WO1996025416A1

WO1996025416A1 - Thiophene compounds and medicinal use thereof

Info

Publication number: WO1996025416A1
Application number: PCT/JP1996/000296
Authority: WO
Inventors: Hiroshi Tanaka; Shinji Kirihara; Koreichi Kimura; Hiroshi Yasumatsu
Original assignee: Yoshitomi Pharmaceutical Industries, Ltd.
Priority date: 1995-02-13
Filing date: 1996-02-13
Publication date: 1996-08-22

Abstract

A thiophene compound represented by general formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein R?1 and R2¿ are the same or different and each represents hydrogen, alkyl, etc., or R?1 and R2¿ together with the adjacent nitrogen atom to which they are bonded may form a ring; R3 represents aryl having halogeno, alkyl, etc. on its aromatic ring, etc.; X represents CH¿2?, S, SO or SO2; Y represents an alkylene chain such as methylene, ethylene, etc.; and the bond represented by the solid line and the dotted line stands for a single or double bond. The compound is useful as a medicine with little side effect such as an anxiolytic drug, a sleep inducing drug, an antiepileptic drug, a remedy for panic troubles, etc. Because of being well absorbed in vivo and showing a high bioavailability rate, it is excellent from the viewpoints of pharmacokinetics and pharmaceutics.

Description

Item s

Thiophone compounds and their pharmaceutical uses

ΓTech iff field J

The present invention relates to a thiofuyun compound useful as a medicine such as an anxiolytic, an antiepileptic, a sleep-inducing agent, and a remedy for panic disorder.

r Background technology J

With the discovery of the benzodiazepine receptor (BZR) in the central nervous system (Science et al., 198: 849 (1977)), research on the mechanism of action of benzodiazepine (BZ) drugs has been further advanced. did. For more than 30 years, BZ drugs have been widely used as a drug standard for the treatment of anxiety neurosis, but their τ monoamino acid (GAB A) ZBZR-chlor channel raft combination (Naunyn—Sch hm ied eb) erg. Arch. Pharrma col., 321: 260 (1 982)), has a wide range of central nervous system depressive effects, not only anxiolytic effects, but also sedation, muscle relaxation, alcoholic strength, « It also produces side effects such as labor and dependence formation, which is a major problem when using flooring.

Against this background, over the past 10 years! : Ri! Many compounds that act on BZR in S are synthesized, and detailed neurochemical analysis of how they act on BZR in armpits and BZ-based anxiolytic drugs Research on the development of more selective anxiolytic compounds with reduced side effects has been actively conducted (Trend sin Pharmacol. Sci., 13:76 (1992) Year) ) . For example, various non-benzodiazepine compounds exhibiting an affinity for BZR for the purpose of dissociating anxiolytic activity and side effects have been studied, and are described in U.S. Pat. No. 4,849,421 and U.S. Pat. No. 264, U.S. Pat. No. 5,153,194, U.S. Pat. No. 5,175,162, WO 93/04069, etc., in benzocepinopyridazine compounds, thienochepinopyridazine compounds, thienocinnoline Compounds and chenopiclobutapyridazine compounds have been reported. However, even with the compounds described in the above patent publications, The intensity of the activity itself is not sufficient.

In general, compounds that act on the GABA / BZR-cool channel fit combination can be expected to be useful as medicaments such as antiepileptic drugs and sleep inducers, in addition to anxiolytics. However, in the pharmacological test described in the above patent, antagonism against spasticity induced by bicuculline, a chemical spastic agent, has been reported, but the largest anti-epileptic drug commonly used as screening is used. ¾ 擎 There is no description or no effect on spastic S (MES).

Incidentally, in general, many compounds having a 2 H-pyridazin 1.3-one structure are poorly soluble in water, and the compounds described in these patents are no exception. Therefore, it can be inferred from the physicochemical properties of these compounds listed in the patent that, when administered orally, the absorption from the intestinal tract is not necessarily good. Also, since it is difficult to inject a compound that is hardly soluble in water into a living body as a drug in the crotch, it is difficult to use these compounds listed in the patent as an injection on the K bed. Pharmaceutical techniques would be required.

Furthermore, among compounds acting on the GABAZBZR-chlorochanel conjugate, there are few known drugs other than albrazolam that have been shown to be effective as drugs for treating fearful disorders.

In addition, European Patent Publication No. 1 694 443 discloses a benzocinnoline compound having an amino group, but its action is reduced E, vasodilation, antithrombotic action and the like. Only therapeutic agents have been described.

"Disclosure of Invention J

The present inventors have found that a compound having not only its pharmacological properties but also excellent properties in pharmacology and pharmacokinetics, that is, there is a large discrepancy between the main-effect pharmacological dose and the dose for producing side effects, and Develop centrally acting drugs, such as anxiolytics, antiepileptics, sleep-inducing drugs, and drugs for panic disorders, which have strong active strength, are water-soluble, have good oral absorption, and have high bioavailability. The purpose of this study was to consider. As a result, The authors reported that a novel thiophene represented by the following general formula (I): a compound having a high affinity for BZR, less side effects, more selective anxiolytic activity, anti-MES activity, Shows panic disorder effect, and is superior in water solubility to the compounds described in the above patents, and not only can be used as an injection, but also has good absorption by oral administration, and The high rate of use in the body has led to the discovery of novel thiophane compounds that are extremely useful as medicines, such as anxiolytics, antiepileptics, sleep-inducing drugs, and drugs for treating depression.

That is, the present invention provides a compound represented by the general formula

(Wherein, R ¹ .R ′ are the same or different and represent hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl, or R ¹ and R ² are bonded and instantaneously bonded. C R ′ which represents a group forming a ring together with an atom represents aryl or heteroaryl having at least a monovalent group selected from halogen, hydroxy, alkyl and alkoxy on the aromatic ring, and X is CH ₂ , S Represents SO or SO, Y represents a linear or branched alkylene chain having 1 to 8 carbon atoms, and a bond represented by a solid line or a dot represents a single bond or a double bond )

Or a pharmaceutically acceptable salt thereof.

Further, the present invention provides a thiophene compound represented by the general formula (I), a medicament comprising the optical isomer or a pharmaceutically acceptable salt thereof, and a thiophan Xone compound represented by the formula (I): A pharmaceutical composition comprising an optical isomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier is also provided.

最良 Best way to carry out the invention J

The definition of each symbol in the above-mentioned one-branch type (I) is as follows.

The alkyl in R ¹ , R and R represents an alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, preferably methyl and ethyl, and particularly preferably methyl. Cycloalkyl refers to cycloalkyl having a prime number of 3 to 6, such as cyclobutyl, cyclopentyl, and cyclohexyl, with cyclobutyl and cyclohexyl being preferred. Aryl means phenyl or naphthyl, with phenyl being preferred. Heteroaryl refers to pyridyl, frill, phenyl, and the like. Aralkyl refers to aralkyl in which a is substituted with an alkyl having 1 to 4 carbon atoms, and represents benzyl, phenylethyl, phenylpropyl, phenylbutyl, and benzyl is preferred. Heteroarylalkyl refers to pyridylmethyl, pyridylethyl, furylmethyl, furylethyl, chenylmethyl, chenylethyl and the like. R ¹ and R ² are both hydrogen, or one of them is hydrogen or an alkyl having about 1 to 4 carbon atoms, and the other is an alkyl having 1 to 4 carbon atoms, a cycloalkyl having 3 to 6 carbon atoms, or a fuunyl Or those that are benzyl are preferred.

R ′ and R ² are combined to form a ring together with the elementary S atom that is in immediate contact with the group, such as diridino, 1-pyrrolidinyl, biperidino, piperazine, 11-yl, homopiperazine, 11-yl, Morpholino, Thiomorpholino, 4-Methylbiperidino, 4-Methylpiperazine-111, 4-Ethylbiperazine-1-1-yl, 4-Furbi-peridino, 4-Fe-birubiperazine--1 4-yl, 4-pyridylbiperazine-1-11-yl, 4-furylbiperazine-1-111-yl, 4-Chenylbi-perazine-1-1-yl, 4-benzylbiperidino, 4-phenyl-perylino Peridino, 4- (2-pyridylmethyl) piperidino, 4- (3-pyridylmethyl) piperidino, 4- (4-pyridylmethyl) biperidino, 4- (2-furylmethyl) biperidino, 4- (3-furylmethyl ). Piperidino, 4-1 (2—Che Nilmethyl) biperidino, 4- (3- (Chenylmethyl) piperidino, 4-benzylbiperazine-11-yl, 4-phenylethylperiperine-11-yl, 4-phenylphenylpyrperazine-1-11-yl, 4-phenylbutylpiperazine-1 1-yl, 4-pyridylmethylbiperazine 1-yl, 4-pyridylethylpiperazine 1-yl, 4-furylmethylbiperazine — 1-yl, 4-furylethylbiperazine 11-yl, 41-methylmethylbiperazine, 11-yl, 4-chloroethylbiperazine, etc. In addition, as a group which forms a ring together with the nitrogen atom to which R ¹ .R ^s is bonded and instantaneously contacts, it may contain a nitrogen or oxygen atom in addition to the nitrogen atom. And a group in which the cyclic amino group may be substituted with an alkyl having 1 to 4 carbon atoms or phenyl, is preferred, for example, pyrrolidinyl, piperidino, morpholino, 4-methylbiperazine-111-yl, 4-phenyl- Rubiperazine and the like.

The Ariru in R ³ phenyl, naphthyl and the like, in particular phenylene Le virtuous preferable. Heteroaryl includes pyridyl, furyl and chenyl, with pyridyl being particularly preferred. Halogen as a substituent of these is fluorine, chlorine, bromine or iodine, and alkyl is alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl. Alcoquin refers to alkoxy having 1 to 4 carbon atoms such as methkin, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and tertiary butoxy. R ³ is preferably phenyl or pyridyl having one S-substituent selected from halogen, alkyl having 1 to 4 carbon atoms, and alkyne having 1 to 4 carbon atoms on the aromatic ring. Examples thereof include phenyl, 4-methylphenyl, 4-methoxyphenyl and 5-chloro-2-pyridyl, and particularly preferred is 4-chlorophenyl.

X is preferably CH ₂ or S 0 _2, in particular S 0 ₂ is preferred.

A straight or branched alkylene group having 1 to 8 primes in Y is methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, methylmethylene, dimethylmethylene, 1 Monomethylethylene, 2-methylethylene, 1,1-dimethylethylene, 2, 2-dimethylethylene, ethylmethylene, getylmethylene, 1-ethylethylene, 2-ethylethylene, 1-methyltrimethylene, 2-methyltrimethylene,

Represents 3-methyltrimethylene and the like, with methylene, methylmethylene, ethylene, trimethylene, tetramethylene and pentamethylene being preferred.

The bond represented by the solid line and the dotted line is preferably a double bond.

Pharmaceutically acceptable clay of the compound of the general formula (I) includes salts with inorganic acids such as carrier acid, hydrocyanic acid, sulfuric acid, and acetic acid, K acid, maleic acid, quenic acid, L-tartaric acid, Examples include salts with organic acids such as fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid. Further, a hydrate of the present compound (I) is also included.

When the compound (I) contains an asymmetric atom, it can be obtained in the form of a racemic mixture or an optically active compound. When the compound (I) has at least a divalent asymmetric atom, individual diastereomers or their diastereomers can be obtained. Obtained as a mixture. The present invention also includes these mixtures and individual isomers. The present invention also contains stereoisomers. Preferred compounds in the general formula (I) are those in which R ¹ , R, are the same or different and represent hydrogen, methyl, ethyl or cyclobutyl, R, is 4-chlorophenyl,

4 represents monomethylphenyl, 4-methoxyphenyl or 5-chloro-2-pyridyl, X represents CH ₂ , S, SO or SO ₂ , Y represents methylene or methylethylene, and the bond represented by the dotted line with the actual building Is a thiophene compound showing a double bond.

Particularly preferred compounds include the following thiophene compounds or pharmaceutically acceptable salts thereof.

2- (4-chlorophenyl) 1,5,6-dihydro-9-dimethylaminomethyl thieno [2 ', 3': 2,3] chepino [4,5-c] pyridazine-1 3 (2H) one 7, 7—dioxide,

2- (4-chlorophenyl) 1,5,6-dihydro-1 9-dimethylaminomethylthieno [2 ', 3': 2,3] chepino [4,5-c] pyridazine-1 3 (2H) 1 On 7-oxide, 2-(4-chlorophenyl) 1, 6-dihydro 9-dimethylaminomethylthieno [2,, 3 ': 2.3] Chepino [4.5-c] pyridazine 1 3 (2H) 1one,

5,6-dihydro 9-dimethylaminomethyl-2- (4-methylphenyl) -thieno [2 ', 3': 2,3] chepino [4,5-c] pyridazine-1 3 (2H) 1-on 7,7-dioxide ,

5,6-dihydro 9-dimethylaminomethyl-2- (4-methoxinyl) -thieno [2 ', 3': 2,3] chepino [4,5-c] pyridazine-1 3 (2H) one 7, 7—dioxide,

2- (4-chlorophenyl) -1,5,6-dihydro 9-methylaminomethylthieno [2,, 3 ': 2,3] Chepino [4,5-c] pyridazine-1 3 (2H) — on 7, 7—dioxide,

9-Aminomethyl-2- (4-chlorophenyl) 1,5,6-dihydrothieno [2 ', 3': 2,3] Chepino [4,5-c] pyridazine-1 (2H) 1-on 7, 7—dioxide,

2- (4-chlorophenyl) 1 9-Jetylaminomethyl5.6.-Dihydrothieno [2 ', 3': 2,3] Chepino [4,5-c] pyridazine-1 3 (2H) On 7, 7—dioxide,

2- (4-chlorophenyl) 1-91-ethylaminomethyl-5,6-dihydrothieno [2 ', 3': 2, 3] Chepino [4,5-c] pyridazine-1 3 (2H) — ON 7. 7—Dioxide,

2- (5-Chloro-2-pyridyl) -1,5,6-dihydro 9-dimethylamino methylthieno [2 ', 3': 2,3] Chepino [4,5-c] pyridazine-1 3 (2H) —one 7 , 7—dioxide,

2- (5-Chloro-2-pyridyl) -1-9-dimethylaminomethyl-2,5,6,7-tetrahydro-3H-thieno [2,, 3 ': 6,7] Cyclohepta [2-1c] pyridazine 3 (2H) — ON, 2- (4-phenylphenyl) -1-9-dimethylaminomethyl-2,5,6,7-tetrahydro 3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazine-1 3 (2H) One on,

9-Dimethylaminomethyl-2- (4-methylphenyl) -1,2,5,6.7-tetrahydro 3H-thieno [2..3 ': 6,7] cyclohepta [1,2-c] pyridazine-1 3 ( 2H) — ON,

2- (4-phenylphenyl) 1,5-6-dihydro-9-1 (1-dimethylaminomethyl) -thieno [2 ', 3': 2,3] Chepino [4.5-c] pyridazine-1 3 (2H) 7, 7—dioxide,

2-((4-cyclophenyl) -1-9-1 ((N-cyclobutyl-N-methylamino) methyl) -1,5,6-dihydrothithieno [2 ', 3': 2,3] Chepino [4,5 — C] pyridazine-1 3 (2H) —one 7,7-dioxide,

2-((4-N-phenyl) 1-9-1 ((N-ethyl-N-methylamino) methyl) 1,5,6-dihydrothithieno [2 ', 3': 2, 3] Chepino [4, 5-c ] Pyridazine-1 3 (2H) -on 7,7-dioxide,

R—2— (4-chlorophenyl) 1,5,6-dihidro 9-1 (1-dimethylaminoethyl) -thieno [2,3 ': 2,3] Chepino [4,5—c] pyridazine 3 ( 2 H) one 7,7-dioxide,

S-2- (4-chlorophenyl) 1-5,6-dihydro 9- (1-dimethylaminoethyl) -thieno [2 ', 3': 2,33 Chepino [4,5-c] pyridazine-3 (2H ) — On 7, 7 — dioxide,

2- (4-phenyl-phenyl) 1-9-1 (1- (N-ethyl-N-methylamino) ethyl) 1,5,6-dihidrothieno [2 '. 3': 2, 3] Chepino [4, 5- C ] Pyridazine 1 (2H) 1 7,7-dioxide,

R—2— (4-phenyl phenyl) 1-9-1 (1- (N-ethyl-N-methylamino) ethyl) 1,5,6-dihydroαthieno [2 ', 3': 2, 3] Cepino [ 4, 5—c] pyridazine-1 3 (2Η) —one 7, 7—dioxide, S- 2-(4-phenyl) 1-9 (1-(N-ethyl-N-methylamino) ethyl) 1, 6-dihydrothieno [2 ', 3': 2.3] Chepino [4.5] — C] pyridazine-1 3 C2H) one 7.7 dioxide,

2- (4-phenylphenyl) 1 9-1 (1- (N-cyclobutyl-N-methylamino) ethyl) 1,5,6-dihydrothieno [2 ', 3 *: 2,3] Chepino [4,5 — C] pyridazine-1 3 (2H) —on 7,7—dioxide,

R—2— (4-chlorophenyl) 1 9- (1- (N-cyclobutylpyr-1-N-methylamino) ethyl) 1,5,6-dihydrothieno [2 ', 3': 2,3] Cepino [4,5—c] pyridazine 1 3 (2H) one 7,7—dioxide,

S—2— (4-chlorophenyl) 1 9- (11- (N-cyclobutylpyr-1-N-methylamino) ethyl) 1,5,6-dihydrothieno [2 ', 3': 2,3] Chebino [4, 5—c] pyridazine-1 3 (2H) one 7,7-dioxide.

The method for synthesizing the compound of the present invention is as follows.

