JP2856020B2 - Triazolopyridazine derivatives, their production, intermediates and agents - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel triazolopyridazine derivative, a method for producing the same, an intermediate and an agent. The triazolopyridazine derivative of the present invention has an antiallergic action, an anti-inflammatory action and an anti-PAF (platelet activating factor) action, and is effectively used as an antiasthmatic agent or the like by suppressing bronchospasm or bronchoconstriction.

[0002]

2. Description of the Related Art At present, while many triazolopyridazine compounds are being synthesized as effective drugs against various kinds of 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

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, disclosed in JP-A-62-292784.

Embedded image And salts thereof, which are disclosed to be useful as bronchodilators for reducing bronchospasm.

[0003]

However, although many kinds of anti-asthmatics are commercially available today, none of them have been developed yet which are satisfactory in terms of efficacy, sustainability and safety. Therefore, there is a need for the development of new compounds that exhibit more effective anti-allergic, anti-inflammatory, and anti-PAF effects and have excellent properties as anti-asthmatic agents such as durability and safety.

[0004]

Means for Solving the Problems The present inventors have proposed [1,
As a result of intensive studies on the chemical modification at the 6-position of [2,4] triazolo [1,5-b] pyridazine, a novel [1,2,2] in which the above-mentioned known compound is completely different in chemical structure from the 6-position substituent. 4] Producing a triazolo [1,5-b] pyridazine compound, which exhibits unexpectedly excellent antiallergic action, antiinflammatory action, anti-PAF action and excellent durability and safety. The present inventors have found that these compounds can be used as effective anti-asthmatic agents because they suppress bronchospasm and bronchoconstriction, and have completed the present invention based on these. That is, the present invention provides (1)
General formula

Embedded image [Wherein, R ¹ represents a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom, and R ² and R ³
Each represents a hydrogen atom or a lower alkyl group which may have a substituent; R ² and R ³ may form a 5- to 7-membered ring together with adjacent —C ＝ C—; 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 lower alkyl group which may have a substituent) or a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent A divalent group derived from R ⁶ and R ⁷
Represents a hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent or an aryl group which may have a substituent,
⁶ and R ⁷ may form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom, m represents an integer of 0 to 4, and n represents an integer of 0 to 4 . Or a salt thereof,

(2) The lower alkyl group which may have a substituent is hydroxy, amino, carboxyl, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 The compound according to the above (1), which is a C _1-6 alkyl group _optionally having 1 to 4 substituents selected from alkyl-carbonyloxy and a halogen atom; _5-7 The compound according to the above (1), which is a cycloalkene, benzene, pyrrole, pyridine or piperidine; (4) a divalent group derived from a 3- to 7-membered homocyclic ring

Embedded image A compound according to the above (1), wherein (5) a divalent group derived from a 3- to 7-membered heterocyclic ring is

Embedded image The compound according to the above (1), wherein (6) the cycloalkyl group optionally having a substituent is hydroxy, amino,
It may have 1 to 4 substituents selected from carboxyl, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 alkyl-carbonyloxy and halogen atom. The compound according to the above (1), which is a C _3-6 cycloalkyl group; (7) the aryl group optionally having a substituent may be a C _3-6 cycloalkyl group;
_1-6 alkyl, optionally substituted amino, acetamido, hydroxy, carboxyl, nitro, C _1-6
The compound according to the above (1), wherein the compound is a C _6-14 aryl group optionally having 1 to 5 substituents selected from alkoxy, C _1-6 alkyl-carbonyloxy and a halogen atom,

(8) An optionally substituted C _1-6 alkyl is hydroxy, amino, mono- or di-C
The compound according to the above (7), which is C _1-6 alkyl optionally having 1 to 4 substituents selected from _1-6 alkylamino, C _1-6 alkoxy and a halogen atom,
(9) The above-mentioned (7), wherein the amino which may have a substituent is an amino which may have one or two substituents selected from C _1-6 alkyl and 5- to 7-membered cyclic amino. The compound according to (10), wherein the nitrogen-containing heterocyclic group is

Embedded image The compound according to the above (1), wherein (11) a 3- to 7-membered homocyclic ring or an optionally substituted heterocyclic or nitrogen-containing heterocyclic group may be substituted _Optionally substituted C _1-6 alkyl, optionally substituted amino, hydroxy, carboxyl, nitro, C
The compound according to the above (1), which is 1 to 5 selected from _1-6 alkoxy and a halogen atom, and (12) the C _1-6 alkyl which may have a substituent is hydroxy, amino, mono- or It is carbonyloxy and one to four may have a substituent group C _1-6 alkyl selected from halogen atoms - di -C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 alkyl The compound according to the above (11), (13) the amino optionally having a substituent is
A compound according to the above (11), which is an amino optionally having one or two substituents selected from _1-6 alkyl, C _1-6 acyl and 5- to 7-membered cyclic amino, (14) R
(1) the compound according to the above (1), wherein ¹ is a hydrogen atom or a C _1-3 alkyl group, or (15) R ² and R ³ are each a hydrogen atom or a C _1-3 alkyl group, or (16) The compound according to the above (1), wherein Y forms a cyclohexene or benzene together with C = C-,

Embedded image Wherein R ⁴ ′ and R ⁵ ′ are (i) a hydrogen atom or (ii) hydroxy, amino, carboxyl, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy, C _{1 And} represents a C _1-3 alkyl group _optionally having 1 to 4 substituents selected from _-6 alkyl-carbonyloxy and a halogen atom. Or a group represented by

Embedded image (17) R ⁶ and R ⁷
Is a hydrogen atom or a C _1-3 alkyl group; (18) a compound according to (1), wherein X is an oxygen atom; (19) R ¹ , R ² and R ³ are each A hydrogen atom or a C _1-3 alkyl group;

Embedded image [Wherein R ^{4 ″} and R ^{5 ″} each represent a hydrogen atom or a C _1-3 alkyl group. Or a group represented by

Embedded image , R ⁶ and R ⁷ are each a hydrogen atom or a C _1-3 alkyl group, X is an oxygen atom, m is an integer of 1 to 3, and n is an integer of 1 to 4,
(20) R ¹ and R ² are both hydrogen atoms, R ³ is a C _1-3 alkyl group, and Y is a group represented by the formula

Embedded image [Wherein, R ⁴ ′ ″ and R ⁵ ″ ″ represent a C _1-3 alkyl group. Or a group represented by

Embedded image , R ⁶ and R ⁷ are both a hydrogen atom, X is an oxygen atom, m is 1, and n is an integer of 1 to 4,

(21) 6- (2,2-diethyl-3-sulfamoyl-1-propoxy) -7-methyl [1,
(2) 6- (2,2-Diethyl-6-sulfamoyl-1-hexyloxy) -7-, the compound according to (1), which is 2,4] triazolo [1,5-b] pyridazine.
The compound according to the above (1), which is methyl [1,2,4] triazolo [1,5-b] pyridazine;
The compound according to the above (1), which is (2,2-diethyl-5-sulfamoyl-1-pentyloxy) -7-methyl [1,2,4] triazolo [1,5-b] pyridazine, (24) 6 The compound according to the above (1), which is-(2,2-diethyl-4-sulfamoyl-1-butoxy) -7-methyl [1,2,4] triazolo [1,5-b] pyridazine;

(25) An anti-asthmatic agent containing the compound [I] or a salt thereof. (26) An anti-PAF agent containing the compound [I] or a salt thereof. (27) An antiallergic agent comprising the compound according to (1), (28) a general formula

Embedded image [In the formula, Z ¹ represents a reactive group, and R ¹ , R ² and R ³ have the same meaning as described above. A compound represented by the 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 are as defined above. A method for producing the compound according to the above (1), which comprises reacting the compound represented by the general formula (1)

Embedded image [Wherein, Z ² , 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. A method for producing the compound according to the above (1), which comprises reacting the compound represented by the formula (1) or a salt thereof,

(30) General formula

Embedded image [Wherein, W represents a leaving group, R ¹ , R ² , R ³ , X, Y,
m and n are as defined above. A compound represented by the general formula

Embedded image Wherein R ⁶ and R ⁷ are as defined above. A process for producing the compound according to the above (1), which comprises reacting the compound represented by the general formula (1)

Embedded image [Wherein, R ¹ , R ² , R ³ , X, Y, W, m and n have the same meaning as described above. Or a salt thereof. 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.

As used herein, the term "lower alkyl" means, for example, a linear or branched C _1-6 alkyl group. As the C _1-6 alkyl group, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, n-hexyl and the like are used. The term “cycloalkyl group” means, for example, a C _3-6 cycloalkyl group. C
_{As the 3-6} cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like are used. The term "aryl" refers to, for example, C
_6-14 means an aryl group or the like. 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, ethylamino, propyl Mono- or di-C _1-6 alkylamino such as amino, dimethylamino, diethylamino and the like, lower alkoxy (for example, methoxy, ethoxy, propoxy,
C _1-6 alkoxy such as hexyloxy, etc.), lower alkylcarbonyloxy (eg, C _1-6 alkylcarbonyloxy such as acetoxy, ethylcarbonyloxy, etc.) and halogen atoms (fluorine, chlorine, bromine,
1 to 4 selected from iodine and the like are used.

Examples of the substituent which the "aryl group" may have include lower alkyl which may have a substituent, amino which may have a substituent, amino, acetamido, hydroxy, carboxyl, Nitro, lower alkoxy (eg, methoxy, ethoxy, propoxy, etc.
_C1-6 alkoxy, etc.), lower alkyl - carbonyloxy (e.g., selected acetoxy, C _1-6, etc. alkylcarbonyloxy) and halogen atoms (fluorine, such as ethyl carbonyloxy, chlorine, bromine, iodine) or the like 1 ~ 5 are used. Here, lower alkyl (for example, C _1-6 such as methyl, ethyl, n-propyl, etc.)
Examples of the substituent which the alkyl group may have include, for example, a mono- or di-amino such as hydroxy, amino, mono- or di-lower alkylamino (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino and the like). -C _1-6 alkylamino, etc.), lower alkoxy (eg, C _1-6 alkoxy such as methoxy, ethoxy, propoxy, hexyloxy, etc.) and halogen atoms (fluorine, chlorine, bromine, iodine, etc.). One to four are used. Examples of the substituent which the amino group may have include, for example, C _1-6 alkyl (eg, methyl, ethyl, propyl, etc.) and 5- to 7-membered cyclic amino (eg, pyrrolidino, morpholino, piperidino, piperazino, etc.) One or two selected from the following are used. As the term "halogen atom", for example, fluorine, chlorine, bromine, iodine and the like are used.

The term "5- to 7-membered ring formed with adjacent -C = C-" means, for example, 1 to 4 hetero atoms selected from nitrogen, oxygen, sulfur and the like in addition to carbon. It means a 5- to 7-membered ring which may contain an atom. Specifically, 5- or 6-membered cyclic hydrocarbons such as C _5-7 cycloalkenes such as cyclopentene, cyclohexene and cycloheptene and benzene and the like, and 5- or 6-membered carbon and nitrogen atoms such as pyrrole, pyridine and piperidine. Nitrogen-containing heterocycles and the like are frequently used. The term "3- to 7-membered homocyclic ring" means, for example, a 3- to 7-membered cyclic hydrocarbon consisting only of carbon atoms. Specifically, for example, C _3-7 cycloalkane such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, for example, cyclopropene,
C _3-7 cycloalkenes such as cyclobutene, cyclopentene, cyclohexene and cycloheptene, and benzene are frequently used. The divalent group derived from the “3- to 7-membered homocyclic ring” refers to a hydrogen atom from one carbon atom in the above-mentioned 3- to 7-membered cyclic hydrocarbon or two different hydrogen atoms. It means a divalent group in which one hydrogen atom is removed from each carbon atom. Specifically, for example,

Embedded image Etc. are used, and preferably

Embedded image Etc., more preferably

Embedded image Are often used.

The term "3- to 7-membered heterocyclic ring" refers to a 3- to 7-membered heterocyclic ring which may contain, for example, 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur and the like in addition to carbon. It means a 7-membered heterocyclic ring and the like. 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” means two hydrogen atoms from the same carbon atom in the above-mentioned 3- to 7-membered heterocyclic ring, or two hydrogen atoms from two different atoms, respectively. It means a divalent group from which one hydrogen atom has been removed. In particular,
For example

Embedded image Are used. The term “nitrogen-containing heterocyclic group” includes, for example, one nitrogen atom, and may further include, for example, one to three heteroatoms selected from a nitrogen atom, an oxygen atom, a sulfur atom, and the like. Or a group in which one hydrogen atom has been removed from a nitrogen atom in a ring such as a 13-membered nitrogen-containing heterocycle. Specifically, for example,

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

The "3- to 7-membered homocyclic ring", "3 to 7"
Examples of the substituent which the “membered heterocycle” and the “nitrogen-containing heterocyclic group” may have include, for example, lower alkyl optionally having a substituent, amino optionally having a substituent, hydroxy, Carboxyl, nitro, lower alkoxy (for example, C _1-6 alcohol such as methoxy, ethoxy, propoxy, etc.)
Xy) and halogen atoms (fluorine, chlorine, bromine,
1 to 5 selected from iodine and the like are used. Where lower alkyl (eg, methyl, ethyl,
Examples of the substituent which the C _1-6 alkyl group such as n-propyl may have include, for example, hydroxy, amino, mono- or di-lower alkylamino (eg, methylamino, ethylamino, propylamino, dimethyl amino,
Mono- or di-C _1-6 alkylamino such as diethylamino and the like, lower alkoxy (eg C _1-6 alkoxy such as methoxy, ethoxy, propoxy and hexyloxy), lower alkylcarbonyloxy (eg acetyloxy, C such as ethylcarbonyloxy
One to four selected from _1-6 alkyl-carbonyloxy, 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 (for example, methyl, ethyl, propyl and the like), acyl (for example, C _1-6 alkyl such as formyl, acetyl, propionyl and butyryl)
One or two members selected from _1-6 acyl and the like and 5- to 7-membered cyclic amino (for example, pyrrolidino, morpholino, piperidino, piperazino and the like) are used.

