JPS62123181A - Novel benzothiazine derivative - Google Patents

Abstract

NEW MATERIAL:A benzothiazine derivative of formula I (R<1> is H, lower alkyl, halogen, nitro, hydroxy, lower alkoxy, lower alkanoyloxy, amino, lower- alkylamino or lower alkoxycarbonyl; R<2> is H, lower alkyl, C3-C6 cycloalkyl; R<3> is H, lower alkyl, hydroxy; R<4> is H, lower alkyl; A, B are 1-6C alkylene) and its salts. EXAMPLE:3, 4-Dihydro-2-[ 5-methoxy-2-[4-[N-methyl-N-[2-[3, 4-methylenedioxy) phenoxy]ethyl]amino]butoxy]phenyl}-4-methyl-3-oxo-2H-1,4-benzothiazine. USE:It is used for circulatory diseases such as hypertension or thrombosis. PREPARATION:For example, a reaction is carried out as shown in the reaction equation to give the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The compound of the present invention has platelet aggregation inhibitory activity, calcilam antagonistic activity, etc., and is useful as a therapeutic agent for cardiovascular diseases.

[Prior Art] Not much research has been conducted on benzothiazine derivatives useful as pharmaceuticals, and in particular, published documents prior to the present invention that disclose compounds useful for cardiovascular diseases, which is the object of the present application, are published by the same inventor as the present application. Japanese patent publication 59-1 by
48771 etc. 8 The present inventors further researched the above technology and discovered a useful new compound 0 The chemical structure of the compound of the present application is characterized in that the phenyl group at the 2-position of the benzothiazine ring is substituted or unsubstituted phenyl. It has a side chain containing an oxy group, and is disclosed in Japanese Patent Application Laid-Open No. 148771/1983.
Other prior art related to compounds having a benzothiazine ring that are not disclosed by J. Krapc.
ho (U, S, Pat, No.

3166554), 5tearns etc. (U, S, Pat
, No. 3555156) and 5tanley
O, etc. (Can, Pat.

No. 717979), but the structures of the compounds disclosed in these patents are different from those of the present compound, and the purpose of the invention is also different. That is, J, Kr
The apcho patent is aimed at the treatment of Birkinnon's disease, the patents such as 5tearns are aimed at insecticides, and the patents such as 5tan167 are aimed at drugs with anticholinergic and antihistamine effects. That is.

[Problems to be Solved by the Invention] The usefulness of compounds in which the phenyl group at the 2-position of the benzothiazine ring has a side chain containing a substituted or unsubstituted phenyloxy group has not been known. The basic objective is to find more useful therapeutic agents for circulatory system diseases.

Means and Effects for Solving Problem c] The present invention is based on the general formula [I] [wherein R1 is a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a hydroxy group, a lower alkoxy group, a lower alkanoyloxy group, Indicates one or more groups selected from an amine group, a lower alkylamino group, or a lower alkoxycarbonyloxy group.

R2 represents a hydrogen atom, a lower alkyl group, or a (C-C6) cycloalkyl group.

R3 is a hydrogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a halogen atom, a nitro group, a lower alkylenedioxy group, a lower alkanoyloxy group, a lower alkanoyl group, an amino group, a lower alkylamino group, a lower alkanoylamino group, or Lower alkoxycarbonyloxy R4 represents a hydrogen atom or a lower alkyl group.

A and B are the same or different and represent a lower alkylene group having 1 to 6 carbon atoms, n represents 3 or 4, the same applies hereinafter. ] The present invention relates to compounds represented by the following and salts thereof, methods for producing them, and therapeutic agents for circulatory system diseases containing these compounds as active ingredients.

To explain the groups defined above in more detail, a lower alkyl group refers to an alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, and a halogen group, and a halogen atom refers to a fluorine atom. , chlorine, bromine, etc., lower alkoxy group refers to alkoxy having 1 to 6 carbon atoms such as methoxy group, nidoxy group, propoxy group, hexyloxy group, and lower alkanoyloxy group refers to acetyloxy group, It refers to an alkanoyloxy group having 1 to 6 carbon atoms such as propionyloxy group and hexanoyloxy group, and (CNCB) cycloalkyl group refers to an alkanoyloxy group having 3 to 6 carbon atoms such as cyclopropyl group and cyclohexyl group. It represents a cycloalkyl group, and a lower alkylenedioxy group represents a group in which an alkylene group having 1 to 6 carbon atoms is present between two oxygen atoms, such as a methylenedioxy group or an ethylenedioxy group; The lower alkanoyl group refers to an alkanoyl group having 1 to 6 carbon atoms such as an acetyl group, a propionyl group, and a hexanoyl group.

The compound of the present invention can be produced, for example, by the following method.

[H] [[] [wherein, A method of reacting with amine derivatives.

That is, a method of reacting a compound represented by general formula [TV] with a compound represented by general formula [V].

That is, a method of reacting a compound represented by general formula [VI] with a compound represented by general formula [■].

The reactions shown above are usually carried out under basic conditions.

