JPH05213960A - Condensed pyridazine compound and its medicinal use - Google Patents

Abstract

PURPOSE:To provide the new compound reduced in the adverse actions such as muscular relaxation actions and useful as a selective antianxiety agent. CONSTITUTION:A compound of formula I [R<1> is carboxyl, formyl, cyano, acyl, etc.; R<2> is H, 1-8C alkyl, hydroxyalkyl, substituted aryl, aralkyl, etc.; A is S, -CH=CH-; E is -CH2-, -S(O)m- ((m) is 0-2); (n) is 1, 2; the bond represented by the full line and the dotted line is a single bond or double line; but when A is S, E is -CH2-, and when A is -CH=CH-, E is -S(O)m- and (n) is 2]. For example, 8-acetyl-2-(4-chlorophenyl)-4,4a,5,6-tetrahydrothieno[2,3-h]cinnoline- 3(2H)-one. The compound of formula I is obtained e.g. by reacting a compound of formula II with a compound of formula III (R<3> is alkyl, haloalkyl, etc.) in the presence of a dehydrating agent such as polyphosphoric acid.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a fused pyridazine compound useful as a selective anxiolytic drug and its pharmaceutical use.

[0002]

2. Description of the Related Art Benzodiazepine (BZP) derivatives represented by diazepam have been used as anxiolytic agents. However, BZP
It is known that the system drugs show clinically excellent anxiolytic action, but also have side effects such as sedation, muscle relaxation, sleep enhancement, and alcohol enhancement action at a usual dose. Therefore,
It is desired to develop a drug that does not have these side effects and exhibits a selective anxiolytic effect. On the other hand, recent pharmacological studies have revealed that a receptor showing a specific affinity for BZP derivatives exists in the central nervous system [Science, vol. 19].
8, 848 (1977)]. With the discovery of BZP receptors in the central nervous system, research on the mechanism of action of BZP drugs has advanced further. BZP receptor is γ-aminobutyric acid (GA
It has been suggested that BZPs express a pharmacological action through the action of GABA by forming a complex with the BA) receptor and Cl ^- ionophore. That is, a compound acting on the BZP receptor can be positioned within a continuous action spectrum from the enhancement (agonist) to the inhibition (inverse agonist) of the action of GABA, and its full pharmacological properties are taken into consideration. -Classifications are made into full agonists, partial agonists, antagonists, partial inverse agonists and inverse agonists. recent years,
The search for anxiolytic drugs that selectively act on anxiety with few side effects such as sedation, muscle relaxation, alcohol potentiating action, and dependence related to BZP drugs is under way. In the course of these studies, BZP has no BZP structure,
Many compounds having a high affinity for the P receptor have been found (JP-A-1-6278 and JP-A-1-250383).
Japanese Patent Laid-Open No. 2-167285). Of these, the compounds classified as BZP partial agonists are largely separated from side effects and show a selective pharmacological action on anxiolytic activity, and thus are attracting attention as a new type of anxiolytic drug.

[0003]

The present inventors have found that non-BZP
As a result of intensive research aimed at developing a selective and highly safe anxiolytic drug having a skeleton, it has a high affinity for the BZP receptor and further has a property as a BZP partial agonist. Therefore, they have found a novel fused pyridazine compound having few side effects and exhibiting a more selective anxiolytic action. That is, the present invention is: General formula

[0004]

[Chemical 2]

[Wherein R ¹ is carboxyl, formyl,
Cyano, hydroxyiminomethyl, acyl, alkoxycarbonyl, aralkyloxycarbonyl, heteroarylalkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkoxyalkyl, arylalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, acyloxyalkyl, hydroxy It represents alkyl, acyloxyalkanoyl, alkoxyalkanoyl, hydroxyalkanoyl, aryloxyalkanoyl, haloalkanoyl, aralkyloxyalkanoyl, heteroarylalkyloxyalkanoyl or heteroaryloxyalkanoyl. R ² is hydrogen, alkyl having 1 to 8 carbons, hydroxyalkyl, alkanoyloxyalkyl, aryl, aralkyl, heteroaryl or aromatic ring having halogen, hydroxy, amino, nitro, cyano, alkyl having 1 to 4 carbons. , Carbon number 1-4
Represents an aryl, aralkyl or heteroaryl having at least one substituent selected from the group consisting of alkoxy, alkanoylamino having 2 to 5 carbons, haloalkyl, acyloxy, alkoxycarbonyl having 2 to 5 carbons and carboxyl. .. A is a sulfur atom or-
CH = CH- is shown. E is -CH ₂ - or -S (O)
_m − (m represents 0, 1 or 2). n represents 1 or 2. The actual battle and the bond represented by the dotted line indicate a single bond or a double bond. However, when A is a sulfur atom, E is-
CH ₂ —, when A is —CH═CH—, E is —S
(O) _m − (m represents 0, 1 or 2) and n represents 2. ] A fused pyridazine compound represented by

2. R ² is halogen on the aromatic ring and has 1 carbon atom
A fused pyridazine compound according to the above 1, which is an aryl having at least one substituent selected from the group consisting of 4 alkyl and 1 to 4 alkoxy.

3. A represents a sulfur atom and E represents —CH ₂ —
The condensed pyridazine compound according to the above 1, wherein

4. A represents -CH = CH- and E represents -S
(O) _m − (m represents 0, 1 or 2), and n is 2, wherein the condensed pyridazine compound is 1.

5. The compound of the general formula (I) is 8-acetyl-2- (4-chlorophenyl) -4,4a, 5,6-tetrahydrothieno [2,3-h] cinnoline-3 (2
H) -one, 2- (4-chlorophenyl) -4,4a,
5,6-Tetrahydro-8-propionylthieno [2,
3-h] cinnoline-3 (2H) -one, 8-butyryl-2- (4-chlorophenyl) -4,4a, 5,6-tetrahydrothieno [2,3-h] cinnoline-3 (2
H) -one, 8-benzoyl-2- (4-chlorophenyl) -4,4a, 5,6-tetrahydrothieno [2,3
-H] Cinnoline-3 (2H) -one, 8-acetyl-
4,4a, 5,6-Tetrahydro-2- (4-methylphenyl) thieno [2,3-h] cinnoline-3 (2H)
-One, 9-acetyl-2- (4-chlorophenyl)-
2,4,4a, 5,6,7-Hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c]
Pyridazin-3-one, 9-acetyl-2- (4-chlorophenyl) -2,5,6,7-tetrahydro-3H-
Thieno [2 ', 3': 6,7] cyclohepta [1,2-
c] pyridazin-3-one, 2- (4-chlorophenyl) -9-formyl-2,5,6,7-tetrahydro-
3H-thieno [2 ′, 3 ′: 6,7] cyclohepta [1,2-c] pyridazin-3-one, 8- (1-hydroxyethyl) -4,4a, 5,6-tetrahydro-2
-(4-Methylphenyl) thieno [2,3-h] cinnoline-3 (2H) -one, 8-acetyl-5,6-dihydro-2- (4-methylphenyl) thieno [2,3-
h] cinnoline-3 (2H) -one, 8- (1-hydroxyethyl) -5,6-dihydro-2- (4-methylphenyl) thieno [2,3-h] cinnoline-3 (2H)
-One, 8-chloroacetyl-4,4a, 5,6-tetrahydro-2- (4-methylphenyl) thieno [2,3
-H] Cinnoline-3 (2H) -one, 8-acetoxyacetyl-4,4a, 5,6-tetrahydro-2- (4
-Methylphenyl) thieno [2,3-h] cinnoline-
3 (2H) -one, 8- (2-acetoxyethyl)-
4,4a, 5,6-Tetrahydro-2- (4-methylphenyl) thieno [2,3-h] cinnoline-3 (2H)
-One, 4,4a, 5,6-tetrahydro-8- (2-
Hydroxyethyl) -2- (4-methylphenyl) thieno [2,3-h] cinnoline-3 (2H) -one, 10
-Acetyl-2- (4-chlorophenyl) -5,6-dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one, 2- (4-chlorophenyl)-
10- (1-hydroxyethyl) -5,6-dihydro-
[1] Benzothieno [5,4-c] pyridazine-3
(2H) -one, 10-acetyl-2- (4-chlorophenyl) -5,6-dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one 7,7
-Dioxide, 2- (4-chlorophenyl) -10-
(1-Hydroxyethyl) -5,6-dihydro- [1]
Benzothieno [5,4-c] pyridazine-3 (2H)
-One 7-oxide, 2- (4-chlorophenyl)-
10- (1-formyloxyethyl) -5,6-dihydro- [1] benzothiepino [5,4-c] pyridazine-
3 (2H) -one 7-oxide, 2- (4-chlorophenyl) -5,6-dihydro-10-propionyl-
[1] Benzothieno [5,4-c] pyridazine-3
(2H) -one, 10-butyryl-2- (4-chlorophenyl) -5,6-dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one, 2-
(4-chlorophenyl) -10- (1-hydroxybutyl) -5,6-dihydro- [1] benzothiepino [5,5
4-c] pyridazin-3 (2H) -one, 2- (4-chlorophenyl) -10- (1-hydroxyethyl)-
5,6-Dihydro- [1] benzothiepino [5,4-
c] pyridazin-3 (2H) -one 7,7-dioxide, 10-acetyl-2- (4-chlorophenyl)-
5,6-Dihydro- [1] benzothiepino [5,4-
c] pyridazin-3 (2H) -one 7-oxide,
10-chloroacetyl-2- (4-chlorophenyl)-
5,6-Dihydro- [1] benzothiepino [5,4-
c] pyridazin-3 (2H) -one, 2- (4-chlorophenyl) -2,3,5,6-tetrahydro-3-oxo- [1] benzothiepino [5,4-c] pyridazine-
10-carboxylic acid methyl ester and 2- (4-chlorophenyl) -2,3,5,6-tetrahydro-3-oxo- [1] benzothiepino [5,4-c] pyridazine-10-carboxylic acid selected from the above. 1, a fused pyridazine compound,