Method (1)

General formula

(Wherein represents hydrogen or alkyl, and other symbols are as defined above). In a suitable solvent, for example, methanol, ethanol, chloroform, dichloromethane, dichloroethane or In a solvent that does not hinder the reaction, such as any of these mixed solvents, the general formula

(In the formula, each symbol is as defined above.)

And acid-added clays such as acid clay, hydrobromide clay, sulfate, citrate, oxalate, and reducing agents such as sodium borohydride and sodium cyanoborohydride In the presence, kept under ice-cooling or room temperature from I to 24 hours, the general formula

(Wherein each symbol is as defined above,

Is obtained.

Method (2)

General formula

(In the formula, R ^s represents a substituent such as hydrogen, a paratoluenesulfonyl group, a methanesulfonyl group, a trifluoromethanesulfonyl group, and other symbols are as defined above.) Or the general formula

(In the formula, A represents halogen such as chlorine, bromine or iodine, and other symbols are as defined above.)

In a suitable solvent such as N, N-dimethylformamide, chloroform, dichloromethane, dichloroethane, benzene, toluene, etc. By reacting the compound of the general formula (III) with the compound of the general formula (III) at room temperature to 100 at room temperature for 1 to 24 hours in the presence of triethylamine, pyridine or the like, the compound of the general formula (I) can be obtained.

Method (3)

-The compound of the formula (II) and the compound of the formula (III) are mixed in a suitable solvent, for example, chloroform, dichloromethane, dichloroethane, benzene, toluene, tetrahydrofuran, getyl ether or a mixed solvent thereof. Add a dehydrating agent such as Molecular Sieves 3A in a solvent that does not inhibit the reaction in the presence or absence of an acid catalyst such as paratoluenesulfonic acid, or remove water from the reaction system using a GeneStark cooler. While keeping it at 0 to 8 (1 to 5 hours at TC.) Then add a reducing agent such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, diisobutyl aluminum hydride, etc. The compound of the general formula (IV) can be obtained by keeping from C at room temperature for 1 to 24 hours.

Method (4)

—Split (V) or single-split (VI) compound in a suitable solvent such as N, N— In a solvent that does not hinder the reaction, such as dimethylformamide, methonitrile, water, methanol, and hexamethylphosphoramide, add an azidating agent such as sodium azide, lithium azide, trimethylsilyl azide, silver azide, and the like. From 100 to 1 to 24 o'clock

(In the formula, each symbol is as defined above.)

Is obtained. In addition, the obtained compound is dissolved in three solvents, for example, borohydride, in a solvent that does not hinder the reaction, such as chloroform, dichloromethane, dichloroethane, benzene, toluene, tetrahydrofuran, getyl ether, or any mixed solvent thereof. Chemical reduction method such as sodium, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, or triethylsilane in trifluorosulfonic acid or a suitable catalyst such as palladium, rhodium, ruthenium, platinum, etc. Below, the catalytic reduction method is used to keep the temperature at 10 to 15 O'C for 5 minutes to 24 hours, and the general formula

(In the formula, each pound sign is as defined above.)

The compound represented by is obtained.

Method (5)

A solvent which does not hinder the reaction of the carbonyl compound of the general formula (II) in a suitable solvent, for example, chloroform, dichloromethane, dichloroethane, benzene, toluene, tetrahydrofuran, getyl ether or any of these S-solvents By reacting medium and hydroxylamine, the general formula

(In the formula, each symbol is as defined above.)

After forming the oxime represented by the formula, in a suitable solvent, for example, a solvent that does not hinder the reaction, such as σ-form, dichloromethane, dichloromethane, benzene, toluene, tetrahydrofuran, methyl ether, or any mixed solvent thereof Medium, sodium borohydride, lithium borohydride, lithium aluminum hydride, dibutyl dimethyl aluminum hydride, or a chemical reduction method such as triethylsilan in trifluoro ^ acid or a suitable catalyst such as palladium, rhodium , In the presence of ruthenium, platinum, etc., by keeping it at 10 to 150 to 5 to 24 hours by a catalytic reduction method, etc.

(X) (Wherein each symbol is as defined above,

The compound represented by is obtained.

Method (6)

General formula

(In the formula, R * represents hydrogen, alkyl, cycloalkyl, aralkyl or heteroalkyl, and other symbols are as defined above.)

In a suitable solvent, for example, in a solvent that does not hinder the reaction, such as chloroform-form, dichloromethane, dichloroethane, benzene, toluene, tetrahydro π-furan, getyl ether, or any mixed solvent thereof. For example, in the presence of potassium charcoal, triethylamine, pyridine, etc.

R ^T -A (XII)

(Wherein, R ⁷ represents alkyl, cycloalkyl, aralkyl or heteroarylalkyl, and A has the same meaning as described above.)

By reacting with the compound of formula (1) for 24 hours at 0 to 100,

(XII!)

(In the formula, each symbol is as defined above.)

Is obtained.

Method (7)

The compound of the general formula (XI) is dissolved in a suitable solvent, for example, in a solvent that does not inhibit the reaction, such as methanol, ethanol, chloroform, dichloromethane, dichloroethane or any mixed solvent thereof.

R ⁷ -CHO (X IV)

(Wherein, R ⁷ has the same meaning as described above.)

And the compound represented by the formula (XIII) by keeping the mixture for 1 to 24 hours under ice-cooling or at room temperature in the presence of a reducing agent such as sodium borohydride, sodium borohydride sodium, or the like. Is obtained.

Method (8)

Solvents of formula (V) or (VI) can be converted to solvents that are suitable, for example, ethanol, methanol, N, N-dimethylformamide, chloroform, dichloromethane, dichloroethane, benzene, toluene, water or any of these. By reacting with a cyanating agent such as potassium cyanide, sodium cyanide, or cyanide in a solvent that does not hinder the reaction, such as any mixed solvent of

(In the formula, each symbol is as defined above.)

Is obtained. Further, this compound is dissolved in a suitable solvent, For example, sodium borohydride, lithium borohydride, lithium aluminum in a solvent that does not hinder the reaction, such as chloroform, dichloromethane, dichloroethane, benzene, toluene, tetrahydrofuran, getyl ether, or any mixed solvent thereof 1 O 'by a chemical reduction method such as hydride, diisobutylaluminum hydride, or triethylsilane in trifluoro ^ acid or a catalytic reduction method in the presence of a suitable catalyst such as palladium, rhodium, ruthenium, platinum, etc. From C to 15 O'C for 5 minutes to 24 hours, the general formula

(In the formula, each symbol is as defined above.)

The compound represented by is obtained.

The compounds represented by the one-armed formula (11), (V) and (VI) can be synthesized by the following method.

Method for synthesizing compounds of one-armed type (II)

1. General formula

(In the formula, each £ is synonymous with the above.)

In a solvent that does not inhibit the reaction of, for example, tetrachloride, chloroform, methane, dichloroethane, etc., dichloromethyl methyl ether and Lewis acid, such as aluminum chloride, titanium tetrachloride By keeping at 0 to 8 ox: for 1 to 8 hours in the presence of tin chloride, boron trifluoride, zinc chloride, etc., the compound of the general formula (II) in which R * is hydrogen can be obtained.

2. When the compound of the general formula (XVII) is heated in an acidic solvent, for example, trifluoroacetic acid, acetic acid, hydrochloric acid or a mixed solvent thereof in the presence of hexamethylenetetramine, the compound is hydrogen. The compound of the formula (II) is obtained.

3. N. N-dimethylformamide or N-methylformanilide and oxyphosphorus chloride in a suitable solvent such as chloroform, dichloromethane, dichloroethane or no solvent at 0 to room temperature. After 3 hours, the compound of general formula (XV II) is added, and 0 to 8 (TC for 1 to 24 hours) gives a single-arm (II) compound in which R * is hydrogen .

4. Compound of formula (XV II) in 3 equivalent solvents, such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, etc., Lewis acid such as aluminum chloride, titanium tetrachloride, tin chloride, trichloride, etc. General formula in the presence of boron fluoride, zinc chloride, etc.

R ⁴ one CO - A (XV III)

(Wherein, represents hydrogen, alkyl, cycloalkyl, aralkyl, heteroarylalkyl, and A has the same meaning as described above.)

The compound of the general formula (II) is obtained by adding the acid halide represented by the formula (1) and keeping at 0 to 80 at I to 8 hours.

5. A compound of the general formula (II) obtained by the method described in the above 1, 2, 3 or 4 (wherein X represents S, and other symbols are as defined above). Medium, for example, in solvents such as hydrochloric acid, hydrochloric acid, trifluoroacetic acid, dichloromethane, chloroform, hydrogen tetrachloride, dichloroethane, etc. Add a freezing agent such as oxide, tamenhydrobaroxide,

By keeping at 0 to 5 O 'C, compounds of general formula X is SO or S 0 ₂ (II) is obtained.

Method for synthesizing compounds represented by general formula (V) and general formula (VI)

1. A compound which does not hinder the reaction of a compound of the general formula (II) in a suitable solvent, for example, chloroform, dichloromethane, dichloroethane, benzene, toluene, tetrahydrofuran, getyl ether or any mixed solvent thereof. Medium, sodium borohydride, lithium borohydride, lithium aluminum hydride, disobutylaluminum hydride, or a chemical reduction method such as triethylsilane in trifluorosulfonic acid or a suitable catalyst such as palladium, rhodium In the presence of platinum, ruthenium, platinum, etc., by keeping the temperature from 10 to 150 at 5 to 24 hours by the contact reduction method, the general formula

(In the formula, each symbol is as defined above.)

The compound represented by is obtained.

The compound is further dissolved in a suitable solvent such as carbon tetrachloride, chloroform, dichloromethane, dichloroethane, benzene, toluene, etc., in a solvent that does not interfere with the reaction, para-toluenesulfone fil chloride, methanesulfonic acid chloride, trifluoride. Methanesulfone ft chloride, anhydrous methanesulfone », trifluoromethanesulfonic anhydride, etc., and a base such as triethylamine, pyridine, potassium sulfate, etc., for 1 to 6 hours under ice-cooling or room temperature.ー Koko ceremony ( The compound of V) is obtained.

2. Add the compound of general formula (XIX) in the absence of a solvent or in a solvent such as dichloroethane which does not hinder the reaction, and add carbon tetraoxide or carbon tetrafluoride or carbon tetraiodide in the presence of triphenylphosphine; The compound of the general formula (VI) can be obtained by reacting the mixture under ice cooling, at room temperature or under heating.

3. — The compound of formula (XIX) in the absence of a solvent or in a solvent that does not inhibit the reaction of carbon tetrachloride, chloroform, dichloromethane, dichloroethane, etc. By reacting with 'C, a compound of the general formula (VI) in which A is chlorine is obtained.

4. Compound of general formula (XIX) without solvent or in a solvent that does not inhibit the reaction of carbon tetrachloride, chloroform, dichloromethane, dichloroethane, etc., phosphorus tribromide, phosphorus pentabromide, thionyl bromide, etc. The compound of the general formula (VI) wherein A is bromine can be obtained by adding the brominating agent of the formula (1) and reacting it at 110 to 100.

5. General formula

(In the formula, each symbol is as defined above.)

And a halogenating agent, for example, N-promosuccinimide (NBS), N-chlorosuccinimide (NCS), N-hydrosuccinimide (NIS), and the like as radical initiators, for example, dibenzoylperoxide, 2, By heating and refluxing for 1 to 3 hours in the presence of 2 'monoazobisisobutyronitrile (AI BN), etc., a single branch (VI) (where A represents chlorine, bromine, or iodine, and Y is CH ₂ And the other symbols are as defined above. ) Is obtained.

6. The compound of formula (XVII) is dissolved in a suitable solvent, for example, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, etc., in a solvent that does not inhibit the reaction. Lewis acid, for example, aluminum chloride, titanium tetrachloride, chloride General formula in the presence of tin, boron trifluoride, zinc chloride, etc.

A-Z-C O-A (X X I)

(In the formula, Z represents a straight or branched chain alkyl having 0 to 7 carbon atoms, and A has the same meaning as described above.)

By adding the acid halide represented by and maintaining at 0 to 8 O'C for 1 to 8 hours, one KX.J,

(In the formula, each symbol is as defined above.)

The compound represented by is obtained.

The compound is then placed in a suitable solvent, such as chloroform, dichloromethane, dichloroethane, benzene, toluene, tetrahydrofuran, dimethyl ether, or any mixture of these solvents that does not interfere with the reaction. Chemical reduction methods such as lithium borohydride, lithium aluminum hydride, diisobutylaluminum dimethyl hydride, or triethylsilane in trifluorosulfonic acid or a suitable catalyst such as palladium, rhodium, ruthenium, platinum, etc. By keeping the temperature from -1O'C to 15O'C for 5 minutes to 24 hours, for example, the compound of the general formula (VI) can be obtained. 7. Compounds of the single-branch type (xv I i) in a suitable solvent, for example, in a solvent that does not hinder the reaction, such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, etc .; General formula in the presence of aluminum, titanium tetrachloride, tin chloride, boron trifluoride, zinc chloride, etc.

A-Y-A (X X I I I)

(In the formula, each symbol is as defined above.)

By adding the alkyl halide represented by the formula below and keeping at 0 to 80 for 1 to 8 hours, the compound of the general formula (VI) can be obtained.

8.—React the compound of formula (VI) with ethanol, methanol, N, N-dimethylformamide, chloroform, dichloromethane, methane, dichloroethane, benzene, toluene, water, or any mixture of these. In a non-inhibiting solvent, directly hydroxylate with sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, copper hydroxide, etc., or sodium sulfate, potassium sulfate, calcium drunkate, sodium benzoate, etc. The general formula is obtained by hydrolyzing an ester obtained by reacting an alkali metal salt of an aromatic or aliphatic carboxylic acid of

(XXIV)

(In the formula, each pound sign is as defined above.)

The compound represented by is obtained.

In addition, this compound is dissolved in a suitable solvent, for example, a solvent that does not hinder the reaction, such as carbon tetrachloride, chloroform, dichloromethane, dichloroethane, benzene, and toluene. Medium, para-toluenesulfonic acid chloride, methanesulfonic acid chloride, trifluorene sulfonic acid chloride, anhydrous methanesulfone bell, anhydrous trifluoromethanesulfonic acid, etc., and bases such as triethylamine, pyridine, potassium sulfate, etc. By keeping the temperature for 1 to 6 hours under ice-cooling or at room temperature, a compound of the general formula (V) which is an R ^s force, a paratoluenesulfonyl group, a methyl sulfonyl group or a trifluoromethyl sulfonyl group is obtained. .

The compound of the present invention thus obtained can be isolated and purified by a conventional method such as a recrystallization method and a column chromatography method. When the resulting product is racemic, it is separated into the desired optically active form, for example, by fractional recrystallization of a salt with an optically active acid, or by passing through a column filled with an optically active carrier. Can be. Individual diastereomers can be separated by means of fractional crystallization, chromatography and the like. These can also be obtained by using optically active starting compounds and the like. In addition, the stereoisomer can be isolated into a single moth by a re-ft method, a column chromatography method, or the like.

The thiophene compound of the general formula (I), its optical isomer or a pharmaceutically acceptable salt thereof according to the present invention has a high affinity for a benzodiazepine receptor and induces chemical spasticity such as bicuculline. It shows antagonism to the drug and has a strong anxiolytic effect in conflict tests, making it useful as an anxiolytic and sleep-inducing agent. In addition, the compound of the present invention has a strong inhibitory effect on maxima *, and is therefore useful as an antiepileptic drug. Furthermore, from the results of the conditioned fear test, it is expected to be an effective drug for panic disorder. On the other hand, the compound of the present invention is also characterized in that it has little effect on somatic functions such as muscle relaxation action, and has little side effect because alcohol has strong action and amnestic action. Therefore, the compound of the present invention can be used as a medicament such as a selective anxiolytic drug, a sleep inducer, an antiepileptic drug or a drug for treating phobia disorder with few side effects.

—When the thiophene compound of formula (I), its optical isomer or a pharmaceutically acceptable salt thereof is used as a medicament, the compound of the present invention is converted into a pharmaceutically acceptable carrier (excipient, Pharmaceutical compositions or preparations (eg, pills, pills, capsules, granules, etc.) obtained by mixing with binders, disintegrants, glazes, odorants, emulsifiers, diluents, solubilizing agents, etc. Preparations, syrups, emulsions, elixirs, suspensions, solutions, injections, infusions or suppositories) can be administered orally or parenterally. The pharmaceutical composition can be formulated according to a usual method. In the present specification, parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion and the like. So-called injectable preparations, for example, sterile injectable aqueous or oleaginous preparations can be converted by a method known in the art using a suitable dispersing or wetting agent and a suspending agent. . The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally administrable diluent, for example, an aqueous solution, or a solvent. Examples of acceptable vehicles or solvents that can be used include water, Ringer's solution, isotonic saline and the like. In addition, sterile, fixed oils can also be employed as conventional solvents or suspending solvents. For this purpose, any non-volatile oil and fatty acid can be used, including natural or synthetic or semi-synthetic lipoprotectant oils or fatty acids, and natural or synthetic or semi-synthetic mono-, di- or triglycerides. Suppositories for bile administration are solid at room temperature, such as cocoa butter and polyethylene glycol, but non-irritating excipients that respond quickly to the drug, but are liquid at intestinal temperature and It can be manufactured by mixing with a substance that releases the drug by melting. Examples of solid dosage forms for oral administration include the above-mentioned ones such as powders, granules, tablets, bills and capsules. In such dosage forms, the active ingredient compound comprises at least three additives, such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginate, chitin, chitosan, It can be mixed with vectins, gum tragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic bolimers or glycerides. Such dosage forms may also comprise, as usual, additional additives, such as inert diluents, magnesium diluent, and the like. Lubricants such as mustearate, preservatives such as parabens and sorbins, antioxidants such as ascorbic acid, natocoprol and cysteine, disintegrants, binders, 增 thickeners, buffers, sweeteners, Flavoring agents, perfumes and the like. Tablets and pills can also be prepared by enteric coating. Liquids for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, solutions and the like, which are inert diluents commonly used in the art, such as water. May be included.

