JPS60231669A - 1,5-benzothiazepine derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1> is lower alkyl, lower alkoxy, OH; R<2> is H, lower alkanoyl; R<3> is lower alkyl; R<4>, R<5> are, i) when R<1> is other than OH, lower alkyl, lower alkoxy, F, OH in one group and H in the other or lowder alkoxy in both of them; ii) when R<1> is OH, lower alkyl, F, OH in one group and H in the other or lower alkoxy in both]. EXAMPLE:(+ or -)-cis-2-(4-Methoxyphenyl-3-acetoxy-5-[2-( N-methylamino )ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride. USE:It has an activity of inhibiting blood platelet coagulation and used as a preventive or remedy for a variety of thromboses. PREPARATION:The reaction of a compound of formula II (R<6> is lower alkyl; one of R<7> and R<8> is lower alkyl and the other is H, or both of them are lower alkoxy) with another compound of formula III (Q is H; X<1> is halogen) gives a compound of formula I.

Description

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

(Prior Art) The main cause of thrombus formation is said to be the interaction between blood components, particularly platelets, blood coagulation factors, etc., and blood vessel walls. For example, when damage occurs to a blood vessel wall, platelets in the bloodstream aggregate on exposed endothelial tissue of the blood vessel, such as collagen. A substance that aggregates platelets is released from this aggregate,
Growth of platelet aggregates is promoted. Furthermore, the aggregates thus formed are stabilized by fibrin.

This leads to the formation of a blood clot. Therefore, as one of the drugs for suppressing thrombus formation, a drug that suppresses platelet aggregation during the above-mentioned thrombus formation process is considered, and aspirin and the like have been used as platelet aggregation inhibitors.

(Objectives of the Invention) One object of the present invention is to provide novel 1,5-benzothiazepine derivatives, and another object is to provide novel 1.5-benzothiazepine derivatives.
The object of the present invention is to provide a method for producing 5-benzothiazepine derivatives.

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

H (However, R1 represents lower alkyl, lower alkoxy or hydroxy; R2 represents a hydrogen atom, lower alkanoyl, benzyl or benzoyl); 73 represents lower alkyl; R4 and R5 represent lower alkyl.

^) When R' is lower alkyl or lower alkoxy, one is lower alkyl or lower alkoxy.

It represents a fluorine atom, benzyloxy, hydroxy or lower alkylthio, and the other is a hydrogen atom, or both are lower alkoxy.

B) When R' is hydroxy, one is lower alkyl, fluorine atom, hydroxy, or lower alkylthio, and the other is hydrogen atom.

or both represent lower alkoxy. ) The compound (1) of the present invention or a salt thereof has an excellent platelet aggregation inhibiting effect. For example, when we investigated the inhibitory effect on collagen-induced aggregation of human platelets, we found that the compound of the present invention (=)-cis-2-(4-methylphenyl)-3-hydroxy-5-(2-(N-methyl IC of amino)ethylc8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride 1/2 permanent
,.

(Concentration required to suppress platelet aggregation induced by collagen by 50%) was 0.003 to 0.03 μs/−. Incidentally, the IC6 of aspirin (chemical name niacetylsalicylic acid), which is known to have a similar effect,
° was approximately 20 μm9/-.

In this way, the compound (I) of the present invention has an excellent platelet aggregation inhibitory effect.2 For example, cerebral infarction, cerebral thrombosis, transient cerebral ischemia, myocardial infarction, coronary artery thrombosis, 5 pulmonary artery infarction, peripheral vascular embolism. Treatment for diseases such as thrombosis, thrombosis, thrombovasculitis, embolism, etc.

It can be used for palliation and prevention.

The compound of the present invention is represented by general formula (1).

R1 is lower alkyl such as methyl, ethyl, propyl, butyl; methoxy, ethoxy, propoxy.

Lower alkoxy or hydroxy such as butoxy
pg is a hydrogen atom, acetyl, propionyl.

Lower alkanoyl such as butyryl, isobutyryl; benzyl or benzoyl; R3 is lower alkyl such as methyl, ethyl, propyl, butyl; R4 and R
5 is A) When R' is lower alkyl or lower alkoxy, one is lower alkyl such as methyl, ethyl, propyl, butyl; "methoxy, ethoxy.

Lower alkoxy such as propoxy, butoxy; fluorine atom, benzyloxy, hydroxy or methylthio,
It is lower alkylthio such as ethylthio, propylthio, or butylthio, and the other is a hydrogen atom, or both are lower alkoxy such as methoxy, ethoxy, propoxy, or butoxy.

B) When R' is hydroxy, one is methyl,
Lower alkyl such as ethyl, propyl, butyl, fluorine atom, hydroxy or methylthio.

Is it a lower alkylthio such as ethylthio, propylthio, or butylthio, and is the other a hydrogen atom?

Or both are lower alkoxy such as methoxy, ethoxy, propoxy, and butoxy.

Among these, preferred compounds are those represented by the general formula (1)
R1 is methyl, methoxy or hydroxy, R2 is a hydrogen atom, acetyl, propionyl, butyryl, isobutyryl, benzyl or benzoyl, and R3
is methyl and R4 and R5 are A) When R' is methyl or methoxy, one is methyl, methoxy, fluorine atom, benzyloxy, hydroxy or methylthio, and the other is hydrogen atom, or both are methoxy Yes.

B) When R' is hydroxy, one is methyl,
Examples include compounds in which R is a fluorine atom, hydroxy or methylthio, and the other is a hydrogen atom, or both are methoxy; more preferred compounds include those in general formula (I) where R1 is methyl or methoxy;
Examples include those in which 2 is a hydrogen atom or acetyl, R3 is methyl, and one of R4 and R5 is methyl, methoxy or hydroxy, and the other is a hydrogen atom.

Since the compound (1) of the present invention has two asymmetric carbon atoms at the 2- and 3-positions of the 1,5-hengetiazepine skeleton, 2
Species stereoisomers (i.e. cis and trans isomers) or four optical isomers [i.e.

(+)-cis, (-)-cis, (+)-trans and (
-)-1-lance isomer], but the present invention also includes these isomers and 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, compound (I) can be prepared by the following [Method A] to [Method F]
It can be manufactured according to the following.

[Method A]

Compound (I) has the general formula (where R6 represents lower alkyl or lower alkoxy, one of pl and R8 is lower alkyl, lower alkoxy, fluorine atom, benzyloxy or lower alkylthio, and the other is hydrogen atom) mosquito.

or R2 and R both represent lower alkoxy
3 has the same meaning as above. ) A compound represented by the general formula (wherein R2, R6, R? and R8 have the same meanings as above) or a salt thereof and a compound represented by the general formula (where Q represents a hydrogen atom or a protective group) represents a halogen atom, and R3 has the same meaning as above. ), and when the substituent Q is a protecting group, the protecting group can be removed from the compound (IV).

[Method B]

General formula of compound (1) (However, R9 represents lower alkyl or phenyl.

R3, R6, R7 and R8 have the same meanings as above.

) is the compound represented by the general formula (where R3, R6, R7, Ra and Q have the same meanings as above) or a salt thereof and the general formula (% formula %) (however, R9 has the same meaning as above) ) or a reactive derivative thereof to produce a compound represented by the general formula (wherein R3, R6, R7, R11, R, 9 and Q have the same meanings as above). However, when the substituent Q is a protecting group, it can be produced by removing the protecting group from the compound (■).

H (However, R3, R6, R7 and R8 have the same meanings as above.) The compound represented by (■) or a salt thereof is deacylated to form the general formula U (However, n3.Rh, R7, R11 and Q has the same meaning as above.) If the substituent Q is a protecting group, the protecting group is removed from the compound (■) [Method D] Of compound (I) , general formula (where R11 is a hydrogen atom, lower alkanoyl or benzoyl; one of 17+2 and R11 is lower alkyl,
a fluorine atom, hydroxy or lower alkylthio,
The other is a hydrogen atom, and n3 has the same meaning as above. ) The compound represented by the general formula (where RIG represents lower alkyl, R3, RII, R
I! and RI3 have the same meanings as above. ) or a salt thereof can be produced by dealkylation.

[E method]

Among compounds (I), the compounds represented by the general formula (wherein R3, R6, R? and R8 have the same meanings as above) are compound (V) or a salt thereof and the general formula (wherein Xi represents a halogen atom). ) is reacted with a compound represented by the general formula (wherein R3,
R6, R7, Re and Q have the same meanings as above. ) When the substituent Q is a protecting group, it can be produced by removing the protecting group from the compound (XI).

