KR910005853B1 - Process for producing benzothio pyrano (4,3-c) pyridazine compounds - Google Patents

Abstract

None.

Description

Method for preparing benzothiopyrano [4,3-C] pyridazine compound

The present invention relates to novel pharmaceutically useful benzothiopyrano [4,3-C] pyridazines.

European Patent Application No. 124314A discloses a potent such as 2,4,4a, 5-tetrahydro-7- (1H-imidazol-1-yl) -3H-indeno [1,2-C] pyridin-3-one Compounds that have cardiac and antihypertensive action are described and described in Journal of Medical Chemistry (J.Med, Chem.), Vol. 24, P. 830 (1981), describe immunosuppressive 2- (4-chlorophenyl) benzothiopyrano [4,3-C] piperazol-3-ones and the like.

The present invention has been intensively studied to synthesize effective compounds and to develop useful drugs to find benzothiopyrano [4,3, -C] pyridazine backbones, which are not known in the prior art, including the above-mentioned documents. It was.

As a result of such a study, the present inventors found that the novel benzothiopyrano [4,3, -C] pyridinine compound represented by the following general formula (I) exhibits anti-anxiety action and useful action. Was completed.

The present invention relates to a benzothiopyrano [4,3, -C] -pyrididine compound represented by the following general formula.

은 단일결합 또는 이중결합이다.Wherein R ¹ and R ² are the same or different and each is hydrogen, halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C _1-4 alkyl, C _1-4 alkoxy, or C _{2- 5} alkanoylamido, R ³ is hydrogen, C _1-10 alkyl, hydroxy-C _1-4 alkyl, C _2-5 alkanoyloxy-C _1-4 alkyl, pyridyl, aryl aryl-C _{1- At least 4} alkyl, or at least one selected from the group consisting of halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C _1-4 alkyl, C _1-4 alkoxy and C _2-5 alkanoylamido on an aromatic ring Aryl or aryl-C _1-4 alkyl substituted with one substituent, n is 0,1 or 2, and a bond between positions 4 and 4a

Is a single bond or a double bond.

By definition, when describing each symbol of the general formula (I), halogen includes fluorine, chlorine, bromine and iodine; C _1-4 alkyl includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl; C _1-4 alkoxy includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and tert-butoxy; C _2-5 alkanoyl amidos include, for example, acetylamido, propionyl amido, butylyl amido and pivaloyl amido; Hydroxy-C _1-4 alkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutal; C _2-5 alkanoyloxy-C _1-4 alkyl is, for example, acetoxymethyl, acetoxyethyl, acetoxypropyl, acetoxybutyl, propionyloxymethyl, propionyloxyethyl, propionyloxypropyl and propoxy Butyl; C _1-8 alkyl means straight or branched alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, secondary-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, Octyl, 2-ethylhexyl, nonyl and decyl; Aryl-C _1-4 alkyl includes, for example, benzyl, phenylethyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphthylethyl, nathylpropyl and naphthylbutyl; And aryl includes, for example, phenyl and naphthyl.

Compounds of general formula (I) having chiral carbon atoms can be prepared in racemates or optically active isomers, and compounds (I) having at least two chiral atoms can be prepared in the respective diastereomers. Or as a mixture thereof. The invention also encompasses mixtures thereof and the respective isomers. The present invention also includes a stereomer.

이 단일결합 또는 이중결합인 화합물이다.Compounds in which the general formula (I) is preferred, in which R ¹ and R ² are the same or different, are hydrogen, halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C _1-4 alkyl, C _{1- At least 4} alkoxy or C _2-5 alkanoyl amido and R ³ is selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro C _1-4 alkyl and C _1-4 alkoxy on the aryl or aromatic ring Aryl substituted with one substituent, n is 0,1 or 2, and a bond between positions 4 and 4a

It is a compound which is a single bond or a double bond.

이 단일결합인 화합물이다.More preferred compounds of formula (I) are those wherein R ¹ and R ² are the same or different and are each hydrogen, halogen or C _1-4 alkyl, R ³ is aryl substituted with at least one halogen on an aryl or aromatic ring, n is 0, 1 or 2, and the bond between positions 4 and 4a

It is a compound which is a single bond.