6. The compound of general formula (I) is 9-acetyl-2- (4-chlorophenyl) -2,4,4a, 5.
6,7-Hexahydro-3H-thieno [2 ', 3':
6,7] Cyclohepta [1,2-c] pyridazine-3-
The condensed pyridazine compound according to the above 1, which is on.

7. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in 1 above and a pharmaceutically acceptable additive;

8. The present invention relates to an anxiolytic drug containing the compound described in 1 above as an active ingredient.

In the above general formula (I), the acyl in R ¹ is alkanoyl group having 2 to 5 carbon atoms such as acetyl, propionyl, butyryl, isobutyryl, phenylacetyl, 3-phenylpropionyl, 2-phenylpropionyl, etc. An arylalkanoyl group having 2 to 5 carbon atoms in the alkanoyl part, an arylcarbonyl group such as benzoyl, 1-naphthoyl and 2-naphthoyl,
Heteroarylcarbonyl groups such as 2-, 3- or 4-nicotinoyl, 2- or 3-thenoyl, 2- or 3-furoyl, alkanoyl such as pyridylacetyl, pyridylpropionyl, thienylacetyl, thienylpropionyl, furylacetyl, furylpropionyl and the like. Is a heteroarylalkanoyl group having 2 to 5 carbon atoms. The alkoxy part of the alkoxycarbonyl is an alkoxy having 1 to 4 carbon atoms, such as methoxycarbonyl,
What is aralkyloxycarbonyl such as ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, etc.
Benzyloxycarbonyl, 2-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl, etc., and the alkyl part of the heteroarylalkyloxycarbonyl is alkyl having 1 to 4 carbon atoms, which is pyridylmethoxycarbonyl, pyridylethoxycarbonyl, thienylmethoxycarbonyl. , Thienylethoxycarbonyl, furylmethoxycarbonyl, furylethoxycarbonyl and the like. Aryloxycarbonyl means phenoxycarbonyl, naphthyloxycarbonyl and the like, and heteroaryloxycarbonyl means pyridyloxycarbonyl, thienyloxycarbonyl, furyloxycarbonyl and the like. The alkoxy part and the alkyl part in the alkoxyalkyl each have 1 to 4 carbon atoms,
Methoxymethyl, methoxyethyl, methoxypropyl,
Methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl and the like are shown. The alkoxy part and the alkyl part in the arylalkoxyalkyl each have 1 to 4 carbon atoms and represent benzyloxymethyl, 2-phenylethoxymethyl, 3-phenylpropoxymethyl and the like. The alkyl part of aryloxyalkyl is alkyl having 1 to 4 carbon atoms, and is phenoxymethyl, phenoxyethyl, phenoxypropyl, phenoxybutyl, 1-naphthoxymethyl, 1-naphthoxyethyl, 1-naphthoxypropyl, 1-naphthoxybutyl. , 2-naphthoxymethyl, 2-naphthoxyethyl, 2-naphthoxypropyl, 2-naphthoxybutyl and the like. The alkyl part of the heteroaryloxyalkyl is an alkyl having 1 to 4 carbon atoms and includes pyridyloxymethyl, thienyloxymethyl, furyloxymethyl and the like.

Acyloxyalkyl means 1-formyloxyethyl, 1-formyloxypropyl, acetoxymethyl, propionyloxymethyl, 1- or 2-.
The alkanoyl moiety such as acetoxyethyl, 1- or 2-propionyloxyethyl, 1- or 3-acetoxypropyl, 1- or 3-propionyloxypropyl has 1 to 5 carbon atoms, and the alkyl moiety has 1 to 4 carbon atoms.
Alkanoyloxyalkyl groups, benzoyloxymethyl, benzoyloxyethyl, benzoyloxypropyl, benzoyloxybutyl, and other aroyloxyalkyl groups having 1 to 4 carbon atoms, nicotinoyloxymethyl, tenoyloxy Heteroarylcarbonyloxyalkyl groups in which the alkyl part such as methyl and furoyloxymethyl has 1 to 4 carbon atoms, and alkanoyl parts such as phenylacetyloxymethyl, phenylpropionyloxymethyl and phenylacetyloxyethyl have 2 to 5 carbon atoms. And an alkyl moiety having 1 to 4 carbon atoms, an arylalkanoyloxyalkyl group, pyridylacetyloxymethyl, pyridylpropionyloxymethyl, thienylacetyloxymethyl, thienylpropionyl Kishimechiru, furyl acetyloxymethyl, alkanoyl portion such as furyl propionyloxymethyl is 2-5 carbon atoms, the alkyl portion indicating, for example, heteroaryl alkanoyloxy group is 1-4 carbon atoms. The alkyl part of hydroxyalkyl is alkyl having 1 to 4 carbon atoms, and is hydroxymethyl, 1- or 2-hydroxyethyl, 1-, 2- or 3-hydroxypropyl, 1-, 2-, 3- or 4 -Hydroxybutyl and the like are shown.

Acyloxyalkanoyl means an alkanoyloxyalkanoyl group having 2 to 5 carbon atoms in both alkanoyl moieties such as acetoxyacetyl, acetoxypropionyl and acetoxybutyryl, benzoyloxyacetyl, benzoyloxypropionyl and benzoyloxybutyryl. Has 2 to 5 carbon atoms in the alkanoyl part of
The number of carbon atoms of both alkanoyl moieties such as arylcarbonyloxyalkanoyl group, phenylacetyloxyacetyl, phenylacetyloxypropionyl, etc.
5 arylalkanoyloxyalkanoyl groups, nicotinoyloxyacetyl, thenoyloxyacetyl, furoyloxyacetyl and other heteroarylcarbonyloxyalkanoyl groups having 2 to 5 carbon atoms in the alkanoyl moiety, pyridylacetyloxyacetyl,
Both alkanoyl moieties such as thienylacetyloxyacetyl and furylacetyloxypropionyl have 2 to 2 carbon atoms.
5 heteroarylalkanoyloxyalkanoyl groups are shown. The alkoxy part of alkoxyalkanoyl is an alkoxy having 1 to 4 carbon atoms, and the alkanoyl part is an alkanoyl having 2 to 5 carbon atoms, and is methoxyacetyl, ethoxyacetyl, propoxyacetyl, butoxyacetyl, methoxypropionyl, ethoxypropionyl, propoxy. Propionyl, butoxypropionyl and the like are shown. The alkanoyl part of hydroxyalkanoyl is an alkanoyl having 2 to 5 carbon atoms and represents hydroxyacetyl, hydroxypropionyl, hydroxybutyryl and the like. The alkanoyl portion of aryloxyalkanoyl is alkanoyl having 2 to 5 carbon atoms, and includes phenoxyacetyl, phenoxypropionyl, phenoxybutyryl and the like. The alkanoyl part of haloalkanoyl is an alkanoyl having 2 to 5 carbon atoms and represents bromoacetyl, chloroacetyl, bromopropionyl, chloropropionyl, bromobutyryl, chlorobutyryl, trifluoroacetyl and the like. The alkanoyl part of aralkyloxyalkanoyl is alkanoyl having 2 to 5 carbon atoms and represents benzyloxyacetyl, benzyloxypropionyl, 2-phenylethoxyacetyl and the like. The alkyl part of the heteroarylalkyloxyalkanoyl is an alkyl having 1 to 4 carbon atoms, and the alkanoyl part is an alkanoyl having 2 to 5 carbon atoms, which is pyridylmethoxyacetyl, thienylmethoxyacetyl, furylmethoxyacetyl, pyridylethoxyacetyl, Examples thereof include thienylethoxypropionyl and furylethoxyacetyl. The alkanoyl part of the heteroaryloxyalkanoyl is an alkanoyl having 2 to 5 carbon atoms and represents pyridyloxyacetyl, thienyloxyacetyl, furyloxyacetyl and the like.