In the above formula, R ¹ represents a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom. As R ¹ , for example, a hydrogen atom or C _1-3 alkyl (eg, methyl, ethyl, n-propyl, etc.) is preferable, and a hydrogen atom is particularly frequently used. R ² and R ³ each represent a hydrogen atom or a lower alkyl group which may have a substituent, and R ² and R ³ are adjacent to each other by —C ＝ C
And-may form a 5- to 7-membered ring. As R ² , for example, a hydrogen atom, C _1-3 alkyl (for example, methyl
, Ethyl, n-propyl and the like). In particular, hydrogen atoms and the like are frequently used. As R ³ , for example, a hydrogen atom or a C _1-3 alkyl group (eg, methyl, ethyl, n-propyl, etc.) is preferable, and a C _1-3 alkyl group is particularly frequently used. Further, R ² and R ³ are adjacent to each other.
It is also preferable to form a 5- to 7-membered cyclic hydrocarbon together with-, particularly to form cyclohexene, benzene and the like. X is an oxygen atom or S (O) p (p is 0
Or an integer of 2). X is preferably, for example, an oxygen atom or S, and particularly an oxygen atom is frequently used. Y is the formula

Embedded image [Wherein, R ⁴ and R ⁵ have the same meaning as described above. Or a divalent group derived from a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent. Y
Is, for example, the formula

Embedded image Wherein R ⁴ ′ and R ⁵ ′ are as defined above. And the like are preferred. The “C _1-3 alkyl group” represented by R ⁴ ′ and R ⁵ ′ is methyl, ethyl,
n-propyl, i-propyl is the “C _1-3 alkyl group”
As the “substituent” which may be possessed, the same as the substituent which the “lower alkyl” may have are used. Preferred R ⁴ ′ and R ⁵ ′ include a hydrogen atom or C _1-3 alkyl (eg, methyl, ethyl, n-propyl and the like), particularly C _1-3 alkyl (eg, methyl, ethyl, n-propyl). Etc.) are frequently used.
Further, it is also preferable that Y is a divalent group derived from a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent, for example,

Embedded image And more preferably

Embedded image Are often used, especially

Embedded image Is the most frequently used.

R ⁶ and R ⁷ are each 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. And R ⁶ and R ⁷ may form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom. R ⁶ and R ⁷ are, for example, a hydrogen atom, C
_1-3 alkyl (for example, methyl, ethyl, n-propyl and the like) and the like are preferable, and particularly a hydrogen atom and the like are 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,
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 salt of the 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) And tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid and benzenesulfonic acid). 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,
Salts may be formed with alkali metals or alkaline earth metals, such as potassium, calcium, magnesium, ammonia, etc.) or organic bases, such as 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 , R ¹ , R ² and R ³ have the same meaning as described above. A compound represented by the general formula

Embedded image [In the formula, Z ² , X, Y, R ⁶ , R ⁷ , m and n have the same meanings as described above. Or a salt thereof. Examples of the reactive group represented by Z ¹ include halogen (eg, chlorine, bromine, iodine), C _6-10 arylsulfonyloxy (eg, benzenesulfonyloxy, p-tolylsulfonyloxy), and C _1-4 alkylsulfonyl. Oxy (for example, methanesulfonyloxy) or the like is used. Z
^When X is an oxygen atom or a sulfur atom, for example, a hydrogen atom or an alkali metal such as sodium, potassium or the like is used as a group which is removed by reacting with Z ¹ represented by ² , and X is -SO- Alternatively, in the case of -SO _2- , an alkali metal such as sodium or potassium is used. In this reaction, compound [III] or a salt thereof is added to 1 mol of compound [II] or a salt thereof,
Usually, 1 to 5 mol, preferably 1 to 2 mol is used. This reaction is usually carried out in the presence of a base, such as 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 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, and amides such as dimethylformamide and dimethylacetamide. And an inert solvent such as sulfoxides such as dimethyl sulfoxide. The reaction temperature is usually 10 to 200 ° C, preferably 50 to 100 ° C. The reaction time is generally 30 minutes to 24 hours, preferably 1 to 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 , 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,
Compound [V] per mole of compound [IV] or a salt thereof
Or 1 to 5 mol, preferably 1 to 2 mol of a salt thereof is used. This reaction is usually carried out in the presence of a base, such as 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 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, and amides such as dimethylformamide and dimethylacetamide. And an inert solvent such as sulfoxides such as dimethyl sulfoxide. The reaction temperature is usually 10 to 20
0 ° C., preferably 50 to 150 ° C. The reaction time is generally 30 minutes to 24 hours, preferably 1 to 1 hour.
0 hours.

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

Embedded image Wherein W, R ¹ , R ² , R ³ , X, Y, m and n have the same meaning 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 halogen (eg, chlorine, bromine, iodine), C _6-10 arylsulfonyloxy (eg, benzenesulfonyloxy, p-tolylsulfonyloxy), and C _1-4 alkylsulfonyl. Oxy (for example, methanesulfonyloxy)
And the like, and among them, halogen (eg, chlorine, bromine, iodine) and the like are preferable. In this reaction, the compound [VII] or a salt thereof is used in an amount of usually 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of the compound [VI] or a salt thereof. This reaction is usually carried out using alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, nitriles such as acetonitrile, and amides such as dimethylformamide and dimethylacetamide. And an inert solvent such as sulfoxides such as dimethyl sulfoxide. The reaction temperature is generally -20 to 100C, preferably -10 to 50C. The reaction is usually performed for 30 minutes to 5 hours,
Preferably, it is 1 to 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],
The method for producing [V], [VI] and [VII] or a salt thereof will be described. Salts of these compounds include, for example, salts with inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid),
Alternatively, organic acids (eg, acetic acid, formic acid, propionic acid,
Fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid,
For example, salts with malic acid, oxalic acid, benzoic acid, methanesulfonic acid, and 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, or magnesium) or an organic base (E.g., tri-C _1-3 alkylamine such as triethylamine).

The starting compound [II] or a salt thereof can be prepared, for example, by the method described in Journal of Organic Chemistry (J. Or
g. Chem.) 39, 2143 (1974) or a method analogous thereto. The starting compound [III] or a salt thereof and the compound [V] or a salt thereof can be prepared, for example, by using Chem. Beriche (Chem. Be.
r.) 91, 2130 pages (1958), Journal
Of Organic Chemistry (J. Org. Chem.)
52, 2162 (1987), JP-A-3-22
It can be synthesized by the method described in 3287 or the like or a method analogous thereto. The starting compound [IV] or a salt thereof is described in, for example, JP-A-3-2.
It can be manufactured by the method described in 23287 or the like or a method analogous thereto. The starting compound [VI] or a salt thereof is, for example, a compound represented by the formula (1):

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 [VIII] is used usually in an amount of 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of the compound [II] or 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 [IX] is usually used in an amount of 1 to 5 mol per 1 mol of the compound [IV] or a salt thereof,
Preferably, 1 to 2 mol is 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. Starting compound [VII] or a salt thereof, starting compound [VIII]
And the starting compound [IX] can be produced 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,
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 is from 1 There are about three. As a carboxyl protecting group,
For example, optionally substituted C _1-6 alkyl (eg, methyl, ethyl, n-propyl, i-propyl, n
-Butyl, tert-butyl and the like), phenyl, trityl, silyl and the like. As these substituents, a halogen atom (eg, fluoro, chloro, bromo, iodo, etc.), formyl, C _1-6 alkyl-carbonyl (eg, acetyl, ethylcarbonyl, butylcarbonyl, etc.), a nitro group and the like are used. And the number of substituents is about 1 to 3.

Examples of the hydroxyl-protecting group include C _1-6 alkyl which may have a substituent (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, etc.) Phenyl, C _7-10 aralkyl (eg, benzyl), formyl, C _1-6 alkyl-carbonyl (eg, acetyl, ethylcarbonyl, etc.), phenyloxycarbonyl, benzoyl, C
_7-10 aralkyl-carbonyl (such as benzylcarbonyl), pyranyl, furanyl, silyl and the like are used. These substituents include a halogen atom (eg, fluoro, chloro, bromo, iodo, etc.), C _1-6
Alkyl (for example, methyl, ethyl, n-propyl and the like), phenyl, _C7-10 aralkyl (for example, benzyl and the like), nitro group and the like are used, and the number of substituents is about 1 to 4. Further, as a method for removing the protecting group,
A method known per se or a method similar thereto is used,
For example, a method of treating with acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or the like is used.

The compound [I] of the present invention or a salt thereof is
It has excellent anti-allergic, anti-inflammatory and anti-PAF (platelet activating factor) effects and low toxicity (acute toxicity: LD ₅₀ > 2 g / kg). , Rats, cattle, etc.) as safe anti-asthmatic agents. 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, capsules, granules, fine granules, powders, syrups, injections, and inhalants. These preparations are prepared according to a conventional method. As the carrier for oral preparations, for example, substances commonly used in the field of oral preparations such as starch, mannitol, crystalline cellulose and sodium carboxymethylcellulose are used. As the carrier for injection, for example, distilled water, physiological saline, glucose solution, infusion agent and the like are used. In addition, additives generally used in pharmaceutical preparations can be appropriately added. The dosage of these preparations varies depending on age, body weight, symptoms, administration route, number of administrations and the like.
/ Kg, more preferably 1 to 10 mg / kg, 1 or 2 times daily
It is advisable to administer it in divided doses. The administration route may be oral or parenteral.

[0025]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, Formulation Examples, and Experimental Examples, but the present invention is not limited thereto. The detection of the fraction containing the target substance in Examples was carried out by TLC (Thin Layer Chromat
ography, thin layer chromatography). In the TLC observation, the 60F ₂₅₄ Merck (Merck) manufactured as a TLC plate, UV as detection method
A detector was adopted. Example 1 Preparation of 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) [1,2,4] triazolo [1,5-b] pyridazine 60% oily sodium hydride 0.42 g was added to dimethylformamide After suspending in 15 ml, 3-hydroxy-2,2-dimethyl-1-propanesulfonamide (0.878 g) was added, and the mixture was stirred at room temperature under reduced pressure for 30 minutes, and then treated with 6-chloro [1,2,4] triazolo [ 0.773 g of [1,5-b] pyridazine was added and stirred at room temperature for 1 hour. 40 ml of ice water was added to the reaction solution, followed by 1N hydrochloric acid to adjust the pH to 6;
The precipitated crystals were collected by filtration and washed with 20 ml of water and 20 ml of ethyl ether. The obtained crystals were recrystallized from hot ethanol to give 1.16 g of the title compound. Mp 181-184 ° C. Elemental _{analysis: C 10 H 15 N 5 O} 3 Calculated S (%): C, 42.10 ; H, 5.30; N, 24.55 Found (%): C, 41.87; H, 5.28; N, 24.59

Example 2 Preparation of 6- (2,2-diethyl-3-sulfamoyl-1-propoxy) [1,2,4] triazolo [1,5-b] pyridazine 60% oily sodium hydride 0.64 g Was suspended in 20 ml of dimethylformamide, 1.56 g of 3-hydroxy-2,2-diethyl-1-propanesulfonamide was added, and the mixture was stirred at room temperature under reduced pressure for 30 minutes. ] Triazolo [1,5-b] pyridazine (1.24 g) was added, and the mixture was stirred at room temperature for 1.5 hours. 100 ml of ice water was added to the reaction solution, followed by 1N hydrochloric acid.
The precipitate was taken as H6, and the precipitated crystals were collected by filtration and washed with 20 ml of water and 20 ml of ethyl ether. The obtained crystals were recrystallized from hot ethanol to give 1.57 g of the title compound. Melting point: 194 ° -197 ° C. Elemental analysis: C ₁₂ H ₁₉ N ₅ O ₃ S.0.5 EtOH Calculated (%): C, 46.41; H, 6.59; N, 20.82 Found (%): C, 46.33; H, 6.68; N, 20.99

Example 3 Preparation of 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-methyl [1,2,4] triazolo [1,5-b] pyridazine 3-hydroxy-2 , 2-Dimethyl-1-propanesulfonamide (0.44 g) was dissolved in tetrahydrofuran (5 ml), N, N-dimethylformamide dimethyl acetal (0.5 ml) was added, the mixture was allowed to stand at room temperature for 10 hours, and concentrated under reduced pressure. Dissolve in 4 ml, 60
After adding 0.2 g of oily sodium hydride and stirring at room temperature under reduced pressure for 30 minutes, 0.37 g of 6-chloro-7-methyl [1,2,4] triazolo [1,5-b] pyridazine was added. In addition, the mixture was stirred at room temperature (about 15 to 20 ° C.) for 1 hour. The reaction mixture was added with 50 ml of ice water, followed by 30 ml of 1N hydrochloric acid and refluxed for 1 hour, and then adjusted to pH 6 with sodium hydrogen carbonate. The precipitated crystals were collected by filtration and recrystallized from aqueous methanol to give the title compound 0. .1
2 g were obtained. Melting point: 216-218 ° C Elemental analysis: C ₁₁ H ₁₇ N ₅ O ₃ S Calculated (%): C, 44.14; H, 5.72; N, 23.39 Found (%): C, 44.13; H, 5.74; N, 23.19

