JPH11240882A - Condensed pyridazine derivative, its production and use thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having excellent antiallergic effect, anti-platelet activation factor effect, eosinophilic chemotacticity inhibitory effect and the like, also excellent in safety and stability, and useful as a medicament. SOLUTION: This new compound (a salt thereof) is shown by formula I [A and B are such that one of them is nitrogen, the other being CH, or both of them being CH; R<1> is H, a halogen or the like; R<2> and R<3> are each H, a hydrocarbon or the like; X is oxygen or S(O)p , ((p) is 0-2); Y is a group of formula II (R<4> and R<5> are each H or a hydrocarbon), a 3-to 7-membered homocyclic group or the like; R<6> and R<7> are such that one of them is an acyl, the other being H, a hydrocarbon or the like; (m) and (n) are each 0-4], e.g. 6-[2,2-dimethyl-3-(N-acetylsulfamoyl)-propoxy]-7-isopropyl[1,2,4]triaz olo[1,5- b]pyridazine. The compound of formula I is obtained, for example, by reaction of a compound of formula III or a salt thereof with a compound of formula IV or a salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel condensed pyridazine derivative, a method for producing the same, and an agent. The condensed pyridazine derivative of the present invention has an anti-allergic effect, an anti-inflammatory effect, an anti-PAF (platelet activating factor) effect, and the like, and suppresses bronchospasm and bronchoconstriction. It has an inhibitory effect on eosinophil chemotaxis, and is effectively used as a medicament such as a preventive / therapeutic agent for allergic skin diseases, a preventive / therapeutic agent for allergic rhinitis, and a preventive / therapeutic agent for atopic dermatitis.

[0002]

2. Description of the Related Art At present, while many triazolopyridazine compounds are being synthesized as drugs against diseases, US Pat.

Embedded image Wherein each R and R ³ is a hydrogen atom or a lower alkyl (at least one is lower alkyl of R and R ^3), R ¹
And R ² together with a nitrogen atom represent a heterocyclic group selected from pyrrolidine, piperidine, piperazine or morpholine. Or a salt thereof, USP 4,
In 136 and 182, the formula

[0003]

Embedded image [In the formula, R represents a hydrogen atom, phenyl or lower alkylcarbonylamino, R ¹ represents morpholino or piperidino, and R ² represents a hydrogen atom or lower alkyl. However,
When at least one of R and R ² is a group other than a hydrogen atom, and R is phenyl, R ¹ is morpholino and R ²
Is lower alkyl. Or a salt thereof, as disclosed in JP-A-62-292784.

[0004]

Embedded image Or a salt thereof is disclosed as a bronchodilator for reducing bronchospasm. Also, EP05
62439A1 has anti-allergic action, anti-PAF action,
As a compound having an anti-asthmatic effect, WO96 / 08496 discloses a compound having an eosinophil chemotactic inhibitory effect.

[0005]

DISCLOSURE OF THE INVENTION The present invention provides a novel compound which has excellent antiallergic action, anti-PAF action, eosinophil chemotaxis inhibitory action and the like, and is useful as a medicine.

[0006]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, a compound in which the side chain terminal sulfamoyl group substituted by the condensed pyridazine ring is substituted by an acyl group is chemically synthesized. Although the synthesis was thought to be difficult, the first successful synthesis and the present inventors have unexpectedly found that the compound has a unique chemical structure characterized by having the terminal acyl group. Has excellent antiallergic action, anti-PAF action, eosinophil chemotaxis inhibitory action, etc., and also has excellent drug properties. For example, it has excellent safety and stability, and is a clinically useful drug (pro (Including drugs).
The present inventors have completed the present invention based on these findings. That is, the present invention

(1) General formula

Embedded image Wherein, A and B are one of the other represents CH, or both are CH nitrogen atom, R ¹ represents a hydrogen atom or an optionally substituted hydrocarbon group or a halogen atom, R ² And R ³ each represent a hydrogen atom or a hydrocarbon group which may have a substituent, and R ² and R ³ may be adjacent to each other by -C
= C- may form a 5- to 7-membered ring, X represents an oxygen atom or S (O) p (p represents an integer of 0 to 2), and Y represents a formula

Embedded image (R ⁴ and R ⁵ each represent a hydrogen atom or a hydrocarbon group which may have a substituent) or a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent And R ⁶ and R ^{7 each} represents an acyl group, the other represents a hydrogen atom or a hydrocarbon group which may have a substituent, and R ⁶ and R ⁷ are adjacent to each other. And m and n each represent an integer of 0 to 4), or a salt thereof;

(2) General formula

Embedded image Wherein, R ^1a represents a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom, R ^2a and R
^3a represents a hydrogen atom, a lower alkyl group which may have a substituent or a cycloalkyl group which may have a substituent, and R ^2a and R ^3a are 5 to 5 together with an adjacent -C = C-. X ^a may represent an oxygen atom or S (O) p (p represents an integer of 0 to 2), and may form a 7-membered ring;
Y ^a formula

Embedded image Wherein R ^4a and R ^5a each represent a hydrogen atom or a lower alkyl group which may have a substituent, or a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent And R ^6a and R ^7a each have an acyl group, and the other has a hydrogen atom, a lower alkyl group which may have a substituent, or a substituent. a cycloalkyl group or an optionally substituted aryl group, R ^6a and R ^7a may be formed a good lactam ring optionally substituted together with the adjacent nitrogen atom, m ^a
And n ^a is the (1) represented by each an integer of 0 to 4] The compound according to claim,

(3) R ^1a and R ^2a are hydrogen atoms, R ^3a is a lower alkyl group which may have a substituent, X ^a is an oxygen atom, and Y ^a is a formula

Embedded image (Wherein R ^4b and R ^5b each represent a hydrogen atom or a C _1-3 alkyl group), one of R ^6a and R ^7a is a hydrogen atom, and the other is a C _1-6 alkyl which may be substituted. carbonyl group, a compound of the (2) above, wherein m ^a is and n ^a is an integer of 0 to 4, (4) 6- [2,2-dimethyl-3-(n-acetyl-sulfamoyl) -1 -Propoxy] -7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine according to item (1), (5) 6- [2,2-diethyl-3- (N -Acetylsulfamoyl) -1-propoxy] -7-methyl [1,
(4) The compound according to (1), which is triazolo [1,5-b] pyridazine;

(6) (i) General formula

Embedded image Wherein Z ¹ represents a reactive group, A, B, R ¹ , R ² and R ³
Has the same meaning as described in the above item (1)] or a salt thereof and a general formula

Embedded image [In the formula, Z ² represents a group capable of reacting with Z ¹ and leaving, X, Y, R
⁶ , R ⁷ , m and n have the same meaning as described in the item (1)]
Reacting with the compound represented by or a salt thereof,

(Ii) General formula

Embedded image [In the formula, Z ² represents a group capable of reacting with Z ¹ and leaving;
¹ , R ² , R ³ and X have the same meanings as described in item (1)], or a salt thereof and a compound represented by the general formula

Embedded image [Wherein Z ¹ represents a reactive group, Y, R ⁶ , R ⁷ , m and n
Has the same meaning as described in item (1)] or a salt thereof,

(Iii) General formula

Embedded image [Wherein, W represents a leaving group, A, B, R ¹ , R ² , R ³ ,
X, Y, m and n have the same meanings as described in item (1)]
Or a salt thereof and a general formula

Embedded image Wherein R ⁶ and R ⁷ have the same meaning as described in the above item (1) or a salt thereof,

(Iv) General formula

Embedded image [In the formula, Z ² represents a group capable of reacting with Z ¹ and leaving;
¹ , R ² , R ³ , X, Y, R ⁶ , m and n have the same meanings as described in the above item (1)] or a salt thereof and a general formula Z ¹ -R ⁷ [IX] [ Wherein Z ¹ is a reactive group, and R ⁷ is as defined in item (1)] or a salt thereof, or

(V) General formula

Embedded image [In the formula, Z ² represents a group capable of reacting with Z ¹ and leaving;
¹ , R ² , R ³ , X, Y, R ⁷ , m and n have the same meanings as described in the item (1)] or a salt thereof and a general formula Z ¹ -R ⁶ [XI] [ Wherein Z ¹ is a reactive group, and R ⁶ is as defined in item (1), or a salt thereof. Or a method for producing the salt thereof.

