KR920001136B1 - Process for the preparation of oxadiazine compounds - Google Patents

Abstract

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Description

Method for preparing oxadiazine compound

The present invention relates to a process for the preparation of an oxadiazine compound or a pharmaceutically acceptable acid addition salt thereof.

Oxadiazine compounds of the invention are represented by the general formula:

Wherein R ¹ and R ² are each hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy _, C _1-4 alkoxy-C _1-4 alkoxy, phenylnuclear halogen, C _1-4 alkyl and C ₁ -C _{1-4 alkoxyphenyl-1,} which may be optionally substituted with one or more substituents selected from the group consisting of _{1-4-alkyl-oxy,} or the phenyl nucleus is halogen, C _{1 - 4} alkyl and C _{1 to 4} selected from the consisting of alkoxy crowd Phenyl, which may be optionally substituted with one or more substituents; X is -S-, -CH = N- or -C (R ³ ) = C (R ⁴ )-, wherein R ³ and R ⁴ are each hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _{1 ~ 4} alkoxy -C _{1 ~ 4} alkoxy or phenyl nucleus is halogen, C _{1 ~ 4} alkyl and C _{1 ~ 4} alkoxy phenyl which may be optionally substituted with one or more substituents selected from the group consisting of -C _{1 ~ 4} alkyl-oxy.

Halogen herein is chlorine, bromine, fluorine and iodine; C _1-4 alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl; C _1-4 alkoxy is methoxy, ethoxy, propoxy, isopropoxy, butoxy or t-butoxy; C _1-4 alkoxy-C _1-4 alkoxy is methoxymethoxy, ethoxymethoxy, propoxymethoxy, butoxymethoxy, methoxyethoxy, butoxyethoxy, methoxypropoxy, ethoxypropoxy Epoxy, propoxypropoxy, butoxypropoxy, methoxybutoxy, ethoxybutoxy, propoxybutoxy or butoxybutoxy; Phenyl-C _1-4 alkyl-oxy, wherein the phenyl nucleus may be optionally substituted with one or more substituents selected from the group consisting of halogen, C _1-4 alkyl and C _1-4 alkoxy, is benzyloxy, phenylethoxy, phenylprop Foxy, phenylbutoxy, chlorobenzyloxy, bromobenzyloxy, methylbenzyloxy, ethylbenzyloxy, propylbenyloxy, butylbenzyloxy, methoxybenzyloxy, ethoxybenzyloxy, propoxybenzyloxy, butoxybenzyloxy , Dichlorobenzyloxy, dimethylbenzyloxy, trimethoxybenzyloxy, chlorophenylethoxy, bromophenylethoxy, methylphenylethoxy, ethylphenylethoxy, propylphenylethoxy, butylphenylethoxy, methoxyphenylethoxy , Ethoxyphenylethoxy, propoxyphenylethoxy, butoxyphenylethoxy, dichlorophenylethoxy, dimethylphenylethoxy, trimethoxyphenylethoxy, chlorophenylpropoxy, methylphenylpropoxy, chlorophenylbutoxy or Methylphenylbutox .; And phenyl, wherein the phenyl nucleus may be optionally substituted with one or more substituents selected from the group consisting of halogen, C _1-4 alkyl and C _1-4 alkoxy, is phenyl, chlorophenyl, bromophenyl, fluorophenyl, methylphenyl, ethyl Phenyl, propylphenyl, butylphenyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, butoxyphenyl, dichlorophenyl, dimethylphenyl or trimethoxyphenyl.

The compound of general formula (I) can be prepared by subjecting the compound of general formula (II) to ring-closure reaction.

In formula, Q <^3> is halogen and others are the same as the above definition.

The reaction is carried out in the presence of alkali hydroxides such as sodium or potassium hydroxide, alkali carbonates such as sodium or potassium carbonate, alkali hydrogen carbonates such as sodium bicarbonate or potassium hydrogen carbonate or sodium hydride in the presence of methanol, ethanol, acetone, methyl ethyl ketone, methyl It is usually carried out in a suitable solvent such as isobutyl ketone, dimethylformamide or dimethyl sulfoxide at room temperature to the boiling point of the solvent used for several hours to several ten hours.

Starting compounds of the general formula (II) may be prepared by reacting a compound of the general formula (III) with a compound of the general formula (IV).

Wherein Q ³ and Q ⁴ are each halogen and others are the same as the above definitions.

