir for hours. 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, and eluted with ethyl acetate: triethylamine (50: 1). The desired fractions are collected, concentrated under reduced pressure, dissolved in 5 ml of ethyl acetate, and 4 ml of 4N hydrogen chloride in ethyl acetate 2.4 ml
And then concentrated again. Recrystallized from acetone: ethyl acetate (1: 1), collected by filtration, dried and the title compound 1.3
9 g were obtained. Mp 183-185 ° C. Elemental _{analysis: C 32 H 42 N 5 O} 2 Cl 3 · H 2 O Calculated (%): C, 58.85; H, 6.79; N, 10.72 Found (%): C, 58.82 ; H, 6.52; N, 10.67

Reference Example B104 Production of 2- [6- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid Ethyl 2- [6- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate Trihydrochloride 1.08 g in ethanol The mixture was dissolved in 8 ml, 1N aqueous sodium hydroxide solution (8.5 ml) was added, and the mixture was heated under reflux for 2 hours. After cooling, concentrate under reduced pressure, dilute the residue with water,
The pH was adjusted to 4.5 by adding 1N hydrochloric acid. Add acetone, crystallize, wash with water-acetone (2: 1) and dry to give the title compound
435 mg were obtained. Mp 176-178 ° C. Elemental _{analysis: C 30 H 35 N 5 O} 2 · 0.5H 2 O Calculated (%): C, 71.12; H, 7.16; N, 13.82 Found (%): C, 70.79; H, 6.86; N, 13.87

Reference Example B105 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 and 1.03 g of ethyl 2- (6-chloro-3-methylimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate
Stir at 160 ° C for 7.5 hours. After cooling, 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, and eluted with ethyl acetate: methanol: triethylamine (50: 5: 1). Collect the desired fractions, concentrate under reduced pressure, dissolve in 5 ml of ethyl acetate,
0.96 ml of an N-ethyl acetate solution of hydrogen chloride 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: Calculated as C ₃₄ H ₄₅ N ₅ O ₃ Cl ₂ 1.5 H ₂ O (%): C, 60.98; H, 7.22; N, 10.46 Actual (%): C, 60.70; H , 6.95; N, 10.34

Reference Example B106 Production of ethyl [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -2-methylimidazo [1,2-b] pyridazin-3-yl] carboxylate 4- ( Diphenylmethoxy) -1-piperidinepropanamine
1.98 g and 1.46 g of ethyl (6-chloro-2-methylimidazo [1,2-b] pyridazin-3-yl) carboxylate were combined with 1-methyl-2-
The solution was dissolved in 15 ml of pyrrolidone, and 1.05 ml of N-ethyldiisopropylamine was added, followed by stirring at 120 ° C for 40 hours. After cooling, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol: triethylamine (50: 5: 1). The desired fractions were collected and concentrated, and the residue was mixed with ethyl ether-hexane (1: 2), and the precipitated crystals were collected by filtration, washed with hexane, and dried to give the title compound 412.
mg was obtained. Melting point 117-119 ° C Elemental analysis: Calculated as C ₃₁ H ₃₇ N ₅ O ₃ (%): C, 70.56; H, 7.07; N, 13.27 Found (%): C, 70.16; H, 6.93; N , 13.01

Reference Example B107 Production of [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -2-methylimidazo [1,2-b] pyridazin-3-yl] carboxylic acid [6- [ Dissolve 770 mg of ethyl 3- [4- (diphenylmethoxy) piperidino] propylamino] -2-methylimidazo [1,2-b] pyridazin-3-yl] carboxylate in 5 ml of ethanol and add 1N
3.2 ml of an aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 3.5 hours. After cooling, concentrate under reduced pressure, dilute the residue with water,
The mixture was washed with ethyl acetate and adjusted to pH 4.5 with 1N hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and ethyl acetate,
Drying afforded 265 mg of the title compound. Mp 101-103 ° C. Elemental _{analysis: C 29 H 33 N 5 O} 3 · 0.5H 2 O Calculated (%): C, 68.48; H, 6.74; N, 13.77 Found (%): C, 68. 63; H, 6.7
7; N, 13.91

Reference Example B108 2- [6- [3- [4- (diphenylmethylamino) piperidino] propylamino] imidazo [1,2-b] pyridazine-
Preparation of ethyl 2-yl] -2-methylpropionate 4- (diphenylmethylamino) -1-piperidinepropanamine 3.12 g and 2- (6-chloroimidazo [1,2-b] pyridazine
1.72 g of ethyl 2-yl) -2-methylpropionate
Stir at ℃ for 3 hours. After cooling, 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, and eluted with ethyl acetate: methanol: triethylamine (50: 5: 1). The desired fractions are collected and concentrated under reduced pressure.
(1: 3) was added to crystallize, collected by filtration, washed with hexane and dried to give 1.83 g of the title compound. Melting point 115-117 ° C Elemental analysis: C ₃₃ H ₄₂ N ₆ O ₂ Calculated (%): C, 71.45; H, 7.63; N, 15.15 Found (%): C, 71.40; H, 7.70; N , 14.94

Reference Example B109 Production of 2- [6- [3- [4- (diphenylmethylamino) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid 2 Dissolve 612 mg of ethyl [-[6- [3- [4- (diphenylmethylamino) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate in 5 ml of ethanol and add 1N water 2.2 ml of an aqueous sodium oxide solution was added, and the mixture was heated under reflux for 6 hours. After cooling, the mixture was concentrated under reduced pressure, the residue was diluted with water, washed with ethyl acetate, and adjusted to pH 5 with 1N hydrochloric acid.
The mixture was saturated with sodium chloride, extracted with tetrahydrofuran, and the extract was dried over magnesium sulfate. The mixture was concentrated under reduced pressure, powdered by adding ethyl ether, collected by filtration, and dried to obtain 503 mg of the title compound. Amorphous elemental analysis: Calculated as C ₃₁ H ₃₈ N ₆ O ₂・ 2.7H ₂ O ・ 0.8Et ₂ O (%): C, 64.93; H, 7.87; N, 13.28 Actual (%): C, 64.99; H, 7.72; N, 12.85

Reference Example B110 Ethyl 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-ethylbutyrate dihydrochloride Production 4- (diphenylmethoxy) -1-piperidinepropanamine
3.03 g and 1.38 g of ethyl 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-ethylbutyrate were stirred at 160 ° C. for 1.5 hours and then at 180 ° C. for 2 hours. After cooling to 90 ° C, ethanol and overlay water were added, extracted with ethyl acetate,
The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and ethyl acetate: methanol: triethylamine (10
0: 5: 2). The desired fractions were collected, concentrated under reduced pressure, dissolved in 5 ml of ethyl acetate, added with 1.4 ml of a 4N solution of hydrogen chloride in ethyl acetate, and concentrated again. The residue was triturated with ethyl ether, dried and dried to give the title compound 893
mg was obtained. Amorphous Elemental _{analysis: C 35 H 47 N 5 O} 3 Cl 2 · Et 2 O Calculated (%): C, 64.10; H, 7.86; N, 9.58 Found (%): C, 63.78; H, 7.57; N, 9.96

Reference Example B111 Production of N- [3-chloro-6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazine-2-carbonyl] glycine ethyl ester 4 -(Diphenylmethoxy) -1-piperidinepropanamine
0.649g and N- (3,6-dichloroimidazo [1,2-b] pyridazine
0.53 g of (-2-carbonyl) glycine ethyl ester
Dissolve in 7 ml of methyl-2-pyrrolidone, add 0.345 ml of N-ethyldiisopropylamine, and in an oil bath (90-100 ° C).
Stir for hours. After cooling, ice water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol: triethylamine (185: 15: 2). The desired fraction was collected and recrystallized from ethyl acetate to give 0.711 g of the title compound. Melting point 178-180 ° C Elemental analysis: Calculated as C ₃₂ H ₃₇ N ₆ O ₄ Cl (%): C, 63.51; H, 6.16; N, 13.89 Found (%): C, 63.56; H, 6.21; N, 13.78

Reference Example B112 N- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazine-2-carbonyl] -β-
Preparation of alanine ethyl ester 4- (diphenylmethoxy) -1-piperidinepropanamine
0.649 g with N- (6-chloroimidazo [1,2-b] pyridazine-2-
0.594 g of carbonyl) -β-alanine ethyl ester
Dissolve in 7 ml of 1-methyl-2-pyrrolidone, add 0.345 ml of N-ethyldiisopropylamine, and in an oil bath (90-100 ° C)
Stir for hours. After cooling, ice water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and ethyl acetate: methanol: triethylamine (37
0: 30: 4). The desired fraction was collected and recrystallized from ethyl ether to give 0.347 g of the title compound. Mp 83-86 ° C. Elemental analysis: Calculated as _{C 33 H 40 N 6 O 4} (%): C, 67.79; H, 6.90; N, 14.37 Found (%): C, 68.05; H, 6.87; N , 14.38

Reference Example B113 Production of sodium 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate 2 A solution of-[6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid (528 mg) in methanol (2 mL) At 2
A normal aqueous sodium hydroxide solution (0.47 mL) was added, and the mixture was stirred at room temperature for 5 minutes. This solution was diluted with 2-propanol and concentrated under reduced pressure. The residue was dissolved in 2-propanol and concentrated again under reduced pressure. 2-Propanol and ethyl ether were added to the residue, and the precipitated powder was collected by filtration to give the title compound (47
4 mg). Amorphous elemental analysis: Calculated as C ₃₁ H ₃₆ N ₅ O ₃ Na ・ 0.5H ₂ O (%): C, 66.65; H, 6.68; N, 12.54 Actual (%): C, 66.45; H, 6.54; N, 12.53

Reference Example B114 Production of 6- [5- [4- (diphenylmethoxy) piperidino] pentylamino] [1,2,4] triazolo [1,5-b] pyridazine 4- (diphenylmethoxy) -1- Piperidine pentanamine
0.705 g and 0.309 g of 6-chloro [1,2,4] triazolo [1,5-b] pyridazine were stirred at 135-140 ° C. for 1.5 hours. After cooling, layered water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over sodium sulfate. Concentrate under reduced pressure,
The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol: triethylamine (95: 5: 1).
The desired fraction was collected, recrystallized from ethyl ether, and dried to obtain 0.629 g of the title compound. Melting point 96-98 ° C Elemental analysis: C ₂₈ H ₃₄ N ₆ O ・ H ₂ O Calculated (%): C, 70.12; H, 7.36; N, 17.52 Actual (%): C, 70.29; H, 7.19; N, 17.62

Reference Example B115 1- [4- (Diphenylmethoxy) piperidino] -3-[([1,2,4] triazolo [1,5-b] pyridazin-6-yl) amino] -2-propanol Production 0.675 g of 1-amino-3- [4- (diphenylmethoxy) piperidino] -2-propanol and 6-chloro [1,2,4] triazolo [1,5-
b] 0.335 g of pyridazine was stirred at 135-140 ° C for 3 hours. After cooling, the aqueous layer was added, and the mixture was extracted with ethyl acetate-tetrahydrofuran (2: 1). The extract was washed with brine and dried over sodium 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). Collect the desired fractions, recrystallize from ethyl acetate, dry and dry the title compound.
0.509 g was obtained. Melting point 82-87 ° C Elemental analysis: Calculated as C ₂₆ H ₃₀ N ₆ O ₂・ H ₂ O (%): C, 65.53; H, 6.77; N, 17.63 Actual (%): C, 65.36; H , 6.50; N, 17.25

Reference Example B116 tert-butyl [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [1,5-b] pyridazin-2-yl] carboxylate Preparation of 4- (diphenylmethoxy) -1-piperidinepropanamine
563 mg and 442 mg of tert-butyl (6-chloro [1,2,4] triazolo [1,5-b] pyridazin-2-yl) carboxylate are added to pyridine 5
The mixture was dissolved in ml and stirred at 80 ° C for 13.5 hours. After cooling, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol: triethylamine (50: 5: 1). The desired fraction was collected and concentrated under reduced pressure, and the residue was crystallized by adding ethyl acetate, collected by filtration, washed with ethyl ether, and dried to obtain 365 mg of the title compound. 133-135 ° C Elemental analysis: Calculated for C ₃₁ H ₃₈ N ₆ O ₃ (%): C, 68.61; H, 7.06; N, 15.49 Found (%): C, 68.18; H, 6.81; N , 15.46

