KR850001351B1 - Process for preparing benzoxazole - Google Patents

Abstract

Benzoxazoles and their derivatives I [R1 = C1-6 alkyl, optionally substituted hydroxy, mercapto; R4 = H, methyl; R5 = methyl; X = O, S were prepared. Thus, N-cyclohexyl-N'-[2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)-pyridazinone-6-yl)-phenyl thio urea was cyclized with dicyclohexylcarbodiimide to give 51.9% 5-methyl6-[2'-cyclohexylamino-benzoxazole-5'-yl -4,5-dihydro3(2H)-pyridazinone, which at 0.1 mg/kg i.v. reduced blood pressure in cats 32 mm initially and after 45 min and increased cardiac concentration.

Description

[Name of invention]

Method for preparing benz oxazole

Detailed description of the invention

The present invention relates to the addition of benz oxazole and benzothiazole of general formula (I), their optically active colon and their physiologically poisonous addition salts with organic or inorganic acids or bases, which are effective for the treatment of cardiovascular diseases. It relates to a manufacturing method.

의 그룹(여기서, R₂는 수소원자, 탄소수 1내지 3의 알콕시 그룹에 의해 치환될 수 있는 탄소수 1내지 7의 직쇄 또는 측쇄알킬 그룹 ; 탄소수 3내지 7의 사이클로알킬그룹 ; 탄소수 1내지 3의 알콕시그룹 1 또는 2개에 의해 치환될 수 있는 페닐그룹으로 치환된 탄소수 1내지 3의 알킬그룹 ; 탄소수 1내지 3의 알킬 또는 알콕시그룹, 트리플루오로메틸, 니트로 또는 시아노그룹, 불소, 염소 또는 브롬원자에 의해 치환될 수 있는 페닐그룹, 이 전술한 일-치환된 페닐그룹중의 하나는 추가로 탄소수 1내지 3의 알킬 그룹 하나 또는 두개,탄소수 1내지 3의 알콕시그룹 또는 불소,염소 또는 브롬원자에 의해 치환될 수 있고 ; 또는 총 탄소수 2내지 4의 알콕시카르보닐그룹을 나타내며,In the general formula, R ₁ is a hydroxy or mercapto group optionally substituted by an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 3 to 6 carbon atoms; Phenylalkyl having 1 to 3 carbon atoms in the alkyl moiety and phenyl nucleus may be mono-, di- or trisubstituted with substituents which may be the same or different from each other selected from alkoxy groups, halogen atoms and / or amino groups of 1 to 3 carbon atoms. Hydroxy or mercapto groups substituted with groups; An alkyl group of 1 to 3 carbon atoms optionally substituted by a phenyl group; A phenyl group optionally substituted by a methoxy or cyano group or a halogen atom, or a formula

Wherein R ₂ is a hydrogen atom, a straight or branched chain alkyl group having 1 to 7 carbon atoms which may be substituted by an alkoxy group having 1 to 3 carbon atoms; a cycloalkyl group having 3 to 7 carbon atoms; alkoxy having 1 to 3 carbon atoms An alkyl group of 1 to 3 carbon atoms substituted by a phenyl group which may be substituted by groups 1 or 2; an alkyl or alkoxy group of 1 to 3 carbon atoms, trifluoromethyl, nitro or cyano group, fluorine, chlorine or bromine A phenyl group which may be substituted by an atom, one of the foregoing mono-substituted phenyl groups may further comprise one or two alkyl groups of 1 to 3 carbon atoms, alkoxy groups of 1 to 3 carbon atoms or fluorine, chlorine or bromine atoms Or an alkoxycarbonyl group having 2 to 4 carbon atoms,

R ₃ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms),

R ₄ and R ₅ are groups that may be the same or different from each other,

A hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and X represents an oxygen or sulfur atom.

In addition, in the compound of formula (I) according to the present invention,

R ₁ is for example hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, neopentoxy, hexoxy, allyloxy, crotyloxy, Pentenyloxy, hexenyloxy, benzyloxy, methoxy-benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 3-phenylpropoxy, mercapto, methyl mercapto, ethyl mercapto, propyl-mercapto , Isopropyl mercapto, butyl mercapto, isobutyl mercapto, tertiary butyl mercapto, pentyl mercapto, neopentyl mercapto, tertiary pentyl mercapto, hexyl mercapto, allyl mercapto, crotyl mercapto, pen Tenyl mercapto, hexenyl mercapto, benzyl mercapto, methoxybenzyl mercapto, chlorobenzyl mercapto, bromobenzyl mercapto, dimethoxybenzyl mercapto, 1-phenylethyl mercapto, 2-phenylethyl mercapto, 2- (methoxyphenyl) -ethylmercapto, 2- (dimethoxyphenyl) -ethylmercapto, 2- (chlorophenyl)- Tilmercapto, 2- (chloro-methoxyphenyl) -ethylmercapto, 2- (amino-dichloropetyl) -ethylmercapto, 3-phenylpropylmercapto, methyl, ethyl, propyl, isopropyl, benzyl, 1 -Phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, phenyl, methoxyphenyl, cyanophenyl, chlorophenyl, bromophenyl, fluorophenyl, amino, methylamino, Ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino, isopentylamino, neopentylamino, tert-pentylamino, hexylamino, heptylamino, dimethylamino, di Ethylamino, diisopropylamino, methyl-ethylamino, methyl-propylamino, ethyl-isopropylamino, methyl-butylamino, ethyl-pentylamino, methyl-heptylamino, methoxyethylamino, methoxypropylamino, meth Methoxybutylamino, methoxypentylamino, methoxy Heptylamino, ethoxyethylamino, propoxypropylamino, N-methylethoxyethylamino, N-ethylmethoxypropylamino, cyclopropylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, N-methyl-cyclo Hexylamino, N-ethyl-cyclohexylamino, N-propyl-cyclohexylamino, phenylamino, methylphenylamino, dimethylphenylamino, trimethylphenylamino, ethylphenylamino, propylphenylamino, isopropylphenylamino, methoxyphenylamino , Dimethoxyphenylamino, isopropoxyphenylamino, fluorophenylamino, difluoro-phenylamino, chlorophenylamino, dichlorophenylamino, bromophenylamino, dibromophenylamino, trifluoromethyl-phenylamino , Nitrophenylamino, cyanophenylamino, methylfluorophenylamino, methylchlorophenylamino, methoxychloro Phenylamino, methoxybromophenylamino, methoxycyanophenylamino, methoxytrifluoromethylphenylamino, methoxynitrophenylamino, ethoxynitrophenylamino, propoxynitrophenylamino, benzylamino, 1-phenylethylamino , 2-phenylethylamino, 3-phenylpropylamino, methoxybenzylamino, dimethoxybenzylamino, 2-dimethoxyphenylethylamino, 2-diethoxyphenylethylamino, 2-dipropoxyphenylethylamino, 2- (Methoxy-ethoxy-phenyl) -ethylamino, N-methylphenylamino, N-ethyl-methylphenylamino, N-methylmethoxyphenylamino, N-ethyl-dimethoxy-phenylamino, N-methyl-benzylamino, N-ethyl-2-phenylethylamino or N-methyl-methoxybenzylamino group, and