[F method]

Among compounds (1), the compound represented by the general formula (wherein R3, R6 and 117+1 have the same meanings as above) is represented by the general formula (however, R31R6+ R'' and Q have the same meanings as above). A compound represented by the general formula (wherein +R3+'R6+R'' and Q have the same meanings as above) is prepared by debenzylating the shown compound or a salt thereof, and when the substituent Q is a protecting group, can be produced by removing the protecting group from the compound (X I[I).

The protecting group used in the method of the present invention is 9
Substituted or unsubstituted benzyloxycarbonyl, such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl; tert, -butoxycarbonyl, β
, β, β-trichloroethoxycarbonyl, substituted or unsubstituted lower alkoxycarbonyl such as iodoethoxycarbonyl; benzyl, p-methoxybenzyl, 3,4-
Mention may be made of the conventional protecting groups for amino groups such as substituted or unsubstituted phenyl-lower alkyl such as dimethoxybenzyl.

In addition, the compound (I
As the salt of I), an alkali metal salt such as sodium salt or potassium salt can be used; on the other hand, compound (I),
Salts of (V), (■), (IX) and (XII) include hydrochloride, hydrobromide, and perchlorate.

addition salts of inorganic acids such as hydroiodide and oxalate;
maleate, fumarate, succinate.

Addition salts of organic acids such as methanesulfonate salts can be used.

The reactions of [Method A] to [Method F] will be explained in detail below.

[Method A]

The condensation reaction between compound (II) or a salt thereof and compound (I[[) or a salt thereof is performed in the presence or absence of an alkaline reagent, at the bottom right
It can be carried out in a suitable solvent.

When compound (n) is used in free form, the condensation reaction is preferably carried out in the presence of an alkaline reagent. As the alkaline reagent, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; and alkali metal hydrides such as sodium hydride can be suitably used. As the solvent, it is preferable to use, for example, acetone, ethyl acetate, dimethyl sulfoxide, dimethyl formamide, dioxane, etc., and the condensation reaction is carried out at 20 to 100°C.
It is particularly preferable to carry out the reaction at a temperature of 25 to 70°C.

When the substituent Q in compound (IV) thus produced is a protecting group, a conventional method can be applied to remove the protecting group. For example, when the protecting group is substituted or unsubstituted benzyloxycarbonyl, the protecting group can be removed by treating compound (IV) with an acid in a suitable solvent. As the acid, hydrogen bromide, hydrogen chloride, trifluoroacetic acid, etc. are preferably used, and as the solvent, acetic acid is used.

Benzene, ethyl acetate, methylene chloride, 1,2-dichloroethane, chloroform, toluene, chlorobenzene, etc. can be used. The removal reaction is from 0 to 40℃
It is particularly preferable to carry out the reaction at a temperature of 0 to 25°C.

When the protecting group is tert,-butoxycarbonyl, the protecting group can be removed by treating compound (TV) with an acid in a suitable solvent.

Acids include hydrogen bromide, hydrochloric acid, and trifluoroacetic acid.

It is preferable to use formic acid or the like, and the solvent is acetic acid.

Water etc. can be used. The removal reaction is -10-5
Preferably it is carried out at 0°C, especially from 0 to 40°C.

When the protecting group is β, β, β-trichloroethoxycarbonyl, compound (IV) is diluted with zinc-acetic acid for 20 to 60
The protecting group can be removed by treatment at 20-60°C, and when the protecting group is iodoethoxycarbonyl, the protecting group can be removed by treating compound (IV) with zinc-methanol at 20-60°C. Protecting groups can be removed.

Furthermore, when the protecting group is substituted or unsubstituted phenyl-lower alkyl, the protecting group can be removed by a substituent such as benzyloxycarbonyl, etc.
The protecting group can be removed by converting the compound into a compound and then treating with an acid.

For example, conversion of substituted or unsubstituted phenyl-lower alkyl to benzyloxycarbonyl
It can be carried out by reacting (Q-substituted or unsubstituted phenyl-lower alkyl) with benzyloxycarbonyl halide (eg, benzyloxycarbonyl chloride) in a suitable solvent. As the solvent, benzene, toluene, xylene, dioxane, tetrahydrofuran, etc. can be used, and the conversion is 50 to 130
It is preferred to carry out the reaction at a temperature of 80 to 100°C. For the subsequent removal of benzyloxycarbonyl, the above-mentioned method for removing the protecting group can be applied.

[Method B]

The reaction between compound ('V) or a salt thereof and the reactive derivative of compound (Vl) can be carried out in a suitable solvent in the presence or absence of an acid absorber. Reactive derivatives of compound (VI) include acid anhydrides such as acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, and benzoic anhydride; acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride, and benzoyl chloride. Examples include acid halides such as. Examples of deoxidizers include pyridine, triethylamine, N-methylpiperidine,
Examples include N-methylmorpholine, N-methylpyrrolidine, N-ethyl-N, and N-diisopropylamine.

Examples of solvents include pyridine, benzene, dioxane, and tetrahydrofuran.

Preferably, toluene, methylene chloride, acetic acid, etc. are used. In the reaction, when excess acetic anhydride is used as a reactive derivative of compound (Vl).

Since the acetic anhydride also acts as a solvent, it is not necessarily necessary to use another solvent. When carrying out the reaction, when an acid anhydride is used as the reactive derivative of compound (VI), it is preferably carried out at 20 to 130°C, and when an acid halide is used as the reactive derivative, the reaction is carried out at 20 to 130°C.
Preferably it is carried out at a temperature of -60°C.

On the other hand, the reaction between compound (V) or a salt thereof and compound (Vl) can be carried out in a suitable solvent in the presence of a condensing agent. Examples of condensing agents include N,N'-dicyclohexylcarbodiimide, N,N'-carbonyldiimidazole, and ■-methyl-2-halopyridinium iodo salt (
For example, ■-methyl-2=bromopyridinium iodo salt), methoxyacetylene, triphenylphosphine-
Examples include carbon tetrachloride. As the solvent, it is preferable to use methylene chloride F, L2-dichloroethane, chloroform, Hensen, toluene, tetrahydrofuran, dioxane, and the like. The reaction is carried out at 0-80°C, especially at 1
Preferably, the reaction is carried out at a temperature of 0 to 40°C.

In the compound (■) produced in this way, the substituent Q
When is a protecting group, the protecting group removal method in [Method A] can be applied to remove the protecting group.

The raw material compound (V) in the above method corresponds to the intermediate product (IV) in [Method A] in which RZ is a hydrogen atom.

[C method]

The deacylation reaction of compound (■) or a salt thereof can be carried out by treating the compound with an acid or alkaline reagent in a suitable solvent. As the acid, for example, hydrochloric acid or hydrobromic acid can be used, and as the alkaline reagent, sodium hydroxide can be used.

Alkali metal hydroxides such as potassium hydroxide, sodium acids, alkali metal carbonates such as potassium carbonate, etc. can be used. As the solvent, it is preferable to use alkanols such as methanol and ethanol, water, and mixtures thereof. When using an acid, the reaction temperature is 0 to 100℃1
In particular, it is preferably carried out at 20 to 60°C, and when an alkaline reagent is used, it is preferably carried out at 0 to 100°C, particularly preferably 10 to 50°C.

When the substituent Q in the compound (V[) produced in this way is a protecting group, the protecting group removal method in [Method A] can be applied to remove the protecting group.

[D method]

The dealkylation reaction of compound (IX) or a salt thereof can be carried out by treating the compound with a boron trihalide such as boron tribromide in a suitable solvent. Methylene chloride is used as a solvent.

It is preferable to use chloroform, 1,2-dichloroethane, chlorobenzene, etc. The reaction is carried out at -50~25℃
It is particularly preferable to carry out the reaction at -10 to 25°C.

[E method]

The reaction between compound (V) or a salt thereof and compound (X) can be carried out in a suitable solvent in the presence of an acid absorbing agent. Examples of deoxidizing agents include alkali metal hydrides such as sodium hydride, alkali metal amides such as sodium amide, and the like. As the solvent, it is preferable to use, for example, dimethylformamide, dimethylsulfoxide, benzene, tetrahydrofuran, dioxane, or the like. The reaction is 0
Preference is given to carrying out at a temperature of -80°C, especially 25-60°C.

When the positional group Q in compound (XI) thus produced is a protecting group, the protecting group removal method in [Method A] can be applied to remove the protecting group.