Reference Example B117 Production of [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [1,5-b] pyridazin-2-yl] carboxylic acid 4 -(Diphenylmethoxy) -1-piperidinepropanamine
2.33 g and (6-chloro [1,2,4] triazolo [1,5-b] pyridazin-2-yl) carboxylic acid 714 mg were stirred at 175 ° C. for 30 minutes. After cooling, add water-ethyl acetate-ethanol to the reaction mixture.
(2: 2: 1) was added for crystallization, collected by filtration, washed with water-ethyl acetate-ethyl ether (2: 1: 2) and dried to give the title compound
598 mg were obtained. Mp 135-138 ° C. Elemental _{analysis: C 27 H 30 N 6 O} 3 · 0.5H 2 O Calculated (%): C, 65.44; H, 6.31; N, 16.96 Found (%): C, 65.76; H, 6.13; N, 16.97

Reference Example B118 Production of methyl [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [1,5-b] pyridazin-7-yl] carboxylate 4- (diphenylmethoxy) -1-piperidinepropanamine
Dissolve 1.42 g and 929 mg of methyl (6-chloro [1,2,4] triazolo [1,5-b] pyridazin-7-yl) carboxylate in 20 ml of N, N-dimethylformamide and add 1.51 ml of N-ethyldiisopropylamine. In addition, the mixture was stirred at 70 ° C. for 6 hours. After cooling,
Water was added and the mixture was saturated with sodium chloride, extracted with ethyl acetate-tetrahydrofuran (1: 1), and the extract was dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and ethyl acetate: methanol: triethylamine.
(50: 5: 1). The desired fractions were collected and concentrated, and the residue was treated with ethyl acetate-ethyl ether-hexane (1:
2: 1) was added for crystallization, collected by filtration, washed with hexane and dried to give 905 mg of the title compound. Melting point: 120-122 ° C Elemental analysis: Calculated as C ₂₈ H ₃₂ N ₆ O ₃ (%): C, 67.18; H, 6.44; N, 16.79 Found (%): C, 67.11; H, 6.54; N , 16.87

Reference Example B119 Production of [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [1,5-b] pyridazin-7-yl] carboxylic acid [ Dissolve 1.58 g of methyl 6- [3- [4- (diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [1,5-b] pyridazin-7-yl] carboxylate in 10 ml of ethanol 1
8.0 ml of N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1.5 hours. After cooling, the mixture was concentrated under reduced pressure, the residue was diluted with water, washed with ethyl acetate, and adjusted to pH 4.5 with 1N hydrochloric acid. The mixture was saturated with sodium chloride, extracted with tetrahydrofuran, and the extract was dried over magnesium sulfate. The crystals obtained by concentration under reduced pressure were washed with ethyl ether, collected by filtration and dried to give 788 mg of the title compound. Melting point 207-209 ° C Elemental analysis: Calculated as C ₂₇ H ₃₀ N ₆ O ₃・ 0.5H ₂ O (%): C, 65.44; H, 6.30; N, 16.96 Actual (%): C, 65.17; H, 6.19; N, 16.90

Reference Example B120 N- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [1,5-b] pyridazine-2-carbonyl] glycine ethyl ester Preparation of 4- (diphenylmethoxy) -1-piperidinepropanamine
1.41 g and 1.23 g of N- (6-chloro [1,2,4] triazolo [1,5-b] pyridazine-2-carbonyl) glycine ethyl ester
It was dissolved in 17 ml of N, N-dimethylformamide, and 1.50 ml of N-ethyldiisopropylamine was added. The mixture was stirred at room temperature for 28 hours and then at 60 ° C. for 19 hours. After cooling, aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate-tetrahydrofuran (1: 1), and the extract was dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and ethyl acetate:
Elution with methanol: triethylamine (50: 5: 1). The desired fraction was collected, concentrated, recrystallized by adding tetrahydrofuran, collected by filtration, washed with ethyl ether, and dried to give 987 mg of the title compound. Mp 175-177 ° C. Elemental analysis: Calculated as _{C 31 H 37 N 7 O 4} (%): C, 64.12; H, 6.60; N, 16.88 Found (%): C, 63.99; H, 6 .5
2; N, 16.85

Reference Example B121 N- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [1,5-b] pyridazine-2-carbonyl] -2, Preparation of 2-dimethylglycine ethyl ester fumarate 4- (diphenylmethoxy) -1-piperidinepropanamine 1.56 g and N- (6-chloro [1,2,4] triazolo [1,5-b] pyridazine-2 -Carbonyl)-
1.50 g of 2,2-dimethylglycine ethyl ester was dissolved in 20 ml of N, N-dimethylformamide, and 1.65 ml of N-ethyldiisopropylamine was added, followed by stirring at 70 ° C. for 16 hours. After cooling, aqueous sodium bicarbonate 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, and ethyl acetate: methanol: triethylamine (50: 5: 1)
Eluted. The desired fraction was collected and concentrated, and 880 mg of the obtained oil was dissolved in 5 ml of ethanol.
Fumaric acid (170 mg) was added and the mixture was concentrated. Ethyl ether was added and the mixture was powdered, washed with ethyl ether, filtered, collected and dried to obtain 931 mg of the title compound. Amorphous elemental analysis: Calculated as C ₃₇ H ₄₅ N ₇ O ₈・ H ₂ O ・ 0.5Et ₂ O (%): C, 60.76; H, 6.80; N, 12.72 ; H, 6.85; N, 12.34

Reference Example B122 Preparation of isopropyl [6- [3- [4- (diphenylmethoxy) piperidino] propoxy] [1,2,4] triazolo [1,5-b] pyridazin-2-yl] carboxylate 4 -(Diphenylmethoxy) -1-piperidinepropanol 65
Dissolve 3mg in N, N-dimethylformamide 10ml and 60%
Add 88 mg of oily sodium hydride, and add
Stir for 1.5 hours. The reaction mixture was cooled with ice, (6-chloro [1,2,
4] 483 mg of isopropyl triazolo [1,5-b] pyridazin-2-yl) carboxylate was added, and the mixture was stirred at the same temperature for 3.5 hours. Ice water was added, and ethyl acetate-tetrahydrofuran (1:
The extract was extracted in 1), and the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-methanol (10: 1). The desired fraction was collected and concentrated, and the precipitated crystals were washed with ethyl ether, filtered, collected and dried to obtain 462 mg of the title compound. Mp 126-127 ° C. Elemental analysis: Calculated as _{C 30 H 35 N 5 O 4} (%): C, 68.03; H, 6.66; N, 13.22 Found (%): C, 68.01; H, 6.79; N , 13.42

Reference Example B123 Production of [6- [3- [4- (diphenylmethoxy) piperidino] propoxy] [1,2,4] triazolo [1,5-b] pyridazin-2-yl] carboxylic acid [6 1.85 g of isopropyl [-[3- [4- (diphenylmethoxy) piperidino] propoxy] [1,2,4] triazolo [1,5-b] pyridazin-2-yl] carboxylate in tetrahydrofuran 18m
The mixture was dissolved in l, and 3.8 ml of a 1N aqueous solution of sodium hydroxide was added thereto, followed by stirring at room temperature for 3.5 hours. After cooling, concentrate under reduced pressure, dilute the residue with water, wash with ethyl acetate and add 1N hydrochloric acid.
The pH was adjusted to 4.5. Ethanol-acetone (1: 2) was added for crystallization, and the crystals were collected by filtration, washed with water and ethyl acetate, and dried to obtain 1.33 g of the title compound. Mp 173-177 ° C. Elemental _{analysis: C 27 H 29 N 5 O} 4 · 2.5H 2 O Calculated (%): C, 60.89; H, 6.43; N, 13.15 Found (%): C, 60.86; H, 6.21; N, 13.06

Reference Example B124 N- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [1,5-b] pyridazine-2-carbonyl] -2, Production of 2-dimethylglycine N- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [1,5-b] pyridazine-2-carbonyl] -2, 1.71 g of 2-dimethylglycine ethyl ester
Dissolve in ethanol (6 ml) and 1N aqueous sodium hydroxide
4.5 ml was added and stirred at room temperature for 2 hours. Under ice-cooling, 1N hydrochloric acid was added to adjust the pH to 5, and the obtained crystals were washed with water and ethyl acetate, filtered, collected and dried to give 1.24 g of the title compound.
I got Mp 247-249 ° C. Elemental _{analysis: C 31 H 37 N 7 O} 4 · H 2 O Calculated (%): C, 63.14; H, 6.67; N, 16.63 Found (%): C, 63.09; H , 6.81; N, 16.70

Reference Example B125 Production of N- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [1,5-b] pyridazine-2-carbonyl] glycine 928 mg of N- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] [1,2,4] triazolo [1,5-b] pyridazine-2-carbonyl] glycine ethyl ester in ethanol 7m
The mixture was dissolved in l, and 2.2 ml of a 1N aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 1.5 hours. Concentrate under reduced pressure, dilute the residue with water, add 1N hydrochloric acid to pH 4.5, wash the obtained crystals with water, acetone and ethyl acetate, collect by filtration,
Drying afforded 443 mg of the title compound. Melting point 256-258 ° C Elemental analysis: Calculated as C ₂₉ H ₃₃ N ₇ O ₄・ 1.5H ₂ O (%): C, 61.04; H, 6.36; N, 17.18 Actual (%): C, 61.29; H, 6.28; N, 17.35

Reference Example B126 N- [6- [3- [4- (diphenylmethoxy) piperidino] propoxy] [1,2,4] triazolo [1,5-b] pyridazine-2-carbonyl] -2,2 Preparation of 1-dimethylglycine ethyl ester 1.5 fumarate [6- [3- [4- (diphenylmethoxy) piperidino] propoxy] [1,2,4] triazolo [1,5-b] pyridazin-2-yl] carboxylic 986mg of acid and 0.38ml of N-ethyldiisopropylamine
Was suspended in 10 ml of N, N-dimethylformamide, and N, N ′
361 mg of -carbonyldiimidazole was added, and the mixture was stirred at room temperature for 3 hours. Ethyl 2-aminoisobutyrate hydrochloride 372mg
And stirred for 43 hours, followed by stirring at 60 ° C. for 5 hours. Add ice water and add ethyl acetate-tetrahydrofuran (1: 1)
The extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol: triethylamine (50: 1: 1). The desired fractions are collected, concentrated under reduced pressure, and dissolved in 5 ml of ethanol.
9 mg was added and the mixture was concentrated. Ethanol-ethyl acetate (1: 3) was added for crystallization, washed with ethyl ether, collected by filtration and dried to give 581 mg of the title compound. 127-130 ° C Elemental analysis: Calculated as C ₃₉ H ₄₆ N ₆ O ₁₁ (%): C, 60.45; H, 5.98; N, 10.85 Found (%): C, 60.06; H, 5.91; N , 10.80

Reference Example B127 Production of N- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -3-methylimidazo [1,2-b] pyridazine-2-carbonyl] glycine ethyl ester 4 -(Diphenylmethoxy) -1-piperidinepropanamine
1.17 g and 0.891 g of N- (6-chloro-3-methylimidazo [1,2-b] pyridazine-2-carbonyl) glycine ethyl ester are dissolved in 10 ml of 1-methyl-2-pyrrolidone and N-ethyldiisopropylamine 0.517 ml in an oil bath (90-100
(° C) for 15 hours. After cooling, ice water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol: triethylamine (90: 10: 1). The desired fraction was collected and recrystallized from ethyl acetate-ethyl ether (1: 1) to obtain 0.629 g of the title compound. Melting point 158-160 ° C Elemental analysis: Calculated as C ₃₃ H ₄₀ N ₆ O ₄ (%): C, 67.79; H, 6.90; N, 14.37 Found (%): C, 67.52; H, 6.92; N , 14.13