R ₄ or R ₅ may each represent a hydrogen atom, methyl, ethyl, propyl or isopropyl group.

Preferred compounds of general formula (I) include hydroxy or mercapto groups in which R ₁ is optionally substituted by an alkyl group or an allyl group having 1 to 3 carbon atoms; Hexyl mercapto, methoxybenzyl mercapto, or 2- (amino-dichlorophenyl) -ethyl mercapto group; An alkyl group having 1 to 3 carbon atoms optionally substituted with a phenyl group; Cyanophenylamino- or dimethylamino group; An alkylamino group having 1 to 5 carbon atoms which may be substituted by a methoxy group; Phenylamino group wherein the phenyl nucleus may be substituted by methyl, methoxy, trifluoromethyl, cyano- or nitro group, chlorine or bromine atom; Dichlorophenylamino, dibromophenylamino, dimethoxyphenylamino, methoxy-nitrophenylamino, trimethylphenylamino, cyclohexylamino, dimethoxyphenylethylamino or ethoxycarbonylamino group;

R ₄ represents a hydrogen atom or a methyl group,

R ₅ represents a methyl group,

X represents an oxygen or sulfur atom, in particular a compound in which the pyridazino group is at position 5 and physiologically toxic addition salts thereof.

Particularly preferred compounds of formula (I) are the compounds of formula (Ia) and their physiologically toxic addition salts.

In the above formula, R ₁ is mercapto, methyl mercapto, hydroxy, ethoxy, 4-methoxyphenylamino, 2- (4-amino-3, 5-dichlorophenyl) -ethylmercapto, amino, dimethylamino Or a cyclohexylamino group; Alkylamino groups having 1 to 5 carbon atoms; Or a phenylamino group optionally substituted by one or two methoxy groups,

X represents oxygen or a sulfur atom, in particular X preferably represents an oxygen atom.

The novel compound of general formula (I) according to the present invention is prepared by the following method.

a) optionally produced in the reaction mixture and then the compound of formula (II) is closed.

In the above general formula, R ₁ , R ₄ , R ₅ and X are as defined above, Y represents a hydrogen atom or an acyl group, Z represents a nucleophilic free group, Y is for example acyl group as acetyl, propionyl , Benzoyl or p-toluenesulfonyl group, Z is for example chlorine or bromine atom, hydroxy, methoxy, ethoxy, benzyloxy, mercapto, methyl mercapto, ethyl mercapto, propyl mercapto, benzyl Mercapto, phenyl mercapto, or this midazolylcarbonyl group.

This reaction is optionally carried out in a solvent such as tetrahydrofuran, dioxane, benzene, toluene, dimethylformamide, dimethylethylene glycol or sulfolane, N, N'-dicyclohexyl carbodiimide, carbonyldiimidazole, p- 25 ° to 300 ° C. in the presence of a condensing agent such as toluenesulfonic acid, phosphorus oxychloride, thionyl chloride, hydrochloric acid, sulfuric acid, phosphoric acid or polyphosphoric acid, etc., preferably the boiling point temperature of the reaction mixture, for example 50 ° to 285 ° C. It is suitable to carry out at a temperature of. However, this reaction can also be carried out in the molten state.

b) The carboxylic acid compounds of the following general formula (III), their anhydrides, esters, thioesters, amides, imidazolides or halides are reacted with hydrazine.

In the general formula, R ₁ , R ₄ , R ₅ and X are as defined above.

The reaction is carried out in solvents such as methanol, ethanol, isopropanol, glacial acetic acid, propionic acid and / or in excess hydrazine or hydrazine hydrate, from 0 ° to 200 ° C, for example 20 ° to 150 ° C, preferably the boiling point temperature of the reaction mixture. In some cases it is suitable to carry out in the presence of acid as a condensing agent such as sulfuric acid or p-toluenesulfonic acid. However, this reaction can also be carried out without solvent.

c) The following compound of formula (IV) is alkylated with a compound of formula (V).

