JPS60202871A - 1,5-benzothiazepine derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is lower alkyl or lower alkoxy; R<2> is H or lower alkanoyl; R<3> and R<4> are lower alkyl; R<5> is lower alkyl, lower alkoxy, NH2, lower alkylthio, OH, benzyloxy or CF3; n is 2 or 3) and its acid addition salt. EXAMPLE:(+ or -)-cis-2-( 4-methylphenyl )-3-acetoxy-5-[2-( dimethylamino )ethyl]-8-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one oxalic acid salt. USE:Hypotensor, cerebral and coronary vasodilator, and thrombocyte coagulation suppressing agent. PREPARATION:The compound of formula I can be prepared by condensing the novel substance of formula II or its salt with the compound of formula III (X is halogen). The novel substance of formula II can be synthesized e.g. from the compound of formula IV and the compound of formula V (R<8> is lower alkyl).

Description

DETAILED DESCRIPTION OF THE INVENTION (Technical Field) The present invention relates to a novel 1,5-benzothiazepine derivative useful as a pharmaceutical compound and a method for producing the same.

(Prior Art) U.S. Pat. No. 3,562,257 describes 2-(4-methoxyphenyl)-3-hydroxy (or acetoxy)-5
-(2-(dimethylamino)ethyl]-7-chloro2
．． 3-dihydro-1,5-benzothiazepine-4 (5H
Various benzothiazepine derivatives, including 7-chloro-1,5-benzothiazepine derivatives such as )-one, have been shown to have antidepressant, tranquilizing, and/or coronary vasodilatory effects.

(Object of the invention) The object of the present invention is to provide a novel 1,5-benzothiazepine derivative and its synthetic intermediate, and another object is to provide a method for producing the 1,5-benzothiazepine derivative. Another object is to provide a pharmaceutical composition containing the compound as an active ingredient.

(Structure and Effects of the Invention) The object compound of the present invention is a 1°5-benzothiazepine derivative represented by the following general formula or a pharmacologically acceptable acid addition salt thereof.

(However, 1 lil is lower alkyl or lower alkoxy.

R2 is a hydrogen atom or lower alkanoyl 1173 and R
Both 4 represent lower alkyl, R% represents lower alkyl, lower alkoxy, amino, lower alkylthio, hydroxyl group, benzyloxy or trifluoromethyl, and n represents 2 or 3.

) Compound (I) of the present invention or a pharmacologically acceptable acid addition salt thereof has excellent antihypertensive action and/or cerebral/coronary vasodilatory action.

In particular, the compound (1) of the present invention is characterized by its strong antihypertensive action and the durability of its action. For example, compound (1)
When administered orally to spontaneously hypertensive rats, the compound of the present invention, (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(2-(dimethylamino)ethyl]-8-methoxy Administration of 2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride/monoethanol at 30 μ/kg not only lowered the blood pressure of the rats by 14 wHg 1 hour after administration, but also Even 4 hours after administration, the level of Hg decreased by 94 mm.

In addition, when compound (1) was intraarterially administered under severe anesthesia to examine its cerebral vasodilatory effect, (1) the compound of the present invention (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-
5-(2-(dimethylamino)ethyl-8-methyl-
2,3-dihydro-1゜5-benzothiazepine-4 (5
H)-one hydrobromide and (+)-cis-2-(4
-methoxyphenyl)-3-acetoxy-5-(2-(
dimethylamino)ethyl)-7-methyl-2,3-dihydro-1,5-benzothiazepine-4C5H)-one.
Hydrobromide/quarter hydrate is pavaberine [6゜7-
It exhibits a cerebral vasodilatory effect that is approximately 12 times stronger than that of cymethoxy-1-veratrylisoquinoline.

On the other hand, when the coronary vasodilator effect was investigated by the Langendorff method using 2 isolated guinea pig hearts, 1 compound of the present invention was found (±
)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(2-(dimethylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepine-
4(5H)-one hydrochloride/monoethanol exhibits a coronary vasodilator effect that is about 10 times stronger than papaverine.

In addition, the compound (I) of the present invention exhibits an excellent platelet aggregation inhibiting effect and also has low toxicity.

It is useful as a prophylactic, ameliorating, or therapeutic agent for hypertension; brain diseases such as cerebral vasospasm, cerebral infarction, and stroke; and heart diseases such as angina pectoris, arrhythmia, and myocardial infarction.

In the compound of the present invention, in the general formula (1), R1 is lower alkyl such as methyl, ethyl, propyl, or butyl, or lower alkoxy such as methoxy, ethoxy, propoxy, or butoxy, and R2 is a hydrogen atom or acetyl, propionyl, or butyryl. It is a lower alkanoyl like
R3 and R4 are both lower alkyl such as methyl, ethyl, propyl, butyl, and R5 is methyl, ethyl,
Lower alkyl such as propyl, butyl, methoxy, ethoxy.

Examples include compounds in which n is lower alkoxy such as cy, propoxy, butoxy, lower alkylthio such as amino, methylthio, ethylthio, propylthio, butylthio, hydroxyl group, benzyloxy or trifluoromethyl, and n is 2 or 3, and Preferred compounds include:
In general formula (I), R1 is methyl or methoxy, pg is a hydrogen atom or acetyl, R3 and R4 are both methyl, and R5 is methyl, methoxy, amino,
Examples include compounds in which R1 is methoxy, nt is acetyl, and R3 and R4 are both methyl in the general formula (1). Mention may be made of compounds in which is methyl or methoxy and n is 2.

Since the compound (1) of the present invention has two asymmetric carbon atoms at the 2- and 3-positions of the pentthiazepine skeleton, it has 22 types of stereoisomers (i.e., cis and trans isomers) or 4 types of optical isomers. body [i.e. (+)-cis, (=)-cis, (
+)-)lance and (-)-trans isomers], but the present invention also includes these isomers or mixtures thereof. However, among these compounds, the cis isomer, especially the (+)-cis isomer, is preferred as a compound for pharmaceutical use.

According to the present invention, the compound (I) has the general formula (wherein R1,
1711 and R5 have the same meanings as above. ) or a salt thereof, and a compound represented by the general formula (173. R4 and n have the same meanings as above) and a compound represented by the general formula (173. R4 and n have the same meanings as above). be able to.

In addition, among compound (1), the general formula (where R6 is lower alkyl, lower alkoxy, lower alkylthio, hydroxyl group, benzyloxy or trifluoromethyl; R? represents lower alkanoyl; Ill, l?
', R' and n have the same meanings as above. ) is a compound represented by the general formula (where, ill, R3, R4, R6 and n have the same meanings as above) or a salt thereof and the general formula %formula%() (however, R? is the same as above). ) or a reactive derivative thereof.

Furthermore, among compounds (I), compounds in which R2 is a hydrogen atom, that is, compounds represented by the general formula (II, 113. R', R' and n have the same meanings as above), are represented by the general formula (II, 113. , R', R3,R', R5,R) and n have the same meanings as above. ) It can be produced by hydrolyzing the compound or its salt.

Furthermore, among compounds (1), compound 5 in which R5 is water or an acid group, that is, a compound represented by the general formula (wherein Hl, R2, R3, R4 and n have the same meanings as above), is a compound represented by the general formula (however, R1, R2, R2, R4 and n have the same meanings as above.) It can be produced by subjecting the compound represented by the following to a debenzylation reaction.