[F method]

The debenzylation reaction of compound (Xll) or a salt thereof can be carried out by a conventional method such as treating the compound with an acid in a suitable solvent. Hydrogen bromide is preferably used for the acid treatment, and the solvent is acetic acid, methylene chloride, benzene, or ethyl acetate.

It is preferable to use a mixture of these. The reaction is preferably carried out at -10 to 40°C, especially at 0 to 20°C. In addition, among compounds (XI), when the substituent Q is substituted or unsubstituted benzyloxycarbonyl or substituted or unsubstituted lower alkoxycarbonyl, the protecting group can be simultaneously removed by the above reaction.

When the substituent Q in the compound (X III) produced in this way is a protecting group, removal of the protecting group requires [A
The protective group removal method described in [Act] can be applied.

Raw material compounds (II), (V), (■) of the present invention
, (IX) and (XII) have two asymmetric carbon atoms at the 2- and 3-positions of the 1,5-benzothiazepine skeleton.

Although there are four types of optical isomers [i.e. (+)-cis, (-)-cis, (+)-trans and (-)-) lance isomers], all of the above reactions do not involve racemization. To proceed, compound (■) is used as the starting compound.

Optically active compound (1-a) by using an optically active form of (V), (■), (IX) or (XI[)
.

(I-b), (I-c), (I-d), (
I-e) or (I-f) can be obtained.

Compound (n), which is a raw material compound of the present invention, can be produced by, for example, the following [method a], [method b], etc.

[method a]

6 [Method b] 8 (II-a) (I[-b) (However, R14 represents lower alkyl, and RI5 represents lower alkanoyl, benzyl or benzoyl.

R6, R7 and R8 have the same meanings as above. ) [a
According to the method], compound (n) is produced by reacting compound (XIV) and compound (XV) to produce compound (U-a),
If necessary, the compound (II-b) can be produced by acylating or benzylating the compound.

According to [method b], compound (II) is compound (XIV)
and compound (XV) to produce compound (XVI), and if necessary, the compound is hydrolyzed to form compound (XV), and then compound (XVI) or compound (XV) is subjected to intramolecular ring closure. It can be produced by preparing a compound (n-a) and, if necessary, acylating or benzylating the compound to obtain a compound (n-b).

In the first step in [method a], the reaction between compound (XIV) and compound (XV), the mixture of compound (XIV) and compound (XV) is mixed with a suitable solvent (for example).

xylene, diphenyl ether, p-cymene, etc.) or without a solvent by heating to 150 to 165°C, and the reaction can be carried out in an inert gas (e.g., argon gas, nitrogen gas, etc.). is suitable. In this reaction, compound (XVI) along with compound (na)
is produced and compound (II-a) has two stereoisomers (i.e.

If obtained as a mixture of cis and trans isomers), their separation can be carried out using a suitable solvent (e.g.

This can be carried out by fractional crystallization using the difference in solubility in ethanol, ethyl acetate, etc.) or by column chromatography.

In the first step in [Method b], the reaction between compound (XIV) and compound (XV) is carried out using a mixture of compound (XIV) and compound (XV) in a suitable solvent (for example).

It can be carried out at 20 to 110° C. in toluene, acetonitrile, benzene, dioxane, xylene, etc.) or without a solvent. In the reaction, the starting compound (XV)
, if its trans isomer is used, the compound (X
VI) is obtained primarily as the threoisomer.

The subsequent optional hydrolysis of compound (XVI) involves dissolving the compound in a suitable solvent (eg, methanol).

0 with alkaline reagents (e.g., potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, etc.) in alkanols such as ethanol, water, mixed solvents thereof, etc.
This can be carried out by processing at ~100°C. Compound (XV) thus obtained can be separated into each optically active form by using an optically resolving agent such as optically active p-hydroxyphenylglycine alkyl ester, if necessary.

The intramolecular ring-opening reaction of compound (XV) or the racemic or optically active form of compound (XV) thus obtained is carried out using these compounds in a suitable solvent (for example, xylene, toluene, diphenyl ether).

p-cymene, acetic acid, etc.) or without solvent, 110-160
This can be carried out by heating to °C. Also,
The intramolecular ring-closing reaction of compound (XVI) was carried out using methylsulfinyl anion (CH35) in dimethylsulfoxide.
It can also be carried out at 0 to 50°C in the presence of OCt+z (prepared from dimethyl sulfoxide and sodium hydride).

On the other hand, the acylation reaction of compound (II-a), which is an optional step in (method a) and [method b], converts the compound into compound (
Similar to the acylation of V), compound (■-a) is converted into compound (V).
The hensylation reaction of compound (I[-a) can be carried out by reacting with compound (II-a) or a reactive derivative thereof, similar to the hensylation reaction of compound (V).
) can be carried out by reacting with compound (X).

When compound (I) of the present invention is used as a medicament, it can be used both as a free base and as a pharmacologically acceptable acid addition salt thereof. Examples of pharmacologically acceptable acid addition salts include hydrochloride, hydrobromide, hydroiodide, and perchlorate.

Inorganic acid addition salts such as sulfate, phosphate; organic acid addition salts such as oxalate, maleate, fumarate, 2-(4-hydroxybenzoyl)benzoate, succinate, methanesulfonate. Examples include salt. These salts can be easily obtained by treating, for example, compound (1) with an acid.

Compound (1) or a pharmacologically acceptable acid addition salt thereof can be administered intracranially or parenterally.

When the compound (1) of the present invention or a pharmacologically acceptable acid addition salt thereof is used as a medicine, the compound (I)
can be used as a pharmaceutical formulation mixed with pharmaceutical excipients suitable for oral or parenteral administration. As such excipients, for example, 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 (I) of the present invention or its pharmacologically acceptable acid addition salt depends on the administration method.

Although it varies depending on the patient's age, weight, condition, and type of disease, it is usually about 0.05 to 50 kg/kg,
Particularly preferred is about 0.5 to 20 μ/kg for oral administration, and about 0.05 to 10 μ/kg for parenteral administration (eg, intravenous injection).

9 In this specification, lower alkyl, lower alkylthio, lower alkoxy, and lower alkanoyl are alkyl having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, and 2 to 4 carbon atoms, respectively. 5 represents alkanoyl.

2 In this specification, "threo" means that the hydroxyl group and the substituted phenylthio group substituted at the 2- and 3-positions of propionic acid have a threo-type configuration (i.e., the two substituents are in the main chain in the Fischer projection diagram). located on the opposite side of ).

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

Experimental Example 1 (in vitro rat and human platelet aggregation inhibitory effect) Nine volumes of blood collected from rats or humans were diluted with 3.8% (W
/V) Platelet-suspended plasma (PPP) was prepared by mixing with 1 volume of trisodium citrate aqueous solution and centrifuging the mixture. The remaining blood is further centrifuged to determine platelet aggregation ability51
(PPP) was prepared. The platelet count of rat PRP is P
PP was added to adjust the platelet count to 0.8-IX 106/3, while the human PRP platelet count was adjusted to 4x10 by adding PPP.
It was adjusted to 5/la'.

After stirring a mixture of 200 μl of diluted PRP and 25 μl of the sample solution at 37°C for 2 minutes, a collagen solution [Biochimica Kogyo Biophysicica Acta 0. Volume 186, No. 254
(1969)] 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 platelet aggregation inhibitory effect of the test compound was expressed as IC5° (concentration required to inhibit collagen-induced platelet aggregation by 50%). The results are shown in Tables 1 and 2 below.

Table 1 *The IC5° of niacetylsalicylic acid was approximately 45 μg/-.

Table 2 *ICs of Niacetylsalicylic Acid. is about 20 μg ZII
&Met.

(Ex-vivo rat platelet aggregation inhibitory action) An aqueous sample solution (sample dose: 10 µ/kg) is orally administered to male and female SD rats that have been fasted for about 20 hours, and blood is collected from the abdominal aorta 3 hours later. This blood has 9 volumes and 3.8% (
W/V) mixed with an aqueous solution of trisodium citrate,
By centrifuging the mixture, platelet-suspended plasma (
PRP) was prepared.

The remaining blood is further centrifuged to produce platelet-free plasma (PPP).
was prepared. Add PPP to PRP platelet count to 0.8
It was adjusted to ~l xlO'/fi'. Diluted PRP225
Collagen solution (prepared according to the method described in Experimental Example 1) 2 μl
5 μl was added to cause platelet aggregation. Platelet aggregation ability was measured by Born's method to determine the platelet aggregation inhibitory effect of the sample. The compounds shown in Table 3 below had a platelet aggregation inhibition rate of 50% or more.