(여기서 R₂'는 전술한 페닐기를 제외하고는 R₂및 R₃에서 정의한 바와 같음)의 그룹을 나타내며, R₁'는 페닐그룹 또는 탄소수 1내지 3의 알콕시그룹에 의해 임의로 치환된 탄소수 1내지 3의 알킬그룹, 이때 페닐핵은 탄소수 1내지 3의 알킬 또는 알콕시그룹, 할로겐원자 및/또는 아미노그룹에 의해 일-, 이- 또는 삼 치환될 수 있고 ; 탄소수 1내지 3의 알콕시그룹에 의해 임의로 치환된 탄소수 4내지 7의 알킬그룹 ; 탄소수 3내지 6의 알케닐그룹 ; 또는 탄소수 3내지 7의 사이클로 알킬그룹을 나타내며,Wherein R ₄ , R ₅ and X are as defined above and A is a hydroxy or mercapto group or formula

Wherein R ₂ ′ is as defined in R ₂ and R ₃ except for the phenyl group described above, and R ₁ ′ is 1 to 3 carbon atoms optionally substituted by a phenyl group or an alkoxy group having 1 to 3 carbon atoms. An alkyl group of 3, wherein the phenyl nucleus may be mono-, di-, or trisubstituted by an alkyl or alkoxy group having 1 to 3 carbon atoms, a halogen atom and / or an amino group; An alkyl group having 4 to 7 carbon atoms optionally substituted by alkoxy group having 1 to 3 carbon atoms; Alkenyl groups having 3 to 6 carbon atoms; Or a cycloalkyl group having 3 to 7 carbon atoms,

U represents a nucleophilic exchangeable group such as a halogen atom or sulfonic acid ether radical, for example a chlorine, bromine or iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy or methoxy sulfonyloxy group.

This alkylation reaction is carried out with phenylalkyl halides, alkylhalides, dialkylsulfates or trialkyloxonium-tetra fluoroborates such as benzylchloride, phenylethylbromide, methyl iodide, dimethylsulfate, diethyl sulfate or ethyl bromide Using a corresponding alkylating agent such as, preferably in a solvent such as methanol, ethanol, methanol / water, dimethylformamide or dioxane, optionally a base such as sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium methylate or potassium carbonate. In the presence of is carried out at a temperature below the boiling point of the solvent used.

When the radicals R ₄ and R ₅ do not have the same meaning, based on the optically active carbon atom at the 5-position of the pyridazinone ring, the obtained general formula (I) compound can be separated into the optically active colon. . This separation is suitably carried out by fractional crystallization of the corresponding salt with an optically active acid such as tartaric acid, dibenzoyl tartaric acid, malic acid, camphoric acid or camphorsulfonic acid or by chromatography with an optically active adsorbent.

The compounds of general formula (I) obtained can also be converted to their physiologically poisonous addition salts with organic or inorganic acids or bases. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

The compounds of the general formulas (II) and (III) used as starting compounds can be prepared by methods known in the publication. Thus, for example, the compound of formula (II) is reacted with the corresponding 3- (nitro-hydroxybenzoyl) -butyric ester with hydrazine, followed by reduction of the nitro group and the reaction of the obtained compound with the corresponding carboxylic acid derivative It can manufacture.

Compound of formula (III) is prepared by reacting the compound of formula (VI) with malonic ester.

The obtained compound is in turn saponified and decarboxylated, the chlorine atom is substituted with hydroxy or mercapto group, the nitro group is reduced and the amino compound obtained is reacted with the corresponding carboxylic acid derivative and then ring-closed to give the desired benzoxazole or thia Make pawns

Compounds of formula (IV) used as starting materials can be prepared by ring closure of the corresponding thiourea, suitably by the process of a) of the present invention.

As already mentioned above, the novel compounds of the general formula (I) of the present invention, their optically active colon and their acid addition salts with physiologically toxic inorganic or organic acids, have been described for their activity against cardiovascular disease, That is, cardiac action, hypotensive action and / or antithrombotic action. The following compounds were tested for biological properties.

A = 5-Methyl-6- [2'-ethylamino-benz oxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone,

B = 5-methyl-6- [2'-cyclohexylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone,

C = 5-methyl-6- [2'-n-butylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone,

D = 5-Methyl-6- [2 '-(4-methoxyphenylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone,

E = 5-methyl-6- (2'-mercapto-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone,

F = 5-methyl-6- (2'-hydroxy-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone,

The following tests were performed.

1. Platelet aggregation measurements according to Born and Cross, J. physiol 170,397 (1964)

Platelet aggregation measurements are made in platelet-rich plasma of healthy people. Messrs containing 1 mg of collagen fiber per ml. Sigma, St. The addition of collagen, a commercial product from Louis, USA, is added and the decrease in optical density is measured and recorded with a photometer. The aggregation rate (V _max ) is measured by the inclination angle of the density curve. The optical density (od) is measured at the point that most of the light is transmitted through the curve. To cause maximum aggregation, about 0.01 ml of collagen solution is added to 1 ml of platelet rich plasma.

The results are shown in the following table.

2. Measurement of cat blood pressure lowering and contractile force increasing

This test is performed using cats anesthetized with pentobarbital sodium (40 mg / kg intraperitoneal). This animal breathes spontaneously. Arterial blood pressure is measured in the abdominal aorta with a statham pressure transmitter (P23DC). The effect of increasing contractile force is measured by measuring the pressure in the left atrium using a catheter tip manometer (millar PC350A). Shrinkage scale dp / dt _max is recorded by analogical differential circuit. Test substance is injected into the femoral vein. Physiological sodium hypochlorite solution or polydiol 200 is used as solvent. At least three cats for each substance are tested and the dose is 0.1 or 2.0 mg / kg (intravenously). The test substance remains active for at least 45 minutes.

The following table shows the mean values.

3. Acute Toxicity

Acute toxicity of the test compound is determined after oral administration to rats (observation period: 14 days).

Compounds of formula (I) prepared according to the present invention, acid salts with their optically active colon and their physiologically toxic inorganic or organic acids, are based on their pharmaceutical properties to treat elastic heart failure or angina pectoris. And / or for prevention of arterial occlusion and thrombosis.

Compounds of general formula (I) and their physiologically toxic acid addition salts can be administered in conventional formulations such as tablets, coated tablets, powders, suspensions, suppositories, or ampoules. Single dose for adults is 10 to 50 mg (intravenous administration), 1 to 4 times a day, preferably 20 to 40 mg, and the dose for oral administration is 50 to 150 mg, preferably 75 to 100 mg to be.

Next, the preparation examples of the starting materials used in the preparation method of the present invention will be described.

