JP2959587B2 - Triazolopyridazine compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to novel and pharmaceutically useful triazolopyridazine compounds.

[0002]

2. Description of the Related Art JP-A-1-250383 discloses compounds having an anxiolytic effect, such as 5,6-dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one. JP-A-63-295577 discloses that
10-phenyl-6H- useful as an anxiolytic and the like
[1] Benzothiopyrano [4,3-c] [1, 2, 4]
Compounds such as triazolo [3,4-f] pyridazine are
Further, JP-A-2-202889 discloses 6,7-dihydro-11- useful as an anxiolytic and anti-dementia drug.
Phenyl [1] benzothiepino [5,4-c] [1,
Compounds such as [2,4] triazolo [4,3-b] pyridazine are disclosed. Also, Arch. Pharm.
einheim) 321, 735-738 (1988).
h) Cinnoline and 1,2,4-triazolo-
A method for synthesizing (4 ^′ , ^3′- b) thieno (2,3-h) cinnoline is known.

[0003]

DISCLOSURE OF THE INVENTION The present invention relates to a useful medicine,
In particular, it is an object of the present invention to provide a non-benzodiazepine skeleton compound having an affinity for a benzodiazepine receptor.

[0004]

According to the present invention, there is provided a compound of the general formula

Embedded image (Wherein R ¹ and R ² are the same or different and are hydrogen, halogen, hydroxyl, trifluoromethyl, nitro, cyano, lower alkyl, acyl or lower alkoxy, and R ³ is lower alkyl, cycloalkyl, substituted or unsubstituted Aryl or substituted or unsubstituted heteroaryl, X is C
H ₂ or S (O) _n , where n is 0, 1 or 2. m represents 1 or 2. The present invention relates to a triazolopyridazine compound represented by the formula:

When the symbols of the general formula (I) are explained by definition, halogen means fluorine, chlorine, bromine and iodine, and lower alkyl means methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tertiary butyl. Acyl is acetyl, propionyl, butyryl, benzoyl and the like; lower alkoxy is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary
Butoxy, cycloalkyl is cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., aryl is phenyl, naphthyl, etc., and heteroaryl is thienyl, pyridyl, furyl, etc., and these aryl and heteroaryl are The ring may have at least one substituent selected from halogen, trifluoromethyl, nitro, amino, lower alkyl and lower alkoxy.

When the compound (I) of the present invention has an asymmetric atom, it can be obtained in the form of a racemic mixture or an optically active compound. Obtained as a stereomer or a mixture thereof. The present invention also includes these mixtures and individual isomers. The present invention also includes stereoisomers.

The method for synthesizing the compound of the present invention is as follows. Method 1 The compound of the general formula (I) has the general formula

Embedded image (Wherein Z represents a halogen such as chlorine or bromine, and other symbols are as defined above) and a compound represented by the general formula R ³ —CONHNH ₂ (III) (wherein R ³ is And a compound represented by the following formula: The reaction proceeds by heating to reflux for 3 to 22 hours in methanol, ethanol, propanol, butanol, ethylene glycol monomethyl ether, ethylene glycol, benzene, toluene, xylene or the like, preferably propanol, butanol or ethylene glycol monomethyl ether.

Method 2 The compound of the general formula (I) can be synthesized by reacting the compound of the general formula (II) with hydrazine hydrate.

(Wherein each symbol is as defined above) or an acid adduct thereof, and a general formula R ³ —COOH (V) (wherein R ³ is as defined above). ) Or a reactive derivative thereof (acid halide, ester, acid anhydride, etc.). The reaction is carried out, if necessary, in the presence of a dehydrating agent (triethylamine, pyridine, sodium acetate, potassium acetate, potassium carbonate, sodium carbonate, etc.)
Proceed in a suitable solvent (benzene, toluene, xylene, chloroform, methylene chloride, etc.)