The alkyl having 1 to 8 carbon atoms in R ² is linear or branched, and is methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tertiary butyl, pentyl, isopentyl, Neopentyl, hexyl, heptyl, octyl, 2-ethylhexyl, etc.,
The alkyl part of hydroxyalkyl is alkyl having 1 to 4 carbon atoms, and is hydroxymethyl, 1- or 2-hydroxyethyl, 1-, 2- or 3-hydroxypropyl, 1-, 2-, 3- or 4 -Hydroxybutyl and the like are shown. The alkanoyl part of alkanoyloxyalkyl is alkanoyl having 2 to 5 carbon atoms, and the alkyl part is alkyl having 1 to 4 carbon atoms, and acetoxymethyl,
Acetoxyethyl, acetoxypropyl, acetoxybutyl, propionyloxymethyl, propionyloxyethyl, propionyloxypropyl, propionyloxybutyl, etc., aryl is phenyl, naphthyl, etc., and aralkyl is aryl having 1 to 4 carbon atoms. Substituted, benzyl, phenylethyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl, and the like, heteroaryl with pyridyl, thienyl, furyl, pyrazolyl, imidazolyl, pyrimidinyl, pyridazinyl, Examples include benzimidazolyl. In addition, halogen is chlorine, bromine, fluorine, iodine having 1 to 4 carbon atoms.
Alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl and the like, and alkoxy having 1 to 4 carbons is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary. Butoxy and the like, acyloxy is C2-5 alkanoyloxy or benzoyloxy such as acetyloxy, propionyloxy, butyryloxy and isobutyryloxy, and the alkyl part of haloalkyl is C1-4 alkyl. Therefore, fluoromethyl, bromomethyl, chloromethyl, iodomethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and the like are the alkoxycarbonyl having 2 to 5 carbon atoms. , Methoxycarbonyl, ethoxy Carbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
Isobutoxycarbonyl, tertiary butoxycarbonyl and the like and alkanoylamino having 2 to 5 carbon atoms include acetylamino, propionylamino, butyrylamino, pivaloylamino and the like.

When compound (I) of the present invention has an asymmetric atom, it can be obtained in the form of a racemic mixture or an optical isomer, and when it has at least two asymmetric atoms, As a diastereomer or a mixture thereof. The invention also includes mixtures and individual isomers thereof. The present invention also includes stereoisomers. In the compound of the general formula (I), the compound having a carboxyl group includes metal salts such as sodium, potassium and calcium, amine salts with methylamine, diethylamine, triethylamine and the like, and salts with amino acids such as lysine, ornithine and arginine. Be done.

The compound of the present invention can be synthesized, for example, by the following method.

Method (1) General formula

[0020]

[Chemical 3]

(Wherein each symbol has the same meaning as defined above) and the general formula R ³ COOH (2) (wherein R ³ is alkyl, haloalkyl, alkoxyalkyl, aryloxyalkyl, aryl, aralkyl, Represented by heteroaryl or heteroarylalkyl) or a reactive derivative thereof (acid halide, acid anhydride, mixed acid anhydride, ester, etc.) is reacted. When the compound of general formula (2) is a free carboxylic acid, the reaction is carried out at room temperature to 150 ° C. in the presence of a dehydrating agent such as polyphosphoric acid. When an acid halide (acid chloride, acid bromide, acid iodide, etc.) is used as the reactive derivative of the general formula (2), the reaction is carried out using a suitable solvent such as benzene, toluene, chloroform, methylene chloride or dichloroethane. In the presence of a Lewis acid (aluminum chloride, tin chloride, iron chloride, etc.) in a solvent that does not inhibit the reaction from −10 ° C. to 100 ° C. for 5 minutes to 20
It is done by keeping time. By this method (1), the general formula

[0022]

[Chemical 4]

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained.

Method (2) The compound obtained by the method (1) is treated with a suitable solvent such as methanol, ethanol, propanol, butanol, acetic acid and the like which does not inhibit the reaction, sodium borohydride, lithium aluminum hydride and triethyl. By keeping the temperature at -10 ° C to 150 ° C for 5 minutes to 20 hours by a chemical reduction method such as silane or in the presence of a suitable catalyst such as palladium, rhodium or platinum, R ¹ is 1- It is possible to obtain compounds of general formula (I) which are hydroxyalkyl, lower alkoxyalkyl, aryloxyalkyl and the like. These are the general formulas

[0025]

[Chemical 5]

(Wherein R ³ _a represents alkyl, alkoxyalkyl, aryloxyalkyl or heteroaryloxyalkyl, and when R ³ _a is alkyl, Y is-.
CH (OH) - a, R ³ _a is alkoxyalkyl, aryloxyalkyl, when heteroaryloxy alkyl Y is -CH ₂ - shows a. Each other symbol has the same meaning as described above. ).

Method (3) General formula obtained by Method (2)

[0028]

[Chemical 6]

(Wherein R ³ _a represents alkyl, and other symbols have the same meanings as defined above) and a compound represented by the general formula R ⁴ COOH (5) (wherein R ⁴ is hydrogen, Which represents alkyl, aryl, aralkyl or heteroaryl) by reacting with a carboxylic acid represented by

[0030]

[Chemical 7]

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained. The reaction proceeds in a suitable solvent (a solvent such as benzene or toluene that does not inhibit the reaction) or without a solvent at room temperature to 150 ° C. The reaction also proceeds in the presence of a base such as triethylamine.

Method (4) General formula obtained by Method (1)

[0033]

[Chemical 8]

(Wherein, X represents halogen, and other symbols have the same meanings as defined above), and a general formula obtained by reacting the compound represented by the formula with pyridine.

[0035]

[Chemical 9]

(Wherein each symbol has the same meaning as defined above), the pyridinium compound represented by the general formula is hydrolyzed.

[0037]

[Chemical 10]

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained. The reaction is carried out with a suitable solvent,
For example, in the presence of alkali (sodium hydroxide, potassium hydroxide, barium hydroxide, etc.) in a solvent that does not inhibit the reaction such as water, methanol, ethanol, butanol, etc.
The reaction proceeds by keeping the temperature at room temperature to solvent reflux temperature for 1 hour to 10 hours.

Method (5) The compound of the general formula (8) obtained by the method (4) is subjected to a suitable acid catalyst (sulfuric acid, hydrochloric acid, phosphoric acid, paratoluenesulfonic acid, etc.) in an alcohol such as methanol, ethanol or butanol. By keeping at room temperature to solvent reflux temperature for 1 to 24 hours, or by using an acid halide of the compound of the general formula (8) and phenol, naphthol, benzyl alcohol, phenethyl alcohol or the like in a suitable solvent (benzene, toluene, methylene). Chloride, etc.) in the presence of a deoxidizing agent (triethylamine, pyridine, potassium carbonate, sodium hydrogencarbonate, etc.) at room temperature to solvent reflux temperature for 1 to 24 hours to give a compound of the general formula

[0040]

[Chemical 11]

(Wherein R ³ _b represents alkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl, and other symbols have the same meanings as described above).