Production Example I

N-ethyl-N '-[2-hydroxy-5- (5-methyl--4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] thiourea

10.8 g (50 mmol) of 2-amino-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol is suspended in 250 ml of tetrahydrofuran. . This suspension is mixed with 25 ml (0.29 mol) of ethyl isothiocyanate and refluxed for 3.5 hours to form a clear solution in a short time. After the reaction time, the mixture is evaporated and crystallized by adding ether to the yellow oily residue. The precipitated product is suction filtered, washed with ether and dried at room temperature.

Yield: 13.0 g (91.5% of theory)

Melting Point: 137 ° to 139 ° C, C ₁₄ H ₁₈ N ₄ O ₂ S (306.4)

Calculation: C54.88 H5.92 N18.29 S10.47

Found: 55.10 6.10 17.90 10.30

Production Example II

2-ethylamino-5- (3-methyl-4-oxo-butyric acid-4-yl) -benzoxazole

3.24 g (10.0 mmol) of N-ethyl-N '-[2-hydroxy-5- (3-methyl-4-oxo-butyric acid-4-yl) -phenyl] thiourea in 150 ml of tetrahydrofuran Dissolve. This solution is mixed with 4.17 g (20.0 mmol) of N, N'-dicyclohexylcarbodiimide and refluxed for 5 hours. After reflux, the solution is evaporated to 1/2 volume, heated for a while and then cooled until crystals form. The product obtained is suction filtered, recrystallized in tetrahydrofuran and dried at room temperature.

Yield: 0.71 g (24.3% of theory)

Melting Point: 160 ° to 162 ° C

The production method of the present invention will be described in more detail with reference to the following examples.

Example 1

5-Methyl-6- [2'-methylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

3.36 g (11.5 mmol) N-methyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] Thiourea is dissolved in 150 ml of tetrahydrofuran. This solution is mixed with 3.13 g (15 mmol) of N, N'-dicyclohexyl carbodiimide and refluxed for 5 hours. After reflux, the reaction mixture is evaporated to 1/2 volume, heated briefly and cooled until crystals form. The product obtained is suction filtered, recrystallized in methanol and dried at room temperature.

Yield: 0.84 g (28.3% of theory)

Melting point: 241 ° to 242 ° C, C ₁₃ H ₁₄ N ₄ O ₂ S (258.3)

Calculation: C60.46 H5.46 N21.69

Found: 60.28 5.61 21.50

Example 2

5-Methyl-6- [2'-n-butylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

Nn-butyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] in a similar manner to Example 1 Prepared from thiourea.

Yield: 39.7% of theoretical amount

Melting Point: 186 ° to 188 ° C, C ₁₆ H ₂₀ N ₄ O ₂ (300.4)

Calculated Value: C63.98 H6.71 N18.65

Found: 63.99 6.96 18.54

Example 3

5-Methyl-6- [2'-isopropylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

N-isopropyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl in a similar manner to Example 1 ] From thiourea.

Yield: 52% of theoretical amount

Melting Point: 239 ° to 241 ° C, C ₁₅ H ₁₈ N ₄ O ₂ (286.34)

Calculation: C62.92 H6.34 N19.57

Found: 62.65 6.33 19.25

Example 4

5-Methyl-6- [2'-cyclohexylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

N-cyclohexyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl in a similar manner to Example 1 ] From thiourea.

Yield: 59.1% of theoretical amount

Melting Point: 235 ° to 237 ° C, C ₁₈ H ₂₂ N ₄ O ₂ (326.4)

Calculated Value: C66.24 H6.79 N17.16

Found: 66.00 6.90 16.99

Example 5

5-Methyl-6- [2 '-(3,4-dimethoxyphenethylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

N-3,4-dimethoxyphenethyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone- in a similar manner to Example 1 6-yl) -phenyl] thiourea.

Yield: 48.2% of theoretical amount

Melting point: 70 ° to 72 ° C, C ₂₂ H ₂₄ N ₄ O ₄ × hydrochloric acid (444.93)

Calculated Value: C 59.39 H 5.87 N 12.59 Cl 7.99

Found: 59.40 5.69 12.89 8.00

Example 6

5-Methyl-6- [2'-phenylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

5 ml of hydrazine hydrate (99%) are added in portions to 20 ml of glacial acetic acid at about 20 ° C. with stirring and ice cooling. 6.5 g (20.0 mmol) of 2-phenylamino-5- (3-methyl-4-oxo-butyric acid-4-yl) -benzoxazole is then added to the reaction mixture and the resulting suspension is refluxed. After 1 hour the suspension is cooled to room temperature and diluted with water. The precipitated product is suction filtered, washed with water and dried at 80 ° C.

Yield: 2.80 g (43.7% of theory)

Melting Point: 214 ° to 217 ° C, C ₁₈ H ₁₆ N ₄ O ₂ (320.34)

Example 7

5-Methyl-6- [2 '-(2-chloroanilino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

N-2-chlorophenyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) in a similar manner to Example 1 -Phenyl] thiourea.

Yield: 33.9% of theoretical amount

Melting Point: 193 ° to 195 ° C, C ₁₈ H ₁₅ N ₄ O ₂ (354.8)

Calculated Value: C 60.93 H 4.26 N 15.79 Cl 9.99

Found: 60.90 4.25 15.93 10.20

Example 8

5-Methyl-6- [2 '-(4-trifluoromethylphenylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

N-4-trifluoromethyl-phenyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone- in a similar manner to Example 1 6-yl) -phenyl] thiourea.

Yield: 57.3% of theoretical amount

Melting Point: 249 ° to 251 ° C, C ₁₉ H ₁₅ N ₄ O ₂ F ₃ (388.36)

Calculated Value: C 58.76 H 3.89 N 14.42

Found: 59.00 4.13 14.31

Example 9

5-Methyl-6- [2 '-(3-4-dichlorophenylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

N-3,4-dichlorophenyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6- in a similar manner to Example 1 From 1) -phenyl] thiourea.