(Wherein each symbol is as defined above) is synthesized. Further, the compound of the general formula (I) is obtained by heating and refluxing the compound of the general formula ( VI ) in a solvent such as isopropyl alcohol, butanol and ethylene glycol monomethyl ether for 10 to 20 hours.

Method 3 In a compound of the formula (I) where X = S (O) _n , n = 0
By subjecting a compound of the formula to an oxidation reaction,
Compounds where n = 1 or 2, ie, oxide or dioxide compounds, can be synthesized. The reaction is carried out in an appropriate solvent in an oxidizing agent (hydrogen peroxide, peracetic acid, perbenzoic acid, m-
Chloroperbenzoic acid, sodium hypobromite, etc.) in the presence of m-chloroperbenzoic acid in a methylene chloride solvent at room temperature for 10 to 20 hours. The compound of n = 1 is preferentially obtained by keeping for 5 minutes to 5 hours, and the compound of n = 2 is obtained by keeping at 30-100 ° C. for 2-10 hours.

Method 4 In the general formula (I), the compound wherein R ² is acyl is represented by the general formula:

Embedded image (Wherein each symbol is as defined above) and a compound represented by the general formula: R ⁴ —COOH (VIII) (wherein, R ⁴ represents alkyl, aryl, haloalkyl, pyridyl, thienyl, and furyl.) Can be synthesized by reacting with a compound represented by the following formula: The reaction is carried out in an appropriate solvent, for example, a solvent such as benzene or toluene, which does not hinder the reaction, or without a solvent, in the presence of a dehydrating agent (polyphosphoric acid, phosphorus pentoxide, etc.) for 10 to 1
Perform at 50 ° C.

Method 5 In the general formula (I), the compound in which R ² is acyl is a compound of the general formula (VII) and a general formula R ⁴ —COZ ² (IX) (wherein Z ² represents halogen, and ⁴ has the same meaning as described above.). The reaction is carried out in a suitable solvent such as benzene, toluene, chloroform, dichloromethane, a solvent which does not inhibit the reaction such as dichloroethane, etc.
The reaction is performed at -10 ° C to 100 ° C for 30 minutes to 5 hours in the presence of a suitable Lewis acid (such as tin chloride, iron chloride, aluminum chloride, and zinc chloride).

The compound of the general formula (II) can be synthesized, for example, by the following method. Method 6 General formula

Embedded image (Wherein each symbol is as defined above) and hydrazine or a hydrate thereof is reacted with a compound represented by the general formula

Embedded image (Wherein each symbol is as defined above). The reaction proceeds by heating and refluxing for 5 to 20 hours in a suitable solvent, for example, an alcoholic solvent such as methanol, ethanol, or propanol or a solvent that does not inhibit the reaction such as benzene or toluene.

The compound of the general formula (XI)
At 60 ° C., 1- to 1.5-fold molar amount of bromine is added dropwise in an acetic acid solvent [Journal of Medicinal Chemistry]
(J. Med. Chem.) Vol. 14, p. 262 (1971)]
Or a method in which a compound having a single bond at its binding site is reacted with sodium-m-nitrobenzenesulfonate (Bachmann method, British Patent No. 1168291).
By the general formula

Embedded image (Wherein each symbol is as defined above). Alternatively, the compound of the general formula (XII) may be obtained by converting the compound of the general formula (XI) to a sulfoxide (dimethyl sulfoxide, diphenyl sulfoxide, phenylvinyl sulfoxide, dibenzyl sulfoxide,
In the presence of p-tolylsulfoxide, methylphenylsulfoxide, resorcinol sulfoxide and the like, an appropriate acid (hydrohalic acid such as hydrobromic acid, hydrochloric acid, hydroiodic acid, alkyl such as methanesulfonic acid and trifluoromethanesulfonic acid) Sulfonic acid, acetic acid, formic acid, aliphatic carboxylic acid such as trifluoroacetic acid, arylsulfonic acid such as p-toluenesulfonic acid, or a mixture thereof) for 30 minutes to 30 hours from 0 ° C. to near the boiling point of acid It can also be manufactured by doing.