Reference Example B128 Preparation of 6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -2-isopropylimidazo [1,2-b] pyridazine hydrochloride 4- (diphenylmethoxy) -1-piperidine Propanamine
(2.60 g), 6-chloro-2-isopropylimidazo [1,2-b] pyridazine (0.783 g), and potassium iodide (0.133 g)
Was stirred at 190 ° C. for 5 hours under a nitrogen atmosphere.
The reaction mixture was cooled to 100 ° C., and ethanol (2 mL) was added dropwise, followed by cooling to room temperature. To this mixture was added an aqueous solution of sodium hydrogen carbonate (0.40 g), and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with water, filtered, and concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography (ethyl acetate, then ethyl acetate: methanol: triethylamine
500: 25: 1 followed by 50: 5: 1). This was dissolved in methanol, a 10% hydrogen chloride / methanol solution (3 mL) was added, and the mixture was concentrated under reduced pressure to obtain the title compound (1.13 g). Amorphous Elemental _{analysis: C 30 H 38 N 5 OCl} · 0.75H 2 O Calculated (%): C, 67.52; H, 7.46 Found (%): C, 67.32; H, 7.42

Reference Example B129 2- [6- [3- [4- [phenyl (2-thienyl) methylamino] piperidino] propylamino] imidazo [1,2-b] pyridazine-2-
Preparation of ethyl yl] -2-methylpropionate trihydrochloride 1.44 g of 4- [phenyl (2-thienyl) methylamino] -1-piperidinepropanamine and 2- (6-chloroimidazo [1,2-b]
Ethyl (pyridazin-2-yl) -2-methylpropionate 585m
g in 3 ml of 1-methyl-2-pyrrolidone, and
Stir for hours. After cooling, ethanol and saturated aqueous sodium hydrogen carbonate were 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, and eluted with ethyl acetate: methanol: triethylamine (50: 5: 1). The desired fraction was collected and concentrated. The residue was dissolved in 5 ml of ethyl acetate, 0.86 ml of 4N hydrogen chloride in ethyl acetate was added, and the mixture was concentrated under reduced pressure. Crystallized from ethanol-ethyl acetate (1: 4), collected by filtration and dried to give 609 mg of the title compound. Mp 175-178 ° C. Elemental _{analysis: C 31 H 43 N 6 O} 2 SCl 3 · H 2 O Calculated (%): C, 54.11; H, 6.59; N, 12.21 Found (%): C, 54.17 ; H, 6.49; N, 12.08

Reference Example B130 Ethyl 2- [6- [3- [4- (hydroxydiphenylmethyl) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate Dihydrochloride Preparation of Salt 427 mg of 4- (hydroxydiphenylmethyl) -1-piperidinepropanamine and 235 mg of ethyl 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate
Stir at 160 ° C for 3.5 hours. After cooling, ethanol and saturated aqueous layer were added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol: triethylamine (50: 5: 1). The desired fractions are collected and concentrated.The residue is dissolved in 5 ml of ethyl acetate, and 0.23 ml of 4N hydrogen chloride in ethyl acetate is added.
And concentrated. The residue was triturated with ether, collected by filtration and dried to give 216 mg of the title compound. Amorphous elemental analysis: Calculated as C ₃₃ H ₄₃ N ₅ O ₃ Cl ₂・ H ₂ O ・ 0.5Et ₂ O (%): C, 61.49; H, 7.37; N, 10.24 Actual (%): C , 61.47; H, 7.36; N, 9.87

Reference Example B131 Ethyl 2- [6- [3- [3- (diphenylmethoxy) pyrrolidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate dihydrochloride Preparation of 3- (diphenylmethoxy) -1-pyrrolidinepropanamine
1.53 g and 660 mg of ethyl 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate were added to 1-methyl-
It was dissolved in 3 ml of 2-pyrrolidone and stirred at 170 ° C. for 8 hours.
After cooling, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and ethyl acetate: methanol: triethylamine (50:50).
5: 1). Collect and concentrate the desired fractions,
The residue was dissolved in 5 ml of ethyl acetate, and 0.81 ml of a 4N solution of hydrogen chloride in ethyl acetate was added, followed by concentration. The residue was triturated with ether, collected by filtration and dried to give the title compound 87
7 mg were obtained. Amorphous Elemental _{analysis: C 32 H 41 N 5 O} 3 Cl 2 · H 2 O Calculated (%): C, 60.75; H, 6.85; N, 11.07 Found (%): C, 60.50; H, 6.55; N, 10.81

Reference Example B132 2- [6- [3- [4- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-oxy) piperidino] propylamino] imidazo [1,2-b Production of ethyl [pyridazin-2-yl] -2-methylpropionate 4- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5
1.69 g of (-oxy) -1-piperidinepropanamine and 2- (6-
Add 645 mg of ethyl chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate to 1-methyl-2-pyrrolidone
Dissolve in 3 ml and stir at 170 ° C for 7 hours. After cooling, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and 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). The desired fractions were collected, concentrated, subjected to silica gel column chromatography again, and eluted with methylene chloride: methanol: triethylamine (100: 1: 2). The desired fraction was collected and concentrated to obtain 340 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.21 (3H, t, J = 7.0 Hz), 1.52-2.20
(8H, m), 1.64 (6H, s), 2.43-2.60 (2H, m), 2.70-2.92 (2H,
m), 2.95-3.10 (2H, m), 3.28-3.62 (5H, m), 6.14 (2H, d, J =
7.0Hz), 6.29 (1H, d, J = 9.4Hz), 6.40-6.50 (1H, brs), 7.0
5-7.22 (6H, m), 7.33-7.43 (2H, m), 7.54 (1H, d, J = 9.4Hz).

Reference Example A1 Preparation of 4- (diphenylmethoxy) -1-piperidinepropanol 2.67 g of 4- (diphenylmethoxy) piperidine was dissolved in 20 ml of N, N-dimethylformamide, and 1.09 ml of 3-bromopropanol and 1.66 g of potassium carbonate were dissolved. And stirred at room temperature for 40 hours. Ice water was poured, extraction was performed with ethyl acetate, and 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,
Elution was performed with ethyl acetate: methanol: triethylamine (90: 10: 1). The desired fraction was collected and concentrated to give 2.32 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.5-2.4 (10H, m), 2.58 (2H, t, J = 5H
z), 3.3-3.6 (1H, m), 3.78 (2H, t, J = 5Hz), 5.50 (1H, s),
Reference Example A2 Production of 4- (diphenylmethoxy) -1-piperidinebutanol 1.05 g of 4- (diphenylmethoxy) piperidine was dissolved in 10 ml of N, N-dimethylformamide, and the mixture was treated with 4-bromobutyl acetate. ) 0.57ml and potassium carbonate 652mg were added and stirred at 50 ° C for 3 hours. Pour ice water, extract with ethyl ether,
The extract was washed with brine and dried over magnesium sulfate.
Concentrate under reduced pressure, dissolve the residue in 15 ml of ethanol, and add 1N
8 ml of an aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The crystals precipitated by concentration under reduced pressure were collected, washed with ethyl ether, dried and 1.21 g of the title compound
I got ¹ H-NMR (CDCl ₃ ) δ ppm: 2.95 (2H, t, J = 5 Hz), 1.6-3.4 (13H,
m), 3.74 (2H, t, J = 5Hz), 5.43 (1H, s), 7.2-7.5 (10H, m).

Reference Example A3 Preparation of 4- (diphenylmethoxy) -1-piperidinehexanol 1.00 g of 4- (diphenylmethoxy) piperidine was dissolved in 10 ml of N, N-dimethylformamide, and 0.49 ml of 6-bromo-1-hexanol was added. 0.56 g sodium carbonate and potassium carbonate
0.62 g was added and stirred at 100 ° C. for 1 hour. Ice water was poured, extraction was performed with ethyl acetate, and the extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and ethyl acetate: methanol:
Elution with triethylamine (90: 10: 1). The desired fraction was collected and concentrated to give 1.24 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.2-2.0 (12H, m), 2.0-2.2 (2H, m),
2.30 (2H, t, J = 8Hz), 2.6-2.9 (2H, m), 3.3-3.6 (1H, m),
3.63 (2H, t, J = 6Hz), 5.52 (1H, s), 7.1-7.5 (10H, m). Reference Example A4 Production of 2- [2- [4- (diphenylmethoxy) piperidino] ethoxy] ethanol 4 Dissolve 1.30 g of-(diphenylmethoxy) piperidine in 10 ml of N, N-dimethylformamide, add 0.52 ml of 2- (2-chloroethoxy) ethanol, 0.73 g of sodium iodide and 0.81 g of potassium carbonate and stir at 100 ° C for 1 hour. Was. Ice water was poured, extraction was performed with ethyl acetate, and 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 (90: 10: 1). The desired fraction was collected and concentrated to give 1.47 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.6-2.4 (6H, m), 2.54 (2H, t, J = 6H
z), 2.6-3.0 (2H, m), 3.3-3.5 (1H, m), 3.5-3.8 (6H, m),
5.50 (1H, s), 7.1-7.5 (10H, m).

Reference Example A5 Production of 2- [2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy] ethanol 1.00 g of 1- (diphenylmethyl) piperazine was dissolved in 10 ml of N, N-dimethylformamide, (2-chloroethoxy)
0.42 ml of ethanol, 0.59 g of sodium iodide and 0.66 g of potassium carbonate were added, and the mixture was stirred at 100 ° C. for 1 hour. Pour ice water, extract with ethyl acetate, wash the extract with brine,
Dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with dichloromethane: ethyl acetate: methanol (10: 10: 1). The desired fraction was collected and concentrated to give 1.47 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 2.3-2.8 (8H, m), 2.57 (2H, t, J = 6H
z), 3.5-3.8 (6H, m), 4.21 (1H, s), 7.1-7.5 (10H, m). Reference Example A6 2-tert-butyl-6-chloro [1,2,4] triazolo [1 Step A: Dissolve 36 g of N- (6-chloropyridazin-3-yl) pivalamide oxime N, N-dimethylpivalamide in 85 ml of toluene and add 11.3 ml of phosphorus oxychloride dropwise under ice-cooling 24 at room temperature
Stir for hours. There 3-amino-6-chloropyridazine
12.0 g was added and stirred at 60-70 ° C for 24 hours. After cooling, ethyl acetate was added, and the mixture was washed with a 2N aqueous solution of sodium hydroxide and brine, and dried over sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and hexane:
Eluted with ethyl acetate: triethylamine (50: 50: 2). Collect the desired fractions and add N ^2- (6-chloropyridazine-3
6.38 g of -yl) -N ¹ , N ¹ -dimethylpivalamidine are obtained.
The mother liquor was purified by silica gel column chromatography to further obtain 6.07 g of amidine. Dissolve 12.5 g of the obtained amidine derivative in 60 ml of methanol and add hydroxylamine hydrochloride.
Dissolve 4.31 g in methanol (40 ml) and add the solution.
Stir for 2 hours. Under reduced pressure, methanol was concentrated to half the volume, and the precipitated crystals were collected by filtration, washed with water and ethyl ether, and dried to obtain 10.44 g of the title compound. Melting point: 128-130 ° C Elemental analysis: Calculated as C ₉ H ₁₃ N ₄ OCl (%): C, 47.27; H, 5.73; N, 24.50 Found (%): C, 47.28; H, 5.59; N, 24.34 Step B: 4.07 g of N- (6-chloropyridazin-3-yl) pivalamide oxime was suspended in 170 ml of chloroform, 8.3 ml of phosphorus oxychloride was added dropwise, and the mixture was heated under reflux for 5 hours. After cooling, ice water and a 2N aqueous solution of sodium hydroxide were added, and the mixture was extracted with chloroform. 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 hexane: ethyl acetate (5: 1).
Collect the desired fractions and concentrate to give 1.12 g of the title compound
I got Melting point 95-97 ° C Elemental analysis: C ₉ H ₁₁ N ₄ Cl · 0.3H ₂ O Calculated (%): C, 50.03; H, 5.41; N, 25.93 Actual (%): C, 50.23 H, 5.
12; N, 25.90