Dosage will depend on age, weight, general health, g, gender, diet, time of administration, mode of administration, excretion rate, drug combination, and the extent of the condition the patient is treating at the time, or other It is determined by considering the factors. The compound of the present invention or a pharmaceutically acceptable salt thereof can be used safely with low toxicity, and the daily dose depends on the patient's condition and body weight, the type of compound, the administration route, and the like. However, parenterally, for example, subcutaneously, intravenously, intramuscularly, or rectally, it is administered at about 0.1 to 10 Omg / person, and orally at about 1 to 50 OmgZ / day. Is done. Hereinafter, the present invention is not limited to these examples by the ability to specifically explain the present invention with raw material production examples, examples, formulation prescription examples, and experimental examples.

Raw material production example 1

2- (4-chlorophenyl) 1,5,6-dihydrothieno [2 ', 3': 2,3] Chepino [4,5-c] pyridazine-1 3 (2H) -one 22 g, dichloromethane 3 42 g of aluminum chloride was added to a mixture of 00 ml and 1 to 5 ml of dic σπ methyl methyl ether under ice-cooling. After stirring for 10 minutes at room temperature, 50 minutes The mixture was stirred at 60 ° C for 1 hour. The reaction solution was poured into ice water and extracted with black-mouthed form. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was subjected to silica gel column chromatography. The amorphous powder obtained from the area eluted with a mixed solvent of hexane and ethyl ethyl ester was crystallized from ethanol.

7 8-1 7 9 -C (decomposed) as pale yellow crystals of 2- (4-chlorophenyl) -5,6-dihydro-9-formylcheno [2 '. 3': 2.3] Chepino [4,5-c 19.5 g of pyridazine-1 (2H) —one were obtained.

Raw material production example 2

2- (4-chlorophenyl) 1,5,6-dihydrothieno [2 ', 3': 2,3] Chepino [4,5-c] pyridazine-1 3 (2H) 0.7 g of trione and trifluoroacetic acid Hexamethylenetetramine (0.28 g) was added to the 3.0 ml mixture. After stirring at 90 ° C for 1 hour, water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The resulting residue was subjected to silica gel column chromatography. The amorphous powder obtained from the fraction eluted with a mixed solvent of hexane and ft-ethyl acid was crystallized from ethanol to obtain 2-y (as melting point 178-179'C (decomposed) as pale yellow crystals. 4 1,6-dihydro-9, 1-formylcheno [2 ', 3': 2.3] Cepino [4.5-c] pyridazine-1 3 (2H) 1 0.4 g Was done. Raw material production example 3

N-methylformanilide 14.4m1 and phosphorus oxychloride 10.8m1 were stirred for 1 hour under ice-cooling, and then ice-cooled 2- (4-chlorophenyl) 1,5,6- Dihydrothieno [2 ', 3: 2.3] Chepino [4,5-c] pyridazine-13 (2H) one 20 g was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was poured into iced water, neutralized with carbon dioxide, and extracted with black hole form. The organic layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography. The obtained product was recrystallized from a mixed solvent of methanol and chloroform, to give 2- (4-chlorophenyl) -1.5 as pale yellow crystals (decomposed) in 178-179. 6-Jihi draw 9-formylcheno [2 ', 3': 2.3] Chepino [4, 5-c] pyridazine-1 3 (2H) -one 12 g was obtained. Raw material production example 4

2- (4-chlorophenyl) 1,5,6-dihydrodrothieno [2.3 ': 2, 3] Chepino [4,5-c] pyridazine 1 (2Η) -one 1.0 g, dichloromethan 1 Om 1 and 0.48 ml of a mixture of chloroperic acid chloride ゥ 1.92 g of muchloride was added. After stirring for 10 minutes under ice-cooling, the mixture was stirred at room temperature for 4 hours, the reaction solution was poured into ice water, and extracted with chloroform. The organic calendar was washed with water, dried over anhydrous magnesium sulfate, and the residue obtained by distilling off the solvent was subjected to silica gel gel chromatography. 2- (4-Chlorophenyl) -1,5,6-dihydro-9- (4-Chloro-l-l-oxoptyl) -thieno [2] '. 3': 2, 3] Chepino [4,5—c] pyridazine-1 3 (2H) 29 g were obtained per one.

'NMR (CDC 1,) <5: 7.87 (1H.s), 7.65 (2H.d), 7.46 (2H, d), 6.96 (1H, s) , 3.67 (2H, t), 3.43 (2H, t), 2.93 (2H.t), 2.21 (2H, dt)

Raw material production example 5

2- (4-phenyl-phenyl) 1,5,6-dihidro 9-1 (4-chloro-1-1-oxobutyl) -thieno [2,, 3 ': 2, 3] Chepino [4, 5—c] pyridazi To a mixture of 29 g of -3 (2H) -one and 10 ml of trifluoroacetic acid was added 1.14 ml of triethylsilane, and the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into water and made alkaline with potassium carbonate. The extract was extracted with a black hole form, and the organic J1 was washed with water and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography, and a pale yellow oil was obtained from the area eluted with a mixed solvent of chloroform and methanol. This was crystallized from isopropyl ether to give 9- (4-chloropropyl) -12- (4-chlorophenyl) as pale yellow crystals with a melting point of 115-117 (decomposed). One 5, 6-dihydrothieno [2 ', 3 ': 2,3] Cepino [4,5-c] pyridazine-1 3 (2H) was obtained and 40 g was obtained.

Raw material production example 6

2- (4-chlorophenyl) -1,5-dihydro-9-formylcheno [2 ', 3': 2,3] chepino [4,5-c] pyridazine-1- (2H) —one 7.8 g To a mixture of 250 ml of dichloromethane was added 9.4 g of methacroporous benzoic acid at room temperature, and the mixture was stirred at room temperature for 30 minutes. The precipitated crystals were filtered and recrystallized with a mixed solvent of chloroform and methanol to give 2- (4-chlorophenyl) as colorless crystals with a melting point of 250-25 l'C (decomposed). , 6—Jihi draw 9-formylcheno [2 ', 3': 2,3] Chepino [4,5—c] pyridazine-1 3 (2H) -one 7,7-dioxide 7.2 g was obtained. Was.

Raw material production example 7

2- (4-chloro-phenyl) 1,5,6-dihydro-1-formylcheno [2,, 3 ': 2.3〗 Cepino [4,5-C] pyridazine-1 3 (2H) 1 g 7 g A mixture of 100 ml of roloform and 100 ml of methanol was added to the mixture under ice cooling. 2. Ig of sodium hydrogen chloride was added, and the mixture was stirred for 1 hour under ice cooling. The reaction solution was poured into ice water, extracted twice with a black hole form, and the organic JB was washed with water and dried over anhydrous magnesium sulfate. The residual S obtained by distilling off the solvent was crystallized from ethanol to give 2- (4-chlorochlorophenyl) -1,5,6-dihydrochloride as a pale yellow crystal at point 187-189'C (decomposition). Rho 9-hydroxymethylthieno [2 ', 3': 2,3] Cepino [4,5-c] pyridazine-1 3 (2H) -one 6.3 g was obtained.

Raw material production example 8

2- (4-chlorophenyl) -1,2,5,6,7-tetrahydro-3H-thieno [2,, 3 ': 6,7] cyclohep [1, 2-c] pyridazin-3-one 6.6 g, and as a colorless liquid crystal having a melting point of 170-172 as 2-((4-chlorophenyl))-19-formyl-1,2,5.6.7-tetrafluoroethylene Rahi draw 3 H-thieno [2, 3 ': 6.7] cyclohepta [1.2-c] pyridazine-3-one 2.8 g was obtained.

Raw material production example 9

2— (5—ChloroD—2-pyridyl) 1, 2, 5, 6, 7—tetrahydrochloride 3 H— Thieno [2 ', 3': 6,7] Cyclohexane [1.2-c] pyridazine-13-one In a similar manner to Raw Material Production Example 3 using 5.7 g, »point 16 6- 1 6 7 'C as pale yellow crystals of 2- (5-chloro-2-pyridyl) -1 9-formyl-1 2,5,6,7-tetrahydro 3H-thieno [2', 3 ': 6,7] Cyclohexane [1,2-c] pyridazin-3-one 2.5g was obtained.

Raw material production example 10

2- (4-methylphenyl) -1,2,5.6,7-tetrahydro-3H-thieno

[2 *, 3 ': 6.7] Cyclohepta [1,2-c] pyridazin-3-one, pale yellow with melting point 127-129 by the same method as in Raw Material Production Example 3 As crystals 9-formyl-12- (4-methylphenyl) -1,2,5,6,7-tetrahydrido 3H-thieno [2,, 3 ': 6.7] ] Pyridazin-3-one was obtained.

Raw material production example 1 1

2- (4-Methoxy phenyl) 1,2,5,6,7-tetrahydro-1 3H-Cheno [2 ', 3': 6,7] Cyclohepta [1,2-c] pyridazine-1 3- On In the same manner as in Raw Material Production Example 3, 9-formyl- 12- (4-methoxyphenyl) was obtained as pale yellow crystals with a melting point of 131-132'C. Tetrahydro-3H-thieno [2 ', 3': 6,7] cyclohexane [1,2-c] pyridazin-3-one was obtained.

Raw material production example 1 2

2— (5-chloro-1-2-pyridyl) -1,5,6-dihydrothieno [2 ', 3':

2.3] Cepino [4,5-c] pyridazin-3- (2H) -one Using 2.9 g, according to the same method as in Raw Material Production Example 3 and the same method as in Di, a light yellowish S having a melting point of 220-222'C 2-(5-Chloro-2-pyridyl) 1-5,6-Dihidro 9-Formylcheno

[2 ', 3': 2.3] Cepino [4, 5—c] pyridazine-3 (2H) one-on

0.85 g was obtained.

Raw material S example 1 3

5, 6-Dihydro-2- (4-methylphenyl) -thieno [2 ', 3': 2, 3] Chepino [4, 5-c] pyridazine-1 3 (2H) 1-one 3.9 g raw material production By the same method as in Example 3, the light yellow crystal at the sensitivity point 157-159 was obtained as 5,5. 6-dihydro-9-formyl-1- (4-methylphenyl) -thieno [2 ', 3': 2,3] cepino [4,5-c] pyridazine-13 (2H) -one gave 9 g.

Raw material production example 1 4

5,6-dihydro-2- (4-methoxyphenyl) -thieno [2 ', 3': 2,3] Chepino [4,5-c] pyridazine-1 3 (2H) one 3.9 g According to a method similar to that of Raw Material Production Example 3, 5,6-dihydro-9-formyl-12- (4-methoxyphenyl) -thieno [2 ', 3' : 2, 3] Cepino [4, 5—c] pyridazine-1 3 (2H) —one 1.5 g was obtained.

Raw material production example 1 5

2,4- (4-chlorophenyl) 1-4,4 a. 5,6-tetrahydrothieno [2 ', 3': 2.3] Chepino [4,5-c] pyridazine-1 3 (2H) -one 5. To a mixture of 8 g, 150 ml of dichloromethane and 2.6 ml of chloroperic acid chloride, 11 g of aluminum chloride was added under ice-cooling. After stirring for 10 minutes under ice cooling, 4 o'clock The reaction solution was poured into iced water and extracted with black-mouthed form. After the organic layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography. From the fraction eluted with a mixed solvent of chloroform and methanol, 2- (4-chloro-2-methyl) -1-91 (2-chloroacetyl) -1 was obtained as pale yellow crystals with a melting point of 232-23 3'C. 5.6-Tetrahydrothieno [2 ', 3': 2,3] Chepino [4,5-c] pyridazine-13 (2H) one One 4.1 g was obtained.

Raw material production example 1 6

2- (4-chloropiphenyl) 1- 9- (2-chloroacetyl) 1-4,4a, 5,6-tetrahydrocheno [2 ', 3': 2.3] Chepino [4.5-c] 3.4 ml of triethylsilane was added to a mixture of 4.1 g of pyridazine-3 (2H) one and 7 Oml of trifluorosulfonic acid, and the mixture was searched at room temperature for 48 hours. The reaction solution was poured into water and made alkaline with potassium carbonate. The extract was extracted with black-mouthed form, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The residual port obtained by distilling off the solvent was subjected to silica gel column chromatography, and the fraction eluted with a mixed solvent of chloroform and methanol was obtained as pale yellow crystals with a melting point of 103-105 as 9-( 2-Chloroethyl) 1 2— (4-chlorophenyl) 1-4, 4 a. 5,6-tetrahydrothieno [2 ', 3': 2, 3] Chepino [4, 5—c] pyridazine 1 3 (2H ) -On 2.8 g were obtained. Raw material production example 1

9-1- (2-Chloroethyl) 1-2- (4-chlorophenyl) 1-4,4a, 5.6-Tetrahydrothieno [2 ', 3 ": 2,3] Chepino [4,5-c] pyridazine To a mixture of 2.8 g of 3 (2H) one and 5.8 ml of dichloromethane was added 3.10 g of methacrylic acid benzoic acid, and the mixture was stirred at room temperature for 16 hours. The mixture was extracted with chloroform and the organic layer was extracted, washed with water, dried over anhydrous magnesium sulfate, and the residue obtained by distilling off the solvent was recrystallized from chloroform-ethanol to give a ¾ point 2. 1 9—22 1 as pale yellow crystals 9-1- (2-chloroethyl) -2— (4-chlorophenyl) 1,4,4 a. 5.6—Tetrahydrocheno [2 ', 3': 2 3] Cepino [4,5-c] pyridazin-3- (2H) -one 7,7-dioxide 2.75 g was obtained.

2,4- (4-chlorophenyl) 1-4,4a.5,6-tetrahydrocheno [2'.3 ': 2,3] cepino [4,5-c] pyridazine-1 3 (2H) —one 6 g, a mixture of 80 ml of dichloromethane and 3.0 ml of dichloromethyl methyl ether To the mixture was added 11 g of aluminum chloride under ice cooling, and the mixture was stirred at room temperature for 10 minutes, and then stirred at 50 to 60 for 1 hour. The reaction solution was poured into ice water, extracted with chloroform, the organic calendar was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue S obtained was subjected to silica gel column chromatography. From the fraction eluted with the mixed solvent of hexane and ethyl acetate, 2- (4-chlorophenyl) -1,4,4a, 5,6-tetrahydro-9 was obtained as yellow crystals with a melting point of 22-7-228. One formyl-thieno [2 ', 3': 2, 3] chepino [4, 5-c] pyridazine 13 (2H) one-one 2.4 g was obtained.

Raw material production example 1 9

Under ice-cooling, add 19 g of aluminum chloride and 3.6 ml of acetyl chloride to 8 mL of dichloromethane and add 2- (4-chloropiphenyl) -1,5,6-dihydrothieno [2, 3 ' 2.3] Chepino [4,5-c] pyridazine-13 (2H) -one A solution of 10 g of dichloromethane in 80 ml was added dropwise over 30 minutes. After refluxing at 50-60 ° C for 1 hour, the reaction solution was poured into ice water and extracted with chloroform. The organic calendar was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. 9-acetyl — 2- (4-chlorophenyl) 1,5,6-dihydrothieno [2,. 3 ': 2, 3] Chepino [4,5—c The pyridazine-1 (2H) -one 14.5 ir was obtained. Raw material production example 20

9-Acetyl-2- (4-chlorophenyl) -1,5,6-dihydrothieno [2 ', 3': 2,3] Chepino [4,5-c] pyridazine-1 3 (2H) -one 1.5 g, To a mixture of 100 ml of dichloromethane and 100 ml of methanol was added 0.5 g of sodium borohydride under ice, and the mixture was stirred at Iffltt for 1 hour under ice cooling. The reaction solution was poured into ice water, extracted twice with a black hole form, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was crystallized from ethanol to give 2- (4-chlorophenyl) -1,5,6-dihydro-1-91- (1-) as pale yellow crystals with a melting point of 230-231. 1.6 g of hydroxyethyl) -thieno [2 ', 3: 2,3] cepino [4,5-c] pyridazine-13 (2H) one.

Raw material production example 2 1

2-(4-phenyl phenyl) 1, 5, 6-dihidro 9-(1-hydroxydoxy)-thieno [2 ', 3': 2, 3] chepino [4, 5-c] pyridazine 1 3 (2H 3. One g of 3.3 g was dissolved in 300 ml of dichloromethane, and 3.662 of benzoic acid was added under ice-cooling, followed by stirring at room temperature for 2 hours. 5% NaHCO 3 Thorium water was added, and the mixture was extracted three times with a black hole form, washed with water and dried over anhydrous magnesium magnesium. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of chloroform and methanol to give 21- (4-chlorophenyl) -1,5 as pale yellow crystals at a decomposition point of 229-230. 6-dihydro-9-1 (1-hydroxyethyl) thieno [2 ', 3': 2.3] chepino [4,5-c] pyridazine-1 3 (2Η) one 3 7,7-dioxide 0.1 3 g were obtained.