Method (6) General formula obtained by Method (1)

[0043]

[Chemical 12]

(In the formula, p represents 1 to 3, and other symbols have the same meanings as described above.) And a haloalkanoyl compound represented by the general formula R ⁵ COOH (10) (R ⁵ is alkyl or aryl) , Aralkyl, heteroaryl or heteroarylalkyl) is reacted with a metal salt of a carboxylic acid (sodium, potassium, lithium, etc.). The reaction is carried out in a suitable solvent such as acetic acid, chloroform, methylene chloride, benzene, toluene, N, N-dimethylformamide, etc. that does not inhibit the reaction at room temperature to 150 ° C. for 1 to 20 hours.

[0045]

[Chemical 13]

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained. In addition, the general formula (11)
The compound of formula (2) is reduced by a method similar to method (2) to give a compound of general formula

[0047]

[Chemical 14]

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained.

Method (7) A compound of the general formula (3b) is prepared by converting a metal salt of an alcohol represented by the general formula R ⁵ OH (13) (wherein R ⁵ is as defined above) (sodium, potassium, Lithium). The reaction is carried out in a suitable solvent such as methanol, ethanol, tetrahydrofuran, benzene, toluene and N, N-dimethylformamide at room temperature to 150 ° C. for 1 hour to 20 ° C.
General formula by keeping time

[0050]

[Chemical 15]

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained.

Method (8) General formula

[0053]

[Chemical 16]

(Wherein Z represents CH ₂ , CO and other symbols have the same meanings as described above), and the compound represented by the formula (I) is used in a suitable solvent such as acetic acid, methanol, ethanol, butanol or water. -10 in the presence of an aqueous solution of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid or the like, or an alkali such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, potassium carbonate in a solvent that does not inhibit the reaction. By reacting at ℃ to 150 ℃ for 1 to 20 hours

[0055]

[Chemical 17]

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained.

Method (9) The compound of the general formula (16) is treated with a suitable solvent such as methanol, ethanol, propanol, butanol, N, N.
-A deoxidizing agent in a solvent that does not inhibit the reaction such as dimethylformamide, tetrahydrofuran, benzene, and toluene.
For example, in the presence of sodium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, etc., the general formula R ⁶ X (17) (wherein R ⁶ represents alkyl, aryl or aralkyl , X has the same meaning as described above.) And a compound represented by the general formula by reacting at room temperature to 150 ° C. for 1 to 20 hours.

[0058]

[Chemical 18]

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained.

Method (10) The pyridinium compound of the general formula (7) obtained by the method (4) and the general formula R ⁷ OH (19) (in the formula, R ⁷ represents alkyl, aryl, aralkyl or heteroaryl). By reacting a metal salt of an alcohol (sodium, potassium, lithium, etc.) represented by the general formula

[0061]

[Chemical 19]

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained. The reaction proceeds in a suitable solvent, for example, a solvent such as methanol, ethanol, propanol, benzene, toluene, tetrahydrofuran, dimethylformamide, which does not inhibit the reaction, at room temperature to the reflux temperature of the reaction solvent for 1 to 10 hours.

Method (11) In the compound of the general formula (I), in which the bond represented by the solid line and the dotted line is a double bond, the compound in which the bond is a single bond is added in an acetic acid solvent at 20 to 60 ° C. 1 to 1.5
Double molar amount of bromine is added dropwise [Journal of Medicinal Chemistry (J. Med. Chem.) Vol. 14, 26.
2 (1971)] or a compound whose binding site is a single bond with sodium-m-nitrobenzenesulfonate (Bachmann method, British Patent No. 11).
No. 68291).

Method (12) By subjecting the compound of the general formula (I) to the Vilsmeier-Haack reaction, the general formula

[0065]

[Chemical 20]

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained. Reaction is from 0 ℃ to 100
It is carried out by reacting a formylating agent such as N, N-dimethylformamide or N-methylformanilide at 10 ° C. for 10 minutes to 10 hours in the presence of phosphorus oxychloride.

Method (13) The compound represented by the general formula (21) is treated with sodium borohydride, sodium cyanoborohydride, hydrogenated in a solvent such as methanol, ethanol, propanol, butanol or tetrahydrofuran which does not inhibit the reaction. With a reducing agent such as aluminum lithium, -10 to 50 ℃
By maintaining the temperature for 5 minutes to 3 hours,

[0068]

[Chemical 21]

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained.

Method (14) The compound represented by the general formula (21) and hydroxylamine hydrochloride in the presence of a suitable deoxidizing agent such as sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine and the like. By reacting, the general formula

[0071]

[Chemical formula 22]

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained. The reaction is carried out with a suitable solvent,
The reaction proceeds by keeping the temperature at room temperature to the boiling point of the solvent for 30 minutes to 20 hours in a solvent that does not inhibit the reaction, such as ethanol, methanol, acetone, toluene, and benzene.

Method (15) The compound represented by the general formula (23) is reacted with a dehydrating agent such as acetic anhydride or trifluoroacetic anhydride.

[0074]

[Chemical formula 23]

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained. The reaction is carried out with a suitable solvent,
-1 in the presence or absence of a suitable deoxidizing agent such as triethylamine in a solvent such as tetrahydrofuran, methylene chloride, chloroform, or toluene that does not inhibit the reaction.
The process proceeds by keeping the temperature at 0 ° C to around the boiling point of the solvent for 10 minutes to 24 hours.

Method (16) A compound represented by the general formula (24) and an alcohol represented by the general formula R ⁸ OH (25) (R ⁸ represents lower alkyl) are combined with a suitable acid, for example, By reacting in the presence of hydrochloric acid, sulfuric acid, phosphoric acid, etc., the general formula

[0077]

[Chemical formula 24]

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained. The reaction is carried out with a suitable solvent,
For example, the reaction proceeds in a solvent such as toluene or benzene that does not inhibit the reaction, or in the absence of a solvent at room temperature to 100 ° C. for 1 to 24 hours.

Method (17) In the compound of the general formula (I) in which E is —S (O) _m —, the compound of m = 1 or 2 is synthesized by subjecting the compound of m = 0 to an oxidation reaction. You can The reaction is carried out in a suitable solvent such as acetic acid, formic acid, chloroform,
-10 ° C in the presence of an oxidizing agent (hydrogen peroxide, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, sodium hypobromite, etc.) in a solvent that does not inhibit the reaction such as methylene chloride.
To 100 ° C. for 5 minutes to 20 hours.

The compound of the present invention thus obtained can be isolated and purified by a conventional method such as a recrystallization method or a column chromatography method. When the obtained product is racemic, for example, by fractional recrystallization of a salt with an optically active acid,
Alternatively, the desired optical isomer can be resolved by passing through a column packed with an optically active carrier. The individual diastereomers can be separated by means such as fractional crystallization, chromatography and the like. These can also be obtained by using an optically active raw material compound. In addition, stereoisomers can be isolated by a recrystallization method, a column chromatography method, or the like.

Among the compounds of the general formula (1) which are the starting compounds, the compounds represented by the solid and dotted lines are single bonds, that is, the compounds of the general formula

[0082]

[Chemical 25]

(Wherein each symbol has the same meaning as defined above)

[0084]

[Chemical formula 26]

(Wherein each symbol has the same meaning as defined above) and a compound represented by the general formula R ² --NHNH ₂ (28) (wherein R ² has the same meaning as defined above). General formula obtained by reacting with a hydrazine derivative or an acid addition salt thereof

[0086]

[Chemical 27]

It can be obtained by subjecting a compound represented by the formula (wherein each symbol has the same meaning as defined above) to a ring closure reaction. The reaction proceeds by heating under reflux for 5 to 20 hours in a suitable solvent, for example, an alcohol solvent such as methanol, ethanol, propanol or the like, or a solvent which does not inhibit the reaction such as benzene or toluene, and then the compounds of the general formula (1a) and (29) A) compound. When the hydrazine derivative of the general formula (28) is an acid addition salt, it is reacted in the presence of a deoxidizing agent (sodium acetate, potassium acetate, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, pyridine, triethylamine, etc.). General formula (2
When the compound of 9) is obtained, the compound of general formula (1a) can be obtained by heating under reflux in acetic acid for 5 to 10 hours.

Next, in the compound of the general formula (1), the compound represented by the solid line and the dotted line is a double bond, that is, the compound of the general formula

[0089]

[Chemical 28]

The compound of the formula (wherein each symbol has the same meaning as defined above) can be synthesized by subjecting the compound of the general formula (1a) to an oxidation reaction. The reaction is carried out in a suitable solvent, for example, an acidic solvent such as acetic acid, trifluoroacetic acid or methanesulfonic acid, in the presence or absence of a suitable acid (hydrohalic acid such as hydrobromic acid), and a suitable sulfoxide. Add dimethyl sulfoxide, diphenyl sulfoxide, methylphenyl sulfoxide, etc.
The reaction proceeds from around ℃ to around the boiling point of the solvent,
Compounds of general formula (1b) can be prepared.