Further, the obtained compound of the general formula (XII) and a compound represented by the general formula POZ ³ (XIII) (wherein Z ³ represents a halogen such as chlorine or bromine) are heated at 50 to 100 ° C. To obtain a compound of the general formula (II). The compound of the general formula (I) thus produced can be isolated and purified by a conventional method such as column chromatography and recrystallization.

[0015]

The compound of the formula (I) thus obtained has a high affinity for benzodiazepine receptors and is useful as an anxiolytic. It is also useful as an antidote for overdose or intoxication of existing anxiolytics such as diazepam. Further, it is also useful as an anti-dementia drug.

When the compound of the present invention is used as a medicament, it is mixed with appropriate pharmacologically acceptable excipients, carriers, diluents, etc., to give tablets, capsules, granules, syrups, injections, suppositories. Alternatively, it can be administered in the form of a powder or the like. The dose is, for example, in the case of oral administration, usually 5 to 5 per adult per day.
The dose is about 500 mg, which can be administered once or in several divided doses.

[0017]

EXAMPLES The present invention will be described in detail with reference to Examples and Examples, but the present invention is not limited thereto.

Reference Example 1 5,6-dihydro-9-methylthieno [2 ^' , 3 ^' :
2,3] thiepino [4,5-c] pyridazine-3 (2
55.1 g of phosphorus oxychloride was added to 15 g of H) -one at room temperature, and the mixture was heated and stirred at 60 ° C for 2 hours. After cooling, the reaction solution is poured into water, stirred for several hours, and the precipitated crystals are collected by filtration. Recrystallization from ethanol gave 3-chloro-5,6-dihydro-9-methylthieno [2 ^' , 3 ^' : 2,3] thiepino [4,5-
c] 9.8 g of pyridazine are obtained.

Reference Example 2 9-bromo-5,6-dihydrothieno [2 ^' , 3 ^' :
2,3] thiepino [4,5-c] pyridazine-3 (2
34.0 g of H) -one is added to 164.5 g of phosphorus oxychloride at 60 ° C, and the mixture is further stirred at 90 ° C for 3 hours. After cooling, the reaction solution is poured into water, stirred for several hours, and the precipitated crystals are collected by filtration. Recrystallization from methanol gives a melting point of 170-
9-bromo-3-chloro- as white crystals at 172 ° C.
32.0 g of 5,6-dihydrothieno [2 ^' , 3 ^' : 2,3] thiepino [4,5-c] pyridazine are obtained.

Reference Example 3 9-ethyl-5,6-dihydrothieno [2 ^' , 3 ^' :
2,3] thiepino [4,5-c] pyridazine-3 (2
13.7 g of H) -one is added to phosphorus oxychloride at 60 ° C and further stirred at 70 ° C for 2 hours. After cooling, pour the reaction solution into water and stir for several hours. The precipitated crystals were collected by filtration and recrystallized from ethanol to give a melting point of 158 to 159 ° C.
As white crystals of 3-chloro-9-ethyl-5,6-dihydrothieno [2 ^' , 3 ^' : 2,3] thiepino [4,5
-C] 7.7 g of pyridazine are obtained.

Example 1 9-bromo-3-chloro-5,6-dihydrothieno [2
^' , 3 ^' : 2,3] Thiepino [4,5-c] pyridazine and 5.0 g of benzoylhydrazine are suspended in 70 ml of butanol and refluxed for 5.5 hours. After cooling, the precipitated crystals were collected by filtration and recrystallized from chloroform-ethyl acetate to give 2-bromo-5,6-dihydro-10-phenylthieno [2 ^' , 3 ^' as white crystals having a melting point of 246 to 248 ° C. 2,3] thiepino [5,6-e]
4.0 g of [1,2,4] triazolo [4,3-b] pyridazine are obtained.