For example, the compound represented by general formula (I) of this invention can be manufactured by the method described below.

Method (i)

The following general formula (III) is reacted with a hydrazine derivative, a hydrate thereof, or an acid addition salt thereof, followed by cyclization of the obtained compound of general formula (IV):

[In the above formulas, each symbol is the same as defined above.]

In a suitable solvent, the reaction is carried out by refluxing for 5 to 20 hours under heating in an alcoholic solvent such as methanol, ethanol or protanol to prepare the compounds represented by the above formulas (I) and (IV). do.

When the hydrazine derivative represented by the general formula (III) is used in the form of its acid addition salt, in the presence of an acid scavenger (e.g., sodium acetate, potassium acetate, sodium hydrogencarbonate, sodium carbonate or potassium carbonate) Carbonate), and the above reaction is carried out. The obtained compound represented by the general formula (IV) is refluxed for 5 to 10 hours under heating in acetic acid to obtain a compound represented by the general formula (I).

Method (ii)

A process for preparing a compound of the general formula (I) wherein n is 1 or 2 (ie, an oxide or a dioxide compound), characterized in that the mixture of the general formula (I) wherein n is 0 is oxidized.

The reaction is carried out by maintaining the reaction system for 1 to 10 hours at 10 to 100 ° C. in a suitable solvent in the presence of an oxidizing agent (eg peracetic acid, perbenzoic acid or m-chloroperbenzoic acid). If the reaction is continued for 1 to 5 hours at room temperature in the presence of hydroxy peroxide using acetic acid as a solvent, compound (I) having n is preferably prepared, whereas the reaction system is prepared at 30 to 100 ° C. If it is kept for 2-10 hours, compound (I) whose n is 2 is obtained.

Method

A process for preparing compound (I) wherein R ³ is C _1-4 alkyl, hydroxy-C _1-4 alkyl, C _2-5 alkanoyloxy-C _1-4 alkyl or aryl-C _1-4 alkyl. A compound of formula (I) wherein R ³ is hydrogen is reacted with a compound of formula (V):

R ⁴ -X (Ⅴ)

[ _Wherein R ⁴ is C _1-4 alkyl, hydroxy-C _1-4 alkyl, C _2-5 alkanoyloxy-C _1-4 alkyl or aryl-C _1-4 alkyl, and X is reactive Atom or group (e.g., halogen, such as chlorine or bromine, or methanesulfonyloxy, toluenesulfonyloxy or benzenesulfonyloxy).]

Acid scavengers (e.g. sodium hydride, sodium amide, sodium methoxide) in suitable solvents such as non-polar solvents (e.g. benzene, toluene or xylene), polar solvents (e.g. N, N-dimethylformamide or acetonitrile) The reaction is carried out at 0-50 ° C. for 1-10 hours in the presence of a seed, sodium ethoxide, potassium hydroxide or sodium hydroxide).

Method

Compounds represented by the general formula (I) wherein the bond between the 4 position and the 4a position are a double bond are described in J. Med, chem, vol. 14, p. Bromine is added dropwise to compound (I) wherein the bond is a single bond in isetic acid, as described in 262 (1971), or as described in British Patent No. 1,168,291, It can be prepared by reacting with nitrobenzenesulfonate (Bahaman method).

The reaction is preferably carried out by dropwise addition of 1 to 1.5 times the molar amount of bromine to the compound in acetic acid.

Method

Substituents R ¹ , R ² or R ³ of the compound obtained by the above methods (i) to (i) are characterized by being replaced with other substituents by a conventional method of organic chemical synthesis.

For example, the said method includes reaction which reduces a nitro group to an amino group; Reaction which acylates an amino group with lower alkanoic acid; There is a reaction that converts an amino group to a cyano group (eg Sandmeier reaction or Gartermann reaction).

Each isomer can be separated by the conventional method as follows. In summary, fractional crystallization of salts using optically active acids, or fractional recrystallization of salts using optically active acids, or column chromatography packed with optically active carriers, provides optical It can be classified as active isomers. Each diastereomer can be separated by methods such as fractionation or chromatography. In addition, the compounds described above can be obtained using optically active starting materials. In addition, the stereomer can be separated by a method such as recrystallization or column chromatography.