Example 4 Preparation of 7,8-dimethyl-6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) [1,2,4] triazolo [1,5-b] pyridazine 60% oil 1.38 g of sodium hydride was suspended in 30 ml of dimethylformamide, 2.51 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide was added, and the mixture was stirred at room temperature under reduced pressure for 1 hour. There, 6-chloro-7,8-dimethyl [1,2,4] triazolo [1,5
-B] 2.56 g of pyridazine was added, and the mixture was stirred at room temperature for 3 hours. 100 ml of ice water was added to the reaction solution, followed by adding 5N hydrochloric acid to adjust the pH to 6, and extraction was performed three times with ethyl acetate: tetrahydrofuran (2: 1).
And dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.
Elution was carried out with dichloromethane: methanol (30: 1).
The fraction containing the desired compound was concentrated to obtain 0.63 g of the title compound. Mp 175-177 ° C. Elemental _{analysis: C 12 H 19 N 5 O} 3 Calculated S (%): C, 45.99 ; H, 6.11; N, 22.35 Found (%): C, 46.27; H, 6.14; N, 22.16

Example 5 6- (2,2-Diethyl-3-sulfamoyl-1-propoxy) -7-methyl [1,2,4] triazolo [1,
5-b] Production of pyridazine 0.672 g of 60% oily sodium hydride was suspended in 20 ml of dimethylformamide, and 3-hydroxy-2,2-
1.72 g of diethyl-1-propanesulfonamide was added, and the mixture was stirred at room temperature under reduced pressure for 1 hour. There 6-chloro-7-methyl [1,2,4] triazolo [1,5-b]
1.35 g of pyridazine was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. 70 ml of ice water was added to the reaction solution, followed by adding 5N hydrochloric acid to adjust the pH to 6, followed by extraction three times with ethyl acetate: tetrahydrofuran (2: 1). The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and dichloromethane: ethyl acetate: methanol (10: 9) was used.
10: 1). The fraction containing the desired product was concentrated, and 50 ml of 5N hydrochloric acid was added to the residue, and the mixture was heated under reflux for 30 minutes.
After cooling, the mixture was concentrated under reduced pressure, water was added to the residue, water was added, and the mixture was extracted three times with ethyl acetate: tetrahydrofuran (1: 1). The extract was washed once with a saturated saline solution and dried over magnesium sulfate. . After concentration under reduced pressure, the residue was recrystallized from hot 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

Example 6 Preparation of 6- (2,2-diethyl-3-sulfamoyl-1-propoxy) -7-methyl [1,2,4] triazolo [1,5-b] pyridazine 1.38 g of (N-dimethylaminomethylene) aminosulfonyl-2,2-diethyl-1-propanol
Was added to a solution of 30 ml of tetrahydrofuran in 0.23 g of 60% oily sodium hydride, and the mixture was stirred at room temperature for 1 hour.
0.74 g of 6-chloro-7-methyl [1,2,4] triazolo [1,5-b] pyridazine was added to the reaction mixture,
The mixture was heated under reflux for 1 hour under stirring. After cooling, the reaction solution was adjusted to pH 6 with 1N hydrochloric acid, and ethyl acetate: tetrahydrofuran (1: 1) was added.
Extracted in 1). After the extract was washed with water and dried, the solvent was distilled off, and 14 ml of 6N hydrochloric acid was added to the residue, followed by stirring at 110 ° C. for 30 minutes. After cooling, 100 ml of water was added to the reaction solution, and the precipitated crystals were collected by filtration. Recrystallization from methanol gave 1.16 g of the title compound. Melting point: 208-209 ° C Elemental analysis: C ₁₃ H ₂₁ N ₅ O ₃ S Calculated (%): C, 47.69; H, 6.46; N, 21.39 Found (%): C, 47.46; H, 6.44 N, 21.59 This product was recrystallized from hot ethanol to give the ethanol-containing crystals obtained in Example 5.

Example 7 6- (2,2-Dimethyl-4-sulfamoyl-1-butoxy) -7-methyl [1,2,4] triazolo [1,
Preparation of 5-b] pyridazine Performed using 4-hydroxy-3,3-dimethyl-1-butanesulfonamide and 6-chloro-7-methyl [1,2,4] triazolo [1,5-b] pyridazine The title compound was prepared as in Example 5. Melting point: 214-215 ° C. Elemental analysis: C ₁₂ H ₁₉ N ₅ O ₃ S Calculated (%): C, 45.99; H, 6.11; N, 22.35 Found (%): C, 45.80; H, 5.91 N, 22.56 NMR (d ₆ -DMSO) δ: 1.06 (6H, s), 1.80-1.95 (2
H, m), 2.33 (3H, s), 2.97-3.09 (2H, m), 4.09 (2H, s), 6.75 (2
H, s), 8.16 (1H, s), 8.38 (1H, s).

Example 8 Preparation of 6- (2,2-dimethyl-5-sulfamoyl-1-pentyloxy) -7-methyl [1,2,4] triazolo [1,5-b] pyridazine The title compound was prepared in the same manner as in Example 5 using 4,4-dimethyl-1-pentanesulfonamide and 6-chloro-7-methyl [1,2,4] triazolo [1,5-b] pyridazine. . Mp: 171-172 ° C. Elemental _{analysis: C 13 H 21 N 5 O} 3 Calculated S (%): C, 47.69 ; H, 6.46; N, 2
1.39 found (%): C, 47.45; H, 6.39;
N, 21.18 NMR (CDCl ₃ ) δ: 1.05 (6H, s), 1.45-1.59 (2H, m),
1.66-1.82 (2H, m), 2.33 (3H, s), 2.96 (2H, t, J = 7.8Hz), 4.08
(2H, s), 6.72 (2H, bs), 8.15 (1H, s), 8.37 (1H, s).

Example 9 Preparation of 6- (2,2-dimethyl-6-sulfamoyl-1-hexyloxy) -7-methyl [1,2,4] triazolo [1,5-b] pyridazine The title compound was prepared in the same manner as in Example 5 using 5,5-dimethyl-1-hexanesulfonamide and 6-chloro-7-methyl [1,2,4] triazolo [1,5-b] pyridazine. . Mp: 161-163 ° C. Elemental _{analysis: C 14 H 23 N 5 O} 3 Calculated S (%): C, 49.25 ; H, 6.79; N, 20.51 Found (%): C, 48.99; H, 6.68 N, 20.74 NMR (d ₆ -DMSO) δ: 1.05 (6H, s), 1.38-1.60 (4
H, m), 1.67-1.98 (4H, m), 2.37 (3H, s), 3.15 (2H, t, J = 7.8H
z), 4.14 (2H, s), 4.77 (2H, bs), 7.78 (1H, s), 8.25 (1H, s).

Example 10 Preparation of 6- (2,2-diethyl-6-sulfamoyl-1-hexyloxy) -7-methyl [1,2,4] triazolo [1,5-b] pyridazine The title compound was produced in the same manner as in Example 5 using 5,5-diethyl-1-hexanesulfonamide and 6-chloro-7-methyl [1,2,4] triazolo [1,5-b] pyridazine. . Melting point: 132-133 ° C Elemental analysis: C ₁₆ H ₂₇ N ₅ O ₃ S Calculated (%): C, 52.01; H, 7.37; N, 18.95 Found (%): C, 51.89; H, 7.10 N, 19.08 NMR (CDCl ₃ ) δ: 0.85 (6H, t, J = 7.4 Hz), 1.35-1.55
(8H, m), 1.78-1.98 (2H, m), 3.13 (2H, t, J = 8.0Hz), 4.18 (2H, m
s), 4.76 (2H, bs), 7.77 (1H, s), 8.25 (1H, s).

Example 11 Preparation of 6- (2,2-diethyl-5-sulfamoyl-1-pentyloxy) -7-methyl [1,2,4] triazolo [1,5-b] pyridazine 5-hydroxy- The title compound was produced in the same manner as in Example 5 using 4,4-diethyl-1-pentanesulfonamide and 6-chloro-7-methyl [1,2,4] triazolo [1,5-b] pyridazine. . Melting point: 157-158 ° C NMR (CDCl ₃ ) δ: 0.86 (6H, t, J = 7.4 Hz), 1.46 (4H,
q, J = 7.4Hz), 1.48 (2H, t, J = 7.6Hz), 1.79-1.98 (2H, m), 2.36
(3H, s), 3.07 (2H, t, J = 7.6Hz), 4.21 (2H, s), 5.54 (2H, bs),
7.76 (1H, s), 8.24 (1H, s).

Example 12 6- (2,2-Diethyl-4-sulfamoyl-1-butoxy) -7-methyl [1,2,4] triazolo [1,
Production of 5-b] pyridazine 4- (N, N-dimethylaminomethylene) aminosulfonyl-2,2-diethyl-1-butanol and 6-chloro-7-methyl [1,2,4] triazolo [1,5 -B]
The title compound was produced in the same manner as in Example 6 using pyridazine. Melting point: 148-149 ° C Elemental analysis: C ₁₄ H ₂₃ N ₅ O ₃ S Calculated (%): C, 49.25; H, 6.79; N, 20.51 Found (%): C, 48.99; H, 6.68 _{; N, 20.24 NMR (d 6} -DMSO) δ: 0.84 (6H, t, J = 7.0Hz), 1.42
(4H, q, J = 7.0Hz), 1.76-1.91 (2H, m), 2.31 (3H, s), 2.89-3.0
3 (2H, m), 4.11 (2H, s), 6.77 (2H, bs), 8.15 (1H, s), 8.39 (1H,
s).

Example 13 6- (2,2-pentamethylene-3-sulfamoyl-
Preparation of 1-propoxy) -7-methyl [1,2,4] triazolo [1,5-b] pyridazine 3- (N, N-dimethylaminomethylene) aminosulfonyl-2,2-pentamethylene-1-propanol And 6
-Chloro-7-methyl [1,2,4] triazolo [1,
5-b] The title compound was produced in the same manner as in Example 6 using pyridazine. Melting point: 268-270 ° C Elemental analysis: C ₁₄ H ₂₁ N ₅ O ₃ S Calculated (%): C, 49.54; H, 6.24; N, 20.63 Found (%): C, 49.19; H, 6.22 N, 20.40 NMR (d ₆ -DMSO) δ: 1.28-1.89 (10H, m), 2.34 (3
H, s), 3.34 (2H, s), 4.43 (2H, s), 6.94 (2H, bs), 8.16 (1H, s),
8.39 (1H, s).

Example 14 Preparation of 6- (3,3-dimethyl-5-sulfamoyl-1-pentyloxy) -7-methyl [1,2,4] triazolo [1,5-b] pyridazine 5- (N , N-Dimethylaminomethylene) aminosulfonyl-3,3-dimethyl-1-pentanol and 6-chloro-7-methyl [1,2,4] triazolo [1,5-
b] The title compound was produced in the same manner as in Example 6 using pyridazine. Melting point: 143 ° -144 ° C. Elemental analysis: C ₁₃ H ₂₁ N ₅ O ₃ S Calculated (%): C, 47.69; H, 6.46; N, 21.39 Found (%): C, 47.50; H, 6.53 N, 21.13 NMR (d ₆ -DMSO) δ: 1.00 (6H, s), 1.66-1.89 (4
H, m), 2.30 (3H, s), 2.94-3.10 (2H, m), 4.43 (2H, t, J = 6.8H
z), 6.77 (2H, bs), 8.16 (1H, s), 8.39 (1H, s).

Example 15 Preparation of 6- (4,4-dimethyl-6-sulfamoyl-1-hexyloxy) -7-methyl [1,2,4] triazolo [1,5-b] pyridazine , N-Dimethylaminomethylene) aminosulfonyl-4,4-dimethyl-1-hexanol and 6-chloro-7-methyl [1,2,4] triazolo [1,5-
b] The title compound was produced in the same manner as in Example 6 using pyridazine. Melting point: 154-155 ° C Elemental analysis: C ₁₄ H ₂₃ N ₅ O ₃ S Calculated (%): C, 49.25; H, 6.79; N, 20.51 Found (%): C, 48.98; H, 7.02 N, 20.86 NMR (d ₆ -DMSO) δ: 0.91 (6H, s), 1.29-1.46 (2
H, m), 1.57-1.88 (4H, m), 2.30 (3H, s), 2.85-3.04 (2H, m), 4.
35 (2H, t, J = 6.3Hz), 6.75 (2H, bs), 8.15 (1H, s), 8.37 (1H,
s).

Example 16 6- (2,2-pentamethylene-4-sulfamoyl-
Preparation of 1-butoxy) -7-methyl [1,2,4] triazolo [1,5-b] pyridazine 4- (N, N-dimethylaminomethylene) aminosulfonyl-2,2-pentamethylene-1-butanol And 6-
Chloro-7-methyl [1,2,4] triazolo [1,5
-B] The title compound was produced in the same manner as in Example 6 using pyridazine. Melting point: 208-209 ° C Elemental analysis: C ₁₅ H ₂₃ N ₅ O ₃ S Calculated (%): C, 50.97; H, 6.56; N, 19.81 Found (%): C, 51.24; H, 6.55 _{; N, 19.58 NMR (d 6} -DMSO) δ: 1.32-1.65 (10H, m), 1.86-
2.03 (2H, m), 2.32 (3H, s), 2.90-3.04 (2H, m), 4.16 (2H, s),
6.75 (2H, bs), 8.14 (1H, s), 8.38 (1H, s).