Raw material production example 2 2

2— (4-chlorophenyl) 1,5,6-dihydrothieno [2 ′, 3 ′: 2,3] Chepino [4,5—c] pyridazine-1 3 (2 H) —one 10.0 g, dichloro To a mixture of 150 ml of roetane and 4.1 ml of 3-chlorobutionic acid chloride was added 19.2 g of aluminum chloride under ice-cooling, and the mixture was stirred for 10 minutes under ice-cooling, and then stirred at room temperature. Stirred for hours. The reaction solution was poured into ice water and extracted with black-mouthed form. The organic β was washed with water and dried over anhydrous magnesium. To the remaining 3 して obtained by distilling off the solvent was added 10 Om1 of trifluorociftic acid and 8.9 ml of triethylsilane, and the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into water, made alkaline with potassium carbonate, and extracted with black-mouthed form. The organic layer was washed with water, dried over anhydrous magnesium triluate, and the residual S obtained by distilling off the solvent was subjected to silica gel column chromatography. Crystallized oily fraction obtained from the fraction eluted with a mixed solvent of form and methanol was crystallized with a mixed solvent of hexane and ethanol to give a pale yellow crystal with a melting point of 1 13 to 1 16'C. As 2-((4-chlorophenyl) -1,5-dihydro-9- (3-chlorobutyl) -thieno [2,3 ': 2.3] Cepino [4,5-c] pyridazine-1 ( 2H) -ON 1.58 g was obtained.

Raw material production example 2 3

2- (4-chlorophenyl) -1,5,6-dihydrothieno [2,, 3 ': 2.3] Chepino [4,5-c] pyridazine-1 3 (2H) -one 3.0 dichloromethane 5 Om l To a mixture of 2.3 ml of 5 and chlorovaleryl dichloride was added 5.7 g of aluminum chloride under ice cooling, and the mixture was stirred for 10 minutes under ice cooling, and then stirred at room temperature for 14 hours. The reaction solution was poured into ice water and extracted with black-mouthed form. The organic JB was washed with water and dried over anhydrous magnesium sulfate. To the residue obtained by distilling off the solvent were added 40 ml of trifluoroacid and 4.2 ml of triethylsilane, and the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into water, made alkaline with potassium hydroxide, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was applied to a silica gel column chromatography. The oil obtained from the fraction eluted with a mixed solvent of chloroform and methanol was crystallized with a mixed solvent of hexane and isoprene virether to give a pale yellow melting point of 98-10 O'C. As crystals, 2- (4-chlorophenyl) -1,5,6-dihydro-9- (5-chloropentyl) -thieno [2 ', 3': 2.3] chepino [4,5-c] bilidindin-3 ( 2H) -ON 3.42 g was obtained.

Example 1

2- (4-Chlorofurinyl) -1-5,6-dihydro-9-formylcheno [2 ', 3': 2,3] Chepino [4.5-c] pyridazine-1 3 (2H) -one 33.9 g, methanol 700 ml and chloroform 350 ml were added to dimethylamine hydrochloride (36.8 g), and the mixture was stirred at room temperature for 30 minutes. Further, 11.3 g of sodium cyanoborohydride was added to the reaction solution, and the mixture was stirred for 18 hours. Reaction solution in ice water The extract was extracted with black-mouthed form, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under high pressure, and the resulting residue was subjected to silica gel column chromatography to obtain a pale yellow amorphous powder from the area eluted with a mixed solvent of ethyl acetate and methanol. This was recrystallized from isopropyl alcohol to give 2- (4-chlorophenyl) -15.6-dihydro-9-dimethylaminomethylthieno [2 'as pale yellow crystals with a melting point of 124-126 ^e C (decomposed). , 3 ·: 2,3] Cepino [4,5-c] pyridazine-3 (2H) -one 22.5 g was obtained.

This compound can also be synthesized by the following method.

2- (4-chlorophenyl) 1,5,6-dihydro-9-methylthieno [2 ', 3': 2,3] Chepino [4,5-c] pyridazine-1 3 (2H) -one 1 g and tetrachloride To a mixture of 5 Om 1 of carbon, 540 mg of N-promosuccimide (NBS) and 14 O mg of dibenzoyl baroxide were added, and the mixture was heated under reflux for 1 hour. Next, N, N-dimethylformamide (1 Oml) was added to the remaining port to dissolve it, and then dimethylamine hydrochloride (27 Omg) and potassium silicate (19 Omg) were added, followed by stirring at room temperature for 24 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, to obtain a pale yellow amorphous powder from the fraction eluted with a mixed solvent of ethyl ethyl phosphate and methanol. This was recrystallized from isopropyl alcohol to give 2- (4-chlorophenyl) -1,5,6-dihydro-9-dimethylaminomethylthieno as pale yellow crystals with a melting point of 124-126 (decomposition). 2 ', 3': 2, 3] Cepino [4, 5-c] pyridazine-1 (2H) 1-one 0.6 g was obtained,

2- (4-chlorophenyl) 1,5,6-dihydro-9-dimethylaminomethylthieno [2 ', 3': 2.3] Chepino [4,5—c] pyridazine-1 3 (2Η) -one 26.2 g was dissolved in 20 Om 1 of penic acid, 14.7 ml of 30% hydrogen peroxide was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into aqueous sodium bisulfite and made alkaline with potassium carbonate. The extract was extracted three times with a black hole form, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and ethanol was added to the obtained white amorphous powder to crystallize it. The obtained white crystals were reconstituted from a mixed solvent of ethanol and chloroform, converted to the hydrochloride, and recrystallized with a mixed solvent of ethanol and water to give a melting point of 276-277'C (decomposition). As white crystals 2- (4-chlorophenyl) -5.6-dihydro-1-9-dimethylaminomethylthieno [2 ', 3': 2,3] Chepino [4,5-c] pyridazine-1 3 (2H) -one There was obtained 14.6 g of 7,7-dioxide monohydrochloride. Example 3

Maleate 2-(4 phenyl phenyl) 1, 5, 6-dihidro 9-formylcheno [2 ', 3': 2, 3] chepino [4, 5-c] pyridazine-1 3 (2H) -one 2.0 g Then, 1.8 g of methylamine hydrochloride and 0.73 g of potassium carbonate were added to a mixture of 3 Om 1 of methanol and 3 Om 1 of chloroform, and the mixture was stirred at room temperature for 4 hours. The insoluble material was removed, and the solvent was distilled off under reduced pressure. To the residue obtained, 4 Oml of methanol, 2 Om1 of chloroform and 0.6 g of sodium borohydride were added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was poured into ice water, extracted with a black hole form, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the remaining ffi was subjected to silica gel column chromatography. The pale yellow amorphous powder obtained from the fraction eluted with a mixed solvent of chloroform and methanol was converted to a maleate salt and reconstituted from a mixed solvent of ethanol and water to give a powder with a melting point of 20 C (decomposition). 2- (4-chlorophenyl) -1,5,6-dihydro-9-methylaminomethylthieno [2 ', 3 *: 2.3] Chepino [4,5-c] pyridazine-1 (2H) as pale yellow crystals 5 g of 1 'maleic acid salt were obtained.

2-(4-phenyl) 1, 5, 6-dihydro-9-methylaminomethylthieno [2 ', 3': 2, 3] Chepino [4.5-c] pyridazine 1 3 (2Η) 1 on · Using 0.96 g of 1-maleic acid, 2- (4-chlorophenyl) -5.6-dihydro 9-mel as white crystals having a melting point of 180 (decomposed) in the same manner as in Example 2 Aminomethylthieno [2 ', 3': 2.3] Chepino [4, 5—C] pyridazine-1 3 (2H) 1-one 7, 7-dioxide '1 maleate 0. 56 g was obtained.

Real

2- (4-chlorophenyl) 1,5,6-dihydro 9-hydroxymethylmethyl [2 ', 3': 2.3] Chepino [4,5-c] pyridazine-1 3 (2H To a mixture of 1.0 g of methylene chloride, 3 Om1 of methylene chloride and 1.48 ml of triethylamine was added 0.62 ml of methanesulfonyl chloride under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into iced water, extracted with black hole form, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 10 ml of methylene chloride and 50 ml of an ammonia solution of ammonia were added to the remaining 3E, followed by stirring at room temperature for 20 hours. The reaction solution was poured into ice water, extracted with a black hole form, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residual S obtained was subjected to silica gel column chromatography. From the fraction eluted with a mixed solvent of chloroform and methanol, a light yellow amorphous powder of 9-aminoamino-2- (4-phenylphenyl) -1,5,6-dihydrothieno [2 ', 3': 2,3] Cepino [4,5-c] pyridazine-1 3 (2H) -one 0.42 g was obtained.

'H-NMR (CDC 13) 5: 7.63-7.67 (2 H, m), 7.41-7.46 (2H, m), 7.19 (1 H, s ), 6.99 (1H, s), 4.03 (2H, s), 3.34 (2H, t), 2.86 (2H.t), l.63 (br s . 2H)

1 · tartaric acid clay

9-Aminomethyl-2- (4-chlorophenyl) -1-5.6-dihydrothieno [2 ', 3': 2.3] Chepino [4,5-c] pyridazine-1-3 (2H) -one 0.97 g In the same manner as in Example 2, using »as a white crystal at point 2 10—2 13′C (decomposed), 9-aminomethyl-2- (4-chlorophenyl) -1,5,6-dihydrothieno [2 ', 3': 2, 3] Chepino [4, 5—c] pyridazine-1 3 (2 H) —one 7,7-dioxide, 1 L 0.25 g of monotartrate was obtained.

Example 7

2- (4-phenyl phenyl) 1,5,6-dihydro-9-hydroxymethylphenol [2 ', 3': 2,3] Chepino [4,5-c] pyridazine-1 3 (2H) one 1 To a mixture of 0.0 g, 30 ml of methylene chloride and 1.48 ml of triethylamine was added 0.62 ml of methanesulfonyl chloride under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, extracted with a black hole form, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under high pressure, and 2 Oml of dimethylformamide and 0.87 ml of N-methylaniline were added to the remaining S, followed by stirring at 60 rpm for 6 hours. reaction The solution was poured into iced water, extracted with black hole form, washed with water, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography. From the area eluted with a mixed solvent of chloroform and methanol, 2-((4-chlorophenyl) -1,5,6-dihydro-9-1 (N-methyl-N-phenylaminomethyl), a pale yellow amorphous powder, was obtained. -Thieno [2,, 3 ': 2, 3] Chepino [4, 5-c] pyridazine-1 3 (2H) -one 0.87 g was obtained.

Ή-NMR (CDC 1) 5: 7.62-7.67 (2 H, m), 7.41-7.46 (2H, m), 7.2 1-7.28 (2H, m), 7.13 (1H, s), 6.92 (1H.s), 6.84-6.76 (3H, m), 4.61 (2H.s), 3.31 (2H, t), 3.00 (3H.s), 2.84 (2H, t)

2- (4-chloroσ-phenyl) -1,5,6-dihydro-9-1 (Ν-methyl-1-phenylaminomethyl) -thieno [2 ', 3': 2.3] Chepino [4,5-c] pyridazine In the same manner as in Example 2 using 0.87 g of 3 (2Η) one-one, 2- (4-chlorophenyl) was obtained as yellow crystals of (decomposed) with a melting point of I13-116. 5.6.-Dihydro 9- (N-methyl-N-phenylaminomethyl) -thieno

[2,, 3 ': 2.3] Chepino [4, 5—c] pyridazine 1 (2H) 1 on

0.31 g of 7,7-dioxide was obtained. Example 9

A similar procedure was carried out using getylamine in place of N-methylaniline of Example 7 to give a white amorphous powder, 2- (4-monochlorophenyl) -19-ethylaminomethyl-5,6-dihydrothieno [2 ', 3 *: 2, 3] Cepino [4.5-c] pyridazine-1 3 (2H) -one.

_{'H-NMR (CDC 1 3} ) 5: 7. 6 3 - 7. 6 7 (2 H, m), 7. 1 one 7. 4 6 (2H, m) , 7. 0 9 (1 H. s ), 6.93 (1H.s), 3.74 (2H, s), 3.33 (2H, t), 2.86 (2H., 2558 (4H, q), 1 . 06 (6H, t)

Real

1 · Fumal ft salt

2- (4-chlorophenyl) 1-9-Jetylaminomethyl-5,6-dihydrothieno [2 ', 3': 2.3] Chepino [4,5-c] pyridazine-1 3 (2H) -1 Using 1.03 g of ON, as a white antagonist of (decomposed) at points 172—173 at the points 172—173 by the same method as in Example 2, 2- (4-chlorophenyl) -19-ethylethylmethyl-5,6- Dihydrothieno [2 ', 3': 2, 3] Cepino [4, 5—c 1 0.49 g of pyridazine-1 (2H) -one-dioxide / 1-fumarate was obtained.

Example 1 1

By using N-methylbiperazine in place of N-methylaniline of Example 7, a similar procedure was carried out to obtain a white amorphous powder of 2- (4-chlorophenyl) -1,5,6-dihydro-9-1 (4-methylbiberazine-1-). Le) Methyl-Ceno [2 ', 3': 2.3] Cepino [4, 5-c] pyridazine 13 (2H) 1-one was obtained.

Ή-NMR (CDC 1) δ: 7.63-7.68 (2 H, m), 7.41-7.46 (2H.m), 7.1 1 (1 H, s), 6.93 (1H, s), 3.67 (2H, s), 3.34 (2H, t), 2.86 (2H.t), 2.48-2.56 ( 6 H, m), 2.30 (3H, s) 18 1 (2H, br)

2 Maleate

2- (4-phenylphenyl) 1-5.6-dihydro-9-1 (4-methylbiperazin-1-yl) methyl-cheno [2 ', 3': 2, 3] chepino [4.5-c] pyridazine, 3 ( 2H) — ON Using 1.0 g, in the same manner as in Example 2. »Point 1 54-1 55 * C (decomposition) as white crystals of 2- (4-chlorophenyl) -1,5,6-dihydro-9-1 (4-methylbiperazine-11-yl) methyl-cheno [2 ' , 3 ': 2.3] Chepino [4,5-c] pyridazine-1 (2H) one 7,7-dioxide-2maleic acid ¾0, 56 g was obtained.

Example 13

N-benzyl-N-methylamine was used in place of N-methylaniline of Example 7, and the same procedure was followed to obtain a light yellow amorphous powder of 9- (N-benzyl-N-methylamino) methyl-2- (4 1-, 6-Dihydrocheno [2 ', 3': 2,3] Cepino [4,5-c] pyridazine-13 (2H) one was obtained.

H-NMR (CDC 1) d: 7.63-7.69 (2H, m), 7.41-7.46 (2H, m), 7.23-7.40 (5H , m), 7.11 (1H.s), 6.93 (1H.s), 3.69 (2H, s), 3.57 (2H.s), 3.34 (2H, t), 2.85 (2 H, t), 2.28 (3 H, s)

% Acid salt 9- (N-benzyl-N-methylamino) methyl-2- (4-chlorophenyl) 1,5,6-dihydrothieno [2 ', 3': 2.3] Chepino [4,5-c] pyridazine-3 Using 1.5 g of (2H) -one, the same procedure as in Example 2 was repeated to obtain 9- (N-benzyl-N-methylamino) methyl-2- as a white crystal having a sensitivity of 248-249'C (decomposed). (5.6-dihydrothieno [2 ', 3 ·: 2,3] Chepino [4,5-c] pyridazine-1 3 (2H) -one 7,7 dioxide ■ monohydrochloride 0. 92 g were obtained.

A similar procedure was carried out using piperidine in place of N-methylaniline of Example 7 to give a light yellow amorphous powder of 2- (4-chlorophenyl) -1,5,6-dihydro 9-biperidinomethyl Thieno [2 ', 3': 2, 3] Chepino [4,5-c] pyridazine-3 (2H) one was obtained.

Ή-NMR (CDC 1 a) d: 7.6-7.69 (2H, m), 7.41-7.46 (2H, m), 7.09 (1H.s) ), 6.93 (1H, s), 3.62 (2H.s), 3.33 (2H.t), 2.86 (2H, t), 2.44 (4H, s) t), 1.55-1.63 (4 H, m), 1.3-1.47 (2 H.m) Example 16

2— (4-chlorophenyl) 1,5,6-dihydro-9-biperidinomethyl [2 '. 3': 2.3] Chepino [4,5—c] pyridazine 1 3 (2H) 1 year old Using the same method as in Example 2 and using 48 g, 2- (4-phenylphenyl) -1,5— as pale yellow crystals at point 2 110—212′C (decomposition) Dihydro-91 piperidinomethylthieno [2 ', 3': 2, 3] Chepino [4, 5-c] pyridazine-1 3 (2H> -one 7,7-dioxide monohydrochloride 0.43 g Example 1 7

By using N-phenylbiperazine in place of N-methylaniline of Example 7 and performing the same procedure, 2- (4-chlorophenyl) -1,5 was obtained as pale yellow crystals having a melting point of 204-206 (decomposed). 6-Dihydro-91 (4-phenylbiperazin-11-yl) methyl-cheno [2 ', 3': 2.3] Chepino [4,5-c] pyridazine-13 (2H) one was obtained.

1-salt 黢 salt

2- (4-chlorophenyl) 1,5,6-dihydro-9-1 (4-phenylbiperazine-1-11) methyl-thieno [2 ', 3': 2.3] Chepino [4,5-c] Using 1.0 g of pyridazine 1-3 (2H) -one, 2- (4-chlorophenyl) -15 as a pale yellow crystal having a melting point of 205-208-C (decomposed) was obtained in the same manner as in Example 2. , 6—Jihi Draw 9-1- (4-phenylbiperazine-1-11yl) Methyl-Ceno [2 ', 3': 2, 3] Chepino [4, 5-c] Pyridazine-1 3 (2H) —On 7 0.25 g of 7,7-dioxide / 1 hydrochloric acid clay was obtained.