The compounds of general formula (I) thus obtained are treated by conventional methods of treating with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid or phosphoric acid or organic acids such as malonic acid, citric acid, tartaric acid, fumaric acid, succinic acid, maleic acid or methanesulfonic acid. It can be converted into a pharmaceutically acceptable acid addition salt thereof.

The superior efficacy of the compounds of the invention is illustrated in the following pharmaceutical experiments.

1. Effect on platelet aggregation in vitro

Blood samples from rats weighing 400-450 g are mixed with 1/10 volume of 3.8% sodium citrate solution. Citric acid treated blood is centrifuged at 200 x g for 10 minutes to obtain platelet-rich plasma. The test compound is added to the platelet-rich plasma thus obtained and left at 37 ° C. for 2 minutes. Platelet aggregation is induced by addition of 10 ⁻⁵ M adenosine diphosphate (final concentration) and measured with a Born type 6channel aggergometer (Journal of physiology, vol. 162, p67, 1962.).

Calculate 50% inhibitory concentration (IC ₅₀ , μg / ml) for the control. The results are summarized in Table 1. Aspirin and ticlopidine were used as comparative compounds.

[result]

TABLE 1

2. Effects on Platelet Aggregation in Vitro

[Way]

Test compounds are orally administered to mice weighing 400-450 g. After 2 hours, a blood sample is taken from the rat and mixed with 1/10 volume of 3.8% sodium citrate solution. Citric acid treated blood is centrifuged at 200 x g for 10 minutes to obtain platelet-rich plasma. ^10-5 M adenosine diphosphate (final concentration) is added to induce platelet aggregation and measured with the same aggregation meter as described in the above method.

The percentage of inhibition for the control group administered with the solvent is calculated. The results are summarized in Table 2.

[result]

The present invention examines five male mice for acute toxicity to the compound. Five days after oral administration of the compound, mice are observed and mortality is assessed. All animals survive upon 100 mg / kg administration of the compounds of Examples 1,2 and 3.

The results of various pharmaceutical experiments, including the above-mentioned experiments, demonstrate that the compounds of the present invention or their pharmaceutically acceptable acid addition salts exhibit potent hull platelet aggregation, blood flow and vibration and anti-inflammatory activity. Therefore, these compounds are useful as active substances or components of antithrombosis, antianginal, coronary artery circulatory, brain circulatory, peripheral circulatory, analgesic and anti-inflammatory.

The compounds of the present invention may be orally or parenterally to a human, eg, intravenously, intraperitoneally or subcutaneously, in the form of pharmaceutical compositions such as tablets, sugar-coated tablets, powders, granules, pills, syrups, injectable solutions or suppositories. Can be safely administered.

Pharmaceutical compositions can be prepared, for example, by mixing a therapeutically effective amount of a compound of the invention with conventional, pharmaceutically acceptable additives such as excipients, diluents or extenders. The choice of such additives is determined by the preferred dosage form, the solubility of the compound and the standard pharmaceutical practice.

The dosage may vary depending on the disease to be treated or the condition of the patient, but the daily dosage for adults is preferably 10-1000 mg, divided once to several times.

Pharmaceutical preparations: 100 mg of active ingredient-containing film-coated tablets

(a) composition of tablets

100.0 mg of the compound of Example 1

Lactose 30.0mg

10.0mg cornstarch

Polyvinyl Pyrrolidone 3.0mg

Microcrystalline Cellulose 12.0mg

Talc 4.0mg

1.0 mg magnesium stearate

(b) Composition of Film Coating

Hydroxypropylmethyl cellulose 8.5mg

Polyethylene Glycol 6000 0.5mg

Talc 1.0mg

A mixture of the compound of Example 1, lactose and cornstarch, which is an active ingredient, is kneaded with an aqueous polyvinyl pyrrolidone solution, granulated with 16 meshes, and dried at 50 ° C. to obtain granules having a moisture content of 3 to 4%. . The dried granules are filtered through 24 meshes and mixed with microcrystalline cellulose, talc and magnesium stearate. The mixture is compressed with a punch of 7.5 mm in diameter to give tablets weighing 160 mg each. The tablets thus obtained are film-coated with hydroxypropylmethyl cellulose, polyethyleneglycol 6000 and talc to give film-coated tablets each weighing 170 mg.

The present invention is described in more detail with reference to the following examples. However, the present invention is not limited by the following examples.