(7) A medicament characterized by containing the compound according to (1) or a salt thereof, and (8) a medicament characterized by containing the compound according to (1) or a salt thereof. Provided are an anti-PAF agent, an eosinophil chemotaxis inhibitor, an anti-asthma agent, an anti-allergic agent, a preventive / therapeutic agent for allergic skin disease, a preventive / therapeutic agent for allergic rhinitis or a therapeutic agent for atopic dermatitis. Further, when compound [I] or a salt thereof contains an asymmetric carbon in the structure, an optically active compound and a racemic mixture are also included in the scope of the present invention.

In the above formula, as the halogen atom represented by R ¹ , for example, fluorine, chlorine, bromine or iodine is used. R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ or R
Examples of the hydrocarbon group represented by ⁷ include (1) an alkyl group (eg, methyl, ethyl, n-propyl, i-
C _1-15 alkyl groups such as propyl, n-butyl, i-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and pentadecyl; , N-propyl, i-propyl, n-
Lower (C _1-6 ) alkyl groups such as butyl, i-butyl, tert-butyl, pentyl and hexyl; and (2) cycloalkyl groups (eg lower (C _1-6 ) alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl).
_3-6 ) cycloalkyl group, etc.), (3) alkenyl group (for example, C _2-10 alkenyl group such as vinyl, allyl, 2-methylallyl, i-propenyl, 2-butenyl, 3-butenyl, 3-octenyl and the like) And lower (C _2-6 ) alkenyl groups such as vinyl, allyl, 2-methylallyl, i-propenyl, 2-butenyl and 3-butenyl, and (4) alkynyl groups (eg, ethynyl, 2-propynyl). A C _2-10 alkynyl group such as 3,3-hexynyl and the like, among which a C _2-6 alkynyl group such as ethynyl, 2-propynyl and 3-hexynyl, etc., (5) a cycloalkenyl group (for example, cyclopropenyl, 1- Cyclobutenyl, 2-cyclobutenyl, 1-cyclopentenyl, 2
- cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, etc. C _3-10 cycloalkenyl groups such as 3-cycloheptenyl, among others cyclopropenyl, 1-cyclobutenyl, 2-cyclobutenyl , 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1
Lower (C) such as -cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 3-cycloheptenyl and the like.
_3-8 ) cycloalkenyl group), (6) aryl group (for example, phenyl, tolyl, xylyl, biphenyl,
1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-
A C _6-14 aryl group such as phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl, 1-azulenyl, 2-azulenyl, 4-azulenyl, 5-azulenyl, 6-azulenyl, etc.) or (7) aralkyl group ( For example, a chain or cyclic hydrocarbon group such as a C _7-16 aralkyl group such as benzyl and phenethyl is used.

Examples of the substituent which the above “hydrocarbon group” may have include, for example, lower alkyl which may have a substituent, amino which may have a substituent, and a substituent. Cyclic amino (eg, 5- to 7-membered cyclic amino such as pyrrolidino, morpholino, thiomorpholino, piperidino, piperazino, etc.), acetamido, hydroxy, carboxyl, nitro, lower optionally substituted Alkoxy (for example, C _1-6 alkoxy such as methoxy, ethoxy, propoxy and the like), lower alkyl-carbonyloxy (for example, C _1-6 alkyl-carbonyloxy such as acetoxy, ethylcarbonyloxy and the like) and halogen atom (for example, Fluorine,
Chlorine, bromine, iodine, etc.) are used. Where lower alkyl (eg, methyl,
Examples of the substituent which the C _1-6 alkyl group such as ethyl and n-propyl) and the lower alkoxy may have include, for example, hydroxy, amino, mono- or di-lower alkylamino (for example, methylamino, ethyl Mono- or di-C _1-6 alkylamino such as amino, propylamino, dimethylamino, diethylamino and the like, lower alkoxy (for example, methoxy, ethoxy, propoxy,
One to four selected from C _1-6 alkoxy such as hexyloxy) and halogen atoms (fluorine, chlorine, bromine, iodine, etc.) are used. As the substituent which the amino group or cyclic amino group may have, for example, one or two selected from C _1-6 alkyl (for example, methyl, ethyl, propyl and the like) and the like are used.

As the hydrocarbon group, "alkyl group (preferably lower alkyl group)", "alkenyl group (preferably lower alkenyl group)", "alkynyl group (preferably lower alkynyl group)", "cycloalkyl group" (Preferably a lower cycloalkyl group, an aryl group (preferably a C _6-14 aryl group) and an aralkyl group (preferably a C _7-16 aralkyl group) And the like may include substituents which the above "hydrocarbon group" may have. Among them, for example, hydroxy, amino, carboxyl, nitro, mono- or di-lower alkylamino (for example, methylamino , ethylamino, propylamino, dimethylamino, mono diethylamino - like or di -C _1-6 alkylamino), lower alkoxy (E.g., methoxy, ethoxy,
C _1-6 alkoxy such as propoxy and hexyloxy, etc., lower alkyl-carbonyloxy (eg C _1-6 alkyl-carbonyloxy such as acetoxy and ethylcarbonyloxy) and halogen atoms (fluorine, chlorine, bromine, iodine) And the like are preferably used. -C where R ² and R ³ are adjacent
The 5- to 7-membered ring formed together with ＣC- may include, for example, 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, a sulfur atom and the like in addition to the carbon atom. A seven-membered ring or the like is used. Specifically, C _5-7 cycloalkenes such as cyclopentene, cyclohexene and cycloheptene, 5- to 7-membered cyclic hydrocarbons such as benzene, and 5 or 6 carbon atoms and nitrogen atoms such as pyrrole, pyridine and piperidine. A membered nitrogen-containing heterocycle or the like is frequently used.

The “3- to 7-membered homocyclic ring” of the divalent group derived from the “3- to 7-membered homocyclic ring” represented by Y includes, for example, a 3- to 7-membered cyclic ring consisting only of carbon atoms. Hydrogen or the like is used. Specifically, for example, C _3-7 cycloalkane such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, for example, cyclopropene, cyclobutene, cyclopentene,
C _3-7 cycloalkenes such as cyclohexene and cycloheptene, and benzene are frequently used. Examples of the divalent group derived from the “3- to 7-membered homocyclic ring” include, for example, two hydrogen atoms from one carbon atom in the aforementioned three- to seven-membered cyclic hydrocarbon, For example, a divalent group obtained by removing one hydrogen atom from carbon atoms may be used.

Specifically, for example,

Embedded image Etc. are used, and preferably

Embedded image Etc., more preferably

Embedded image Are often used.

The "3- to 7-membered heterocycle" of the divalent group derived from the "3- to 7-membered heterocycle" represented by Y includes, for example, nitrogen, oxygen, sulfur A 3- to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from atoms or the like is used. Specifically, for example, oxetane, tetrahydrofuran, tetrahydropyran, pyrrole, azetidine, pyrrolidine, piperidine, piperazine, tetrahydrothiophene, homopiperidine, morpholine and the like are used. The divalent group derived from the “3- to 7-membered heterocyclic ring” includes two hydrogen atoms from the same carbon atom in the above-described 3- to 7-membered heterocyclic ring, or two hydrogen atoms from two different atoms. A divalent group from which one hydrogen atom has been removed is used. Specifically, for example,

Embedded image Are used.

Examples of the substituent which the “3- to 7-membered homocyclic ring” and “3- to 7-membered heterocyclic ring” may have include, for example, lower alkyl which may have a substituent, Optionally substituted amino, cyclic amino optionally substituted (for example, 5- to 7-membered cyclic amino such as pyrrolidino, morpholino, piperidino, piperazino, etc.),
Hydroxy, carboxyl, nitro, lower alkoxy optionally having substituents (eg, C _1-6 alkoxy such as methoxy, ethoxy, propoxy, etc.) and halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) One to five selected from the above are used. Here, the substituent which the lower alkyl (for example, C _1-6 alkyl group such as methyl, ethyl, n-propyl and the like) and the lower alkoxy may have, for example, hydroxy, amino, mono- or di- Lower alkylamino (eg, methylamino, ethylamino, propylamino,
Mono- or di-C _1-6 alkylamino such as dimethylamino, diethylamino, etc., lower alkoxy (eg, C _1-6 alkoxy such as methoxy, ethoxy, propoxy, hexyloxy, etc.), lower alkyl-carbonyloxy (eg, , C _1-6 alkyl, such as acetyloxy, ethyl carbonyloxy - carbonyloxy, etc.) and a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.) 1 to 4 selected from like are used. Examples of the substituent which the amino group or the cyclic amino group may have include, for example, C _1-6 alkyl (for example,
Methyl, ethyl, propyl, etc.), acyl (eg, C _1-6 such as formyl, acetyl, propionyl, butyryl etc.)
One or two selected from acyl and the like are used.

