JPS63310891A - Condensed pyridazine compound - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is lower alkyl or (substituted)phenyl; R<2> and R<3> are H, (substituted)aralkyl or (substituted) heteroaralkyl; R<4> is H, alkyl, (substituted)phenyl, (substituted)heteroaryl, (substituted)aralkyl, (substituted)heteroaralkyl or -A-NR<5>R<6> (R<5> and R<6> are H, lower alkyl, etc.; A is lower alkylene)] or acid addition salt thereof. EXAMPLE:4-(4-Fluorobenzyl)-1,6-dimethyl-1,2,4-triazolo[4,3-b]pyridazine. USE:Pentylenetetrazole antagonist, electric shock convulsion inhibiting agent, phenylquinone inhibiting agent, carrageenan edema inhibiting agent, diuretic and platelet aggregation inhibiting agent. PREPARATION:A compound expressed by formula II (Z is halogen) is subjected to heat reflex with a compound expressed by the formula R4CONHNH2 in a solvent such as isopropanol for 10-20hr to carry out condensation and ring closure reaction.

Description

DETAILED DESCRIPTION OF THE INVENTION OBJECTS OF THE INVENTION The present invention relates to novel and pharmaceutically useful fused pyridazine compounds or pharmaceutically acceptable acid addition salts thereof.

[Structure of the invention]

The present invention is based on the general formula [wherein R1 is lower alkyl, pheonyl or substituted,
R'', R' are the same or different and are hydrogen, aralkyl, substituted aralkyl, heteroarylkyl or substituted heteroaralkyl, R4 is hydrogen, alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, heteroaralkyl,
Substituted heteroaralkyl or of the formula A-NR'R'
(Here, Rs and Ra may be the same or different and represent hydrogen, lower alkyl, or aralkyl, or may be combined with adjacent nitrogen atoms and contain a nitrogen atom, substituted nitrogen atom, oxygen atom, or sulfur atom. Indicates a group forming a good 5- to 6-membered heterocycle.

A represents lower alkylene. ) represents a group.

] The present invention relates to a fused pyridazine compound or a pharmaceutically acceptable acid addition salt thereof.

In this specification, lower alkyl refers to alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tertiary butyl, and alkyl refers to methyl, ethyl, propyl, isopropyl, butyl, Alkyl having 1 to 10 carbon atoms such as isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, octyl, 2-ethylhexyl, nonyl, decyl, etc., and aralkyl include benzyl, benzhydryl, phenylethyl, phenylpropyl, phenylbutyl, etc. Heteroaralkyl refers to pyridylmethyl, pyridylethyl, pyridylbutyl, furylmethyl, furylethyl, thenylmethyl, thenylethyl, etc., and heteroaryl refers to pyridyl, furyl,
The substituents of substituted phenyl, substituted aralkyl, substituted heteroaryl, or substituted heteroaralkyl include halogen (chlorine, bromine, fluorine, etc.), lower alkyl, lower alkoxy (methoxy, ethoxy, propoxy, isopropoxy, butoxy), etc. , alkoxy having 1 to 4 carbon atoms such as tertiary butoxy), trifluoromethyl, nitro, or amino, and is a nitrogen atom formed by bonding with an adjacent nitrogen atom, a substitution chamber 4 The heterocycle consisting of a 5- to 6-membered ring which may contain an elementary atom, an oxygen atom, or a sulfur atom includes pyrrolidinyl, piperidino, 1-piperazinyl, 4-methyl-1-piperazinyl, 4-benzyl-1-piperazinyl, Morpholino, thiomorpholino, etc., and lower alkylene means alkylene having 1 to 4 carbon atoms such as methylene, ethylene, propylene, trimethylene, and tetramethylene.

Pharmaceutically acceptable acid addition salts of the compound of general formula (1) include inorganic acid addition salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, fumarate, maleic acid Examples include organic acid addition salts such as salts, malates, citrates, tartrates, p-)luenesulfonates.

In the present invention, the compound of general formula (1) can be synthesized, for example, by a method known per se as shown below.

A compound represented by the general formula (in the formula, Z represents a halogen, and the other symbols have the same meanings as above) and a compound represented by the -a formula % formula % (3) A method of subjecting to a condensation ring-closing reaction.

The reaction is carried out in a suitable solvent (methanol, ethanol, isopropyl alcohol, ethylene glycol, ethylene glycol monomethyl ether, benzene, toluene, xylene, etc.), preferably in a solvent such as isopropyl alcohol, ethylene glycol monomethyl ether, etc.
The process is suitably carried out by heating under reflux for 0 to 20 hours.