Examples of preferred bases include sodium hydride, potassium carbonate, sodium carbonate, sodium hydroxide, sodium alcoholade, triethylamine, pyridine, N,N
- Inorganic or organic bases such as dimethylaniline.

Further, the above reaction can be carried out without using a base by using an excess amount of the amine component involved in the reaction.

Although the compounds of the present invention have stereoisomers, all of them are included in the present invention.

The optically active form of the compound [I] of the present invention can be obtained using a racemic form by known methods, such as optical resolution using an optically active organic acid such as mandelic acid, fractionation using a cellulose triacetate column, and the like. Furthermore, in the method for producing the compound of the present invention [11] described above, the compound of the present invention [I] can be obtained as an optically active compound by using a raw material for an optically active compound.

An example of a method for producing an optically active raw material is shown below.

[In the formula, R5 represents a carboxylic acid residue having one or more asymmetric carbon atoms.] First, a carboxylic acid [[ ] having an asymmetric carbon atom and a racemic form [TV] are combined using a condensing agent such as DCC. The formula [IX
] A diastereomer mixture is obtained. Then, after separating this diastereomeric mixture, R” GO-
The optically active form of the compound represented by formula [IV] is obtained by removing the group by hydrolysis, reduction, or the like. Using this optically active form, an optically active form of the compound CI of the present invention] can be obtained.

Conditions such as the solvent and reaction temperature used in the above reaction are not particularly limited and can be appropriately selected depending on the type of base, the solubility of the reaction components, etc.

The compounds of the present invention can be in the form of pharmaceutically acceptable salts. Examples of salts include hydrochloride, sulfate, phosphate, lactate, maleate, fumarate, oxalate, methanesulfonate, paratoluenesulfonate, and the like.

The compounds of the present invention can be administered orally or parenterally. Dosage forms include tablets, capsules, granules, powders,
Examples include skewers, injections, and eye drops. Dosage depends on symptoms,
It depends on the dosage form, etc., but usually 1 to 5,000 doses per day.
mg, preferably IQ Nl, 000 mg, is administered once or in several doses.

The compounds of the present invention have platelet aggregation inhibitory effects and calcium antagonistic effects, and are useful for circulatory system diseases such as hypertension, thrombosis, and arrhythmia. Below, as an example of a pharmacological test to explain the effects of the compounds of the present invention, a test example regarding calcium antagonism will be shown.

As a representative example of the compound of the present invention, 3,4-dihydro-2-[
5-methoxy-2-[4-[N-methyl-N-[2-[
(3,4-methylenedioxy)phenoxy]ethyl]amino]bu)+cy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate (hereinafter abbreviated as the present compound A) , 3,4-dihydro-2-[5
-methoxy-2-[3-[N-methyl-N-[2-[(
3,4-methylenedioxy)phenoxy]ethylcoamino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate (hereinafter
The compound of the present invention is abbreviated as B), 3,4-dihydro-2-[
5-methoxy-2-[4-[N-methyl-N-[2-[
(3,4-dimethoxy)phenoxy]ethyl]amino]
Butoxy]phenyl]-4-methyl-3-oxo-2H
-1,4-benzothiazine oxalate (hereinafter abbreviated as the present compound C) was used in the test.

As a comparative compound, 3゜4-dihydro-2-[5-methoxy-2-[4- [N-Methyl-(3,4-dimethoxy)phenethylamino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate (melting point L45-147°C) was used.

[Pharmacological test] (Method for measuring calcium antagonistic activity) A guinea pig colon cord isolated at 32°C is suspended in an organ bath filled with Krebs solution, and oxygen containing 5% carbon dioxide gas is blown into the organ bath. Remove Ca"""kr
Suspend in EBS liquid.

Muscles were pretreated with test compounds for 5 min before addition of Ca C12, and contractions elicited by Ca C12 (3×10 M) were recorded isotically.

Calcium antagonistic activity was expressed as the concentration of the test compound exhibiting 50% inhibition (IC5o) of Ca''-induced contractions.

(Experimental results) Compound IC [M] Wood compound ThA 3, 2 X 10-7 A
[llz Compound B 2, 4 X I O-7 Wood J
ilHf, compound C2, 9x 10-7 comparison compound
3.2X10-6 [Example] Example 1 3.4-dihydro-2-[5-methoxy-2-[4-[
N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]butoxy]phenyl]
-4-Methyl-3-dihydro-2H-1,4-benzothiazine oxalate 3,4-dihydro-
2-(2-hydroxy-5-methoxyphenyl)-3-
A solution of oxo-2H-1,4-benzothiazine (0.9 g) in anhydrous dimethylformamide (10 ml) was added dropwise with stirring, and after the addition was completed, the mixture was stirred for 15 minutes.

Add 4-[N-methyl-N-[2-[(3,4
A solution of (methylenedioxy)phenoxy]ethylcoamino]butoxypromide (1.2 g) in anhydrous dimethylformamide (10 ml) was added dropwise with stirring and stirred at 50°C for 2 hours.
ml) and 2N hydrochloric acid (50 ml), and the organic layer was separated and concentrated under reduced pressure. Dissolve the residue in ethyl acetate,
Wash with N aqueous sodium hydroxide solution and then with saturated saline. The organic layer is dried with anhydrous sodium sulfate and concentrated under reduced pressure.