[0091]

[Operation and effect of the invention]

Experimental Example 1: Substitution ability for benzodiazepine (BZP) receptor A specific benzodiazepine receptor avidity test was conducted on Life Science Vol. 20, 2101 (197).
7 years). The crude synaptosome fraction was isolated from the cerebral cortex of 9-10 week-old male Wistar rats, and 120 mM sodium chloride and 5 m
50 mM Tris-HCl buffer containing M potassium chloride (p
It was suspended in H7.4) and used for the experiment. Next, several concentrations of the test compound and tritiated diazepam (final concentration 2 nM) were added to the synaptosome suspension and reacted at 0 ° C. for 20 minutes. This suspension is then added to Whatman (Whatma
n) After filtering with 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 nonradioactive diazepam from the total binding amount. The affinity of test compounds for the benzodiazepine receptor is assessed by their ability to displace tritiated diazepam from its binding site and is expressed as a Ki value. The results are shown in Table 1.

Experimental Example 2: Action on GABA-induced chlorion current (Concentration-Clamp method) Using the sensory nerve cell bodies isolated from bullfrog dorsal root ganglia, the method of Akaike et al. [Journal of Physiology (London) ( J. Physiol. (London)), 379, 171 (1986))
It was carried out according to. Under fixed membrane potential (V _H = -50 mV)
In addition, GABA (3 × 10 ^-6 M) induced chloric current (I
_cl ) was isolated and the effect of the test compound on the peak value of I _cl was examined. The result is a relative value (relativeI _cl ) when the I _cl value induced by GABA 3 × 10 ⁻⁶ M alone is 1.
It showed with. The results are shown in Table 1.

Table 1 ───────────────────────────── Test Compound BZP Receptor Binding Strength Relative I _cl ¹⁾ (Example No. ⁾ ) Ki (nM) ───────────────────────────── 18 4.2 1.38 ────────── ─────────────────────

1): British Journal of Pharmacology (Br.J.Pharmacol.) Volume 98, 735-740 (1)
989), I _cl = about 2 or more is a full agonist, I _cl
cl = about 1.3 to 1.9 is classified as a partial agonist.

Experimental Example 3: Anti-anxiety Effect This is carried out according to the method of Vogel et al. [Psychopharmacology, 21, 1 (1971)]. Male Wistar rats weighing 150-200 g are used in groups of 10-14. Water is cut off for 72 hours prior to the experiment. The experimental setup consists of a light box and a dark box with a water supply nozzle, allowing animals to freely move in and out of both boxes. One hour after the oral administration of the test compound, the animal is placed in a light box, and an electric shock is given through a water supply nozzle and a floor grit every 20 licks. Immediately after the first shock of the animal, the number of shocks is measured for 3 minutes, the significant difference from the methylcellulose administration group is examined, and the minimum effective dose (MED) is determined by t-test.

Experimental Example 4: Muscle Relaxation Effect The test compound was orally administered to 10 male mice per group, and 1
After the lapse of time, it is placed on a 2.8 cm diameter rotating rod which rotates at a speed of 11 times per minute, and the number of animals falling within 1 minute is counted. Dosage of test compound to drop 50% of animals 5
It is determined by the probit method as a 0% effective dose (ED ₅₀ , mg / kg).

Experimental Example 5 Anesthetic enhancing effect A test compound is orally administered to a group of 7 male mice kept in a thermostatic chamber at 26 ° C., and 1 hour later, hexobarbital 40 mg / kg is intraperitoneally administered. 15 and 30 minutes after hexobarbital administration, the righting reflex (righting r
test for loss of eflex). The dose of the test compound that eliminates the righting reflex over 50 seconds in 50% of the animals is determined by the probit method as the 50% effective dose (ED ₅₀ , mg / kg).

Experimental Example 6: Acute toxicity 300 mg / kg of the compound of Example 18 was intraperitoneally administered to 5 male ddY mice per group.
There were no deaths until the day. Similarly, 1
When 000 mg / kg was orally administered, no death occurred for 5 days after the administration.

From various pharmacological experiments, including those described above,
The compound of the general formula (I) of the present invention is a benzodiazepine (B
It has a high affinity for the ZP) receptor and has an antagonistic effect against chemical convulsants such as bicuculline. In particular, the compound of the present invention has a high affinity for the type I receptor of the BZP receptor, and further exhibits the property as a BZP partial agonist from electrophysiological experiments, and therefore has a muscle relaxing action, an anesthesia enhancing action, a sedative action, It is widely used as an anxiolytic drug that selectively acts on anxiety because it has a large deviation from side effects such as sleep / alcohol enhancement. The compounds of the present invention are also useful in in vivo experimental systems such as Vogel.
Et al. Water-lick method, elevated plus maze method [Costall et
al. (Br. J. Pharmacol., 96, 312 (1989)); Meert et al. (Dru
g.Develop.Res., 18,119 (1989)); Singh et al. (Br.J.Pha
rmacol., 104,239 (1991))], social interaction method [Fil
e et al (J. Neurosci.Methods, 2,219 (1980))], light-dark box method
[Jones et al. (Br.J.Pharmacol., 93, 985 (1988))] shows strong anxiolytic activity even in anxiolytic models and is largely separated from side effects (muscle-relaxing action, anesthesia enhancing action) Since it is recognized, it can be used as a highly safe anxiolytic drug.

When the compound of the general formula (I) of the present invention is used as a medicine, it is mixed with a therapeutically effective amount of the compound and an additive such as a pharmacologically acceptable excipient, carrier or diluent. , Tablets, capsules, granules, syrups, injections,
It can be administered in the form of suppositories or powders. In the case of oral administration, for example, the dose is usually 5 to 500 per adult per day.
It is about mg and can be administered once or in several divided doses.

[0101]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited thereto.

Example 1 2- (4-chlorophenyl) -5,6-dihydro-
[1] Benzothieno [5,4-c] pyridazine-3
To a mixture of 102 g of (2H) -one, 1000 ml of dichloroethane and 102 g of acetic anhydride was added 306 g of aluminum chloride under ice cooling. After stirring at room temperature for 10 minutes, the mixture is stirred at 50 ° C to 60 ° C for 6 hours. The reaction solution is poured into ice water, the organic layer is separated and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from a mixed solvent of chloroform and ethanol to give 10-acetyl-2- (4-chlorophenyl) -5,6 as white crystals.
64 g of dihydro- [1] benzothieno [5,4-c] pyridazin-3 (2H) -one.1 / 3 hydrate are obtained.
Melting point 178-179 ° C

Example 2 10-Acetyl-2- (4-chlorophenyl) -5,6
-Dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one 64 g, methanol 500 m
6.4 g of sodium borohydride was added to a 500 ml solution of chloroform in the mixture of 1 under ice cooling and stirring. After stirring at room temperature for 1 hour, the reaction solution is concentrated under reduced pressure. Water is added to the residue and extracted twice with chloroform. The chloroform layer is collected, washed with water, and dried over magnesium sulfate. The solvent was distilled off, and the obtained crystals were recrystallized from ethanol to give 2- (4-chlorophenyl) -10- as white crystals.
(1-Hydroxyethyl) -5,6-dihydro- [1]
Benzothieno [5,4-c] pyridazine-3 (2H)
-59 g of on-1 / 2 hydrate are obtained. Melting point 122-124
℃

Example 3 10-Acetyl-2- (4-chlorophenyl) -5,6
To a solution of 2 g of dihydro- [1] benzothieno [5,4-c] pyridazin-3 (2H) -one and 20 ml of formic acid is added 3 ml of 30% hydrogen peroxide solution. After stirring at room temperature for 5 hours, the reaction solution is poured into water and the precipitated crystals are collected by filtration.
The obtained crystals were recrystallized from dimethylformamide to give white crystals of 10-acetyl-2- (4-chlorophenyl) -5,6-dihydro- [1] benzothiepino [5,4-c] pyridazine-3 (2H). -On 7,7
-1.9 g of dioxide are obtained. Melting point 274-275 ° C