Yield: 73.5% of theoretical amount

Melting Point: 253 ° to 256 ° C, C ₁₈ H ₁₄ N ₂ O ₂ (389.3)

Calculated Value: C 55.54 H 3.63 Cl 18.22

Found: 55.40 3.83 18.14

Example 10

5-Methyl-6- [2 '-(4-bromophenylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

N-4-bromophenyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl in a similar manner to Example 1 ) -Phenyl] thiourea.

Yield: 65.4% of theoretical amount

Melting Point: 243 ° to 245 ° C, C ₁₈ H ₁₅ N ₄ O ₂ Br (390.27)

Calculation: C55.40 H3.87 N14.36 Br20.48

Found: 55.00 4.05 13.95 20.76

Example 11

5-Methyl-6- [2 '-(4-methoxyphenylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

N-4-methoxyphenyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl in a similar manner to Example 1 ) -Phenyl] thiourea.

Yield: 40.3% of theoretical amount

Melting Point: 220 ° to 222 ° C, C ₁₉ H ₁₈ N ₄ O ₃ (350.4)

Calculated Value: C65.13 H5.18 N15.99

Found: 65.30 5.20 15.83

Example 12

5-Methyl-6- [2 '-(2-methoxy-4-nitrophenylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

N-2-methoxy-4-nitrophenyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone in a similar manner to Example 1 -6-yl) -phenyl] thiourea.

Yield: 65.6% of theoretical amount

Melting Point: 223 ° to 225 ° C, C ₁₉ H ₁₇ N ₅ O ₅ (395.4)

Calculated Value: C57.82 H4.33 N17.71

Found: 58.27 4.25 18.17

Example 13

5-Methyl-6- [2 '-(4-methylphenylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

N-4-methylphenyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl)-in a similar manner to Example 1 Phenyl] thiourea.

Yield: 52.1% of theoretical amount

Melting Point: 273 ° to 275 ° C, C ₁₉ H ₁₈ N ₄ O ₂ (334.39)

Calculated Value: C 68.25 H 5.43 N 16.76

Found: 68.10 5.59 16.88

Example 14

5-Methyl-6- [2 '-(2,4,6-trimethylphenylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

N-2,4,6-trimethylphenyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone- in a similar manner to Example 1 6-yl) -phenyl] thiourea.

Yield: 76.4% of theoretical amount

Melting Point: 225 ° to 228 ° C, C ₂₁ H ₂₂ N ₄ O ₂ (362.4)

Calculated Value: C69.59 H6.12 N15.46

Found: 69.79 6.37 15.65

Example 15

5-Methyl-6- [2 '-(4-cyanophenylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

N-4-cyanophenyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl in a similar manner to Example 1 ) -Phenyl] thiourea.

Yield: 59.7% of theoretical amount

Melting Point: 318 ° to 320 ° C, C ₁₉ H ₁₅ N ₅ O ₂ (345.37)

Calculation: C66.08 H4.38 N20.28

Found: 66.14 4.58 20.03

Example 16

5-Methyl-6- [2 '-(ethoxycarbonylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

N-ethoxycarbonyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) in a similar manner to Example 1 -Phenyl] thiourea.

Yield: 19.8% of theoretical amount

Melting Point: 235 ° to 239 ° C, C ₁₅ H ₁₆ N ₄ O ₄ (316.33)

Calculated Value: C56.95 H5.10 N17.71

Found: 55.81 5.14 17.08

Example 17

5-Methyl-6- [2'-n-pentylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

Nn-pentyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] in a similar manner to Example 1 Prepared from thiourea.

Yield: 52.3% of theoretical amount

Melting Point: 154 ° to 155 ° C, C ₁₇ H ₂₂ N ₄ O ₂ (314.4)

Calculated Value: C64.95 H7.05 N17,82

Found: 65.26 7.12 17.88

Example 18

5-Methyl-6- [2'-ethylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

N-ethyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] in a similar manner to Example 1 Prepared from thiourea.

Yield: 71.9% of theoretical amount

Melting Point: 244 ° to 246 ° C, C ₁₄ H ₁₆ N ₄ O ₂ (272.3)

Calculation: C61.95 H5.98 N20.85

Found: 61.75 5.92 20.57

Example 19

5-Methyl-6- [2 '-(3-methoxypropylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

N-3-methoxypropyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl in a similar manner to Example 1 ) -Phenyl] thiourea.

Yield: 55.5% of theoretical amount

Melting Point: 153 ° to 154 ° C, C ₁₆ H ₂₀ N ₄ O ₃ (316.4)

Calculation: C60.75 H6.37 N17.71

Found: 61.00 6.40 17.56

Example 20

5-Methyl-6- [2'-amino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] thiourea in a similar manner to Example 1 .

Yield: 42.1% of theoretical amount

Melting Point: 285 ° to 287 ° C

Example 21

5,5-dimethyl-6- [2 '-(α-phenylethyl) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

a) 4- (4-chlorophenyl) -3,3-dimethyl-4-oxo-butyric acid

30 g (0.688 mole) of sodium hydride (50% oil suspension) is added to 1,200 mL of anhydrous tetrahydrofuran at room temperature and the mixture is stirred for 15 minutes. 52 g (0.228 mol) of 4- (4-chlorophenyl) -3-methyl-4-oxobutyric acid are added in portions and then the reaction mixture is refluxed for 2 hours. The mixture is then cooled to 40 ° C. and 64 ml (1.02 mol) of methyl iodide are added dropwise. After refluxing for another 3 hours, the reaction mixture is cooled to room temperature and added with stirring, and the organic portion is distilled in a rotary evaporator. The aqueous alkali solution is washed twice with petroleum ether and acidified with concentrated hydrochloric acid. The precipitated oil crystallizes on further stirring. The crystals are suction filtered, washed with water and dried.