The condensation reaction between compound (II) or a salt thereof and compound (II) or a salt thereof can be carried out in a suitable solvent in the presence or absence of an alkaline reagent.

Examples of the salts of compound (II) include alkali metal salts such as sodium salts and potassium salts.

When compound (II) is used in free form, the condensation reaction is preferably carried out in the presence of an alkaline reagent, such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, carbonic acid, etc. Alkali metal carbonates such as potassium, alkali metal hydrides such as sodium hydride, and the like can be suitably used. Examples of solvents include acetone, ethyl acetate, and dimethyl sulfoxide.

It is preferable to use dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, etc., and the condensation reaction is preferably carried out at θ to 100°C, especially 20 to 70°C.

The reaction between compound (I-a) or a salt thereof and the reactive derivative of compound (IV) can be carried out in a suitable solvent in the presence or absence of an acid absorbing agent. Examples of the salt of compound (1-a) include acid addition salts such as hydrochloride and hydrobromide.

Examples of reactive derivatives of the compound (mV) include acid anhydrides such as acetic anhydride and propionic anhydride, and acid halides such as acetyl chloride and propimenyl chloride. Examples of deoxidizers include pyridine, triethylamine, N-methylpyridine, N-methylmorpholine,
Examples include N-methylpyrrolidine, N-ethyl-N, and N-diisopropylamine. Examples of solvents include acetic acid.

Preferably, chloroform, dichloromethane, dimethylformamide, tetrahydrofuran, etc. are used. In the reaction, when excess acetic anhydride is used as the reactive derivative of compound (TV), it is not necessarily necessary to use another solvent because the acetic anhydride also acts as a solvent. When carrying out the reaction, compound (IV)
When using an acid anhydride as a reactive derivative of
The reaction is preferably carried out at 40°C, and when an acid halide is used as the mono-reactive derivative, it is preferably carried out at -10 to 100°C.

On the other hand, when compound (TV) is used in the form of a free acid, the condensation reaction between the compound and compound (1-a) or a salt thereof can be carried out in a suitable solvent in the presence of a condensing agent.

The condensing agent is 1, for example, N.

N'-dicyclohexylcarbodiimide, N,N'-carbonyldiimidazole, 1-methyl-2-halopyridinium iodo salt (e.g. l-methyl-2-bromopyridinium iodo salt), methoxyacetylene, triphenylphosphine - Examples include carbon tetrachloride. As the solvent, for example, methylene chloride, 1,2-dichloroethane, chloroform, benzene, toluene, tetrahydrofuran, dioxane, etc. are preferably used. preferable.

Hydrolysis of compound (I-c) or a salt thereof can be carried out by treating compound (I-c) with acid or alkali in a suitable solvent. Examples of the salt of compound (I-c) include acid addition salts such as hydrochloride and hydrobromide. As the acid, 2, for example, mineral acids such as hydrochloric acid and sulfuric acid can be used, and as the alkaline reagent, 3, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate are used. can. Examples of solvents include water,
Preferably, alkanols such as methanol, -I-'tanol, propatool or mixtures thereof are used.

The reaction is 0 to 100 for both acid treatment and alkali treatment.
It is preferred to carry out the reaction at a temperature of 25 to 90°C.

The debenzylation reaction of compound (1-e) or a salt thereof can be carried out by a conventional method such as acid treatment in an appropriate solvent. Examples of the salt of compound (1-e) include acid addition salts such as hydrochloride and hydrobromide. In the case of acid treatment, the acid can be, for example, hydrobromide, and the solvent can be, for example, acetic acid, methylene chloride, benzene, ethyl acetate, or a mixture thereof. The reaction is carried out at -10 to 40°C, especially 0 to 20°C.
It is preferable to carry out the test at

Raw material compounds (II), (1-a), (I-
Since c) and (1-e) have two asymmetric carbon atoms at the 2- and 3-positions of the benzothiazepine skeleton, they have four optical isomers [i.e., (+)-cis, (-)- Sis.

(+)-) lance, (-)-trans isomers], but since all of the above reactions proceed without racemization, compounds (II), (I a), (
By using the optically active forms of 1-c) and (1-s), the corresponding optically active compounds (T''), (I-
b), (T-d) and (1-f) can be obtained, respectively.

The starting compound (If) of the present invention is a new compound, and can be produced, for example, according to the following reaction formula.

(A method) (Method B) (C method) (However, R51 is lower alkyl or lower alkoxy.

nitro, lower alkylthio, hydroxyl group, benzyloxia or trifluoromethyl R8 represents lower alkyl
R1, R% and R7 have the same meanings as above. ) According to (Method A), compound (H) is produced by reacting compound (V) and compound (Vl) to produce compound (If-a>,
If necessary, the compound (II-b) can be produced by reacting the compound (II-a) with the compound (■) or a reactive derivative thereof.

According to (Method B), compound (II) is prepared by reacting compound (V) and compound (VI) to produce compound (■), and if necessary, hydrolyzing the compound (■) to produce compound ( ■) Toshi 1
Next, compound (■) or (■) is subjected to intramolecular ring closure to produce compound (U-a), and if necessary, compound (II-
It can be produced by reacting a) with compound (IV) or a reactive derivative thereof to form compound (U-b).

According to (C method), compound (n) is reacted with compound (■) and compound (V[) to produce compound (X), and then compound (X) is reduced to form compound (■), If necessary, the compound (■) is hydrolyzed to form a compound (■). 9 Then, compound (■) or (■) is intramolecularly closed to form a compound (I[
-a) and, if necessary, react the compound (II-a) with the compound (mV) or a reactive derivative thereof to obtain the compound (■-b).

The first step of (Method A), that is, compound (V) and compound (Vl
), a mixture of compound (V) and compound (Vl) is reacted with 15
This can be carried out by heating to 0 to 160°C. This reaction is preferably carried out under an inert gas (eg, argon) atmosphere.

When the compound <■-a> is obtained as a mixture of stereoisomers (i.e., cis and trans isomers).

By utilizing the difference in solubility of these mixtures in solvents such as lower alkanols (e.g. ethanol),
Orgo 1 can be separated into each stereoisomer by column chromatography.

Furthermore, compound (II-a) has an optical activity of, for example, 1
By using an optical resolution agent such as -(2-naphthylsulfonyl)pyrrolidine-2-carbonyl chloride,
It can be separated into each optical isomer. for example,
(±)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-methoxy-2,3-dihydro-1,5-
The optical resolution of benzothiazepin-4(5H)-one is achieved by reacting the compound with (S)-1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl chloride and then separating the two diastereomers produced. This can be carried out by performing fractional crystallization using the difference in solubility in a solvent, and then hydrolyzing the obtained diastereomer.

The first step of (Method B). That is, compound (V) and compound (Vl
) can be carried out by heating a mixture of compound (V) and compound (VI) to 25 to 110°C in a suitable solvent (e.g., toluene, benzene, acetonitrile, dioxane) or without a solvent. can. If the trans isomer is used as the starting compound (VI) in the reaction, compound (■) can be obtained as a threo isomer.