The residue is purified on a silica gel column. The resulting oil was dissolved in ethyl acetate, a solution of oxalic acid in ethyl acetate was added, and the precipitated crystals were collected by filtration to yield 1.4 g (73%) of the title compound.
).

Melting point 160-162℃ (ethanol-water) IR (KB
r, cnf, the same below unless otherwise specified): 1655, L5
84,1499,1475°1400.1356,12
77.1238°1205.1185,1132.10
34 The following compounds can be obtained in the same manner as in Example 1.

3.4-dihydro-2-[5-methoxy-2-[3-[
N-Methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate : Melting point 130-131℃ (ethanol) IR: 1654
, 1473, 1239° 1209.1183.1033 Hydrochloride: Melting point 133-134.5°C (ethanol) IR: 24
16,1654,1478°1236.1182.10
34 3.4-dihydro-2-[2-[4-[N-(2-(4
-methoxyphenoxy)ethyl]N-methylamino]butoxy]-5-methoxyphenyl]-4-methyl-3-
Oxalate-2H-1,4-benzothiazine oxalate melting point 149-150°C (ethanol-water) IR:
1674. 1473, 1238.

1218, 1037 3.4-dihydro-2-[5-methoxy-2-[3-[
N-Methyl-N-[2-((3,4,5-trimethoxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothia9F Melting point 137~ 139°C (ethanol-ethyl acetate) IR: 1715.1653.1589.

1489, 1457 3,4-dihydro-2-[4-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)
phenoxy]ethyl]amino]propoxy]phenyl
-4-Methyl-3-oxo-2H-1.4-benzothiazine oxalate Melting point 146-148°C (ethanol) IR: 1648, 1582, 1473.

1399.1356 3.4-dihydro-2-[4-[2-[N-methyl-N
-[2-[(3,4-methylenedioxy)phenoxy]
ethyl]amino]ethoxy]phenyl]-4-methyl-
3-oxo-2H-1,4-benzothiazine oxalate Melting point 97-102°C (acetone) IR: 1647, 1478.1398° 1237.11
82 3.4-dihydro-2-[5-methoxy-2-[2-[
N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amine]ethoxy]phenyl]
-4-Methyl-3-oxo-2H-1,4-benzothiazine oxalate Melting point 129-131.5°C (ethyl acetate-methanol) IR: 1645, 1474, 1399° 1236.11
83 3.4-dihydro-2-[5-methoxy-2-[4-[
N-methyl-N-[2-[(3,4-dimethoxy)phenoxy]ethyl]amino]butoxy]phenyl]-3-
Oxo-2H-1,4-benzothiazine hydrochloride IR2 1653 (C=O) 2- [4-[4-[N-[2-(2-chlorophenoxy)ethyl]-N-ethylamine]butoxy]phenyl] -3,4-dihydro-4-methyl-3-oxo-2H
-1,4-benzothiazine hydrochloride IR: 1655 (C=O) 3.4-dihydro-2-[5-methoxy-2-[4-[
N-Methyl-N-((3,4-methylenedioxy)phenoxy]methylamino]butoxy]phenyl]-4-methyl-3-okita 2H-1,4-benzothiazine oxalate IR: 1654 (C=O ) Example 2 3.4-dihydro-2-[5-methoxy-2-[3-[
N-Methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate 2-[2-(3-bromopropoxy)-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2F (-1,4-benzothiazine (1,2 g) and sodium carbonate (0 , 4 g) in dimethylformamide (5 ml), N-methyl-2-[(3,4-methylenedioxy)phenoxyconitylamine (0.8 g)
and stirred at 80°C for 2 hours.

The reaction solution was mixed with chloroform (50ml) and 2Nl acid (50ml).
1) and then operated in the same manner as in Example 1 to obtain the title compound 1.3 (70%).

Melting point 130-131℃ (ethanol) IR: 16
54. 1473. 1239°1209.1183.
1033 The following compound can be obtained in a similar manner to Example 2.

3.4-dihydro-2-C2-[4-[N-[2-[(
2,6-dimethoxy)phenoxy]ethyl-N-methyl]amino]butoxy]-5-methoxyphenyl]-4-
Methyl-3-year-old xo-28-1,4-benzothiazine
Hydrochloride IR: 1652, 1473, 1238° 1207
．． 1104 3.4-dihydro-2-[5-chloro-2-[3-[N
-Methyl-N-[2-[(3,4-methylenedioxy)
phenoxy]ethyl]amino]propoxy]phenyl]
-4-Methyl-3-oxo-2H-1,4-benzothiazine fumarate Melting point 116-118°C (ethanol) IR: 16
54,1474,1357゜1265, 1240 3.4-dihydro-2-[2-[4-[N-[2-(5
-indanyloxy)ethyl]-N-methylamino]butoxyco-5-methoxyphenylcol-methyl-3-
Oxo-2H-1,4-benzothiazine oxalate Melting point 145-146°C (ethanol-water) IR: 1
673.1474,1239.