Reference Example A7 Production of methyl 6-chloro [1,2,4] triazolo [1,5-b] pyridazine-2-carboxylate Step A: 6-chloro [1,2,4] triazolo [1, 5-b] pyridazine-2
6-chloro-2-methyl [1,2,4] triazolo [1,5-b] pyridazine-carboxylate 10.0 g was added to 55 ml of concentrated sulfuric acid under ice-cooling, and sodium dichromate dihydrate 19.4 was added at the same temperature. g was added little by little to room temperature and stirred for 4 days. About 200ml of ice water under ice water
Was added, and the precipitated crystals were collected by filtration, washed with water and ethyl ether, and dried to obtain 9.74 g of the title compound. Melting point 221 ° C (decomp.) Elemental analysis: C ₆ H ₃ N ₄ O ₂ Cl Calculated (%): C, 36.29; H, 1.52; N, 28.22 Actual (%): C, 35.96; H, 1.59; N, 28.12 Step B: 6-chloro [1,2,4] triazolo [1,5-b] pyridazine-2
-Carboxylic acid 3.02g in N, N-dimethylformamide 50ml
, And 3.15 ml of N-ethyldiisopropylamine was added. While stirring under ice water, 1.14 ml of methyl iodide was added. After stirring at room temperature for 19 hours, about 200 ml of ice water was added and the precipitated crystals were collected by filtration, washed with water and ethyl ether, and the crystals obtained by silica gel column chromatography purification from the mother liquor were combined and dried to give the title compound. 2.91 g was obtained. Melting point: 208-209 ° C Elemental analysis: Calculated as C ₇ H ₅ N ₄ O ₂ Cl (%): C, 39.55; H, 2.37; N, 26.35 Found (%): C, 39.65; H, 2.46; N, 26.34

Reference Example A8 Production of ethyl 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate Method A Step A: 6-chloroimidazo [1,2-b ] Ethyl pyridazine-2-acetate 3-amino-6-chloropyridazine 11.2 g in 150
The mixture was suspended in 2 ml of ethyl 4-chloroacetoacetate, and the mixture was refluxed for 24 hours. After cooling, the mixture was concentrated under reduced pressure, and the residue was adjusted to pH 7 with an aqueous sodium hydrogen carbonate solution and 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 hexane: ethyl acetate (2: 3). The desired fraction was collected to obtain 12.7 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.29 (3H, t, J = 7 Hz), 3.89 (2H, s),
4.23 (2H, q, J = 7Hz), 7.05, 7.85 (1H, d, J = 9Hz each), 7.95 (1
H, s). Step B: Dissolve 6.8 g of ethyl 6-chloroimidazo [1,2-b] pyridazine-2-acetate in 50 ml of N, N-dimethylformamide, and stir under ice-water with 60% oily sodium hydride.
2.46 g was added little by little, brought to room temperature and stirred for 30 minutes. Add 4.36 ml of methyl iodide under ice water and add
Stir for hours. Ice water was poured, extraction was performed with ethyl acetate, and 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 hexane: ethyl acetate (2: 1). The desired fractions were collected and concentrated to give 4.06 g of the title compound. Melting point 64-65 ° C Elemental analysis: C ₁₂ H ₁₄ N ₃ O ₂ Cl Calculated (%): C, 53.84; H, 5.27; N, 15.70 Found (%): C, 53.85; H, 5.16; N, 15.80 Method B The title compound can also be synthesized by the following method. Suspension of 3-amino-6-chloropyridazine (80.0 g), ethyl 4-bromo-2,2-dimethyl-3-oxobutanoate (201 g), and disodium hydrogenphosphate (131 g) in ethanol (300 mL) The suspension was heated to reflux for 8 hours. Water (300 mL) in the reaction mixture
And extracted twice with ethyl acetate (300 mL). The combined organic layer was washed twice with water (600 mL) and a saturated aqueous sodium chloride solution (300 mL), dried over magnesium sulfate, treated with activated carbon, filtered, and concentrated under reduced pressure. Diisopropyl ether (200 mL) was added to the residue, and the insolubles were filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate 100: 1, 2: 1, followed by 1: 1) and crystallized from hexane to obtain the title compound (99.3 g).

Reference Example A9 Preparation of methyl 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate 10.1 g of 3-amino-6-chloropyridazine was added to methanol 120
The mixture was suspended in 2 ml of methyl 4-chloroacetoacetate, and the mixture was refluxed for 20 hours. After cooling, the mixture was concentrated under reduced pressure, and the residue was adjusted to pH 7 with an aqueous sodium hydrogen carbonate solution and extracted with ethyl ether. 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 hexane: ethyl acetate (1: 4). The desired fractions were collected to obtain 9.15 g of methyl 6-chloroimidazo [1,2-b] pyridazine-2-acetate. 6-
Methyl chloroimidazo [1,2-b] pyridazine-2-acetate 9.15 g
Was dissolved in 70 ml of N, N-dimethylformamide, 3.5 g of 60% oily sodium hydride was added little by little under ice water while stirring, and the mixture was returned to room temperature and stirred for 30 minutes. Under ice water, 6.3 ml of methyl iodide was added, and the mixture was stirred at room temperature for 5 hours. Ice water was poured, extraction was performed with ethyl acetate, and 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 hexane:
Eluted with ethyl acetate (1: 1). The desired fraction was collected and concentrated to give 14.1 g of the title compound. Melting point: 92-93 ° C Elemental analysis: Calculated for C ₁₁ H ₁₂ N ₃ O ₂ Cl (%): C, 52.08; H, 4.77; N, 16.56 Found (%): C, 52.01; H, 4.60; N, 16.59

Reference Example A10 Preparation of 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionic acid 2- (6-chloroimidazo [1,2-b]
Methyl pyridazin-2-yl) -2-methylpropionate 1.4
0 g was dissolved in tetrahydrofuran (15 ml), 1N aqueous sodium hydroxide solution (9 ml) was added, and the mixture was stirred at room temperature for 3 hours. After concentrating under reduced pressure, the residue was adjusted to pH 4 by adding 1N hydrochloric acid, and the precipitated crystals were collected by filtration to obtain 1.06 g of the title compound. Melting point 159-161 ° C Elemental analysis: Calculated for C ₁₀ H ₁₀ N ₃ O ₂ Cl (%): C, 50.12; H, 4.21; N, 17.53 Found (%): C, 50.36; H, 4.34; N, 17.32 Reference Example A11 Preparation of tert-butyl 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate 2- (6-chloroimidazo [1,2-b 0.863 g of [pyridazin-2-yl) -2-methylpropionic acid was suspended in 10 ml of toluene, and 2.6 ml of N, N-dimethylformamide di-tert-butyl acetal was added, followed by stirring at 80 ° C. for 1 hour. After cooling, the mixture was diluted with ethyl acetate, washed with an aqueous solution of sodium hydrogen carbonate, and dried over magnesium sulfate. After concentrating under reduced pressure, ethyl ether was added to the residue, and the precipitated crystals were collected and dried to give the title compound (0.52 g). ¹ H-NMR (CDCl ₃ ) δ ppm: 1.43 (9H, s), 1.64 (6H, s), 7.02,
7.87 (1H, d, J = 9Hz each), 7.84 (1H, s).

Reference Example A12 Preparation of 6-chloro-2-methoxyimidazo [1,2-b] pyridazine 6-chloro-2-hydroxyimidazo [1,2-b] pyridazine 2.6
9 g was suspended in 30 ml of N, N-dimethylformamide,
Add 838 mg of oily sodium hydride little by little, and add
Stir for 0 minutes. Under ice water, 1.2 ml of methyl iodide was added, and the mixture was stirred at room temperature for 3 days. Ice water was poured, extraction was performed with ethyl acetate, and 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 hexane: ethyl acetate (5: 1). The desired fractions are collected and concentrated to give the title compound 1.05 g
I got Melting point: 134-136 ° C Elemental analysis: Calculated as C ₇ H ₆ N ₃ OCl (%): C, 45.79; H, 3.29; N, 22.89 Found (%): C, 45.68; H, 3.27; N, 22.79 Reference Example A13 Preparation of 4- (diphenylmethoxy) -1-piperidinepentanamine 3.70 g of potassium phthalimide was dissolved in 20 ml of N, N-dimethylformamide, 5.4 ml of 1,5-dibromopentane was added, and the mixture was stirred at room temperature for 15 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 hexane-ethyl acetate (4: 1). The desired fractions were collected to give 4.68 g of N- (5-bromopentyl) phthalimide as an oil. Dissolve 4.68 g of N- (5-bromopentyl) phthalimide and 4.25 g of 4- (diphenylmethoxy) piperidine in 30 ml of N, N-dimethylformamide, add 2.42 g of potassium carbonate, and add
Stir for 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 hexane-ethyl acetate-triethylamine (50:
50: 1). Collect the desired fractions and add N- [5- [4
6.67 g of-(diphenylmethoxy) piperidino] pentyl] phthalimide were obtained as an oil. Dissolve 6.6 g of N- [5- [4- (diphenylmethoxy) piperidino] pentyl] phthalimide in 30 ml of ethanol and add 0.694 ml of hydrazine monohydrate.
Was added and the mixture was heated under reflux for 3 hours. After cooling, the mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the precipitated crystals were collected, dissolved in 15 ml of 1N aqueous sodium hydroxide solution and 20 ml of water, extracted with ethyl acetate, and the extract was washed with brine and washed with sodium sulfate. Dried. The crystals obtained by concentration under reduced pressure were collected to obtain 3.29 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.2-2.9 (18H, m), 3.3-3.6 (1H, m),
5.52 (1H, s), 7.1-7.4 (10H, m).

Reference Example A14 Preparation of 1-amino-3- [4- (diphenylmethoxy) piperidino] -2-propanol 3.70 g of potassium phthalimide was dissolved in 20 ml of N, N-dimethylformamide, and 2.58 ml of epibromohydrin was added. And stirred at room temperature for 15 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 concentrating under reduced pressure, ethyl ether was added to the residue, and the precipitated crystals were collected to obtain 3.7 g of N- (2-oxiranylmethoxy) phthalimide. Dissolve 0.61 g of N- (2-oxiranylmethoxy) phthalimide and 0.802 g of 4- (diphenylmethoxy) piperidine in 10 ml of ethanol.
The mixture was refluxed for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate. The desired fraction was collected to give 1.30 g of N- [3- (4-diphenylmethoxy) piperidino-2-hydroxypropyl] phthalimide as an oil. Ethanol
Dissolve in 10 ml and add 0.14 ml of hydrazine monohydrate.
The mixture was refluxed for 3 hours. After cooling, the mixture was concentrated under reduced pressure, and ethanol was added to the residue.The precipitated crystals were collected, dissolved in 1N aqueous sodium hydroxide solution (3 ml) and water (10 ml), extracted with ethyl acetate, and the extract was washed with brine and dried over sodium sulfate. did. The crystals obtained by concentration under reduced pressure were collected to give the title compound
0.76 g was obtained. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.2-3.0 (12H, m), 3.3-3.55 (1H,
m), 3.55-3.8 (1H, m), 5.52 (1H, s), 7.1-7.5 (10H, m).

Reference Example A15 Production of 4- [bis (4-fluorophenyl) methoxy] -1-piperidinepropanamine 25 g of 4,4'-difluorobenzophenone was dissolved in ethanol-tetrahydrofuran (180 ml-60 ml) and hydrogenated under ice cooling. 2.16 g of sodium borohydride was added and stirred at room temperature for 30 minutes. After concentration under reduced pressure, the residue was diluted with ice water and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The oil (29.2 g) obtained by concentration under reduced pressure was dissolved in 800 ml of toluene, and 4-hydroxypiperidine (11.6 g) was dissolved.
g and 23.7 g of p-toluenesulfonic acid monohydrate
Heated to reflux for an hour. After cooling, the mixture was concentrated under reduced pressure, ice water and 130 ml of 1N aqueous sodium hydroxide solution were added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The oil obtained by concentrating under reduced pressure (34.5 g)
Dissolve in 100 ml of N, N-dimethylformamide, 16.3 g of N- (3-bromopropyl) phthalimide and 10.5 g of potassium carbonate
And stirred at room temperature for 20 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 hexane-ethyl acetate (1:
It eluted in 2). Collect the desired fractions and add N- [3- [4-
20.5 g of [bis (4-fluorophenyl) methoxy] piperidino] propyl] phthalimide was obtained as an oil. 20.5 g of this oil was dissolved in 150 ml of ethanol, and 2.02 ml of hydrazine monohydrate was added, followed by heating under reflux for 3 hours. After cooling,
Concentrate under reduced pressure, add ethanol to the residue, collect the precipitated crystals, dissolve in 40 ml of 1N aqueous sodium hydroxide solution, extract with ethyl acetate-tetrahydrofuran (2: 1), wash the extract with brine, and add sodium sulfate. Dried. Concentration under reduced pressure gave 12.07 g of the title compound as an oil. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.5-2.2 (10H, m), 2.36 (2H, d, J = 7H
z), 2.74 (2H, d, J = 7Hz), 3.3-3.5 (1H, m), 5.47 (1H, s), 6.
9-7.4 (8H, m).