-Go'l! 2- A compound represented by the general formula (in the formula, each symbol has the same meaning as above) synthesized by the reaction of the compound of the general formula (2) and hydrazine hydrate or an acid addition salt thereof and the general formula % A method of reacting a carboxylic acid represented by the formula % (5) (wherein R4 has the same meaning as above) or a reactive derivative thereof (acid halide, ester, acid anhydride, mixed acid anhydride, etc.).

The reaction is carried out using a deoxidizing agent (triethylamine, pyridine, sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, etc.) as necessary, and an appropriate solvent (benzene, potassium carbonate, etc.).
Toluene, xylene, chloroform, methylene chloride, etc.) to synthesize a compound represented by the general formula (in the formula, each symbol has the same meaning as above), and further synthesize isopropyl alcohol, ethylene glycol monomethyl ether, etc. in a solvent of 10 to
It can be obtained by heating under reflux for 20 hours.

On the other hand, a compound represented by the general formula (in the formula, X represents a halogen, and the other symbols have the same meanings as above) and a compound represented by the general formula (in the formula, each symbol has the same meaning as above) and how to react.

The reaction is carried out in an appropriate solvent (a solvent that does not inhibit the reaction, such as methanol, ethanol, isopropyl alcohol, tetrahydrofuran, benzene, toluene, chloroform, methylene chloride, etc.) at room temperature or under reflux of the solvent used.
Compound (8) may be used in excess, or a suitable deoxidizing agent (
pyridine, triethylamine, potassium carbonate, sodium carbonate, etc.) for 1 to 12 hours.

The compound of general formula (1) obtained by the above method can be used to produce an acid addition salt by a conventional method.

The acid used can be appropriately selected from inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, and phosphoric acid, and organic acids such as fumaric acid, maleic acid, malic acid, citric acid, tartaric acid, and p-toluenesulfonic acid.

〔Effect of the invention〕

The compound of the present invention is novel and has pharmacological effects such as pentylentitrazole antagonistic activity, electric shock convulsion suppressive effect, phenylquinone suppressive effect, carrageenan edema suppressive effect, diuretic effect, and platelet aggregation suppressive effect, and has pharmaceutical effects. It is useful as

When the compound of the present invention is used as a medicine, it may be mixed with carriers, excipients, diluents, solubilizing agents, etc. to form tablets, granules, powders, injections, external preparations, infusion preparations, etc. preferable. The dosage may vary depending on the patient's age, weight, symptoms, etc., but it is approximately 10 to 500 ml per day for adults.
It is preferable to take it in divided doses several times a day.

〔Example〕

The present invention will be explained below with reference to Examples, but the present invention is not limited thereto.

Example 1 4-(4-fluorohensyl)-3-hydrazino-6-
Add 4.6 g of methylpyridazine to 10 ml of acetic anhydride and keep at 80-90°C on a water bath for 2 hours.

The mixture is then poured into water, made alkaline using a 10% aqueous sodium hydroxide solution, and extracted with chloroform. The extract is washed with water, dried over anhydrous potassium carbonate, and concentrated under reduced pressure. When the obtained crystals were recrystallized from isopropyl ether, 4-(4-fluorohensyl)-1,6-dimethyl-1,2,4-triazolo(4
, 3-b] 3.9 g of pyridazine were obtained. Melting point 112
~114°C Example 2 Using 4-(2-chlorobenzyl)-3-hydrazino-6-methylpyridazine, reaction and treatment were carried out in the same manner as in Example 1, resulting in colorless needle crystals of 4-(2 -chlorobenzyl)-1,6-dimethyl-1,2,4-triazolo(4
, 3-b]pyridazine was obtained. Melting point 123-125
°C Example 3 When 3-hydrazino-4-(4-methoxybenzyl)-6-methylpyridazine is used in place of 4-(4-fluorobenzyl)-3-hydrazino-6-methylpyridazine in Example 1, 4 - (4-methoxybenzyl)-1,
6-dimethyl-1.2゜4-triazoloC4,3-b)
Pyridazine was obtained. Melting point: 139-140°C Example 4 5.0 g of 4-(2-chlorobenzyl)-3-hydrazino-6-methylpyridazine is added to 10 Ill of butanoic anhydride and kept at 100-110°C on an oil bath for 3 hours. Pour onto ice water, add 10% hydroxide solution to make alkaline, and extract with chloroform. The extract is dried over anhydrous potassium carbonate and concentrated under reduced pressure. When the crystals formed after standing were recrystallized from a mixed solvent of n-hexane and isopropyl ether, a colorless powder of 4-(2-chlorobenzyl)-6-methyl-1-propyl-1,2°4-triazolo 2.5 g of (4,3-b)pyridazine was obtained. Melting point 58-60°C Example 5 6-(4-bromophenyl)-4-(2-chlorobenzyl)- in place of 4-(4-fluorobenzyl)-3-hydrazino-6-methylpyridazine in Example 1 When using 3-hydrazinopyridazine, 6-(4-bromophenyl)-4-(2-chlorobenzyl)-1-methyl-1,
2,4-)riazolo(4,3-b)pyridazine was obtained. Melting point: 128-130°C Example 6 When 4-benzyl-3-hydrazino-6-methylpyridazine is used in place of 4-(4-fluorobenzyl)-3-hydrazino-6-methylpyridazine in Example 1,
4-Benzyl-1,6-dimethyl-1.2.4-)riazolo(4,3-b)pyridazine is obtained. Melting point 106
．． 5-107°C Example 7 5-(2-chlorobenzyl)-3-hydrazino-6-phenylpyridazine is used in place of 4-(4-fluorobenzyl)-3-hydrazino-6-methylpyridazine in Example 1. and 5-(2-chlorobenzyl)-1-methyl-6-phenyl-1,2,4-)riazolo(4,3-
b) Pyridazine was obtained. Melting point: 165-166°C Example 8 When propionic anhydride is used in place of acetic anhydride in Example 1, 1-ethyl-4-(4-fluorobenzyl)-6-
Methyltriazolo(4,3-b)pyridazine was obtained. Melting point 93-95°C Example 9 4-(4-fluorobenzyl)-3-hydrazino-6-
Dissolve 6 g of methylpyridazine in 100 ml of chloroform, add 7.2 g of anhydrous potassium carbonate, and add 5.4 g of 2-chlorobenzoyl chloride in portions with stirring. After being kept at room temperature for about 3 hours, it was washed with water and concentrated under reduced pressure to obtain crude 3-(2-chlorobenzoylhydrazino)-4-(4-fluorobenzyl)-6-methylpyridazine. After adding this to 100 ml of toluene and 6 ml of acetic acid, the mixture was heated under reflux for about 3 hours.