First step of (C method). That is, compound (IX) and compound (V
The reaction with l) can be carried out by heating a mixture of compound (IX) and compound (■) to 20 to 80°C in a suitable solvent (eg, acetonitrile, toluene, benzene). In the subsequent second step, that is, the reduction reaction of compound (X), the compound is heated at 0 to 50°C using a reducing agent (for example, a hydrochloric acid solution of stannous chloride) in a suitable solvent (for example, acetic acid).
This can be carried out by treatment with or catalytic reduction.

(Method B) and (Method C), the compound (
(2) The hydrolysis of the compound is carried out using an alkaline reagent (e.g., potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, etc.) in an appropriate solvent (e.g., aqueous methanol, aqueous ethanol, etc.). This can be carried out by processing at °C.

The compound (■) thus obtained has optically active p-
It can be separated into each optical isomer by using an optical resolving agent such as hydroxyphenylglycine alkyl ester. For example (±)-threo-2-hydroxy-3-(2-amino-5-methylphenylthio)-3
-(4-Methoxyphenyl)propionic acid is optically resolved by reacting the compound with an optically active p-hydroxyphenylglycine alkyl ester to form a diastereomeric salt, and then dissolving the diastereomeric salt due to the difference in solubility in a solvent. This can be carried out by performing fractional crystallization using a methane compound and treating the obtained diastereomeric salt with an acid or an ion exchange resin.

The intramolecular ring-closing reaction of the racemate or optical isomer of the compound (■) or (■) thus obtained is carried out by reacting these compounds in a suitable solvent (for example, xylene, etc.) or without a solvent,
This can be carried out by heating to 110 to 160°C. In addition, the intramolecular ring closure reaction of compound (■) was carried out in dimethyl sulfoxide with methylsulfinyl carbanion (
(prepared from HsSOCHz, dimethyl sulfoxide and sodium hydride) at 0-50<0>C. Furthermore, the intramolecular ring-closing reaction of compound (■) can be carried out using a condensing agent (for example, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide, It can also be carried out at -10 to 70°C in the presence of a mixture of '-dicyclohexylcarbodiimide and 1-hydroxybenzotriazole).

Acylation of compound (II-a), which is an optional step in (Method A), (Method B) and (Method C), is carried out in the same manner as in the acylation of compound (1-a). (However, R7 has the same meaning as above.) It can be carried out by reacting with a compound represented by (R7 has the same meaning as above) or a reactive derivative thereof.

Among the above reactions, when the compound (■) is hydrolyzed and the compound is amino, it is preferable to protect the substituent with a conventional protecting group such as hensyloxycarbonyl during one reaction.

Note that all of the above reactions can be carried out without racemization.

When the compound (1) of the present invention is used as a medicine, it can be used as a free base or as a pharmacologically acceptable acid addition salt thereof. Pharmaceutically acceptable acid addition salts include 2, for example, inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, and phosphate; oxalate; Examples include organic acid addition salts such as maleate, fumarate, tartrate, and methanesulfonate. These salts can be easily obtained by treating, for example, compound (1) with an acid.

Compound N) or a pharmacologically acceptable acid addition salt thereof can be administered either orally or parenterally.

When the compound of the present invention (N or a pharmacologically acceptable acid addition salt thereof) is used as a pharmaceutical, the compound (1) is mixed with a pharmaceutical excipient suitable for oral or parenteral administration and used as a pharmaceutical preparation. Examples of such excipients include starch, lactose, glucose,
Potassium phosphate, corn starch, gum arabic,
Stearic acid and other common pharmaceutical excipients can be suitably used. Pharmaceutical preparations are tablets and pills.

It may be a solid preparation such as a capsule or suppository, or a liquid preparation such as a solution, suspension, or emulsion. Furthermore, when administered parenterally, this pharmaceutical preparation can also be used as an injection.

The daily dosage of the compound (1) of the present invention or a pharmacologically acceptable salt thereof varies depending on the method of administration, age and weight of the patient, condition and type of disease, but is usually about 0.0
5 to 10 μ/kg is preferable.

Particularly preferred is about 0.5 to 10 cm/kg for oral administration, and about 0.05 to 2 cm/kg for parenteral administration (eg, intravenous injection).

2 In this specification, lower alkyl, lower alkoxy, lower alkanoyl, and lower alkylthio respectively refer to alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkanoyl having 2 to 4 carbon atoms, and alkanoyl having 1 to 4 carbon atoms, respectively. represents alkylthio.

In this specification, the term 'threo' refers to a group having a hydroxyl group substituted at the 2- and 3-positions of propionic acid. The substituents are located on opposite sides of the main chain).

Hereinafter, the present invention will be further explained in detail by giving experimental examples, working examples, and manufacturing examples.

Experimental example 1 (hypertensive effect) Specimen dissolved or suspended in water (dose: 30 or 10
Spontaneous hypertensive rats (0 ■/kg) were fasted overnight (
1 group: 3 animals). The systolic blood pressure of rats was measured by the plethysmograph method (The Journal of Laboratory and Clinical Medicine 0. Vol. 78, p. 957 (1971)). The antihypertensive effect of the sample was observed 1 hour and 4 hours after administration. The results are shown in Table 1 below.

Table 1 *) All of the above test compounds are (±)-cis isomers.

The dosage is ■/kg.

1**) Bzl represents a benzyl group.

Experimental Example 2 (Cerebral vasodilatory effect) A large male (body weight: 11-14 kg) was treated with bendoparbital sodium salt (intravenous administration, dose: 30 mg /
kg) was anesthetized. The blood flow in the vertebral artery was measured using an electromagnetic flowmeter under artificial respiration. The specimen was dissolved in a 5% glucose aqueous solution, and the solution was injected into the peristaltic artery. The cerebral vasodilatory effect of the sample was determined as the efficacy ratio to papaverine calculated from the V effect curve. The results are shown in Table 2 below.

Experimental Example 3 (Coronary vasodilatory effect) The effect on coronary blood flow of the isolated heart of a guinea pig (body weight: approx. 281 cm) was investigated using the Langendorff method. perfusion with a solution (saturated with a gas mixture of 95% oxygen and 5% carbon dioxide).The perfusion pressure was maintained at 40 cm water column.

The specimen was dissolved in 5% glucose solution and 0.1% per heart.
- injected into the perfusate at a volume of -. The outflow perfusate was measured using a drip counter and was defined as coronary blood flow.

The compounds shown below increased coronary blood flow at a dose of 10 μJ/
0.5 in the heart. It was more than Q/min. On the other hand, papaverine showed an increase in coronary blood flow at a dose of 10μ in the above experiment.
II/Heart was 0.5 J/min or more.

Table 3 *) Bzl represents a benzyl group.

Experimental Example 4 (Platelet aggregation inhibitory effect) Blood was collected from the abdominal aorta of SD-strain male rats anesthetized with ether. 7) Nine volumes of blood were mixed with one volume of 3.8 W/V% citric acid/trisodium salt aqueous solution, and the mixture was centrifuged to prepare platelet warm blood Wi (PPP). The remaining blood was further centrifuged to determine platelet aggregation ability WI (
PPP) was prepared. PRP platelet count PPP”?:
: Adjusted to 0.8-l xlO6/n3. diluted PRP
200. After stirring a mixture of +71 and 25 μl of sample solution (final concentration of sample: 100 μ3/-) at 37°C for 2 minutes, a collagen solution [Biochimica Kogyo Biophysica Acta 9. Volume 186, page 254 (1969)] 25
μm was added to cause platelet aggregation. Platelet aggregation ability was determined by Pawn's method [Nature 0. Vol. 194, p. 927 (1962)] to determine the platelet aggregation inhibiting effect of the sample. The compound shown below is acetylsalicylic acid (
100μm1/d) showed an inhibitory effect on platelet aggregation equivalent to or higher than that of 100μm1/d).