Real

1 'hydrochloride

2- (4-chlorophenyl) -1-5.6-dihydro-9- (4-chlorobutyl) -thieno [2,3 ': 2,3] Chepino [4,5-c] pyridazine 1 3 ( To a mixture of 0.9 g of 2H) one and 20 ml of black form, 3 Om1 of dimethylamine in methanol was added, and the mixture was stirred at 80 ° C for 6.5 hours. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography. The pale yellow oil obtained from the fraction eluted with a mixed solvent of By recrystallizing with pill alcohol, »(224-226) as brown crystals of (decomposed) at point 224-226 2- (4-chlorophenyl) -1,5,6-dihydro-1-9-1 (4-dimethylaminoaminoptyl) -thieno [2 ', 3': 2, 3] Cepino [4, 5—c] pyridazine-1 3 (2H) —one '0.69 g of 1 hanic acid clay was obtained.

2- (4-chlorophenyl) 1,5-dihydro-9-1 (4-dimethylaminobutyl) thieno [2 ', 3': 2.3] chepino [4,5-c] pyridazine-3 (2H) Using 0.63 g of ON, as a pale yellow crystal having a melting point of 156-158'C (decomposed) in the same manner as in Example 2, 2- (4-chlorophenyl) -1,5,6-dihydrodraw 9-1- (4-Dimethylaminobutyl) -thieno [2 ', 3': 2,3] Chepino [4,5-c] pyridazine-1 3 (2H) one 7,7-dioxide.1 Hydrochloride 0.1 g was gotten.

Implementation

2- (4-chlorophenyl) 1.5.6-Dihydro-9-formylcheno [2 '3': 2.3] Chepino [4,5-c] pyridazine-1 3 (2H) -one 7, 1 0.3 g of benzylamine hydrochloride and 5 mg of paratoluenesulfonic acid were added to a mixture of 1 g of 1-dioxide, 100 ml of methanol, 100 ml of chloroform and 100 ml of black mouth form and 0.5 g of powdered molecular sieve 3A (trade name). The mixture was heated under reflux for 5 hours, and 0.5 g of sodium borohydride was added to the reaction mixture under ice cooling, and the mixture was searched for 30 minutes. The reaction solution was poured into ice water and extracted with black-mouthed form. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was subjected to silica gel column chromatography. The pale yellow amorphous powder obtained from the area eluted with a mixed solvent of chloroform and methanol was converted into a maleate salt, and recrystallized from ethanol to give (decomposed) pale yellow crystals with a melting point of 208-209. 9-benzylaminomethyl-2- (4-chlorophenyl) 1,5,6-dihydrothieno [2 ', 3': 2,3] chepino [4,5-c] pyridazine-1 3 (2H) one 7, Dioxide, 1 maleate 45 Omg was obtained.

Implementation

Example 21 The same procedure was repeated, except that benzylamine was used in place of benzylamine, to give 2-((4-chlorophenyl) 1.5) as a pale yellow crystal having a melting point of 259-260-C (decomposed). 6-Dihydro-9 1-bip mouth aminomethyl cheno [2 ', 3': 2,3] Chepino [4,5-c] pyridazine-1 3 (2Η) —one 7,7 dioxide monohydrochloride 0 .7 g were obtained. Example 2 3

Hydrochloride

The same procedure was repeated, except that dimethylamine hydrochloride was used in place of dimethylamine hydrochloride of Example 1 to obtain 2- (4 monochlorophenyl) as pale yellow crystals having a sensitivity of 2557-259'C (decomposed). 1) 6,6-Dihydro-9-bromoviraminomethylthieno [2'3 ": 2.3] Chepino [4,5-c] pyridazine-13 (2H) -one / 1 hydrochloride was obtained.

Example 2 4

1Salt B salt

By using ethylamine hydrochloride in place of the dimethylamine citrate of Example 1, a similar method was carried out to obtain 2- (4-chlorophenyl) -1.5 as a pale yellow powder having a melting point of 117-119C. , 6-Dihydro-9-ethylaminomethylthieno [2 ', 3': 2.3] Chepino [4,5-c] pyridazine-13 (2H) -one'1 hydrochloride was obtained. Implementation

A similar method was carried out using cyclobutamine pyramine instead of dimethylamine hydrochloride of Example 1 to obtain 2 (4-chlorophenyl) as a pale yellow crystal with a sensitivity of 2 16 -218'C (decomposed). 1 9-cyclopropylaminomethyl-5,6-dihydrothieno [2'.3 ': 2,3〗 Cepino [4,5—c] pyridazine-13 (2H) one / 1 monohydrochloride was obtained. .

2- (4-chlorophenyl) 1,5,6-dihydro 9-ethylaminomethylthieno [2 '. 3': 2,3] chepino [4,5-c] pyridazine 1 3 (2Η) 1 using an on-1 hydrochloride 0. 6 5 g, as a pale yellow crystalline 2- (4 one Kurorofuweniru) of melting point ^{2 0 0- 2 0 3 e C} ( decomposition) by the same method as in example 2 one 5, 6 —Dihydro 9-ethylaminomethylthieno [2 ', 3': 2,3] Cepino [4,5—c] pyridazine-1 3 (2H) one 7,7-dioxide.1 hydrochloride 0. 5 g were obtained. Example 2

2- (4-chlorophenyl) 1.9-formyl-1,5.6.7-tetrahydro-3H-thieno [2 ', 3': 6,7] cyclohexyl [1,2, c] pyridazine In the same manner as in Example 1 using 0.5 g of 13-one, 2- (4-chlorophenyl) -19-dimethylaminomethyl was obtained as a pale yellow crystal having a melting point of 131-133. 2,5,6,7-tetrahydro-3H-thieno [2 ', 3': 6,7] 0.23 g of pyridazin-3-one pyridazine-3-one was obtained.

Example 2 8

2- (5-chloro-2-pyridyl) -1-formyl-1,2,5.6.7-tetrahydro-3H-thieno [2 ', 3': 6,7] cyclohexane [1, 2 — C] Pyridazin-3-one 0.5 g was obtained in the same manner as in Example 1 to give 2- (5-chloro-2-pyridyl) -1 as a pale yellow crystal having a melting point of 1 5 1 to 1 5 3 9-Dimethylaminomethyl-2,5.6,7-tetrahydro-3H-thieno [2,, 3 ': 6,7] cyclohepta [1,2-c] pyridazin-3-one 0.25 g was obtained. Is Example 2 9

9-formyl-1-2- (4-methylfuunyl) -1,2,5,6,7-tetrahydro-13H-thieno [2 ', 3': 6,7] cyclohep [1, 2-c] pyridazine 1-31 In the same manner as in Example 1 using ON, 9-dimethylaminomethyl-2- (4-methylphenyl) -1,2,5.6,7 as pale yellow crystals at point 120-122 -Tetrahydro-1H-thieno [2 ', 3': 6.7] Cyclohexane

[1,2—c] pyridazin-3-one was obtained.

Example 30

9-formyl-1-2- (4-methoxyphenyl) -1,2,5,6,7-tetrahydro 3H-thieno [2 ', 3': 6.7] Cyclohexane [1.2-c] By using pyridazin-3-one in the same manner as in Example 1, 9-dimethylaminomethyl-2- (4-methoxyphenyl) -1,2 was obtained as pale yellow crystals having a melting point of 133-134. 5,6,7-Tetrahydro-13H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one was obtained. Implementation 3 1

2— (5—black n—2—pyridyl) 1,5,6-dihydro-9—formylcheno C2 '. 3': 2.3] Chepino [4,5—c] pyridazine-1 3 (2H) one 0. Using 5 g, by the same method as in Example 1, 2- (5-chloro-1--2-pyridyl) -15,6-dihydro-9-dimethylaminomethylthieno [2 ', 3: 2,3] Cepino [4,5-c] pyridazine-1 3 (2H) -one 0.3 1 g was obtained.

Example 3 2

5,6-Dihidro 9-formyl-1-2- (4-methylphenyl) -thieno [2 '3': 2.3] Chepino [4,5-c] pyridazine-1 3 (2H) -one 0.5 7 g In the same manner as in Example 1, a pale yellow crystal having a melting point of 148-149 was used as B to give 5,6-dihydro-9-dimethylaminomethyl-2-((4-methylphenyl) monothieno [2 ', 3': 2.3] Chepino [4, 5—c] pyridazine-1 3 (2H) —one 0.25 g was obtained. Example 3 3

5,6-dihydro-9-formyl-1-2- (4-methoxyphenyl) -thieno [2 ', 3': 2,3] chepino [4,5-c] pyridazine-1 (2H) In the same manner as in Example 1, using 4,4 g of 5,6-dihydro-9-dimethylaminomethyl-2- (4-methoxyphenyl) -thieno yellow oil

[2,, 3 ': 2, 3] Chepino [4, 5—c] pyridazine-13 (2H) one 0.2 g was obtained. Further, this compound was used to produce 5,6-dihydro-9-dimethylaminomethyl-2- (4-methoxyphenyl) -thieno as a pale yellow crystal having a melting point of 176-178- () as in Example 2. ', 3': 2.3] Chepino [4,5-c] pyridazine-13 (2H) one 7,7-dioxide 0.12 g was obtained.

Example 3 4

2- (5-Chloro-2-pyridyl) -1,5,6-dihydro-9-dimethylaminomethylthieno [2'.3 ': 2,3] Cepino [4,5-c] pyridazine-1 3 (2H) -one 0.26 g, melting point 199-1 As pale yellow crystals in 201, 2- (5-chloro-2-pyridyl) -1,5,6-dihydro 9-dimethylaminomethylthieno [2 ', 3': 2.3] Chepino [4,5- c] Pyridazine-1 3 (2H) -on 7, dioxide 0.15 fi: was obtained.

Example 3 5

5. 6-Dihydro-9-dimethylaminomethyl-2- (4-methylphenyl) -thieno [2 ', 3': 2,3] Chepino [4,5-c] pyridazine-1 3 (2H) one 0.33 g, and as a pale yellow crystal having a melting point of 176-17-17 • C, 5,6-dihydro-9-dimethylaminomethyl-2- (4-methylphenyl) -thieno [2 ' , 3 ': 2,3] Cepino [4,5-c] biridazine-1 3 (2H) -one 7,7-dioxide 0.23 g was obtained.

Example 3 6

9- (2-Chloroethyl) 1 2- (4-Chlorophenyl) 1,4,4a, 5,6-tetrahydrothieno [2,3 ': 2,3] Chepino [4.5-c] pyridazine-3 ( 2Η) -on 7,7-dioxide 1 g, toluene 25 ml and dimethyl 0.38 g of potassium carbonate, 0.45 g of potassium iodide and 2 ml of morpholine were added to a mixture of 25 ml of chillformamide, and the mixture was stirred at 85 for 24 hours. The reaction solution was poured into ice water and extracted with black-mouthed form. The organic calendar was washed with water, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was subjected to silica gel column chromatography. <From the area eluted with a mixed solvent of chloroform and methanol, the melting point was 223- twenty two

7'C as a light brown crystal 2- (4-chloromorphine) -19- (2-morpholinoethyl) -1-4.4 a. 5,6-tetrahydrothieno [2,, 3: 2,3〗 Chebi [4,5-c] pyridazine-1 3 (2H) -one 7,7-dioxide 0.35 g was obtained.

Example 37

2- (4-chlorophenyl) 1-9-1 (2-morpholinoethyl) 1,4,4a, 5,6-tetrahydrocheno [2,, 3 *: 2,3] Chepino [4,5-c] To a mixture of 0.3 g of pyridazine-3 (2H) -one 7,7-dioxide and 25 ml of a 15% hydrous acid-acid solution was added 0.05 ml of dimethyl sulfoxide under ice-cooling. The mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water and extracted with black-mouthed form. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off, and the residual S obtained was subjected to silica gel column chromatography. From the fraction eluted with a mixed solvent of chloroform and methanol, 2- (4-chlorophenyl) -191- (2-morpholinoethyl) -15.6 was obtained as pale-colored crystals with a melting point of 22 1 -223. —Dihydrothieno [2 ′, 3 ′: 2.3] Chepino [4,5—c] pyridazine-13 (2H) one 7,7 Dioxide 0.12 g was obtained. Real 3 8

In the pressure bottle, 9-1 (2-chloroethyl) -1- (4-chlorophenyl) -1,4-a. 5, 6-tetrahydrodreno [2,, 3 ': 2.3] Cepino [4.5- c] A mixture of 1 g of pyridazine-13 (2H) -one 7,7-dioxide and 100 ml of a 196 dimethylamine-ethanol solution was heated at 85 for 12 hours. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography. From the fraction eluted with a mixed solvent of chloroform and methanol, a light brown mp of 209--21 O'C was formed. As crystals, 2- (4-chlorophenyl) 9-1 (2-dimethylaminoethyl) 1,4,4a, 5.6-tetrahydrothieno [2 ', 3': 2,3] Chepino [4,5- c] Pyridazine-1 3 (2H) -one 7.7-dioxide 0.13 g was obtained c Example 39

2- (4-chlorophenyl) 1-9-1 (2-dimethylaminoethyl) 1,4,4 a. 5,6-tetrahydrothieno [2 ', 3': 2.3] Chepino [4,5-c] To a mixture of 0.1 g of pyridazine-3 (2H) -one 7,7-dioxide and 3 ml of a 15% hydrobromic acid monoacetic acid solution was added 0.018 ml of dimethyl sulfoxide under ice cooling. In addition, in the same manner as in Example 37, 2- (4-chlorophenyl) -191- (2-dimethylaminoethyl) -1,5,6- as a pale-colored crystal at tt point 131-I34 Dihydrodrothieno [2 ', 3': 2, 3] Chepino [4,5-c] pyridazine-1 3 (2H) -one 7,7-dioxide 0.07 g was obtained.

Example 40

2- (4-Chlorophenyl) -1-5.6-dihydro-9-dimethylaminomethylthieno [2 ', 3': 2,3] Chepino [4,5-c] pyridazine-3- (2H) one 2. 0 g was dissolved in 15 ml of sulfuric acid, 0.57 ml of 30-fi hydrogen peroxide was added, and the mixture was stirred at room temperature for 3 hours and 1 hour. The reaction solution was poured into aqueous sodium hydrogen sulfite, made alkaline with carbonated lime, and extracted three times with chloroform. Organic) g was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The remaining S was subjected to silica gel column chromatography, and the amorphous powder obtained from the fraction eluted with a mixed solvent of chloroform and methanol was recrystallized with isopropyl alcohol to give a melting point of 150-I5I-C (decomposition ) As white crystals of 2- (4-chlorophenyl) -1,5,6-dihydro 9-dimethylaminomethylthieno [2 ', 3': 2,3] cepino [4,5-c] pyridazine-1 3 (2H ) 1.0 g of one-one 7-oxide was obtained. Example 4 1

By using pyrrolidine in place of N-methylaniline of Example 7 and performing the same procedure, a yellow intact powder of 2- (4-chlorophenyl) -1,5,6-dihydro-191- (11-vinyl) was obtained. Lizinylmethyl> -thieno [2 ', 3': 2, 3] Cepino [4,5-c] pyridazine-13 (2H) one.

'H-NMR (CDC 1,) <5: 7.63-7.68 (2 H, m), 7.41-7.46 (22, m), 7.12 (1H. s), 6.93 (1H, s), 3.78 (2H.s), 3.33 (2H, t), 2.85 (2H, t), 2.57 -2.62 (3H.m), 1.67-1.86 (5H.m)

2- (4-chlorophenyl) 1,5,6-dihydro-1 9- (1-pyrrolidinylmethyl) -thieno [2,, 3: 2,3] chepino [4,5-c] pyridazine-1 3 (2H) 0.5 g of 1-one was obtained in the same manner as in Example 2 as light brown crystals having a melting point of 202-203 • C (decomposed). 1-pyrrolidinylmethyl) 1-thieno [2 ', 3': 2, 3] Cepino [ 4, 5—c] Pyridazine-13 (2H) -ondoxide, monomaleate 0.5 g was obtained.

1 hydrochloride

By using N-cyclohexyl N-methylamine in place of N-methylaniline of Example 7, the same procedure was followed to give 2- (4-chloromethyl) as white crystals (decomposed) with a melting point of 253-254. 1 9 1 (N-cyclohexyl-1 N-methylaminomethyl) 1, 5,6-dihydrothieno [2 ', 3': 2, 3] Chepino [4,5-c] pyridazine 1 3 (2H) 1 '1 The hydrochloride was obtained.

Real

Hydrochloride hydrochloride

2- (4-chlorophenyl) 1-9-1 (N-cyclohexyl N-methylaminomethyl) 1,5,6-dihydrocheno [2 ', 3': 2,3] Chepino [4,5-c] pyridazine In the same manner as in Example 2 using 3 (2H) -one'1 hydrochloride, 2- (4-chlorophenyl) -191- (N) was obtained as pale yellow crystals having a melting point of 273-274 (decomposition). —Cyclohexyl N-methylaminomethyl) -1,5,6-dihydrothieno [2 ', 3': 2.3] Cepino [4,5—c] pyridazine-1 3 (2 H) One-one 7,7-dioxide monohydrochloride was obtained <

Example 4 5

2- (4-phenyl phenyl) 1,5,6-dihydro-9-methylthieno [2 ', 3': 2,3] Chepino [4,5-c] pyridazine-1 3 (2H) one 2 g and carbon tetrachloride To the mixture of 60 ml, 1.ig of N-promosquimide (NBS) and 14 Omg of dibenzoylperoxide were added, and the mixture was heated under reflux for 1 hour and concentrated under reduced pressure. Next, 20 ml of N, N-dimethylformamide was added to and dissolved in the remaining S, and 48 Omg of morpholine and 38 Omg of potassium carbonate were added, followed by stirring at room temperature for 2.5 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the remaining S was applied to a silica gel column. fit From the fraction eluted with the mixed solvent of acid ethyl and methanol, 2-((4-chlorophenyl)) 1,5,6-dihydrol 9-morpholinomethyl as pale yellow crystals with a melting point of 168-170 Thieno [2 ', 3': 2, 3] Chepino [4.5-c] pyridazine-1 3 (2H) -one 1.5 g was obtained.