3.4-dihydro-2-[4-[4-[N-methyl-N
-[2-[(3,4-methylenedioxy)phenoxy]
ethyl]amino]butoxy]phenyl]-4-methyl-
3-oxo-2H-1,4-benzothiazine oxalate Melting point 105-108°C (ethanol) IR: 16
46,1582,1476°1399.1357 3.4-dihydro-2-[5-methoxy-2-[4-[
N-methyl-N-[2-(phenoxy)ethyl]amino]butoxy]phenyl]-4-methyl-3-xo2
H-1,4-Benzothiazine oxalate IR: 1655 (C=O) 3.4-dihydro-2-[5-methoxy-2-[5-[
N-Methyl-N-[2-[(3,4,5-trimethoxy)phenoxy]ethyl]amino]pentyloxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR : 1655 (C=0) 3.4-dihydro-2-[5-methoxy-2-[4-[
N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]butoxy]phenyl]
-3-Oxo-2H-1,4-benzothiazine hydrochloride IR: 1655 (C=O) 3.4-dihydro-2-[5-chloro-2-[3-[N
-Methyl-N-[2-[(3,4-dimethoxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-
Methyl-3-saiki/-2H-1,4-benzothiazine
Hydrochloride IR+ 1655 (C-0) 3.4-dihydro-2-[5-methoxy-2-[3-[
N-methyl-N-[2-(4-methoxyphenoxy)ethyl]amino]propoxy]phenyl]-3-oxo-
2H-1,4-Benzothiazine fumarate IR: 1656 (C=O) 3.4-dihydro-2-[2-[3-[N-[2-(2
-fluorophenoxy)ethyl-N-methylcoamino]
propoxy]-5-methoxyphenyl]-4-methyl-
3-Oxo-2H-1,4-benzothiazine hydrochloride IR+ 1656 (C=O) 2- [4-[4-[N-cyclopropyl-N-[2-
(4-nitrophenoxy)ethyl]amino]butoxy]
phenyl]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR+ 1656 (C=O) 3.4-dihydro-2-[5-methoxy-2-[ 3-[
N-Methyl-N-(2-[(3,4-dimethoxy)phenoxy]ethyl]amine]propoxy]-4-nitrophenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR+1654 (C=O) 3.4-dihydro-2-[2-[4-[N-ethyl-N
-[2-[(2,3,4-trimethoxy)phenoxy]
ethyl]amino]butoxy]-5-methoxyphenyl]
-4-Methyl-3-oxo-2H-1,4-benzothiazine oxalate I R: 1 653 (C=0)3,4-dihydro-2-[5-methoxy-N-[2-[3- [2-[
(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochloride IR: 1
656 (C=O) 3.4-dihydro-2-[2-[4-[N-[2-(4
-/70lophenoxy)ethyl]-N-cyclohexylamino]butoxy]-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR: 1655 (C=O) 3.4-dihydro-4-methyl-2-[4-[3-[N
-[2-[(3,4,5-1 methoxy)
phenoxy]ethyl]amine]broboxycophenyl]
-3-oxo-2H-1,4-benzothiazine hydrochloride IR: 1657 (C=O) 3.4-dihydro-2-[4-(5-[N-cyclohexyl-N-[2-(4-methyl phenoxy)ethyl]amino]pentyloxy]phenyl]-4-methyl-3-
Oxo-2H-1,4-benzothiazine hydrochloride IR: 1658 (C=O) 3.4-dihydro-2-[4-[5-[N-methyl-N
-[(2,3,4-trimethoxy)phenoxy]methylamino]pentyloxy]phenyl]-4-methyl-3
-Oxo-2H-1,4-benzothiazine hydrochloride IR: 1655 (C=O) Example 3 3.4-dihydro-2-[5-methoxy-2-[3-[
N-Methyl-N-[2-[(3,4-methylenedioxy)phenoxyconityl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate 3.4-dihydro-2-[5-methoxy-2-[3-(
methylamino)propoxy]phenyl]-4-methyl-
3-oxo-2H-1,4-benzothiazine (1,2g
) and triethylamine (0.4 g) in ethanol (
10ml) solution of 2-[(3,4-methylenedioxy)
Phenoxy]ethyl methanesulfonate (1.0g)
was added and heated under reflux for 2 hours. L,
The residue was mixed with chloroform (50 ml) and 2Nfliic acid (50 ml).
ml) and the following procedure was carried out in the same manner as in Example 1 to obtain 1.3 g (65%) of the title compound. The melting point and IR were consistent with the values in Example 2.

The following compounds can be obtained in the same manner as in Example 3.

3.4-dihydro-2-[2-[4-[N-[2-((
3,4-dimethoxy)phenoxy]ethyl-N-methyl]amino]butoxy]-5-methoxyphenyl]-4-
Methyl-3-oxy”/-2H-1,4-benzothiazine oxalate Melting point 167-168°C (ethanol-water) IR: 1
653.1500.1458.

