JPS621398B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the general formula The present invention relates to a novel benzopyran derivative or a salt thereof.

In the above formula, R represents an amino acid residue selected from glycine, β-alanine, phenylglycine, methionine, or proline, an alkanoyl group, a hydroxy-substituted alkanoyl group, a phenyl-substituted alkanoyl group, or a pyridylcarbonyl group.

According to the invention, compounds of the general formula () are of the formula It can be produced by the following methods (i) to (iii) using the compound represented by or its acid addition salt (hydrochloride, etc.) as a starting material.

Method (i): Compound of formula () and general formula R ¹ COX () (wherein R ¹ is a group obtained by removing the carbonyl moiety from the residue of the above amino acid, an alkyl group, a hydroxy-substituted alkyl group, a phenyl-substituted alkyl group) , a pyridyl group, and X represents a halogen).

In the compound of general formula (), the amino group and the hydroxyl group are protected by a protecting group such as a tertiary butyloxycarbonyl group, a benzyloxycarbonyl group, and a benzyl group, and the carboxyl group is protected by a tertiary butyloxy group, a methyl group, It can be protected with a protecting group such as ethyl group or benzyl group.

The reaction is carried out in pyridine or in a solvent such as tetrahydrofuran, dioxane, benzene, chloroform, methylene chloride, etc., using triethylamine, N-methylmorpholine, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc. as a deoxidizer, and cooled. Proceed for 2 to 48 hours under stirring, or at room temperature and with heating if necessary. After the reaction is completed, insoluble matter is removed, the solvent is distilled off under reduced pressure, and the residue is extracted with ethyl acetate, chloroform, benzene, etc., and washed with water. If necessary, wash with 1N hydrochloric acid and 4% aqueous sodium hydrogen carbonate solution. The organic layer is dried over magnesium sulfate or sodium sulfate and concentrated under reduced pressure. The resulting residue can be solidified in most cases by adding n-hexane, petroleum ether, ether, etc. Furthermore, if necessary, silica gel column chromatography can be performed for purification using a chloroform-methanol-based developing solvent. Note that protective groups such as amino groups, hydroxyl groups, and carboxyl groups can be removed by an appropriate method. for example,
A tertiary butyloxycarbonyl group or a tertiary butyloxy group can be removed in trifluoroacetic acid or hydrochloric acid at room temperature for 10 to 30 minutes. Furthermore, benzyl groups and benzyloxycarbonyl groups can be removed by catalytic reduction in a solvent such as methanol, ethanol, dioxane, tetrahydrofuran, etc. using a 5-10% palladium on carbon catalyst at room temperature for 2-6 hours. Furthermore, if necessary, it can also be removed using hydrogen fluoride under cooling.

Method (ii): A method of reacting a compound of formula () with a compound represented by the general formula (R ¹ CO) ₂ O () (wherein R ¹ has the same meaning as above).

The reaction is carried out in a solvent such as chloroform, methylene chloride, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, etc.
It proceeds by using ~1.5 equivalents of triethylamine, N-methylmorpholine, etc., and stirring from cold to room temperature for 2 to 24 hours. Compound()
may be used in an amount of 1 to 1.5 equivalents, or in large excess if necessary. The treatment after the reaction is completed is according to method (i).

Method (iii): A method of reacting a compound of formula () with a compound represented by the general formula R ¹ COOH () (wherein R ¹ has the same meaning as above).

The reaction can be carried out by applying a method that usually generates a peptide bond, such as a mixed acid anhydride method, a DCC method, an active ester method, an azide method, and an Eintsuf method.

When using the DCC method, the reaction consists of tetrahydrofuran, methylene chloride,
In a solvent such as acetonitrile, dimethylformamide, dimethyl sulfoxide, etc., from cold to room temperature 2
Proceed under stirring for ~48 hours. For the compound (), usually carboxylic acid () is used in an amount of 1 to 1.2 equivalents, triethylamine or N-methylmorpholine is added in an amount of 1.2 to 1.3 equivalents, and dicyclohexylcarbodiimide (DCC) is added in an amount of 1.2 to 1.5 equivalents (if necessary). , 3 to 4 equivalents can also be added). Furthermore, if necessary, 1 to 2 equivalents of a reaction accelerator such as 1-oxy-benzotriazole may be used (Eintsuf method). The treatment after the reaction is completed is according to method (i).

Furthermore, as a special example, when the substituent R in the compound of general formula () contains an amino group, it is converted into a hydroxyl group by an appropriate method (for example, sodium nitrite-hydrochloric acid, etc.). It can also be converted.

For example, the compound of formula () is
Formula obtained by the method described in No. 93932 It can be produced by reacting the compound represented by or its acid addition salt (such as hydrochloride) with phenyl isothiocyanate and treating the reaction product with an acid.