Example 1

A mixture of 5 g of N'-chloroacetyl-2-methylimidazole 1,2-a pyridine-3-carbohydrazide and 5 g of potassium carbonate in 50 ml of dimethylformaldehyde was heated to 70-80 ° C. for 2 hours. Stir while. After filtering the insolubles, the filtrate is concentrated under reduced pressure and water is added to the resulting residue. The insoluble material was collected by filtration, washed with water, and then recrystallized with methanol to give 2- (2-methylimidazo (1,2-a) pyridin-3-yl) -4 as a white crystal which was melt-decomposed at 278 to 280 ° C. 1.2 g of, 6-dihydro-1,3,4-oxadiazine-5-one are obtained.

Example 2

A mixture of 6 g of N'-chloroacetyl-2,8-dimethylamidazo (1,2-a) pyridine-3-carbohydrazide and 10 g of potassium carbonate in 50 ml of dimethylformamide was heated to 70-90 ° C. And stir for 1.5 hours. After cooling the reaction mixture, the insoluble material was collected by filtration, washed with water, recrystallized with a mixture of chloroform and methanol, and then melted and decomposed at a temperature of 310 to 313 ° C., 2- (2,8-dimethylamidazo (1,2-). a) pyridin-3-yl) -4,6-dihydro-1,3,4-oxadiazine-5-one is obtained.

Example 3

A mixture of 21 g N'-chloroacetyl-2,6-dimethylamide crude (1,2-a) pyridine-3-carbohydrazide and 30 g potassium carbonate in 200 ml of methyl ethyl ketone and 100 ml of dimethylformamide Reflux and stir for 5 hours. The insolubles are filtered off, the solvent is distilled off, and water is added to the fished residue. The precipitated crystals were collected by filtration, recrystallized with methanol, and 2- (2,6-dimethylimidazo (1,2-a) pyridin-3-yl) -4,6-di of white crystals which was melt-decomposed at 313 占 폚. 3 g of hydro-1,3,4-oxadiazine-5-one are obtained.

[Production example of starting compound]

8 g of 50 g of chloroform at 5-10 ° C. in a mixture of 14.8 g of 2,6-dimethylimidazo 1,2-a pyridine-3-carbohydrazide and 7.36 g of triethylamine in 300 ml of cooled chloroform Chloroacetyl chloride solution is added dropwise under stirring. After the mixture is stirred for 30 minutes, the reaction temperature is raised to room temperature and the resulting mixture is further stirred for 30 minutes. N'-chloroacetyl-2,6-dimethylimidazo (1,2-a) pyridine-3-carbohydrazide was added to the reaction mixture and the precipitated crystals were collected by filtration and melted and decomposed at 290 to 291 ° C. 21 g is obtained.

Example 4

A mixture of 16 g of N'-chloroacetyl-6-methylimidazo [2,1-b] thiazole-5-carbohydrazide and 14 g of potassium carbonate in 160 ml of dimethylformamide was heated to 50-60 ° C. Heat and stir for 4 hours. After filtering the insoluble substance, dimethylformamide is distilled off and ethanol is added to the residual oil. The precipitated crystals were collected by filtration, recrystallized with methanol, and 2- (6-methylimidazo [2,1-b] thiazol-5-yl) -4,6- of pale yellow crystals which were melt-decomposed at 274-275 ° C. 5.2 g of dihydro-1,3,4-oxadiazine-5-one are obtained.

The following compounds can be prepared by methods similar to the above.

(5) 2- (2,7-dimethylimidazo [1,2-a] pyridin-3-yl) -4,6-dihydro-1,3,4-oxadiazine-5-one hydrochloride, Melt decomposition at 260 to 262 ° C.

(6) 2- (6-bromo-2-methylimidazo [2,1-a] pyridin-3-yl) -4,6-dihydro-1,3,4-oxadiazine-5- Hydrochloride, melt decomposition at 283-285 ° C.

(7) 2- (3-methyl-6-phenylimidazo [2,1-b] thiazol-5-yl) -4,6-dihydro-1,3,4-oxadiazine-5- Melt decomposition at 308 to 310 ° C.

(8) 2- (3-phenylimidazo [2,1-b] thiazol-2-yl) -4,6-dihydro-1,3,4-oxadiazine-5-one, 214- Melt decomposition at 217 ° C.

(9) 2- (2-phenylimidazo [1,2-a] pyridin-3-yl) -4,6-dihydro-1,3,4-oxadiazine-5-one, 227-231 Melt decomposition at ℃.

(10) Melt at 2- (imidazo [2,1-b] thiazol-3-yl) -4,6-dihydro-1,3,4-oxadiazine-5-one at 287 to 288 ° C. decomposition.