Example 4 6

2- (4-phenylphenyl) -1,5,6-dihydric α-9-morpholinomethyl eno [2, .3 ': 2.3] Chepino [4, 5—c] pyridazine-1 3 (2 2)- 2- (4-chlorophenyl) -5,6-dihydro-9-morpholinomethylthieno as a pale yellow crystal at point 216-220 using 0.6 g of [2 ', 3': 2,3] Cepino [4,5-c] pyridazine-1 3 (2H) -one 7'7-dioxide 0.12 g was obtained.

By performing the same operation as in the above method, the following compounds and acid addition salts thereof are obtained.

Example 4 7

2-(4 phenyl phenyl)-9-cyclohexylaminomethyl-5, 6-dihydrothieno [2 ', 3': 2, 3] Chepino [4.5- c] pyridazine-l 3 (2H) 1-one

Example 4 8

ϊ) '6-Dihydro-9-dimethylaminomethyl-2- (4-methoxyphenyl) thieno [2', 3 ': 2.3] Chepino [4, 5-c] pyridazine-1 3 (2Η)

• p-TosOH

2- (4-chlorophenyl) 1-cyclobutyrylaminomethyl-5,6-dihydrocheno [2 ', 3': 2.3] Chepino [4.5-c〗 pyridazine-1 3 (2H) -one 1 g was dissolved in 2 Oml of sulfuric acid, 0.74 ml of 30 3 hydrogen oxide was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into ice water, made alkaline with potassium citrate, and extracted three times with ethyl citrate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The light yellow amorphous powder obtained by evaporating the solvent under reduced pressure was converted to p-toluenesulfonate, which was then recrystallized from methanol to give a light yellow crystal having a melting point of 238-24 O'C (decomposed). 2- (4-chlorophenyl) -9-cyclobutylaminomethyl-5,6-dihydrothithieno [2 ', 3': 2,3] Cepino [4,5-c] pyridazine-1 3 (2H) —one 0.8 g of 7,7-dioxide / p-toluenesulfonic acid salt was obtained.

Example 5 0

2- (4,6-phenyl) 1-cyclohexylaminomethyl-5,6-di Hydrothieno [2 ', 3 ·: 2, 3] Cepino [4, 5— c] pyridazine-1 3 (2H) one 7,7-dioxide

Example 5 1

2- (4-chlorophenyl) -1-9-propylaminomethyl-5,6-dihydrothieno [2 ', 3': 2,3] Chepino [4,5-c] pyridazine 1 3 (2 Η) 1 7 , 7—dioxide

Example 5 2

2- (4-chlorophenyl) 1,5,6-dihydro 9-1 (1-dimethylaminoethyl) -thieno [2 '. 3': 2, 3] Chepino [4,5-c] pyridazine 1 3 (2Η) One on

β 9 Example 5 3

2- (4-chlorophenyl) 1,5,6-dihydro-9- (1-dimethylaminoethyl) -thieno [2.3.3 ': 2, 3] chepino [4,5-c] pyridazine 1 3 (2H) 1-one 7—Oxide

2-(4-phenyl phenyl) 1, 6-dihidro 9-1 (1-hidrokinethyl)-thieno [2 ', 3': 2, 3] chepino [4, 5-c] pyridazine 1 3 (2 H) -On 7,7-dioxide (2.1 g), dimethylformamide (21 ml) and triethylamine (1.61 ml) were added with methanesulfonyl chloride (0.84 ml) under ice-cooling, and the mixture was stirred at room temperature. Stir for 1 hour. The reaction solution was transferred to a shield tube, 30 ml of a solution of dimethylamine in tetrahydrofuran was added, and the mixture was stirred at 100 and then for 7 hours. The reaction solution was poured into ice water, extracted with a black hole form, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. A pale yellow amorphous powder was obtained from the fraction eluted with a mixed solvent of formaldehyde and methanol, and this was recrystallized from isopropyl alcohol. 2- (4-chlorophenyl) -5,6-dihydro 9- (1-dimethylaminoethyl) -thieno [2 '3': 2.3] Cepino as a pale yellow crystal with a melting point of 160 4, 5—c] Pyridazine-1 3 (2 H) —one 7,7—dioxide 0.35 g was obtained.

Example 5 5

2- (4-chlorophenyl) 1-91-formyl-1,4,4a, 5.6-tetrahydridothieno [2 3 ': 2,3] chepino [4,5-c] pyridazine-1 3 (2H) To a mixture of 2.35 g of ION, 100 ml of methanol and 100 Om1 of chloroform was added 2.8 g of dimethylamine diacid, and the mixture was stirred at room temperature for 30 minutes. Further, 0.9 g of sodium cyanoborohydride was added to the reaction solution, and the mixture was stirred for 18 hours. The reaction solution was poured into ice water, extracted with a black hole form, the organic layer was washed with water, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography. From the area eluted with a mixed solvent of ethyl acetate and methanol, a light yellow amorphous powder of 2- (4-alk α-phenyl) was obtained. 1, 4, 4 a. 5, 6-tetrahydro-9-dimethylaminomethyl-cheno [2 '. 3': 2, 3] chepino [4, 5-c] pyridazin-3 (2H) —one 0.75 g Was done.

_{Ή-NMR (CDC 1 a)} 5:. 7. 5 1 - 7. 5 7 (2 H. m), 7. 30 one 7. 39 (. 2H m) 7. 1 3 C 1 H, s). 3.81-3.74 (1H.m) .3.47-3.58 (2H, m), 3.11-3.20 (1H, m), 2.91- 3.05 (1H.m), 2.63 (1H.dd, J = 2.0, 17.2Hz) .2.28 (6H, s) .2.02-2.1 7 (1H.m). Example 5 6

· Hydrochloride

2- (4-chlorophenyl) 1,4,4a, 5,6-tetrahydro-9-dimethylaminomethyl-cheno [2 '. 3': 2.3] Chepino [4,5-c] biridazine 0.75 g of 1 (2H) 1one was dissolved in 6 ml of sulfuric acid, 0.42 ml of 30% hydrogen peroxide was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into aqueous sodium hydrogen sulfite, made alkaline with potassium carbonate, and extracted three times with a black hole form. The organic layer was washed with water and dried over anhydrous magnesium, and the solvent was distilled off under reduced pressure. The obtained white intact powder was reconstituted with ethanol and recrystallized with ethanol to give 2- (4-chlorophenyl) -4,4a, 5 as pale yellow crystals with a melting point of 182-185. 6-tetrahydro-9-dimethylaminomethyl-cheno [2 ', 3': 2, 3] chepino [4, 5—c] pyridazine-1 3 (2H) one 7,7-dioxide * 0.73 g of hydrochloride was gotten.

Example 57

2- (4-chlorophenyl) 1,5,6-dihydro-9-1 (1-hydr σ-kisechyl) -thieno [2,, 3 ': 2, 3] chepino [4, 5—c] pyridazine 1 3 ( 2H) -On 0.95 ml of methanesulfonyl chloride was added to a mixture of 1.6 g, 15 Oml of methylene chloride and 2.28 ml of triethylamine under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, extracted with a black hole form, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 20 ml of methylene chloride and 6 Oml of an ammonia solution of ammonia were added to the resulting residue, followed by stirring at room temperature for 20 hours. The reaction solution was poured into ice water and extracted with black-mouthed form. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and from the area eluted with a mixed solvent of chloroform and methanol, a light yellow amorphous powder of 9- (1-1-aminoethyl) -12- (4-chloro-fuunil) was obtained. One 5.6-dihydrothieno [2 ', 3': 2,3] chepino [4,5-c] pyridazine-13 (2H) -one 0.22 g was obtained.

'H-NMR (CDC 13) <5: 7.63-7.68 (2H, m), 7.41-7.47 (2H.m) .7.11 (1H, s ), 6.93 (1 H.s), 4.33 (1Η, q, J = 6.6Hz), 3.33 (2Η, t, J = 6.6Hz) .2.86 (2Η) 1.70 (2H.br). 1.48 (3H.d, J = 6.6Hz).

· ^¾K¾

9 1 (1 aminoethyl) 1 2— (4 1-methyl phenyl) 1 5, 6-dihydro σ thieno [2 ', 3': 2, 3] Chepino [4, 5— c] pyridazine 1 3 ( 2Η) Using 0.22 g of one-one, as a white crystal having a melting point of 2 19—22 I, as a white crystal having a melting point of 2 9— (1—aminoethyl) —1—— 5,6 dihydrothieno [2,, 3 ': 2, 3] chepino [4.5-c] pyridazine 0.1 g of 3 (2H) -one 7,7-dioxide / 1¾S salt was obtained <Example 5 9

2- (4-phenyl phenyl) 1 9-1 (3-chlorobutyl pill) 1,5,6-dihydrorothieno [2 ', 3': 2, 3] Cepino [4,5-c] pyridazine 1 3 (2 H) To a mixture of 58 g / one and 30 ml of chloroform in form was added 40 ml of dimethylamine tetrahydrofuran / furan solution, and the mixture was added at 80 ° C. The solvent was distilled off, and the residue was subjected to silica gel column chromatography. 2- (4-chlorophenyl) -5,6-dihydro 91- (3-dimethylaminobutyryl) -thieno [2 ', 3], a brown oily substance from the fraction eluted with a mixed solvent of chloroform and methanol ': 2.3] Chepino [4,5-c] pyridazine-1 (2H) one 0.96 g was obtained.

'H-NMR (CDC 1,) 5: 7.64-7.68 (2H.m) .7.42-7.46 (2H, m), 7.00 (1H.s) , 6.93 (1 H. s), 3.32 (2H, t, J = 6.6 Hz). 2.78-2.87 (2 H, m), 2.32 (2H, t , J = 6.6Hz), 2.24 (6H, s), 1.8-1.9 (2H, m).

Tan acid

2- (4-chlorophenyl) 1,5,6-dihydro-91 (3-dimethylaminopropyl) -thieno [2 ', 3: 2,3] chepino [4,5-c] pyridazine 1 3 (2H) 1 Using 0.96 g of ON, as a pale yellow crystal having a melting point of 182-184 as a pale yellow crystal in the same manner as in Example 2, 2- (4-chlorophenyl) -1,5,6-dihydro 91- (3- Dimethylaminobutyryl) -thieno [2 ', 3': 2.3] chepino [4,5-c] pyridazine-13 (2H) one 7,7-dioxide.1 hydrochloride 0.4 g Obtained.

Example 6 1

2- (4-pi-phenyl) 1-9-1 (5-pentyl pentyl) 1,5,6-dihydrorothieno [2 ', 3': 2, 3] Cepino [4, 5-c] pyridazine 1 3 (2H ) To a mixture of 3.4 g of 1one and 4 OmI of chloroform was added 5 Oml of a solution of dimethylamine in tetrahydrofuran, and the mixture was stirred at 80 for 18 hours. The residue S obtained by distilling off the solvent was subjected to silica gel column chromatography. 2- (4-Chlorophenyl) -1,5,6-dihydro 91- (5-dimethylaminopentyl) -thieno [2 '] of brown amorphous powder from the fraction eluted with the solvent mixture of form-form and methanol , 3 ·: 2.3] Chepino [4.5-c] pyridazine-1 3 (2H) -one 2.37 g was obtained.

Ή-NR (CDC 1,) 5: 7.64-7.68 (2H, m) .7.42-7.46 (2H, m), 6.99 (1H, s), 6 93 (1 H, s), 3.32 (2Η, t, J = 6.6 Hz). 2.85 (2 H, t, J = 6.6 Hz), 2.79 (2H.t.J = 7.3Hz), 2.28 (2H.q, J = 7.3Hz) 2.24 (6H, s), 1.65-1.76 (2H, m) 1.4-1.5 (2H, m), 33-1.42 (2H.m).

Example 6 2

2- (4-chlorophenyl) 1,5,6-dihydro-9- (5-dimethylaminopentyl) -thieno [2 ', 3': 2,3] Chepino [4,5-c] pyridazine 1 3 (2H In the same manner as in Example 2 using 2.3 g of 2-one (4-monobutyral) -1,5,6-dihydro-1-9 as pale yellow crystals with a melting point of 155-11-157 1- (5-dimethylaminopentyl) -thieno [2 ', 3': 2.3] chepino [4,5-c] pyridazine-1 3 (2H) one 7.7-dioxide ρ-toluenesulfonate 0.5 g was obtained.

Example 6 3

Clay salt

2-(4-phenyl)-1-1-formyl-5.6-dihydrodrothieno [2 ', 3 *: 2.3] chepino [4, 5-c] pyridazine-3 (2H) -one 2 g, To a mixture of 60 ml of methanol and 30 ml of chloroform was added 1.8 ml of pyruamine cyclobutene, and the mixture was stirred at room temperature for 30 minutes. In addition, the cyano borohydride was added to the reaction mixture. 0.67 g of sodium hydrogen chloride was added and the mixture was stirred for 5 hours. The reaction solution was poured into ice water, oil was removed with a black form, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue S was subjected to silica gel column chromatography to obtain a pale yellow amorphous powder from the area eluted with a mixed solvent of ethyl acetate and methanol. This was converted into a hydrochloride and recrystallized from methanol to give 2- (4-phenylphenyl) -19-cyclopropylamino as a pale yellow product with a melting point of 216-218'C (decomposed). 0.58 g of methyl-5,6-dihydrothieno [2 ', 3': 2,3] cepino [4,5-c] pyridazine-13 (2H) -one / 1 hydrochloride was obtained.

Example 64

2- (4-phenylphenyl) 1 9-cyclobutyrylaminomethyl-5,6-dihydrothieno [2 ', 3 *: 2,3] chepino [4,5-c] pyridazine-1 3 (2H) 1.6 ml of 37% aqueous solution of formaldehyde and 1.3 g of sodium cyanoborohydride were added to a mixed solution of 4 g of 1-one monohydrochloride and 150 ml of ethanol, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water, extracted with a black form, washed with water, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography, and a pale yellow amorphous powder was obtained from the fraction eluted with a mixed solvent of chloroform and methanol. This was recrystallized from ethanol to give 2- (4-chlorophenyl) -191-((N-cyclopropyl-1-N-methylamino) methyl) -1-5 as pale yellow crystals with a melting point of 108-110. , 6—dihydrocheno

[2 ', 3': 2, 3] Cepino [4.5-c] pyridazine-13 (2H) one 0.8 g was obtained. Example 6 5

2- (4-phenylphenyl) -19-((N-cyclobutyl-N-methylamino) methyl) 5.6-dihidrocheno [2'.3 ': 2.3] Cepino [4.5] —C] Pyridazine-1 3 (2H) —one 1.5 g was dissolved in 25 ml of acetic acid, 1 ml of 30 hydrogen oxide was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into ice water, made alkaline with potassium carbonate, and extracted with ethyl acetate three times. The organic S was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue S was subjected to silica gel column chromatography, and a pale yellow amorphous powder was obtained from the area eluted with a mixed solvent of chloroform and methanol. The pale yellow crystals obtained by recrystallization from ethanol were converted into hydrochloride salts, and then recrystallized from ethanol to give 2-(-) as pale yellow crystals with a melting point of 2 16-2 19 • C (decomposed). 4-Chloroph: L-nil) 1-9-1 ((N-cyclopropyl pill-N-methylamino) methyl) 1,5,6-Dihydrocheno [2 ', 3': 2, 3] Chepino [4, 5-c] 0.58 g of pyridazine-1 (2H) -one 7.7-dioxide monohydrochloride was obtained.

Example 6 6

Rain tt¾ 2- (4-chlorophenyl) -1,5,6-dihydro-1 9-hydroxymethyl-Ceno [2 ', 3: 2.3] Cepino [4,5-c] pyridazine-1 3 (2H)- To a mixture of 1.2 g of N, N-dimethylformamide 1 Oml and triethylamine im1 was added 0.5 ml of methanesulfonyl chloride under ice-cooling, and the mixture was stirred at room temperature for 1 hour and further added with N Then, 1 ml of ethyl methylamine and 1 ml of triethylamine were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into iced water, oiled out with a black form, washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The remaining brew was subjected to silica gel column chromatography, the yellow oil obtained from the surface eluted with K-ethyl was converted to maleate, and then recrystallized from ethanol to give 2- (4-monochlorophenyl). 〉 1 9 1 ((Ν-ethyl-Ν-methylamino) methyl) 1 5.6-Dihidrothieno [2 '. 3': 2, 3] Chepino [4, 5— c] biridazin-3 (2H) 0.5 g of 'I maleate was obtained.