The compound of the general formula (II) of the present invention is a novel compound. For example, methyl iodide is added to the compound of the following general formula (VI) in isetone, and the mixture is maintained at room temperature for 2 to 5 hours to give a fourth order. An ammonium compound was prepared, and potassium cyanide or sodium cyanide was added in methanol or dimethyl formamide, followed by stirring at 40 to 50 ° C. for 4 to 8 hours to prepare a cyanide compound of the following general formula (IV). Concentrated hydrochloric acid is added, and the reaction mixture is stirred at 80 to 100 ° C. for 8 to 10 hours to obtain a compound of the following general formula (II ′):

[In the above formulas, each symbol is the same as defined above.]

For reference, representative compounds represented by the general formulas (VII) and (II ′) having the physical constants are as follows: Compound (VII): α- (6-chloro-2,3-dihydro-4- Oxo-4H-1-benzothiopyran-3-yl) -acetonitrile, melting point 148-150 ° C. α- (2,3-dihydro-6-methyl-4-oxo-4H-1-benzothiopyran-3 -Yl) -acetonitrile, melting point 114-116 ° C Compound (II '): α- (2,3-dihydro-4-oxo-4H-1-benzothiopyran-3-yl) -acetic acid, melting point 110- 113 ° C α- (6-chloro-2,3-dihydro-4-oxo-4H-1-benzothiopyran-3-yl) -acetic acid, melting point 167-169 ° C α- (2,3-dihydro- 6-Fluoro-4-oxo-4H-1-benzothiopyran-3-yl) -acetic acid, melting point 141-143 degreeC α- (2,3-dihydro-4-oxo-6-methyl-4H-1- Benzothiopyran-3-yl) -acetic acid, melting point 113-115 degreeC

The compound represented by the general formula (I) of the present invention has a high affinity of 10 ^-6 to 10 ^-8 M for the benzodiazepine receptor while antagonizing the chemical spasms inducing agent such as bicuculin or pentylenetetrazole. On the other hand, it is useful as an anti-anxiety agent because of its small effect on physical action such as muscle relaxation activity. The compounds are also useful as neutralizers for overdose and also to alleviate the footiness of anti-anxiety agents such as diazapam.

The pharmacological activity of the compounds of the invention is described below along with their experimental methods:

1) Substitution Capability for Benzodiazepines Receptors

Experiments with Particular Binding to Benzodiazepines Receptors.

The experiment is carried out by the following method (method described in the European Journal of Pharmacology. Vo. 51. p. 129 (1978) and Life Science, vol. 20, p. 1201 (1977)).

In summary, the crude synaptosomal fraction is isolated from the brain blood of a 9-10 week old Wistar male and suspended in 50 mM Tris-HCl buffer (pH 7.4) with 120 ml sodium chloride and 5 mM potassium chloride.

To the neuroconjugate suspension prepared above, test compounds of different concentrations and tritium diazepam (final concentration: 2 nM) are added, and the mixture is incubated at 0 ° C. for 20 minutes. The suspension is then filtered with a Whitman GF / Non-glass fiber filter. Thereafter, the filter is washed with the above buffer, and the reflectance remaining in the filter is measured by liquid scintillation spectroscopy.

Specific binding is calculated by subtracting the binding in the presence of unlabeled diazepam with ^10-6 M from the total binding.

By the above experimental method, the affinity of the compound of the present invention with respect to the benzodiazepine water-soluble body is evaluated as the ability to substitute tritium diazepam from the binding site and expressed as Ki value.

The results are summarized in Table 1 below.

TABLE 1

2) anti-bicuculin effect

Experiments on the antibicouculin effect are carried out by the following method (method described in Life Science, vol. 21, p. 1779 (1977)).

In summary, a group of 7-14 males (ddY-species) weighing 20-28 g are used. One hour after oral administration of the test compound, intravenous injection of (+) bicuculin (0.6 mg / kg) is observed, and the appearance of tonic spasm within 5 minutes is determined to determine the ED ₅₀ , 50% effective amount.