Table 3 Example 1 (1)(±)-cis-2-(4-methoxyphenyl)-
3-hydroxy-8-methyl-2,3-dihydro-1,
5-benzothiazepin-4(5H)-one 2I, powdered potassium hydroxide 0.4211 and dimethyl sulfoxide 1
5- Stir the mixture at 50°C for 30 minutes. After the reaction,
2-(N-benzyloxycarbonyl-N-
A solution of 2.64.9 of ethyl chloride (methylamine) in dimethyl sulfoxide was added, and the mixture was heated at 50°C for 30 minutes.
Stir for days. The mixture is poured into ice water and extracted with ethyl acetate. The extract was washed with saturated brine, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (HIXi chloroform-ethyl acetate (10:1)
), (±)-cis-2-(4-
methoxyphenyl)-3-hydroxy-5-(2-(N
-benzyloxycarbonyl-N-methylamino)ethylcou8-methyl-2<3>-dihydro-1,5-benzothiazepin-4(5H)-one 2.95.9 is obtained as an oil.

(2) (±)-cis-2-(4-methoxyphenyl)-
3-Hydroxy-5-(2-(N-benzyloxycarbonyl-N-methylamino)ethylc8-methyl-2
,3-dihydro-1,5-benzothiazepine-4 (5H
)-one 2.49i A mixture of acetic anhydride 15- and pyridine 5- is stirred at 100°C for 2 hours. Acetic anhydride and pyridine are distilled off from the mixture under reduced pressure using a cold machine. Furthermore, by repeating the operation of adding toluene to the residue and distilling off the solvent under reduced pressure twice, (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(2-(N 3.083 of -benzyloxycarbonyl-N-methylamino)ethylcy-8-methyl-2,3-dihydro-1°5-benzothiazepin-4(5H)-one is obtained as an oil.

(3) (±)-cis-2-(4-methoxyphenyl)-
3-acetoxy-5-(2-(N-benzyloxycarbonyl-N-methylamine)ethylcy8-methyl-2
,3-dihydro-1,5-benzothiazepine-4 (5H
)-on 3.0B, 9. A mixture of acetic acid 10- and 25% hydrogen bromide-acetic acid 5- is stirred at room temperature for 2 hours. After the reaction, the solvent is distilled off from the mixture under reduced pressure. Add toluene to the residue, filter the precipitated crystals, and wash with ether. After converting the crystal (hydrobromide) into a free base and further converting it into a hydrochloride,
By recrystallization from ethanol, (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5
-(2-(N-methylamino)ethyl).

-8-Methyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-one, hydrochloride, 1/2 water Example
2-6 Corresponding raw material compounds in Example 1-(11, (2) and (3)
By treating in the same manner as above, the following compound is obtained.

Table 4 Note: All the above compounds are (±)-cis isomers.

*: Recrystallized from a mixture of isopropanol and ether.

**: Recrystallized from ethanol.

*Material: Recrystallized from a mixture of dimethylformamide and ethanol.

Examples 7 and 8 Corresponding raw material compounds were used in Example 1-(1), (21 and (3)
) to obtain the following compound.

Table 5 Note: Both of the above compounds are (±)-cis isomers.

*: Recrystallized from ethanol.

Book* Recrystallized from a mixture of dimethylformamide and ethanol.

Example 9 (1) (-)-cis-2-(4-methoxyphenyl)
-3-hydroxy-8-methyl-2,3-dihydro-1
, 5-benzothiazepine-4(5H)-one 6.3.9
．． A mixture of 4.65 g of 2-(N-benzyl-N-methylamino)ethyl chloride hydrochloride, 7.2 g of potassium carbonate and 80 g of acetone is refluxed for 20 hours. Filter off the insoluble matter using a refrigerator, and remove the solvent from the filtrate under reduced pressure. By converting the remainder into perchlorate and recrystallizing it from methanol,
(-)-cis-1-(4-methoxyphenyl)-3-hydroxy-5-(2-(N-benzyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro~1°5
-Benzothiazepine-4(5H)-one perchlorate 1
Obtain 0.8 g.

M, p, 178-181°C [α) -86,1° (C = 0.18. Methanol) (2) (-)-cis-2-(4-methoxyphenyl)
-3-hydroxy-5-(2-(N-benzyl-N-methylamino)ethylcou-8-methyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-one perchlorate 10.1 as the free base and the compound was treated with acetic anhydride 8
Add 0- and pyridine 1- and heat to 100°C for 4 hours. Acetic anhydride and pyridine are distilled off from the mixture under reduced pressure using a cold machine.

By adding benzene to the residue and distilling off the solvent under reduced pressure, (-)-cis-2-(4-methoxyphenyl)
-3-acetoxy-5-(2-(N-benzyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one IO,
37 g are obtained as an oil.

+31 (-)-cis-2-(4-methoxyphenyl)
-3-acetoxy-5-C2-(N-benzyl-N-methylamino)ethylcou8-methyl-2+ 3-dihydro-1,5-benzothiazepin-4(5H)-one 10
．． 9 g of benzyloxycarbonyl chloride was added to a mixture of 37 FI and 125 benzene under reflux.
The solution is added dropwise over 30 minutes and refluxed for 4 hours. By distilling off the solvent under reduced pressure from the mixture in a cold machine, (-)-
cis-2-(4-methoxyphenyl)-3-acetoxy-5,-(2-(N-benzyloxycarbonyl-N-
methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 11
．． 8.9 is obtained as an oil.

(41(-)-cis-2-(4-methoxyphenyl)-
3-acetoxy-5-C2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2
,3-dihydro-1,5-benzothiazepine-4 (5H
)-one 11.8i A mixture of 25% hydrogen bromide-acetic acid 25- and vinegar M50- is stirred at room temperature for 2 hours. Anhydrous ether 800% is added to the mixture, and the insoluble powder is filtered off and dissolved in acetone. Ether is added to the solution, and the precipitated insoluble powder is collected by filtration and dissolved in water. The solution is made alkaline with aqueous ammonia and extracted with chloroform.

After washing the extract with water and drying, the solvent was distilled off under reduced pressure. By converting the residual aroma into oxalate and recrystallizing it from ethanol, (
-)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(2-(N-methylamino)ethyl]-8
-Methyl-2°3-dihydro-1,5-benzothiazepine-4(5H)-one oxalate is obtained.

M, p, 166-168°C [α) -79,4° (C = 0.36. Methanol) Examples 10-15 (However, in compounds Navi, R1 represents methoxy, and in compound Navi R1 represents methyl.) The following compound is obtained by treating the corresponding starting compound in the same manner as in Example 9-(11).

Note: All the above compounds are cis isomers.

Book: Recrystallized from methanol.

**: Recrystallized from ethanol.

This book*: Recrystallized from a mixture of methanol and ether.

(However, in Example Nos. 10 to 14, R1 represents toxy, and in Example 11kl15, R1 represents methyl.) The corresponding raw material compounds were added to Examples 9-+21. (31 and (4
) Same as *: Recrystallized from ethanol.

**: Recrystallized from methanol.

***: Recrystallized from isopropanol.

＊＊＊＊: Recrystallized from a mixture of isopropanol and ether.

Example 16 (l)(±)-cis-2-(4-methylphenyl)-3
-hydroxy-8-methyl-2,3-dihydro-1,5
-Benzothiazepine-4(5H)-one 5.96.9.
2-(N-Benzyloxycarbonyl-N-methylamino)ethyl chloride 5.89f9゜Potassium hydroxide 1
．． A mixture of 6M and dimethyl sulfoxide 85- was treated in the same manner as in Example 1-(11), and the crude product was subjected to silica gel chromatography [solvent: benzene-ethyl acetate (9:
1) By purifying with ), (±)-cis-2
-(4-methylphenyl)-3-hydroxy-5-(2
-(N-benzyloxycarbonyl-N-methylamino)ethylcou-8-methyl-2,3-dihydro-1,5-
Benzothiazepine-4(5H)-one 7,89.9 is obtained as an oil.

(2) (±)-cis-2-(4-methylphenyl)-3
-hydroxy-5-(2-(N-benzyloxycarbonyl-N-methylamino)ethyl-8-methyl-2,
3-dihydro-1,5-benzothiazepine-4 (5H)
-one 1.6i benzoyl chloride 0.69.9. The mixture of pyridine 5- and benzene 2w& is stirred at room temperature for 2 hours. After the reaction, the mixture is poured into ice water and extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off under reduced pressure to obtain (±)-cis-2-(4-methylphenyl)-3-benzoyloxy-5-(2-(N-benzyloxycarbonyl-N-). 2.14 g of methylamino)ethylcou 8-methyl-2,3-dihydro-1,5-benzothiazepine-4 (5H>-one) are obtained as an oil.