Example 67

Acid salt

2- (4-chlorophenyl) 9-1 ((N-ethyl-N-methylamino) methyl) 1,5,6-dihydrothieno [2 ', 3': 2.3] Chepino [4,5-c] pyridazine 0.85 g of -3 (2H) -one was dissolved in 10 ml of acetic acid, 0.58 ml of 30% hydrogen peroxide was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into ice water, made alkaline with potassium carbonate, and extracted three times with ethyl acetate. After the attached S was washed with water, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residual S was subjected to silica gel column chromatography, and a pale yellow amorphous powder was obtained from a fraction eluted with a mixed solvent of chloroform and methanol. After converting this to hydrochloride, isopropyl alcohol

7 β By reconstituting _β at »point 23 8-240 'C (decomposition) as pale yellow crystals of 2- (4-chlorophenyl) -191-((Ν-ethyl-Ν-methylamino) methyl) -1,5 6-dihydrocheno [2 ', 3': 2, 3] chepino [4,5-c] pyridazine-1 3 (2H) -one 7,7-dioxide monohydrochloride 0.2 g was obtained, performed Example 6 8

Salted female

2- (4-chlorophenyl) 1,5,6-dihydro-1- 9-hydroxymethyl chen [2 ', 3': 2,3] Chepino [4,5-c] pyridazine-1 3 (2H) one To a mixture of 1.2 g, 10 ml of N, N-dimethylformamide and 1 ml of triethylamine was added 0.5 ml of methanesulfonyl chloride under ice-cooling, and the mixture was stirred at room temperature for 1 hour. 1.3 ml of triamine and 1 ml of triethylamine were added and stirred at room temperature for 3 hours. The reaction solution was poured into ice water, extracted with a black hole form, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the remaining S was subjected to silica gel column chromatography to obtain 1 g of a yellow oil from a fraction eluted with a mixed solvent of chloroform and methanol. The obtained yellow oily substance was dissolved in 15 ml of dichoric acid, and 0.66 ml of 30% hydrogen oxide was added thereto, followed by stirring at room temperature for 4 hours. The reaction solution was poured into ice water, made alkaline with potassium carbonate, and extracted three times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The remaining brew was subjected to silica gel column chromatography, and a pale yellow amorphous powder was obtained from the fraction eluted with a mixed solvent of black form and methanol. This was converted into a salt, and recrystallized from ethanol to give 2-((4-chlorophenyl) -191-((N-methyl-N-) as a pale yellow crystal at »242-243'C (decomposition). Propylamino) methyl) I5.6-dihydrothieno [2'.3 ': 2.3] Chepino [4,5-c] pyridazine-1 3 (2H) -one 7,7-dioxide monohydrochloride 0.4 g was obtained. Example 6 9

2- (4-phenyl phenyl) 1 9-1 ((Ν-cyclobutyl propyl-1Ν-methylamino) methyl) 1 5.6-Dihydrocheno [2,, 3 ': 2, 3] Chepino [4, 5] — C] Pyridazine-1- (2Η) -one is dissolved in drunk acid, reacted with 30¾ hydrogen peroxide, treated, and purified to give 2- (4-chlorophenyl) -19-1 ((Ν— Cyclobutyryl 1- (methylamino) methyl) -1,5,6-dihydrothieno C 2 ', 3': 2,3] Cepino [4,5-c] pyridazine-13 (2Η) —one 7-oxide.

Example 70

2- (4-chlorophenyl) -1-91 ((Ν-ethyl-Ν-methylamino) methyl) -1,5,6-dihydrothieno [2 ·, 3 ': 2,3] Chepino [4,5-c] pyridazine Dissolve 1 3 (2H) 1one in sulfuric acid, add hydrogen hydride and react, then treat and purify to obtain 2- (4-chloro-fuunil) 1 9-1 ((N-e Cyl-N-methylamino) methyl) -1,5,6-dihydrothieno [2 ', 3': 2.3] Chepino [4,5-c] pyridazine-13 (2H) one 7-oxide.

Example 7 1

2- (4-monophenyl) -1,5,6-dihydro-9- (1-dimethylaminoethyl) -thieno [2 ′, 3 ′: 2.3] chepino [4, 5-c] Pyridazine-13 (2H) one is optically resolved on an optically active HP LC column to give R-2- (4-chlorophenyl) -1,5,6-dihydro-91- (1-dimethyla). Minoethyl) -thieno [2 ', 3': 2,3] chepino [4,5-1c] pyridazine-13 (2H) -one is obtained.

Example 72

Example 52 2- (4-chlorophenyl) -1-5.6-dihydro-9- (1-dimethylaminoethyl) -thieno obtained in Example 2 [2,, 3 ': 2,3] Chepino [4,5 -c] Pyridazine-3 (2H) one was optically resolved on an optically active HPLC column to give S-2- (4-chlorophenyl) -1-5.6-dihydro-9- ( 1-Dimethylaminoethyl) -thieno [2 ', 3.2.3] Chepino [4, 51-c] pyridazine-13 (2H) one.

Example 7 3

Example 53 2- (4-chlorophenol) obtained in Example 3—5,6-dihydro 9- (1-dimethylaminoethyl) -thieno [2 ′, 3 ′: 2, 3] Chepino [4 , 5—c] pyridazine-l-3 (2H) -one 7-oxide was optically resolved on an optically active HPLC column to give R-2- (4-chlorophenyl) -5,6-dihydro-9 1- (1-Dimethylaminoethyl) -thieno [2 ', 3': 2.3] chepino [4,5-c] pyridazine-13 (2H) -one 7-oxide is obtained, Example 74.

2- (4-chlorophenyl) -1,5,6-dihydro-9- (1-dimethylaminoethyl) -thieno [2'.3 ·: 2,3] obtained in Example 53 3, Chepino [4,5 — C] Pyridazine 13 (2H) 1-one 7-oxide was optically resolved on an optically active HPLC column to give S-2- (4-chlorophenyl) -1,5,6-dihydro 9, 1-dimethylaminoethyl) -thieno [2 ', 3': 2, 3] Epino [4,5-c] pyridazine-l-3 (2H) -l-oxide is obtained, Example 7 5

2- (4-chlorophenyl) -1,5,6-dihydro-9- (I-dimethylaminoethyl) -thieno obtained in Example 5 [2 ′, 3 ′: 2,3] Chepino [4,5 — C] Pyridazine-3 (2H) -one 7,7-dioxide was optically resolved on an optically active HP LC column to give R—2- (4-chlorophenyl) -1,5,6-dihydro-9-1 ( 1-Dimethylaminoethyl) -thieno [2 ', 3 ·: 2.3] Chepino [4,5-c] pyridazine-13 (2H) one 7,7-dioxide is obtained.

Example 7 6

2- (4-monochlorophenyl) -1.5,6-dihydro-9- (1-dimethylaminoethyl) -thieno [2 ', 3': 2.3] chepino [4,5-c obtained in Example 54 The pyridazine-l-3 (2H) -one 7,7-dioxide was optically resolved on an optically active HP LC column to give S-2-((4-chlorophenyl)>-5,6-dihydrol 9-l (1 -Dimethylaminoethyl) -thieno [2 ', 3': 2, 3] Cepino [4,5-c] pyridazine-13 (2H) one-dioxide is obtained.

Example 77

The same operation was carried out using N-ethyl-N-methylamine in place of ammonia of Example 57 to give 2- (4-chlorophenyl) -9-1 (1- (N-ethyl-N-methylamino). Ethyl) 1,5,6-dihydrothieno [2 ', 3': 2.3] Chepino [4,5-c] pyridazine-1 3 (2H) 1one is obtained. Example 78

2- (4-phenylphenyl) 1-9-1 (1- (N-ethyl-N-methylamino) ethyl) 1,5,6-dihydrothieno [2 '. 3': 2, 3] Chepino [4, 5- c] The pyridazine 13 (2H) 1one was optically resolved on an optically active HPLC column to give R—2— (4-chlorofurnyl) 191- (11- (N-ethyl-N-methylamino) ethyl) 1 5 , 6-dihydrothieno [2 ', 3': 2, 3] chepino [4.5-c] pyridazine-1 3 (2H) -one. Example 7 9

2- (4-phenyl phenyl) 1 9-1 (1-(N-ethyl-N-methylamino) ethyl) 1 5.6-Dihedro-Ceno [2 ', 3': 2, 3] Cepino [4, 5- c] Pyridazine-13 (2H) one was optically resolved by an optically active HPLC column to give S-2- (4-chlorophenyl) 9-11 (N-ethyl-N-methylamino) ethyl. One 5, 6—dihidrothieno [2 ', 3': 2, 3] Chepino [4, 5-c] pyridazine one 3 (2H) Oneone is obtained.

Example 8 0

2- (4-chlorophenyl) 1 9-1 (1- (N-ethyl-N-methylamino) ethyl) 1,5,6-dihydrothieno [2,, 3 ': 2, 3] Chepino [4, 5—c] Using pyridazine-1- (2H) -one, and in the same manner as in Example 70, 2- (4-chlorophenyl) -9-1-1 (N-ethyl-N-methylamino) ethyl-5 , 6-Dialdehyde α Thieno [2 ', 3': 2.3] Chepino [4, 5-c] pyridazine-1 3 (2H) -one 7-oxide. Example 8 1

2- (4-phenyl phenyl) 1 9-1 (1- (N-ethyl-N-methylamino) ethyl) 1 5.6-Dihydrothieno [2 ', 3': 2.3] Chepino [4, 5-c] Pyridazine 1 3 (2H) 1one 7-year-old oxide was optically resolved on an optically active HPLC column to give R-2- (4-chlorophenyl) 19- (11- (N-ethyl-N-methylamino) ethyl) 5,6-Dihydrothieno [2 ', 3': 2.3] Cepino [4.5-c] pyridazine-13 (2H) one 7-oxide is obtained.

Example 82

2- (4-chlorophenyl) 1-91 C 1-(N-ethyl-N-methylamino) ethyl) 1,5,6-dihydrothieno [2 ', 3': 2, 3〗 Cepino [4.5-c] Pyridazine 13 (2H) 1-one 7-oxide was optically resolved on an optically active HPLC column to give S-2- (4-chlorophenyl) 19- (11- (N-ethyl-N-methylamino) ethyl. 1) 6,6-dihydrothieno [2 ', 3 *: 2, 3] chepino [4, 5—c] pyridazine 1 3 (2H) 1-one 7-oxy Can be obtained,

Example 8 3

2- (4-chlorophenyl) 9-1 (11- (N-ethyl-N-methylamino) ethyl) 1,5,6-dihydrothieno [2 ', 3': 2.3] Chepino [4,5-c] Using pyridazine-1 3 (2H) -one, in the same manner as in Example 2, 2- (4-chlorophenyl) 9-1 (11- (N-ethyl-N-methylamino) ethyl) 1,5 6-Dihydrothieno [2 ', 3': 2,3] Cepino [4,5-c] pyridazine-13 (2H) one 7,7-dioxide is obtained.

Example 8 4

2- (4-phenylphenyl) 1 9-1 (1- (N-ethyl-N-methylamino) ethyl) 1,5,6-dihydrothieno [2 '. 3': 2, 3] Chepino [4, 5- c] By optical resolution of pyridazine-1 3 (2H) -one 7,7-dioxide by optically active HP LC column, R-2- (4-chlorophenyl) 1 91-1 (1-1 (N-ethyl) N-methylamino) ethyl) 5.6.-Dihydrodrothieno [2 '3': 2.3] Chepino [4,5-c] pyridazine 1 3 (2H) 1 7.7 Dioxide can be obtained <

Example 8 5

2- (4-chlorophenyl) 1-9-1 (1- (N-ethyl-N-methylamino) ethyl) 1-5.6-dihydrothieno [2 ', 3': 2,3] Cepino [4,5-c] Pyridazine-I 3 (2H) -one 7,7-dioxide was optically resolved by optically active HPL C column to give S-2- (4-chlorophenyl) 9-1-1 (1-1 (N-ethyl-N —Methylamino) ethyl) 1,5,6-Dihydrothieno [2 ', 3: 2.3] Chepino [4.5-c] pyridazine-13 (2H) —one 7,7 Dioxide is obtained.

Example 8 6

Example 57 The same procedure was repeated using N-cyclobutyryl-N-methylamine in place of the ammonia of Example 7 to give 2- (4-chlorophenyl) 19- (1-1 (N-cyclo Provir-1-N-methylamino) ethyl-1-5,6-dihydrocheno [2 ', 3': 2.3] Cepino [4,5-c] pyridazine-1 3 (2H) one. Example 8

2- (4-chlorophenyl) 9-1-1 (N-cyclobutylpyr-1-N-methylamino) ethyl 5.6-dihydrothieno [2'.3 ': 2,3] Cepino [

4.5—c] Pyridazin-3- (2H) -one was optically resolved on an optically active HPLC column to give R-2- (4-chlorophenyl) 9-1-1 (N-cyclobutane). Pill-1-N-methylamino) ethyl-1-5,6-dihydrothieno [2 ', 3'

: 2.3] Cepino [4.5-c] pyridazine-1 3 (2H) -one is obtained. Example 8 8

2- (4-chlorophenyl) 9-1-1 (N-cyclopropyl-1-N-methylamino) ethyl-5,6-dihydrothieno [2, .3 ': 2, 3] Chepino [4, 5] — C] Pyridazine-1 3 (2H) —one is resolved by optical resolution on an optically active HPLC column to give S—2— (4-chlorophenyl) 9-1-1 (1- (N-cyclopropyl pill N) —Methylamino) ethyl) 1,5,6-Dihydrothieno [2 ', 3 ·: 2,3] Chepino [4.5-c] pyridazine-1 3 (2H) -one. Example 8 9

2- (4-chlorophenyl) -1-9-1-1 (N-cyclobutyl-1-N-methylamino) ethyl-15.6-dihydrothieno [2 ', 3': 2.3] Chepino [4 5- (c) pyridazine-1 (2H) 1one and 2- (4-chloroinyl) 19-1 (1- (N-cyclobutyl-N-methylamino) by the same method as in Example 70. 1) 6-Dihydrothieno [2 ·, 3 ': 2.3] Chepino [4.5-c] pyridazine 13 (2H) one 7-oxide. Example 90

2- (4-phenyl phenyl) 9-1 (1- (cyclo-butyl propyl-methyl-amino) ethyl) 1,5,6-dihydrothieno [2'.3 *: 2,3] Chepino [4. 5—c] Pyridazine-1 3 (2Η) -one 7-oxide was optically resolved on an optically active HP LC column to give R—2— (4-chlorophenyl) 9-1-1 (N-cyclobutane). Mouth building N-methylamino) ethyl) 1,5,6-dihydrothieno [2'.3 ': 2,3] Chepino [4.5.-c〗 pyridazine-1 3 (2H) one-on 7-oxide .

Θ 1 Example 9 1

2- (4-phenylphenyl) 1 9-1 (1- (N-cyclobutylpyr-1-N-methylamino) ethyl) 1,5,6-dihydrothieno [2,, 3 ': 2, 3] Chepino [4, 5—c] Pyridazine-1 3 (2H) 1-one 7-oxide was optically resolved on an optically active HP LC column to give S—2— (4-chlorophenyl) 1 9-1 (1- (N-cyclobutane). N-Methylamino) ethyl-1,5-dihydrothieno [2 ', 3': 2,3] Chepino [4,5-c] pyridazine-1 3 (2H) -on 7-oxide.

Example 92

2- (4-chlorophenyl) 1-9-1 (1- (N-cyclobutylpyr-1-N-methylamino) ethyl) 1,5,6-dihydrothieno [2,, 3 ': 2, 3] Cepino [4. 5- (c) pyridazine-l-3 (2H) -one and 2- (4-chlorophenyl) 9-1 (1- (N-cyclobutyryl-N-) were prepared in the same manner as in Example 2. Methylamino) ethyl) 1,5,6-dihydrothieno [2 ', 3': 2,3] cepino [4,5—c] pyridazine-1 3 (2H) —one 7,7-dioxide C

Example 9 3

2- (4-chlorophenyl) 1-9-1 (1- (N-cyclobutyl-N-methylamino) ethyl) 1,5,6-dihydrothieno [2 ', 3': 2, 3] Cepino [4. 5—c] Pyridazine-3 (2H) —one 7,7-dioxide was optically resolved on an optically active HPLC column to obtain R—2- (4-chloroph: << nil) 1 9 1 (1 1 ( N-cyclopropyl-1- (N-methylamino) ethyl) -1,5,6-dihydrodrothieno [2 ', 3': 2,3] Cepino [4.5-c] pyridazine-1 3 (2H) —one 7,7 —Dioxide is obtained.

Example 9 4

2- (4-chlorophenyl) 1 9-1 (1- (N-cyclobutyl-pi-r-N-methylamino) ethyl) 1,5,6-dihydrothieno [2 ', 3': 2.3] Chepino [4. 5-c] Pyridazine-1 3 (2H) 1one 7,7-Dioxide was optically resolved on an optically active HPLC column to give S-2- (4-chlorophenyl) 19- (11- (N-cyclobutane). Mouth pill (N-methylamino) ethyl) 1,5—Jihi θ 3 Dolothieno [2 ', 3 ·: 2.3] Cepino [4,5-c] pyridazine-1 3 (2H) -one 7,7-dioxide is obtained.

In the above examples, HP LC stands for high performance liquid chromatography (high gh per r ol r man c e li qu id ch rom o t o gr aphy).

Formulation example 1

The pharmaceutical preparation containing 1 Omg of the compound (I) of the present invention can be prepared, for example, by the following formulation.

Compound (I) 10.0 mg

Lactose 58.5 mg

Corn starch 25. Omg Microcrystalline cellulose 20. Omg

Polyvinylpyrrolidone K 30 2.Omg talc 4.0 mg magnesium stearate 0.5 mg

1 20.Omg

Compound (I) is pulverized with an atomizer to obtain a fine powder having an average particle diameter of 10 microns or less. Compound (I), lactose, corn starch and microcrystalline cellulose are thoroughly mixed in a kneading machine, and then voribylpyrrolidone K-130 size liquid is added to form a mixture. The kneaded material is granulated through a 200-mesh seol, dried in a hot air dryer with 50 hot air dryers to a moisture content of 3-4%, passed through a 24-mesh sieve, and then mixed with talc and magnesium stearate. Then, press using a rotary punch with a flat punch having a diameter of 8 mm.

EXPERIMENTAL EXAMPLE 1: (E 换 function for benzodiazepine receptor

3 H—FNZ (flunitrazebam) binding test was carried out according to the method described in Life Science, Volume 20, page 2101 (1977). Crude Synopsis prepared from the cerebral cortex of 9 10-year-old Wistar rat One fraction was suspended in 5 OmM Tris-hydrochloride buffer (pH 7.4) containing 12 OmM sodium chloride and 5 mM potassium chloride, and used in a narrow space.