Reference Example A16 Production of 4- [bis (4-methylphenyl) methoxy] -1-piperidinepropanamine 25 g of 4,4'-dimethylbenzophenone was dissolved in ethanol-tetrahydrofuran (180 ml-60 ml) and hydrogenated under ice cooling. 2.23 g of sodium borohydride was added and the mixture was stirred at room temperature for 24 hours. The crystals precipitated by adding ice water to the residue after concentration under reduced pressure were collected and dried, and the obtained crystals (30.5 g) were treated with 800 ml of toluene.
Then, 11.9 g of 4-hydroxypiperidine and 24.9 g of p-toluenesulfonic acid monohydrate were added, and the mixture was heated under reflux for 3 hours. After cooling, concentrate under reduced pressure and add ice water (100 ml) and 1N
An aqueous sodium hydroxide solution (140 ml) was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and ethyl acetate-methanol-triethylamine (9
0: 10: 1). Collect the desired fractions 4-
32.8 g of [bis (4-methylphenyl) methoxy] piperidine was obtained as an oil. 16.4 g of 4- [bis (4-methylphenyl) methoxy] piperidine in N, N-dimethylformamide 100 m
l, and N- (3-bromopropyl) phthalimide 14.2g
And 8.15 g of potassium carbonate, and the mixture was stirred at room temperature for 16 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 hexane-ethyl acetate (1: 2). The desired fractions were collected to obtain 21.2 g of N- [3- [4- [bis (4-methylphenyl) methoxy] piperidino] propyl] phthalimide as an oil. 20.5 g of this oil was dissolved in 150 ml of ethanol, 2.18 ml of hydrazine monohydrate was added, and the mixture was heated under reflux for 3 hours. After cooling, the mixture was concentrated under reduced pressure, ethanol was added to the residue, and the precipitated crystals were collected and dissolved in 40 ml of 1N aqueous sodium hydroxide solution.
The extract was extracted in 1), and the extract was washed with brine and dried over sodium sulfate. Concentration under reduced pressure gave 10.5 g of the title compound as an oil. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.4-2.9 (14H, m), 2.31 (6H, s), 3.
3-3.50 (1H, m), 5.46 (1H, s), 7.11, 7.22 (each 4H, d, J = 8
Hz).

Reference Example A17 N- (6-chloroimidazo [1,2-b] pyridazine-2-carbonyl)
Preparation of glycine ethyl ester 6-chloroimidazo [1,2-b] pyridazine-2-carboxylic acid 0.5
93 g of N, N-dimethylformamide was suspended in 7.5 ml of N, N-dimethylformamide.
0.535 g of N'-carbonyldiimidazole and 0.46 g of glycine ethyl ester hydrochloride were added, and the mixture was stirred at room temperature for 30 minutes. Add 0.457 ml of triethylamine and add 1 more
Stir for hours. Ice water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water and dried to give the title compound 0.749.
g. Melting point 190-191 ° C Elemental analysis: Calculated as C ₁₁ H ₁₁ N ₄ O ₃ Cl (%): C, 46.74; H, 3.92; N, 19.82 Found (%): C, 46.70; H, 4.03; N, 19.75 Reference Example A18 Preparation of 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionamide 2- (6-chloroimidazo [1,2-b] pyridazine- 1.20 g of 2-yl) -2-methylpropionic acid to N, N-dimethylformamide
Dissolve in 8 ml and add N, N'-carbonyldiimidazole 0.892
g was added and stirred at room temperature for 30 minutes. Thereto, 0.321 g of ammonium chloride and 0.832 ml of triethylamine were added under ice cooling, and the mixture was stirred at room temperature for 3 hours. Ice water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water and dried to obtain 0.697 g of the title compound. Melting point 194-195 ° C Elemental analysis: Calculated as C ₁₀ H ₁₁ N ₄ OCl (%): C, 50.32; H, 4.65; N, 23.47 Found (%): C, 50.34; H, 4.60; N, 23.43

Reference Example A19 2- (6-Chloroimidazo [1,2-b] pyridazin-2-yl) -N, N, 2
Preparation of -trimethylpropionamide Dissolve 0.959 g of 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionic acid in 6 ml of N, N-dimethylformamide, Carbonyldiimidazole 0.7
14 g was added and stirred at room temperature for 60 minutes. Then, under ice cooling, 0.392 g of dimethylamine hydrochloride and 0.665 of triethylamine
The mixture was added and stirred at room temperature for 3 hours. Brine 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). The desired fraction was collected and concentrated, and the resulting crystals were collected by filtration to give the title compound 0.608 g
I got Melting point: 149-151 ° C Elemental analysis: Calculated as C ₁₂ H ₁₅ N ₄ OCl (%): C, 54.04; H, 5.67; N, 21.01 Found (%): C, 53.90; H, 5.85; N, 21.04 Reference Example A20 Preparation of 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropanol 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl 0.719 g of 2-methylpropionic acid in 15 ml of tetrahydrofuran
, And 0.535 g of N, N'-carbonyldiimidazole was added thereto, followed by stirring at room temperature for 60 minutes. Thereto was added 1.15 g of tetra-n-butylammonium borohydride under ice cooling, and the mixture was stirred at room temperature for 1 hour. 2 ml of 5N hydrochloric acid was added to the reaction solution, and the mixture was concentrated under reduced pressure. Aqueous sodium bicarbonate was added to the residue to adjust the pH to 7, followed by extraction 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. The desired fraction was collected and concentrated, and the resulting crystals were collected by filtration to give 0.488 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.39 (6H, s), 3.72 (2H, s), 7.04,
7.82 (each 1H, d, J = 9.5Hz), 7.76 (1H, s).

Reference Example A21 N- (6-chloroimidazo [1,2-b] pyridazine-2-carbonyl)
Preparation of -2,2-dimethylglycine ethyl ester 6-chloroimidazo [1,2-b] pyridazine-2-carboxylic acid 1.2
8 g was suspended in 12 ml of N, N-dimethylformamide, and N, N '
1.16 g of -carbonyldiimidazole was added, and the mixture was stirred at room temperature for 30 minutes. 1.20 g of 2-aminoisobutyric acid ethyl ester hydrochloride and 1.00 ml of triethylamine were added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. Water was added, and the precipitated crystals were collected by filtration, the filtrate was extracted with ethyl acetate, and the extract was washed with brine and dried over magnesium sulfate. Concentrate under reduced pressure,
The crystals were combined with the filtered crystals and subjected to silica gel column chromatography, and eluted with hexane: ethyl acetate (2: 1). The desired fraction was collected and concentrated under reduced pressure to obtain 1.20 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.28 (3H, t, J = 7.2 Hz), 1.70 (6H,
s), 4.25 (2H, q, J = 7.0 Hz), 7.13 (1H, d, J = 9.4 Hz), 7.87 (1
H, brs), 7.89 (1H, d, J = 9.6Hz), 8.41 (1H, s). Reference Example A22 2- (3,6-dichloroimidazo [1,2-b] pyridazin-2-yl)- Two
Preparation of ethyl 2-methylpropionate 4.07 g of ethyl 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate is suspended in 60 ml of ethyl acetate, and N-chlorosuccinimide 2.13 g was added, and the mixture was heated under reflux for 4 hours. After cooling, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with hexane: ethyl acetate (5: 1). The desired fractions were collected and concentrated under reduced pressure to obtain 4.48 g of the title compound. Melting point 66-67 ° C Elemental analysis: C ₁₂ H ₁₃ N ₃ O ₂ Cl ₂ Calculated (%): C, 47.70; H, 4.34; N, 13.91 Found (%): C, 47.67; H, 4.23 ; N, 13.93

Reference Example A23 Production of methyl 2- (6-chloro-7-methylimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate Step A: 6-chloro-7-methylimidazo [1,2-b] pyridazine-2
-Preparation of methyl acetate Suspend 15.3 g of 6-amino-3-chloro-4-methylpyridazine in 200 ml of methanol
25.0 ml was added and the mixture was heated under reflux for 36 hours. After cooling, the mixture was concentrated under reduced pressure.
And extracted with ethyl acetate, and the extract was washed with saline,
Dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with hexane: ethyl acetate (1: 4). The desired fractions were collected to give 14.3 g of the title compound. Melting point 98-99 ° C Elemental analysis: Calculated for C ₁₀ H ₁₀ N ₃ O ₂ Cl (%): C, 50.12; H, 4.21; N, 17.53 Found (%): C, 50.07; H, 4.25; N, 17.74 Step B: Suspend 4.8 g of 60% oily sodium hydride in 150 ml of N, N-dimethylformamide, and stir under ice water while stirring 6-chloro-7-methylimidazo [1,2-b] pyridazine-2- Add 11.4 g of methyl acetate little by little, return to room temperature, and add
Stir for a minute. 7.5 ml of methyl iodide was added under ice water, and the mixture was stirred at room temperature for 6 hours. Ice water was poured, extraction was performed with ethyl acetate, and 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 hexane: ethyl acetate (1: 1). Collect the desired fractions and concentrate to give 9.17 g of the title compound
I got Melting point 109-110 ° C Elemental analysis: C ₁₂ H ₁₄ N ₃ O ₂ Cl Calculated (%): C, 53.84; H, 5.27; N, 15.70 Found (%): C, 53.96; H, 5.19; N, 15.86

Reference Example A24 Production of isopropyl 1- (6-chloroimidazo [1,2-b] pyridazin-2-yl) cyclopentanecarboxylate Step A: 1- (6-chloroimidazo [1,2-b] Preparation of methyl pyridazin-2-yl) cyclopentanecarboxylate Methyl 6-chloroimidazo [1,2-b] pyridazine-2-acetate 5.4
8 g was dissolved in 42 ml of N, N-dimethylformamide, and while stirring under ice cooling, 1.07 g of 60% oily sodium hydride was added little by little, and the mixture was returned to room temperature and stirred for 1.5 hours.
Under ice cooling, 3.19 ml of 1,4-dibromobutane was added dropwise, and the mixture was stirred at room temperature for 18 hours. Ice water was poured, extracted with ethyl acetate, and the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: hexane (1: 3).
The desired fraction was collected and concentrated under reduced pressure to give 1.72 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.63-1.85 (4H, m), 2.10-2.38 (2H,
m), 2.42-2.68 (2H, m), 3.69 (3H, s), 7.02 (1H, d, J = 9.4Hz),
7.84 (1H, s), 7.86 (1H, d, J = 8.6Hz). Step B: Dissolve 0.81ml of concentrated sulfuric acid in 30ml of 2-propanol and add 1- (6-chloroimidazo [1,2-b] pyridazine 1.7 g of methyl 2--2-yl) cyclopentanecarboxylate was added, and the mixture was heated under reflux for 7.5 hours. After cooling, the mixture was concentrated under reduced pressure, neutralized by adding aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. Concentrate under reduced pressure,
The precipitated crystals were collected by filtration, washed with hexane, and dried to give 1.30 g of the title compound. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, and eluted with hexane: ethyl acetate (3: 1). The desired fraction was collected, concentrated under reduced pressure, and dried to obtain 356 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.18 (3H, s), 1.21 (3H, s), 1.68-
1.85 (4H, m), 2.13-2.32 (2H, m), 2.45-2.60 (2H, m), 4.94
-5.13 (1H, m), 7.02 (1H, d, J = 9.6Hz), 7.83 (1H, s), 7.86
(1H, d, J = 9.4Hz).