Example 17 Preparation of 6- (2-isopropyl-3-sulfamoyl-1-propoxy) -7-methyl [1,2,4] triazolo [1,5-b] pyridazine 3- (N, N- Dimethylaminomethylene) aminosulfonyl-2-isopropyl-1-propanol and 6-chloro-7-methyl [1,2,4] triazolo [1,5-
b] The title compound was produced in the same manner as in Example 6 using pyridazine. Melting point: 196-197 ° C Elemental analysis: C ₁₂ H ₁₉ N ₅ O ₃ S Calculated (%): C, 45.99; H, 6.11; N, 22.35 Found (%): C, 45.85; H, 6.18 _{; N, 22.00 NMR (d 6} -DMSO) δ: 0.97 (3H, d, J = 6.8Hz), 0.98
(3H, d, J = 6.8Hz), 1.98-2.19 (1H, m), 2.25-2.43 (1H, m), 2.3
1 (3H, s), 3.03-3.27 (2H, m), 4.40-4.59 (2H, m), 6.93 (2H, b
s), 8.16 (1H, s), 8.39 (1H, s).

Example 18 6- (2-Ethyl-2-methyl-3-sulfamoyl-
Production of 1-propoxy) -7-methyl [1,2,4] triazolo [1,5-b] pyridazine 3- (N, N-dimethylaminomethylene) aminosulfone-2-ethyl-2-methyl-1-methyl-1- Propanol and 6-
Chloro-7-methyl [1,2,4] triazolo [1,5
-B] The title compound was produced in the same manner as in Example 6 using pyridazine. Melting point: 189-190 ° C Elemental analysis: C ₁₂ H ₁₉ N ₅ O ₃ S Calculated (%): C, 45.99; H, 6.11; N, 22.35 Found (%): C, 46.17; H, 6.18 N, 22.19 NMR (d ₆ -DMSO) δ: 0.90 (3H, t, J = 7.4 Hz), 1.20
(3H, s), 1.66 (2H, q, J = 7.4Hz), 2.34 (3H, s), 3.22 (2H, d, J =
3.6Hz), 4.31 (2H, s), 6.93 (2H, bs), 8.16 (1H, s), 8.39 (1H,
s).

Example 19 Preparation of 6- (2,2-diethyl-3-sulfamoyl-1-propoxy) -2,7-dimethyl [1,2,4] triazolo [1,5-b] pyridazine 3- ( (N, N-dimethylaminomethylene) aminosulfonyl-2,2-diethyl-1-propanol and 6-chloro-2,7-dimethyl [1,2,4] triazolo [1,
5-b] The title compound was produced in the same manner as in Example 6 using pyridazine. Melting point: 221-222 ° C. Elemental analysis: C ₁₂ H ₂₃ N ₅ O ₃ S Calculated (%): C, 49.25; H, 6.79; N, 20.51 Found (%): C, 49.36; H, 6.56 N, 20.71 NMR (d ₆ -DMSO) δ: 0.88 (6H, t, J = 7.2 Hz), 1.62
(4H, q, J = 7.2Hz), 2.31 (3H, s), 2.49 (3H, s), 3.21 (2H, s), 4.
31 (2H, s), 6.93 (2H, bs), 8.02 (1H, s).

Example 20 Preparation of 2,7-dimethyl-6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) [1,2,4] triazolo [1,5-b] pyridazine 3- ( (N, N-dimethylaminomethylene) aminosulfonyl-2,2-dimethyl-1-propanol and 6-chloro-2,7-dimethyl [1,2,4] triazolo [1,
5-b] The title compound was produced in the same manner as in Example 6 using pyridazine. Melting point: 217-218 ° C Elemental analysis: C ₁₂ H ₁₉ N ₅ O ₃ S Calculated (%): C, 45.99; H, 6.11; N, 22.35 Actual (%): C, 46.02; H, 5.99 ; N, 22.36

Example 21 6- (2-ethyl-2-methyl-3-sulfamoyl-
Preparation of 1-propoxy) -2,7-dimethyl [1,2,4] triazolo [1,5-b] pyridazine 3- (N, N-dimethylaminomethylene) aminosulfonyl-2-ethyl-2-methyl- 1-propanol and 6
The title compound was produced in the same manner as in Example 6 using -chloro-2,7-dimethyl [1,2,4] triazolo [1,5-b] pyridazine. Mp: 194-195 ° C. Elemental _{analysis: C 13 H 21 N 5 O} 3 Calculated S (%): C, 47.69 ; H, 6.46; N, 21.39 Found (%): C, 47.63; H, 6.32 ; N, 21.57

Example 22 Preparation of 6- (2,2-diethyl-3-sulfamoyl-1-propoxy) -2,8-dimethyl [1,2,4] triazolo [1,5-b] pyridazine 3- ( (N, N-dimethylaminomethylene) aminosulfonyl-2,2-diethyl-1-propanol and 6-chloro-2,8-dimethyl [1,2,4] triazolo [1,
5-b] The title compound was produced in the same manner as in Example 6 using pyridazine. Melting point: 159-160 ° C Elemental analysis: C ₁₄ H ₂₃ N ₅ O ₃ S Calculated (%): C, 49.25; H, 6.79; N, 20.51 Found (%): C, 49.04; H, 6.65 ; N, 20.36

Example 23 2,7-dimethyl-6- (2,2-pentamethylene-4
-Sulfamoyl-1-butoxy) [1,2,4] triazolo [1,5-b] pyridazine 4- (N, N-dimethylaminomethylene) aminosulfonyl-2,2-pentamethylene-1-butanol and 6-
The title compound was produced in the same manner as in Example 6 using chloro-2,7-dimethyl [1,2,4] triazolo [1,5-b] pyridazine. Melting point: 204-205 ° C Elemental analysis: C ₁₆ H ₂₅ N ₅ O ₃ S Calculated (%): C, 52.30; H, 6.86; N, 19.06 Found (%): C, 52.45; H, 6.90 ; N, 18.78

Example 24 6- (3-Sulfamoyl-1-propoxy) [1,
Preparation of 2,4] triazolo [1,5-b] pyridazine 60% oily sodium hydride (0.48 g) was suspended in dimethylformamide (12 ml), and 3-hydroxy-1-propanesulfonamide (0.835 g) was added. The mixture was stirred under reduced pressure for 30 minutes. There, 6-chloro [1, 2,
4] Triazolo [1,5-b] pyridazine 0.928 g
And stirred at room temperature for 18 hours. Ice water 40
Then, 1N hydrochloric acid was added to adjust the pH to 6, the salt was saturated, and the mixture was extracted with tetrahydrofuran. The extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl ether was added to the residue for crystallization, and the obtained crystals were recrystallized from hot methanol to obtain 0.811 g of the title compound. Melting point: 145 ° -147 ° C. Elemental analysis: C ₈ H ₁₁ N ₅ O ₃ S Calculated (%): C, 37.35; H, 4.31; N, 27.22 Found (%): C, 37.48; H, 4.33 ; N, 26.95

Example 25 6- [3- (N, N-dimethylsulfamoyl) -1-
Propoxy] [1,2,4] triazolo [1,5-b]
Production of pyridazine 0.252 g of 60% oily sodium hydride was suspended in 10 ml of dimethylformamide, and 1.0 g of N, N-dimethyl-3-hydroxypropane-1-sulfonamide was added, followed by stirring at room temperature under reduced pressure for 30 minutes. . Thereto was added 0.928 g of 6-chloro [1,2,4] triazolo [1,5-b] pyridazine, and the mixture was stirred at room temperature for 1.5 hours. 30 ml of ice water was added to the reaction solution, and 1N hydrochloric acid was further added thereto to adjust the pH.
4.0, and the precipitated crystals were collected by filtration. Hot methanol 3
Recrystallization from 0 ml gave 1.255 g of the title compound. Mp: 151-153 ° C. Elemental _{analysis: C 10 H 15 N 5 O} 3 Calculated S (%): C, 42.10 ; H, 5.30; N, 24.55 Found (%): C, 42.17; H, 5.21 ; N, 2
4.69

Example 26 Preparation of 6- [3- (1-methyl-4-piperazinylsulfonyl) -1-propoxy] [1,2,4] triazolo [1,5-b] pyridazine 60% oily hydrogen 0.21 g of sodium chloride was suspended in 10 ml of dimethylformamide, and 1.12 g of 3- (1-methyl-4-piperazinylsulfonyl) -1-propanol was suspended.
Was added and the mixture was stirred at room temperature under reduced pressure for 75 minutes. There 6
0.773 g of -chloro [1,2,4] triazolo [1,5-b] pyridazine was added, and the mixture was stirred at room temperature for 1.5 hours. 40 ml of ice water was added to saturate the salt, and the mixture was extracted with tetrahydrofuran. The extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and dichloromethane: methanol (10:10) was used.
The target fraction was eluted in 1) and concentrated to give the title compound (1.03).
2 g were obtained. Mp: 140-141 ° C. Elemental _{analysis: C 13 H 20 N 6 O} 3 Calculated S (%): C, 45.87 ; H, 5.92; N, 24.69 Found (%): C, 45.67; H, 5.94 ; N, 24.90

Example 27 6- (3-Sulfamoyl-1-propylthio) [1,
Preparation of 2,4] triazolo [1,5-b] pyridazine 1.94 ml of methyl 3-mercaptopropionate was dissolved in 20 ml of methanol, 7.5 ml of 2N sodium methoxide (methanol solution) and 6-chloro [1,2,2 4] 0.773 g of triazolo [1,5-b] pyridazine was added, and the mixture was heated under reflux for 30 minutes. After cooling, the solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue, and the obtained crystals were collected by filtration.
The crystals were suspended in 20 ml of tetrahydrofuran, 0.997 g of 3-iodo-1-propanesulfonamide was added, and the mixture was heated under reflux for 2.5 hours. After cooling, the reaction mixture was concentrated under reduced pressure, 20 ml of ice water was added to the residue, the pH was adjusted to 4 with 1N hydrochloric acid, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from methanol to obtain 0.856 g of the title compound. Mp: 130-131 ° C. Elemental _{analysis: C 8 H 11 N 5 O} 2 S 2 Calculated (%): C, 35.15; H, 4.06; N, 25.62 Found (%): C, 35.17; H, 4.06; N, 25.55

Reference Example 1 93.6 ml of a 1.6 mol n-butyllithium hexane solution was stirred at -5 to 0 ° C. while stirring in a solution of 22.2 ml of ethyl 4-chloro-2,2-dimethylbutyrate diisopropylamine in 150 ml of tetrahydrofuran. And stirred for 30 minutes. The reaction solution was cooled to -78 ° C, 19.0 ml of ethyl isobutylate was added dropwise, and the mixture was stirred for 45 minutes, and then 11.9 ml of 1-bromo-2-chloroethane.
Of tetrahydrofuran was added dropwise. After stirring the reaction solution at -78 ° C for 1 hour and then at room temperature for 2 hours, an excess amount of aqueous ammonium chloride solution is added, and the mixture is extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off, and the residue was distilled under reduced pressure to give the title compound (24.7).
g were obtained as a colorless oil. Boiling point: 54-56 ° C./0.25 mmHg NMR (CDCl ₃ ) δ: 1.22 (6H, s), 1.26 (3H, t, J = 7.0H)
z), 2.06 (2H, t, J = 8.1Hz), 3.51 (2H, t, J = 8.1Hz), 4.14 (2H,
q, J = 7.0Hz).

Reference Example 2 Ethyl 2,2-dimethyl-4-thiocyanobutyrate Ethyl 4-chloro-2,2-dimethylbutyrate 2
2.1 g and 14.5 g of potassium thiocyanate were dissolved in 100 ml of dimethylformamide and stirred at 100 ° C. for 7 hours. The reaction solution was added to 500 ml of water and extracted with ethyl ether. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off. The residue was distilled under reduced pressure to give 16.4 g of the title compound.
Was obtained as a colorless oil. Boiling point: 109-111 ° C./0.3 mmHg NMR (CDCl ₃ ) δ: 1.24 (6H, s), 1.2
7 (3H, t, J = 7.2 Hz), 2.00-2.12.
(2H, m), 2.86-2.97 (2H, m), 2.
86-2.97 (2H, m), 4.15 (2H, q, J
= 7.2 Hz).

Reference Example 3 Ethyl 4-aminosulfonyl-2,2-dimethylbutyrate 42.5 g of ethyl 2,2-dimethyl-4-thiocyanobutyrate was dissolved in a mixed solution of 200 ml of acetic acid and 200 ml of water, and stirred vigorously. 10 to 15 chlorine gas
C. for 3 hours. After stirring at room temperature for 30 minutes, the reaction solution was added to 500 ml of water, and extracted with dichloromethane. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off, the residue was dissolved in dichloromethane (250 ml), and ammonia gas was passed at 10 to 15 ° C. for 2 hours. The insoluble material was removed by filtration, the filtrate was washed with water, dried (MgSO ₄ ), and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and eluted with hexane: ethyl acetate (3: 1) to give the title compound 4
0.7 g was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.23 (6H, s), 1.26 (3H, t, J = 7.2H
z), 2.00-2.13 (2H, m), 3.06-3.19 (2H, m), 4.14 (2H, q, J = 7.2
Hz), 4.86 (2H, br).