As the acyl group represented by R ⁶ or R ⁷ , for example, an acyl group derived from a fatty acid, an acyl group derived from a sulfonic acid, an acyl group derived from a carbonate ester, an acyl group derived from carbamic acid and the like are used. As the acyl group derived from a fatty acid, for example, an acyl group derived from a C _1-14 fatty acid is used, and specifically, for example, formyl, acetyl,
C _1-6 alkylcarbonyl groups (C _1-6 acyl groups) such as ethylcarbonyl and propylcarbonyl, benzoyl,
C _6-14 aryl-carbonyl such as 1-naphthoyl, 2-naphthoyl, phenylacetyl and the like are used. Among them, a C _1-3 acyl group such as acetyl is preferable.
As the sulfonic acid-derived acyl group, for example, a C _1-6 alkylsulfonyl group, a C _6-14 arylsulfonyl group and the like are used. As the C _1-6 alkylsulfonyl group,
For example, methanesulfonyl, ethanesulfonyl, propanesulfonyl and the like are used, and among them, a C _1-3 alkylsulfonyl group such as methanesulfonyl is preferable. C
_{As the 6-14} arylsulfonyl group, for example, benzenesulfonyl, p-toluenesulfonyl, naphthalenesulfonyl and the like are used, and among them, a _C6-12 arylsulfonyl group such as benzenesulfonyl is preferable. Examples of the carbonic acid ester-derived acyl group include, for example, a C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl, and a C _6-14 alkoxy group such as benzooxycarbonyl, 1-naphthyloxycarbonyl and 2-naphthyloxycarbonyl. An aryloxy-carbonyl group and the like are used. Examples of the carbamic acid-derived acyl group include a mono- or di-C _1-6 alkylaminocarbonyl group such as methylaminocarbonyl and ethylaminocarbonyl, and a mono- or di-C _6-14 arylamino group such as phenylaminocarbonyl. A carbonyl group or the like is used. These acyl groups may have a substituent on the alkyl or aryl moiety, for example,
Substituents and the like which the above “hydrocarbon group” may have are used. Among them, for example, hydroxy, amino,
Carboxyl, nitro, mono- or di-lower alkylamino (eg, mono- or di-C _1-6 alkylamino such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), lower alkoxy (eg, methoxy , Ethoxy, propoxy, hexyloxy and other C _1-6 alkoxy), lower alkyl-carbonyloxy (eg, acetoxy, ethylcarbonyloxy and other C _1-6 alkyl-carbonyloxy) and halogen atoms (fluorine, chlorine, One to four selected from bromine, iodine, etc.) are preferably used.

The lactam ring formed by R ⁶ and R ⁷ together with the adjacent nitrogen atom may be, for example, one or three nitrogen atoms, oxygen atoms, sulfur atoms and the like in addition to the nitrogen atom of the lactam ring. 3 to 13 members (preferably 3 to 9 members) optionally containing a hetero atom
And a group obtained by removing one hydrogen atom from a nitrogen atom in a ring such as a lactam ring. Specifically, for example,

Embedded image A 3- to 9-membered, preferably 4- to 6-membered lactam ring is commonly used.

Examples of the substituent which the lactam ring may have include, for example, lower alkyl which may have a substituent, amino which may have a substituent, and a substituent which has a substituent. Cyclic amino (for example, pyrrolidino, morpholino, thiomorpholino, piperidino, piperazino, etc .;
To 7-membered cyclic amino, etc.), acetamido, hydroxy, carboxyl, nitro, optionally substituted lower alkoxy (eg, C _1-6 alkoxy such as methoxy, ethoxy, propoxy, etc.), lower alkyl-carbonyloxy (Eg, C _1-6 alkyl-carbonyloxy such as acetoxy, ethylcarbonyloxy, etc.) and 1 to 5 atoms selected from halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) are used. Where lower alkyl (eg, methyl, ethyl,
Examples of the substituent which the C _1-6 alkyl group such as n-propyl) and the lower alkoxy may have include, for example,
Hydroxy, amino, mono- or di-lower alkylamino (e.g., mono-methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.
Or di-C _1-6 alkylamino), lower alkoxy (eg, C _1-6 alkoxy such as methoxy, ethoxy, propoxy, hexyloxy, etc.) and halogen atom (fluorine, chlorine, bromine, iodine, etc.). One to four of them are used. As the substituent which the amino group or cyclic amino group may have, for example, one or two selected from C _1-6 alkyl (for example, methyl, ethyl, propyl and the like) and the like are used.

In the above formula, one of A and B represents a nitrogen atom and the other represents CH, or both A and B represent CH. However, as A and B, one is a nitrogen atom and the other is a C atom.
The case where H represents is preferred, and the case where A represents CH and B represents a nitrogen atom is particularly preferred. When A or (and) B is CH, R ¹ may be substituted on the carbon atom. As R ¹ , for example, a hydrogen atom, a lower alkyl group which may have a substituent, a lower cycloalkyl group which may have a substituent, a lower alkenyl group which may have a substituent, A lower alkynyl group which may have a substituent, a lower cycloalkenyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent Alternatively, a halogen atom or the like is preferable, and among them, a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom is preferable. The "lower alkyl group" of the "lower alkyl group optionally having substituent (s)", the "lower cycloalkyl group" of the "lower cycloalkyl group optionally having substituent (s)", and ""Lower alkenyl group" of "optionally lower alkenyl group", "lower alkynyl group" of "optionally substituted lower alkynyl group", "optionally substituted lower cycloalkenyl" Group "," lower cycloalkenyl group "," optionally substituted aryl group "
`` Aralkyl group '' of `` aryl group '' and `` aralkyl group optionally having substituent (s) '' have the same meanings as described above, and `` lower alkyl group optionally having substituent (s) '', A lower cycloalkyl group optionally having substituent (s), a lower alkenyl group optionally having substituent (s), a lower alkynyl group optionally having substituent (s), The "optionally substituted lower cycloalkenyl group", the "optionally substituted aryl group", and the "optionally substituted aralkyl group" also have the same meaning as described above. . R ¹ is a hydrogen atom,
A lower (C _1-6 ) alkyl group or a halogen atom is preferred, and a hydrogen atom or a C _1-3 alkyl group (eg, methyl, ethyl, n-propyl, etc.) is more preferred. Is done.

As R ² and R ³ , for example, a hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, and a substituent A good lower alkenyl group, a lower alkynyl group which may have a substituent, a cycloalkenyl group which may have a substituent, an aryl group which may have a substituent or A lower aralkyl group or the like is preferable, and among them, a hydrogen atom, a lower alkyl group optionally having a substituent or a lower cycloalkyl group optionally having a substituent is preferable. "Lower alkyl group" of the "lower alkyl group optionally having substituent (s)",
"Cycloalkyl group" of "cycloalkyl group optionally having substituent (s)", "lower alkenyl group" of "lower alkenyl group optionally having substituent (s)", ""Lower alkynyl group" of "lower alkynyl group", "cycloalkenyl group" of "cycloalkenyl group optionally having substituent (s)", "aryl" of "aryl group optionally having substituent (s)" The `` aralkyl group '' of the `` group '' and the `` aralkyl group optionally having substituent (s) '' have the same meaning as described above, and `` a lower alkyl group optionally having substituent (s) '', Optionally substituted cycloalkyl group, `` optionally substituted lower alkenyl group '', `` optionally substituted lower alkynyl group '', `` optionally substituted Good cycloalkenyl group "," having a substituent There aryl group which may "and" may have a substituent group "substituent aralkyl group""is also as defined above. As R ² and R ³ , a hydrogen atom or a lower (C _1-6 ) alkyl group is preferred, and a hydrogen atom or a C _1-3 alkyl group (eg, methyl, ethyl, n-propyl, i-propyl, etc.) is preferred. Is more preferred. Particularly, it is preferable that R ² represents a hydrogen atom and R ³ represents a C _1-6 alkyl group.

X represents an oxygen atom or S (O) p (p is an integer of 0 to 2). Of these, an oxygen atom or S is preferable, and an oxygen atom is particularly used. Y is the formula

Embedded image Wherein R ⁴ and R ⁵ are as defined above, or a divalent group derived from a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent. Indicates that Y
For example, the expression

Embedded image [Wherein, R ^4a and R ^5a each represent a hydrogen atom or a lower alkyl group which may have a substituent]. As the lower alkyl group represented by R ^4a and R ^5a , those similar to the aforementioned lower alkyl group which may have a substituent as R ¹ are used. Among them, R ^4a and R ^5a are preferably a hydrogen atom or a C _1-3 alkyl group (eg, methyl, ethyl, n-propyl and the like), and particularly a C _1-3 alkyl group (eg, methyl, ethyl, n-propyl and the like are frequently used, and among them, a methyl group is preferred.