Table 4 Example 1 (±)-cis-2-(4-methylphenyl)-3-hydroxy-5-(2-(dimethylamino)ethyl-8-
A mixture of 0.93 of methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 10 of acetic anhydride is stirred at 110° C. for 4 hours. After cooling, the solvent is distilled off from the mixture under reduced pressure, benzene is added to the residual aroma, and the solvent is further distilled off under reduced pressure. The residual scent is oxalate and chloroform.

By recrystallizing from a mixture of ethanol and ether, (±)-cis-2-(4-methylphenyl)-3
-acetoxy-5-(2-(dimethylamino)ethyl-8-methoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one oxalate 1.15.9
get. Yield: 95% M, p, 209-211°C (decomposition) Examples 2-6 (A) The following compounds are obtained by subjecting the corresponding raw material compounds to G treatment in the same manner as in Example 1.

Note: All of the above compounds are (±)-cis isomers.

This) Recrystallization from ethanol**) Recrystallization from a mixture of isopropanol and ether**) Recrystallization from methanol Example 7 (±)-cis-2-(4-methylphenyl)-3-hydroxy-5 -(2-(dimethylamino)ethyl]-8-
By treating methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one in the same manner as in Example 1, (±)-cis-2-(4-methylphenyl)-
3-acetoxy-5-(1-(dimethylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained. Yield: 86%,
p, 1s4-186°C (recrystallized from a mixture of isopropanol and ether) Example 8 (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-(2-<dimethylamino)ethyl ]-7
-Medoxy 2.3-dihydro-1゜5-benzothiazepine-4(5H)-one hydrochloride 1g, acetic anhydride 1.5
．． & and acetic acid 1.5. I! The mixture was stirred at 110°C for 4 hours. After cooling, the solvent was distilled off from the mixture under reduced pressure, and benzene was added to the residual aroma.

Furthermore, the solvent is distilled off under reduced pressure. By recrystallizing the residual aroma from a mixture of ethanol and ether.

(±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(2-(dimethylamino)ethyl]-7
-Medoxy 2,3-dihydro-1,5-benzothiazepine-4 (5I()-one hydrochloride 1/2 hydrate 0.
Obtain 87 g. Yield near 8%, p, zts~218
°C Examples 9 and 10 The following compounds are obtained by treating the corresponding starting compounds in the same manner as in Example 8.

Table 6 Note) Both of the above compounds are (±)-cis isomers.

*) Recrystallization Example 11 from a mixture of ethanol, chloroform and ether (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-(2-(dimethylamino)ethyl)-8
A mixture of 5.05.9 of -methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 20 of acetic anhydride and 0.1 of pyridine is stirred at 110°C for 4 hours. After cooling, the solvent was distilled off from the mixture under reduced pressure, and benzene was added to the residual aroma.

Furthermore, the solvent is distilled off under reduced pressure. The residual aroma is converted into hydrobromide,
By recrystallizing from a mixture of ethanol and ether, (+)-cis-2-(4-methoxyphenyl)-3
-acetoxy-5-(2-(dimethylamino)ethyl)
-8-Methyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrobromide 6.374.
Get 9. Yield: 96% M, p, 151-152°C (decomposition) Examples 12-19 The following compounds are obtained by treating the corresponding starting compounds in the same manner as in Example 11.

Table 7 Note) All of the above compounds are monocis isomers.

,) Recrystallized from isopropanol Original version) Recrystallized from a mixture of ethanol and ether Original version) Recrystallized from ethanol *) Bzl represents a benzyl group.

Example 20 (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-6-methyl-2,3-dihydro-115-benzothiazepin-4(5H)-one 2°81g1 dimethylaminoethyl A mixture of 1.35 L of chloride hydrochloride, 2.73 L of potassium carbonate, and 40 L of acetone was heated under reflux for 16 hours. After cooling, inorganic substances are filtered off and washed with chloroform. The filtrate and washing liquid were combined, the solvent was distilled off, the residual aroma was converted into a hydrochloride salt, and the mixture was recrystallized from a mixture of ethanol and ether to form (±)-cis2.
=(4-methoxyphenyl)-3-hyF+=1xy~5
- (2-(dimethylamino)ethyl-6-methyl-
2,3-dihydro-1,5-benzothiazepine-4 (5
2.93.9 of H)-one hydrochloride 3/4 hydrate are obtained. Yield near 7% N, ρ, 112-115°C Examples 21-27 The following compounds are obtained by treating the corresponding starting compounds in the same manner as in Example 2o.

Table 8 Note: All of the above compounds are (±)-cis isomers.

*) Recrystallized from a mixture of ethanol and ether * * * Recrystallized from ethanol * * * Recrystallized from ethyl acetate * *) Bzl represents a benzyl group.

Examples 28-30 +1 0 -HCl The following compounds are obtained by treating the corresponding raw material compounds in the same manner as in Example 20.

Table 9 Note: All of the above compounds are (±)-cis isomers.

*) Recrystallized from ethyl acetate **) Recrystallized from a mixture of ethanol and ether ***
) Recrystallized from a mixture of ethyl acetate and isopropyl ether ****) Bzl represents a benzyl group.

Examples 31 to 36 The following compounds are obtained by treating the corresponding starting compounds in the same manner as in Example 2o.

Table 10 Note: All of the above compounds are cis isomers and free bases.

This) Recrystallization from ethyl acetate Examples 7'37 and 38 The following compounds were obtained by treating the corresponding starting compounds in the same manner as in Example 20.

Table 11 Note) Both of the above compounds are (±)-cis isomers.

*) Recrystallization from a mixture of isopropanol and ether **) Recrystallization from chloroform Example 39 (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-7-medoxy-2,3-dihydro- 1,5-
Benzothiazepine-4(5H)-one 0.828.9.
Potassium hydroxide 0.301 and dimethyl sulfoxide 1
The mixture of 5- is stirred at room temperature for 2 hours. Furthermore, 0.396.9% of dimethylaminoethyl chloride hydrochloride was added to the mixture, and the mixture was stirred at room temperature for 16 hours. After the reaction, the mixture is poured into ice water and extracted with ethyl acetate. Further, the extract was extracted with 10% hydrochloric acid, potassium carbonate was added, and p
Adjust to around H10. The alkaline solution was extracted with ethyl acetate, the extract was washed with water, the solvent was distilled off after drying, and the residue was recrystallized from a mixture of ethyl acetate and n-hexane to obtain (±)-cis-2-( 0.82 g of 4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-7-medoxy 2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained. .

Yield: 82% range, ρ, 127-129°C Hydrochloride of this product: M, p, 212-214°C (recrystallized from a mixture of chloroform, ethanol and ether) Examples 40 and 41 Table 12 Note) Above Both compounds are (±)-cis isomers.