Yield: 52g (94.7% of theory)

Melting Point: 95 ° to 97 ° C

b) 4- (4-chloro-3-nitrophenyl) -3,3-dimethyl-4-oxo-butyric acid

48 g (0.2 moles) of 4- (4-chlorophenyl) -3,3-dimethyl-4-oxobutyric acid are added in portions to 500 ml of fuming nitric acid at −15 ° C. and −10 ° C. with stirring. After stirring at −10 ° C. for 30 minutes, the reaction mixture is poured into iced water, the precipitated product is suction filtered, washed with water, neutralized and dried.

Yield: 47.5 g (83.1% of theory)

Melting Point: 118 ° ~ 120 ℃

c) 2-nitro-4- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -chlorobenzene

43 mL of hydrazine anhydride (99%) is stirred, ice-cooled and added in portions to 400 mL of glacial acetic acid at about 20 ° C. 43 g (0.15 mole) of 4- (4-chloro-3-nitrophenyl) -5,5-dimethyl-4-oxo-butyric acid is then added and the reaction mixture is refluxed for 1 hour. After cooling the reaction mixture is diluted with water and the precipitated product is suction filtered, washed again with water and dried.

Yield: 33g (78.1% of theory)

Melting Point: 193 ° to 194 ° C

d) 2-nitro-4- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol

28 g (0.1 mole) of 2-nitro-4- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -chlorobenzene was suspended in 750 ml of glycol and This suspension is mixed with a solution of 40 g of powdered potassium hydroxide dissolved in 250 m of glycol. The resulting solution is heated at 160 ° C. for 2 hours and cooled to room temperature, then the solution is poured into about 3 L of ice water and acidified with concentrated hydrochloric acid. The precipitated product is suction filtered. The filtrate is extracted four times with 250 ml of ethyl acetate and the organic phase is dehydrated over sodium sulfate and dried. The residue and solid product are combined, triturated with water, filtered off with suction and dried.

Yield: 20 g (76% of theory)

Melting Point: 211 ° to 213 ° C

e) 2-amino-4- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol

20 g (0.076 mole) of 2-nitro-4- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) phenol dissolved in 600 ml of dimethylformamide Is reduced using hydrogen (5 bar) and 2 g of Pd / C (10%) catalyst in a parr apparatus at room temperature. When absorption of hydrogen stops, the catalyst is aspirated off and the filtrate is evaporated. Once a solid product is obtained, it is triturated with ether. After suction filtration the product is washed with ether and dried.

Yield: 17 g (96% of theory)

Melting Point: 260 ° to 263 ° C

f) 2- (2-phenylpropionylamino) -4- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol

2.8 g (0.012 mol) of 2-amino-4- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol with 40 ml of anhydrous tetrahydrofuran And 40 ml of anhydrous dimethylformamide. 3.03 g (0.018 mol) of 2-phenylpropionic acid chloride is added dropwise at room temperature. After 1.5 hours the reaction mixture is added to water with stirring and washed several times with ethyl acetate. The organic phase is dehydrated with sodium sulfate and evaporated. The product obtained is purified by column chromatography (silica gel, nucleus size: 0.05-0.20 mm, eluent: chloroform / ethanol 1%). The product obtained is used for the next reaction in an impure state.

Yield: 1.7 g (38.8% of theory)

g) 5,5-dimethyl-6- [2 '-(α-phenylethyl) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

1.7 g (0.0046 moles) of 2- (2-phenylpropionylamino) -4- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol It is suspended in 12 ml of sulfolane and the suspension is refluxed for 5 hours. The hot reaction product is then poured into iced water with stirring. The precipitated oily product is extracted with ethyl acetate and the organic phase is dehydrated with sodium sulfate. The residue obtained is purified by column chromatography (silica gel, nucleus size: 0.05-0.20 mm, eluent: chloroform / ethanol 1%). The corresponding fractions are combined and filtered through charcoal and then evaporated. The oily residue is crystallized with petroleum ether.

Yield: 1 g (62.5% of theory)

Melting Point: 131 ° to 135 ° C, C ₂₁ H ₂₁ N ₃ O ₂ (347.4)

Calculation: C72.61 H6.09 N12.10

Found: 72.18 6.30 11.91

Example 22

5-Methyl-6- [2'-amino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

2.1 g (0.0072 mole) N- [2-hydroxy-5- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] thiourea { Alkaline valence to N'-benzoyl-N- [2-hydroxy-5- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] thiourea Dissolve and dissolve in 40 mL of anhydrous tetrahydrofuran. 2.05 g (0.01 mol) of N, N'-dicyclohexyl-carbodiimide are added and the reaction mixture is refluxed for 2 hours under stirring. After cooling to room temperature, the precipitated product is suction filtered and washed with tetrahydrofuran. The reaction product is suspended with 1N ammonia, stirred for 30 minutes, filtered off with suction, washed with water and dried.

Yield: 1.0 g (54% of theory)

Melting Point:> 250 ° C., C ₁₃ H ₁₄ N ₄ O ₂ (258.3)

Calculated Value: C60.45 H5.46 N21.69

Found: 60.67 5.41 21.44

Example 23

5-Methyl-6- [2'-dimethylamino-benzothiazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

a) 4- (3-amino-4-mercaptophenyl) -3-methyl-4-oxobutyric acid

27 g (0.1 mole) of 4- (3-nitro-4-chlorophenyl) -3-methyl-4-oxo-butyric acid and 72 g (0.3 mole) of sodium sulfide x 9 H ₂ O were added to the solution in 500 ml of water. Add and heat on steam bath for 35 minutes. After cooling to 10 ° C., the pH of the reaction mixture is adjusted to 4.5 using glacial acetic acid. The reaction mixture is then extracted several times with ethyl acetate and the organic phase is dehydrated with sodium sulfate and dried. The residue obtained is used for the reaction of the next step in an impure state.