Reference Example A25 Production of isopropyl 1- (6-chloroimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxylate Step A: 1- (6-Chloroimidazo [1,2-b] (Pyridazin-2-yl)
Preparation of methyl cyclopropanecarboxylate Methyl 6-chloroimidazo [1,2-b] pyridazine-2-acetate 5.9
3 g was dissolved in N, N-dimethylformamide (45 ml), and while stirring under ice-cooling, 2.31 g of 60% oily sodium hydride was added little by little, and the mixture was returned to room temperature and stirred for 40 minutes. Under ice-cooling, 2.49 ml of 1,2-dibromoethane was added dropwise at room temperature.
Stir for 14 hours. Pour ice water, extract 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 hexane: ethyl acetate (2: 1). The desired fractions are collected and concentrated under reduced pressure to give the title compound
3.67 g was obtained. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.60-1.68 (2H, m), 1.70-1.85 (2H,
m), 3.75 (3H, s), 7.00 (1H, d, J = 9.6Hz), 7.77 (1H, d, J = 9.
Step B: Dissolve 1.82 ml of concentrated sulfuric acid in 70 ml of 2-propanol to give 1- (6-chloroimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxylic acid 3.44 g of methyl was added, and the mixture was heated under reflux for 7.5 hours. After cooling, the mixture was concentrated under reduced pressure, neutralized by adding aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. Concentrate under reduced pressure,
The precipitated crystals were collected by filtration, washed with ether and hexane, and dried to give 1.98 g of the title compound. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, and eluted with hexane: ethyl acetate (5: 1). The desired fractions are collected, concentrated under reduced pressure, dried and 650 mg of the title compound
I got Melting point: 112-114 ° C Elemental analysis: Calculated for C ₁₃ H ₁₄ N ₃ O ₂ Cl (%): C, 55.82; H, 5.04; N, 15.02 Found (%): C, 55.75; H, 5.17; N, 14.99

Reference Example A26 Production of ethyl 2- (6-chloro-3-methylimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate Step A: 6-chloro-3-methylimidazo [1,2-b] pyridazine-2
-Ethyl acetate 3-amino-6-chloropyridazine 2.44g in ethanol 37m
l-ethyl 4-bromo-3-oxopentanoate 8.40
g was added and the mixture was heated under reflux for 18 hours. After cooling, the mixture was concentrated under reduced pressure, the pH of the residue was adjusted to 7 by adding aqueous sodium hydrogencarbonate, ethyl ether was added, and the precipitate was collected by filtration. Extract with ethyl ether,
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 hexane: ethyl acetate (1: 1). The desired fractions were collected to give 2.63 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.27 (3H, t, J = 7.1 Hz), 2.54 (3H,
s), 3.85 (2H, s), 4.19 (2H, q, J = 7.1Hz), 6.99 (1H, d, J = 9.
6Hz), 7.82 (1H, d, J = 9.6Hz). Step B: 6-chloro-3-methylimidazo [1,2-b] pyridazine-2
-5.41 g of ethyl acetate in 40 ml of N, N-dimethylformamide
And add 1.87 g of 60% oily sodium hydride little by little while stirring under ice-cooling.
Stir for a minute. Under ice cooling, 3.32 ml of methyl iodide was added, and the mixture was stirred at room temperature for 15 hours. Ice water was poured, extracted with ethyl acetate, and the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with hexane: ethyl acetate (3: 1). The desired fraction was collected and concentrated under reduced pressure to obtain 2.69 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.21 (3H, t, J =
7.2 Hz), 1.69 (6H, s), 2.48
(3H, s), 4.47 (2H, q, J = 7.2H
z), 7.21 (1H, d, J = 9.6 Hz),
7.88 (1H, d, J = 9.6 Hz).

Reference Example A27 Ethyl 6-chloro-2-methylimidazo [1,2-b] pyridazine-3-carboxylate 12.9 g of 3-amino-6-chloropyridazine was added to ethanol 250
suspended in 1 ml of ethyl 2-chloro-3-oxobutanoate 18.1 g
Was added and the mixture was heated under reflux for 6 hours. After cooling, the mixture was concentrated under reduced pressure, the pH of the residue was adjusted to 7 by adding aqueous sodium hydrogencarbonate, ethyl ether was added, and the precipitate was collected by filtration. The mixture was extracted with ethyl ether, and the extract was washed with saturated saline and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, ethanol-1N aqueous sodium hydroxide solution (1: 1) was added, and the precipitated crystals were collected by filtration, and the filtrate was concentrated again. The residue was crystallized by adding ethyl acetate,
Filtration and collection gave 3.09 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.45 (3H, t, J = 7.2 Hz), 2.74 (3H,
s), 4.18 (2H, q, J = 7.2Hz), 6.97 (1H, d, J = 9.4Hz), 7.85 (1H
Reference Example A28 Production of N- (6-chloro [1,2,4] triazolo [1,5-b] pyridazine-2-carbonyl) glycine ethyl ester 6-chloro [1 , 2,4] Triazolo [1,5-b] pyridazine-2-carboxylic acid 2.86 g and N-ethyldiisopropylamine 2.72 ml
Was suspended in 30 ml of N, N-dimethylformamide, and N, N'-
2.63 g of carbonyldiimidazole was added, and the mixture was stirred at room temperature for 1 hour. Glycine ethyl ester hydrochloride was added to the reaction mixture.
2.21 g was added, and the mixture was stirred at room temperature for 5 hours. Water was added, and the precipitated crystals were collected by filtration, washed with water and ether, and dried to give 2.93 g of the title compound. Mp 175-177 ° C. Elemental _{analysis: C 10 H 10 N 5 O} 3 Calculated Cl (%): C, 42.34 ; H, 3.55; N, 24.69 Found (%): C, 42.40; H, 3.56; N, 24.76

Reference Example A29 Preparation of ethyl 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-ethylbutanoate Step A: 4-bromo-2,2-diethyl-3-oxobutane Production of ethyl acetate 11.5 g of ethyl 2,2-diethyl-3-oxobutanoate was added to acetic acid 5
Dissolve in 0 ml, add 1 ml of 25% hydrobromic acid in acetic acid,
Under a water bath, a solution of 3.50 ml of bromine in 10 ml of acetic acid was added dropwise. After stirring at room temperature for 3 hours, the mixture was concentrated under reduced pressure, and the residue was dissolved in hexane, washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. Concentrate under reduced pressure to give the title compound
16.4 g was obtained. ¹ H-NMR (CDCl ₃ ) δ ppm: 0.65-0.90 (6H, m), 1.28 (3H, t, J =
7.2Hz), 1.80-2.15 (4H, m), 4.09 (2H, s), 4.22 (2H, q, J =
Step B: Ethyl 4-bromo-2,2-diethyl-3-oxobutanoate
13.2 g, 3.89 g of 3-amino-6-chloropyridazine, baking soda 5.
76 g was suspended in 33 ml of ethanol and heated under reflux for 1 day. After cooling, water was poured, extracted with diisopropyl ether, and 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 hexane: ethyl acetate (4: 1). Collect the desired fractions and concentrate under reduced pressure to give the title compound.
5.20 g were obtained. Melting point 68-70 ° C Elemental analysis: C ₁₄ H ₁₈ N ₃ O ₂ Cl Calculated (%): C, 55.85; H, 6.13; N, 14.21 Found (%): C, 55.86; H, 6.07; N, 13.99

Reference Example A30 Production of 4- (diphenylmethylamino) -1-piperidinepropanamine Step A: N- [3- [4- (diphenylaminomethyl) piperidino]
Preparation of propyl] phthalimide 7.38 g of N- (3-bromopropyl) phthalimide and 7.07 g of 4- (diphenylmethylamino) piperidine are dissolved in 80 ml of N, N-dimethylformamide, and 4.04 g of potassium carbonate is added, followed by 17 hours at room temperature. I stirred it. 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 hexane-ethyl acetate-triethylamine (50: 50: 2). The desired fractions were collected and concentrated under reduced pressure to obtain 9.65 g of the title compound as an oil. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.08-1.30 (2H, m), 1.42-1.64 (2H,
m), 1.74-1.92 (4H, m), 2.25-2.42 (1H, m), 2.34 (2H, t, J =
7.2Hz), 2.65-2.83 (2H, m), 3.73 (2H, t, J = 6.9Hz), 4.96
(1H, s), 7.12-7.40 (10H, m), 7.65-7.73 (2H, m), 7.78-7.
88 (2H, m). Step B: N- [3- [4- (diphenylaminomethyl) piperidino]
9.65 g of propyl] phthalimide was dissolved in 40 ml of ethanol, and 1.08 ml of hydrazine monohydrate was added, followed by heating under reflux for 3.5 hours. After cooling, diisopropyl ether was added to the reaction solution, and the precipitated crystals were collected, washed with diisopropyl ether, dissolved in 1N aqueous sodium hydroxide solution (45 ml), tetrahydrofuran (20 ml), water (20 ml), and extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over sodium sulfate. The mixture was concentrated under reduced pressure to obtain 4.02 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.23-1.67 (4H, m), 1.82-1.98 (4H,
m), 2.29-2.36 (2H, m), 2.32-2.52 (1H, m), 3.73 (2H, t, J =
7.4Hz), 2.71 (2H, d, J = 6.8Hz), 2.73-2.9. (2H, brm), 5.0
2 (1H, s), 7.10-7.57 (10H, m).

Reference Example A31 Preparation of N- (3,6-dichloroimidazo [1,2-b] pyridazine-2-carbonyl) glycine ethyl ester N- (6-chloroimidazo [1,2-b] pyridazine-2 -Carbonyl)
0.86 g of glycine ethyl ester was suspended in 30 ml of ethyl acetate, 1.2 g of N-chlorosuccinimide was added, and the mixture was heated under reflux for 20 hours. After cooling, 30 ml of tetrahydrofuran was added, and the mixture was washed with an aqueous solution of sodium thiosulfate and brine, and dried over magnesium sulfate. After concentration under reduced pressure, ethyl ether was added to the residue, and the precipitated crystals were collected by filtration, washed with ethyl ether, and dried to give the title compound (0.552 g). ¹ H-NMR (CDCl ₃ ) δ ppm: 1.32 (3H, t, J = 7.2 Hz), 4.27 (2H, d,
J = 5.6Hz), 4.27 (2H, q, J = 7.2Hz), 7.21,7.91 (each 1H, d,
J = 9.6 Hz), 7.82 (1H, t, J = 5.6 Hz). Reference Example A32 N- (6-chloroimidazo [1,2-b] pyridazine-2-carbonyl)
Preparation of β-alanine ethyl ester 6-chloroimidazo [1,2-b] pyridazine-2-carboxylic acid 1.9
8 g was suspended in 25 ml of N, N-dimethylformamide, and N, N '
1.78 g of -carbonyldiimidazole was added, and the mixture was stirred at room temperature for 1 hour. Thereto was added 1.69 g of β-alanine ethyl ester hydrochloride and 1.53 ml of triethylamine, and the mixture was further stirred for 3 hours. Ice water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water and dried to give 2.57 g of the title compound.
I got Melting point 132-134 ° C Elemental analysis: Calculated for C ₁₂ H ₁₃ N ₄ O ₃ Cl (%): C, 48.58; H, 4.42; N, 18.88 Found (%): C, 48.43; H, 4.33; N, 18.68

Reference Example A33 Preparation of ethyl 6-chloro-3-methylimidazo [1,2-b] pyridazine-2-carboxylate 5.83 g of 3-amino-6-chloropyridazine was added to 70 ml of ethanol.
l-methyl 3-bromo-2-oxobutyrate 9.75 g and N-
Ethyldiisopropylamine (8.6 ml) was added, and the mixture was heated under reflux for 5 hours. After cooling, the mixture was concentrated under reduced pressure, and the residue was adjusted to pH 7 with an aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate-tetrahydrofuran (1: 1), and the extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, ethyl acetate was added to the residue, and the precipitated crystals were collected, washed with ethyl acetate, and dried to give 3.90 g of the title compound. Mp 170-171 ° C. Elemental _{analysis: C 10 H 10 N 3 O} 2 Calculated Cl (%): C, 50.12 ; H, 4.21; N, 17.53 Found (%): C, 50.28; H, 4.18; N, 17.23 Reference Example A34 Production of N- (6-chloro-3-methylimidazo [1,2-b] pyridazine-2-carbonyl) glycine ethyl ester 6-chloro-3-methylimidazo [1,2-b] 3.9 g of ethyl pyridazine-2-carboxylate was suspended in 40 ml of tetrahydrofuran, and 30 ml of a 1N aqueous sodium hydroxide solution was added thereto.
Stir for 3 hours. Concentrate under reduced pressure and add 50 ml of water to the residue.
Crystals precipitated by adding 1N hydrochloric acid to pH 4 were collected by filtration and dried to obtain 2.55 g of 6-chloro-3-methylimidazo [1,2-b] pyridazine-2-carboxylic acid. This carboxylic acid
Dissolve 1.27g in N, N-dimethylformamide 20ml,
Add 1.07 g of N, N'-carbonyldiimidazole and add
Stir for 30 minutes. Then add 0.922 g of glycine ethyl ester hydrochloride and 0.915 ml of triethylamine and add 3 more.
Stir for hours. 60 ml of ice water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water and dried to give the title compound.
1.18 g was obtained. Melting point 192-195 ° C Elemental analysis: Calculated as C ₁₂ H ₁₃ N ₄ O ₃ Cl (%): C, 48.58; H, 4.42; N, 18.88 Found (%): C, 48.65; H, 4.13; N, 18.93