*) Recrystallization rate from a mixture of chloroform, ethanol and ether *) Recrystallization example from methanol 42 (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(2-(dimethylamino) Ethyl]-8
-benzyloxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 1.51? , 25% hydrogen bromide-acetic acid 5- and acetic acid 5- are stirred at room temperature for 17 hours. After the reaction, ether is added to the 9-wire mixture, and the precipitated crystals are collected by filtration.

By washing the crystals with ether and recrystallizing them from ethanol, (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(2-(dimethylamino)ethyl]-8-hydroxy-2 ,3-dihydro-1,5-
Benzothiazepine-4(5H)-one hydrobromide 0
．． Get 911. Yield: 61% M, p, 208.5-211.5°C Example 43 (±)-cis-2-(4-methylphenyl)-3-hydroxy-5-C2-(dimethylamino)ethyl]- 8-
Benzyloxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 1.71f9. Acetic anhydride 1
A mixture of 1- and pyridine 5- is stirred at 100°C for 3 hours. After cooling, the solvent is distilled off from the mixture under reduced pressure, benzene is added to the residual aroma, and the solvent is further distilled off under reduced pressure. Add 25% hydrogen bromide-acetic acid 4.1& and acetic acid 8- to the residual aroma, and stir at room temperature for 21 hours. After the reaction, the solvent is distilled off from the mixture, the residual aroma is washed with ether, and then dissolved in water. The aqueous solution was adjusted to pH around 9 with potassium carbonate and extracted with chloroform. After washing the extract with water and drying, the solvent was distilled off and the residual aroma was converted into oxalate, which was then recrystallized from methanol to obtain (±)-cis-2-(4-methylphenyl)-3-acetoxy-5. -(2-(dimethylamino)ethyl-8-hydroxy-2,3-dihydro-1,5-
Benzothiazepine-4(5H)-one l/2 oxalate 0°711 is obtained. Yield: 49% M, p, 171-174°C (decomposition) Example 44 (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(2-(dimethylamino)ethyl-8
-Hydroxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrobromide 0.93#,
5% sodium hydroxide aqueous solution 10- and ethanol 5-
The mixture is stirred at room temperature for 2 hours. After the reaction, the mixture was adjusted to pH 4 with 10% hydrochloric acid and then adjusted to pl+8 with sodium hydrogen carbonate. The precipitated crystals are collected by filtration, and the filtrate is concentrated under reduced pressure, and further precipitated crystals are collected by filtration. The precipitated crystals were combined to form a hydrochloride, and then recrystallized from a mixture of dimethylformamide and ethanol.

(±)-cis-2-(4-methoxyphenyl)-3,8
-dihydroxy-5-(2-(dimethylamino)ethyl)-2,3-dihydro-1,5-penzothiazepi 7-4
(5H)-Oar hydrochloride o, 535 g are obtained. yield:
69% M, p, 248.5-251.5°C (decomposition) Example 4
5 (±)-cis-2-(4-methylphenyl)-3-acetoxy-5-(2-(dimethylamino)ethyl-8-
By treating hydroxy-2,3-dihydro-1°5-benzothiazepine-4(5H)-one hydrobromide in the same manner as in Example 44, (±)-cis-2-(4
-methylphenyl)-3,8-dihydroxy-5-(2
-(dimethylamino)ethyl)-2,3-dihydro-1
,5-benzothiazepine-4(5H)-one hydrochloride.
A quarter hydrate is obtained. Yield: 46%, p, 261-265°C Example 46 (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-methoxy-2,3-dihydro-1,5-
Benzothiazepine-4(5H)-one 406■,2-(
A mixture of 170 μm of dimethylamino)ethyl chloride hydrochloride, 370 μm of potassium carbonate, and 30 μm of acetone was added to the
Heat to reflux for an hour. After cooling, the inorganic matter is filtered off and washed with warm acetone. The filtrate and washing liquid were combined, and the solvent was distilled off under reduced pressure. By converting the residual aroma into hydrochloride and recrystallizing it from a mixture of chloroform, ethanol and ether,
(±)-cis-2-(4-methoxyphenyl)-3-
Acetoxy-5-(2-(dimethylamino)ethyl-8-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, hydrochloride, monoethanol 4)
Obtain 40n+g. Yield: ya, o% n, p, 192-194°C [Production of raw material compounds] Production example 1 2-amino-4-methoxythiophenol 13I and (
The mixture of ±)-trans-3-(4-methoxyphenyl)glycidic acid methyl ester 17.6.9 is heated at 160° C. for 16 hours under an argon atmosphere. After cooling, ethanol was added to the mixture, the precipitated crystals were collected by filtration, and recrystallized from chloroform to give (±)-cis-2-(4-
methoxyphenyl)-3-hydroxy-7-medoxy2,3-dihydro-1,5-benzothiazepine-t(5
'H)-one 4.5219 is obtained.

q, 9. 220-222°C By distilling off the solvent from the liquid obtained above (ethanol and chloroform solution) and purifying the residual aroma by silica gel chromatography (solvent: chloroform), (±)-cis-2-(4 -methoxyphenyl)-3-hydroxy-7-medoxy2,3-dihydro-1,5-penzothiazepi7-4 (5H)-off2.9.9 and (±)-trans-2-(4-methoxyphenyl )-3-hydroxy-7-medoxy2.3-
1.13 of dihydro-1,5-benzothiazepin-4(5H)-one is obtained.

Trans isomer: M, p, 189 to 190°C (recrystallized from a mixture of ethyl acetate and n-hexane) Production Examples 2 to 10 The following compounds are obtained by treating the corresponding raw material compounds in the same manner as in Production Example 1.

Table 13 Note: All the above compounds are racemic.

This) Production Example 2 (cis isomer) is from ethyl acetate.

Production Example 2 (trans isomer) was prepared from a mixture of ethyl acetate and n-hexane, Production Examples 3 and 5 were prepared from a mixture of dimethylformamide and ethanol, Production Example 4 was prepared from a mixture of chloroform and n-hexane, Production Example 6 and 7 is recrystallized from dimethylformamide (±)-threo-2-hydroxy-3-(4-methoxyphenyl)-3-(2-amino-3-methylphenylthio)propionic acid methyl ester is simultaneously produced. .

n, p, 98-110℃ (recrystallized from ethanol) *) It is a hemihydrate.

****) Bzl represents a benzyl group.

Production Examples 8 to 10 (K) The following compounds are obtained by treating the corresponding raw material compounds in the same manner as in Production Example 1.

Table 14 Note: All the above compounds are racemic.

Bzl represents a benzyl group.

Production example 11 (a) 2-amino-5-methyl-thiophenol 29
．． 1.9. (±)-trans-3-(4-methoxyphenyl)glycidic acid methyl ester 47.88 and toluene 300. tl mixture to 60-65 °C for 3 days 1
It is then heated to 70-80°C for 2 days. After the reaction, the solvent was distilled off from the mixture under reduced pressure.

Add benzene to the residual aroma and extract with hydrochloric acid (concentrated hydrochloric acid diluted 1:1 with water). The extract is neutralized with potassium carbonate and further extracted with benzene. After washing the extract with water and drying, benzene is distilled off. The residual aroma was purified by silica gel chromatography [solvent: benzene-ethyl acetate (10:1)] and recrystallized from a mixture of ethanol and isopropyl ether to obtain (±)-threo-2-hydroxy-1-(2
-amino-5-methylphenylthio)-1-(4-methoxyphenyl)propionic acid methyl ester 15, EL
Get 9.