REFERENCE EXAMPLE 4 4-Hydroxy-3,3-dimethyl-1-butanesulfonamide A suspension of lithium aluminum hydride (0.35 g) in tetrahydrofuran (30 ml) was stirred under ice-cooling with ethyl acetate.
-Aminosulfonyl-2,2-dimethylbutyrate1.
A solution of 5 g of tetrahydrofuran in 8 ml was added dropwise. After the addition, the mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 30 minutes. Hydrogenated tetrahydrofuran was added to the reaction solution to decompose excess lithium aluminum hydride and neutralized with 2N hydrochloric acid.
Extracted with ethyl acetate. Wash the extract with water and dry (MgS
After O ₄ ), the solvent was distilled off. The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (1: 1) to obtain 0.94 g of the title compound. Melting point: 75-76 ° C Elemental analysis: C ₆ H ₁₅ NO ₃ S Calculated (%): C, 39.75; H, 8.34; N, 7.73 Found (%): C, 39.80; H, 8.10; N, 7.
92

Reference Example 5 4- (N, N-dimethylaminomethylene) aminosulfonyl-2,2-dimethyl-1-butanol 4-hydroxy-3,3-dimethyl-1-butanesulfonamide 2.3 g of toluene 40 ml N, N-
1.59 g of dimethylformamide dimethyl acetal was added, and the mixture was stirred at 70 ° C. for 40 minutes. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl ether to obtain 2.86 g of the title compound. NMR (CDCl ₃ ) δ: 0.91 (6H, s), 1.69-1.84 (2H, m),
1.94 (1H, t, J = 4.8Hz), 2.98-3.11 (2H, m), 3.05 (3H, s), 3.14
(3H, s), 3.34 (2H, d, J = 4.8Hz), 8.05 (1H, s).

Reference Example 6 3- (N, N-dimethylaminomethylene) aminosulfonyl-2,2-diethyl-1-propanol 6.0 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide, A mixture of 4.0 g of N-dimethylformamide dimethyl acetal and 60 ml of toluene was stirred at 100 ° C. for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-chloroform-methanol (20: 20: 1) to obtain 6.4 g of the title compound as a colorless oil. NMR (CDCl ₃ ) δ: 0.84 (6H, t, J = 7.4 Hz), 1.49 (4H,
q, J = 7.4Hz), 3.05 (4H, s), 3.15 (3H, s), 3.64 (2H, s), 8.05 (1
H, s).

Reference Example 7 3- (N, N-dimethylaminomethylene) aminosulfonyl-2,2-pentamethylene-1-propanol 3-hydroxy-2,2-pentamethylene-1-propanesulfonamide and N, N -The title compound was produced in the same manner as in Reference Example 5 using dimethylformamide dimethyl acetal. NMR (CDCl ₃ ) δ: 1.36-1.73 (10H, m), 2.72 (1H, b
r), 3.05 (3H, s), 3.14 (2H, s), 3.15 (3H, s), 3.72 (3H, s), 8.0
5 (1H, s).

Reference Example 8 4- (N, N-dimethylaminomethylene) aminosulfonyl-1-iodo-2,2-dimethylbutane 4-hydroxy-3,3-dimethyl-1-butanesulfonamide 5.5 g, N , N-dimethylformamide dimethyl acetal (3.98 g) and benzene (50 ml) were stirred at 80 DEG C. for 1 hour. The solvent was distilled off, the residue was dissolved in 50 ml of dichloromethane, and 6.6 ml of trifluoromethanesulfonic anhydride was added dropwise with stirring under ice cooling.
After stirring for 20 minutes after the addition, 2,6-lutidine 4.7 was added.
ml was added thereto and reacted at 0 ° C. for further 20 minutes. 100 ml of water was added to the reaction solution, and extracted with ethyl acetate. The extract was washed sequentially with an aqueous solution of potassium hydrogen sulfate and water, dried, and then the solvent was distilled off. The obtained oil was dissolved in 100 ml of acetone, 13.5 g of sodium iodide was added, and the mixture was refluxed for 2 hours while stirring. After cooling, water was added to the reaction solution, which was extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (3: 1). The fractions containing the desired compound were collected and concentrated, and the residue was crystallized from isopropyl ether to obtain 8.44 g of the title compound. Was. Melting point: 81-82 ° C Elemental analysis: C ₉ H ₁₉ IN ₂ O ₂ S Calculated (%): C, 31.22; H, 5.53; N, 8.09 Found (%): C, 31.67; H, 5.68; N, 8.18 NMR (CDCl ₃ ) δ: 1.07 (6H, s), 1.78-1.91 (2H, m),
2.92-3.04 (2H, m), 3.06 (3H, s), 3.12 (2H, s), 3.16 (3H, s),
8.05 (1H, s).

Reference Example 9 1-cyano-4- (N, N-dimethylaminomethylene)
Aminosulfonyl-2,2-dimethylbutane 4- (N, N-dimethylaminomethylene) aminosulfonyl-1-iodo-2,2-dimethylbutane 1.85
g, potassium cyanide 0.49 g, 18-crown-6
A mixture of 0.06 g and 30 ml of dimethyl sulfoxide was stirred at 100 ° C. for 14 hours. After cooling, add 1
After adding 00 ml, the mixture was extracted with ethyl acetate. Wash the extract with water,
After drying (MgSO ₄ ), the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography using 70 g of silica gel, eluted with ethyl acetate-hexane (9: 1), the fractions containing the desired product were collected and concentrated, and the residue was crystallized from ethyl ether to give the title compound. 1.11 g were obtained. Mp: 53-54 ° C. Elemental _{analysis: C 10 H 19 N 3 O} 2 S Calculated (%): C, 48.96; H, 7.81; N, 17.13 Found (%): C, 48.88; H, 7.82; N, 16.77 NMR (CDCl ₃ ) δ: 1.10 (6H, s), 1.82-1.94 (2H, m),
2.27 (2H, s), 2.96-3.07 (2H, m), 3.05 (3H, s), 3.15 (3H, s),
8.04 (1H, s).

Reference Example 10 Methyl 5-aminosulfonyl-3,3-dimethylvalerate A mixture of 0.49 g of the cyano compound obtained in Reference Example 9 and 10 ml of concentrated hydrochloric acid was stirred at 120 to 130 ° C. for 16 hours. Concentrate to dryness under reduced pressure, dissolve the residue in 12 ml of methanol,
Four drops of concentrated sulfuric acid were added, and the mixture was heated under reflux for 14 hours. After methanol was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate.
After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off. The residue was subjected to column chromatography using 60 g of silica gel, and eluted with ethyl acetate-hexane (4: 1) to give the title compound 0.1. 35 g was obtained as an oil. NMR (CDCl ₃ ) δ: 1.05 (6H, s), 1.84-1.98 (2H, m),
2.25 (2H, s), 3.10-3.23 (2H, m), 3.68 (3H, s), 5.01 (2H, br).

Reference Example 11 5- (N, N-dimethylaminomethylene) aminosulfonyl-3,3-dimethyl-1-pentanol 0.352 g of the methyl ester obtained in Reference Example 10 was dissolved in 10 ml of tetrahydrofuran, and the solution was cooled with ice. While stirring, a suspension of 0.101 g of lithium aluminum hydride in 20 ml of tetrahydrofuran was added dropwise. After stirring at the same temperature for 40 minutes, the reaction mixture was added to aqueous tetrahydrofuran,
Neutralized with 2N hydrochloric acid and extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off. The residue was dissolved in 8 ml of toluene, 0.24 g of N, N-dimethylformamide dimethyl acetal was added, and the mixture was heated with stirring at 80 ° C. for 45 minutes. After evaporating the solvent, the residue was silica gel (60 g).
The mixture was subjected to column chromatography using and eluting with chloroform-methanol (20: 1) to afford the title compound 0.1.
286 g were obtained as an oil. Elemental _{analysis: C 10 H 22 N 2 O} 3 Calculated S (%): C, 47.97 ; H, 8.86; N, 11.19 Found (%): C, 47.71; H, 8.62; N, 11.44 NMR (CDCl ₃ ) δ: 0.94 (6H, s), 1.52 (2H, t, J = 7.2H
z), 1.67-1.81 (3H, m), 2.94-3.06 (2H, m), 3.04 (3H, s), 3.14
(3H, s), 3.70 (2H, t, J = 7.2Hz), 8.03 (1H, s).

Reference Example 12 5- (N, N-dimethylaminomethylene) aminosulfonyl-1-iodo-3,3-dimethylpentane 5- (N, N-dimethylaminomethylene) aminosulfonyl- obtained in Reference Example 11 0.23 g of 3,3-dimethyl-1-pentanol was dissolved in 10 ml of dichloromethane, and 0.24 ml of trifluoromethanesulfonic anhydride was added dropwise while stirring under ice cooling. After the dropwise addition, the mixture was stirred at the same temperature for 20 minutes, and 0.18 ml of 2,6-lutidine was added, followed by stirring for another 20 minutes. Water was added to the reaction solution, and extracted with dichloromethane. The extract was washed successively with an aqueous solution of potassium hydrogen sulfate and water, dried (MgSO ₄ ), and the solvent was distilled off. The residue was dissolved in 15 ml of acetone, 0.5 g of sodium iodide was added, and the mixture was heated under reflux for 2 hours. After cooling, add water to the reaction solution,
Extracted with ethyl acetate. Wash the extract with water and dry (MgS
After O ₄ ), the solvent was distilled off. 50 g of silica gel residue
And column chromatography, eluting with ethyl acetate-hexane (4: 1) to afford the title compound 0.26
7 g were obtained. Mp: 105-106 ° C. Elemental _{analysis: C 10 H 21 IN 2 O} 2 S Calculated (%): C, 33.34; H, 5.88; N, 7.78 Found (%): C, 33.57; H, 5.97; N, 8.09

Reference Example 13 1-cyano-5- (N, N-dimethylaminomethylene)
Aminosulfonyl-3,3-dimethylpentane 7.2 g of 5- (N, N-dimethylaminomethylene) aminosulfonyl-1-iodo-3,3-dimethylpentane obtained in Reference Example 12, 1.95 g of potassium cyanide, 18
A mixture of 0.26 g of crown-6 and 100 ml of dimethyl sulfoxide was stirred at 90 ° C. for 5 hours. After cooling, 300 ml of water was added to the reaction solution, which was extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography using 100 g of silica gel, and eluted with ethyl acetate: chloroform (5: 1). The fractions containing the desired product were collected and concentrated to give 4.23 g of the title compound as a colorless oil. Obtained. NMR (CDCl ₃ ) δ: 0.94 (6H, s), 1.57-1.80 (4H, m),
2.32 (2H, t, J = 7.6Hz), 2.91-3.04 (2H, m), 3.05 (3H, s), 3.15
(3H, s), 8.05 (1H, s).

Reference Example 14 Methyl 6-aminosulfonyl-4,4-dihexyl hexanate 1-cyano-5- (N, N-dimethylaminomethylene) aminosulfonyl-3,3-dimethylpentane 3 obtained in Reference Example 13. A mixture of 0.6 g and 30 ml of concentrated hydrochloric acid was stirred at 120 to 130 ° C. for 10 hours. The residue was dissolved in 50 ml of methanol, 0.3 ml of concentrated sulfuric acid was added, and the mixture was heated under reflux for 6 hours. After methanol was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. Wash the extract with water,
After drying (MgSO ₄ ), the solvent was distilled off and silica gel 100
g and column chromatography, eluting with ethyl acetate-hexane (2: 1) to give the title compound 2.9.
5 g were obtained as an oil. NMR (CDCl ₃ ) δ: 0.93 (6H, s), 1.54-1.85 (4H, m),
2.30 (2H, t, J = 8.0Hz), 3.10 (2H, d, J = 8.0Hz), 3.68 (3H, s),
4.89 (2H, br).

Reference Example 15 6- (N, N-dimethylaminomethylene) aminosulfonyl-4,4-dimethyl-1-hexanol Methyl 6-aminosulfonyl-4, obtained in Reference Example 14,
Dissolve 3.3 g of 4-dimethylhexanate in 20 ml of tetrahydrofuran and stir under ice-cooling while stirring 0.79 g of lithium aluminum hydride in 100 ml of tetrahydrofuran.
The ml suspension was added dropwise. After stirring at the same temperature for 40 minutes,
The reaction solution was neutralized with aqueous tetrahydrofuran and then with 2N hydrochloric acid and extracted with ethyl acetate. Wash the extract with water and dry (M
After gSO ₄ ), the solvent was distilled off. Residue is 50m in toluene
Then, 1.85 ml of N, N-dimethylformamide dimethyl acetal was added, and the mixture was heated and stirred at 80 ° C. for 1 hour. After evaporating the solvent, the residue was subjected to column chromatography using 80 g of silica gel and eluted with chloroform-methanol (20: 1) to obtain 3.15 g of the title compound as an oil. NMR (CDCl ₃ ) δ: 0.90 (6H, s), 1.20-1.33 (2H, m),
1.46-1.78 (4H, m), 1.61 (1H, s), 2.98 (2H, t, J = 6.4Hz), 3.05
(3H, s), 3.14 (3H, s), 3.62 (2H, t, J = 6.4Hz), 8.04 (1H, s).

Reference Example 16 Ethyl 5-bromo-2,2-dimethylvalerate 126 ml of a 1.6 mol n-butyllithium hexane solution was added at -5 to 0 ° C. while stirring with 28.7 ml of diisopropylamine in 150 ml of tetrahydrofuran while stirring. For 30 minutes. Cool the reaction to −78 ° C.
After 26.7 ml of ethyl isobutyrate was added dropwise, the mixture was stirred for 1 hour, and 41.8 g of 1,3-dibromopropane was added dropwise. The reaction solution was stirred at -78 ° C for 1 hour and then at room temperature for 2 hours, poured into an aqueous ammonium chloride solution, and extracted with ethyl acetate. Wash the extract with water and dry (MgS
After O ₄ ), the solvent was distilled off and the residue was distilled under reduced pressure to obtain 40.3 g of the title compound as a colorless oil. Boiling point: 76-78 ° C./0.27 mmHg NMR (CDCl ₃ ) δ: 1.19 (6H, s), 1.25 (3H, t, J = 7.2H)
z), 1.31-1.60 (4H, m), 3.30-3.50 (2H, m), 4.12 (2H, q, J = 7.2
Hz).