(3) (±)-cis-2-(4-methylphenyl)-3
-benzoyloxy-5-(2-(N-benzyloxycarbonyl-N-methylamino)ethyl)-8-methyl-2,3-dihydro-1,5-benzothiazepine-4(
A mixture of 2.14 g of 5H)-one, 25% hydrogen bromide-acetic acid and 2 tlll of acetic acid is stirred at room temperature for 2 hours.

After the reaction, ether is added to the mixture and the precipitated crystals are collected by filtration. After thoroughly washing the crystals with ether, water is added to the crystals. Add ammonia water to the mixture to make it alkaline.
Extract with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off under reduced pressure, and the residual aroma was converted to oxalate, which was then recrystallized from a mixture of dimethylformamide and ethanol to obtain (±)-cis-2-(4-methylphenyl). -3-
Benzoyloxy-5-[2-(N-methylamino)ethyl-8-methyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-one oxalate o, s
Get s g.

, p, 212-213.5°C Example 17 (±)-cis-2-(4-methylphenyl)-3-hydroxy-5-(2-(N-hensyloxycarbonyl-
N-methylamino)ethylcou 8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 1.38i isobutyryl chloride 0.45i pyridine 5tI & and benzene 211 & mixture as an example 16
- Process in the same way as (2).

The product (±)-cis-2-(4-methylphenyl)-3-isobutyryloxy-5-(2-(N-benzyloxycarbonyl-N-methylamino)ethyl-8
-Methyl-2,3-dihydro=1,5-benzothiazepin-4(5H)-one was treated in the same manner as in Example 16-(3) to obtain (±)-cis-2-(4- methylphenyl)-3-isobutyryloxy-5-(2-(
0.40 # of N-methylamino)ethyl-8-methyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-one oxalate is obtained.

M, p, 188.5-190.5°C (decomposition) Example 1
8 (±)-cis-2-(4-methylphenyl)-3-hydroxy-5-C2-(N-benzyloxycarbonyl-
N-methylamino)ethyl-8-methyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-one, 35 g, n-butyryl chloride 0.44 L Pyridine 5. Example 16-(
2), and the product (±)-cis-2-
(4-methylphenyl) -3-n-butyryloxy-
5-(2-(N-benzyloxycarbonyl-N-methylamino)ethyl-8-methyl-2,3-dihydro-
By treating 115-benzothiazepin-4(5H)-one in the same manner as in Example 16-+31, (±)
-cis-2-(4-methylphenyl)-3-n-butyryloxy-5-(2-(N-methylamino)ethyl]-
0.43.9 of 8-methyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-one oxalate is obtained.

M, p, 185.5-186°C Example 19 (±)-cis-2-(4-methylphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-
N-Methylamino)ethyl 8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 1.46i Propionyl chloride 0.42i Example of a mixture of pyridine 5 and benzene 2- 16-(21
The product (±)-cis-2-(4
-methylphenyl)-3-propionyloxy-5-(
1(N-benzyloxycarbonyl-N-methylamino)ethyl-8-methyl-2,3-dihydro-1゜5-
Benzothiazepin-4(5H)-one in Example 16'1
By processing in the same manner as in 3), (±)-cis-2
-(4-methylphenyl)-3-propionyloxy-
5-(2-(N-methylamino)ethyl-8-methyl-2,3-dihydro-1,5-henzothiazepine-4(
0.45 Fl of 5H)-one 1/2 oxalate is obtained.

M, p, 128-132°C Example 20 (1)(±)-cis-2-(4-methoxyphenyl)-
3-Hydroxy-8-benzyloxy to 2゜3-dihydro-1,5-henzothiazepin-4(5H)-one 5L
l-(N-benzyloxycarbonyl-N-methylamino)ethyl chloride 3.83, potassium hydroxide 1.18
Example 1-
By processing in the same manner as (1), (±)-cis-
2-(4-methoxyphenyl)-3-hydroxy-5'
-(2-(N-benzyloxycarbonyl-N-methylamino)ethyl2-8-benzyloxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one3
．． 75 lI is obtained as an oil.

(2) (±)-cis-2-(4-methoxyphenyl)-
3-Hydroxy-5-(2-(N-pendizothiazepin-4(5H)-one) 3.755. A mixture of acetic anhydride 23- and pyridine 8- is treated analogously to Example 1-(2). (±)-cis-1(4-methoxyphenyl)-3-acetoxy-5-(2-(N-benzyloxycarbonyl-N-methylamino)ethyl-8-benzyloxy-2,3-dihydro- 4.18 # of 1,5-benzothiazepin-4(5H)-one is obtained as an oil.

(3) (±)-cis-2-(4-methoxyphenyl)-
3-acetoxy-5-(2-(N-benzyloxycarbonyl-N-methylamino)ethyl-8-benzyloxy-2,3-dihydro-1,5-benzothiazepine-
A mixture of 4(5H)-one 2.3119° 25% hydrogen bromide-acetic acid 3.5t& and acetic acid 7- is stirred at room temperature for 1 hour. Ether is added to the mixture and the precipitated crystals are collected by filtration.

After washing the crystals with ether, they are suspended in water and an aqueous sodium bicarbonate solution is added. The suspension was extracted with chloroform and the aqueous layer was referred to as aqueous layer I. ), after washing the extract with water and drying.

The solvent is removed under reduced pressure. The residual fragrance was removed by silica gel chromatography [solvent: chloroform-ethanol (9:1)]
), and the obtained oil (0.29 #) was made into a hydrochloric acid salt and recrystallized from a mixture of ethanol and ether to give (±)-cis-2-(4-methoxyphenyl)-3-acetoxy- 5-[2-(N-methylamino)
Ethylcou 8-benzyloxy-2,3-dihydro-1
,5-benzothiazepine-4(5H)-one hydrochloride 0
．． Obtain 211I.

M, p, 175-178°C (decomposition) An aqueous sodium bicarbonate solution is added to the aqueous layer (2) obtained above, and the mixture is extracted with chloroform. After washing the extract with water and drying, the solvent is distilled off under reduced pressure. By converting the residual aroma into hydrochloride and recrystallizing it from ethanol, (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-
5-(2-(N-methylamino)ethyl-8-hydroxy-213-dihydro-1,5-benzothiazepine-
4(5H)-one hydrochloride 1/2 hydrate 0.22,
! ? get.

M, p, 242-245°C (decomposition) Example 21 (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(1(N-hensyloxycarbonyl-
N-methylamino)ethylcou 8-benzyloxy-2
,3-dihydro-1,5-benzothiazepine-4 (5H
A mixture of 1.97 L of 25% hydrogen bromide-acetic acid and 7 L of acetic acid is stirred at room temperature for 3 hours. After the reaction,
Ether is added to the mixture and the precipitated crystals are collected by filtration. The crystals are washed with ether and dissolved in water. The solution is made alkaline with aqueous ammonia and extracted with chloroform. After washing the extract with water and drying, the solvent was distilled off under reduced pressure, and the residual aroma was purified by silica gel chromatography [solvent: chloroform-ethanol (9:1)] to obtain 0.58 g of an oily substance.
By converting it into hydrochloride and recrystallizing it from ethanol,
(±)-cis-2-(4-methoxyphenyl)-3-
0.54 # of acetoxy-5-C2-(N-methylamino)ethyl-8-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride is obtained.

The physical property values of this compound were consistent with those of the compound obtained in Example 20-(3).

Example 22 (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(2-(N-methylamino)ethyl]-
8-Methyl-2,3-dihydro-1°5-benzothiazepine-4(5H)-one hydrobromide 1.1.9.5
% sodium hydroxide aqueous solution 10- and ethanol 5ff
11! The mixture is stirred at room temperature for 3 hours. After the reaction, water is added to the mixture and extracted with ethyl acetate. The extract is washed with brine, dried, and the solvent is distilled off under reduced pressure. The residual aroma is converted into hydrochloride.

By recrystallization from ethanol, (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5
-(2-(N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepine-4(5
0.46.9 of H)-one hydrochloride is obtained.

M, p, 230-232℃ (decomposition) Examples 23-26 Table 8 where the corresponding raw material compounds are treated in the same manner as in Example 22 Note: All the above compounds are (±)-cis isomers.

* Recrystallized from rainbow methylformamide.

Nene: Recrystallized from ethanol.

