JPS62158267A - 4-alkyl-1,5-benzothiazepin derivative and preparation thereof - Google Patents

Abstract

NEW MATERIAL:4-Alkyl-2,3,4,5-tetrahydro-1,5-benzothiazepin derivative of formula I (A is piperidino, substituted piperidino, N-substituted piperazinyl, phenethylamino, substituted phenethylamino; R is lower alkyl) and its acid adduct. EXAMPLE:4-Ethyl-5-[3-[2-(3, 4-dimethoxyphenyl)ethyl]amino]propionyl-2, 3, 4, 5-tetrahydro-1,5-benzothiazepin fumarate. USE:Hypotensor or antiarrhythmic. PREPARATION:A compound of formula II reacts with another compound of formula III (X is halogen) to form a compound of formula V, which is allowed to react with a compound of formula: H-A to give the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a novel 4-furkyl-1,5-benzothiazepine derivative useful as a pharmaceutical and a method for producing the same.

Prior Art While researching 1,5-benzothiazepine derivatives, the present inventors discovered that a series of new compounds, as detailed below, were useful as antihypertensive agents or antiarrhythmic agents. The inventors discovered this and created the present invention.

Structure of the Invention The compound according to the present invention is a compound expected to be useful as a hypotensive agent or an antiarrhythmic agent, and has the general formula (I): (wherein A is a piperidi7 group, a substituted 4-furkyl-2,3,4,5 represented by 7 piperidi groups, N-substituted piperazinyl groups, 7 7-enethylamides, or 7 substituted 7-enethylami groups, and R represents a lower alkyl group. The same applies hereinafter) -tetrahydro-1,5-benzothiazepine derivatives and pharmaceutically acceptable acid addition salts of this compound.

Examples of compounds belonging to the present invention include the following.

(1) 4-ethyl-5-[3-(2-(3,4-nomethoxyphenyl)ethyl)amino1propionyl-2,3
,4,5-tetrahydro-1,5-benzothiazepine 7malate (2) 4-ethyl-5-[3-(4(-2,g,4-trimethylphenyl)methyl)piperazin-1-yl ]Propionyl-2,3,4,5-tetrahydro-1,5
-Benzothiazepine hydrochloride (3) 4-ethyl-5-[3-(4-(4-methoxyphenyl)methyl)biperanon-1-yl 1-propionyl-2,3,4,5-tetrahydro 1° 5-benzothiazepine hydrochloride (4) 4-methyl-5-
[3-(2-phenylethyl)ami7]propionyl-
2,3,4,5-tetrahydro-1,5-benzothiazepine 7malate (5) 4-methyl-5-[3-(2-(3,4-cy'methoxyphenyl)ethyl)ami/ 1 propionyl-2,
3,4,5-tetrahydro-1,5-benzothiazepine 7malate (6) 4-methyl-5-[3-(4-hydroxy-4-
(p-chlorophenyl)-piperidi/1propionyl-
2,3,4,5-tetrahydro-1,5-pentthiazepine fumarate (7) 4-methyl-5-[3-(4-(2,3,4-trimethoxyphenyl)methyl)piperazine-1 -il 1
Propionyl-2,3,4,5-tetrahydro-i,s
-Benzothiazepine 7malate (8) 4-methyl-5
-(3-(4-phenyl)ethyl-piperazin-1-yl 1propionyl-2,3,4,5-tetrahydro-1
, 5-benzothiazepine hydrochloride (9) 4-methyl-5-[3-(4-phenyl)methylbiperazin-1-yl 1-propionyl-2,3,4,5
-tetrahydro-a-i, s-benzothiazepine hydrochloride (10) 4-methyl-5-[3-(4-(3,4-dimethoxyphenyl)methyl)piperazin-1-yl 1-propionyl-2 ,3,4,5-tetrahydro-1,5-
Benzothiazepine hydrochloride (11), 4-methyl-5-(3-piperidi/)propionyl-2,3,4,5-tetrahydro-1,5-penzothiazepine 7malate (12) 4-methyl- 5-[3-(4-(p-methoxyphenyl)methyl)piperazin-1-yl 1-propionyl-2,3,4,5-tetrahydro-1°5-benzothiazepine hydrochloride (13) 4- Ethyl
5-(3-piperidino)propionyl-2,3,4,5
-Tetrahydro-1,5-benzothiazepine 7malate (1'4)4-ethyl-5-[3-(4-phenylethyl)piperazin-1-yl 1propionyl-2,3,4
, 5-tetrahydro-1,5-benzothiazepine hydrochloride The compounds (1) to (14) above are hereinafter referred to as compounds (1) to (14).

The compound of the present invention can be produced as follows.

First, a compound represented by the general formula (■): (wherein R is the same as above) is added to the compound represented by the general formula (III)
CH2-X 11 (III) (wherein, X represents a halogen atom.

The same applies hereinafter) A compound of general formula (IV) is obtained by reacting the compound of formula (IV).

(In the formula, R and However, A
is the same as above) The desired compound of general formula (1) can be obtained by reacting the compound represented by the formula (1). These compounds can be purified by conventional methods and used as they are, or they can be reacted with inorganic acids such as hydrochloric acid and sulfuric acid, and PIi acids such as 7-maric acid, maleic acid, and succinic acid in the form of acid addition salts. used.