The results are summarized in Table 2 below.

TABLE 2

When the compound of the present invention is used as a drug, it can be administered in the form of tablets, capsules, sequestrants, syrups, injections, suppositories, powders, etc., in admixture with pharmaceutically acceptable excipients, carriers, diluents and the like. For example, in adults, the daily dose when administered orally is typically 5 mg to 500 mg in single or repeated doses.

The present invention is explained in more detail with reference to the following examples.

Example 1

10 g of α- (2,3-dihydro-4-oxo-4H-1-benzothiopyran-3-yl) -acetic acid and 12 g of 4-chlorophenylhydrazine hydrochloride were mixed with 5.5 g of sodium acetate in 200 ml of ethanol. It is refluxed for 10 hours under heating. Ethanol was distilled off and 200 ml of acetic acid was added to the residue, and the mixture was refluxed for 10 hours under heating. After distilling off acetic acid, the residue is extracted with chloroform. The extract is washed with water, dried over anhydrous sodium sulfate and the chloroform is distilled off under reduced pressure. Diisopropyl ether is added to the precipitation crystals. Crystals were collected by filtration and acetic acid was recrystallized, then 2- (4-chlorophenyl) -2,3,4,4a-tetrahydro-5H- (1) -benzothiopyrano [4,3-C] pyridazine 11.5 g of 3-one are obtained. Melting Point 146 ~ 147 ℃ Colorless Prism

Example 2

2 g of α- (2,3-dihydro-4-oxo-6-methyl-4H-1-benzothiopyran-3-yl) -acetic acid and 0.8 g of 100% hydrazine hydrate in 50 ml of ethanol were heated under heating. Reflux over time. After about half of the ethanol was distilled off under reduced pressure, the residue was cooled, filtered, and the precipitated crystals were collected and recrystallized with acetic acid to obtain 9-methyl-2,3,4,4a-tetrahydro-5H- (1) benzoti 1 g of opyrano [4,5, -C] pyridazin-3-one is obtained. Melting Point 217 ~ 219 ℃ Colorless Prism

Example 3

Mixed solution of 11.5 g of 2- (4-chlorophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridinzin-3-one in 200 ml of acetic acid 66 ml of 35% hydrogen peroxide were added dropwise while stirring at room temperature. After the addition is complete, the mixture is stirred at room temperature for 3 hours, poured into excess water and extracted with chloroform. The extract is washed with water, dried over anhydrous sodium sulfate and the chloroform is distilled off under reduced pressure. Diisopropyl ether is added to the precipitation crystals. The crystals were collected by filtration and recrystallized with isopropyl alcohol to give 2- (4-chlorophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3, -C] pyridine. 7.7 g of dizin-3-one 6-oxide are obtained. Melting point 181 ~ 183 ℃ Colorless needle crystal

Example 4

2- (4-chlorophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3, -C] pyridin-3-one 6 prepared in Example 3 -Oxide (7.0 g) was separated and purified by silica gel column chromatography using a mixture of hexane and ethyl acetate (3: 1). Crystallization of the crystals obtained from the first fraction of the eluate with isopropyl alcohol gave (4aR *, 6S *)-2- (4-chlorophenyl) -2,3,4,4a-tetrahydro-5H (1). 0.6 g of benzothiopyrano [4,3, -C] pyridazin-3-one 6-oxide is obtained. Melting point 210-213 ° C. Also, when the crystal obtained from the second fraction of the eluent is recrystallized from isopropyl alcohol, (4aR *, 6S *)-2- (4-chlorophenyl) -2,3,4,4a-tetrahydro 5.0 g of -5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one 6-oxide is obtained. Melting Point 190 ~ 192 ℃

Example 5

150 ml of acetic acid in 4.7 g of 2- (4-chlorophenyl) -2,3,4,4a-tetrahydro-5H (1) benzothiopyrano [4,3-C] pyridazin-3-one 6-oxide To 55 ml of 35% hydrogen peroxide was added dropwise while stirring at room temperature. After the addition was completed, the mixture was stirred for 4 hours in a water bath at 40 to 50 ° C. and poured into water. The precipitated crystals were collected by filtration and recrystallized with 50% acetic acid aqueous solution to give 2- (4-chlorophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,5,- 2.9 g of C] pyridazin-3-one 6,6-dioxide are obtained. Melting point 168 ~ 170 ℃ Colorless powder