Reference Example A35 Preparation of 6-chloro-2-isopropylimidazo [1,2-b] pyridazine 3-methyl-2-butanone (5.17 g) in methanol (60 mL)
Bromine (3.1 mL) was added to the solution under ice cooling, and the mixture was stirred for 45 minutes. Water (30 mL) was added thereto, and the mixture was stirred at room temperature for 30 minutes. Water and hexane were added to this mixture, the organic layer was separated, and the aqueous layer was extracted with hexane. The combined organic layer was washed with water and a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Dissolve the residue in ethanol (20 mL) and add 3-amino-6-chloropyridazine
(5.18 g) and sodium bicarbonate (6.30 g)
The mixture was refluxed for 3 hours. Water and ethyl acetate were added to the reaction mixture, the insolubles were filtered, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, treated with activated carbon, filtered, and concentrated under reduced pressure. The residue was suspended in ethyl acetate, insolubles were filtered and concentrated under reduced pressure. The residue was subjected to a column chromatography on a silica gel (hexane: ethyl acetate 3: 1), and recrystallized from hexane to obtain the title compound (1.37 g). Melting point 106-108 ° C Elemental analysis: Calculated as C ₉ H ₁₀ N ₃ Cl (%): C, 55.25; H, 5.15; N, 21.48; Cl, 18.12 Actual (%): C, 55.35; H, 5.10; N, 21.50; Cl, 18.03 Reference Example A36 Production of isopropyl 6-chloro [1,2,4] triazolo [1,5-b] pyridazine-2-carboxylate 6-chloro [1,2,4] triazolo [1,5-b] pyridazine-2-carboxylic acid 2.14 g and N-ethyldiisopropylamine 5.57 ml
Was dissolved in 30 ml of N, N-dimethylformamide, and 3.23 ml of isopropyl iodide was added.
Stir for hours. After cooling, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected and concentrated under reduced pressure to obtain 2.21 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.46 (3H, s), 1.49 (3H, s), 5.33-
5.53 (1H, m), 7.52 (1H, d, J = 9.6Hz), 8.19 (1H, d, J = 9.6H
z).

Reference Example A37 Preparation of N- (6-chloro [1,2,4] triazolo [1,5-b] pyridazine-2-carbonyl) -2,2-dimethylglycine ethyl ester 6-chloro [1,2 2,4] Triazolo [1,5-b] pyridazine-2-carboxylic acid 1.52g and N-ethyldiisopropylamine 1.45ml
Was suspended in 15 ml of N, N-dimethylformamide, and N, N'-
1.37 g of carbonyldiimidazole was added, and the mixture was stirred at room temperature for 3 hours. 1.41 g of 2-aminoisobutyric acid ethyl ester hydrochloride was added to the reaction solution, and the mixture was stirred at room temperature for 4 hours. Add water and extract with ethyl acetate-tetrahydrofuran (1: 1),
The extract was washed with brine and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the precipitated crystals were washed with ethyl ether, collected by filtration, and dried to obtain 1.48 g of the title compound. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate. The desired fractions were collected and concentrated under reduced pressure to obtain 450 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.29 (3H, t, J = 7.1 Hz), 1.73 (6H,
s), 4.26 (2H, q, J = 7.2Hz), 7.52 (1H, d, J = 9.4Hz), 7.94 (1H
H, brs), 8.16 (1H, d, J = 9.4Hz). Reference Example A38 Preparation of isopropyl 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate Isopropanol Dissolve 995mg of concentrated sulfuric acid in 18ml and add 2
1.0 g of methyl-(6-chloroimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate was added, and the mixture was heated under reflux for 40 hours. After cooling, the mixture was concentrated under reduced pressure, neutralized by adding aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. Concentrate under reduced pressure, collect the precipitated crystals, wash with hexane, and dry to give the title compound (794 mg).
I got The filtrate was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with hexane: ethyl acetate (5: 1). The desired fractions were collected and dried to give 215 mg of the title compound. Melting point 100-101 ° C Elemental analysis: Calculated as C ₁₃ H ₁₆ N ₃ O ₂ Cl (%): C, 55.42; H, 5.72; N, 14.91 Found (%): C, 55.46; H, 5.53; N, 14.94

Reference Example B133 Ethyl 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate Disuccinic acid Preparation of salt Ethyl 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate synthesized in Reference Example B40 0.278g
Was dissolved in ethanol (1 mL), succinic acid (0.118 g) was added to the solution, and the mixture was concentrated under reduced pressure. To the residue was added 0.5 mL of tetrahydrofuran to dissolve, 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 ° C (decomposition) Elemental analysis: Calculated as C ₄₁ H ₅₃ N ₅ O _{11 1/3} CH ₃ CO ₂ C ₂ H ₅ (%): C, 61.92; H, 6.83; N, 8.53 Value (%): C, 61.54; H, 6.83; N, 8.50

Reference Example B134 Ethyl 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionate Citrate Preparation of (1: 1) 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-synthesized in Reference Example B40 1.667 g of ethyl methyl propionate
Was dissolved in 8 mL of ethanol, and citric acid monohydrate 0.631 g
Was added and dissolved by heating, 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. Methanol 3
0 mL was added and dissolved by heating, and concentrated under reduced pressure. Ethanol (30 mL) was added to the residue to dissolve it. After standing, the precipitated crystals were collected by filtration, washed with ethanol (10 mL), and dried to give the title compound (2.01 g). Melting point: 176 ° C (decomposition) Elemental analysis: Calculated as C ₃₉ H ₄₉ N ₅ O ₁₀ (%): C, 62.64; H, 6.60; N, 9.36 N, 9.43

Reference Example B135 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid dihydrate Method 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, heated in an oil bath (bath temperature 165-170 ° C.) while passing nitrogen gas, and stirred for 3.5 hours.
After cooling to room temperature, 2000 mL of ethyl acetate and 2000 mL of water were added to carry out liquid separation. The organic layer was washed twice with 1000 mL of water, and the organic layer was concentrated under reduced pressure. 1000 mL of ethanol was added to the residue, and the mixture was concentrated under reduced pressure to give crude 2- [6- [3- [4- (diphenylmethoxy) dibenzylidino] propylamino] imidazo [1,2-b] pyridazine-
588 g of ethyl 2-yl] -2-methylpropionate was obtained as an oil. Dissolve this oil in 1400 mL of ethanol,
59.8 g (1490 mmol) of sodium hydroxide was dissolved in 600 mL of water 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 and the residue was
L and 2,000 mL of ethyl acetate were added to carry out liquid separation. The aqueous layer is washed twice with 1000 mL of ethyl acetate, and the aqueous layer is
L was added. The crystals precipitated by adding 1000 mL of 1N hydrochloric acid to about pH 6 were collected by filtration, washed with 800 mL of water 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%. To 353.6 g of the crude title compound obtained here was added 1240 mL of ethanol, 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 washed with water 2000
The suspension was stirred in a water bath (inner temperature 65-70 ° C) for 1 hour while heating. Cool to room temperature, collect the precipitated crystals by filtration, wash with 1000 mL of water, and dry to obtain 276 g of the title compound.
I got 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 Found (%): C, 66.35; H, 7.29; N, 12.39 Results of powder X-ray diffraction analysis D-plane spacing, Angstrom intensity I / I ₀ (%) 6.94 84 12.88 41 13.72 62 15.10 53 17.56 84 18.70 39 19.24 62 20.66 60 21.06 100 21.76 54 26.42 43 28.24 37

Reference Example B136 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid (anhydride) 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid obtained in Reference Example B135 3.20 g dihydrate
(5.67 mmol) was dissolved in 500 mL of ethanol by heating, and concentrated under normal pressure until the total volume became 250 mL. The crystals precipitated by standing at room temperature were collected by filtration, washed with ethanol, and dried to obtain 2.67 g of the title compound. Melting point 205-206 ° C (decomposition) Elemental analysis: C ₃₁ H ₃₇ N ₅ O ₃ Calculated (%): C, 70.56; H, 7.07; N, 13.27 Found (%): C, 70.42; H, 6.89; N, 13.32 Results of powder X-ray diffraction analysis D-plane spacing, Angstrom intensity I / I ₀ (%) 3.20 32 3.48 100 11.62 30 15.46 35 16.60 37 17.56 33 18.46 72 19.26 33 20.12 30 20.58 38 23.38 32 23.40 33

Reference Example B137 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid dihydrate 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid obtained in Reference Example B136 (Anhydrous) 0.25
0 g was suspended in 10 mL of water and stirred in a water bath (bath temperature: 80 ° C) for 3 hours. After cooling to room temperature, the precipitated crystals were collected by filtration, washed with water, and dried to obtain 0.233 g of the title compound. 2- [6- [3- [4- (diphenylmethoxy)
Piperidino] propylamino] imidazo [1,2-b] pyridazin-2-yl] -2-methylpropionic acid dihydrate is Reference Example B
135, melting point, elemental analysis, powder X
Since the data such as the line diffraction analysis coincided with each other, they were determined to be the same compound.

Reference Example B138 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] -3-methylimidazo [1,2-b] pyridazin-2-yl]-
Production of 2-methylpropionic acid 4- (diphenylmethoxy) -1-piperidinepropanamine
17.0 g and 7.39 g of ethyl 2- (6-chloro-3-methylimidazo [1,2-b] pyridazin-2-yl) -2-methylpropionate
Dissolve in 25 mL of N-methyl-2-pyrrolidinone and at 160 ° C. 8.
Stir for 5 hours. After cooling, an aqueous layer 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, and eluted with ethyl acetate: methanol: triethylamine (50: 5: 1). The desired fractions are collected and concentrated 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. Add 10.4 g of this oil to 100 mL of ethanol
And 18.3 mL of a 5N aqueous sodium hydroxide solution was added thereto, 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 obtain 4.09 g of the title compound. Melting point 219-220 ° C Elemental analysis: Calculated as C ₃₂ H ₃₉ N ₅ O ₃ (%): C, 70.95; H, 7.26; N, 12.93 Found (%): C, 70.85; H, 7.00; N , 13.20

Experimental Example 1 Effect on Histamine-Induced Cutaneous Vascular Hyperpermeability in Guinea Pig Male (Hartley) Hartley guinea pigs (body weight: about 500 g) were used. After shaving the back hair using an electric clipper under diethyl ether anesthesia, 1 ml of 2.5% pontamine sky blue solution is intravenously administered, and immediately into the skin at two places on the left and right of the back.
0.1 ml of a 3 μg / ml histamine solution was administered.
Thirty minutes later the animals were stunned by beating on the head, then the neck was cut off and sacrificed by exsanguination. The back was peeled off, the major axis and minor axis (mm) of each blue spot were measured, the product was determined, and the average value of the products was defined as the vascular permeability index. Each drug was suspended in 5% gum arabic solution and orally administered in a volume of 0.2 ml / 100 g body weight one hour before histamine administration. The animals in the control group received the same volume of 5% gum arabic solution.
The inhibition rate of the subject to the main reaction was calculated according to [Equation 1], and the results are summarized in [Table 1]. [Equation 1] Histamine-induced inhibition of cutaneous vascular hyperpermeability (%) = 100 ×
(1-Vascular permeability index at drug administration / Vascular permeability index of control group)

[0210]

[Table 1]