Reference Example 17 The title compound was prepared in the same manner as in Reference Example 16 using ethyl 6-bromo-2,2-dimethylhexanoate ethyl isobutyrate and 1,4-dibromobutane. Boiling point: 62-64 ° C./0.4 mmHg NMR (CDCl ₃ ) δ: 1.17 (6H, s), 1.25 (3H, t, J = 7.2H)
z), 1.33-1.63 (4H, m), 3.33-3.50 (4H, m), 4.12 (2H, q, J = 7.2
Hz).

Reference Example 18 Ethyl 4-chloro-2,2-diethylbutyrate The title compound was prepared in the same manner as in Reference Example 16 using ethyl 2-ethylbutyrate and 1-bromo-2-chloroethane. Boiling point: 69-72 ° C./0.3 mmHg NMR (CDCl ₃ ) δ: 0.81 (6H, t, J = 7.1 Hz), 1.26 (3H,
t, J = 7.2Hz), 1.61 (4H, q, J = 7.2Hz), 2.07 (2H, t, J = 8.6Hz),
3.45 (2H, t, J = 8.6Hz), 4.15 (2H, q, J = 7.1Hz).

Reference Example 19 Ethyl 5-bromo-2,2-diethylvalerate The title compound was prepared in the same manner as in Reference Example 16 using ethyl 2-ethylbutyrate and 1,3-dibromopropane. Boiling point: 98-102 ° C / 0.3 mmHg NMR (CDCl ₃ ) δ: 0.79 (6H, t, J = 7.
4 Hz), 1.25 (3H, t, J = 7.0 Hz),
1.51-1.86 (8H, m), 3.39 (2H,
t, J = 6.2 Hz), 4.14 (2H, q, J = 7.
0 Hz).

Reference Example 20 The title compound was produced in the same manner as in Reference Example 16 using ethyl 6-bromo-2,2-diethylhexanoate ethyl 2-ethylbutyrate and 1,4-dibromobutane. Boiling point: 125-130 ° C./0.3 mmHg NMR (CDCl ₃ ) δ: 0.80 (6H, t, J = 7.6 Hz), 1.27 (3H,
t, J = 7.0Hz), 1.49-1.78 (4H, m), 1.61 (4H, q, J = 7.6Hz), 2.90
-3.02 (2H, m), 4.15 (2H, q, J = 7.0Hz).

Reference Example 21 Ethyl 2,2-dimethyl-5-thiocyanovalerate 40.3 g of ethyl 5-bromo-2,2-dimethylvalerate obtained in Reference Example 16 and potassium thiocyanate 18.
2 g was dissolved in 120 ml of dimethylformamide,
For 5 hours. The reaction solution was added to 500 ml of water, extracted with ethyl ether, and the extract was washed with water and dried (MgSO 4).
After O ₄ ), the solvent was distilled off. The residue was distilled under reduced pressure to obtain 35.7 g of the title compound as an oil. Boiling point: 116-118 ° C / 0.3mmHg

Reference Example 22 Ethyl 2,2-dimethyl-6-thiocyanohexanate The same procedure as in Reference Example 21 was carried out using ethyl 6-bromo-2,2-dimethylhexanate obtained in Reference Example 17 and potassium thiocyanate. To give the title compound. Boiling point: 123-125 ° C./0.4 mmHg NMR (CDCl ₃ ) δ: 1.17 (6H, s), 1.25 (3H, t, J = 7.2H)
z), 1.33-1.65 (4H, m), 1.73-2.08 (2H, m), 2.94 (2H, t, J = 7.2
Hz), 4.12 (2H, q, J = 7.2Hz).

Reference Example 23 Ethyl 2,2-diethyl-4-thiocyanobutyrate Reference Example 2 using ethyl 4-chloro-2,2-diethylbutyrate obtained in Reference Example 18 and potassium thiocyanate.
The title compound was prepared in the same manner as in 1. Boiling point: 105-108 ° C./0.3 mmHg NMR (CDCl ₃ ) δ: 0.81 (3H, t, J = 7.4 Hz), 0.83 (3H,
(t, J = 7.4Hz), 1.27 (3H, t, J = 7.0Hz), 1.54-1.72 (4H, m), 2.00
-2.13 (2H, m), 2.80-2.92 (2H, m), 4.17 (2H, q, J = 7.0Hz).

Reference Example 24 Ethyl 2,2-diethyl-5-thiocyanovalerate Using Reference Example 2 using ethyl 5-bromo-2,2-diethylvalerate obtained in Reference Example 19 and potassium thiocyanate.
The title compound was prepared in the same manner as in 1. Boiling point: 125-130 ° C./0.3 mmHg NMR (CDCl ₃ ) δ: 0.80 (6H, t, J = 7.6 Hz), 1.27 (3H,
t, J = 7.0Hz), 1.49-1.78 (4H, m), 1.61 (4H, q, J = 7.6Hz), 2.90
-3.02 (2H, m), 4.15 (2H, q, J = 7.0Hz).

REFERENCE EXAMPLE 25 Ethyl 2,2-diethyl-6-thiocyanohexanate Ethyl 6-bromo-2,2-diethylhexanat obtained in Reference Example 20 and potassium thiocyanate were designated in the same manner as in Reference Example 21. The compound was prepared. Boiling point: 145-148 ° C./0.3 mmHg NMR (CDCl ₃ ) δ: 0.78 (6H, t, J = 7.6 Hz), 1.25 (3H,
t, J = 7.0Hz), 1.21-1.68 (8H, m), 1.82 (2H, m), 2.95 (2H, t, J =
(7.4Hz), 4.14 (2H, q, J = 7.0Hz).

Reference Example 26 Ethyl 5-aminosulfonyl-2,2-dimethylvalerate 35.68 g of ethyl 2,2-dimethyl-5-thiocyanovalerate obtained in Reference Example 21 was added to 150 ml of acetic acid and 15 ml of water.
The mixture was dissolved in 0 ml of the mixture, and chlorine gas was passed at 10 to 15 ° C. for 1.2 hours with vigorous stirring. Further at 1
After stirring for an hour, the mixture was extracted with dichloromethane. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off, and the residue was dissolved in 200 ml of dichloromethane.
For 40 minutes. The insoluble material was removed by filtration, the filtrate was washed with water, dried (MgSO ₄ ), and the solvent was distilled off. The residue was subjected to column chromatography using 150 g of silica gel, and eluted with ethyl acetate-hexane (1: 1) to give the title compound 3
0 g was obtained. NMR (CDCl ₃ ) δ: 1.20 (6H, s), 1.26 (3H, t, J = 7.4H
z), 1.61-1.93 (4H, m), 3.11 (2H, t, J = 7.0Hz), 4.14 (2H, q, J =
7.4Hz), 4.88 (2H, br).

Reference Example 27 Ethyl 6-aminosulfonyl-2,2-dimethanehexanate The title compound was obtained in the same manner as in Reference Example 26 except that ethyl 2,2-dimethyl-6-thiocyanohexanoate obtained in Reference Example 22 was used. Was manufactured. NMR (CDCl ₃ ) δ: 1.17 (6H, s), 1.25 (3H, t, J = 7.2H
z), 1.32-1.64 (4H, m), 1.85 (2H, t, J = 7.6Hz), 3.12 (2H, t, J =
7.6Hz), 4.12 (2H, q, J = 7.2Hz), 4.84 (2H, bs).

Reference Example 28 Ethyl 4-aminosulfonyl-2,2-diethylbutyrate The title compound was prepared in the same manner as in Reference Example 26 by using ethyl 2,2-diethyl-4-thiocyanobutyrate obtained in Reference Example 23. did. Mp: 93-94 ° C. Elemental analysis: Calculated _{C 10 H 21 NO 4 S (} %): C, 47.79; H, 8.42; N, 5.57 Found (%): C, 47.73; H, 8.44; N, 5.70 NMR (CDCl ₃ ) δ: 0.83 (6H, t, J = 7.4 Hz), 1.27 (3H,
t, J = 7.0Hz), 1.61 (4H, q, J = 7.4Hz), 2.03-2.16 (2H, m), 2.99
-3.13 (2H, m), 4.17 (2H, q, J = 7.0Hz), 4.84 (2H, bs).

Reference Example 29 Ethyl 5-aminosulfonyl-2,2-diethylvalerate The title compound was produced in the same manner as in Reference Example 26 by using ethyl 2,2-diethyl-5-thiocyanovalerate obtained in Reference Example 24. did. Mp: 66-67 ° C. Elemental analysis: C ₁₁ H ₂₃ NO ₄ Calculated S (%): C, 49.79 ; H, 8.74; N, 5.28 Found (%): C, 49.43; H, 8.81; N, 5.18 NMR (CDCl ₃ ) δ: 0.79 (6H, t, J = 7.4 Hz), 1.26 (3H,
t, J = 7.2Hz), 1.61 (4H, q, J = 7.4Hz), 1.66-1.85 (4H, m), 3.11
(2H, t, J = 6.6Hz), 4.15 (2H, q, J = 7.2Hz), 4.84 (2H, bs).

REFERENCE EXAMPLE 30 Ethyl 6-aminosulfonyl-2,2-diethylhexanate The title compound was prepared in the same manner as in Reference Example 26, using ethyl 2,2-diethyl-6-thiocyanohexanate obtained in Reference Example 25. did. NMR (CDCl ₃ ) δ: 0.77 (6H, t, J = 7.4 Hz), 1.25 (3H,
t, J = 7.2Hz), 1.19-1.40 (2H, m), 1.58 (4H, q, J = 7.4Hz), 1.49
-1.69 (2H, m), 1.85 (2H, m), 3.12 (2H, m), 4.13 (2H, q, J = 7.2H
z), 4.71 (2H, bs).

Reference Example 31 5-Hydroxy-4,4-dimethyl-1-pentanesulfonamide Ethyl 5-aminosulfonyl-2, obtained in Reference Example 26
A solution of 7.1 g of 2-dimethylvalerate in 20 ml of tetrahydrofuran was added dropwise to a suspension of 1.71 g of lithium aluminum hydride in 100 ml of tetrahydrofuran with stirring under ice cooling. After the dropwise addition, the mixture was stirred at 0 ° C. for 40 minutes, added with hydrous tetrahydrofuran to decompose excess lithium aluminum hydride, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off. The residue was subjected to silica gel column chromatography using 100 g of silica gel, and eluted with hexane-ethyl acetate (4: 1) to obtain 3.39 g of the title compound as an oil. NMR (CDCl ₃ ) δ: 0.90 (6H, s), 1.35-1.50 (2H, m),
1.75-1.97 (2H, m), 3.12 (2H, t, J = 7.8Hz), 3.35 (2H, s), 5.04
(2H, bs).

Reference Example 32 6-Hydroxy-5,5-dimethyl-1-hexanesulfonamide Ethyl 6-aminosulfonyl-2, obtained in Reference Example 27
The title compound was produced in the same manner as in Reference Example 31 using 2-dimethylhexanate. NMR (CDCl ₃ ) δ: 0.87 (6H, s), 1.21-1.54 (4H, m),
1.76-1.94 (2H, m), 2.05 (1H, s), 3.16 (2H, t, J = 8Hz), 3.31 (2H
H, s), 5.13 (2H, bs).

Reference Example 33 4-Hydroxy-3,3-diethyl-1-butanesulfonamide Ethyl 4-aminosulfonyl-2, obtained in Reference Example 28
The title compound was produced in the same manner as in Reference Example 31 using 2-diethylbutyrate. Melting point: 79-80 ° C Elemental analysis: Calculated as C ₈ H ₁₉ NO ₃ S (%): C, 45.91; H, 9.15; N, 6.69 Found (%): C, 46.00; H, 9.20; N, 6.69 NMR (CDCl ₃ ) δ: 0.74 (6H, t, J = 7.4 Hz), 1.58 (4H,
q, J = 7.4Hz), 1.50-1.66 (2H, m), 2.83-2.97 (2H, m), 3.11 (2H, m)
H, s), 6.71 (2H, bs).

Reference Example 34 5-Hydroxy-4,4-diethyl-1-pentanesulfonamide Ethyl 5-aminosulfonyl-2, obtained in Reference Example 29
The title compound was produced in the same manner as in Reference Example 31 using 2-diethylvalerate. NMR (CDCl ₃ ) δ: 0.79 (6H, t, J = 7.6 Hz), 1.14-1.45
(6H, m), 1.70-1.89 (2H, m), 2.05 (1H, s), 3.12 (2H, t, J = 7.6H
z), 3.39 (2H, s), 5.18 (2H, bs).

Reference Example 35 6-Hydroxy-5,5-diethyl-1-hexanesulfonamide Ethyl 6-aminosulfonyl-2, obtained in Reference Example 30
The title compound was produced in the same manner as in Reference Example 31 using 2-diethylhexanate. Mp: 64-65 ° C. Elemental analysis: Calculated _{C 10 H 23 NO 3 S (} %): C, 50.60; H, 9.77; N, 5.90 Found (%): C, 50.90; H, 9.58; N, 6.15 NMR (CDCl ₃ ) δ: 0.78 (6H, t, J = 7.2 Hz), 1.15-1.49
(4H, m), 1.23 (4H, q, J = 7.2Hz), 1.67 (1H, s), 1.85 (2H, m), 3.
15 (2H, t, J = 4.6Hz), 3.35 (2H, s), 4.90 (2H, bs).

Reference Example 36 4- (N, N-dimethylaminomethylene) aminosulfonyl-2,2-diethyl-1-butanol 4-hydroxy-3,3-diethyl-1-butanesulfonamide obtained in Reference Example 33 2.0 g of toluene 30 ml
1.2 g of N, N-dimethylformamide dimethyl acetal was added to the solution, and the mixture was stirred at 90 ° C. for 1 hour. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using 70 g of silica gel, and eluted with ethyl acetate-chloroform-methanol (20: 20: 1) to give 2.43 g of the title compound as an oil. Obtained. NMR (CDCl ₃ ) δ: 0.81 (6H, t, J = 7.4 Hz), 1.15-1.38
(4H, m), 1.68-1.80 (2H, m), 1.96 (1H, bs), 2.96-3.07 (2H, m
m), 3.04 (3H, s), 3.14 (3H, s), 3.36 (2H, s), 8.05 (1H, s).