Example 4 2- (4-chlorophenyl) -10- (1-hydroxyethyl) -5,6-dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one 2. 66
g and acetic acid 40 ml solution 30% hydrogen peroxide water 1.57
Add ml. After stirring at room temperature for 4 hours, the reaction solution is poured into water and the precipitated crystals are collected by filtration. The obtained crystals were recrystallized from a mixed solvent of ethanol and isopropyl ether to give white crystals of 2- (4-chlorophenyl) -10-
(1-Hydroxyethyl) -5,6-dihydro- [1]
Benzothieno [5,4-c] pyridazine-3 (2H)
2.17 g of -one 7-oxide are obtained. Melting point 194-
196 ° C

Example 5 2- (4-chlorophenyl) -10- (1-hydroxyethyl) -5,6-dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one 2. 5 g
To a solution of 20 ml of formic acid and 0.7 ml of 30% hydrogen peroxide solution
Add. After stirring at room temperature for 1 hour, the reaction solution was poured into water, the precipitated oily substance was dissolved in chloroform, and an acidic sodium hydrogen sulfite aqueous solution, a sodium hydrogen carbonate aqueous solution,
Then wash with water. The chloroform layer is dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography, and the obtained crystals were recrystallized from ethanol to give 2- (4-chlorophenyl) -10- as white crystals.
(1-Formyloxyethyl) -5,6-dihydro-
[1] Benzothieno [5,4-c] pyridazine-3
1.1 g of (2H) -one 7-oxide are obtained. Melting point 195-196 ° C

Example 6 2- (4-chlorophenyl) -5,6-dihydro-
[1] Benzothieno [5,4-c] pyridazine-3
By carrying out the reaction and treatment in the same manner as in Example 1 using (2H) -one and propionyl chloride, 2-
(4-Chlorophenyl) -5,6-dihydro-10-propionyl- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one is obtained. Melting point 197-198
℃

Example 7 2- (4-chlorophenyl) -5,6-dihydro-
[1] Benzothieno [5,4-c] pyridazine-3
Example 1 using (2H) -one and butyryl chloride
By reacting and treating in the same manner as in 10-butyryl-2- (4-chlorophenyl) -5,6-dihydro- [1] benzothiepino [5,4-c] pyridazine-
3 (2H) -one is obtained. Melting point 179-180 ° C

Example 8 10-Butyryl-2- (4-chlorophenyl) -5,6
When the reaction and treatment were carried out in the same manner as in Example 2 using -dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one, 2- (4-chlorophenyl) was obtained.
-10- (1-hydroxybutyl) -5,6-dihydro- [1] benzothiepino [5,4-c] pyridazine-3
(2H) -on is obtained. Melting point 169-170 ° C

Example 9 2- (4-chlorophenyl) -10- (1-hydroxyethyl) -5,6-dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one was used. When the reaction and treatment are carried out in the same manner as in Example 3, 2- (4
-Chlorophenyl) -10- (1-hydroxyethyl)
-5,6-Dihydro- [1] benzothiepino [5,4-
c] Pyridazin-3 (2H) -one 7,7-dioxide is obtained. Melting point 250-251 ° C

Example 10 10-Acetyl-2- (4-chlorophenyl) -5,6
When the reaction and treatment were carried out in the same manner as in Example 4 using -dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one, 10-acetyl-2- (4-
Chlorophenyl) -5,6-dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one
7-Oxide 1/3 hydrate is obtained. Melting point 231-23
2 ℃ (decomposition)

Example 11 2- (4-chlorophenyl) -5,6-dihydro-
[1] Benzothieno [5,4-c] pyridazine-3
34 g of (2H) -one and 34 of chloroacetyl chloride
g in 250 ml dichloroethane. 53.2 g of anhydrous aluminum chloride is added while maintaining the temperature below 10 ° C. After stirring at the same temperature for 30 minutes, the mixture is stirred at 50 ± 5 ° C. for 5 hours. Then, the reaction solution is poured into ice water and left overnight.
The resulting precipitate was collected by filtration, washed with water, and recrystallized from ethanol. 10-chloroacetyl-2- (4-chlorophenyl) -5,6-dihydro- [1] benzothiepino [5,5]
24.5 g of 4-c] pyridazin-3 (2H) -one are obtained. Melting point 208-210 ° C

Example 12 10-Chloroacetyl-2- (4-chlorophenyl)-
5,6-Dihydro- [1] benzothiepino [5,4-
c] Pyridazin-3 (2H) -one (10.0 g) is added to pyridine (150 ml) and kept at 80 ° C for 5 hours. After concentration under reduced pressure, a small amount of ethanol was added to the residue, the precipitate was collected by filtration, and recrystallized from ethanol to give 1- [2- (4-chlorophenyl) -2,3,5,6-tetrahydro-3-
10.1 g of oxo- [1] benzothiepino [5,4-c] pyridazin-10-ylcarbonylmethyl] pyridinium chloride are obtained. Melting point 188-190 <0> C (decomposition). 1- [2- (4-chlorophenyl) -2,3
2.5 g of 5,6-tetrahydro-3-oxo- [1] benzothiepino [5,4-c] pyridazin-10-ylcarbonylmethyl] pyridinium chloride was dissolved in 100 ml of methanol and cooled to 5 ° C. or lower with sodium methoxy. 0.4 g is added and kept at the same temperature for 30 minutes.
The reaction solution is concentrated under reduced pressure, and a saturated aqueous solution of ammonium chloride is added. Extract with ethyl acetate, wash with water, and dry over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained crude crystals were recrystallized from ethanol to give 2- (4-chlorophenyl) -2,3,5,6-tetrahydro-3-oxo-
[1] Benzothieno [5,4-c] pyridazine-10
-0.3 g of carboxylic acid methyl ester are obtained. Melting point 17
7-178 ° C (decomposition). On the other hand, the precipitate of the extraction residual liquid is collected by filtration and extracted with a dilute aqueous sodium hydroxide solution. The obtained solution was acidified with dilute hydrochloric acid, and the obtained crystal was collected by filtration, washed with water and recrystallized from methanol to give 2- (4-chlorophenyl) -2,3,5,6-tetrahydro-3-oxo- [1] Benzothieno [5,4-c] pyridazine-
0.4 g of 10-carboxylic acid is obtained. Melting point 280 ° C or higher

Example 13 To a suspension of 5.7 g of aluminum chloride in 100 ml of methylene chloride, 2.0 ml of acetyl chloride was added under ice cooling. After that, the mixture was stirred at room temperature for 10 minutes and then ice-cooled again.
4.5 g of (4-chlorophenyl) -4,4a, 5,6-tetrahydrothieno [2,3-h] cinnolin-3 (2H) -one is added and heated to reflux for 2 hours. After cooling, the reaction solution is poured into ice water and extracted with chloroform. The crystals obtained by washing with water and drying over anhydrous magnesium sulfate and distilling off the solvent were recrystallized from a mixed solvent of chloroform and ethanol to give 8-acetyl-2- (4- Chlorophenyl) -4,4
4.7 g of a, 5,6-tetrahydrothieno [2,3-h] cinnoline-3 (2H) -one are obtained.

Example 14 When the same reaction and treatment were carried out using propionyl chloride instead of acetyl chloride used in Example 13, 2- (4) was obtained as white crystals having a melting point of 135-138 ° C.
-Chlorophenyl) -4,4a, 5,6-tetrahydro-8-propionylthieno [2,3-h] cinnoline-
3 (2H) -one is obtained.

Example 15 When butyryl chloride was used in place of the acetyl chloride used in Example 13 and the same reaction and treatment were carried out, 8-butyryl-2- (4- Chlorophenyl) -4,4a, 5,6-
Tetrahydrothieno [2,3-h] cinnoline-3 (2
H) -one is obtained.

Example 16 When benzoyl chloride was used in place of the acetyl chloride used in Example 13 and the same reaction and treatment were carried out, 8-benzoyl-2- (4-chlorophenyl) was obtained as white crystals having a melting point of 162-164 ° C. ) -4, 4a, 5, 6
-Tetrahydrothieno [2,3-h] cinnoline-3
(2H) -one is obtained.

Example 17 2- (4-chlorophenyl) -4 used in Example 13
4a, 5,6-Tetrahydrothieno [2,3-h] cinnoline-3 (2H) -one instead of 4,4a, 5,6
-Tetrahydro-2- (4-methylphenyl) thieno [2,3-h] cinnoline-3 (2H) -one with similar reaction and treatment, melting point 191-193 ° C.
As white crystals of 8-acetyl-4,4a, 5,6-tetrahydro-2- (4-methylphenyl) thieno [2,
3-h] Cinnoline-3 (2H) -one is obtained.