M, p, 11-0 to 112°C The following compound is obtained by treating the corresponding raw material compound in the same manner as above.

Table 15 Note: All of the above compounds are (±)-threo isomers.

*)(±)-cis-2-(4-methoxyphenyl)-3
-hydroxy-8-methylthio-2,3-dihydro-1
, 5-benzothiazepin-4(5H)-one are simultaneously produced.

M, p, 183-184°C (recrystallized from a mixture of dimethylformamide and ethanol) **) Recrystallized from a mixture of ethanol and isopropyl ether (this) Recrystallized from isopropyl ether (this) Recrystallized from ethanol (this) ) isopropanol (b) (±)-threo-2-hydroxy-3-(2-
Amino-5-methylphenylthio)-3-(4-methoxyphenyl)propionic acid methyl ester A mixture of 50d of 53.5% aqueous sodium hydroxide solution and 50d of methanol is stirred at room temperature for 2 hours. After the reaction, 10% hydrochloric acid is added to the mixture under water cooling to adjust the pH to between 3 and 5. The precipitator was collected by filtration, washed with water, dried, and then recrystallized from methanol. (±)-threo-2-hydroxy-3-
(2-amino-5-methylphenylthio)-3-(4-
methoxyphenyl)propion94. 3, get 9.

gate. p. 190-193°C The following compound is obtained by treating the corresponding raw material compound in the same manner as above.

[M.J. Table 16 Note: All of the above compounds are (±)-threo isomers.

Animal) Recrystallized from methanol (c) L-(p-hydroxyphenyl)chrysine methyl ester hydrochloride 45.38'fr-methanol 10
Dissolves in 00-. To this solution, under water cooling, add 1 part potassium hydroxide.
Add a 100+1 solution of 1.711 in methanol and filter off the precipitate (potassium chloride). (±)-Threo-2-hydroxy-3-(2-amino-5-methylphenylthio)-3-(4-methoxyphenyl)propionic acid 37
．． Add 8.9 to the filtrate.

The mixture is heated to 50° C. and 900° C. of methanol is added to form a solution. The solvent is distilled off from the solution under reduced pressure at a temperature below 50°C. Add 200% of ethanol to the residual aroma and refrigerate overnight. Collect the precipitated crystals by filtration (the filtrate is referred to as mother liquor I), and recrystallize from ethanol (the mother liquor is referred to as mother liquor ■). The crystals were further recrystallized from ethanol to obtain (+)-threo-2-hydroxy-3-(2-amino-5-methylphenylthio)-3-(4-methoxyphenyl)propionic acid L -(p -Hydroxyphenyl)chrysine methyl ester salt CM, p, 164-167°C.

[α) + 255.8° (C=0.655.methanol)) 20.7.9 is obtained.

Compound 15.3FI obtained above was mixed with methanol 240
ml and 200 ml of water, add cation exchange resin 27 to the suspension, and stir overnight at room temperature. Filter off the resin and wash the resin with methanol. The filtrate and washing liquid were combined, and the solvent was distilled off under reduced pressure. By adding water to the residual aroma, filtering out the precipitated crystals, and recrystallizing them from ethanol, (
+) -threo-2-hydroxy-3-(2-amino-
7.9 of 5-methylphenylthio)-1-(4-methoxyphenyl)propionic acid is obtained.

M, p, 158-160°C [α) + 296.0' (C=0.290.methanol) The above mother liquors (1) and (2) are combined, concentrated hydrochloric acid 13- is added thereto, and the solvent is distilled off under reduced pressure. Add water to the residual fragrance and filter out the precipitated crystals. The crystal 15.5f9. D-(p-hydroxyphenyl)glycine methyl ester hydrochloride 20.3#
By treating a mixture of 5.28 and potassium hydroxide in the same manner as above, (-)-threo-2-hydroxy-3-(2-amino-5-methylphenylthio)-3
-(4-methoxyphenyl)propionic acid D-(p-
hydroxyphenyl)glycine methyl ester salt CM,
p164-167°C (recrystallized from ethanol).

[α) -254,8° (C=0.949.methanol)) 12.9.9 is obtained.

Compound 15.319 obtained above was treated in the same manner as above to obtain a free acid, (-)-threo-2-hydroxy-3-(2-amino-5-methylphenylthio)-3-( 4-methoxyphenyl)propionic acid 6.5
Get 9.

M, p, 158-160°C (recrystallized from ethanol) [α) -265,3° (C = 0.331.methanol) (b) -Threo-2-hydroxy-3 obtained in -i -(2-amino-4-methylphenylthio)-3-
By treating (4-methoxyphenyl)propionic acid in the same manner as above, it can be optically resolved into the following compounds.

(+)-threo-2-hydroxy-3-(2-amino-
4-Methylphenylthio)-3-(4-methoxyphenyl)propionic acid: M, 9. 168-170°C (recrystallized from ethanol) (α) + 360.3° (C=0.342. methanol) (-)-threo-2-hydroxy-3-(2-amino-
4-Methylphenylthio)-3-(4-methoxyphenyl)propionic acid: Lp, 173-176°C (recrystallized from ethanol) [α) -360,5' (C=0.352.methanol) (d) (+)-threo-2-hydroxy-3-(2-
Amino-5-methylphenylthio)-3-(4-methoxyphenyl)propionic acid 9.9 and xylene 350-
The mixture is refluxed for 24 hours.

After cooling, xylene was distilled off and the residual aroma was recrystallized from ethyl acetate to give (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-methyl-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one 7
, we get 8.9.

M, p, 223-226°C (decomposition) [α) + 123.8° (C=0.707. dimethylformamide) The following compound is obtained by treating the corresponding raw material compound in the same manner as above.

Table 1'rr Note) All of the above compounds are cis isomers.

*) Recrystallized from ethyl acetate, decomposed with M and p above **
) Measured with a dimethylformamide solution ***) Recrystallization production example from a mixture of dimethylformamide and ethanol 12 A mixture of sodium hydride (63% dispersion) 1.53 and dimethyl sulfoxide 25 was heated to 70°C under an argon atmosphere. Heat for 50 minutes. The (±)-threo-2 produced in Production Example 11 (a) -iii was added to the mixture under cooling.
-Hydroxy-3-(2-amino-5-methylthiophenylthio)-3-(4-methoxyphenyl)propionic acid methyl ester 7.9 dimethyl sulfoxide 12m
Add QtV solution dropwise and stir at room temperature for 2 minutes. After the reaction,
The mixture was poured into ice water, and the precipitated crystals were collected by filtration. (±)-cis-2-(4-
methoxyphenyl)-3-hydroxy-8-methylthio-2,3-dihydro-1,5-benzothiazepine-4(
5H)-one 6.7.9 is obtained.

Gate, p, 183-184°C Production Example 11 (±)-Threo-2 produced in (a)-iv
By treating -hydroxy-3-(2-amino-4-methylthiophenylthio)-3-(4-methoxyphenyl)propionic acid methyl ester in the same manner as above,
(±)-cis-2-(4-methoxyphenyl)-3-
hydroxy-7-methylthio-2,3-dihydro-1,
5-benzothiazepin-4(5H)-one is obtained.