Reference Example 37 5- (N, N-dimethylaminomethylene) aminosulfonyl-2,2-diethyl-1-pentanol 5-hydroxy-4,4-diethyl-1-pentane sulfone obtained in Reference Example 34 The title compound was produced in the same manner as in Reference Example 36 using the amide. Mp: 87-88 ° C. Elemental _{analysis: C 12 H 26 N 2 O} 3 Calculated S (%): C, 51.77 ; H, 9.41; N, 10.06 Found (%): C, 51.75; H, 9.47; N, 10.09 NMR (CDCl ₃ ) δ: 0.78 (6H, t, J = 7.4 Hz), 1.18-1.41
(6H, m), 1.64 (1H, s), 1.70-1.85 (2H, m), 2.99 (2H, t, J = 7.6H
z), 3.04 (3H, s), 3.14 (3H, s), 3.37 (2H, s), 8.04 (1H, s).

Reference Example 38 2-isopropyl-1,3-propanediol To a suspension of 4.17 g of lithium aluminum hydride in tetrahydrofuran was added dropwise 15 g of diethyl isopropyl malonate while stirring under ice-cooling. After dropping, the reaction solution is
Stirred at 30 ° C for 30 minutes and then at room temperature for 1 hour. After adding water-containing tetrahydrofuran to decompose excess reagents, the mixture was neutralized with 6N hydrochloric acid, and insolubles were removed by filtration. The filtrate was extracted with ethyl acetate, and the extract was washed with water and dried (MgSO ₄ ). The solvent was distilled off under reduced pressure to obtain 7.47 g of the title compound. NMR (CDCl ₃ ) δ: 0.92 (3H, s), 0.95 (3H, s), 1.49-
1.65 (1H, m), 1.66-1.86 (1H, m), 2.32 (2H, bs), 3.72-3.93 (4
H, m).

Reference Example 39 2-ethyl-2-methyl-1,3-propanediol The same procedure as in Reference Example 38 was carried out using diethyl 2-ethyl-2-methylmalonate to give the title compound. Boiling point: 78-81 ° C./0.3 mmHg NMR (CDCl ₃ ) δ: 0.81 (3H, s), 0.87 (3H, t, J = 7.2H)
z), 1.38 (2H, q, J = 7.2 Hz), 2.48 (2H, bs), 3.54 (4H, s).

Reference Example 40 3-Bromo-2-isopropyl-1-propanol 11.8 g of 2-isopropyl-1,3-propanediol obtained in Reference Example 38 was dissolved in 150 ml of dichloromethane, 26 g of triphenylphosphine was added, and ice was added. N under cooling
17.8 g of -bromosuccinimide were added in small portions.
The reaction solution was stirred under ice cooling for 30 minutes and then at room temperature for 1 hour. After concentration under reduced pressure, the residue was subjected to column chromatography using 100 g of silica gel, and eluted with ethyl acetate-hexane (3: 7) to obtain 11.87 g of the title compound as a colorless oil. NMR (CDCl ₃ ) δ: 0.94 (3H, s), 0.98 (3H, s), 1.40-
1.69 (2H, m), 1.71-1.93 (1H, m), 3.61-3.92 (4H, m).

Reference Example 41 3-bromo-2-ethyl-2-methyl-1-propanol 2-ethyl-2-methyl-1,3-propanol obtained in Reference Example 39
The title compound was produced in the same manner as in Reference Example 40 using propanediol. NMR (CDCl ₃ ) δ: 0.87 (3H, t, J = 7.4 Hz), 0.96 (3H,
s), 1.40 (2H, q, J = 7.4Hz), 1.53 (1H, bs), 3.40 (2H, s), 3.48
(2H, s).

Reference Example 42 3-acetoxy-2-isopropyl-1-propanethiocyanate 3-bromo-2-isopropyl-1-propanol 22
g, potassium thiocyanate (16.5 g) and dimethylformamide (100 ml) were stirred at 100 ° C. for 15 hours. After cooling, 200 ml of diethyl ether and 20 ml of water were added to the reaction solution.
0 ml of the mixture was added, and the organic layer was separated. The aqueous layer was extracted with 150 ml of diethyl ether, and the combined extracts were washed with saturated saline, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. 17.4 g of acetic anhydride and 18.3 g of pyridine were added to the residue.
g was added and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using 200 g of silica gel.
Elution with 5) gave 14.07 g of the title compound as a colorless oil. NMR (CDCl ₃ ) δ: 0.97 (3H, d, J = 7.3 Hz), 1.01 (3H,
d, J = 7.3Hz), 1.84-2.05 (2H, m), 2.08 (3H, s), 2.97-3.24 (2
H, m), 4.03-4.35 (2H, m).

Reference Example 43 3-acetoxy-2-ethyl-2-methyl-1-propanethiocyanate The title was obtained by operating in the same manner as in Reference Example 42 using 3-bromo-2-ethyl-2-methyl-1-propanol. The compound was prepared. NMR (CDCl ₃ ) δ: 0.90 (3H, t, J = 7.4 Hz), 1.03 (3H,
s), 1.46 (2H, q, J = 7.4 Hz), 2.09 (3H, s), 3.07 (2H, s), 3.94 (2
H, s).

Reference Example 44 3-Acetoxy-2-isopropyl-1-propanesulfonamide 10 g of 3-acetoxy-2-isopropyl-1-propanethiocyanate was dissolved in a mixed solution of 50 ml of acetic acid and 50 ml of water, and the mixture was stirred at room temperature with vigorous stirring. Gas was passed for 2 hours. The reaction solution was extracted with dichloromethane, and the extract was washed with saturated saline, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. Dissolve the residue in 100 ml of dichloromethane,
Ammonia gas was passed under ice cooling for 30 minutes while maintaining the reaction temperature at 15 ° C. or lower. After the precipitate was removed by filtration, the filtrate was concentrated, and the residue was subjected to column chromatography using 100 g of silica gel to give methanol-chloroform (1: 2).
Elution with 0) gave 7.9 g of the title compound as an oil. NMR (CDCl ₃ ) δ: 0.96 (3H, d, J = 6.8 Hz), 0.98 (3H,
d, J = 6.8Hz), 1.89-2.07 (1H, m), 2.08 (3H, s), 2.17-2.32 (1
H, m), 3.11-3.19 (2H, m), 4.221-4.29 (2H, m), 4.87 (2H, bs).

Reference Example 45 3-Acetoxy-2-ethyl-2-methyl-1-propanesulfonamide The same operation as in Reference Example 44 was performed using 3-acetoxy-2-ethyl-2-methyl-1-propanethiocyanate. To give the title compound. NMR (CDCl ₃ ) δ: 0.90 (3H, t, J = 7.4 Hz), 1.16 (3H,
s), 1.57 (2H, q, J = 7.4Hz), 2.09 (3H, s), 3.24 (2H, dd, J = 2.5H
z and 4.9Hz), 4.08 (2H, s), 4.86 (2H, bs).

Reference Example 46 3-Hydroxy-2-isopropyl-1-propanesulfonamide 7.0 g of 3-acetoxy-2-isopropyl-1-propanesulfonamide was dissolved in 50 ml of methanol, and the mixture was stirred at room temperature for 28% w / w sodium hydroxide. 6.5 g of methoxide was added and reacted for 30 minutes. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography using 100 g of silica gel. Elution with chloroform-methanol (9: 1) gave 4.4 g of the title compound. Mp: 83-84 ° C. Elemental analysis: Calculated _{C 6 H 15 NO 3 S (} %): C, 39.67; H, 8.34; N, 7.73 Found (%): C, 39.72; H, 8.36; N, 7.78 NMR (d ₆ -DMSO) δ: 0.87 (3H, d, J = 7.0 Hz), 0.87
(3H, d, J = 7.0Hz), 1.79-2.09 (2H, m), 2.85-2.95 (2H, m), 3.4
3-3.59 (2H, m), 4.55 (1H, bs), 6.77 (2H, bs).

Reference Example 47 3-Hydroxy-2-ethyl-2-methyl-1-propanesulfonamide The same operation as in Reference Example 46 was performed using 3-acetoxy-2-ethyl-2-methyl-1-propanesulfonamide. To give the title compound. NMR (CDCl ₃ ) δ: 0.90 (3H, t, J = 7.4 Hz), 1.07 (3H,
s), 1.33-1.68 (2H, m), 2.71 (1H, bs), 3.22 (2H, q, J = 7.4Hz),
3.61 (2H, s), 5.13 (2H, bs).

Reference Example 48 Ethyl 1- (2-chloroethyl) cyclohexanate The title compound was produced in the same manner as in Reference Example 1 using ethyl cyclohexanate. Boiling point: 83-86 ° C./0.25 mmHg NMR (CDCl ₃ ) δ: 1.11-1.68 (8H, m), 1.27 (3H, t, J =
7.2Hz), 2.01 (2H, t, J = 6.7Hz), 1.91-2.16 (2H, m), 3.45 (2H,
t, J = 6.7Hz), 4.16 (2H, q, J = 7.2Hz).

Reference Example 49 Ethyl 1- (2-thiocyanoethyl) cyclohexanate The title compound was produced in the same manner as in Reference Example 2 using ethyl 1- (2-chloroethyl) cyclohexanate. Boiling point: 118-122 ° C / 0.25 mmHg NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.2 Hz), 1.14-1.66 (8H, m),
1.92-2.14 (4H, m), 2.80-2.90 (2H, m), 4.19 (2H, q, J = 7.2H
z).

Reference Example 50 Ethyl 1- (2-aminosulfonylethyl) cyclohexanate The same procedure as in Reference Example 3 was carried out using ethyl 1- (2-thiocyanoethyl) cyclohexanate to produce the title compound. NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.0 Hz), 1.16-1.71
(10H, m), 1.94-2.14 (2H, m), 2.98-3.13 (2H, m), 4.17 (2H, q,
J = 7.0Hz), 4.69 (2H, bs).

Reference Example 51 The title compound was produced in the same manner as in Reference Example 4 using 4-hydroxy-3,3-pentamethylene-1-butanesulfonamidoethyl 1- (2-aminosulfonylethyl) cyclohexanate. did. NMR (CDCl ₃ ) δ: 1.19-1.56 (10H, m), 1.82-1.97 (2
H, m), 2.05 (1H, s), 3.06-3.22 (2H, m), 3.43 (2H, s), 5.27 (2
H, bs).

Reference Example 52 3- (N, N-dimethylaminomethylene) aminosulfonyl-2-isopropyl-1-propanol The same operation as in Reference Example 5 was performed using 3-hydroxy-2-isopropyl-1-propanesulfonamide. To give the title compound. NMR (CDCl ₃ ) δ: 0.91 (3H, d, J = 6.6 Hz), 0.94 (3H,
d, J = 6.6Hz), 1.64 (1H, bs), 1.82-2.11 (2H, m), 3.04 (3H, s),
3.11 (2H, d, J = 6.6Hz), 3.15 (3H, s), 3.63-3.99 (2H, m), 8.06
(1H, s).

Reference Example 53 Using 3- (N, N-dimethylaminomethylene) aminosulfonyl-2-ethyl-2-methyl-1-propanol 3-hydroxy-2-ethyl-2-methyl-1-propanesulfonamide The title compound was produced in the same manner as in Reference Example 5. NMR (CDCl ₃ ) δ: 0.88 (3H, t, J = 7.4 Hz), 1.05 (3H,
s), 1.32-1.73 (2H, m), 3.04 (2H, q, J = 7.4Hz), 3.05 (3H, s),
3.15 (3H, s), 3.56-3.69 (2H, m), 8.05 (1H, s).

Reference Example 54 Reference was made using 4- (N, N-dimethylaminomethylene) aminosulfonyl-2,2-pentamethylene-1-butanol 4-hydroxy-3,3-pentamethylene-1-butanesulfonamide. The title compound was prepared in the same manner as in Example 5. NMR (CDCl ₃ ) δ: 1.22-1.54 (10H, m), 1.80-1.94 (4
H, m), 3.05 (3H, s), 3.14 (3H, s), 3.41 (2H, s), 8.05 (1H, s).

Reference Example 55 N, N-Dimethyl-3-hydroxypropane-1-sulfonamide The title compound was obtained in the same manner as in Reference Examples 44 and 46 using 3-acetoxypropane-1-sulfonyl chloride and dimethylamine. Manufactured. NMR (CDCl ₃ ) δ: 1.91 (1H, broads), 2.0-2.2 (2H,
m), 2.89 (6H, s), 3.0-3.2 (2H, m), 3.7-3.9 (2H, m).

Reference Example 56 3- (1-Methyl-4-piperazinylsulfonyl) -1
-Propanol 3-acetoxypropane-1-sulfonyl chloride and 1
The title compound was produced in the same manner as in Reference Examples 44 and 46 using -methylpiperazine. Mp: 90-93 ° C. Elemental _{analysis: C 8 H 18 N 2 O} 3 Calculated S (%): C, 43.22 ; H, 8.16; N, 12.
60 actual value (%): C, 43.01; H, 8.20; N, 1
2.53

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 10.0 mg of the compound obtained in the above and lactose 60.0 mg
Then, a mixture of 35.0 mg of corn starch and 0.03 ml of a 10% aqueous gelatin solution (3.0 mg as gelatin) was granulated through a 1 mm mesh sieve, 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.