It is also preferred that Y is a divalent group derived from a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent.

Embedded image And more preferably

Embedded image Are often used, especially

Embedded image Is the most frequently used.

One of R ⁶ and R ⁷ represents an acyl group, and the other represents a hydrogen atom or a hydrocarbon group which may have a substituent. In particular, one of R ⁶ and R ⁷ represents an acyl group. ,
The other is preferably a hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or an aryl group which may have a substituent. The "lower alkyl group" of the "lower alkyl group optionally having substituent (s)", the "cycloalkyl group" of the "cycloalkyl group optionally having substituent (s)" and " The "aryl group" of the "optionally substituted aryl group" has the same meaning as described above, "an optionally substituted hydrocarbon group", "an optionally substituted lower alkyl group", " The "substituent" of the "cycloalkyl group optionally having substituent (s)" and the "aryl group optionally having substituent (s)" has the same meaning as described above. In particular, R ⁶ and R ⁷
Is an acyl group derived from a C _1-14 fatty acid (preferably, C _1-14
If on the other hand _{1- 6} alkyl group) is a hydrogen atom are preferred.

It is also preferred that R ⁶ and R ⁷ form a lactam ring together with an adjacent nitrogen atom.

Embedded image A 3- to 9-membered (preferably 4- to 6-membered) lactam ring is frequently used. m represents an integer of 0 to 4.
m is preferably an integer of 1 to 4, more preferably an integer of 1 to 3, especially 1 or the like. n represents an integer of 0 to 4, and n is preferably an integer of 1 to 4, particularly 1 or the like. Above all, it is most preferable that both m and n are 1.

As the compound [I] of the present invention, any compound obtained by combining the specific examples of the above symbols is preferable.

Embedded image Wherein, R ^1a represents a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom, R ^2a and R
^3a represents a hydrogen atom, a lower alkyl group which may have a substituent or a cycloalkyl group which may have a substituent, and R ^2a and R ^3a are 5 to 5 together with an adjacent -C = C-. X ^a may represent an oxygen atom or S (O) p (p represents an integer of 0 to 2), and may form a 7-membered ring;
Y ^a formula

Embedded image Wherein R ^4a and R ^5a each represent a hydrogen atom or a lower alkyl group which may have a substituent, or a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent And R ^6a and R ^7a each have an acyl group, and the other has a hydrogen atom, a lower alkyl group which may have a substituent, or a substituent. A cycloalkyl group or an optionally substituted aryl group, wherein R ^6a and R ^7a may be bonded to an adjacent nitrogen atom to form an optionally substituted lactam ring;
m ^a and n ^a each represent an integer of 0 to 4].

In the above formula, R ^1a , R ^2a , R ^3a , R ^4a ,
As the lower alkyl represented by R ^5a , R ^6a and R ^7a , for example, a linear or branched C _1-6 alkyl group is used. Examples of the linear or branched C _1-6 alkyl group include, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-
Butyl, n-pentyl, n-hexyl and the like are used. Particularly, as the lower alkyl represented by R ^3a , a branched C _3-6 alkyl group (eg, i-propyl, i-butyl, tert-butyl, etc.) is preferable. R ^2a , R ^3a , R
^{As the} “cycloalkyl group” represented by ^6a and R ^7a , for example, a C _3-6 cycloalkyl group is used. As the C _3-6 cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like are used. As the aryl group represented by R ^6a and R ^7a , for example, a C _6-14 aryl group is used. As the C _6-14 aryl group, for example, phenyl, naphthyl and the like are used.

Examples of the substituent which the “lower alkyl” and “cycloalkyl group” may have include, for example, hydroxy, amino, carboxyl, nitro, mono- or di-lower alkylamino (eg, methylamino, Mono- or di-C _1-6 alkylamino such as ethylamino, propylamino, dimethylamino and diethylamino
Lower alkoxy (eg, C _1-6 alkoxy such as methoxy, ethoxy, propoxy, hexyloxy, etc.), lower alkylcarbonyloxy (eg, C _1-6 alkylcarbonyloxy such as acetoxy, ethylcarbonyloxy, etc.) and One to four atoms selected from halogen atoms (such as fluorine, chlorine, bromine, and iodine) are used. Examples of the substituent which the “aryl group” may have include, for example, lower alkyl which may have a substituent, amino which may have a substituent, acetamido, hydroxy, carboxyl, nitro, Lower alkoxy (eg, C _1-6 alkoxy such as methoxy, ethoxy, propoxy, etc.), lower alkyl-carbonyloxy (eg, C _1-6 alkylcarbonyloxy such as acetoxy, ethylcarbonyloxy, etc.) and halogen atoms (fluorine, Chlorine, bromine, iodine, etc.)
1 to 5 selected from the above are used. Here, the substituent which the lower alkyl (for example, a C _1-6 alkyl group such as methyl, ethyl, n-propyl, etc.) may have is, for example, hydroxy, amino, mono- or di-lower alkylamino (Eg, mono- or di-C _1-6 alkylamino such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.),
One to four selected from lower alkoxy (eg, C _1-6 alkoxy such as methoxy, ethoxy, propoxy, hexyloxy, etc.) and halogen atoms (eg, fluorine, chlorine, bromine, iodine) are used. Examples of the substituent which the amino group may have include, for example, C
One or two selected from _1-6 alkyl (eg, methyl, ethyl, propyl, etc.) and 5- to 7-membered cyclic amino (eg, pyrrolidino, morpholino, piperidino, piperazino, etc.) are used.

As the acyl groups represented by R ^6a and R ^7a , those similar to the acyl groups represented by R ⁶ and R ⁷ described above are used. Of these, C _1-6 alkylcarbonyl groups such as formyl, acetyl, ethylcarbonyl, propylcarbonyl and the like are preferable, and particularly, C _1-6 alkylcarbonyl groups such as acetyl and the like are preferable.
_1-3 alkylcarbonyl groups are preferred. ^Examples of the ^optionally substituted lactam ring formed by R ^6a and R ^7a bonded to an adjacent nitrogen atom include the aforementioned optionally substituted lactam ring formed by R ⁶ and R ⁷ together with an adjacent nitrogen atom. The same as described above is used. Above all,

Embedded image A 3- to 9-membered (preferably 4- to 6-membered) lactam ring is frequently used.

As the halogen atom represented by R ^1a , for example, fluorine, chlorine, bromine, iodine and the like are used.
The 5- to 7-membered ring R ^2a and R ^3a is formed together with -C = C-adjacent, -C wherein the R ² and R ³ are adjacent =
The same as the 5- to 7-membered ring formed together with C- are used. For example, in addition to a carbon atom, for example, a nitrogen atom,
A 5- to 7-membered ring which may contain 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and the like is used, and specific examples thereof include cyclopentene, cyclohexene,
5- to 7-membered cyclic hydrocarbons such as C _5-7 cycloalkenes such as cycloheptene and benzene, and 5- or 6-membered nitrogen-containing heterocycles comprising carbon and nitrogen atoms such as pyrrole, pyridine and piperidine are frequently used. Used.
The “3- to 7-membered homocycle” of the divalent group derived from the 3- to 7-membered homocycle represented by R ^4a and R ^{5a includes} the 3- to 7-membered homocycle represented by R ⁴ and R ⁵ described above. The same as the “3- to 7-membered homocyclic ring” of the divalent group derived from the homocyclic ring is used, and for example, a 3- to 7-membered cyclic hydrocarbon consisting only of carbon atoms is used. Specifically, for example, C _3-7 cycloalkane such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, for example, cyclopropene, cyclobutene,
C _3-7 cycloalkenes such as cyclopentene, cyclohexene and cycloheptene, and benzene are frequently used.
The divalent group derived from the “3- to 7-membered homocyclic ring” includes two hydrogen atoms from one carbon atom in the aforementioned three- to seven-membered cyclic hydrocarbon, or two different hydrogen atoms. A divalent group obtained by removing one hydrogen atom from each carbon atom is used.

Specifically, for example,

Embedded image Etc. are used, and preferably

Embedded image Etc., more preferably

Embedded image Are often used.