M, 9.211-214°C (recrystallized from a mixture of dimethylformamide and ethanol) Production example 13 (a) 11 g of 2-amino-4-trifluoromethyl-thiophenyl and (±)-trans-3=(4-methoxy A mixture of 18.5 g of phenyl)glycidic acid methyl ester is heated at 140-150° C. for 17 hours. After cooling,
Isopropyl ether was added to the mixture, the precipitate was collected by filtration, and recrystallized from a mixture of ether and n-hexane to give (±)-threo-2-hydroxy-3-(1
-amino-4-trifluoromethylphenylthio)-3
12.8 g of -(4-methoxyphenyl)propionic acid methyl ester are obtained.

M, p, 135-137°C (b) (±)-threo-2-hydroxy-3-(2-
Amino-4-trifluoromethylphenylthio)-3-
(4-Methoxyphenyl)propionic acid ((±)-threo-2-hydroxy-3-(2-amino-4-trifluoromethylphenylthio)-3-(4) obtained in (a)
-Methoxyphenyl)propionic acid methyl ester is produced in the same manner as in Production Example 1l-(b).

A, 9.183-185°C) 7.8Ii, 1-Hydroxybensylitriazole monohydrate 3. lf9. 100% of tetrahydrofuran and 200% of methylene chloride! '
5.83 of N,N'-dicyclohexylcarbodiimide is added to the mixture at 0-3°C. The compound was heated to 8 at the same temperature.
Stir for 1 hour then at room temperature for 24 hours. After the reaction, the precipitated crystals are collected by filtration and washed with ethyl acetate. The filtrate and washings are combined, washed successively with a 5% aqueous sodium hydrogen carbonate solution and water, dried, and then the solvent is distilled off. By recrystallizing the previously obtained crystals and residual aroma from ethyl acetate, (±)-cis-
2-(4-methoxyphenyl)-3-hydroxy-7-
Trifluoromethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 7S is obtained.

? 1.9. 205-207°C Production Example 11- (±)-Threo-2-hydroxy-3-(2-amino-5-methoxyphenylthio)-3-(4-methoxyphenyl)propionic acid produced by -iii By processing in the same way as above, we get (±)−
Cis-2-(4-methoxyphenyl)=3-hydroxy-8-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained.

M, 9. 204-206°C (recrystallized from acetone) Production example 14 (a) (±)-cis-2-(4-methoxyphenyl)
-3-hydroxy-8-methoxy-2,3-dihydro-
1,5-benzothiazepin-4(5H)-one 43. The mixture of pyridine 13- and methylene chloride 5.1& is cooled with ice water. To the mixture, (S)=1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl chloride ((S) prepared from (S)-1-(2-naphthylsulfonyl)pyrrolidine-2-carboxylic acid and oxalyl chloride in anhydrous benzene) ] Add 4 s of water and stir at room temperature for 3 hours. After the reaction, add water and a mixture of ethyl acetate and chloroform (1:1) to the mixture and separate the organic layer.

The organic layer is washed successively with 10% hydrochloric acid, water, 5% aqueous sodium bicarbonate solution, and water, and after drying, the solvent is distilled off. Dissolve the residual fragrance in benzene and precipitate crystals (3,7i M, p, 148
~150℃ (recrystallized from ethyl acetate) [α) -28,
5° (C=0.755, chloroform)] (The filtrate is referred to as mother liquor I.) 3.6 L of the crystals obtained above chloroform 5-, ethanol 50r11 and 5% sodium hydroxide aqueous solution 50- The mixture is stirred at room temperature for 1 hour. After the reaction, the mixture was washed with water, dried, the solvent was distilled off, and the residual aroma was recrystallized from ethyl acetate to give (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-methoxy- 2,3
-dihydro-1,5-henzothi7'zepi:/-4(5H
)-on 1.4611 is obtained.

M, p, 187-189°C (α) -98,70 (C = 0.290. Dimethylformamide) (b) The solvent is distilled off from the above mother liquor ■ (benzene solution), and the residual aroma is purified by silica gel chromatography. Therefore, the oil Qα)” −68,5′ (C=0.5
39. Chloroform)) 3.4.9 is obtained.

Above oily substance 3.3.9. Chloroform 5-, ethanol 50- and 5% sodium hydroxide aqueous solution 50-
By processing in the same manner as a).

(+)-cis-2-(4-methoxyphenyl)=3-hydroxy-8-methoxy-2,3-dihydro-1,5-
Benzothiazepine-4(5H)-one 1°3s is obtained.

M, p, 187-190°C (recrystallized from ethyl acetate) C(r) +99.0' (C = 0.257. dimethylformamide) Production example 15 (a) 2.4-dinitrothiophenol 33.0 &,
A mixture of (±)-trans-3-(4-methoxyphenyl)glycidic acid methyl ester 41.09 and acetonitrile 410 rI& is stirred at room temperature for 3 days. After the reaction, insoluble matter is filtered off, and the solvent is distilled off from the filtrate. By recrystallizing the residual aroma from a mixture of ethyl acetate and isopropyl ether.

(±)-Threo-2-hydroxy-3-(2,4-dinitrothiophenylthio)-3-(4-methoxyphenyl)propionic acid methyl ester 45.28 is obtained.

M, p, 130-131°C (b) 32.16s of stannous chloride was dissolved in concentrated hydrochloric acid at 23°5,
Dissolve in a mixture of Ijl and acetic acid 120- and add <±
)-Threo-2-hydroxy-3-(2,4-dinitrophenylthio)-3-(4-methoxyf) Stir at 5 to 50°C for 30 minutes. After the reaction, the compound was dissolved in 112 I of sodium hydroxide and 11 I of ice water. .!IN! and chloroform 300
Pour into the mixture of fflT1 at below 0°C. The chloroform layer was separated, washed with water and dried, the solvent was distilled off, and the residual aroma was recrystallized from a mixture of ethanol and isopropyl ether to give (±)-threo-2-hydroxy-3-(2,
4-diaminophenylthio)-3-(4-methoxyphenyl)propionic acid methyl ester 6,24# is obtained.

M, p, 112-114°C (C) (±)-threo-2-hydroxy-3-(2,
4-diaminophenylthio)-3-(4-methoxyphenyl)propionic acid methyl ester 63, sodium bicarbonate 3,9. A mixture of methylene chloride 65- and dimethylformamide 10- was cooled to -60 to -50°C, and benzyloxycarbonyl chloride 2.9-
4.9 methylene chloride TtI & solution was added dropwise and stirred at the same temperature for 3 hours. After the reaction, water is added to the compound at -5°C or below, and the organic layer is separated. After washing the organic layer with water and drying, the solvent is distilled off, the residual aroma is dissolved in a mixture of chloroform and ether, and 18% hydrochloric acid is added to the mixture.

The precipitated crystals are collected by filtration, suspended in chloroform, and an aqueous potassium carbonate solution is added. By separating the chloroform layer, washing with water and drying, and then distilling off the solvent.

(±)-threo-2-hydroxy-3-(2-amino-
4-benzyloxycarbonylaminophenylthio)-
5.7 g of 3-(4-methoxyphenyl)propionic acid methyl ester are obtained as an oil.

(d) (±)-threo-2-hydroxy-3-(2-
Production Example 13-(b
) to be processed in the same way as (±)-Threo-2-
0.88..9 of hydroxy-3-(2-amino-4-benzyloxycarbonylaminophenylthio")-3-(4-methoxyphenyl)propionic acid is obtained as an oil.