In the compound of the general formula () thus obtained, when R is an amino acid residue and its α-carbon is asymmetric, the present invention encompasses any of the L-form, D-form, and DL-form. It is something to do.

Compounds of general formula () can be converted into corresponding acid addition salts (hydrochloride, hydrobromide, sulfate, phosphate, acetate, trifluoroacetate, oxalate,
maleate, citrate, toluenesulfonate, pamoate, etc.), metal salts (sodium, potassium, calcium, aluminum, etc.), ammonium salts, lysine salts, etc.

The compound () of the present invention or its salts has anticancer and antibacterial effects, and is useful not only as a medicine but also as a synthetic intermediate.

When the compound of general formula () or a salt thereof is used as a medicine, it can be used as a tablet or by mixing with pharmaceutically acceptable excipients, carriers, diluents, etc.
It can be administered in the form of capsules, powders, and injections. In the case of oral administration, the dosage may be generally 5 to 100 mg/Kg per day for adults.

Hereinafter, the present invention will be specifically explained with reference to Examples.

Example 1: 3-dichloromethyl-3,4,4a,5,6,7
-hexahydro-3-methyl-1-oxo-4
-(2-phenylacetamide)-5,6,8
-trihydroxy-1H-2-benzopyran 4-amino-3-dichloromethyl-3,4,
4a,5,6,7-hexahydro-3-methyl-1
-Oxo-5,6,8-trihydroxy-1H-
Dissolve 200 mg of 2-benzopyran hydrochloride in 4 ml of tetrahydrofuran and add N while stirring at room temperature.
-Add 62 mg of methylmorpholine, then add 130 mg of phenylacetyl chloride. After stirring at room temperature for 5 hours, the solvent was distilled off under reduced pressure, water and toluene were added, and the mixture was shaken in a separatory funnel. Next, the organic layer is washed with dilute hydrochloric acid, further washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure.