Example 2 2-Bromo-5,6-dihydro-1 obtained in Example 1
0-phenylthieno [2 ^' , 3 ^' : 2,3] thiepino [5,4-e] [1,2,4] triazolo [4,3-
b] To a solution of 1.0 g of pyridazine in 30 ml of formic acid is added at room temperature 0.7 ml of a 30% aqueous hydrogen peroxide solution, and the mixture is left for 18 hours. The reaction solution is poured into water and extracted with chloroform. Further, the extracted solution is washed with a 5% aqueous solution of potassium bisulfite and a saturated saline solution, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the obtained crude crystals were recrystallized from chloroform-ethanol to give 2-bromo-ethanol as yellow crystals having a melting point of 280 ° C or higher.
5,6-dihydro-10-phenylthieno [2 ^' ,
3 ^′ : 2,3] thiepino [5,4-e] [1,2,4]
0.7 g of triazolo [4,3-b] pyridazine 4,4-dioxide are obtained.

Example 2 9-bromo-3-chloro-5,6-dihydrothieno [2
^' , 3 ^' : 2,3] Thiepino [4,5-c] pyridazine (5.0 g) and acetylhydrazine (2.2 g) are suspended in 70 ml of butanol and heated under reflux for 22 hours. After cooling, the precipitated crystals were collected by filtration and recrystallized from methylene chloride-ethanol to give white crystals having a melting point of 250 to 251 ° C.
-Bromo-5,6-dihydro-10-methylthieno [2 ^' , 3 ^' : 2,3] thiepino [5,4-e] [1,
2,4] triazolo [4,3-b] pyridazine 2.1 g
Is obtained.

Example 4 2-bromo-5,6-dihydro-1 obtained in Example 3
0-methylthieno [2 ^' , 3 ^' : 2,3] thiepino [5,4-e] [1,2,4] triazolo [4,3-
b] To a solution of 0.40 g of pyridazine in 18 ml of formic acid is added 0.5 ml of a 30% aqueous hydrogen peroxide solution at room temperature, and the mixture is left for 12 hours. This reaction solution was treated in the same manner as in Example 2 to give 2-bromo-5,6-dihydro-10-methylthieno [2 ^′ , 3 ^′ : 2,3 as white crystals having a melting point of 272 to 274 ° C. Chiepino [5,4-e]
[1,2,4] triazolo [4,3-b] pyridazine
0.26 g of 4,4-dioxide is obtained.

Example 5 3-Chloro-9-ethyl-5,6-dihydrothieno [2
^' , 3 ^' : 2,3] thiepino [4,5-c] pyridazine (1.50 g) and benzoylhydrazine (1.2 g) are suspended in 40 ml of butanol, and heated under reflux for 3 hours. After cooling,
The precipitated crystals were collected by filtration and recrystallized from isopropyl alcohol to give 2-chloromethane as a white crystal having a melting point of 223 ° C.
Ethyl-5,6-dihydro-10-phenylthieno [2
^' , 3 ^' : 2,3] thiepino [5,4-e] [1,2,3
4] 0.52 g of triazolo [4,3-b] pyridazine is obtained.

Example 6 3-chloro-5,6-dihydro-9-methylthieno [2
^' , 3 ^' : 2,3] Thiepino [4, 5-c] [1, 2,
4] Triazolo [4,3-b] pyridazine 5.0 g and benzoylhydrazine 3.8 g were added to 80 ml of butanol.
And heat to reflux for 20 hours. After cooling, the precipitated crystals were collected by filtration and recrystallized from chloroform-ethanol to give 5,6-dihydro-2-methyl-10-phenylthieno [2 ^' , 3 ^' as pale yellow crystals having a melting point of 238 to 240 ° C:
3.4 g of 2,3] thiepino [5,4-e] [1,2,4] triazolo [4,3-b] pyridacin are obtained.