After cooling, wash with sodium bicarbonate water and then with water, and concentrate under reduced pressure. The residual aroma was subjected to column chromatography, and the resulting crystals were recrystallized from a mixed solvent of ethyl acetate and isopropyl ether to yield 1-(2-chlorophenyl)-4-(4-fluorobenzyl)-6 as a colorless powder. -Methyl-1,2,4-triazolo(4,3-b)pyridazine 4
．． 2g was obtained. Melting point 103-105°C Example 10 4-(2-chlorobenzyl)-3-hydrazino-6-
17.5 g of methylpyridazine in 200ml of chloroform
1 and 19.4 g of anhydrous potassium carbonate. Add 9.6 g of α-chloroacetyl chloride little by little while cooling with water. After addition, it is left at room temperature overnight, washed with water, and dried over anhydrous magnesium sulfate. When concentrated under reduced pressure,
Crude 4-(2-chlorobenzyl)-1-chloromethyl-6-methyl-1,2,4-)riazolo(4,3-b)
18 g of pyridazine was obtained. 8 g of this compound is added to 100 ml of ethanol together with 8 g of 4-methylbiperazine, and heated under reflux on a water bath for 5 hours. Concentrate under reduced pressure and extract with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, subjected to column chromatography, and the crystals obtained by adding 20% hydrochloric acid-ethanol were recrystallized from ethanol to obtain colorless powder product 4. -(2-chlorobenzyl)-6-methyl-1-(4-methyl-1-
piperazinylmethyl)-1,2,4-)riazolo(4,
3-b] 5.9 g of pyridazine dihydrochloride was obtained. Melting point: 230-232°C (decomposition) Example 11 When 44% triethylamine-tetrahydrofuran solution is used in place of 4-methylpiperazine in Example 1O, 4.
-(2-chlorobenzyl)-1-dimethylaminomethyl-6-methyl-1,2,4-triazolo(4,3-b)
Pyridazine dihydrochloride was obtained. Melting point 154-157℃
(Decomposition) Example 12 3-chloro-6-methyl-4-(4-methylbenzyl)
and lidazine 4.1 g and isonicotinic acid hydrazide 4
．． Add 3 g to 100 ml of butanol and heat under reflux for 20 hours. The reaction product is concentrated under reduced pressure, water is added, and the resulting crystals are collected by filtration. After washing with water and recrystallizing from ethyl acetate, 6-methyl-4-(4-methylbenzyl)-1-(4-bilidyl)-1,2,4-triazolo(4,3-b)pyridazine is obtained as a powder. 2.7g was obtained. Melting point 132-135°C Example 13 3-chloro-6 in place of 4-(4-fluorobenzyl)-3-hydrazino-6-methylpyridazine in Example 1
-Phenyl-4-(3-pyridyl)pyridazine gives 1-methyl-6-phenyl-4-(3-pyridyl)
-1,2,4-)riazolo(4,3-b)pyridazine was obtained, and when 20% hydrochloric acid-ethanol was added to make the hydrochloride, a dihydrochloride hydrate was obtained. Melting point 235-238
°C (decomposition) Example 14 3-hydrazino-6-methyl-4-(5-methyl-2-chenylmethyl) instead of 4-(4-fluorohensyl)-3-hydrazino-6-methylpyridazine in the actual HMI With pyridazine, 1,6-cymethyl-4-(5
-Methyl-2-chenylmethyl)-1,2,4-)riazolo[4,3-b)pyridazine was obtained. Melting point 115
~118°C Example 15 6-(4-bromophenyl)-3-chloro-4-(2-chlorobenzyl) in place of 3-chloro-6-methyl-4-(4-methylbenzyl)pyridazine in Example 12 ) With pyridazine, 6-(4-)tffmophenyl”
) -4-(2-10 lobenzyl)-1-(4-pyridyl)-1,2,4-triazolo(4,3-b)pyridazine was obtained.

