JPS6049635B2 - 2-phenyl-4H-1,3-thiazine derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 2-phenyl-4H-1,3-thiazine derivatives and methods for producing such derivatives.

That is, the first aspect of the present invention represents a group of the general formula [1] (wherein Z represents the following formula: R.sRl, R2 and R3 may be the same or different, and represent hydrogen or a group having 1 to 2 carbon atoms. The present invention provides a 2-phenyl-bi-1,3-thiazine derivative represented by the formula (indicating an alkyl group).

Conventionally, several methods for producing 4H-1,3-thiazines have been reported, but no method for producing 4H-1,3-thiazines having a carboxyl group or its ester group at the 5-position has yet been reported. It has not been.

According to the method of the present invention, the compound of the general formula [1] is a compound of the general formula [■] (wherein R,, R2 and R3 have the above-mentioned meanings, and R'' is an alkyl group having 1 to 2 carbon atoms. A compound in which the group Z(7)R in the general formula [1] represents an alkyl group having 1 to 2 carbon atoms is obtained by reacting the compound (representing a group) with phosphorus pentasulfide, and if desired, this compound is hydrolyzed. It can be produced by obtaining a corresponding compound of general formula [1] in which R represents hydrogen.

Specifically, according to the second invention, the general formula [■] (
In the formula, R1, R2 and R3 may be the same or different and represent hydrogen or an alkyl group having 1 to 2 carbon atoms, and R'' represents an alkyl group having 1 to 2 carbon atoms. General formula [1''] (in the formula, Z
"represents a group of the following formula: 2-phenyl-4-H-1 represented by R" R1, R2 and R3 have the same meanings as above)
, 3-thiazine derivatives are provided.

Further, according to the third aspect of the present invention, the general formula [old (formula, R1
, R2 and R3 may be the same or different and represent hydrogen or an alkyl group having 1 to 2 carbon atoms, and R'' is an alkyl group having 1 to 2 carbon atoms.
The α-benzamidomethyl-β-keto acid ester represented by the alkyl group of 2) is reacted with phosphorus pentasulfide to form a compound of the general formula [1″] (where Z″ represents a group of the following formula: "R1, R2 and R3 have the same meanings as above)", and then this compound is hydrolyzed to form R of the group z" in the general formula [■"]
2-, characterized in that a corresponding compound is obtained in which ″ is hydrogen;
A method for producing a phenyl-1,3-thiazine derivative is provided.

The reaction of the former compound with phosphorus pentasulfide is usually carried out in a suitable organic solvent such as benzene, toluene, xylene, ethyl ether, etc., preferably at the reflux temperature of the solvent.

In the case where R in the group Z of the compound of formula (1) represents an alkyl group having 1 to 2 carbon atoms, the intermediate compound [1''] in the method of the third invention is usually hydrolyzed with water. This can be carried out in the presence of a base such as sodium oxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., using a solvent such as water, aqueous methanol, or aqueous ethanol.

The compound of general formula [■] used as a raw material is Chem
．． Ber. ,? , 1599 (1959).

The compounds of general formula [1] according to the present invention exhibit interesting pharmacological effects, particularly remarkable antispasmodic effects, and are therefore useful as medicines.

Next, the present invention will be further explained with reference to Examples, but these Examples are not intended to limit the present invention in any way.

Example 1 2-phenyl-6methylated-1,3-thiazine-5-
Ethyl carboxylate and 2-phenylene-6-methylene-5,6-dihydro-1,3-thiazine-5-carboxylate Ethyl 2-benzamidomethylacetoacetate (13.15 ml) dissolved in dry toluene (200 ml)
mg, 50 mmol) was added dropwise to a suspension of phosphorus pentasulfide θ(6.5y) in dry toluene (100 ml) over 3 hours under reflux stirring.

The mixture was stirred for 4 hours and cooled, followed by a 10% aqueous sodium hydroxide solution (200 ml) and ether (100 ml).
1) was added and stirred vigorously to dissolve the precipitated solid. After separating the resulting organic layer, the aqueous layer was extracted with ether and the extracts were combined with the organic layer. This organic layer was heated to 1N
The mixture was extracted with hydrochloric acid (50 mL x 5), and further extracted in the same manner with hydrochloric acid. The 1N hydrochloric acid extract was adjusted to PHL2 with a 10% aqueous sodium hydroxide solution and extracted with ether.

After washing the ether layer FO with water and removing the solvent after drying, 1.614 g (12.4%) of almost pure ethyl 2-phenyl-6-methylene-5,6-dihydro-4H-1,3-thiazine-5-carboxylate was obtained. Obtained. Further, this product was distilled under reduced pressure to obtain a pure product. Bpl4O-142℃/0.
2Tf$LHgO elemental analysis (Cl4Hl5NO2S) Calculated value: C%64.3 Table H%5.7gsN%5.36 Actual value: C%63.99sH%6.1 TonN%5.13 Add the hydrochloric acid extract in the same manner 1.035y of yellow oil was obtained.