***: Recrystallization from a mixture of ethanol and ether Examples 27 to 33 The following compounds were obtained by treating the corresponding raw material compounds in the same manner as in Example 22.

Note: All the above compounds are cis isomers.

*: Recrystallized from ethanol.

Book* Recrystallized from a mixture of dimethylformamide and ethanol.

***: Recrystallized from isopropanol.

＊＊＊＊: Recrystallized from methanol.

Example 34 (11(-)-cis-2-(4-methylphenyl)-3
-hydroxy-8-methyl-2,3-dihydro-1,5
-Benzothiazepine-4(5)()-one 0.90i
2- (N-benzyloxycarbonyl-N-methylamino)ethyl chloride 1°03,9° Potassium hydroxide 0
．． By not treating the mixture of 20 Fl and dimethyl sulfoxide 10- in the same manner as in Example 1-(11), (-
)-cis-2-(4-methylphenyl)-3-hydroxy-5-(2-(N-benzyloxycarbonyl-N-
methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 0.
6211 is obtained as an oil.

(21(-)-cis-2-(4-methylphenyl)-3
-hydroxy-5-(2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,
3-dihydro-1,5-benzothiazepine-4 (5H)
-one 0.73i acetic anhydride 5, Fl and pyridine 0.1
- By treating the mixture of - in the same manner as in Example 1-+21, (-)-cis-2-(4-methylphenyl)-3
-acetoxy-5-(2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,
3-dihydro-1,5-benzothiazepine-4 (5H)
0.92 g of -one are obtained as an oil.

(31(-)-cis-2-(4-methylphenyl)-3
-acetoxy-5-(2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,
3-dihydro-1,5-benzothiazepine-4 (5H)
-on 0.92. y, a mixture of 25% hydrogen bromide-acetic acid 2- and acetic acid 2- is stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off from the mixture under reduced pressure, and toluene was added to the residual aroma.
Furthermore, the solvent is distilled off under reduced pressure. Add ether to the residual aroma, filter out the precipitated crystals, and wash with ether. The crystal 1. A mixture of ethanol 2- and 5% aqueous sodium hydroxide solution 2- is stirred at room temperature for 2 hours. The mixture is brought to pH 8 with acetic acid and extracted with chloroform. After washing the extract with water and drying, the solvent is distilled off under reduced pressure. After converting the remaining metal into a hydrochloride, it was recrystallized from isopropanol to form (-)-cis-2-(
4-methylphenyl)-3-hydroxy-5-(2-(
0.32 g of N-methylamino)ethyl-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride 1/2 hydrate is obtained.

M, p, 128-145°C [α) -103,8° (C=0.29.methanol) Example 35 (+)-cis-2-(4-methylphenyl)-3-hydroxy-8-methyl -2,3-dihydro-1,5-benzothiazepin-4(5H)-one in Example 34-(1)
, +2) and (3), (+
)-cis-2-(4-methylphenyl)-3-hydroxy-5-(2-(N-methylamino)ethyl]-8-methyl-2,3-dihydro-1°5-benzothiazepine-
4(5H)-one hydrochloride hemihydrate is obtained.

M, 9. 130-147°C (Recrystallized from isopropanol) (α) +103.84° (C=0.182.methanol) Example 36 A 50-methylene chloride solution of 6.31 boron tribromide was heated to -50°C. Cooling. Add (-)-cis- to the solution at the same temperature.
2-(4-methoxyphenyl)-3-hydroxy-5-
(2-(N-methylamino)ethyl-8-methyl-2
,3-dihydro-1,5-benzothiazepine-4 (5H
)-one 1.89II in 50.9 methylene chloride is added dropwise over a period of 30 minutes and the mixture is stirred at room temperature for 30 minutes.

After the reaction, the solvent is distilled off under reduced pressure, chloroform is added to the residue, the mixture is poured into ice water, made alkaline by adding an aqueous sodium bicarbonate solution, and the chloroform layer is separated. After washing the chloroform layer with water and drying.

The solvent was distilled off under reduced pressure, and the residue was converted into 2-(4-hydroxybenzoyl)benzoate, which was recrystallized from a mixture of acetone and ether to give (-)-di-2-(4-hydroxyphenyl)-3. -Hydroxy-5-(2-(N
-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-one.
1.77 g of 2-(4-hydroxybenzoyl)benzoate l-hydrate is obtained.

M, 9. 170-174℃ (decomposition) [α) -73
, 14° (C=0.35.methanol) Example 37 (1) 2 (tert, -butoxycarbonylthio)
-4,6-dimethylpyrimidine 0.18g (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-
5-(1-(N-methylamino)ethyl-8-methyl-2,3-dihydro-1,5-benzothiazepine-4(
5H)-one 1.21f9 in dioxane solution 10-
Add under water cooling. After stirring the mixture at room temperature for 4 hours, water is added to the mixture and extracted with ethyl acetate. 1 extract
After washing with 0% hydrochloric acid and brine and drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [solvent: benzene-ethyl acetate (5:1)].

(±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-(2(N-tert,-butoxycarbonyl-N-methylamino)ethyl-8-methyl-2,
3-dihydro-1,5-benzothiazepine-4(5) (
)-one 1.29@ is obtained as an oil.

(2) Sodium hydride (63% dispersion) 0.
21g of (±)-cis-2-(4-methoxyphenyl)
-3-hydroxy-5(2(N-tert.

-butoxycarbonyl-N-methylamino)ethyl-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is added to a solution of 1.25 g of dimethyl sulfoxide 10.1&. After stirring at room temperature for 1.5 hours, a solution of 0.37.9% of benzyl chloride in dimethyl sulfoxide was added to the mixture.

Stir for an additional hour at room temperature. After the reaction, the mixture is poured into ice water and extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off under reduced pressure and the residue was washed with n-hexane to give (±)-cis-2-(4-methoxyphenyl)-3-benzyloxy-5-[2- (N-tert
,-butoxycarbonyl-N-methylamino)ethyl]
1.31 of -8-methyl-2<3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained as an oil.

(3) (±)-cis-2-(4-methoxyphenyl)-
3-benzyloxy-5-(2-(N-tert.

-butoxycarbonyl-N-methylamino)ethylcou 8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and a mixture of 5 parts of formic acid at room temperature. Stir for 1 hour. Ice water is added to the mixture, made alkaline by adding sodium bicarbonate, and extracted with chloroform. After drying the extract, the solvent was distilled off under reduced pressure, and the residue was converted into an oxalate salt, which was then recrystallized from a mixture of ethanol and ether to obtain (±)-cis-1-
(4-methoxyphenyl)-3-benzyloxy-5-
(2-(N-methylamino)ethyl-8-methyl-2
,3-dihydro-1,5-benzothiazepine-4 (5H
)-one oxalate 1/3 hydrate is obtained.

M, p, 131-134°C Example 38 (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-(2-(N-benzyloxycarbonyl-N-methylamino)ethyl 8- Methyl-2,3-
Dihydro-1,5-benzothiazepine-4(5H)-one 2.1,9. A mixture of Hensen's 7 and 25% hydrogen bromide-acetic acid 7 is stirred at room temperature for 2 hours. The solvent was distilled off from the mixture under reduced pressure at room temperature, ether was added to the residue, and the precipitated crystals were collected by filtration and washed with ether. The crystals (hydrobromide) were converted into a free base, further converted into a hydrochloride salt, and then recrystallized from ethanol to obtain (±)-cis-2-
(4-methoxyphenyl)-3-hydroxy-5-C2
-(N-methylamino)ethylcou8-methyl-2,3
-dihydro-1,5-benzothiazepine-4(5H)-
On hydrochloride o,s g is obtained.

M, p, 230-232°C (decomposition) Example 39 (1) (±)-cis-2-(4-methylphenyl)-3
-hydroxy-8-methyl-2,3-dihydro-1,5
-Benzothiazepine-4(5H)-one 2F! , potassium hydroxide 0.45. Example 111 A mixture of 15 parts of dimethyl sulfoxide and 2.583 parts of 2-(N-benzyloxycarbonyl-N-methylamino)ethyl chloride
By processing in the same manner as in 1, (±)-cis-2-(
4-methylphenyl)-3-hydroxy-5-(2-(
2.63 of N-benzyloxycarbonyl-N-methylamino)ethyl]=8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.

(2) (±)-cis-2-(4-methylphenyl)-3
-Hydroxy-5-(2-(N-benzyloxycarbonyl-N-methylamino)ethyl]=8-methyl-2,
3-dihydro-1,5-benzothiazepine-4 (5H)
-one 2.53 was treated in the same manner as in Example 38 to obtain (±)-cis-2-(4-methylphenyl)-3
-Hydroxy-5-C2-(N-methylamino)ethyl-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(,5H)-one hydrochloride 1.18 is obtained.

M, p, 238-243°C (Dimethylformamide Production Example 1 18°2 g of 2-amino-5-methyl-thiophenol and (±)-trans-3-(4-methylphenyl)glycidic acid methyl ester 25. 45 g of the mixture is heated to 160°C for 16 hours under an argon atmosphere.Ethanol is added to the mixture in a refrigerator, the precipitated crystals are collected by filtration, and recrystallized from a mixture of dimethylformamide and ethanol to obtain (±)-cis. -2-(4-methylphenyl)-
3-hydroxy-8-methyl-2,3-dihydro-1,
5-Benzothiazepin-4(5H)-one 5.15.9
get.

M, p, 182.5-184.5°C The following compound is obtained by treating the corresponding raw material compound in the same manner as above.

8 Table 10 Note: All the above compounds are (±)-cis isomers.

N: Recrystallization from a mixed solution of chloroform and n-hexane (obtained as a 1/2 permanent product).

$01 Recrystallized from dimethylformamide **Ne**
(±)-threo-2-hydroxy- with the two above compounds
3-(2-amino-6-fluorophenylthio)-3-
(4-methoxyphenyl)propionic acid methyl ester is produced.

M, I), 110/X-112°C (recrystallized from ethanol) Production example 2 2-amino-5-fluorothiophenol 20° 6 fl
and (±)-trans-3-(4-methylphenyl)glycidic acid methyl ester 27.453
Stir at 0-160°C for 16 hours. In the refrigerator, pour the mixture into benzene and add more 18% hydrochloric acid. The organic layer is separated, washed with water and an aqueous sodium bicarbonate solution, dried, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel chromatography [solvent: chloroform-ethyl acetate (10:1
)] and recrystallized from ethanol.
(±)-cis-2-(4-methylphenyl)-3-hydroxy-8-fluoro-2,3-dihydro-1,5-
Benzothiazepine-4(5H)-one 3.1! Get In.

M, p, 210-213℃ 2-amino-4-methyl-thiophenol 22゜661
1 and (±)-trans-3-(4-methylphenyl)
By treating the mixture of glycidic acid methyl ester 30.978 as above.

(±)-cis-2-(4-methylphenyl)-3-hydroxy-7-methyl-2,3-dihydro-1°5-benzothiazepin-4(5H)-one 2.213 is obtained.

? 1.9. 204-205°C Production Example 3 (1) 2-Amino-5-methyl-thiophenol 29.
1,9. (±)-trans-3-(4-methoxylphenyl)glycidic acid methyl ester 47°83 and toluene 300n! 1 of the mixture was heated to 60-65°C for 3 days.
It is then heated to 70-80°C for 2 days. The solvent was distilled off from the mixture under reduced pressure, benzene was added to the residue, and the mixture was extracted 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 was distilled off under reduced pressure, the residue was purified by silica gel chromatography [solvent: benzene-ethyl acetate (10:1)], and recrystallized from a mixture of ethanol and isopropyl ether to give (±)-threo-2-hydroxy- 3-(2-amino-5-methylphenylthio)-
3-(4-methoxyphenyl)propionic acid methyl ester 15.8.9 is obtained.

M, p, 110-112°C 2-amino-5-methyl-thiophenol and (±)-
By treating trans-3-(4-methylphenyl)glycidic acid methyl ester in the same manner as above, (
±)-threo-2-hydroxy-3-(2-amino-5
-methylphenylthio)-3-(4-methylphenyl)
Propionic acid methyl ester is obtained.

M, p, 114-114.5°C (recrystallized from isopropyl ether) (2) (±)-threo-2-hydroxy-3-(2-amino-5-methylphenylthio)-3-(4-methoxy A mixture of phenyl)propionic acid methyl ester 5I, 5% aqueous sodium hydroxide solution 5o and methanol 5o is stirred at room temperature for 2 hours. After the reaction, the mixture is adjusted to pH 3-5 with 10% hydrochloric acid while cooling with water. Filter the precipitated crystals,
By washing with water, drying, and recrystallizing from methanol, (
±)-threo-2-hydroxy-3-(2-amino-5
-methylphenylthio)-3-(4-methoxyphenyl)propionic acid 4.3.9 is obtained.

M, p, 190-193°C (±)-threo-2-hydroxy-3-(2-amino-
By treating 5-methylphenylthio)-3-(4-methylphenyl)propionic acid methyl ester in the same manner as above, (±)-threo-2-hydroxy-3-
(2-amino-5-methylphenylthio)-3-(4-
methylphenyl)propionic acid is obtained.

M, p, 168-172℃ (3-a) L p-hydroxyphenylglycine methyl ester hydrochloride 45.3.9 methanol 1000
- dissolves in Add potassium hydroxide ii to the solution under water cooling,
7. Add 100 methanol solution of y.

Filter off precipitate # (potassium chloride). 37.8 J of (±)-threo-2-hydroxy-3-(2-amino-5-methylphenylthio)-3-(4-methoxyphenyl)propionic acid is added to the filtrate. Warming the mixture to 50°C,
Add 900ml of methanol to make a solution. 5 from the solution
The solvent was distilled off under reduced pressure at 0°C or below, and 200% of ethanol was added to the residue.
Add W& and refrigerate overnight. (+)-Threo-2-hydroxy -3
-(2-amino-5-methylphenylthio)-3-(4
-methoxyphenyl)propionic acid/L-p-hydroxyphenylglycine methyl ester salt (M, p, 16
4-167℃.

[α) +255.8° (C=0.66, methanol)]20, i is obtained.

15.35% of the salt obtained above was suspended in a mixture of 240% methanol and 200% water, and 27% of the salt obtained above was suspended on a cation exchange resin.
After stirring overnight at room temperature, the resin was filtered off and washed with methanol. The filtrate and washing liquid were combined, and the solvent was distilled off under reduced pressure. Water was added to the residue, the precipitated crystals were collected by filtration, and recrystallized from ethanol to give (+)-threo-2-hydroxy-3-(2-amino-5-methylphenylthio)-3-(4- methoxyphenyl)propionic acid 73 is obtained.

M, p, 158-160°C [α) +296.0° (C=0.29.methanol) Combine the mother liquors I and ① obtained above.

Concentrated hydrochloric acid 13- is added to this, and the solvent is distilled off under reduced pressure.

Add water to the residue and filter the precipitated crystals. The crystal 15°57
9. By treating a mixture of 20.3 g of D-p-hydroxyphenylglycine methyl ester hydrochloride and potassium hydroxide 5, 2.9 in the same manner as above, (-)-threo-2-hydroxy-3- (2-Amino-5-methylphenylthio)-3-(4-methoxyphenyl)propionic acid D-p-hydroxyphenylglycine methyl ester salt [Calendar, p, 164-167°C, recrystallized from ethanol, [α ) −254,86C=0.95. Methanol)) 12.9.9 is obtained.

By treating the salt 15.3.9 obtained above in the same manner as above to obtain the free acid, (-)-threo-2-hydroxy-3-(2-amino-5-methylphenylthio)
-3-(4-methoxyphenyl)propionic acid 6.5
Get Fi.

M, 9. 158-b crystal) [α)-265,30 (C=0.33.methanol) (
3-b) Potassium hydroxide 0.71 FI methanol 1
Add the 〇-solution to a methanol 7〇-solution of L-p-hydroxyphenylglycine methyl ester hydrochloride 2.74.9. Insoluble matter is filtered off and washed with methanol. Combine the filtrate and wash and add (±)-threo-2-hydroxy-3-(2-amino-5-methylphenylthio)
Add -3-(4-methylphenyl)propionic acid 23. Methanol was distilled off from the mixture under reduced pressure, 20% of ethanol was added to the residual aroma, and the mixture was left at 0°C overnight. By filtering the precipitated crystals and recrystallizing them twice from ethanol.

(+)-threo-2-hydroxy-3-(2-amino-
0.41 g of 5-methylphenylthio)-3-(4-methylphenyl)propionic acid L-p-hydroxyphenylglycine methyl ester salt is obtained.

Lp, 170-172 °C (α) +308.640 (C = 0.61. methanol) The salt obtained above was mixed with 2.65.9 and 10% hydrochloric acid 1Or
The solvent is distilled off from the mixture of I& under reduced pressure, water is added to the residual aroma, and the solvent is distilled off from the mixture under reduced pressure. Add water to the remaining amount again, filter out the precipitated crystals, wash with water and dry.