Yield: 27.5 g (about 100% of theory)

b) 5-methyl-6- [2'-dimethylaminobenzothiazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

2.2 g (0.018 mol) of dimethylthio carbamoyl chloride at room temperature, 2.8 g (0.012 mol) of 2-amino-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone- 6-yl) -thiophenol [prepared by reacting 4- (3-amino-4-mercaptophenyl) -3-methyl-4-oxo-butyric acid with hydrazine] was dissolved in 40 ml of anhydrous tetrahydrofuran. Add with stirring. After 20 hours the precipitated product is filtered off. The filtrate is diluted with water and extracted twice with ethyl acetate. The aqueous phase is then alkalized by addition of 2N sodium hydroxide solution and extracted with chloroform. The organic phase is dehydrated with sodium sulfate and evaporated. An oily product is obtained which crystallizes when left overnight. The crude product (1 g) obtained is purified by column chromatography (silica gel, core size: 0.05-0.20 mm, eluent: chloroform / ethanol 1%).

Yield: 550 mg (16% of theory)

Melting Point: 177 ° to 184 ° C., C ₁₄ H ₁₆ N ₄ OS (288.4)

Calculated Value: C58.31 H5.59 N19.43 S11.12

Found: 58.41 5.69 19.12 11.02

Example 24

5-Methyl-6- [2 '-(4-cyanophenyl) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

2.07 g (5.3 mmol) of 1-acetoxy-2- (4'-cyanobenzoylamino) -4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl The solution of) -benzene in 50 ml of sulfolane is mixed with 0.5 ml of 10% hydrochloric acid. After heating at 240 ° C. for 4 hours, the mixture is added to 150 ml of water with stirring and the resulting precipitate is suction filtered. The product is purified by column chromatography (silica gel, chloroform + 1% ethanol).

Yield: 145 mg (8.3% of theory)

Melting Point: 278 ° to 280 ° C, C ₁₉ H ₁₄ N ₄ O ₂ (330.35)

Calculated Value: C69.08 H4.27 N16.96

Found: 68.24 4.34 16.86

Example 25

5-Methyl-6- (2'-hydroxy-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

Suspend 1.08 g (0.005 mole) of 2-amino-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol in 50 ml of anhydrous tetrahydrofuran. The suspension is mixed with 1 g (0.006 mole) of N, N'-carbonyldiimidazole with stirring. After refluxing for 45 minutes, the reaction mixture is evaporated and the residue is stirred with water. The crystals obtained are suction filtered, washed with water and then dehydrated. This crude product is then dissolved in chloroform: methanol = 9: 1 and passed through activated charcoal when hot and the filtrate is evaporated until crystals are formed. The reaction product is cooled in an ice bath and the precipitated product is suction filtered, washed with ether and dried.

Yield: 0.55 g (44.7% of theory)

Melting Point: 250 ° to 253 ° C., C ₁₂ H ₁₁ N ₃ O ₃ (245.2)

Calculated Value: C58.77 H4.52 N17.13

Found: 58.77 4.46 17.22

Example 26

5-Methyl-6- (2'-ethoxy-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

2.19 g (0.01 mol) of 2-amino-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol was suspended in 10 ml of tetraethyl carbonate and 3 ml of dimethyl formamide is added. After heating at 180 ° C. (oil bath) for 1 hour, the reaction mixture is cooled to room temperature and the precipitated product is suction filtered and washed with ether. The reaction product is then recrystallized twice by adding activated charcoal in 100 mL of ethanol.

Yield: 900 mg (33% of theory)

Melting Point: 193 ° to 194 ° C, C ₁₄ H ₁₅ N ₃ O ₃ (273.3)

Calculated Value: C61.53 H5.53 N15.38

Found: 61.59 5.52 15.65

Example 27

5-Methyl-6- (2'-mercapto-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

22 g (0.1 mole) of 2-amino-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol was suspended in 500 ml of ethanol and 24 g (0.15) Mol) potassium ethylxanthogenite is added with stirring. After refluxing for 3 hours the reaction mixture is cooled to room temperature and the precipitated product is filtered off with suction and washed with cold ethanol and ether. The potassium salt obtained is dissolved in 1,000 ml of water, filtered through activated carbon and the filtrate is neutralized with 2N acetic acid. The precipitated product is suction filtered and dried by vacuum dryer.

Yield: 15 g (57.7% of theory)

Melting Point:> 250 ° C., C ₁₂ H ₁₁ N ₃ O ₃ S (261.3)

Calculation: C55.16 H4.24 N16.28 S12.27

Found: 55.09 4.16 15.93 12.10

Example 28

5-Methyl-6- [2'-methylmercapto-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

653 mg (0.0025 mol) of 5-methyl-6- [2'-mercapto-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone in 10 ml of anhydrous dimethyl Dissolve in formamide and mix this solution with 210 mg (0.0025 moles) of sodium bicarbonate. After addition of 2 ml of methyl iodide the reaction mixture is stirred at 40 ° C. for 15 minutes. The reaction mixture is added to water with stirring and extracted with ethyl acetate. The organic phase is dehydrated with sodium sulfate and evaporated. The solid residue obtained is recrystallized in ethanol.

Yield: 340 mg (49.4% of theory)

Melting Point: 178 ° to 180 ° C, C ₁₃ H ₁₃ N ₃ O ₂ S (275.3)

Calculation: C56.71 H4.76 N15.26 S11.65

Found: 56.20 4.78 15.41 11.57

Example 29

5-Methyl-6- (2'-n-hexylmercapto-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

2.99 g (0.01 mol) of 5-methyl-6- (2'-mercapto-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone-potassium salt Dissolve in ml of anhydrous dimethylform amide 1.5 ml of n-hexylbromide is added with stirring and the reaction mixture is stirred for 1 hour at 40 ° C. The reaction mixture is then stirred with water, poured into ethyl acetate and the organic phase is extracted. Dehydrate with sodium sulfate and evaporate The residue obtained is recrystallized from ethanol.