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 10.0 mg of the compound obtained in 1 and 3.0 mg of magnesium stearate were added to an aqueous solution of soluble starch in 0.07
After granulating in ml (7.0 mg as soluble starch)
Dried lactose 70.0 mg and corn starch 50.0
mg. The mixture was compressed to give tablets.

Formulation Example 3 (1) 5.0 mg of the compound of Example 1 (2) 20.0 mg of sodium chloride (3) Distilled water The total amount was 2 ml 5.0 mg of the compound obtained in Example 1 and 20.0 mg of sodium chloride
mg 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.

Experimental Example 1 The results of a pharmacological test of compound [I] of the present invention or a salt thereof are shown. [Effect on platelet activation factor (PAF) -induced guinea pig airway constriction reaction] Male (Hartley) Hartley guinea pigs (body weight: about 500 g) were used. PAF1μg / kg
The airway constriction response of guinea pigs by intravenous administration was measured according to the Konzett-Roessler method (Conchette wrestler). The guinea pig was anesthetized with urethane (1.5 g / kg, i.v.), fixed in a dorsal position, tracheostomized, and connected to a ventilator via a cannula. The side branch of the tracheal cannula was connected to a transducer (model 7020, manufactured by Ugobasile). The amount of air supplied per time is 3 to 7 ml, the number of times of air supply is 70 times / min, the load pressure on the lungs is 10 cmH ₂ O, and the amount of air that overflows is measured using a rectograph (Recte-Hori-
8s, manufactured by Sanei Sokki Co., Ltd.). Galamine (1mg / k
g, intravenous injection) After treatment, 1 μg of PAF /
kg was administered via the jugular vein cannula and the evoked airway constriction response was recorded for 15 minutes. The drug is 30mg / kg and 1
0 mg / kg was suspended in 5% gum arabic solution, respectively.
Oral administration was performed 1 hour before F administration. The results are shown in [Table 1].

[Table 1] Table 1 shows that the compound [I] of the present invention or a salt thereof has an excellent anti-PAF (platelet activating factor) action.

Experimental Example 2 Antiallergic Action 1) Effect on Leukotriene C ₄ -induced Airway Stenosis Response Male Hartley guinea pig (body weight 450)
g) was used. The airway constriction response of guinea pigs by intravenous administration of leukotriene C ₄ 20 μg / kg was measured according to the Konzett-Roessler method.
The guinea pig was anesthetized with urethane (1.5 g / kg, intravenous injection), fixed in a dorsal position, tracheostomized, and connected to a ventilator via a cannula. The side branch of the tracheal cannula was connected to a transducer (model 7020, manufactured by Ugobasile). 1
The air supply amount is 3 to 7 ml, the air supply frequency is 70 times / min, the load pressure on the lungs is 10 cmH ₂ O, and the amount of overflowing air is recorded on a rectograph (Recte-Hori-8S, manufactured by San-Ei side equipment Co., Ltd.) via a transducer. did. Gallamine (1 mg / kg, IV)
After treatment, leukotriene C ₄ 20 dissolved in physiological saline
μg / kg was administered via the jugular vein cannula and the evoked airway constriction response was recorded for 15 minutes. The drug was suspended in 5% gum arabic solution was administered orally 1 hour prior to leukotriene C ₄ dose. The results are shown in [Table 2].

Table 2 Effect on leukotriene C ₄ -induced guinea pig airway constriction response ──────────────────────────────── Dose (mg / kg) Number of animals Airway stenosis rate (%) Suppression rate (%) 対 照 Control group − 6 58.4 ± 1.1 − Example 5 16 43.9 ± 4.8 * 25 3 6 26.7 ± 4.3 ** 54 10 6 18.9 ± 3.8 ** 68 ─────────────────── ───────────── * P <0.05, ** P <0.01 VS control group [Table 2] shows that the compound [I] of the present invention or a salt thereof
It turns out that it has an excellent anti-leukotriene C ₄ action.

2) Effect on endothelin-1-induced airway constriction response Male Hartley guinea pig (body weight about 50)
0 g) was used. The airway constriction response in guinea pigs by intravenous administration of endothelin-1 at 15 μg / kg was measured according to the Konchet-Wrestler method. The guinea pig was anesthetized with urethane (1.5 g / kg, i.v.), fixed in a dorsal position, tracheostomized, and connected to a ventilator via a cannula. In addition, the side branch of the tracheal cannula is connected to a transducer (model 7020,
Ugobasile). The amount of air supplied per time is 3 to 7 ml, the number of times of air supply is 70 times / min, the load pressure on the lungs is 10 cmH ₂ O, and the amount of air that overflows is rectified through a transducer (Recte-Hori-8S, manufactured by San-Ei side equipment). Recorded. After treatment with gallamine (1 mg / kg, intravenous), 15 μg / kg of endothelin dissolved in physiological saline was administered via a jugular vein cannula, and the induced airway constriction reaction was recorded for 15 minutes. The drug was suspended in 5% gum arabic solution and orally administered 1 hour before administration of endothelin-1. The results are shown in [Table 3].

[Table 3] Effect on endothelin-1-induced guinea pig airway constriction response 用量 Dose (mg / mg kg) Number of animals Airway stenosis rate (%) Suppression rate (%) 対 照 Control group − 6 49.5 ± 5.5-Example 5 16 32.6 ± 7.4 34 36 19.1 ± 3.8 ** 61 10 6 7.2 ± 1.0 ** 86 ──────────────────── ──────────── ** P <0.01 VS control group [Table 3] shows that the compound [I] of the present invention or a salt thereof
It turns out that it has an excellent anti-endothelin-I action.

[0114]

The compound [I] of the present invention or a salt thereof is
It has excellent anti-PAF (platelet activating factor) and anti-allergic effects and can be used as a safe anti-asthmatic agent for mammals (human, mouse, dog, rat, cow, etc.).

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int.Cl. ⁶ , DB name) C07D 487/04 145 A61K 31/50 ABF A61K 31/50 ACD CA (STN) REGISTRY (STN)

Claims (39)

(57) [Claims] 1. A compound of the general formula [Wherein, R ¹ represents a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom, and R ² and R ³
Represents a hydrogen atom or a lower alkyl group which may have a substituent, R ² and R ³ may form a 5- to 7-membered ring together with adjacent —CＣC—, and X represents an oxygen atom Or S (O) p (p is an integer of 0 to 2), and Y is a group represented by the following formula: (R ⁴ and R ⁵ each represent a hydrogen atom or a lower alkyl group which may have a substituent) or a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent A divalent group derived from R ⁶ and R ⁷
Represents a hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent or an aryl group which may have a substituent,
⁶ and R ⁷ may form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom, m represents an integer of 0 to 4, and n represents an integer of 0 to 4 . Or a salt thereof. 2. An optionally substituted lower alkyl group is hydroxy, amino, carboxyl, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy,
C _1-6 alkyl - a compound of claim 1, wherein to 1 selected from carbonyloxy and halogen atoms is four may have a substituent group C _1-6 alkyl group. 3. A 5- to 7-membered ring having C _5-7 cycloalkene,
The compound according to claim 1, which is benzene, pyrrole, pyridine or piperidine. 4. A divalent group derived from a 3- to 7-membered homocyclic ring is represented by the formula: The compound according to claim 1, which is 5. A divalent group derived from a 3- to 7-membered heterocycle, The compound according to claim 1, which is 6. A cycloalkyl group which may have a substituent is hydroxy, amino, carboxyl, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 alkyl. The compound according to claim 1, which is a _C3-6 cycloalkyl group _optionally having 1 to 4 substituents selected from -carbonyloxy and a halogen atom. (7) an aryl group which may have a substituent,
Optionally substituted C _1-6 alkyl, optionally substituted amino, acetamido, hydroxy, carboxyl, nitro, C _1-6 alkoxy, C _1-6 alkyl-carbonyloxy and halogen 1 selected from atoms
The compound according to claim 1, which is a C _6-14 aryl group _optionally having 5 to 5 substituents. 8. C _1-6 alkyl optionally having substituent is hydroxy, amino, mono - or di -C _1-6 alkylamino, to 1 selected from C _1-6 alkoxy and halogen C optionally having 4 substituents
The compound according to claim 7, which is _1-6 alkyl. 9. The amino optionally having substituent (s) is C.
The compound according to claim 7, which is an amino optionally having one or two substituents selected from _1-6 alkyl and 5- to 7-membered cyclic amino. (10) the nitrogen-containing heterocyclic group is The compound according to claim 1, which is 11. A substituent which the 3- to 7-membered homocyclic or heterocyclic or nitrogen-containing heterocyclic group may have is a C _1-6 alkyl which may have a substituent or a substituent. Amino, hydroxy, carboxyl, nitro,
The compound according to claim 1, wherein the compound is 1 to 5 selected from C _1-6 alkoxy and a halogen atom. 12. The C _1-6 alkyl which may have a substituent is hydroxy, amino, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 alkyl-carbonyl. The compound according to claim 11, which is C1-6 alkyl _optionally having 1 to 4 substituents selected from oxy and halogen atoms. 13. An optionally substituted amino is represented by C
_1-6 alkyl, C _1-6 acyl and 5 to have 1 or 2 substituents selected from 7-membered cyclic amino is also an amino compound of claim 11. 14. The compound according to claim ¹ , wherein R ¹ is a hydrogen atom or a C _1-3 alkyl group. 15. The compound according to claim 1, wherein R ² and R ³ are each a hydrogen atom or a lower alkyl group which may have a substituent. 16. R ² and R ³ are each selected from a hydrogen atom or a hydroxy, amino, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 alkyl-carbonyloxy and halogen atom. The compound according to claim 1, which is a C1-6 alkyl group _optionally having 1 to 4 substituents. (17) R ² and R ³ are each a hydrogen atom or a C _1-3 alkyl group, or
The compound according to claim 1, which forms cyclohexene or benzene together with C = C-. 18. The compound according to claim 1, wherein R ² and R ³ are each a hydrogen atom or a C _1-3 alkyl group. (19) Y is a compound represented by the formula: Wherein R ⁴ ′ and R ⁵ ′ are (i) a hydrogen atom or (ii) hydroxy, amino, carboxyl, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy, C _{1 And} represents a C _1-3 alkyl group _optionally having 1 to 4 substituents selected from _-6 alkyl-carbonyloxy and a halogen atom. Or a group represented by the formula: The compound according to claim 1, which is 20. The compound according to claim 1, wherein R ⁶ and R ⁷ are each a hydrogen atom or a C _1-3 alkyl group. 21. The compound according to claim 1, wherein X is an oxygen atom. 22. R ¹ , R ² and R ³ are each a hydrogen atom or a C _1-3 alkyl group, and Y is a group represented by the formula: Wherein R ⁴ ″ and R ⁵ ″ are each a hydrogen atom or C
_{1-3 represents} an alkyl group. Or a group represented by the formula: , R ⁶ and R ⁷ are each a hydrogen atom or a C _1-3 alkyl group, X is an oxygen atom, m is an integer of 1 to 3, and n
The compound according to claim 1, wherein is an integer of 1 to 4. 23. R ¹ and R ² are both hydrogen atoms and R ³ is C
_1-3 alkyl group, Y is of the formula [In the formula, R ⁴ ′ ″ and R ⁵ ″ represent a C _1-3 alkyl group. Or a group represented by the formula: , R ⁶ and R ⁷ are both a hydrogen atom, X is an oxygen atom, m is 1 and n is an integer of 1 to 4. 24. 6- (2,2-Diethyl-3-sulfamoyl-1-propoxy) -7-methyl [1,2,4]
The compound according to claim 1, which is triazolo [1,5-b] pyridazine. 25. 6- (2,2-Diethyl-6-sulfamoyl-1-hexyloxy) -7-methyl [1,2,25
4] The compound according to claim 1, which is triazolo [1,5-b] pyridazine. 26. 6- (2,2-diethyl-5-sulfamoyl-1-pentyloxy) -7-methyl [1,2,
4] The compound according to claim 1, which is triazolo [1,5-b] pyridazine. 27. The compound according to claim 1, which is 6- (2,2-diethyl-4-sulfamoyl-1-butoxy) -7-methyl [1,2,4] triazolo [1,5-b] pyridazine. . [28] An anti-asthmatic agent comprising the compound according to [1]. (29) An antiallergic agent comprising the compound according to (1). 30. The anti-asthmatic agent according to claim 28, which is a tablet. 31. The antiallergic agent according to claim 29, which is a tablet. 32. The anti-asthmatic agent according to claim 28, which is an inhalant. 33. The antiallergic agent according to claim 29, which is an inhalant. 34. The anti-asthmatic agent according to claim 28, which is a fine granule. 35. The antiallergic agent according to claim 29, which is a fine granule. 36. The general formula: [In the formula, Z ¹ represents a reactive group, and R ¹ , R ² and R ³ have the same meaning as described in claim 1. Or a salt thereof, and a compound represented by 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 are as defined in claim 1. ]
The method for producing a compound according to claim 1, which comprises reacting the compound represented by the formula (I) or a salt thereof. 37. A compound of the general formula [Wherein, Z ² represents a group capable of reacting with Z ¹ and leaving, R ¹ , R ² ,
R ³ and X are as defined 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 significance as described in claim 1. And a salt thereof. 38. A compound of the general formula [Wherein, W represents a leaving group, R ¹ , R ² , R ³ , X, Y,
m and n are as defined in claim 1. And a salt thereof and a general formula: [Wherein, R ⁶ and R ⁷ are as defined in claim 1. And a salt thereof. 39. A compound of the general formula [Wherein, W represents a leaving group, R ¹ , R ² , R ³ , X, Y,
m and n are as defined in claim 1. Or a salt thereof.