(e) (±)-threo-2-hydroxy-3-(2-
Amino-4-benzyloxycarbonylaminophenylthio)-3-(4-methoxyphenyl)furopionic acid 0
．． Production Example 1 A mixture of 88# and xylene 35tI&
(±)-cis-2-(4-methoxyphenyl)-3-hydroxy-
7-Benzyloxycarbonylamino-2,3-dihydro-1,5-benzothiazepine-4(5H)-one 1
0.45 g of /tetrahydrate are obtained.

M, p, 225-228°C (recrystallized from ethanol) (f) (±)-cis-2-(4-methoxyphenyl)
-3-hydroxy-7-benzyloxycarbonylamino-2,3-dihydro-1,5-benzothiazepine-4
A mixture of (5H)-one quarter hydrate 0,87 El and acetic anhydride 1- is heated to 100-110° C. for 1.5 hours. After cooling, the solvent was distilled off from the mixture under reduced pressure, and chloroform was added to the residual aroma.

Wash sequentially with an aqueous potassium carbonate solution and water, and after drying, the solvent is distilled off. Add 3°5 of 25% hydrogen bromide-acetic acid to the residual aroma, and stir at room temperature for 3 hours. After reaction.

Add anhydrous ether and filter the precipitated crystals. After washing the crystals with anhydrous ether, they are dissolved in chloroform. The chloroform solution was sequentially washed with an aqueous potassium carbonate solution and water, and after drying, the solvent was distilled off and the residual aroma was recrystallized from methanol to obtain (±)-cis-2-(4-methoxyphenyl)-3-acetoxy. 0.33 of -7-amino-2,3-dihydro-1,5-benzothiazepine-4(5H)-one °1 hydrate is obtained.

Gate, p, 248-250°C Production Example 16 (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-7-amino-2,3-dihydro-1,5- obtained in Production Example 15 Benzothiazepine-4(5H)-one
Monohydrate 0.2.9.10% sodium hydroxide aqueous solution 2
-, methanol 30-, chloroform 8- and tetrahydrofuran 2. The mixture of & is stirred at room temperature for 3 hours.

Add acetic acid 0.5- to the mixture to adjust the pH to around 5,
The solvent is removed under reduced pressure. The residual fragrance is dissolved in chloroform, the solvent is washed with water, and after drying, the solvent is distilled off. By adding ether to the residual aroma and filtering off the precipitated crystals, (±)-cis-
2-(4-methoxyphenyl)-3-hydroxy-7-
0.13# of amino-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained.

M, p, 215-218°C (decomposition) Production Example 17 (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-methoxy-2,3- produced in Production Example 13
A mixture of 500 μl of dihydro-1,5-benzothiazepin-4(5H)-one and 358 mg of pyridine in 8-dimethylformamide was cooled on ice, and a solution of 130 μl of acetyl chloride in 2-dimethylformamide was added to the mixture. Add dropwise and stir at room temperature for 1 hour. Pour the reaction solution into ice water and extract with chloroform. The extract is washed with 10% hydrochloric acid and water, dried, and the solvent is distilled off under reduced pressure. By recrystallizing the residual aroma from a mixture of dimethylformamide and ethanol, (±)-cis-2-(4-methoxyphenyl)-
3-acetoxy-8-methoxy-2,3-dihydro-1
, 5-benzothiazepin-4(5H)-one 465. Yield: 82.3% M, p, 218-219°C

Claims (1)

[Claims] 1. General formula (171 is lower alkyl or lower alkoxy. R2 is a hydrogen atom or lower alkanoyl, Rs and R4 are both lower alkyl, R8 is lower alkyl, lower alkoxy, amino 2. Lower alkylthio, hydroxyl group , benzyloxy or trifluoromethyl, n represents 2 or 3) or a pharmacologically acceptable acid addition salt thereof. 2. General formula (where R1 is lower alkyl or lower alkoxy. R1 is a hydrogen atom or lower alkanoyl BS represents lower alkyl, lower alkoxy, amino, lower alkylthio, hydroxyl group, benzyloxy or trifluoromethyl) 1 , 5-benzothiazepine derivative or salt thereof. 3. 1 represented by the general formula (where R1 is lower alkyl or lower alkoxy; Rt is a hydrogen atom or lower alkanoyl; Ha represents lower alkyl, lower alkoxy, amino, lower alkylthio, hydroxyl group, benzyloxy or trifluoromethyl); , a 5-benzothiazepine derivative or a salt thereof, and a compound represented by the general formula (wherein R3 and R4 are both lower alkyl, n is 2 or 3, and X represents a halogen atom) or a salt thereof are subjected to a condensation reaction. . General formula (171.R
2, Rff, R4, R11 and n have the same meanings as above. ) A method for producing a 1,5-benzothiazepine derivative or a pharmacologically acceptable acid addition salt thereof. 4. General formula (ill is lower alkyl or lower alkoxy. R3 and R4 are both lower alkyl, R6 is lower alkyl, lower alkoxy, lower alkylthio, hydroxyl group. Benzyloxy or trifluoromethyl, n is 2 or 3
represents. ) A 1,5-benzothiazepine derivative or a salt thereof is reacted with a compound represented by the general formula %) (wherein R7 represents lower alkanoyl) or a reactive derivative thereof, and if necessary, further The general formula (where Hl, H3, H4, R6
, Hl and n have the same meanings as above. ) A method for producing a 1,5-benzothiazepine derivative or a pharmacologically acceptable acid addition salt thereof. 5. General formula (where ill is lower alkyl or lower alkoxy. R3 and R4 are both lower alkyl. R8 is lower alkyl, lower alkoxy, amino, lower alkylthio. Hydroxyl group, benzyloxy or trifluoromethyl R? is lower alkanoyl, n is lower alkanoyl. 2 or 3) or a salt thereof, and if necessary, further converting the product into a pharmacologically acceptable acid addition salt thereof. A method for producing a 1,5-benzothiazepine derivative represented by the general formula (wherein R1, ill, R4, R5 and n have the same meanings as above) or a pharmacologically acceptable acid addition salt thereof. 6. 1,5-benzothiazepine derivatives represented by the general formula (wherein R1 is lower alkyl or lower alkoxy, R1 is a hydrogen atom or lower alkanoyl, R3 and R4 are both lower alkyl, and n represents 2 or S-C) or a salt thereof is subjected to a debenzylation reaction, and if necessary, the product is further converted into a pharmacologically acceptable acid addition salt thereof (wherein R1, R2, R3, R4 and n are A method for producing a 1,5-benzothiazepine derivative or a pharmacologically acceptable acid addition salt thereof. 7. General formula (where R1 is lower alkyl or lower alkoxy. R2 is a hydrogen atom or lower alkanoyl 1 (2 and R4
are both lower alkyl; R5 represents lower alkyl, lower alkoxy, amino, lower alkylthio, hydroxyl group, benzyloxy or trifluoromethyl; n represents 2 or 3; 1.) A pharmaceutical composition having a hypotensive effect and/or a cerebral/coronary vasodilatory effect, which contains a 1,5-benzothiazepine derivative shown in the following formula or a pharmacologically acceptable acid addition salt thereof as an active ingredient.