The NMR spectrum reveals that this oil is 2-phenyl-6
It is a mixture of ethyl-methyl-1,3-thiazine-5-carboxylate and ethyl 2-phenyl-6-methylene-5,6-dihydro-4H-1,3-thiazine-5-carboxylate in a ratio of 66:34. It was confirmed that there is. This oily substance was separated by silica gel chromatography (eluent: 2% ethyl acetate-benzene) to obtain each pure product. The physical properties of the obtained ethyl 2-phenyl-6-methyl-4H-1,3-thiazine-5-carboxylate are as follows. Bpl38-140ruC/0.4T
! $THg elemental analysis (Cl4Hl5NO2S) calculated value:
C%64.34, H%5.7 Song N%5.36 Actual value: C
%64.22, H%5. Silk, N% 5.3L Example 22-
phenyl-5-ethyl-6-methylene-5,6-dihydro-1,3-thiazine-5-ethyl carboxylate 2-
Ethyl benzamidomethyl-2-ethylacetoacetate (
40y) and phosphorus pentasulfide (12.0q) in the same manner as in Example 1, and in the post-treatment, extraction with hydrochloric acid was performed with only hydrochloric acid, and the following treatment was carried out in the same manner as in Example 1 to obtain an oily substance 11. I got 379.

Further vacuum distillation yields the title compound 8.755y3(22
．． 6%). Bpl52-155℃/0.2? Hg
Elemental analysis (Cl6Hl9NO2S) calculated value: C%66.
40, H% 6.62, N% 4.84 Actual values: C% 66, H% 6.61, N% 4.93 Also, in place of 2-benzamidomethyl-2-ethyl acetate, the following table Using a compound having substituents R1, R2, R3, and R'' (R) shown in Table 1, the same operations as in Example 2 were carried out to obtain product [1] shown in the same table.

4C Example 77 2-Phenyl-6-methyl-1,3-thiazine-5-carboxylic acid 2-phenyl-6-methyl-
Ethyl 1,3-thiazine-5-carboxylate (1.837
y), 0.5N aqueous sodium hydroxide solution (15.4ml
) and ethanol (35ml) at room temperature.
Stir for hours.

After ethanol was then distilled off, the residue was diluted with water (30ml) and extracted with ether. The aqueous layer was adjusted to pH3 with 1N hydrochloric acid.
The chloroform layer was washed with water, dried and concentrated to give the title compound 1.327V (81.3%).
) was obtained. Mpl4O-141℃ elemental analysis (Cl2Hl
lNO2S) Calculated value: C%61.78F. H%4.7 to N%6.00 Actual value: C%61.52, H%4.8 to N
%5.83 Example 8 This example illustrates the antispasmodic action of compounds according to the invention.

The inhibitory effect of the compounds according to the invention on smooth muscle spasm was determined by an in vitro test using the uterine muscle and ileum of rats according to the Magnus method.

In the test, the following muscle contracting agent is placed in a tissue culture medium, the test muscle is suspended in the tissue culture medium to contract, and then the following test agent (
This was carried out by adding the compounds of the present invention and control compounds) to the culture medium. ~ Muscle contracting agent: bradykinin (B
K), acetylcholine (Ach), histamine (HT)
, serotonin (5-HT), barium chloride (BaCl.

) B) Test drug: Compound of the present invention Example 1 (2-phenyl-6-methylene-5,6-dihydro decoy-1,3-
ethyl thiazine-5-carboxylate), compounds of Examples 3 and 5; control compounds - papaverine, anginine, homoc
Romine, atropine.

The test results are shown in the table below according to the 50% antagonistic concentration (concentration required to relax muscle contraction by 50%) of each test compound (Pylml, however, numbers marked with * are Nflml*). .

From the above results, the following is recognized.

(1) The compounds of Examples 1, 3, and 5 all exhibit significant antispasmodic activity, and this activity is superior to that of papaverine, which is a pro-muscular antispasmodic drug and is represented by 1.

(2) Since both have almost no effect on the muscle contraction of BaCI2, it is recognized that these are not muscle relaxing effects, but rather specific effects for each. (3) The repelling K effect of the compound of Example 5 is considerably superior to that of control drug 2, unginine, in a test tube.

Claims (1)

[Claims] 1. General formula [I]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] (in the formula, Z
represents the group R, R_1, R_
2 and R_3 may be the same or different and represent hydrogen or an alkyl group having 1 to 2 carbon atoms. 2 General formula [II]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼[II] (In the formula, R_
1, R_2 and R_3 may be the same or different and represent hydrogen or an alkyl group having 1 to 2 carbon atoms, and R' represents an alkyl group having 1 to 2 carbon atoms) The general formula [I ′] is characterized by the action of phosphorus pentasulfide on a keto acid ester: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [ I ′] (In the formula, Z′ is the following formula: ▲ Mathematical formula, Chemical formulas, tables, etc. are available ▼ or ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ represents the group R'R^1, R_
2 and R_3 have the same meanings as above). 3 General formula [II]: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] [In the formula, R_
1, R_2 and R_3 may be the same or different and represent hydrogen or an alkyl group having 1 to 2 carbon atoms, and R' represents an alkyl group having 1 to 2 carbon atoms) By reacting phosphorus pentasulfide with a keto acid ester, the general formula [I ′]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I ′] (in the formula,
Z' represents the group of the following formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and R'R^1, R_
2 and R_3 have the same meanings as above), and then hydrolyze this compound to obtain a corresponding compound in which R' of the group Z' in the above general formula [I'] is hydrogen. 2-phenyl-4H-1,3
- A method for producing a thiazine derivative.