Yield: 2.4 g (69.6% of theory)

Melting Point: 119 ° to 121 ° C, C ₁₈ H ₂₃ O ₂ S (345.5)

Calculated Value: C62.57 H6.71 N12.16 S9.28

Found: 62.65 6.79 12.17 9.05

Example 30

5-Methyl-6- (2'-allylmercapto-benzoxazol-5'-yl) -4,5-dihydro-3 (2H) -pyridazinone

5-Methyl-6- (2'-mercapto-benzoxazol-5'-yl) -4,5-dihydro-3 (2H) -pyridazinone-potassium salt with allyl in a similar manner to Example 29 Prepared from bromide.

Yield: 73% of theoretical amount

Melting Point: 113 ° to 114 ° C, C ₁₅ H ₁₅ N ₃ O ₂ S (301.4)

Calculated Value: C59.78 H5.02 N13.94 S10.63

Found: 60.01 5.21 14.28 10.50

Example 31

5-Methyl-6- (2'-p-methoxybenzylmercapto-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

5-Methyl-6- (2'-mercapto-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone-potassium salt and p in a similar manner to Example 29 Prepared from methoxybenzyl bromide.

Yield: 66.6% of theoretical amount

Melting Point: 174 ° ~ 176 ° C, C ₂₀ H ₁₉ N ₃ O ₃ S (381.5)

Calculated Value: C62.97 H5.02 N11.02 S8.41

Found: 63.47 5.08 11.34 8.63

Example 32

5-Methyl- [2 '-[2- (4-amino-3,5-dichlorophenyl) -ethylmercapto] -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -Pyridazinone

In a similar manner as in Example 29, 5-methyl-6- (2'-mercapto-benzoxazol-5'-yl) -4,5-dihydro-3 (2H) -pyridazinone-potassium salt and 2 Prepared from-(4-amino-3,5-dichlorophenyl) -ethylbromide.

Yield: 52% of theoretical amount

Melting Point: 205 ° to 208 ° C

Example 33

5-Methyl- [2'-methylbenzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

In a similar manner to Example 21 (g), 2-acetylamino-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol was heated in sulfolane Manufacture.

Yield: 75.3% of theoretical amount

Melting Point: 210 ° to 213 ° C

Example 34

5-Methyl- [2'-isopropylbenzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

In a similar manner to Example 21 (g), 2-isobutyrylamino-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol was added to sulfolane. Prepare by heating.

Yield: 52.5% of theoretical amount

Melting Point: 160 ° to 162 ° C

Example A

Tablets containing 100 mg 5-methyl-6- [2'-ethylaminobenzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

Furtherance :

Content per tablet:

Active Ingredient 100.0mg Carboxymethyl Cellulose 19.0mg

Lactose 50.0mg Magnesium Stearate 1.0mg

Polyvinylpyrrolidone 5.0mg 175.0mg

The active ingredient and lactose are homogenized in an aqueous polyvinylpyrrolidone solution.

Wet Screening: 1.5mm

Drying: in rotary air dryer at 50 ℃

Dry Screening: 1mm

The granules and the remaining auxiliaries are mixed to compress the tablets.

Tablet weight: 175mg

Punch: 8mmΦ

Example B

Coating tablet containing 50 mg of 5-methyl-6- [2'-ethylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

1 Coated Refined Sugar Content:

Active Ingredient 50.0mg Carboxymethyl Cellulose 7.0mg

Dried Corn Starch 20.0mg Magnesium Stearate 1.0mg

Soluble Starch 2.0mg 80.0mg

The active ingredient and starch are homogeneously humidified with an aqueous solution of soluble starch.

Wet Screening: 1.0mm

Dry Screening: 1.0mm

Drying: In rotary air dryer at 50 ℃

The granules and the remaining adjuvant are mixed and compressed into tablets.

Uncoated tablet weight: 80mg

Punch: 6mm

Bending radius: 5 mm

This tablet is coated with a sugar coating in a conventional manner.

Coating tablet weight: 120mg

Example C

Suppositories containing 75 mg of 5-methyl-6- [2'-ethylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

Content per suppository:

[Manufacturing method]

Melt the suppository base. The active ingredient ground at 38 ° C. is dispersed homogeneously in this melt. The suppository base is cooled to 35 ° C and poured into a pre-cooled mold.

Suppository weight: 1.7 g

Example D

Ampoules Containing 25 mg of 5-methyl-6- [2'-ethylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

Furtherance :

Contains per 1 ampoule:

25.0 mg active medium (eg hydroxy-)

0.5 ml of sodium chloride 45.0 mg ethylated hydrated castor oil)

Polyethylene glycol 600 1.0 ml Water for injection up to 5.0 ml

[Manufacturing method]

The active ingredient is dissolved in a mixture of polyethyleneglycol, dissolution medium and about 1/2 amount of water in a suitable vessel with a volume scale with stirring. This solution is mixed with an isotonic solution of sodium chloride and made to the desired volume with water.

Example E

Suspending agent containing 75 mg of 5-methyl-6- [2'-ethylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone per 5 ml

Content per 100ml suspension:

Active ingredient 1.5 g glycerin 5.0 g

Carboxymethyl Cellulose 0.1g Sorbite Solution 70% 20.0g

Methyl p-hydroxybenzoate 0.05g Flavor 0.3g

Propyl p-hydroxybenzoate 0.03 g Distilled water 100.0 ml

Sugar cane sugar 10.0g

[Manufacturing method]

Methyl p-hydroxybenzoate, propyl p-hydroxy benzoate, glycerin and carboxymethylcellulose are dissolved while distilled water is heated to 70 ° C. and stirred.

The solution is cooled to room temperature and the active ingredient is added with stirring to disperse homogeneously. Sugar, soap solution and perfume are then added, dissolved, stirred in vacuo and the suspending agent is evaporated.

Claims (1)

A method for preparing benzoxazole of the following general formula (I), characterized by reacting a carboxylic acid compound of the following general formula (III) with hydrazine.

In the general formula, R ₁ is a formula

R ₂ represents a phenyl group and R ₃ represents a hydrogen atom, and R ₄ and R ₅ may be the same as or different from each other, and represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. , X represents an oxygen atom.