Melting point: 229-231°C Compounds that can be synthesized using the same method are illustrated below.

Example 16 Rhomethyl-1-(4-pyridyl)-4-(2-phenylpropyl)-1,2,4-triazolo(4,3-b
) Pyridazine, melting point 114-115°C Example 17 4-(4-methoxybenzyl)-6-phenyl-1-(
3-pyridyl)-1,2,4-)riazolo(4,3-b
) Pyridazine, melting point 148-150°C Example 18 4-(2-fluorobenzyl)-6-methyl-1-(3
-pyridyl)-1,2,4-triazolo(4,3-b)
Pyridazine, melting point 168-169°C Example 19 4-(2-fluorobenzyl)-1,6-cymethyl-1
．． 2.4-triazolo(4,3-b) and lidazine, melting point 83-84°C Example 20 4-(4-methoxybenzyl)-6-methyl-1-(4
-pyridyl)-1,2,4-triazolo(4,3-b)
Pyridazine, melting point 172-173°C Example 21 4-(2-chlorobenzyl)-1-(3,4°5-trimethoxybenzyl)-6-methyl-1°2.4-)riazolo(4,3- b) and lidazine, melting point 147-149°C Example 22 1-(3,4-dimethoxybenzyl)-6-methyl-4
-(2-chenylmethyl)-1,2,4-triazolo(4,3-b)pyridazine, melting point 176-178°C Example 23 4-(2-chlorobenzyl)-6-methyl-1-(2-
chenylmethyl)-1,2,4-)riazolo(4,3-
b) Pyridazine, melting point 107-108°C Example 24 4-(2-chlorobenzyl)-6-methyl-1-(4-
4-(3,4-dimethoxybenzyl)-6-methyl-1
-(4-pyridyl)-1,2,4-triazolo(4,3
-b) Pyridazine, melting point 187-188°C Example 26 4-(2-methoxybenzyl)-6-methyl-1-(4
-pyridyl)-1,2,44riazolo(4,3-b)pyridazine, melting point 166-168°C Example 27 4-benzyl-6-methyl-1-(2-morpholinoethyl)-1,2,4- ) Riazolo[4,3-b)pyridazine Example 28 4-benzyl-6-methyl-1-(2-piperidinoethyl)-1,2,4-triazolo[4,3-b)pyridazine Example 29 4-benzyl -6-Methyl-1-(1-pyrrolidinylmethyl)-1,2,4-triazolo[4,3-b)pyridazine Example 30 4-Benzyl-1-(3-dibutylaminopropyl)-
6-Methyl-1,2,4-)riazolo[4,3-b)pyridazine Example 31 4-(2-furylmethyl)-1,6-dimethyl-1.2
．． 4-) Riazolo(4,3-b)pyridazine Example 32 4-benzyl-1-(2-furyl)-6-methyl-1,
2,4-triazolo(4,3-b) pyridazine

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1 is lower alkyl, phenyl or substituted phenyl, R^2 and R^3 are the same or different and hydrogen,
Aralkyl, substituted aralkyl, heteroaralkyl or substituted heteroaralkyl, R^4 is hydrogen, alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl or the formula: -A- NR^5R
^6 (Here, R^5 and R^6 are the same or different and represent hydrogen, lower alkyl, or aralkyl, or combine with adjacent nitrogen atoms to form a nitrogen atom, a substituted nitrogen atom, an oxygen atom, or a sulfur atom. 5~ which may contain
Indicates a group forming a 6-membered heterocycle. A represents lower alkylene. ) represents a group. ] A fused pyridazine compound or a pharmaceutically acceptable acid addition salt represented by: