JPH02188575A - 1,5-benzothiazepine-3-carboxylic acid compound - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I {R<1> and R<2> are H, halogen, alkyl or alkoxy; R<3> is alkyl, (substituted)phenyl, (substituted) phenylalkyl, etc.; A is 1-4C alkylene; Z is-OR<7> (R<7> is H, alkyl, phenylalkyl, etc.), group shown by formula II (R<8> and R<9> are H, alkyl, phenylalkyl, etc.), group shown by formula III (p is 1-4; R<10> and R<11>=R<8> or R<9>) or group shown by formula IV [R<12> is R<8>, R<9> or (substituted) phenoxyalkyl; q is 0-4; r is 4-6]} or a salt thereof. EXAMPLE:2,3,4,5-Tetrahydro-4-oxo-5-(2-phenylethyl)-1,5-benzothiazepin- 3-acetic acid. USE:A drug. A preventive and remedy for circulatory diseases such as thrombosis, hypertension or cerebrovascular twitch or angina pectoris or myocardial infraction. PREPARATION:For example, a compound shown by formula V or a reactive derivative thereof is reacted with a compound shown by the formula ZH in an inert solvent in the presence of a condensation agent to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel and pharmaceutically useful 1,5=benzothiazepine-3-carboxylic acid compound or salt.

[Conventional technology]

Many compounds having a 1,5-benzothiazepine skeleton have various pharmacological actions and are also used in clinical settings. Further, French Patent No. 1,469,476 discloses a 1,5-benzothiazepine compound having fungicidal activity.

[Problem to be solved by the invention]

The present invention provides novel 1.5
-benzothiazepine-3-carboxylic acid compound or a salt thereof.

[Means for Solving the Problems] The present invention is directed to the general formula [wherein R1 and Rffi are the same or different and represent hydrogen, halogen, alkyl or alkoxy, and R'' is alkyl, phenyl, substituted phenyl, phenylalkyl, substituted Phenylalkyl, -(C)I.

C0OR' (wherein, R4 represents hydrogen, alkyl, phenylalkyl, substituted phenylalkyl or aminoalkyl, m represents an integer of 1 to 4) or -(CHz
), N CR')(R") (where R' and Rh are the same or different and represent hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or substituted phenylalkyl, or together with the adjacent nitrogen atom, a heterocycle n represents an integer of 1 to 4), and A represents a group having 1 to 4 carbon atoms.
4 linear or branched alkylene, 2 is -OR
” (wherein R7 represents hydrogen, alkyl, phenylalkyl, substituted phenylalkyl or aminoalkyl), -N (R1) (R”) (wherein R”,
R' is the same or different and represents hydrogen, alkyl, phenylalkino-substituted phenylalkyl or aminoalkyl, or a group forming a heterocycle with the adjacent nitrogen atom -), -NH(CHt)pN (R ”)(R
) (Here, R", R"ha are the same*Rike'14f
t represents hydrogen, alkyl, phenylalkyl, substituted phenylalkyl or aminoalkyl, or represents a group forming a heterocycle with the adjacent nitrogen atom, and p is 1 to 4
) or ■ lff1 (where R'1 is hydrogen, alkyl, phenoxyalkyl, substituted phenoxyalkyl, phenylalkyl, substituted phenylalkyl or aminoalkyl, and q is 0 to 4)
r represents an integer of 4 to 6). ] The present invention relates to a 1,5-benzothiazepine-3-carboxylic acid compound represented by the following or a salt thereof.

In this specification, halogen refers to fluorine, chlorine, bromine,
Iodine, alkyl refers to methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, hexyl, octyl, etc., alkoxy refers to methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy, etc., substituted phenyl means 1 to 3 substituents such as halogen, alkyl, alkoxy, and trifluoromethyl on the benzene ring.
phenylalkyl may have a double bond in the alkyl chain, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, diphenylmethyl , styryl, cinnamyl, etc., substituted phenylalkyl refers to phenylalkyl having 1 to 3 substituents such as halogen, alkyl, alkoxy, trifluoromethyl, etc. on the benzene ring, and aminoalkyl refers to aminoalkyl (aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, etc.), alkylaminoalkyl (methylaminomethyl, ethylaminemethyl, butylaminomethyl,
2-methylaminoethyl, 2ethylaminoethyl, 4-
methylaminobutyl, 4-butylaminobutyl, etc.),
Dialkylaminoalkyl (dimethylaminomethyl, diethylaminomethyl, diisopropylaminomethyl, dibutylaminomethyl, 2-dimethylaminoethyl, diethylamineethyl, 3-dimethylaminopropyl, 4-
dimethylaminobutyl, 4-diethylaminobutyl, etc.), cyclic aminoalkyl (1-pyrrolidinylmethyl, piperidinomethyl, morpholinomethyl, 1-piperazinylmethyl, 4-2-substituted [substituents include alkyl, hydroxyalkyl (2- hydroxyethyl, etc.), phenyl,
Substituted phenyl, phenylalkyl, substituted phenylalkyl, etc.) -1-piperazinylmethyl, 2-piperidinoethyl, 3-morpholinopropyl, 4-(1-piperazinyl)butyl, etc.), phenoxyalkyl refers to phenoxymethyl, 2-phenoxy Ethyl, 3-phenoxypropyl, 4-phenoxybutyl, etc., substituted phenoxyalkyl refers to phenoxyalkyl having 1 to 3 substituents such as halogen, alkyl, alkoxy, trifluoromethyl, etc. on the benzene ring, and the adjacent nitrogen The heterocycle formed with atoms is a 5- to 7-membered nitrogen-containing heterocycle which may further contain nitrogen, oxygen, or sulfur, such as 1-pyrrolidinyl, piperidino, 1-piperazinyl, 4- Substituted (substituents have the same meanings as above) -1-piperazinyl, homopiperazinyl, morpholino, thiomorpholino, linear or branched alkylene having 1 to 4 carbon atoms refers to methylene, ethylene, trimethylene, tetramethylene, methyl It means methylene 5, propylene, isopropyl 1 rutin, dimethyl ethylene, etc.

Examples of the salts of the compound of general formula (1) of the present invention include acid addition salts with inorganic or organic acids, and salts with amino acids, amines, and metals. Further, hydrates are also included in the present invention. Furthermore, since the compound of the present invention has a chiral carbon, optical isomers, racemates, diastereomers, etc. based thereon are also within the scope of the present invention.

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

A compound represented by the legislative general formula (in which each symbol has the same meaning as above) or a reactive derivative thereof and a compound represented by the general formula %() (in which 2 has the same meaning as above) A method of reacting with a compound that is

(1) When compound (II) is a free carboxylic acid,
The reaction is carried out using condensing agents such as dicyclohexylcarbodiimide, titanium tetrachloride, phosphorus halides (phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, etc.), diethylchlorophosphite, 0-phenylenechlorophosphite, and ethyldichlorophosphite. in the presence of an inert solvent from cooling to room temperature or warming for one time.

(2) When a symmetrical acid anhydride or an alkyl carbonic acid mixed acid anhydride is used as the reactive derivative of compound (II), the reaction is carried out using triethylamine, pyridine, N
The reaction is carried out in the presence of a tertiary base such as , N-diethylaniline, etc., from cooling to room temperature or heating.

(3) When using an active amide such as acid imidazolide, acid pyrrolisito, or 2,4-diethylaniline as a reactive derivative of compound (II+), the reaction is carried out in an inert solvent,
It is carried out at room temperature or under heating.

(4) Ester (
(methyl ester, ethyl ester, p-nitrophenyl ester, p-chlorophenyl ester, etc.), the reaction is carried out in an inert solvent at room temperature or under heating, preferably under heating to reflux.

Inert solvents used in each of the above condensation reactions include benzene, toluene, methanol, ethanol, ethyl ether, dioxane, tetrahydrofuran, methylene chloride, chloroform, dichloroethane, hexamethylphosphoric triamide, dimethylformamide, etc.
Alternatively, a mixed solvent of these can be appropriately selected and used.

1) - Compounds represented by the general formula (in which each symbol has the same meaning as above) and the compound represented by the general formula % formula % () (X represents halogen and R3 has the same meaning as above). A method of reacting with a compound that is

The reaction is carried out in an appropriate solvent, under cooling to room temperature or under reflux of the solvent used, in the presence of a deoxidizing agent such as sodium hydroxide, potassium carbonate, triethylamine, or sodium hydride.
Progresses in ~24 hours. As the solvent, any solvent that does not inhibit the reaction, such as chloroform, benzene, toluene, acetone, ethyl ether, dioxane, tetrahydrofuran, dimethylformamide, and hexamethylphosphorustriamide, can be used.

The compound of general formula (I) of the present invention thus obtained can be isolated and purified by conventional methods such as recrystallization and chromatography alone or in an appropriate combination.

Furthermore, due to the presence of a chiral carbon in the compound of general formula (1), the desired product is usually produced as a racemic mixture or diastereomer mixture, but these can be separated into optical isomers by conventional methods such as fractional crystallization and chromatography. can be optically divided into Furthermore, optical isomers can be produced using optically active raw material compounds.

The compound of general formula (1) of the present invention includes hydrochloric acid, hydrobromic acid,
Acid addition salts can be obtained by treatment with inorganic acids such as sulfuric acid and phosphoric acid or organic acids such as maleic acid, fumaric acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid using conventional methods. can. Also, lysine,
It can also be a salt with an amino acid such as ornithine, an amine such as triethylamine, benzylamine, or a metal such as sodium, potassium, lithium, calcium, zinc, aluminum.

When the compound of the present invention or a salt thereof is used as a medicine, it is usually mixed with carriers, excipients, diluents, solubilizing agents, etc. and administered to patients requiring treatment as tablets, powders, capsules, injections, etc. Can be safely administered. The dosage varies depending on the type of disease, patient's condition, etc., but it is usually administered at a dose of 1 to 50°/day for adults, either once or in several divided doses.

- The following margin 1 [Action and Effect of the Invention] The compound of general formula (1) of the present invention has an action of increasing blood flow in the peristaltic artery (cerebrovascular) of mammals, and also has a high serotonin S2 receptor Because it has a blocking effect, an adrenergic alpha 1 receptor blocking effect, and a calcium antagonistic effect, it is effective against cerebral circulation disorders such as blood clots, high blood pressure, cerebrovascular constriction, and transient ischemic attacks, as well as angina pectoris and myocardial infarction. It is useful as a prophylactic or therapeutic agent.

〔Example〕

EXAMPLES Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited thereto.

Example 1 2.3,4.5-tetrahydro-4-oxo-1,5-
50 g of benzothiazepine-3-ethyl acetate was added to a dimethylformamide 130ad solution with stirring under water cooling.
Add 2.6 g of % lithium hydride in portions. After stirring at room temperature for 1 hour, 2-phenylethyl bromide 10.1
Add 8 g. Stir at room temperature for 1 hour, pour the reaction mixture into ice water, extract the separated oil with ethyl acetate, wash with water,
Dry over magnesium sulfate, and evaporate the solvent under reduced pressure. The resulting oil was purified by silica gel chromatography (eluted with chloroform) to yield 2.3,4.5-tetrahydro-4-oxo-5-(2-phenylethyl).
13 g of an oily product of 1,5-benzothiazepine-3-ethyl acetate is obtained.

To 11 g of this oil, 3.6 g of methanol 110-1 sodium hydroxide and 36-g of water are added, heated to 50-60°C, and stirred for 3 hours. Concentrate the reaction solution, and add dilute hydrochloric acid to the residue to make it acidic. The precipitated crystals were collected by filtration, washed with water, and recrystallized from chloroform-isopropyl ether to yield 2,
3.4.4 g of 5-tetrahydro-4-oxo-5-(2-phenylethyl)-1,5-benzothiazepine-3-acetic acid are obtained. Melting point 140-143°C Example 2 1.25 g of 1-hydroxybenzotriazole into a mixture of 3 g of the compound obtained from Example 1, 30 m of dimethylformamide and 1.9 g of 4-amino-1-(2-phenylethyl)piperidine. and stir at room temperature for 30 minutes. Next, 2 g of N,N' dicyclohexylcarbodiimide is added under water cooling, and the mixture is further stirred for 12 hours. Water is added to the reaction solution, extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (eluted with chloroform-ethanol), and the resulting crystals were recrystallized from isopropyl alcohol-isopropyl ether to give N-(1-(2-phenyl) ethyl-4-piperidyl)
-2,3,4,5-tetrahydro-5-(2-phenylethyl)-4-oxo-1,5-benzothiazepine-3
=2.3 g of acetate amide are obtained. Melting point: 146-149°C Example 3 4.2 g of 2.3,4.5-tetrahydro-3-(1-(2-phenylethyl)-4-piperidylcarbamoyl)-4-oxo-1,5-benzothiazepine Add 0.6 g of 60% sodium hydride to an 80% solution of dimethylformamide under water-cooling and stirring, and stir at room temperature for 1 hour. Next, add 2 g of ethyl bromoacetate and stir at room temperature for 2 hours. Reaction liquid. Pour into water, extract with ethyl acetate, wash with water,
After drying with magnesium sulfate, concentrate. The residue was purified by silica gel chromatography, and the resulting crystals were recrystallized from ethanol-isopropyl ether to yield 2,
3.4.5-Tetrahydro-3-(1-(2-phenylethyl)-4-piperidylcarbamoyl]-4-oxo-1,5-benzothiazepine-5-ethyl acetate 2.0 g
get. Melting point 163-164°C Example 4 3 g of the compound obtained according to Example 1 in chloroform 30
- Hethionyl chloride lId is added to the solution, and after stirring at 40°C for 1 hour, the solvent is distilled off under reduced pressure.

A mixture of 3 g of 1-diphenylmethylpiperazine, 30-dichloroform and 1-triethylamine is added to the remaining residue, and the mixture is stirred at room temperature for 3 hours. The solvent is distilled off under reduced pressure and the residue is purified by silica gel chromatography, and oxalic acid is added to the resulting oil to form a salt. When this is recrystallized from isopropyl alcohol, 2.3.4.5-tetrahydro-5-(2-phenylethyl)-3-((4-diphenylmethyl)-1-piperazinyl)carbonylmethyl)-1,5- 0.6 g of benzothiazepine-4-one oxalate is obtained. Melting point: 194-195°C (decomposition) Similarly, the following compounds are produced.