Example 18 2- (4-chlorophenyl) -4 used in Example 13
4a, 5,6-Tetrahydrothieno [2,3-h] cinnoline-3 (2H) -one instead of 2- (4-chlorophenyl) -2,4,4a, 5,6,7-hexahydro-3H- When the same reaction and treatment were carried out using thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one, 9-acetyl- was obtained as white crystals having a melting point of 128 to 130 ° C. 2- (4-chlorophenyl)-
2,4,4a, 5,6,7-Hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c]
Pyridazin-3-one is obtained.

Example 19 9-Acetyl-2- (4-chlorophenyl) -2,4
4a, 5,6,7-hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one 1.2 g of 15% hydrobromide-acetic acid solution was added. Dimethyl sulfoxide 0.23 m at room temperature with stirring
Add l. After reacting for 15 minutes at the same temperature, add 0.5 to the reaction solution.
Pour into% aqueous sodium bisulfite. After extraction with chloroform, the extract is washed with water and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent is subjected to silica gel column chromatography. The crystals obtained from the fraction eluted with chloroform were recrystallized from ethanol to give a melting point of 164 to 166.
9-acetyl-2- (4-chlorophenyl) -2,5,6,7-tetrahydro-3H-thieno [2 ′, 3 ′: 6,7] cyclohepta [1,2-c] as white crystals at ℃
0.4 g of pyridazin-3-one is obtained.

Example 20 To 0.45 g of N-methylformanilide was added 0.33 ml of phosphorus oxychloride, and the mixture was stirred at room temperature for 1 hour. After that, 2-
0.5 g of (4-chlorophenyl) -2,5,6,7-tetrahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one was added,
React for 2 hours at room temperature. It is poured into ice water, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate.
After concentration under reduced pressure, the obtained residue is subjected to silica gel column chromatography.
The crystals obtained from the fraction eluted with (SiO ₂ : 40 g) and eluted from chloroform were recrystallized from a mixed solvent of chloroform-ethanol to give 2- (4-chlorophenyl) as pale yellow powder crystals with a melting point of 170-172 ° C. 0.25 g of -9-formyl-2,5,6,7-tetrahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one are obtained.

Example 21 8-Acetyl-4,4a, 5,6-tetrahydro-2-
To a suspension of 1.3 g of (4-methylphenyl) thieno [2,3-h] cinnoline-3 (2H) -one in methanol,
Under ice cooling, 300 mg of sodium borohydride is added and stirred for 3 hours. After that, methanol is concentrated under reduced pressure to about half, water is added, extracted with chloroform, washed with saturated saline, and dried with anhydrous magnesium sulfate. After concentration under reduced pressure,
The obtained residue is subjected to silica gel column chromatography (SiO ₂ : 30 g).
The mixed solvent of chloroform and methanol (98:
The crystals obtained from the fraction eluted from 2) were recrystallized from a mixed solvent of ethyl acetate-hexane to give a melting point of 129-14.
8- (1-hydroxyethyl) -4,4a, 5,6-tetrahydro-2- (4-methylphenyl) thieno [2,3-h] cinnoline-3 as pale yellow powder crystals at 5 ° C
570 mg of (2H) -one are obtained.

Example 22 To a suspension of 6.4 g of aluminum chloride in methylene chloride, 2.3 ml of acetyl chloride was added under ice cooling, and the mixture was stirred for 10 minutes. Then, 5,6-dihydro-2- (4-methylphenyl) thieno was added. [2,3-h] Cinnoline-3 (2H) -one 4.
Add 7 g of methylene chloride solution and stir for 30 minutes at room temperature,
Heat to reflux for an additional hour. It is poured into ice water, extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (SiO ₂ : 100 g), and the crystals obtained from the fraction eluted from chloroform were recrystallized from a mixed solvent of chloroform-methanol to give a melting point of 240 to 242 ° C. 8-acetyl-5,6-dihydro-2- as white powder crystals of
3.7 g of (4-methylphenyl) thieno [2,3-h] cinnoline-3 (2H) -one are obtained.

Example 23 8-Acetyl-5,6-dihydro-2- (4-methylphenyl) thieno [2,3-h] cinnoline-3 (2H)
600 mg of -one is suspended in 100 ml of methanol, 70 mg of sodium borohydride is added with stirring under ice cooling, and the mixture is stirred for 3 hours. It is poured into ice water, extracted with chloroform, washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (SiO 2
₂ : 20 g), and the crystals obtained from the fraction eluted with a mixed solvent of chloroform and methanol (98: 2) were recrystallized from a mixed solvent of ethyl acetate-hexane to give a melting point of 14
8- (1-hydroxyethyl) -5,6-dihydro-2- (4-methylphenyl) thieno [2,3-h] cinnoline-3 (2H) as pale yellow powder crystals at 6 to 148 ° C.
300 mg of on are obtained.

Example 24 A suspension of 20.3 g of aluminum chloride in methylene chloride was added,
After adding 8.1 ml of chloroacetyl chloride under ice cooling,
4,4a, 5,6-Tetrahydro-2- (4-methylphenyl) thieno [2,3-h] cinnoline-3 (2H)
A solution of methylene chloride (15 g) in ON was added and the mixture was heated under reflux for 8 hours. It is poured into ice water, extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (SiO ₂ : 600 g), and the raw material was extracted from the first fraction eluted from chloroform.
2 g was obtained, and the crystals obtained from the second fraction were recrystallized from a mixed solvent of chloroform-ethanol to give a melting point of 16
8-Chloroacetyl-4,4a, 5,6-tetrahydro-2- (4-methylphenyl) thieno [2,3-h] cinnoline-3 (2 as pale yellow powder crystals at 9 to 171 ° C.
H) -one 6.5 g is obtained.

Example 25 5.8 g of 8-chloroacetyl-4,4a, 5,6-tetrahydro-2- (4-methylphenyl) thieno [2,3-h] cinnolin-3 (2H) -one was added to acetic acid. 100 ml
Then, 12 g of potassium acetate is added and the mixture is stirred for 5 hours.
After pouring into ice water and filtering the precipitated crystals, the filtrate is extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue obtained was combined with the filtered crystals and silica gel column chromatography (SiO ₂ : 200 g).
The crystals obtained from the fraction eluted with chloroform were recrystallized from a mixed solvent of chloroform-methanol to give white powder crystals having a melting point of 144 to 145 ° C.
4.4 g of acetoxyacetyl-4,4a, 5,6-tetrahydro-2- (4-methylphenyl) thieno [2,3-h] cinnoline-3 (2H) -one are obtained.

Example 26 8-acetoxyacetyl-4,4a, 5,6-tetrahydro-2- (4-methylphenyl) thieno [2,3-
h] Cinnoline-3 (2H) -one (3 g) was dissolved in trifluoroacetic acid (30 ml), triethylsilane (2.7 ml) was added, and the mixture was stirred at room temperature for 24 hours. It is poured into ice water, neutralized with potassium carbonate, extracted with chloroform, washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (SiO ₂ : 10
The crystals obtained from the fraction eluted with chloroform were recrystallized from a mixed solvent of ethyl acetate-hexane to give white powder crystals having a melting point of 73 to 75 ° C.
(2-acetoxyethyl) -4,4a, 5,6-tetrahydro-2- (4-methylphenyl) thieno [2,3-
h] 2.0 g of cinnoline-3 (2H) -one are obtained.

Example 27 8- (2-acetoxyethyl) -4,4a, 5,6-tetrahydro-2- (4-methylphenyl) thieno [2,2]
3-h] Cinnoline-3 (2H) -one (1.5 g) was suspended in methanol (50 ml) and, under ice cooling, potassium carbonate (0.7 g).
5 ml of an aqueous solution of is added and stirred for 1 hour. It is poured into ice water, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained crystal was recrystallized from a mixed solvent of chloroform-ethanol to give 4,4a, 5 as a white powder crystal having a melting point of 159 to 160 ° C.
6-tetrahydro-8- (2-hydroxyethyl) -2
1.3 g of-(4-methylphenyl) thieno [2,3-h] cinnoline-3 (2H) -one are obtained.