Add n-hexane-ether (1:1),
Upon taking, 105 mg of the title compound is obtained as white crystals. Melting point 105-109°C (decomposition) Example 2: 4-acetamido-3-dichloromethyl-3,
4,4a,5,6,7-hexahydro-3-methyl-1-oxo-5,6,8-trihydroxy-1H-2-benzopyran 4-amino-3-dichloromethyl-3,4,
4a,5,6,7-hexahydro-3-methyl-1
-Oxo-5,6,8-trihydroxy-1H-
350 mg of 2-benzopyran hydrochloride in 5 ml of pyridine
and add 700 mg of acetic anhydride while stirring. After stirring at room temperature for 5-10 minutes, the solvent is distilled off and water is added. Extract with chloroform and wash with water and dilute hydrochloric acid. The chloroform layer was dried over magnesium sulfate, and the chloroform layer was distilled off under reduced pressure.
When ethyl acetate is added to the oily residue, the title compound precipitates out as white crystals, which are collected. yield
180mg. Melting point 254-255°C (decomposition) Example 3: 3-dichloromethyl-3,4,4a,5,6,7
-hexahydro-3-methyl-1-oxo-4
-(L-prolylamide)-5,6,8-trihydroxy-1H-2-benzopyran trifluoroacetate 4-amino-3-dichloromethyl-3,4,
4a,5,6,7-hexahydro-3-methyl-1
-Oxo-5,6,8-trihydroxy-1H-
Dissolve 200 mg of 2-benzopyran hydrochloride in 4 ml of tetrahydrofuran and add 0.08 ml of triethylamine. Dry ice - with methanol - 10~0℃
N-tertiary butyloxycarbonyl-L-proline anhydride 120
Add mg. Stir at the same temperature for 1 hour, then at room temperature for 24 hours. After the reaction is completed, insoluble matter is removed and the liquid is concentrated under reduced pressure. Dissolve the residue in ethyl acetate and shake with water. The ethyl acetate layer is washed with water, 1N hydrochloric acid, and 4% aqueous sodium bicarbonate solution, dried over magnesium sulfate, and then concentrated under reduced pressure. When the obtained pale yellow oil is crystallized by adding n-hexane, about 200 mg of pale yellow crystals are obtained. This was done in a solvent system of chloroform-methanol (10:1),
When purified by silica gel column chromatography,
150 mg of white crystals are obtained. Melting point 210-212℃ (decomposition). This is then treated with trifluoroacetic acid under cooling.
Dissolve in 0.5-1 ml and leave for 30 minutes. Remove trifluoroacetic acid under reduced pressure and add ether.
The title compound precipitates as white crystals and is collected. Yield 80mg. Melting point 244-245°C (decomposed) Example 4: 4-(β-alanylamide)-3-dichloromethyl-3,4,4a,5,6,7-hexahydro-3-methyl-1-oxo-5,6 ,8-trihydroxy-1H-2-benzopyran trifluoroacetate 4-amino-3-dichloromethyl-3,4,
4a,5,6,7-hexahydro-3-methyl-1
-Oxo-5,6,8-trihydroxy-1H-
200 mg of 2-benzopyran hydrochloride and 106 mg of N-tertiary butoxycarbonyl-β-alanine were mixed with 5 ml of tetrahydrofuran-methylene chloride (1:1).
and cooled to -10 to 0°C. Add 62 mg of N-methylmorpholine while stirring. Then 10
After a few minutes, 140 mg of dicyclohexylcarbodiimide was added, and the mixture was stirred at the same temperature for 1 hour. Then leave it in the refrigerator overnight. When treated according to Example 3, 120 mg of white crystals of the protected intermediate are obtained. Melting point 145-149°C (decomposition). Further treatment according to Example 3 yields 80 mg of the title compound as white crystals. Melting point 145-148°C (decomposed) Example 5: 4-(D-2-amino-2-phenylacetamide)-3-dichloromethyl-3,4,4a,
5,6,7-hexahydro-3-methyl-1-
Oxo-5,6,8-trihydroxy-1H-
2-benzopyran hydrochloride 4-amino-3-dichloromethyl-3,4,
4a,5,6,7-hexahydro-3-methyl-1
-Oxo-5,6,8-trihydroxy-1H-
2-benzopyran hydrochloride 200mg and N-tertiary butyloxycarbonyl-D-phenylglycine
170mg and 1-oxy-benzotriazole 90
Dissolve mg in 4 ml of tetrahydrofuran, -10 to 0
Cool to ℃. While stirring, add 62 mg of N-methylmorpholine and after 10-15 minutes add 140 mg of dicyclohexylcarbodiimide. Stir for an additional hour at the same temperature and then leave in the refrigerator overnight. After the reaction is completed, the treatment is carried out according to Example 3.
200 mg of white crystals of the target N-tertiary butoxycarbonyl derivative are obtained. Melting point 164-165.5℃
(Disassembly). Next, this is dissolved in a few drops of concentrated hydrochloric acid under cooling and immediately concentrated under reduced pressure. Crystallize by adding ether and take off to give 150 mg of the title compound as white crystals. Melting point 178-180°C (decomposition) Example 6: 3-dichloromethyl-3,4,4a,5,6,7
-Hexahydro-4-(L-2-hydroxypropionylamide)-3-methyl-1-oxo-5,6,8-trihydroxy-1H-2-benzopyran 4-(L-2-aminopropionylamino)-
3-dichloromethyl-3,4,4a,5,6,7-
hexahydro-3-methyl-1-oxo-5,
Dissolve 210 mg of 6,8-trihydroxy-1H-2-benzopyran hydrochloride in 4 ml of water, add a few drops of concentrated hydrochloric acid, and add 70 mg of sodium nitrite while stirring at room temperature. After 1-2 hours, add another drop of concentrated hydrochloric acid and 70 mg of sodium nitrite. Continue stirring at the same temperature for an additional 4 to 5 hours. After the reaction is complete,
Add water to the reaction solution and extract with ethyl acetate. After drying with sodium sulfate, it is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography using a solvent system of chloroform-methanol (10:1) to obtain 80 mg of the title compound as white crystals. Melting point: 241-244°C (decomposition) The following compounds are produced according to the above examples.

◎ 3-dichloromethyl-3,4,4a,5,6,
7-hexahydro-4-(L-methionylamide)-3-methyl-1-oxo-5,6,8-
Trihydroxy-1H-2-benzopyran trifluoroacetate, melting point 106-110℃ (decomposition) ◎ 4-(L-2-amino-2-phenylacetamide)-3-dichloromethyl-3,4,4a,
5,6,7-hexahydro-3-methyl-1-
Oxo-5,6,8-trihydroxy-1H-
2-benzopyran trifluoroacetate, melting point
137-138℃ (decomposition) ◎ 4-Glycylamide-3-dichloromethyl-
3,4,4a,5,6,7-hexahydro-3-
Methyl-1-oxo-5,6,8-trihydroxy-1H-2-benzopyran trifluoroacetate, melting point 144-147℃ (decomposition) ◎ 3-dichloromethyl-3,4,4a,5,6,
7-hexahydro-3-methyl-1-oxo-
4-(2-pyridylcarbonylamide)-5,
6,8-trihydroxy-1H-2-benzopyran, melting point 139-140℃ (decomposition) ◎ 3-dichloromethyl-3,4,4a,5,6,
7-hexahydro-3-methyl-1-oxo-
4-stearoylamide-5,6,8-trihydroxy-1H-2-benzopyran, melting point 118~
120℃ (decomposition)

Claims (1)

[Claims] 1. General formula A novel benzopyran derivative or its salts represented by: (In the formula, R represents an amino acid residue selected from glycine, β-alanine, phenylglycine, methionine, or proline, an alkanoyl group, a hydroxy-substituted alkanoyl group, a phenyl-substituted alkanoyl group, or a pyridylcarbonyl group.)