Example 7 (9-bromo-5,6-dihydrothieno [2 ^' , 3 ^' :
To a suspension of 10.0 g of [2,3] thiepino [4,5-c] pyridazin-3-yl) hydrazine in 60 ml of chloroform was added 8.7 g of benzoyl chloride at room temperature with stirring, followed by stirring for 10 minutes. The precipitated crystals are collected by filtration and washed with ethanol to give N-benzoyl-N ^' -(9-bromo-5,6-dihydrothieno [2 ^' , 3 ^' : 2,3] thiepino [4,5-c]. 8.7 g of (pyridazin-3-yl) hydrazine hydrochloride are obtained. Next, N-benzoyl-N
^' -(9-bromo-5,6-dihydrothieno [2 ^' , 3
^' : 2,3] thiepino [4,5-c] pyridazine-3-
Ill) hydrazine hydrochloride 8.4 g pyridine 70 ml
The solution is heated at reflux for 2 hours. After cooling, the reaction solution is poured into ice water, and the precipitated crystals are collected by filtration. After washing with water, chloroform
When recrystallized from ethyl acetate, the same 2-bromo-5,6-dihydro-10-phenylthieno [2 ^′ , 3 ^′ : 2,3] thiepino [5,4-
e] [1,2,4] triazolo [4,3-b] pyridazine 6.1 g (melting point 246-248 ° C) is obtained.

Hereinafter, the compounds shown in the following table can be synthesized in the same manner.

[0029]

[Table 1]

[0030]

The pharmacological action of the compound of the present invention will be described below together with experimental methods. Experimental Example 1: Substitution ability for benzodiazepine A specific benzodiazepine receptor binding test was performed using Life Science, Vol. 20, page 2101 (19).
77 years). The crude synaptosome fraction was separated from the cerebral cortex of male Wistar male rats aged 9 to 10 weeks, and a 50 mM Tris-HCl buffer (pH 7.0) containing 120 mM sodium chloride and 5 mM potassium chloride was used.
The suspension was used in 4). Next, several concentrations of the test compound and tritiated diazepam (final concentration 2 nM) were added to the synaptosome suspension, and the mixture was allowed to react at 0 ° C. for 20 minutes. The suspension is then added to Whatman
After filtering through a GF / B glass fiber filter and washing the filter with the above buffer, the radioactivity remaining on the filter was measured with a liquid scintillation counter. The specific binding amount was a value obtained by subtracting the binding amount obtained in the presence of 10 ^-6 M non-radioactive diazepam from the total binding amount. The affinity of a test compound for the benzodiazepine receptor, as assessed by its ability to displace tritiated diazepam from its binding site, is expressed as a Ki value. As a result, the Ki value of the compound of Example 5 was 1.
The Ki value of the compound of 4 nM and Example 6 was 0.1 nM.

Experimental Example 2: Anti-bicuculline Action Life Science No. 2
1, anti-bicuculline action test was conducted according to the method of 1779 (1977). Male d weighing 20-28 g
dY mice were used as 7-14 groups per group. One hour after the test compound was orally administered, (+) bicuculline 0.6 m
g / kg was administered intravenously, and the presence or absence of tonic extension convulsions within 5 minutes was examined to determine the 50% effective concentration (ED ₅₀ value).

Continuation of the front page (51) Int.Cl. ⁶ identification code FI C07D 495/22 C07D 495/22 (56) References JP-A-64-6278 (JP, A) JP-A-2-167285 (JP, A) JP-A-2-202889 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 495/14 C07D 495/22 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula (Wherein R ¹ and R ² are the same or different and each represents hydrogen, halogen, hydroxyl, trifluoromethyl, nitro, cyano, lower alkyl, acyl or lower alkoxy, and R ³ represents lower alkyl, cycloalkyl, substituted or unsubstituted A triazolopyridazine compound represented by aryl or substituted or unsubstituted heteroaryl, wherein X represents CH ₂ or S (O) _n , n represents 0, 1 or 2; m represents 1 or 2.