Example 6

60% while stirring in a mixed solution of 2 g of α- (2,3-dihydro-6-fluoro-4-oxo-4H-1-benzothiopyran-3-yl) acetic acid dissolved in 20 ml of N, N-dimethylformamide 0.4 g of sodium hydride is added. After the mixed solution is stirred for 1 hour on a 40-50 ° C. water bath, the mixed solution is cooled to room temperature, and 2.4 g of methyl iodide is added to the mixed solution. The mixture is stirred for 3 hours on a water bath at about 30 DEG C, distilled under reduced pressure, and the residue is extracted with chloroform. The extract is washed with water and dried over magnesium sulfate anhydride. Chloroform is distilled off under reduced pressure and diisopropyl ether is added to the precipitated crystals. The crystals were collected by filtration and recrystallized from ethanol to give 9-fluoro-2-methyl-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazine-. 1 g of 3-one is obtained. Melting Point 125 ~ 128 ℃ Colorless Prism

Example 7

30 ml of acetic acid in 1.7 g of 2- (4 chlorophenyl) -9-methyl-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one 1.2 g of bromine is added dropwise to the mixed solution dissolved in the solution while stirring in a water bath at 40 to 50 ° C. After the addition is finished, the mixture is stirred at 50 ° C. for 3 hours and poured into excess water. The precipitated crystals were collected by filtration and recrystallized with acetic acid to give 2- (4-chlorophenyl) -9-methyl-2,3-dihydro-5H- (1) benzothiopyrano- [4,3, -C]. 0.5 g of pyridazin-3-one is obtained. Melting Point 200 ~ 206 ℃ Yellow Powder

The following compounds can be prepared in a similar manner to the above examples.

Example 8

2-phenyl-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano- [4,3-C] pyridazin-3-one melting point 103-106 ° C

Example 9

2- (4-methylphenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 116 ° C to 165 ° C

Example 10

2- (4-methoxyphenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 163 to 118 ° C

Example 11

2- (3,4-dichlorophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 135-136 ° C

Example 12

2- (3,4-Dichlorophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one 6-oxide melting point 184 ~ 187 ℃

Example 13

2- (4-bromophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 167-169 ° C.

Example 14

9-chloro-2- (4-fluorophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 130 to 131 ℃

Example 15

9-chloro-2- (4-chlorophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 134-136 ℃

Example 16

9-chloro-2- (4-fluorophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one 6-jade Seed melting point 241 ~ 243 ℃ (decomposition)

Example 17

9-chloro-2- (4-chlorophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one 6-oxide Melting Point 209 ~ 211 ℃

Example 18

2- (4-chlorophenyl) -9-fluoro-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 253 to 256 ℃

Example 19

2- (4-chlorophenyl) -9-fluoro-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one 6-jade Seed melting point 188 ~ 191 ℃

Example 20

9-fluoro-2- (3-trifluoromethylphenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 192 ~ 194 ℃

Example 21

9-fluoro-2- (4-nitrophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 188 to 190 ℃

Example 22

2- (4-methoxyphenyl) -9-methyl-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 146 to 148 ℃

Example 23

2- (4-chlorophenyl) -9-methyl-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one 6-oxide Melting Point 186 ~ 189 ℃

Example 24

2- (4-chlorophenyl) -9-methyl-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 169 to 171 ℃

Example 25

2- (4-chlorophenyl) -9-methyl-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one 6,6- Dioxide melting point 164 ~ 167 ℃

Example 26

9-chloro-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 211-212 ° C

Example 27

2- (2-acetoxyethyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 82-86 ° C.