1217.1198 3.4-dihydro-2-[5-methyl-2-[3-[N
-Methyl-N-[2-[(3,4-methylenedioxy)
phenoxy]ethyl]amino]furboxy]phenyl]
-4-Methyl-3-oxo-2H-1,4-benzothiazine fumarate Melting point 114-116°C (ethanol) IR: 16
52. 1582. 1466°1355. 1304 3.4-dihydro-2-[4-[3-[N-[2-(5
-indanyloxy)ethyl-N-methyl]amine]propoxy]-5-methoxyphenyl]-4-methyl-3
-oxo-2H-1,4-benzothiazine oxalate Melting point 107-109°C (ethyl acetate) IR: 1661
,1472,1240°1214.104L 3.4-dihydro-2-[5-methoxy-2-[2-[
N-Methyl-N-[3-[(3,4-methylenedioxy)phenoxy]propyl]amino]ethoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate Melting point 121-126℃ (ethanol) IR: 1627
,1464,1354°1276.1181 3.4-dihydro-4-methyl-2-[4-[4-[N
-Methyl-N-(2-[(3,4-methylenedioxy)
phenoxy]ethyl]aminocobutoxy]phenyl]-
3-Oxo-2H-1,4-benzothiazine Shu M
jlIR: 1654 (C=O) 3.4-dihydro-2-[4-[4-[N-[2-(2
-Fluorophenoxy)ethyl]amino]phthoxy]fecol]-4-methyl-3-oxo-2H-1,4-benzothiazine m acid salt IR+ 1660 (C=O) 3.4-dihydro-2-[4- [4-[N-methyl-N
-[2-(2-chlorophenoxy)ethyl]amine]butoxy]phenyl] -3-oxo-2H-1,4-benzothiazine fumarate IR: 1662 (C=O) 3.4-dihydro-2-[ 5-methoxy-2-[3-[
N-Methyl-N-[(3,4-dimethoxy]phenoxy]methylamino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochloride IR+ 1658 (C-=O) Implementation Example 4 3.4-dihydro-2-[5-methoxy-2-[4-[
N-methyl-N-[2-[(3,4,5-trimethoxy)phenoxy]ethyl]amino]butoxy]phenyl]
-4-Methyl-3-oxo-2H-1,4-benzothiazine oxalate 2- [2-(4-bromobutoxy)-5-methoxyphenyl 1-3.4-dihydro-4-methyl-3-year-old Ztanol (loml) of xo2H-1,4-benzothiazine (1,3g) and triethylamine (0,4g)
Add N-methyl-2-[(3,4,5-trimethoxy)phenoxy]ethylamine (o, 9 g) to the solution and heat under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was mixed with chloroform (50 ml) and 2N hydrochloric acid. (50 ml), and the following procedure was carried out in the same manner as in Example 1 to obtain 1.5 g of the title compound (
73%).

Melting point 149-151'0 (ethanol-water) IR:
1653, 1591.1499.

1458.1234.1217 The following compound can be obtained in a similar manner to Example 4.

3.4-dihydro-2-[5-methoxy-2-[3-[
N-methyl-N-[2-[(2,6-dimethoxy)phenoxy]ethyl]amino]propoxyJ phenyl]-4
-Methyl-3-oxo-2H-1,4-benzthiazine Hydrochloric acid 1! ! Melting point 185-187℃ (ethanol) I
R: 1654. 1584. 1475.

1351.1243 3.4-dihydro-2-[[3-[N-methyl-N-[
2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]-5-nitrophenyl]-4
-Methyl-3-oxo-2H-1,4-benzothiazine fumarate Melting point 135-137°C (ethanol) IR・1654
．． 1584,1477°1388.1260 3.4-dihydro-2-[5-methoxy-2-[3-[
N-Methyl-N-[3-[(3,4=methylenedioxy)phenoxy]propyl]amine]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate Melting point 146-148℃ (ethanol) IR: 16
59, 1583, 1472.

1355.1238 3.4-dihydro-2-[5-methoxy-2-[4-[
N-Methyl-N-[3-[(3,4-methylenedioxy)phenoxy]propyl]amino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate Melting point 135-138℃ (ethanol) TR: 1653
, 1467.1355° Example 5 3.4-dihydro-2-[5-methoxy-2=[4-[
N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]butoxy]phenyl]
Optical resolution of -4-methyl-3-oxo-2H-1,4-benzothiazine by column chromatography using cellulose IJ acetate. grap
hia, P2.27? (1973) c7)) was injected into a column packed with 750 g and eluted with 95% ethanol to obtain free (÷) and (-). A salt of fumaric acid is obtained by a conventional method to obtain 1.62 g of (+) monolithic fumaric acid and 1.50 g of (−) monolithic fumarate.