Next, a test compound of known degree and trinitrated flunitrazepam (final concentration InM) were added to the synagogue solution, and incubated at 0 for 60 minutes. After that, the buffer solution was filtered through a Whatman GF / B glass fiber filter, and after washing the filter with the above buffer solution, the radioactivity remaining on the filter was measured using a liquid scintillation counter. It was measured.

The binding ability of the compound of the present invention to a benzodiazepine receptor is evaluated by its ability to fi-convert tritiated flunitrazepam from its site, and is represented by a κ i value (nM). As a result of the test, the compound of the present invention showed a high affinity of 100 nM or less for the benzodiazepine receptor.

Experimental Example 2: Anti-bicuculline action

An anti-bicuculline action test was carried out according to the method of Life Science (Life Science) Volume 21, 1779 (1977).

Male ddY mice weighing 20-28 g were used as 7-14 mice per group. One hour after the oral administration of the test compound, (+) bicuculline 0.6 mg / kg was intravenously administered, and the presence or absence of the development of tonic extension spasm (TE) within 5 minutes was observed. The degree (ED _S0傢) was determined by the probit method. As a result, the compound of the present invention showed an ED, ₀ value of 1 OmgZkg (po) or less.

Experimental example 3: Anxiolytic activity (Vogel type conflict test)

The experiment was performed according to the method of Vogel 1 et al. (Psychopharmacology, Vol. 21, p. 1 (1971)). For the test, male or female I-Wister rats, which had been deprived of water 48 hours before the start of the test, were used as 14 to 20 animals per group. The test equipment (Ohara Medical Sangyo) is made of plastic and consists of a bright room (38 x 38 x 20 cm) and a cold room (10 x i 0 x 20 cm). Rats were placed in the room, and air shock (100V or 50V, 0.3 seconds) was performed once every 20 times of drinking water. The rat was shocked for three minutes after the first «qi shock. The test compound was administered intravenously 15 minutes before the test. Compared with the control group (group treated with 0.5% HPMC), the number of drinkings of the test compound-treated group was statistically significant (Mann-Whitney's V test; P <0.05). The amount found was determined as the «small effective dose (MED). As a result, the compound showed a MEDtt of 5 mgZkg (iv) or less.

Experimental Example 4: Effect on maximal cramping (anti-MES effect)

Male d d Y mice were used as 7 or 14 mice per group. One hour after the test compound was injected, an alternating current of 2000 V, 12.5 mA. 0.2 seconds was passed through the cornea through the Bi-S silver ball pole using the Hammer S (* ¾ »: 1 ^ £ 3). The effect on maximal spasticity was determined by the probit method based on the presence or absence of tonic extensibility * and the 50% effective agriculture rate (EDs. Value). As a result, the compound of the present invention had an ED of 1 Omg / kg (p.o.) or less. The value was shown.

Example 5: Conditioned fear test

A group of 10 to 20 male or italian List hood ed rats are used. Transfer the animal to a 20 x 20 x 40 cm plastic experiment device, extinguish it with an illuminated light »for 2 minutes, then turn on the lights that illuminate the experimental equipment and apply for 15 minutes, 3 seconds for 3 minutes. Load 0 mA S-Shock at 15 second intervals. Acquisition trial 24 After 4 hours, the animal is put back into the lighted off-state IS, and after 2 minutes the light is turned on and left for 3 minutes without applying an electric shock. The distance traveled and the number of times the animal rises in the test equipment during the test trial are measured with the automatic movement 5 measurement equipment S (manufactured by SCANET Toyo Sangyo). The test compound is administered a certain period of time before the test trial, and is used as an index to determine whether it antagonizes the decrease in locomotor activity observed in the control group. As a result, the number of movements and the number of rises in the test compound-treated group were tested by the Dunnett method with the control group, and the dose at which significant addition was observed was expressed as the minimum effective dose of the anxiolytic effect.

Experimental example 6: muscle relaxation action The test compound is orally administered to 7 or 14 male d dY mice per group, and placed on a 2.8 cm diameter rotating rod that rotates 1 to 3 times per minute 1 hour later, or female. The test compound is administered intravenously to a male Wistar rat, and after 15 minutes, 7.5 rotations per minute 7.5 times on a rotating rod with a diameter of 5.Ocm, the number of animals falling within 1 minute Count. The dose of test compound for dropping 50% of the animals _{(ED S., Mg / kg} ) was determined by the probit preparative method. As a result, the compound of the present invention exhibited an ED10 value of at least ₁₀ OmgZkg (po) in mice and at least SmgZkg (iv) in rats.

Experimental Example _7: E evening Nord anesthesia sedimentary strength action

7 or 14 male ddY mice and female Wistar rats are used per group. One hour after the oral administration of the test compound (simultaneously for intravenous administration), a 30 νΖνκ ethanol solution for mice and a 20 νΖν% ethanol solution for rats were added at a dose of 1 per 100 g body weight. Administer intraperitoneally with a liquid volume of m 1, and then squeeze it for 10 seconds or more after 15 minutes. The ED, ₀值, and 95% confidence limits are calculated from the number of animals that lose the righting reflex by the Prombit method.

Example 8: Amnestic induction

One group of 10 It-sex Wistar rats is used. The experimental equipment S is a passive avoidance reaction measurement equipment S (manufactured by Ohara Medical Industry Co., Ltd.) consisting of two areas, light and dark, and 15 minutes after intravenous administration of the test compound, the light box (18.5 x 24 x 20.5) Immediately after moving the animal into a dark box (19 x 14 x 20.5 cm), apply a 40V, 0.2 second qi shock to obtain a trial. ¾ Acquisition trial After 24 hours, put the animal in the light box again. 測定 Measure the reaction latency until transfer to the box up to 300 seconds and use it as a retention trial. As a result, the response latency of the retention trial of the test compound treated fi group was tested by the Dunnett t method with the control group, and the dose at which a significant short box was observed was expressed as the minimum effective dose for the effect of inducing amnesia.

Example 9: Acute toxicity

When 30 dmg / kg of the compound of the present invention was orally administered to 10 male ddY mice per group, no deaths were observed up to 5 days after the administration. Experimental Example 10: Solubility in water

The test compound was suspended in distilled water, shaken at 37 for 2 hours, centrifuged, and the solution obtained by water extension was quantified by high performance liquid chromatography. . The compound of the present invention exhibited a solubility of 1% (W / V) or more.

Experimental Example 1 1: Bioavailability

Test compound 5 mg / kg was orally administered intravenously and 1 O mgZ kg, and the blood was collected with time, and the plasma concentration was determined using two groups of sex Wistar rats with 7 rats per group. Was measured by high performance liquid chromatography, and the bioavailability was calculated according to the following equation.

(Blood at oral administration) Medium β-lower calf) / (Lower blood concentration at intravenous administration) χ 2) 1 0 0

The bioavailability of the compound determined by the above formula showed an extremely high value.

As is evident from the abundant pharmacological studies including the above experiments, the one-armed (I) thiophene compound of the present invention or a pharmaceutically acceptable salt thereof has high affinity for the benzodiazepine receptor. Since it has an antagonistic effect on chemical disease * induced 剂 such as bicuculline, and has a strong anxiolytic effect in a conflict test, it is useful as an anxiolytic and a sleep inducer. The present invention compound has a strong inhibiting effect on the maximum ¾ «痙», _c further is useful as an antiepileptic drug, a conch t ioned fear轼effective drug even Kowa悚failure from the result of ft Be expected. On the other hand, the compound of the present invention is also characterized in that it has little effect on somatic functions such as muscle relaxing action, and has little side effects because of its weak alcohol-strengthening action and amnestic-inducing action. Therefore, the compound of the present invention can be used as a medicament such as a selective anxiolytic, a sleep-inducing agent, an antiepileptic or an anxiety disorder treatment drug with few side effects. C Furthermore, the present compound has excellent water solubility. As a result, the compound has good absorption in vivo and extremely high bioavailability, and is excellent in pharmacokinetics and 18 pharmacological properties.

Claims

The scope of the claims

1. General formula

(Wherein R ¹ and R ² are the same or different and represent hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl, or R ^1. R ^J is a bonded nitrogen atom _C R ³ which represents a group forming a ring together with the above represents aryl or heteroaryl having at least one substituent selected from halogen, hydroxy, alkyl and alkody on the aromatic ring, and X is c H ₂ , S shows the SO or S0 _2. binding Y represents Choku縝or branched TECHNICAL chain alkylene Zhen having eight from崁素number 1., represented by the actual kneading and point represents the single bond or a double bond )

Or an optical isomer or a pharmaceutically acceptable salt thereof.

2.R ¹ and R ² are both hydrogen, or one of them is hydrogen or alkyl having 1 to 4 carbons, the other is alkyl having 1 to 4 carbons, cycloalkyl having 3 to 6 carbons, 2. The thiophene compound according to claim 1, which is phenyl or benzyl, an optical isomer or a pharmaceutically acceptable salt thereof.

3. R ^l . ^Ra is bonded to form a cyclic amino group which may contain a nitrogen or oxygen atom in addition to the nitrogen atom together with the contacting nitrogen atom, and the cyclic amino group has 1 to 4 carbon atoms. 2. The thiophene compound according to claim 1, which is a group optionally substituted with alkyl or fuunyl, its optical isomer or pharmaceutically acceptable salt thereof.

4. R and are halogens on the aromatic ring, alkyls with 1 to 4 carbon atoms, and K-prime numbers 1 to 4 3. The thiophene compound according to claim 1, which is a phenyl or pyridyl having one S-substituent selected from lucoquine, an optical isomer or a pharmaceutically acceptable salt thereof.

5. The thiophene compound according to claim 1, wherein X is CH or SC, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

6. The thiophene compound according to claim 1, wherein Y is methylene, methylmethylene, ethylene, trimethylene, tetramethylene or pentamethylene, an optical isomer thereof or a pharmaceutically acceptable clay thereof.

7. The thiol according to claim 1, wherein the bond represented by the solid line and the dotted line is a double bond: a compound of formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

8. R ¹ and R ^J are the same or different and represent hydrogen, methyl, ethyl or cyclopropyl, and R ^s is 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl or 5-chloro-2-pyridyl. X represents CH,, S, SO or S0 », Υ represents methylene or methylmethylene, and the bond represented by the real and dot 示す represents a double bond. Item 3. The thiophene compound according to Item 1, an optical isomer thereof or a pharmaceutically acceptable clay thereof.

9. 2— (4-chlorophenyl) 1,5,6-dihydro-9-dimethylaminomethylthithieno [2 ', 3': 2.3] Chepino [4,5-c] pyridazine-1 3 (2 H) — On 7, 7—dioxide,

2- (4-chlorophenyl) -1,5,6-dihydro-9-dimethylaminomethylthieno [2 ', 3': 2,3] chepino [4,5-c] pyridazine-1 3 (2H) one 7 —Oxide,

2- (4-chlorophenyl) 1,5,6-dihydro-9-dimethylaminomethylthieno [2 ', 3': 2,3] chepino [4.5-c] pyridazine-1 3 (2H) one,

5,6-Dihydro-9-dimethylaminomethyl-2- (4-methylphenyl) -thieno [2 ', 3': 2,3] Cepino [4,5-c] pyridazine-1 3 (2H) one 7,7 —Dioxide, 5,6-Dihydro 9-dimethylaminomethyl-2- (4-methoxyphenyl) -thieno [2 ', 3': 2.3] Chepino [4,5-c] pyridazine-1 3 (2H) -1 On 7, 7—dioxide,

2- (4,1-diphenyl) 1,5,6-dihydro 9-methylaminomethylthieno [2 ', 3': 2,3] Chepino [4,5-c] pyridazine-1 3 (2H) — ON 7, 7—dioxide,

9-aminomethyl-1- (4-chlorophenyl) 1,5,6-dihydrothieno [2'.3 ': 2.3] chepino [4,5-c] pyridazine-1 (2H) one 7.7 —Dioxide,

2- (4-chlorophenyl) 1-9-ethylaminomethyl-5,6-dihydrothieno [2'.3 ·: 2,3] chepino [4,5—c] pyridazine-1 3 (2H) —one 7, 7—dioxide,

2- (4-chlorophenyl) 1,9-ethylaminomethyl-5,6-dihydrothieno [2 '. 3': 2, 3] Chepino [4.5-c] pyridazine-1 3 (2 H) -On 7, 7—dioxide,

2- (5-cyclo-1-2-pyridyl) 1-5.6-dihydro 9-dimethylamino methylthieno [2 ', 3': 2,3] chepino [4.5-c] pyridazine-1 3 (2H) one 7, 7—dioxide,

2- (5-chloro-2-pyridyl) -1-9-dimethylaminomethyl-2,5,6,7-tetrahydro-draw 3H-thieno [2 ', 3': 6,7] cyclohepta [1,2- c] pyridazine-1 3 (2H) — on,

2- (4-chlorophenyl) 1-91-dimethylaminomethyl-2,5,6,7-tetrahydro 3 H-thieno [2,, 3 ': 6.7] Cyclohepta [1.2-c] One pyridazine 3 (2 H) one,

9-dimethylaminomethyl-2- (4-methylphenyl) -1,2,5,6,7-tetrahydro 3H-thieno [2'.3 ': 6.7] cyclohepta [1,2, c] pyridazine 3 (2 H) —ON, 2- (4-chlorophenyl) 1-5,6-dihydro 9- (1-dimethylaminoethyl) -thieno [2 ', 3': 2,3] Chepino [4,5-c] pyridazine 1 3 (2H) 7, 7—dioxide,

2-((4-chlorophenyl) -1-9-1 ((N-cyclobutyl-P-N-methylamino) methyl) -15.6-dihydrodrothieno [2,, 3 ·: 2.3〗 Cepino [4,5 — C] pyridazine-1 3 (2H) —one 7,7-dioxide,

2- (4-chlorophenyl) 9-1-1 ((N-ethyl-N-methylamino) methyl) 5.6-Dihydrodrothieno [2 ', 3': 2.3] Chepino [4.5-c ] Pyridazine 1 (2H) 1 7,7-dioxide,

R—2— (4-chlorophenyl) 1,5,6-dihydro 9-1 (1-dimethylaminoethyl) -thieno [2'.3 ': 2.3] Chepino [4,5-c] pyridazine-3 (2H) One-on 7, 7-dioxide,

S— 2— (4-phenyl phenyl) 1, 5, 6-dihydro 9- 1 (1-dimethylaminoethyl) -thieno [2 ', 3': 2.3] Chepino [4.5- c] pyridazine 3 (2H) —on 7, 7—dioxide,

2- (4-phenyl phenyl) 1-9-1 (1- (N-ethyl-N-methylamino) ethyl) 1-5.6-dihidrothieno [2 '. 3': 2.3] Chepino [4, 5- c] pyridazine-3- (2H) one 7,7-dioxide,

R—2— (4-chlorophenyl) 1-9-1 (1- (N-ethyl-N-methylamino) ethyl) 1,5,6-dihidrothieno [2 ', 3': 2, 3] Cepino [4. 5—c] pyridazine-1 3 (2H) —one 7,7—dioxide,

S—2— (4,4-N-phenyl) 1-9-1 (1- (N-ethyl-N-methylamino) ethyl) 1,5,6-dihidrothieno [2 ', 3': 2.3] Cepino [4, 5—c] pyridazine-1 3 (2H) one 7,7—dioxide,

2- (4-N-cyclophenyl) 1-9-1 (1- (N-cyclobutyl-N-methylamino) ethyl) 1,5,6-Dihidrothieno [2 ', 3': 2, 3] Cepino [4,5—c] pyridazine-1 3 (2H) —one 7,7—dioxide, R—2- (4-cyclophenyl) -191 (1- (N-cyclobutyryl-N-methylamino) ethyl) 1,5,6-dihydrothieno [2,, 3 ': 2,3] Chebino [4.5.c] pyridazine-3- (2H) one 7,7-dioxide, and

S- 2— (4-chlorophenyl) 1 9-1 (1- (N-cyclobutyryl-N-methylamino) ethyl) 1,5,6-dihydrothieno [2 ', 3': 2.3] Chepino [4.5-c] pyridazine-1 3 (2H) -on 7.7-dioxide

2. The thiophene compound according to claim 1, which is selected from: an optical isomer or a pharmaceutically acceptable salt thereof.

1 0. —General formula

(Wherein R ′, R, are the same or different and represent hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl, or R ¹ , R ² is a nitrogen atom bonded to and in contact with K _C R ³ which represents a group forming a ring together with the above represents an aryl or heteroaryl having at least one S group selected from halogen, hydroxy, alkyl and alkoxy on the aromatic ring, and X is CH ₂ , S , SO or SO, Y represents a straight or branched chain alkylene group having 1 to 8 carbon atoms, and a bond represented by a dotted line with Sumi represents a single bond or a double bond. )

Or a pharmaceutically acceptable salt thereof.

1 1. The medicament according to claim 10, which is an anxiolytic.

1 2. The medicament according to item 10, which is an antiepileptic drug.

13. The medicament according to claim 10, which is a sleep inducer.

1 4. Fear 医薬 Drug _c described in item 10 as a therapeutic drug for disorders

1 5. General formula

(Wherein, R ¹ and R ² are the same or different and represent hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl, or R ¹ and R ² are bonded and bonded nitrogen atoms And a group which forms a ring together with.

R ³ represents aryl or heteroaryl having at least a monovalent substituent selected from halogen, hydroxy, alkyl and alkoxy on the aromatic ring. X represents CH _2, S, SO or S0 _2. Y represents a linear or branched alkylene chain having 1 to 8 valences. A bond represented by a solid line and a dotted line indicates a single bond or a double bond. )

A pharmaceutical composition comprising a thiophene compound represented by the formula: or an optical isomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Ten