The divalent group "3-7 membered heterocyclic ring" derived from the 3-7 membered heterocyclic ring represented by R ^4a and R ^5a
Is, for example, 3 represented by R ⁴ and R ⁵ described above.
The same as the “3- to 7-membered heterocyclic ring” of the divalent group derived from a to 7-membered heterocyclic ring, for example, besides a carbon atom, for example, selected from a nitrogen atom, an oxygen atom, a sulfur atom and the like A 3- to 7-membered heterocyclic ring containing 1 to 4 hetero atoms is used. Specifically, for example, oxetane, tetrahydrofuran, tetrahydropyran, pyrrole, azetidine, pyrrolidine, piperidine, piperazine, tetrahydrothiophene, homopiperidine, morpholine and the like are used. The divalent group derived from the “3- to 7-membered heterocycle” includes the aforementioned 3
And a divalent group obtained by removing two hydrogen atoms from the same carbon atom in a 7-membered heterocyclic ring, or removing one hydrogen atom from each of two different atoms, or the like. Specifically, for example,

Embedded image Are used.

Examples of the substituent which the “3- to 7-membered homocyclic ring” and “3- to 7-membered heterocyclic ring” may have include, for example, lower alkyl which may have a substituent, Selected from amino, hydroxy, carboxyl, nitro, lower alkoxy (eg, C _1-6 alkoxy such as methoxy, ethoxy, propoxy, etc.) and halogen atoms (fluorine, chlorine, bromine, iodine, etc.) which may have 1 to 5 are used. Here, the substituent which the lower alkyl (for example, a C _1-6 alkyl group such as methyl, ethyl, n-propyl, etc.) may have is, for example, hydroxy, amino, mono- or di-lower alkylamino (Eg, mono- or di-C _1-6 alkylamino such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.),
Lower alkoxy (eg, C _1-6 alkoxy such as methoxy, ethoxy, propoxy, hexyloxy, etc.),
One to four selected from lower alkylcarbonyloxy (eg, C _1-6 alkyl-carbonyloxy such as acetyloxy, ethylcarbonyloxy, etc.) and halogen atoms (fluorine, chlorine, bromine, iodine, etc.) are used. Examples of the substituent which the amino group may have include, for example, C _1-6 alkyl (eg, methyl, ethyl, propyl, etc.) and acyl (eg, C _1-6 acyl such as formyl, acetyl, propionyl, butyryl, etc.) )
And 5- to 7-membered cyclic aminos (eg, pyrrolidino,
One or two selected from morpholino, piperidino, piperazino and the like are used.

In the above formula (Ia), R ^1a is
For example, a hydrogen atom or C _1-3 alkyl (eg, methyl, ethyl, n-propyl, etc.) is preferred, and a hydrogen atom is particularly frequently used. As R ^2a , for example, a hydrogen atom, C _1-3 alkyl (for example, methyl, ethyl, n-propyl and the like) are preferable. In particular, hydrogen atoms and the like are frequently used. As R ^3a , for example, a hydrogen atom, hydroxy,
A lower alkyl group which may be substituted with an amino, halogen atom, C _1-6 alkoxy or the like is preferable. In particular, a hydrogen atom or a C _1-3 alkyl group (eg, methyl, ethyl, n-propyl, i-propyl, etc.) ) Is preferred, and particularly a C _1-3 alkyl group is frequently used. Further, it is also preferred that R ² and R ³ form a 5- to 7-membered cyclic hydrocarbon together with the adjacent —C ＝ C—, particularly preferably a cyclohexene, benzene or the like. X is preferably, for example, an oxygen atom or S, and particularly an oxygen atom is frequently used.

As Y, for example,

Embedded image Wherein R ^4b and R ^5b are each a hydrogen atom or C
_{Represents 1-3} alkyl. And the like are preferred. As the C _1-3 alkyl group represented by R ^4b and R ^5b , for example, methyl, ethyl, n-propyl, i-propyl is used. As the substituent which the C _1-3 alkyl group may have, the same substituents as those which the “lower alkyl” represented by R ^1a may have are used. Preferred R ^4b and R ^5b are, in particular, C _1-3
Alkyl (for example, methyl, ethyl, n-propyl and the like) and the like are preferable, and methyl is preferable.

As R ^6a and R ^7a , one is a C _1-6 acyl group (for example, formyl, acetyl, ethylcarbonyl, propyl) which may be substituted with hydroxy, amino, halogen atom, C _1-6 alkoxy or the like. Carbonyl) and the other is a hydrogen atom or C _1-3 alkyl (eg, methyl, ethyl, n-propyl, etc.). In particular, one of which may be substituted by hydroxy, amino, halogen atom, C _1-6 alkoxy, etc.
_1-6 acyl group (more preferably, C _1-3 such as acetyl)
And the other is a hydrogen atom. m ^a represents an integer of 0 to 4, preferably among them an integer of 1 to 4, further an integer of 1 to 3, particularly 1 and the like are frequently used. n ^a is an integer of 0 to 4,
Of these, an integer of 1 to 4 is preferable, and 1 is particularly frequently used. Among them, m ^a and n ^a are both case of 1 is most preferable.

Specifically, the compound [I] of the present invention includes 6- [2,2-dimethyl-3- (N-acetylsulfamoyl) -1-propoxy] -7-isopropyl [1,2 , 4] triazolo [1,5-b] pyridazine,
6- [2,2-diethyl-3- (N-acetylsulfamoyl) -1-propoxy] -7-methyl [1,2,
4] Triazolo [1,5-b] pyridazine and the like are preferred. As the salt of compound [I] of the present invention, a physiologically acceptable acid addition salt is particularly preferable. Examples of such salts include salts with inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid) and organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid) , Tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid,
For example, salts with methanesulfonic acid and benzenesulfonic acid) are used. Further, when the compound [I] of the present invention has an acidic group such as -COOH as a substituent, the compound [I] may be an inorganic base (for example, sodium, potassium,
Salts may be formed with alkali metals or alkaline earth metals, such as calcium and magnesium, ammonia and the like, or organic bases (eg, tri-C _1-3 alkylamines such as triethylamine).

Next, a method for producing the compound [I] of the present invention or a salt thereof will be described. The compound [I] of the present invention or a salt thereof is represented by the general formula (A):

Embedded image Wherein Z ¹ , A, B, R ¹ , R ² and R ³ have the same meanings as defined above, or a salt thereof and a compound of the general formula

Embedded image Wherein Z ² , X, Y, R ⁶ , R ⁷ , m and n have the same meanings as defined above, or a salt thereof.

The reactive group represented by Z ¹ includes, for example, halogen (eg, chlorine, bromine, iodine), C
_6-10 arylsulfonyloxy (eg, benzenesulfonyloxy, p-tolylsulfonyloxy), C _1-4
Alkylsulfonyloxy (for example, methanesulfonyloxy) and the like are used. When X is an oxygen atom or a sulfur atom, for example, a hydrogen atom or an alkali metal (eg, sodium, potassium, or the like) is used as the group which reacts with Z ¹ represented by Z ² to leave.
Is —SO— or —SO ₂ —, for example, an alkali metal (eg, sodium, potassium, etc.) is used. In this reaction, the compound [III] or a salt thereof is usually added in an amount of about 1 to 1 mol of the compound [II] or a salt thereof.
About 5 moles, preferably about 1 to about 2 moles are used. In this reaction, the condensation is usually performed in the presence of a base. Examples of the base include alkali metal hydrides (eg, sodium hydride, potassium hydride, etc.) and alkali metal alkoxides (eg, sodium methoxide, Examples thereof include sodium ethoxide, alkali metal hydroxide (eg, sodium hydroxide, potassium hydroxide, etc.), and carbonates (eg, sodium carbonate, potassium carbonate, etc.). In addition, the reaction is carried out with alcohols (eg, methanol, ethanol, etc.), ethers (eg, dioxane, tetrahydrofuran, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), nitriles (eg, acetonitrile) And the like, amides (eg, dimethylformamide, dimethylacetamide, etc.), and sulfoxides (eg, dimethylsulfoxide, etc.). The reaction temperature is usually about 10 to about 200 ° C, preferably about 50 to about 100 ° C. The reaction time is usually about 3
0 minutes to about 24 hours, preferably about 1 to about 6 hours.

The compound [I] of the present invention or a salt thereof is represented by the general formula (B):

Embedded image [Wherein, Z ² , A, B, R ¹ , R ² , R ³ and X have the same meanings as described above. A compound represented by the general formula

Embedded image [Wherein, Z ¹ , Y, R ⁶ , R ⁷ , m and n are as defined above. Or a salt thereof.