Example 28

9-fluoro-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 226 ° C to 228 ° C

Example 29

2- (4-bromophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one 6-oxide melting point 204 to 206 ℃

Example 30

2- (3,4-dichlorophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one 6,6-dioxide Melting Point 165 ~ 166 ℃

Example 31

2- (4-trifluoromethylphenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 124 to 127 ° C

Example 32

2- (4-hydroxyphenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 239 to 240 ° C

Example 33

2- (2-pyridyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 125 ° C to 129 ° C

Example 34

2- (4-chlorophenyl) -2,3-dihydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one 6-oxide melting point 195 to 196 ° C

Example 35

2- (4-chlorophenyl) -9-methoxy-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 143 to 144 ℃

Example 36

2- (4-chlorophenyl) -9-hydroxy-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 214 to 215 ℃

Example 37

2- (4-chlorophenyl) -2,3-dihydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 183 to 185 ° C

Example 38

2- (4-methoxyphenyl) -9-methoxy-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 124 ~ 126 ℃

Example 39

9-fluoro-2- (3-trifluoromethylphenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one 6 , 6-dioxide melting point 150 ~ 153 ℃

Example 40

2- (3-chlorophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 136 ° C to 138 ° C

Example 41

2- (3-chlorophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one 6,6-dioxide melting point 175 ~ 177 ℃

Example 42

2- (4-chlorophenyl) -7-chloro-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 195 to 196 ℃

Example 43

9-fluoro-2- (3-trifluoromethylphenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one 6 -Oxide melting point 170 ~ 173 ℃

Example 44

2- (2-chlorophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 165 to 167 ° C

Example 45

9-methoxy-2- (3-trifluoromethylphenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 149 ~ 151 ℃

Example 46

9-hydroxy-2- (3-trifluoromethylphenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 222 ~ 233 ℃

Example 47

9-fluoro-2- (4-methoxyphenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 123 ~ 125 ℃

Example 48

9-Fluoro-2- (4-hydroxyphenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one melting point 261 ~ 262 ℃

Example 49

2- (4-trifluoromethylphenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one 6-oxide

Example 50

2- (4-fluorophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one

Example 51

2- (4-fluorophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one 6-oxide

Example 52

2- (4-aminophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one

Example 53

2- (4-acetylaminophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one

Example 54

2- (4-propionylamidophenyl) -2,3-dihydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one

Example 55

2- (4-trifluoromethylphenyl) -9-methoxy-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one

Example 56

2- (4-chlorophenyl) -9-nitro-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one

Example 57

9-acetylamido-2- (4-chlorophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one

Example 58

2-phenyl-8-trifluoromethyl-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one

Example 59

8,9-diphenyl-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one

Example 60

2-butyl-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one

Example 61

2- (3-hydroxypropyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one

Example 62

9-amino-phenyl-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one

Example 63

2- (4-chlorophenyl) -2,3-dihydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one 6,6-dioxide

Example 64

2-benzyl-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one

Example 65

2- (3-phenylpropyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one

Example 66

2-octyl-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one

Example 67

2- (4-chlorophenyl) -9-cyano-2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one

Example 68

2- (4-cyanophenyl) -2,3,4,4a-tetrahydro-5H- (1) benzothiopyrano [4,3-C] pyridazin-3-one

In the foregoing specification and the embodiments included therein, although the invention has been suitably described, it should be recognized that various changes and modifications to the invention do not depart from the spirit and scope of the invention.

Claims (5)

Characterized by reacting a compound of the general formula (II) with a hydrazine derivative of the general formula (III), a hydrate thereof or an acid addition salt thereof, and then subjecting the obtained compound of the general formula (IV) to a ring closure reaction, A method for producing a benzothiopyrano [4,3-c] pyridazine compound represented by the following general formula (I).

[Wherein R ¹ and R ² are the same or different and each is hydrogen, halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C _1-4 alkyl, C _1-4 alkoxy or C _2-5 Alkanoylamido, R ³ is hydrogen, C _1-8 alkyl, hydroxy-C _1-4 alkyl, C _2-5 alkanoyloxy-C | _1-4 alkyl, pyridyl, aryl, aryl-C _1-4 alkyl, or halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C _1-4 alkyl, C _1-4 on an aromatic ring Aryl or aryl-C _1-4 aryl substituted with at least one substituent selected from the group consisting of alkoxy and C _2-5 alkanoylamido, n is 0,1 or 2, and a bond between positions 4 and 4a

Is a single bond or a double bond] of benzothiopyrano [4,3-C] pyridazine compounds represented by the following general formula (I) wherein n is 1 or 2, characterized in that the compound of general formula (I) Manufacturing method.