(+) Integral fumaric acid kpA: Melting point 148.5-149.5°C (ethyl acetate-ethanol) [α几 +195.4° (c = 1.0. dimethyl sulfoxide) IR: 3392.2912, 1653° 1473 .13
53,1239゜1204.1184.1033 (-) Monolithic fumarate: Melting point 149-150℃ (ethyl acetate-ethanol) (methyl sulfoxide) IR: 3380,2910,1653゜1473.13
53.1239°1202.1184.1033 The following compound can be obtained in the same manner as in Example 5.

(+)-3,4-dihydro-2-[5-methoxy-2-
[4-[N-methyl-N-[2-[(3,4,5-1limethoxy)phenoxy]ethyl]amino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine Fumarate melting point 133-135℃ (ethanol) chill sulfoxide) IR: 3400, 1664, 1465゜1220.11
25 (-)-3,4-dihydro-2-[5-methoxy-2-
[4-[N-Methyl-N-[2-[(3,4,5-trimethoxy)phenoxy]ethyl]amino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumar Acid salt melting point 133-135°C (ethanol) tyl sulfoxide) IR: 3400.1663.1465.

1219.1126 (+)-3,4-dihydro-2-[5-methoxy-2-
[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]
phenyl]-4-methyl-3-oxo-2H-1,4-
Benzothiazine fumarate Melting point 133-133.5°C (ethanol) chill sulfoxide) IR: 1653, 1470, 1357° 1267.12
39.11B3゜1139.1106,1034.980(-)-3,4
-dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4
-Methyl-3-year-old xo 2H-1,4-benzothiazine fumarate Melting point 133-133.5°C (ethanol) tyl sulfoxide) IR: 1653. 1466, 1357°126
7.1239. 1183°1139.1106,1033.980 Example 6 3.4-dihydro-2-[5-methoxy-2-[4-[
N-methyl-N-[2-((3,4-methylenedioxy)phenol]ethyl]aminobutoxy]phenyl]
Optical resolution of -4-methyl-3-oxo-2H-1,4-benzothiazine using mandelic acid.L-
Add (+)-mandelic acid (0.59 g) and dissolve.

The precipitated crystals were collected and recrystallized from acetone (÷
) 11.45 g of integral L-(÷)-mandelic acid are obtained.

The solution from which the (+) salt was removed is concentrated under reduced pressure, and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Dissolve the residue in 10 ml of acetone and
-(-)-Mandelic acid (0.59 g) was added to form uniform droplets. The precipitated crystals were collected in a furnace and recrystallized from acetone to obtain 1.52 g of D-(-)-mandelate (-).

(S) Integral L-(÷)-mandelate: Melting point 101
~102.5°C Tylsulfoxide) IR:3396,1664,1584°1500.14
90.1478.

1356.1240,1219°1190.1036.755 (=)Uniform D-(-)-mandelate: Melting point 98.
5-100°C Tylsulfoxide) IR: 3392. 1663, 1583
.

1500, 1487, 1477.

1355.1239.1218゜1188, 1035.754 The above mandelic acid salts can be made into free (+) monomers and (-) monomers by a conventional method, and their fumarate salts can be converted into the salts obtained in Example 5. It was consistent with the physical properties of

The following compound can be obtained in the same manner as in Example 6.

(+)-3,4-dihydro-2-[5-methoxy-2-
[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]ami/]propoxy]
phenyl]-4-methyl-3-oxo-2H-1,4-
Benzothiazine (+)-mandelate Melting point 113.5-114.5°C (acetone)tylsulfoxide) IR: 1666.1584, 1489°1280.
1192.1036°(-)-3,4-dihydro-2-[5-methoxy-2-
[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]
phenyl]-4-methyl-3-oxo-2H-1,4-
Benzothiazine (-)-mandelate Melting point 114-115℃ (acetone) Tylsulfoxide) IR: 1664, 1583, 1488゜1280.11
91.1035 Furthermore, the above-mentioned mandelic acid salts can be converted into free (+) and (-) fumarate salts by a conventional method in the same manner as in Example 6, and their physical properties are as shown in Example 5. This was consistent with the physical properties of the obtained tomb.

Example 7 Optically active 3,4-dihydro-2-(2-hydroxy-5
-methoxyphenyl)-4-methyl-3-oxo-2H
Optically active 3,4-dihydro-2-[5-methoxy-2-,[3-[N-methyl-N-(2-[(3,4-methylenedioxy)phenoxy] using -1,4-benzothiazine) ]ethyl]amino]propoxy]phenyl]-4-
Methyl-3-oxo-2H-1,4-benzothiazine
Preparation of fumarate salt (i) 3,4-dihydro-2-(2-hydroxy-5-
methoxyphenyl)-4-methyl-3-oxo-2H-
A solution of 1,4-benzothiazine (24.1 g) in anhydrous dimethylformamide (100 ml) (2S, 4S)
-3-7cetyl-5,5-dimethyl-2-(2-methoxyphenyl)-4-thiazolidinecarboxylic acid) (37,
1g), 4-dimethylaminopyridine (1,95g),
Dicyclohexylcarbodiimide (DCC) (24,8
A solution of g) in anhydrous dimethylformamide (100 ml) was added in order, and the mixture was stirred at room temperature for 3 hours. After removing insoluble materials, water (500 ml) was added and the mixture was extracted with ethyl acetate (1 sentence). Wash with saturated sodium bicarbonate solution, water, and saturated saline in this order, and dry with anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was separated and purified by silica gel column chromatography.
Types of diastereomers, 2-[2-[(2S,
4S) -3-acetyl-5,5-dimethyl-2-(2
-methoxyphenyl)thiazolidinone-4-ylcarbonyloxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine-A 23°7g (yield 50%) ) and -B
22.7 g (48% yield) are obtained.