Then, the compounds shown in the following table are obtained by the same method as in the above-mentioned Examples.

[0130]

[Table 2]

[0131]

[Table 3]

[0132]

[Table 4]

[0133]

[Table 5]

[0134]

[Table 6]

Pharmaceutical Formulation Example A tablet containing 10 mg of the compound of the general formula (I) of the present invention is prepared by the following formulation. Compound of general formula (I) 10.0 mg Lactose 58.5 mg Corn starch 25.0 mg Crystalline cellulose 20.0 mg Polyvinylpyrrolidone K-30 2.0 mg Talc 4.0 mg Magnesium stearate 0.5 mg ────────── ─ 120.0 mg

The compound of the general formula (I) was pulverized with an atomizer to obtain fine powder having an average particle diameter of 10 μm or less.
Lactose, corn starch and crystalline cellulose are thoroughly mixed in a kneader and kneaded with a polyvinylpyrrolidone paste solution. Pass the kneaded product through a 200-mesh screen, 5
Dry at 0 ° C and pass through a 24 mesh screen. Mix talc and magnesium stearate and use a punch with a diameter of 8 mm to obtain tablets weighing 120.0 mg. If necessary, the tablets can be sugar-coated or film-coated.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shuzo Takehara Address: 955, Shoji Takehara, Yoshitomi-cho, Tsukigami-gun, Fukuoka

Claims (8)

[Claims] 1. A general formula: [In the formula, R ¹ is carboxyl, formyl, cyano, hydroxyiminomethyl, acyl, alkoxycarbonyl,
Aralkyloxycarbonyl, heteroarylalkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkoxyalkyl, arylalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, acyloxyalkyl,
It represents hydroxyalkyl, acyloxyalkanoyl, alkoxyalkanoyl, hydroxyalkanoyl, aryloxyalkanoyl, haloalkanoyl, aralkyloxyalkanoyl, heteroarylalkyloxyalkanoyl or heteroaryloxyalkanoyl. R ² is hydrogen, alkyl having 1 to 8 carbons,
Hydroxyalkyl, alkanoyloxyalkyl, aryl, aralkyl, heteroaryl or halogen on the aromatic ring, hydroxy, amino, nitro, cyano, alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons,
Alkanoylamino having 2 to 5 carbon atoms, haloalkyl,
At least one substituent selected from acyloxy, alkoxycarbonyl having 2 to 5 carbon atoms and carboxyl.
It represents an aryl, aralkyl or heteroaryl each having. A represents a sulfur atom or -CH = CH-. E is -CH ₂ - or -S (O) _m - _(m is 0, 1
Or 2 is shown). n represents 1 or 2. The actual battle and the bond represented by the dotted line indicate a single bond or a double bond. However, E when A is a sulfur atom is -CH ₂ - indicates, when A is -CH = CH-, E is -S (O) _m -
(M represents 0, 1 or 2) and n represents 2. ] The condensed pyridazine compound represented by these. 2. R ² is halogen on the aromatic ring and has 1 to 1 carbon atoms.
The fused pyridazine compound according to claim 1, which is an aryl having at least one substituent selected from four alkyls and an alkoxy having 1 to 4 carbons. 3. The fused pyridazine compound according to claim 1, wherein A represents a sulfur atom and E is —CH ₂ —. 4. A represents -CH = CH- and E represents -S.
The fused pyridazine compound according to claim 1, wherein (O) _m- (m represents 0, 1 or 2) and n is 2. 5. The compound of general formula (I) is 8-acetyl-
2- (4-chlorophenyl) -4,4a, 5,6-tetrahydrothieno [2,3-h] cinnoline-3 (2H)
-One, 2- (4-chlorophenyl) -4,4a, 5
6-tetrahydro-8-propionylthieno [2,3-
h] Cinnoline-3 (2H) -one, 8-butyryl-2
-(4-chlorophenyl) -4,4a, 5,6-tetrahydrothieno [2,3-h] cinnoline-3 (2H)-
On, 8-benzoyl-2- (4-chlorophenyl)-
4,4a, 5,6-Tetrahydrothieno [2,3-h]
Cinnoline-3 (2H) -one, 8-acetyl-4,4
a, 5,6-Tetrahydro-2- (4-methylphenyl) thieno [2,3-h] cinnoline-3 (2H) -one, 9-acetyl-2- (4-chlorophenyl) -2,
4,4a, 5,6,7-hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one, 9-acetyl-2- (4-chlorophenyl ) -2,5,6,7-Tetrahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-
c] pyridazin-3-one, 2- (4-chlorophenyl) -9-formyl-2,5,6,7-tetrahydro-
3H-thieno [2 ′, 3 ′: 6,7] cyclohepta [1,2-c] pyridazin-3-one, 8- (1-hydroxyethyl) -4,4a, 5,6-tetrahydro-2
-(4-Methylphenyl) thieno [2,3-h] cinnoline-3 (2H) -one, 8-acetyl-5,6-dihydro-2- (4-methylphenyl) thieno [2,3-
h] cinnoline-3 (2H) -one, 8- (1-hydroxyethyl) -5,6-dihydro-2- (4-methylphenyl) thieno [2,3-h] cinnoline-3 (2H)
-One, 8-chloroacetyl-4,4a, 5,6-tetrahydro-2- (4-methylphenyl) thieno [2,3
-H] Cinnoline-3 (2H) -one, 8-acetoxyacetyl-4,4a, 5,6-tetrahydro-2- (4
-Methylphenyl) thieno [2,3-h] cinnoline-
3 (2H) -one, 8- (2-acetoxyethyl)-
4,4a, 5,6-Tetrahydro-2- (4-methylphenyl) thieno [2,3-h] cinnoline-3 (2H)
-One, 4,4a, 5,6-tetrahydro-8- (2-
Hydroxyethyl) -2- (4-methylphenyl) thieno [2,3-h] cinnoline-3 (2H) -one, 10
-Acetyl-2- (4-chlorophenyl) -5,6-dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one, 2- (4-chlorophenyl)-
10- (1-hydroxyethyl) -5,6-dihydro-
[1] Benzothieno [5,4-c] pyridazine-3
(2H) -one, 10-acetyl-2- (4-chlorophenyl) -5,6-dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one 7,7
-Dioxide, 2- (4-chlorophenyl) -10-
(1-Hydroxyethyl) -5,6-dihydro- [1]
Benzothieno [5,4-c] pyridazine-3 (2H)
-One 7-oxide, 2- (4-chlorophenyl)-
10- (1-formyloxyethyl) -5,6-dihydro- [1] benzothiepino [5,4-c] pyridazine-
3 (2H) -one 7-oxide, 2- (4-chlorophenyl) -5,6-dihydro-10-propionyl-
[1] Benzothieno [5,4-c] pyridazine-3
(2H) -one, 10-butyryl-2- (4-chlorophenyl) -5,6-dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one, 2-
(4-chlorophenyl) -10- (1-hydroxybutyl) -5,6-dihydro- [1] benzothiepino [5,5
4-c] pyridazin-3 (2H) -one, 2- (4-chlorophenyl) -10- (1-hydroxyethyl)-
5,6-Dihydro- [1] benzothiepino [5,4-
c] pyridazin-3 (2H) -one 7,7-dioxide, 10-acetyl-2- (4-chlorophenyl)-
5,6-Dihydro- [1] benzothiepino [5,4-
c] pyridazin-3 (2H) -one 7-oxide,
10-chloroacetyl-2- (4-chlorophenyl)-
5,6-Dihydro- [1] benzothiepino [5,4-
c] pyridazin-3 (2H) -one, 2- (4-chlorophenyl) -2,3,5,6-tetrahydro-3-oxo- [1] benzothiepino [5,4-c] pyridazine-
A compound selected from 10-carboxylic acid methyl ester and 2- (4-chlorophenyl) -2,3,5,6-tetrahydro-3-oxo- [1] benzothiepino [5,4-c] pyridazine-10-carboxylic acid. Item 3. A fused pyridazine compound according to item 1. 6. The compound of general formula (I) is 9-acetyl-
2- (4-chlorophenyl) -2,4,4a, 5,6
7-hexahydro-3H-thieno [2 ', 3': 6,
[7] The fused pyridazine compound according to claim 1, which is cyclohepta [1,2-c] pyridazin-3-one. 7. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable additive. 8. An anxiolytic drug comprising the compound according to claim 1 as an active ingredient.