As the substituted piperidine of general formula (V), 4-hydroxy-4-p-chlorophenyl-piperinone such as
-substituted product, and as N-substituted piperazine, N-(
p-methoxyphenyl)methylpiperazine, N-(2
, 3,4-trimethoxyphenyl)methylbiperanone and the like. As the substituted 7enethyl group, a dimethoxyphenylethyl group can be mentioned.

Further, the compound of general formula (II) which is a starting material is J, O
rg, Chem, 1984+ 49, 116-122
It can be obtained by either of the following routes (a) and (b) according to the method described in p.

“(In the formula, R is the same as above) The reaction between the compound of general formula (II) and the compound of general formula (II) is generally carried out in the presence of a base in an inert solvent that does not participate in this reaction. It will be carried out at

As the solvent, in addition to alfur-based solvents and benzene-based solvents, ether-based solvents such as nooxane and tetrahydrofuran can be used. Examples of the base used include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, pyridine, and triethylamine.

In addition, the reaction between the compound of general formula (1'/) and the compound of general formula (V) is carried out using 2 equivalents of the compound of general formula (V) in an inert solvent that does not participate in this reaction. One equivalent may be used as a deoxidizing agent, or one equivalent may be used in the presence of a base. The base in this case is
Sodium hydroxide, potassium hydroxide, sodium carbonate,
Sodium bicarbonate, pyridine, triethylamine, morpholine, etc. can be used.

The reaction proceeds at room temperature, but may be heated depending on the case.A reference example showing an example of the production of a compound of general formula (tl) and an example of the method of the present invention are listed below. It goes without saying that the invention is not limited to these examples, and that various modifications may be made without departing from the present invention.

(Reference Example 1) 4-ethyl-2,3,4,5-tetrahydro-1,5
-Preparation of benzothiazepine 0-Ami7 5 g of benzenethiol and 5 g of ethyl vinyl ketone were added to 60 ml of benzene, and heated under reflux for 12 hours using a Dean and Stark water separator. After 4, the solvent is distilled off and the residue is distilled under reduced pressure. 115-b 42g, 4-ethyl-2,3-dihydro-1°5
- Obtain benzothiazepines.

Next, 6.4 g of this 4-ethyl-2,3-dihydro-1,5-penzothiazebin was dissolved in 30 ml of methanol, cooled with water, 43.9 g of NaB H was added, and after stirring for 2 hours, 10 ml of acetone was added. Add and concentrate.

Dissolve the residue in benzene, dehydrate with anhydrous sodium sulfate,
The solvent is distilled off (4.8 g). The target product was distilled under reduced pressure to obtain a fraction (3,3
g). Melting point 56-7°C%M, S', (m/
e) 192 (M”), 135 (B, P) (Example 1) 4-ethyl-5-[3-[2-(3,4-dimethoxyphenyl)ethyl 1-amino]propionyl-2°3.4 ．．
5-tetrahydro-1,5-zenzothiazebine, 7-marate salt (compound 1) (Step 1)... 4-ethyl-5-(3-chloro)propionyl-2,3,4,5-tetrahydro- 1゜5
-Production of benzothiazepine Add 4-ethyl-2,3,4゜5- to 30 ml of toluene.
Tetrahydro-1,5-benzothiazepine 2,0g and 1.0 g of pyridine are added, and 1.6 g of 3-chloroprobionyl chloride is slowly added dropwise under water cooling. After the addition, the mixture was stirred at room temperature for 2.5 hours.

After washing the toluene layer with water and dehydrating (anhydrous sodium sulfate), the solvent was distilled off to obtain 3.0 g of the target product (oil).

M, S, (IIl/e), 285 (M” +1 ) (Step 2)... 0.64 g of the compound from the synthesis of compound (1) (Step 1) and 0.82 g of homoveratrylamine in 15+nl of ethanol Dissolve and heat under reflux for 5 hours.After 4 hours, the solvent is distilled off, and the residue is purified by column chromatography (eluent = chloroform:methanol (10:1)) using silica gel (0.6 g). /-l and add an equivalent amount of 7-maric acid to obtain 7-malic acid salt. Melting point: 248-250°C, M, S, (+a/e) 428 (M"-7v-malic acid) 1,
R, 3050, 2500, 1670, 1520, 143
0,1280 cm-' In the same manner as in Example 1, the compound (
2), (3) to (14) were obtained. The structural formula and melting point are shown in the table below.

Claims (2)

[Claims] (1) General formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼・・・(I) (However, in the formula, A is a piperidino group, a substituted piperidino group, an N-substituted piperazinyl group, or a phenethyl group. 4-alkyl-2 represented by an amino group or a substituted phenethyl amino group, and R represents a lower alkyl group, respectively.
, 3,4,5-tetrahydro-1,5-benzothiazepine derivatives, or acid addition salts thereof that are acceptable for pharmaceutical production. (2) General formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・(
II) (In the formula, R represents a lower alkyl group) and the general formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(III
) (However, in the formula, X represents a halogen atom.) General formula (IV) obtained by reacting with a compound represented by: ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・( IV) (R, -represents a substituted piperazinyl group or a substituted or unsubstituted phenethyl amino group) General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼...・・・・・・(
I) A method for producing a 4-alkyl-2,3,4,5-tetrahydro-1,5-benzothiazepine derivative represented by (R and A are the same as above).