Diastereomer A: Roform) IR: 1755, 1646, 1457° 1376.13
28,1279°1242.11B9.1136.

Diastereomer B = Melting point 165-166℃ (benzene-n-hexane loform) 1111756.1 & 53.1457゜1373.13
31,1280゜1244.1192,1139゜(11) To a suspension of sodium borohydride (3.5 g) in absolute ethanol (80 ml) was added the 2-[2-[(2S, 43)-3-acetyl-5,5
-dimethyl-2-(2-methoxyphenyl)thiazolidinon-4-ylcarbonyloxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-
A solution of 2H-1,4-benzothiazine-A (12.0 g) in anhydrous tetrahydrofuran (40 ml) was added under water cooling.
Stir at that temperature for 24 hours. The solvent was distilled off under reduced pressure and water (
150 ml), extracted with ethyl acetate (250 ml), washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting oily residue was subjected to MIL using silica gel column chroma (-)-3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3- 3.0 g (yield 50%) of oxo-28-1,4-benzothiazine is obtained.

Melting point 160.5-161.5℃ (benzene-n-hexane) [α] 25-30, 6' (c=0, 51, chloroform) ER: 3224, 1625.1582゜1429.13
66.1264゜1218.1201 Similarly, 2-[2-[(2S,4S)-3-7cetyl-5.5-dimethyl-2-(2-methoxyphenyl)
Thiazolidinone-4-ylcarbonyloxy]-5-methoxyphenyl]-3゜4-dihydro-4-methyl-3
-oxo-2H-1,4-benzothiazine-B (
+)-3゜4-dihydro-2-(2-hydroxy-5-
methoxyphenyl)-4-methyl-3-oxo-2H-
1,4-benzothiazine is obtained.

Melting point 161.5-162.5°C (benzene-n-hexane) IR: 3220, 1625.15B2.

1429.1366.1264゜1218.1201 (5) (-)-3,4-dihydro- obtained in (ii)
2-(2-hydroxy-5-methoxyphenyl)-4-
Methyl-3-oxo-2H-1゜4-benzothiazine (
To a solution of 6.3 g) in anhydrous tetrahydrofuran (70 ml) were added 3-bromo-1-propatol (8.8 g), ) liphenylphosphine (16.6 g), and diethyl azodicarboxylate (LO, 0 ml) in order, and Stir under air flow for 2 hours. The solvent was distilled off under reduced pressure and purified by silica gel column chromatography to give (-)-3゜4-dihydro-2-(2-
(3-bromopropoxy)-5-methoxyphenyl]-
4.5 g (51%) of 4-methyl-3-oxo-2H-1,4-benzothiazine are obtained.

Melting point: 77-78℃ (ethanol) Roholm) IR: 1643, 1584, 1491.

1464.1359,1271゜1239.1201 Similarly, from (+)-3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (+)-3,
4-dihydro-2-[2-(3-bromopropoxy)-
5-methoxyphenyl]-4-methyl-3-oxo-2
H-1°4-benzothiazine is obtained.

Melting point 78-79°C (ethanol) loform) IR: 1647. 1584. 1492°146
5, 1357. 1271.

1240.1201 Is it? ) (in) (-)-3,4-dihydro-2-(2-(3-bromopropoxy)-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-
Sodium iodide (4.3 g) was added to a solution of benzothiazine (1.2 g) in acetone (30 ml) and heated for 12 hours. The solvent was distilled off under reduced pressure, and water (30%
ml) and extracted with gotyl acetate (50 ml).

The organic layer is washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the resulting residue was dissolved in anhydrous dimethylformamide (20 ml), and N-methyl-2
Add -((3,4-methylenedioxy)phenoxy]ethylamine (0.7 g) and triethylamine (0.3 g) and stir at 50°C for 1.5 hours. After cooling, water (50 ml
l) and extracted with ethyl acetate (80 ml).

The organic layer is washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and a solution of fumaric acid (0.3 g) in ethanol (9 ml) was added to the resulting residue. The precipitated crystals were heated and (−)-3,4-dihydro-2
-[5-methoxy-2-[3-[N-methyl-N-[2
-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenylco-4-methyl-3-
Oki/-2H-1,4-benzothiazine fumarate 1
．． 3 g (70% yield) are obtained.

The physical properties of the above compound were consistent with those of the compound obtained by the method of Example 5.

Similarly (+)-3,4-dihydro-2-[2-(3-
From (÷)-3,4-dihydro-2-[5-methoxy-2
-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4
- Obtain benzothiazine fumarate.