■ 2,3,4.5-tetrahydro-4-oxo-1,
5-benzothiazepine-3,5-diacetic acid, melting point 235~
237℃ (decomposition) ■ 2.3,4.5-tetrahydro-3-methoxycarbonylmethyl-4-oxo-1,5-benzothiazepine-5-acetic acid, melting point 134-136℃◎ N-benzyl-
N-octylcarbamoylmethyl-2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepine-
5-acetic acid, melting point 131-133℃ ■ 2.3.4.5-tetrahydro-5-(3-dimethylaminopropyl)-4-oxo-1,5-benzothiazepine-3-acetate ethyl oxalate , melting point 131-1
33°C ◎ N-(1-(2-phenylethyl)-4-piperidyl)-2,3,4,5-tetrahydro-4-oxo-5
-(2-phenylethyl)-1,5-benzothiazepine-3-acetic acid amide, melting point 146-149°C ◎ N-(1-(2-phenylethyl)-4-piperidylco-5-cinnamyl-2,3 ,4,5tetrahydro-
4-oxo-1,5-benzothiazepine-3-acetic acid amide, melting point 174-175℃◎ N-(1-(3-phenylpropyl)-4-piperidyl) -2,3,4,5-
Tetrahydro-4-oxo-5-(2-phenylethyl)-1,5benzothiazepine-3-acetamide, melting point 171-172°C -1-piperazinylcarbonylmethyl)-4-oxo-
5-(2-phenylethyl)-1,5-benzothiazepine hydrochloride monohydrate, melting point 165-168°C (decomposed) ◎ N-(3-morpholinopropyl)-2,3°4.5
-Tetrahydro-4-oxo-5-(2-phenylethyl)-1,5-benzothiazepine-3-acetic acid amide, melting point 120-122℃◎ 5-benzyl-2,3,4,5
-Tetrahydro-4-oxo-1,5-benzothiazepine-3-acetic acid, melting point 177-179°C ◎ N-(1-(2-phenylethyl)-4-piperidylgo-5-benzyl-2,3,4 ,5-tetrahydro-
4-oxo-1,5-benzothiazepine-3-acetic acid amide, melting point 167-168℃◎ N-(1-(2-(4-
methoxyphenoxy)ethyl-4-piperidyl)-2
,3,4,5-tetrahydro-4-oxo-5-(2-
phenylethyl)-1,5-benzothiazepine-3 = acetic acid amide, melting point 144-146°C ■ 2.3,4.5-tetrahydro-5-(3-(4-
(2-methoxyphenyl)-1-piperazinyl]propyl)-4-oxo-1,5-benzothiazepine-3-acetic acid, melting point 226-227°C (decomposition) ◎ 2.3.4.5-tetrahydro-4 -oxo-5-
(3-piperidinopropyl)-1,5-benzothiazepine-3-acetic acid hydrochloride, melting point 245-246℃ (decomposition) ◎ 2.3.4.5-tetrahydro-5-(3-(4 −
(2-nimethoxyphenyl)-1-piperazinyl]propyl)-4-oxo-1,5-benzothiazepine-3-ethyl acetate dihydrochloride 1/2 hydrate, melting point 99-103
°C @)2.3.4.5-tetrahydro-5-(3-(N-
(2-(3,4-dimethoxyphenyl)ethyl)N-methylaminocopropyl)-4-oxo-1,5-benzothiazepine-3-acetic acid 1/2 fumarate 1/2 hydrate , melting point 178-180°C (decomposition) ◎ N-(1-(2-phenylethyl)-4-piperidyl)-2,3,4,5-tetrahydro-5(4-methoxybenzyl)-4-oxo-1 ,5 benzothiazepine-
3-Acetamide, melting point 166-168°C (decomposed) ◎ N-(1-(2-phenylethyl)-4-piperidylco-5-ethyl-2,3,4,5-tetrahydro-4
-Oxo-1,5-benzothiazepine-3-acetic acid amide, melting point 149-150℃◎ N-(1-(2-phenylethyl)-4-piperidyl)-2,3,4,5-tetrahydro-8 -Methoxy-4-oxo-5-(2-phenylethyl)-1,5-benzothiazepine-3-acetic acid amide, melting point 139-141°C ■2. 3. 4. 5-tetrahydro-8-methoxy-4-oxo-3-(1-(2-phenylethyl)-
4-piperidylcarbamoylmethyl]-5-ethyl acetate, melting point 137-139°C ◎ N-(1-(2-phenylethyl)-4-piperidyl)-2,3,4,5-tetrahydro-5-(2- (3
,4-dimethoxyphenyl)ethyl-4-oxo-1
, 5-benzothiazepine-3-acetamide, melting point 138
~140℃

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. , phenylalkyl, substituted phenylalkyl, -(CH_2)_mCOOR^4(
Here, R^4 is hydrogen, alkyl, phenylalkyl,
substituted phenylalkyl or aminoalkyl, m is 1
Indicates an integer of ~4. ) or -(CH_2)_nN(R
^5) (R^6) (Here, R^5 and R^6 are the same or different and represent hydrogen, alkyl, phenyl, substituted phenyl,
represents phenylalkyl or substituted phenylalkyl, or represents a group forming a heterocycle with adjacent nitrogen atoms; n represents an integer of 1 to 4; ), A is a linear or branched alkylene having 1 to 4 carbon atoms, and Z is -OR^7
(Here, R^7 represents hydrogen, alkyl, phenylalkyl, substituted phenylalkyl or aminoalkyl.), -N(R^8)(R^9) (Here, R^8, R^
9 is the same or different and represents hydrogen, alkyl, phenylalkyl, substituted phenylalkyl or aminoalkyl, or represents a group forming a heterocycle with the adjacent nitrogen atom. ), -NH(CH_2)_pN(R^1^0)(
R^1^1) (Here, R^1^0, -R^1^1 are the same or different and represent hydrogen, alkyl, phenylalkyl,
represents substituted phenylalkyl or aminoalkyl, or
Indicates a group that forms a heterocycle with adjacent nitrogen atoms,
p represents an integer of 1 to 4. ) or ▲Mathematical formulas, chemical formulas, tables, etc.▼ (Here, R^1^2 is hydrogen, alkyl, phenoxyalkyl, substituted phenoxyalkyl, phenylalkyl,
substituted phenylalkyl or aminoalkyl, q is 0
r represents an integer of 4 to 6. ] A 1,5-benzothiazepine-3-carboxylic acid compound or a salt thereof.