In this reaction, the compound [V] or a salt thereof is used in an amount of usually about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of the compound [IV] or a salt thereof. In this reaction, the condensation is usually performed in the presence of a base. Examples of the base include alkali metal hydrides (eg, sodium hydride, potassium hydride, etc.) and alkali metal alkoxides (eg, sodium methoxide, Examples thereof include sodium ethoxide, alkali metal hydroxide (eg, sodium hydroxide, potassium hydroxide, etc.), and carbonates (eg, sodium carbonate, potassium carbonate, etc.). further,
This reaction involves alcohols (eg, methanol, ethanol, etc.), ethers (eg, dioxane, tetrahydrofuran, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), nitriles (eg, acetonitrile, etc.), The reaction can also be carried out in an inert solvent such as amides (eg, dimethylformamide, dimethylacetamide, etc.) and sulfoxides (eg, dimethylsulfoxide, etc.). The reaction temperature is generally about 10 to about 200C, preferably about 50 to about 150C. The reaction time is usually about 3
0 minutes to about 24 hours, preferably about 1 to about 10 hours.

Further, the compound [I] or a salt thereof is
(C) General formula

Embedded image [Wherein, W, A, B, R ¹ , R ² , R ³ , X, Y, m and n have the same meanings as described above. A compound represented by the general formula

Embedded image Wherein R ⁶ and R ⁷ are as defined above. Or a salt thereof.

Examples of the leaving group represented by W include a halogen atom (eg, chlorine, bromine, iodine, etc.), C
_6-10 arylsulfonyloxy group (for example, benzenesulfonyloxy, p-tolylsulfonyloxy, etc.),
A C _1-4 alkylsulfonyloxy group (eg, methanesulfonyloxy) and the like are used, and among them, a halogen atom (eg, chlorine, bromine, iodine, etc.) is preferable. In this reaction, the compound [VII] or a salt thereof is usually added in an amount of about 1 to 1 mol of the compound [VI] or a salt thereof.
About 5 moles, preferably about 1 to about 2 moles are used. In this reaction, usually, alcohols (eg, methanol, ethanol, etc.), ethers (eg, dioxane, tetrahydrofuran, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), nitriles (eg, acetonitrile, etc.) ), Amides (eg, dimethylformamide, dimethylacetamide, etc.), and sulfoxides (eg, dimethylsulfoxide, etc.). The reaction temperature is usually about -20 to about 100C, preferably about -10 to about 50C. The reaction usually takes about 30
Minutes to about 5 hours, preferably about 1 to about 3 hours.

Further, the compound [I] of the present invention is represented by the formula (D)
General formula

Embedded image [Wherein, Z ² , A, B, R ¹ , R ² , R ³ , X, Y, R ⁶ ,
m and n are as defined above) or a salt thereof and a compound represented by the general formula Z ¹ -R ⁷ [IX] wherein Z ¹ and R ⁷ are as defined above. Or reacting with its salt, or

(E) General formula

Embedded image [Wherein, Z ² , A, B, R ¹ , R ² , R ³ , X, Y, R ⁷ ,
m and n are as defined above) or a salt thereof, and a compound represented by the general formula Z ¹ -R ⁶ [XI] wherein Z ¹ and R ⁶ are as defined above. Alternatively, it can be obtained by reacting with a salt thereof.

In the reactions (D) and (E), the compound [IX] or a salt thereof and the compound [IX] or a salt thereof are added to 1 mol of the compound [VIII] or a salt thereof and the compound [IX] or a salt thereof. XI] is usually used in an amount of about 1 to about 5 mol, preferably about 1 to about 2 mol. In this reaction, the condensation is usually performed in the presence of a base. Examples of the base include alkali metal hydrides (eg, sodium hydride, potassium hydride, etc.) and alkali metal alkoxides (eg, sodium methoxide, Examples thereof include sodium ethoxide, alkali metal hydroxide (eg, sodium hydroxide, potassium hydroxide, etc.), and carbonates (eg, sodium carbonate, potassium carbonate, etc.). In addition, this reaction involves alcohols (eg, methanol, ethanol, etc.), ethers (eg, dioxane, tetrahydrofuran, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), nitriles (eg, acetonitrile, etc.) ), Amides (eg, dimethylformamide, dimethylacetamide, etc.) and sulfoxides (eg, dimethylsulfoxide, etc.). The reaction temperature is generally about -20 to about 100C, preferably about -10.
~ 50 ° C. The reaction usually takes about 30 minutes to about 5 hours,
Preferably, it is for about 1 to about 3 hours. The compound [I] thus obtained 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 [I] 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 [I] or a salt thereof is an optically active form, it can be separated into d-form and l-form by ordinary optical resolution means.

Next, the starting compounds [II], [III], [IV],
[V], [VI], [VII], [VIII], [IX], [X],
[XI] or a method for producing the salt thereof will be described. Examples of salts of these compounds include salts with inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid) and organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, Salts with succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) are used. Further, when these compounds have an acidic group such as —COOH as a substituent, an inorganic base (for example, ammonia such as an alkali metal or an alkaline earth metal such as sodium, potassium, calcium, and magnesium) or an organic base (E.g., tri-C _1-3 alkylamine such as triethylamine). The starting compound [II] or a salt thereof is described, for example, in Journal of Organic Chemistry (J. Org. Chem.), 39, 2143 (198).
7 years) or a method analogous thereto. The starting compound [III] or a salt thereof and the compound [V] or a salt thereof are described, for example, in Chem. Ber., Vol. 91, p. 2130 (1958).
Year), Journal of Organic Chemistry (J. Org. Chem.) 52, 2162 (1987)
Year), a method described in JP-A-3-223287 or a method analogous thereto. The starting compound [IV] or a salt thereof is described in, for example, JP-A-3-22328.
7 and the like, or a method analogous thereto.

The starting compound [VI] or a salt thereof can be produced, for example, by reacting (1) the compound [II] or a salt thereof with a compound represented by the formula

Embedded image [Wherein, X, Y, Z ² , W, m and n are as defined above. Or (2) compound (IV) or a salt thereof with a compound of the formula

Embedded image [Wherein, Y, Z ¹ , W, m and n are as defined above. And the like.

In the above reaction (1), the compound [II]
Alternatively, the compound [XII] is used usually in an amount of about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of a salt thereof. This reaction can be carried out in the same manner as in the above-mentioned reaction between compound [II] or a salt thereof and compound [III] or a salt thereof. In the reaction of the above (2), the compound [XIII] is usually added in an amount of about 1 mol per mol of the compound [IV] or a salt thereof.
From about 5 moles, preferably from about 1 to about 2 moles are used. This reaction can be carried out in the same manner as in the above-mentioned reaction between compound [IV] or a salt thereof and compound [V] or a salt thereof. The starting compound [VII] or a salt thereof, the starting compound [XII] and the starting compound [XIII] can be produced by a method known per se or a method analogous thereto.
Starting compound [VIII] or a salt thereof is described in, for example,
The compound can be synthesized by the method described in US Pat. The starting compound [IX] or a salt thereof can be synthesized by a method known per se or a method analogous thereto. The starting compound [X] or a salt thereof can be synthesized, for example, by the method described in JP-A-6-279647 or a method analogous thereto. Starting compound [X
I] or a salt thereof can be synthesized by a method known per se or a method analogous thereto.

The thus obtained starting compounds or salts thereof can be isolated and purified by known means such as solvent extraction, liquid conversion, phase transfer, salting out, crystallization, recrystallization, chromatography and the like. May be used as a raw material in the next step as it is as a reaction mixture without isolation. In each of the above-described reactions of the present invention and each of the reactions for synthesizing the starting compound, when the starting compound has an amino group, a carboxyl group, or a hydroxyl group as a substituent, such a group is generally used in peptide chemistry or the like. The target compound may be obtained by removing the protecting group as needed after the reaction, if necessary. Examples of the amino-protecting group include, for example,
Formyl, optionally substituted C _1-6 alkylcarbonyl (eg, acetyl, ethylcarbonyl, etc.), phenylcarbonyl, C _1-6 alkyl-oxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), phenyl Oxycarbonyl, _C7-10 aralkyl-carbonyl (for example, benzylcarbonyl), trityl, phthaloyl, N, N-dimethylaminomethylene and the like are used. As these substituents,
For example, a halogen atom (e.g., fluoro, chloro, bromo, iodo, etc.), C _1-6 alkyl - carbonyl (e.g., methylcarbonyl, ethylcarbonyl, butylcarbonyl and the like), and nitro groups, the number of substituents About 1 to 3 pieces. Examples of the carboxyl-protecting group include, for example, C _1-6 alkyl which may have a substituent (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, etc.), phenyl , Trityl, silyl and the like are used. Examples of these substituents include a halogen atom (eg, fluoro, chloro, bromo, iodo, etc.), formyl, C _1-6 alkyl-carbonyl (eg, acetyl, ethylcarbonyl,
Butylcarbonyl) and a nitro group, and the number of substituents is about 1 to 3.