Experimental Example 2 1) Preparation of guinea pig eosinophils Horse serum (Bio-Whittaker, I) was added to Hartley male guinea pigs.
nc.) 2 ml was intraperitoneally administered once a week for 8 consecutive weeks. 48 hours after the last administration, 75 ml of physiological saline was intraperitoneally injected,
The recovered solution was centrifuged at 400 × g for 5 minutes. The sediment is called Per
coll solution (specific gravity d = 1.07) suspended in 5ml, Percoll specific gravity discontinuous layer (specific gravity d = 1.112,5ml; d = 1.095,10ml; 1.090,10ml; d = 1.0
85,5 ml) and centrifuged at 1000 × g for 25 minutes (20 ° C.).
The cell layer formed at the interface having a specific gravity of d = 1.112 and d = 1.095 was collected. Erythrocytes mixed into the collected cell sediment were removed by hypotonic treatment (suspension in water for 30 minutes). Wash 3 times with Hanks solution (Hanks-Hepes) containing 10 mM Hepes (Dojindo Chemical), 2%
Han with human serum albumin (Wako Pure Chemical Industries or Sigma)
Suspend in ks-Hepes solution (Hanks-Hepes-HSA), 5.56 × 10 ⁶ cel
adjusted to ls / ml. The eosinophil purity is 90%,
Its viability was over 98%. 2) Inhibition of chemotaxis reaction In a 24-well culture dish in the lower chamber, LT dissolved in Hanks-Hepes-HSA solution
B ₄ (final concentration ^{10 -8 M, Cascade Biochemical Ltd.)} 600μl
And kept at 37 ° C. for 30 minutes in a carbon dioxide gas incubator. In addition, 200 μl of eosinophil suspension (5 × 10 ⁶ cells / ml) incubated in a thermostat at 37 ° C. for 15 minutes was placed in a 24-well culture dish in Chemotaxicell (Polycarbonate membrane, po
resize 3 μm, thickness 10 μm) and then added to the upper chamber. After reacting for 2 hours in a carbon dioxide gas incubator, Che
The motaxicell was removed, and 60 μl of a 2% (W / V) EDTA physiological saline solution was added to the lower room liquid. After cooling on ice, the number of cells that migrated into the lower chamber liquid was counted using a hemocytometer (Coulter Counter (trade name)).
Was measured. The drug was dissolved in N, N-dimethylformamide and added to both the lower and upper chambers to a final concentration of 10 ⁻⁵ M. [Equation 2] Inhibition rate of chemotactic reaction = (1−number of migrated cells upon addition of drug /
The inhibition rate against chemotactic reaction by LTB ₄ drugs non-migrated cell number upon addition) × 100 subject (1 × 10 ^-5 M concentration) was determined. The results are shown in [Table 2].

[0212]

[Table 2]

Experimental Example 3 Effects on intranasal pressure and nasal secretion 1) Drug administration Animals were treated with sodium pentobarbital (30 mg / kg, i.p.
p.) Under anesthesia, the compound of Reference Example B135 and a solvent (0.1%
Sodium dihydrogen phosphate + 0.1% Tween 80) was administered to both guinea pigs in a volume of 20 μL in both nasal passages, and about 0.5 hours later, the following test was performed. 2) Measurement of intranasal pressure and nasal secretion The anesthetized animal was held in a dorsal position, a midline incision was made in the neck to expose the trachea, and a polyethylene tube was inserted into the lower part of the trachea to maintain respiration. Further, a polyethylene tube was inserted into the nasopharynx from the tracheal incision, connected to an artificial respirator via a silicone tube, and air was blown into the nasal cavity at a volume of 4 mL / time, at a frequency of 70 times / minute. The incisor tube was closed with Aron alfa A (registered trademark, Sankyo, Tokyo) in order to prevent air leakage into the oral cavity. Intranasal pressure was measured using a transducer connected to the side branch of a tube inserted into the nasal cavity. The histamine 1000 μg / mL solution was aerosolized by an ultrasonic nebulizer connected between the ventilator and the intranasal tube, and was supplied into the nasal cavity for 3 minutes. The nasal pressure for 15 minutes after the end of histamine insufflation was drawn on an oscillograph, and the area under the curve was determined. In addition, the nasal fluid flowing out of the nasal cavity or accumulated in the nasal cavity was wiped off with a cotton swab for 15 minutes after inhalation of histamine, and the weight was measured with an electronic balance. In addition, if necessary, physiological saline was sprayed into the nasal cavity as a negative control, and the intranasal pressure and nasal secretion were measured. 3) Results Table 3 shows the inhibition rate against intranasal pressure increase when nasal administration of 0.1% and 1.0% solutions of Reference Example B135 compound.

[0214]

[Table 3] Reference Example B135 Table 4 shows the inhibition rate against nasal secretion when nasal administration of 0.1% and 1.0% solutions of the compound.

[Table 4] From these results, it was found that the compound of Reference Example B135 reduced the increase in intranasal pressure and the increase in nasal secretion.

Experimental Example 4 Central transferability 1) Measurement method Reference Example B135 The compound was orally administered to male Hartley guinea pigs (10 or 100 mg / kg), and one hour later, the animals were killed by decapitation. The cerebral cortex and lung tissue were excised, homogenized in a phosphate buffer, and then centrifuged at 4 ° C. at 1,000 × g for 10 minutes. The supernatant was further centrifuged at 5,000 × g for 10 minutes to obtain a crude membrane fraction. . The same membrane fraction was suspended in a buffer solution, the protein concentration was adjusted to 1.0 mg / mL, and a binding experiment with tritium-labeled pyrilamine (2 nM) was performed. to calculate the inhibitory effect on pyrilamine specific binding in the membrane fraction of the brain and lungs in ex vivo binding experiments, the drug was used as an index of selectivity to peripheral histamine H ₁ receptor in vivo when administered orally. 2) Results Table 5 shows the inhibition rate when 100 mg / kg of Reference Example B135 compound was orally administered.

[0216]

[Table 5] Table 6 shows the inhibitory rate of 10 mg / kg of Reference Example B135 compound when orally administered.

[Table 6] From these results, it was found that the compound of Reference Example B135 had reduced central mobilization.

Example 1 Reference Example B135 Compound 1.0 mg Active Drug Sodium Hydrogen Phosphate 10 mg Buffer Crystalline Sodium Dihydrogen Phosphate 1.65 mg Buffer Polyvinylpyrrolidone K30 50 mg Solubilizer Concentrated Glycerin 13 mg Isotonic Agent Propyl Paraoxybenzoate 0.35mg Preservatives Butyl paraoxybenzoate 0.1mg Preservatives Sodium hydroxide Appropriate amount pH adjuster Purified water Add 1ml total The above ingredients are mixed to give a nasal drop.

Example 2 Reference Example B136 Compound 1.0 mg Active Substance Sodium Hydrogen Phosphate 10 mg Buffer Sodium Crystalline Dihydrogen Phosphate 1.65 mg Buffer Polyvinylpyrrolidone K30 50 mg Solubilizer Concentrated Glycerin 13 mg Isotonizing Agent Propyl Paraoxybenzoate 0.35mg Preservatives Butyl paraoxybenzoate 0.1mg Preservatives Sodium hydroxide Appropriate amount pH adjuster Purified water Add 1ml total The above ingredients are mixed to give a nasal drop.

Example 3 Reference Example B135 Compound 1.0 mg Base Drug Lactose 7.0 mg Excipient The above ingredients are mixed to give a nasal drop.

Example 4 Reference Example B136 Compound 1.0 mg Active ingredient Lactose 7.0 mg Excipient The above ingredients are mixed to give a nasal drop.

Reference Example C1 Reference Example B135 Compound 0.05 g Active Substance Boric Acid 1.2 g Buffer Sodium L-Glutamate 0.2 g Buffer sodium edetate 0.005 g Stabilizer Dibutylhydroxytoluene 0.005 g Stabilizer Chlorobutanol 0.1g Preservative Benzalkonium chloride (10w / v%) 0.05mL Preservative l-menthol 0.008g Refreshing agent Macrogol 4000 0.4g Solubilizer Sodium hydroxide qs pH adjuster Sterile purified water Add 100 ml The above ingredients are mixed to form eye drops.

Reference Example C2 Reference Example B136 Compound 0.05 g Active Substance Boric Acid 1.2 g Buffer Sodium L-Glutamate 0.2 g Buffer Sodium Edetate 0.005 g Stabilizer Dibutylhydroxytoluene 0.005 g Stabilizer Chlorobutanol 0.1g Preservative Benzalkonium chloride (10w / v%) 0.05mL Preservative l-menthol 0.008g Refreshing agent Macrogol 4000 0.4g Solubilizer Sodium hydroxide qs pH adjuster Sterile purified water Add 100 ml The above ingredients are mixed to form eye drops.

[0223]

The nasal preparation containing the compound (I) or a salt thereof or a prodrug thereof is useful as an excellent prophylactic / therapeutic agent for allergic rhinitis, hay fever and the like.

Claims (8)

[Claims] (1) Formula (1) [Wherein, Ar ¹ and Ar ² each represent an aromatic group which may have a substituent, and Ar ¹ and Ar ² may form a condensed ring group together with adjacent carbon atoms; Represents a nitrogen-containing heterocyclic ring which may have a substituent, and X and Y
Are the same or different and are each a bond, an oxygen atom, S
(O) p (p represents an integer of 0 to 2), NR ⁴ (R ⁴
Represents a hydrogen atom or a lower alkyl group) or a divalent linear lower hydrocarbon group which may have a substituent and may have 1 to 3 heteroatoms, and A represents a nitrogen atom Or CR ⁷ (R ⁷ represents a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxy group which may have a substituent),
R ¹ , R ² and R ³ are the same or different and each represent a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxy group which may have a substituent, R ⁸ represents a hydrogen atom, a hydroxy group or a carboxyl group which may be substituted with a lower alkyl group. Provided that the nitrogen-containing heterocyclic ring represented by the ring B has the formula (Wherein n represents 0 or 1). Or a salt thereof or a prodrug thereof. 2. The agent according to claim 1, which is an antihistamine and / or an eosinophil chemotactic inhibitor. 3. The agent according to claim 1, which is an antiallergic agent. 4. The agent according to claim 1, which is an agent for preventing or treating allergic rhinitis. (5) 2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2
The agent according to claim 1, comprising -b] pyridazin-2-yl] -2-methylpropionic acid or a salt thereof. 6. A compound of the formula [2- [6- [3- [4- (diphenylmethoxy) piperidino] propylamino] imidazo [1,2]
The agent according to claim 5, wherein the -b] pyridazin-2-yl] -2-methylpropionic acid is dihydrate. 7. A compound of the formula [Wherein, Ar ¹ and Ar ² each represent an aromatic group which may have a substituent, and Ar ¹ and Ar ² may form a condensed ring group together with adjacent carbon atoms; Represents a nitrogen-containing heterocyclic ring which may have a substituent, and X and Y
Are the same or different and are each a bond, an oxygen atom, S
(O) p (p represents an integer of 0 to 2), NR ⁴ (R ⁴
Represents a hydrogen atom or a lower alkyl group) or a divalent linear lower hydrocarbon group which may have a substituent and may have 1 to 3 heteroatoms, and A represents a nitrogen atom Or CR ⁷ (R ⁷ represents a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxy group which may have a substituent),
R ¹ , R ² and R ³ are the same or different and each represent a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxy group which may have a substituent, R ⁸ represents a hydrogen atom, a hydroxy group or a carboxyl group which may be substituted with a lower alkyl group. However, the nitrogen-containing heterocyclic ring represented by the ring B is represented by the formula: (Wherein n represents 0 or 1). Or a salt thereof or a prodrug thereof, which is administered in an effective amount. 8. Formula for producing nasal drops: [Wherein, Ar ¹ and Ar ² each represent an aromatic group which may have a substituent, and Ar ¹ and Ar ² may form a condensed ring group together with adjacent carbon atoms; Represents a nitrogen-containing heterocyclic ring which may have a substituent, and X and Y
Are the same or different and are each a bond, an oxygen atom, S
(O) p (p represents an integer of 0 to 2), NR ⁴ (R ⁴
Represents a hydrogen atom or a lower alkyl group) or a divalent linear lower hydrocarbon group which may have a substituent and may have 1 to 3 heteroatoms, and A represents a nitrogen atom Or CR ⁷ (R ⁷ represents a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxy group which may have a substituent),
R ¹ , R ² and R ³ are the same or different and each represent a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxy group which may have a substituent, R ⁸ represents a hydrogen atom, a hydroxy group or a carboxyl group which may be substituted with a lower alkyl group. Provided that the nitrogen-containing heterocyclic ring represented by the ring B has the formula (Wherein n represents 0 or 1). Or a salt thereof or a prodrug thereof.