(11) 2- (3-methylimidazo [2,1-b] thiazol-2-yl) -4,6-dihydro-1,3,4-oxadiazine-5-one, 256- Melt decomposition at 257 ° C.

(12) melt decomposition at 2-79-imidazo [1,2-a] pyridin-6-yl) -4,6-dihydro-1,3,4-oxadiazine-5-one at 279-281 ° C. .

(13) 2- (imidazo [1,2-a] pyridin-8-yl) -4,6-dihydro-1,3,4-oxadiazine-5-one hydrochloride, melt decomposition at 340 ° C.

(14) 2- (8-benzyloxy-2-methylimidazo [1,2-a] pyridin-3-yl) -4,6-dihydro-1, 3,4-oxadiazine-5- On, melt at 245 to 247 ° C.

(15) 2- (8-methoxy-2-methylimidazo [1,2-a] pyridin-3-yl) -4,6-dihydro-1,3,4-oxadiazine-5- On, melt at 229 to 230 ° C.

(16) 2- (8-ethoxymethoxy-2-methylimidazo [1,2-a] pyridin-3-yl) -4,6-dihydro-1,3,4-oxadiazine- 5-on, melt at 163-164 ° C.

(17) 2- (2,5-dimethylimidazo [1,2-a] pyridin-3-yl) 4,6-dihydro-1,3,4-oxadiazine-5-one, 234- Melt at 236 ° C.

(18) 2- (6-chloro-2-methylimidazo [1,2-a] pyridin-3-yl) 4,6-dihydro-1,3,4-oxadiazine-5-one, Melting at 312-315 ° C.

(19) 2- (8-bromo-2-methylimidazo [1,2-a] pyridin-3-yl) 4,6-dihydro-1,3,4-oxadiazine-5-one .

(20) 2- (8- (4-chlorobenzyloxy) -2-methylimidazo [1,2-a] pyridin-3-yl) 4,6-dihydro-1,3,4-oxadia Gen-5-on.

(21) 2- (8-ethyl-2-methylimidazo [1,2-a] pyridin-3-yl) -4,6-dihydro-1,3,4-oxadiazine-5-one .

(22) 2- (8-isopropyl-2-methylamidazo [1,2-a] pyridin-3-yl) 4,6-dihydro-1,3,4-oxadiazin-5-one.

(23) 2- (8- (4-methylbenzyloxy) -2-methylimidazo [1,2-a] pyridin-3-yl) -4,6-dihydro-1,3,4-oxa Diazin-5-one.

(24) 2- (8- (4-methoxybenzyloxy) -2-methylamidazo [1,2-a] pyridin-3-yl) -4,6-dihydro-1,3,4-oxa Diazin-5-one.

(25) 2- (2- (4-chlorophenyl) imidazo [1,2-a] pyridin-3-yl) -4,6-dihydro-1,3,4-oxadiazine-5-one .

(26) 2- (2- (4-methoxyphenyl) imidazo [1,2-a] pyridin-3-yl) -4,6-dihydro-1,3,4-oxadiazine-5- On.

(27) 2- (2- (4-methoxyphenyl) imidazo [1,2-a] pyridin-3-yl) -4,6-dihydro-1,3,4-oxadiazine-5 -On.

Although the present invention has been sufficiently described in the above specification and examples, it can be readily appreciated that various changes and modifications can be made without departing from the spirit thereof.

Claims (1)

A process for producing an oxadiazine compound represented by the following general formula (I) or a pharmaceutically acceptable acid addition salt thereof, characterized by ring closing reaction of a compound of the following general formula (II).

Wherein R ¹ and R ² are each hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy-C _1-4 alkoxy, phenyl nucleus is halogen, C _1-4 alkyl and C ₁ -C _{1-4 alkoxyphenyl-1,} which may be optionally substituted with one or more substituents selected from the group consisting of _{1-4-alkyl-oxy,} or the phenyl nucleus is halogen, C _{1 - 4} alkyl and C _{1 to 4} selected from the consisting of alkoxy crowd Phenyl which may be substituted with one or more substituents; X is -S-, -CH = N- or -C (R ³ ) = C (R ⁴ )-, wherein R ³ and R ⁴ are each hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _{1 ~ 4} alkoxy -C _{1 ~ 4} alkoxy or phenyl nucleus is halogen, C _{1 ~ 4} alkyl and C _{1 ~ 4} alkoxy phenyl which may be optionally substituted with one or more substituents selected from the group consisting of -C _{1 ~ 4} alkyl-oxy and Q ³ is halogen.