Examples of the hydroxyl-protecting group include, for example, C _1-6 alkyl which may have a substituent (eg, methyl, ethyl, n-propyl, i-propyl, n-propyl)
-Butyl, tert-butyl, etc.), phenyl, C _7-10 aralkyl (eg, benzyl), formyl, C _1-6 alkyl-carbonyl (eg, acetyl, ethyl carbonyl, etc.), phenyloxycarbonyl, benzoyl, C _7-10 aralkyl-carbonyl (such as benzylcarbonyl), pyranyl, furanyl, silyl and the like are used. Examples of these substituents include a halogen atom (eg, fluoro, chloro, bromo, iodo, etc.), C _1-6 alkyl (eg, methyl, ethyl, n-
Propyl), phenyl, _C7-10 aralkyl (eg, benzyl), nitro group, etc., and the number of substituents is about 1 to 4. 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. Do
A method of treating with palladium acetate or the like is used.

The compound [I] of the present invention or a salt thereof has excellent anti-allergic, anti-inflammatory, anti-PAF
(Platelet activating factor), eosinophil chemotaxis, etc., and low toxicity (acute toxicity: LD ₅₀ >
2g / kg), so human or mammal (eg, rat, mouse, rabbit, dog, cow, horse, sheep, monkey, etc.)
Anti-asthmatic, anti-allergic, anti-inflammatory,
It can be used as a medicine such as an anti-PAF agent. Furthermore, the compound [I] of the present invention or a salt thereof suppresses eosinophil chemotaxis, and suppresses infiltration of eosinophils in local areas of allergic and inflammatory reactions. Therefore, it is also useful as a preventive and therapeutic agent for diseases associated with eosinophil infiltration. That is, diseases showing eosinophilia in the human or mammal, for example, allergic diseases such as urticaria, atopic dermatitis, allergic rhinitis, irritable pneumonitis, eczema, herpetic dermatitis, psoriasis, eczema・ Skin diseases such as allergic dermatitis such as dermatitis, contact dermatitis, pruritus, dry dermatitis, acute urticaria and prurigo, eosinophilic pneumonia (PI
It can be used as a preventive or therapeutic agent for respiratory diseases such as E syndrome). The administration route may be oral or parenteral. The preparation used in the present invention may contain other active ingredients other than the compound [I] or a salt thereof as an active ingredient. Examples of such pharmaceutically active ingredients include anti-asthmatic agents (eg, theophylline, procaterol, ketotifen, azelastine, seratrodast, etc.), anti-allergic agents (eg, ketotifen, terfenadine, azelastine, epinastine, etc.), anti-inflammatory agents (eg, , Diclofenac sodium, ibuprofen, indomethacin, etc.), antibacterial agents (eg, cefixime, cefdinir, ofloxacin, tosfloxacin, etc.), and antifungal agents (eg, fluconazole, itraconazole, etc.). 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.

The compound [I] of the present invention or a salt thereof may be used in the form of a bulk powder, but is usually administered in a form prepared together with a pharmaceutical carrier. Specific examples thereof include tablets (including sugar-coated tablets and film-coated tablets), pills, capsules (including microcapsules), granules, fine granules, powders, syrups, emulsions, suspensions, and injections. Preparations, inhalants, ointments, eye drops, nasal drops and the like are used. These formulations are prepared according to a conventional method (for example, a method described in the Japanese Pharmacopoeia). Specifically, the tablet manufacturing method, as it is, the drug, excipients, binders, disintegrants or other suitable additives are added and uniformly mixed, granulated by an appropriate method, Add lubricants, etc. and press or mold, or the drug as it is, excipient, binder,
After disintegrating agent or other suitable additives are added and evenly mixed, they are directly compression-molded, or are directly mixed with pre-made granules, or after adding appropriate additives and evenly mixing, It can also be manufactured by compression molding. In addition, the present agent can contain a coloring agent, a flavoring agent, and the like as needed. Further, the agent can be coated with an appropriate coating agent. In the method of manufacturing an injection, a certain amount of a pharmaceutical is dissolved, suspended or emulsified in a vegetable oil or the like in the case of an aqueous solvent, such as water for injection, physiological saline, Ringer's solution, or a non-aqueous solvent, to a certain amount. Alternatively, a predetermined amount of a drug can be taken and sealed in a container for injection.

As the carrier for oral preparations, for example, substances commonly used in the field of preparations such as starch, mannitol, crystalline cellulose, sodium carboxymethylcellulose and the like can be used. As an injection carrier, for example,
Distilled water, physiological saline, glucose solution, infusion agent and the like are used. In addition, additives generally used in preparations can be appropriately added. In the preparation of the present invention, the content of compound [I] or a salt thereof varies depending on the form of the preparation.
%, Preferably about 0.1 to about 50% by weight, and more preferably about 0.5 to about 20% by weight. The dosage of these preparations varies depending on age, body weight, symptoms, administration route, administration frequency and the like. For example, for an adult asthmatic patient, the active ingredient (compound [I] or a salt thereof) per day
Usually, about 0.1 to about 100 mg / kg, preferably about 1 to about 50 mg / kg, more preferably about 1 to about 10 mg / kg
Is orally administered once or twice a day.
Furthermore, the compound [I] of the present invention or a salt thereof has excellent pharmaceutical properties, and is, for example, excellent in safety and stability and useful as a clinically useful drug (including prodrugs). is there.

[0061]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be more specifically described with reference to Examples, Preparation Examples and Experimental Examples, but the present invention is not limited to these. The detection of the fraction containing the target substance in Examples was carried out by TLC (Thin Layer Chromatography).
atography, thin layer chromatography). In TLC observation, 60F ₂₅₄ manufactured by Merck was used as a TLC plate, and ULC was used as a detection method.
A V detector was employed.

[0062]

【Example】

Reference Example 1 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [1, 2,
4] Production of triazolo [1,5-b] pyridazine 176 g of 2,2-dimethyl-3-hydroxy-1-propanesulfonamide and 6-chloro-7-isopropyl [1,2,4] triazolo [1,5- b] After dissolving 197 g of pyridazine in 2.0 L of tetrahydrofuran, a solution of 202 g of sodium-t-butoxide in 1.0 L of tetrahydrofuran was added, and the mixture was heated at 60 ° C for 80 minutes.
And heated to reflux. 2.0 kg of ice was added to the reaction solution, the pH was adjusted to 4.0 with 107 ml of concentrated hydrochloric acid, and tetrahydrofuran was distilled off under reduced pressure.
After washing with 0 L and 1.0 L of cold 50% acetone / water, 291.6 g of the crude title compound was obtained. The obtained crude title compound 29
1.6 g was dissolved by heating in 3.1 L of 66% ethanol, the insolubles were removed by filtration, and the mother liquor was stirred for 1.5 hours under ice-cooling, and the precipitated crystals were collected to give 264.1 g of the title compound. Mp 197-198 ° C. Elemental _{analysis: C 13 H 21 N 5 O} 3 Calculated S (%): C, 47.69 ; H, 6.46; N, 21.39 Found (%): C, 47.84; H, 6.60; N, 21.33

[0063]

Reference Example 2 Production of 6- (2,2-diethyl-3-sulfamoyl-1-propoxy) -7-methyl [1,2,4] triazolo [1,5-b] pyridazine 60% oily sodium hydride 0.672 g was suspended in 20 ml of N, N-dimethylformamide, and 2,2-diethyl-3-hydroxy-1-propanesulfonamide was prepared.
72 g was added and the mixture was stirred at room temperature under reduced pressure for 1 hour. Thereto was added 1.35 g of 6-chloro-7-methyl [1,2,4] triazolo [1,5-b] pyridazine, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. 70 ml of ice water in the reaction solution
Followed by 5N hydrochloric acid to adjust the pH to 6, and extracted three times with ethyl acetate: tetrahydrofuran (2: 1). The extract was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with dichloromethane: ethyl acetate: methanol (10: 10: 1). The fraction containing the desired compound was concentrated and recrystallized from ethanol to obtain 0.79 g of the title compound. Mp 189-192 ° C. Elemental _{analysis: C 13 H 21 N 5 O} 3 Calculated S · 0.5EtOH (%): C , 47.98; H, 6.90; N, 19.90 Found (%): C, 47.44; H , 6.84; N, 19.93

[0064]