[Wherein R1 and R2 are the same or different and each is hydrogen, halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C _1-4 alkyl, C _1-4 alkoxy or C _2-5 alkanoyl Amido, R 3 is hydrogen, C _{1 -S} alkyl, hydroxy-C _1-4 alkyl, C _2-5 alkanoyloxy-C | _1-4 alkyl, pyridyl, aryl, aryl-C _1-4 alkyl, or halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C _1-4 alkyl, C _1-4 on an aromatic ring Aryl or aryl-C _1-4 alkyl substituted with at least one substituent selected from the group consisting of alkoxy and C _2-5 alkanoylamido, n is 0, 1 or 2, and a bond between positions 4 and 4a

Is a single bond or a double bond.] R ³ is hydrogen to a compound of formula (Ⅰ), characterized by Sikkim compound and reaction of formula (Ⅴ), R ³ is C _1-4 alkyl, hydroxy -C _1-4 alkyl, C _{2 -5} alkanoyloxy-C | _A method for producing a benzothiopyrano [4,3-C] pyridazine compound represented by compound (I), which is _1-4 alkyl or aryl-C _1-4 alkyl.

R ⁴ -X (V) [Wherein R ¹ and R ² are the same or different and each is hydrogen, halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C _1-4 alkyl, C _1-4 alkoxy or C _2-5 Alkanoylamido, R ³ is hydrogen, C _1-4 alkyl, hydroxy-C _1-4 alkyl, C _2-5 alkanoyloxy-C _1-4 alkyl, or aryl-C _1-4 alkyl and R ⁴ is C _1-4 alkyl, hydroxy-C _1-4 alkyl, C _2-5 alkanoyloxy-C _1-4 alkyl, or aryl-C _1-4 alkyl, and X is a reactive atom or group, n is 0, 1 or 2, and the bond between positions 4 and 4a

Is a single bond or a double bond.] Bromine is added dropwise to the mixture of the following formula (I) wherein the bond between the 4-position and the 4-a position is a single bond, and the benzothiopyrano represented by the following general formula (I) 4,3-c] method of preparing a pyridazine compound.

[Wherein R ¹ and R ² are the same or different and each is hydrogen, halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C _1-4 alkyl, C _1-4 alkoxy or C _2-5 Alkanoylamido, R ³ is hydrogen, C _1-8 alkyl, hydroxy-C _1-4 alkyl, C _2-5 alkanoyloxy-C _1-4 alkyl, pyridyl, aryl, aryl-C _{1- At least 4} alkyl, or at least one selected from the group consisting of halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C _1-4 alkyl, C _1-4 alkoxy and C _2-5 alkanoylamido on an aromatic ring Aryl or aryl-C _1-4 alkyl substituted with one substituent, n is 0,1 or 2, and a bond between positions 4 and 4a

Is a single bond or a double bond.] The compound represented by the following general formula (I), wherein the bond is a double bond, characterized by reacting a compound of formula (I), wherein the bond between the 4-position and the 4-a position is a single bond, with sodium m-nitrobenzenesulfonate Process for the preparation of a benzothiopyrano [4,3-c] pyridazine compound.

[Wherein R ¹ and R ² are the same or different and each is hydrogen, halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C _1-4 alkyl, C _1-4 alkoxy or C _2-5 Alkanoylamido, R ³ is hydrogen, C _1-8 alkyl, hydroxy-C _1-4 alkyl, C _2-5 alkanoyloxy-C _1-4 alkyl, pyridyl, aryl, aryl-C _{1- At least 4} alkyl, or at least one selected from the group consisting of halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C _1-4 alkyl, C _1-4 alkoxy and C _2-5 alkanoylamido on an aromatic ring Aryl or aryl-C _1-4 alkyl substituted with one substituent, n is 0,1 or 2, a bond between positions 4 and 4a

Is a single bond or a double bond.]