The physical properties of the above compound were consistent with those of the compound obtained by the method of Example 5.

The following compound can be obtained in the same manner as in Example 7.

(+)-3,4-dihydro-2-[5-methoxy,cy2
-[4-[N-methyl-N-[2-[(3,4,5-)
rimethoxy)phenoxy]ethyl]amino]butoxy]
phenyl]-4-methyl-3-okyne-2H-1,4-
Benzothiazine fumarate (-)-3,4-dihydro-2-[5-methoxy-2-
[4-[N-Methyl-N-[2-((3,4,5-trimethoxy)phenoxy]ethylcoamino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumar Acid salt (+)-3,4-dihydro-2-[5-methoxy-2-
[4-[N-Methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amine]butoxy]phecol]-4-methyl-3-ogiso2H-1,4-benzothia Zine fumarate (-)-3,4-dihydro-2-[5-methoxy-2-
[4-[N-Methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amine]budot-t-cibophenyl 1-4-methyl-3-oxo-2H-1,4
-Benzothiazine fumarate The physical properties of the above compound were consistent with those of the compound obtained by the method of Example 5.

Example 8 (Formulation Example) As a representative example of the compound of the present invention, 3,4-dihydro-2-[
5-methoxy-2-[4-[N-methyl-N-[2-[
(3,4-methylenedioxy)phenoxy]ethylcoamino]butoxy]phenyl]-4-methyl-3-oxo-2H to 1.4-benzothiazine salt tolerant (compound A of the present invention), 3.4-dihydro-2- [5-Methoxy-
2-[3-[N-methyl-N-[2-((3,4-methylenedioxy)phenoxyconityl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,
Various formulations were prepared using 4-benzothiazine fumarate (compound B of the present invention).

(i) Tablet The following tablet was prepared by mixing the compound A or B of the present invention and an excipient and directly compression molding the mixture.

Compound A of the present invention 10IIg crystalline cellulose 4B+g lactose
35B hydroxypropylcellulose-L 4mg Compound B of the present invention
10mg crystalline cellulose 48o+g
Lactose 35B Hydroxypropylcellulose-L 41!1g Stearin Magnesium 31100mg i) Capsules The following capsules were prepared using the compound A or B of the present invention and lactose.

Compound A of the present invention Smg Compound B of the present invention Stng Compound A of the present invention
Alternatively, by changing the mixing ratio of B and lactose, capsules containing the compound of the present invention in amounts of 10 ωg/capsule, 30 mg/capsule, 50 mg/capsule, and 100I118/capsule were also prepared.

(ni)'! IJ, Granules Compound A or B of the present invention, lactose and potato starch were mixed and a methanol solution of hydroxypropylcellulose-L was used as a binder to prepare the following granules in a conventional manner.

Compound A of the present invention 50.

Lactose 55mg Potato starch 201g Hydroxypropylcellulose-L 4mg Compound 8 of the present invention
50B lactose
55mg potato starch 20+g hydroxypropylcellulose-L 4+sg talc
'[130 mg Compound A of the present invention and mannitol are mixed, and made into granules by a conventional method using an aqueous solution of -30 in polyvinylpyrrolidone as a binder.
: product name and using triacetin as a plasticizer) by a conventional method, and the following coated granules were coated with yJ.
Manufactured.

Compound of the present invention A 30 mg Mannitol 46.5n+g Polyvinylpyrrolidone K -307mg Eudragit RL
Granules were prepared for L5 mg Compound B in the same manner.

Compound of the present invention 8 30 mg Mannitol 46.5 + Ig Polyvinylpyrrolidone K -307B Eudragit RL 15 ag[
Effects of the Invention] The present invention provides a novel compound that has platelet aggregation inhibitory activity and calcium antagonistic activity and is useful as a therapeutic agent for circulatory system diseases.

Claims (2)

[Claims] (1) General formula [I] ▲Mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, R^1 is a hydrogen atom, lower alkyl group, halogen atom, nitro group, hydroxy group, lower alkoxy group, lower It represents one or more groups selected from an alkanoyloxy group, an amino group, a lower alkylamino group, or a lower alkoxycarbonyloxy group. R^2 is a hydrogen atom, a lower alkyl group, or (C_3~C
_6) Indicates a cycloalkyl group. R^3 is a hydrogen atom, lower alkyl group, hydroxy group, lower alkoxy group, halogen atom, nitro group, lower alkylenedioxy group, lower alkanoyloxy group, lower alkanoyl group, amino group, lower alkylamino group, lower alkanoylamino group or lower alkoxycarbonyloxy groups, or ▲a mathematical formula, a chemical formula, a table, etc.▼. R^4 represents a hydrogen atom or a lower alkyl group. A and B are the same or different and represent a lower alkylene group having 1 to 6 carbon atoms. n represents 3 or 4. ] Compounds represented by these and their salts. (2) A therapeutic agent for circulatory system diseases, which contains the compound or salt thereof as defined in claim (1) as an active ingredient.