Example 1 6- [2,2-Dimethyl-3- (N-acetylsulfamoyl) -1-propoxy] -7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine Production 6- (2,2-Dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine 10.0 g was added to acetic anhydride 50.
and 4.94 ml of pyridine was added thereto.
Stir at 0 ° C for 15 hours. After cooling, 250 ml of ice water was added and the mixture was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration, washed with water and ethyl ether, dried and dried to give the title compound 10.69.
g was obtained. Mp 188-190 ° C. Elemental _{analysis: C 15 H 23 N 5 O} 4 Calculated S (%): C, 48.77 ; H, 6.27; N, 18.96 Found (%): C, 48.59; H, 6.12; N, 18.85

[0065]

Example 2 Preparation of 6- [2,2-diethyl-3- (N-acetylsulfamoyl) -1-propoxy] -7-methyl [1,2,4] triazolo [1,5-b] pyridazine Production 6- (2,2-Diethyl-3-sulfamoyl-1-propoxy) -7-methyl [1,2,4] triazolo [1,5-b] pyridazine 3.0 g was added to acetic anhydride 20 ml.
And 1.5 ml of pyridine was added thereto.
Stir for hours. After cooling, add 100 ml of ice water and add
After stirring for an hour, the precipitated crystals were collected by filtration, washed with water and ethyl ether, and dried to obtain 3.05 g of the title compound. Mp 190-192 ° C. Elemental _{analysis: C 15 H 23 N 5 O} 4 Calculated S (%): C, 48.77 ; H, 6.27; N, 18.96 Found (%): C, 48.81; H, 6.17; N, 18.99

[0066]

Formulation Example 1 (1) Compound of Example 1 10.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Gelatin 3.0 mg (5) Magnesium stearate 2.0 mg Using a mixture of 10.0 mg of the obtained compound, 60.0 mg of lactose and 35.0 mg of corn starch in 0.03 ml of a 10% gelatin aqueous solution (3.0 mg as gelatin),
After granulating through a 1 mm mesh sieve, it was dried at 40 ° C. and sieved again. The granules thus obtained were mixed with 2.0 mg of magnesium stearate and compressed. The resulting core tablets were coated with a sugar coating in aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were polished with beeswax to obtain coated tablets.

[0067]

Formulation Example 2 (1) Compound of Example 1 10.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg Example 1 10.0 mg of the compound obtained in the above and 3.0 mg of magnesium stearate in 0.07 ml of an aqueous solution of soluble starch
(7.0 mg as soluble starch), dried and mixed with 70.0 mg of lactose and 50.0 mg of corn starch. The mixture was compressed to give tablets.

[0068]

Formulation Example 3 (1) 5.0 mg of the compound of Example 1 (2) 20.0 mg of salt (3) Distilled water The total amount is 2 ml 5.0 mg of the compound obtained in Example 1 and 20.0 mg of salt
Was dissolved in distilled water, and water was added to make a total volume of 2.0 ml.
The solution was filtered and filled under aseptic conditions into 2 ml ampules. The ampoule was sterilized and sealed to obtain a solution for injection.

[0069]

The compound [I] of the present invention or a salt thereof is
It has excellent anti-PAF action, eosinophil chemotaxis inhibitory action, etc., and is useful as a prophylactic / therapeutic agent for asthma, allergic rhinitis, atopic dermatitis and the like. Furthermore, the compound [I] of the present invention or a salt thereof is excellent in safety and stability and can be used as a prodrug.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/00 627 A61K 31/00 627 627H 637 637E 643 643D 31/50 603 31/50 603

Claims (8)

[Claims] 1. A compound of the general formula Wherein, A and B are one of the other represents CH, or both are CH nitrogen atom, R ¹ represents a hydrogen atom or an optionally substituted hydrocarbon group or a halogen atom, R ² And R ³ each represent a hydrogen atom or a hydrocarbon group which may have a substituent, and R ² and R ³ may be adjacent to each other by -C
ＣC— may form a 5- to 7-membered ring, X represents an oxygen atom or S (O) p (p is an integer of 0 to 2), and Y is a compound of the formula (Wherein R ⁴ and R ⁵ each represent a hydrogen atom or a hydrocarbon group which may have a substituent) or a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent And R ⁶ and R ^{7 each} represent an acyl group, the other represents a hydrogen atom or a hydrocarbon group which may have a substituent, and R ⁶ and R ⁷ are adjacent to each other. May form a lactam ring which may be substituted together with the nitrogen atom, and m and n each represent an integer of 0 to 4] or a salt thereof. 2. A compound of the general formula Wherein, R ^1a represents a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom, R ^2a and R
^3a represents a hydrogen atom, a lower alkyl group which may have a substituent or a cycloalkyl group which may have a substituent, and R ^2a and R ^3a are 5 to 5 together with an adjacent -C = C-. X ^a may represent an oxygen atom or S (O) p (p represents an integer of 0 to 2), and may form a 7-membered ring;
Y ^a is the formula: 4] Wherein R ^4a and R ^5a each represent a hydrogen atom or a lower alkyl group which may have a substituent, or a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent And R ^6a and R ^7a each have an acyl group, and the other has a hydrogen atom, a lower alkyl group which may have a substituent, or a substituent. a cycloalkyl group or an optionally substituted aryl group, R ^6a and R ^7a may be formed a good lactam ring optionally substituted together with the adjacent nitrogen atom, m ^a
The compound of claim 1, wherein represented by and n ^a represents an integer of 0 to 4, respectively]. R ^1a and R ^2a are a hydrogen atom, R ^3a is a lower alkyl group which may have a substituent, X ^a is an oxygen atom,
Y ^a is the formula: 5] (Wherein R ^4b and R ^5b each represent a hydrogen atom or a C _1-3 alkyl group), one of R ^6a and R ^7a is a hydrogen atom, and the other is a C _1-6 alkyl which may be substituted. carbonyl group, a compound of claim 2, wherein m ^a is and n ^a is an integer of 0-4. 4. A compound of the formula: 6- [2,2-dimethyl-3- (N-acetylsulfamoyl) -1-propoxy] -7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine. A compound according to claim 1. 5. A compound of the formula: 6- [2,2-diethyl-3- (N-acetylsulfamoyl) -1-propoxy] -7-methyl [1,2,4] triazolo [1,5-b] pyridazine. A compound according to claim 1. (1) General formula: Wherein Z ¹ represents a reactive group, A, B, R ¹ , R ² and R ³
Is the same as defined in claim 1] or a salt thereof and a compound of the general formula: [In the formula, Z ² represents a group capable of reacting with Z ¹ and leaving, X, Y, R
⁶ , R ⁷ , m and n have the same meanings as defined in claim 1] or a salt thereof, or (2)
General formula [In the formula, Z ² represents a group capable of reacting with Z ¹ and leaving;
¹ , R ² , R ³ and X have the same meaning as in claim 1.
And a salt thereof and a compound represented by the general formula: [Wherein Z ¹ represents a reactive group, Y, R ⁶ , R ⁷ , m and n
Has the same meaning as in claim 1) or a salt thereof, or (3) a compound of the general formula [Wherein, W represents a leaving group, A, B, R ¹ , R ² , R ³ ,
X, Y, m and n have the same meanings as defined in claim 1] or a salt thereof, and a compound represented by the general formula: Wherein R ⁶ and R ⁷ are as defined in claim 1.
Reacting with the compound represented by or a salt thereof,
(4) General formula [In the formula, Z ² represents a group capable of reacting with Z ¹ and leaving;
¹ , R ² , R ³ , X, Y, R ⁶ , m and n have the same meanings as defined in claim 1] or a salt thereof and a general formula Z ¹ -R ⁷ [IX] [wherein , Z ¹ is a reactive group, R ⁷ is as defined in claim 1, or a salt thereof, or (5) a compound of the general formula: [In the formula, Z ² represents a group capable of reacting with Z ¹ and leaving;
¹ , R ² , R ³ , X, Y, R ⁷ , m and n have the same meanings as defined in claim 1] or a salt thereof and a general formula Z ¹ -R ⁶ [XI] , Z ¹ is a reactive group, and R ⁶ has the same meaning as defined in claim 1], or a salt thereof. . [7] a pharmaceutical comprising the compound according to [1] or a salt thereof; 8. An anti-PAF agent, an eosinophil chemotactic inhibitor, an anti-asthmatic agent, an anti-allergic agent, an agent for preventing or treating allergic skin diseases, comprising the compound according to claim 1 or a salt thereof. An agent for preventing or treating allergic rhinitis or an agent for preventing or treating atopic dermatitis.