Recrystallization from methanol yields 0.93.9 of (+)-threo-2-hydroxy-3-(2-amino-5-methylphenylthio)-3-(4-methylphenyl)propionic acid.

M, 9. 166-168°C [α) +356.7° (C=0.52. Dimethylformamide) Potassium hydroxide 2.75.9. p-p-hydroxyphenylglycine methyl ester hydrochloride 10.653 and (±)-threo-2-hydroxy-3-(2-amino-
By treating 7.77II of 5-methylphenylthio)-3-(4-methylphenyl)propionic acid in the same manner as above, (-)-threo-2-hydroxy-3-(2
-amino-5-methylphenylthio)-3-(4-methylphenyl)propionic acid D-p-hydroxyphenylglycine methyl ester salt 1.21. l? get.

M, p, 170-172°C (recrystallized from ethanol) [α] -320,61° (C=0.41.methanol) Salt obtained above 1. IEl is processed as above,
By forming the free acid, (-)-threo-2-hydroxy-3-(2-amino-5-methylphenylthio)-
3-(4-methylphenyl)propionic acid 0.3911
get.

Gate, p, 166-168℃ (recrystallized from methanol) [α) -356,23° (C=0.63.dimethylformamide) (41(+)-threo-2-hydroxy-3-(2-amino Reflux for 24 hours while removing water to form a mixture of -5-methylphenylthio')-3-(4-methoxyphenyl)propionic acid 1 and 350 v xylene.

After the reaction, xylene was distilled off from the mixture under reduced pressure, and the residual aroma was recrystallized from ethyl acetate to give (+)-cis-2
-(4-methoxyphenyl)-3-hydroxy-8-methyl-2,3-dihydro-1,5-benzothiazepine-
7.8 g of 4(5H)-one are obtained.

Lp, 223-226°C (decomposition) [α) +123.8° (C=0.71.dimethylformamide) The following compound is obtained by treating the corresponding raw material compound in the same manner as above.

*: Recrystallization from ethyl acetate *: Recrystallization from ethanol Production Example 4 (1) The following compound is obtained by treating the corresponding raw material compound in the same manner as in Production Example 3-(1).

(±)-threo-2-hydroxy-3-(2-amino-
5-Methylthiophenylthio)=3-(4-methoxyphenyl)propionic acid methyl ester M, p, 114-116°C (recrystallized from ethanol) (±)-threo-2-hydroxy-3-(2-amino-
4-Methylthiophenylthio)-3-(4-methoxyphenyl)propionic acid methyl ester M, 9. 130-132°C (recrystallized from ethanol) (2) Sodium hydride (63% dispersion) 1.5
A mixture of 3 and dimethyl sulfoxide 25- is heated to 70° C. for 50 minutes under an argon atmosphere.

(±)-threo-2-hydroxy-3-(2
-amino-5-methylthiophenylthio)-1-(4-
Methoxyphenyl) propionic acid methyl ester 73 dimethyl sulfoxide 12yI! Cool the solution and
Stir for 20 minutes at room temperature.

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
6.73 of (5H)-one is obtained.

Gate, p, 183-184°C The following compound is obtained by treating the corresponding raw material compound in the same manner as above.

(±)-cis-2-(4-methoxyphenyl)-3-hydroxy-7-methylthio-2,3-dihydro-1,5
-Benzothiazepine-4(5H)-one M, 9.211-214°C (recrystallized from a mixture of dimethylformamide and ethanol) (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-9 -Fluoro-2,3-dihydro-1,5-
Benzothiazepine-4(5H)-one M, 9. 217
~220℃ (recrystallized from a mixture of dimethylformamide and ethanol)

Claims (1)

[Claims] 1. General formula (where R1 represents lower alkyl, lower alkoxy or hydroxy; R2 represents a hydrogen atom, lower alkanoyl, benzyl or benzoyl; R3 represents lower alkyl; 94 and R5 are: A) R When ' is lower alkyl or lower alkoxy, one is lower alkyl or lower alkoxy. It is a fluorine atom, benzyloxy, hydroxy or lower alkylthio, and the other is a hydrogen atom, or both are lower alkoxy. B) When R' is hydroxy, one is lower alkyl, fluorine atom, hydroxy or lower alkylthio, and the other is hydrogen atom. or both represent lower alkoxy. ) A 1,5-benzothiazepine derivative or a salt thereof. 2. General formula (where RZ represents a hydrogen atom, lower alkanoyl, benzyl or benzoyl, R6 represents lower alkyl or lower alkoxy, and one of R7 and R11 is lower alkyl, lower alkoxy, fluorine atom, benzyloxy or lower alkylthio) , the other is a hydrogen atom,
or both represent lower alkoxy. ) or a salt thereof is reacted with a compound or a salt thereof represented by the general formula (where R3 represents lower alkyl, Q represents a hydrogen atom or a protecting group, and xi represents a halogen atom) to form a general compound. A compound represented by the formula (where pg, Ill, R6, R?, R11 and Q have the same meanings as above) is prepared, and when the substituent Q is a protecting group, from the compound (IV) 1 represented by the general formula (wherein R2, R3, R6, R'L and R8 have the same meanings as above), characterized by removing the protecting group and, if necessary, converting the product into its salt; A method for producing a 5-benzothiazepine derivative or a salt thereof. 3. General formula (where R3 represents lower alkyl, R6 represents lower alkyl or lower alkoxy, one of R? and R11 is lower alkyl, lower alkoxy, or fluorine atom. benzyloxy or lower alkylthio; the other is hydrogen atom) or both are lower alkoxy, and Q represents a hydrogen atom or a protecting group. ) or a reactive derivative thereof to produce a compound represented by the general formula (wherein R3, R6, R', R8, R and Q have the same meanings as above), When the substituent Q is a protecting group, the protecting group is removed from the compound (■). Furthermore, if necessary, a general formula characterized in that the product is a salt thereof (provided that 1t3.pb, R'1.R11 and R9
has the same meaning as above. ) A method for producing a 1,5-benzothiazepine derivative or a salt thereof. 4. General formula (where R3 represents lower alkyl, R6 represents lower alkyl or lower alkoxy, one of R? and R8 is lower alkyl, lower alkoxy, or fluorine atom, benzyloxy or lower alkylthio, and the other is hydrogen atom) R9 represents lower alkyl or phenyl, and Q represents a hydrogen atom or a protecting group. 'R6, R7, R8 and Q have the same meanings as above.) If the substituent Q is a protecting group, remove the protecting group from the compound (■). A 1,5-benzothiazepine derivative represented by the general formula (R3, Rh, R7 and R11 have the same meanings as above) or a salt thereof, where the product is a salt thereof if necessary. 5. General formula (wherein R3 represents lower alkyl, RIG represents lower alkyl, R11 represents a hydrogen atom, lower alkanoyl or hendiyl, RIZ and R13 represent one lower alkyl, one is a fluorine atom, hydroxy or lower alkylthio,
Indicates that the other is a hydrogen atom. ) or a salt thereof is dealkylated. 1,5-benzothiazepine ta'J represented by the general formula (where +R"+R"lR12 and RI3 have the same meanings as above), which is characterized in that the product is further converted into a salt thereof if necessary. Process for producing a monomer or a salt thereof 6, general formula (where R3 represents lower alkyl, R6 represents lower alkyl or lower alkoxy, one of al and R8 is lower alkyl, lower alkoxy, or fluorine atom; benzyloxy or lower alkylthio; The other is a hydrogen atom or both are lower alkoxy, and Q represents a hydrogen atom or a protective group.) or a salt thereof and the general formula (where It represents a halogen atom) By reacting with the compound shown, the general formula (where ++3. R6, r,
Re and Q have the same meanings as above. ), and when substituent Q is a protecting group, the protecting group is removed from said compound (XI), and if necessary, the product is converted into a salt thereof. H (However, R3, R6, R'l and RB have the same meanings as above.) Process 7 for producing a 1,5-benzothiazepine derivative or its salt represented by the general formula (wherein R3 represents lower alkyl and R6 represents lower alkyl or lower alkoxy, R11 represents a hydrogen atom, represents lower alkanoyl or benzoyl, and Q represents a hydrogen atom or a protecting group. ” and Q have the same meanings as above), and when the substituent Q is a protecting group, the protecting group is removed from the compound (X III), and if necessary, the A method for producing a 1,5-benzothiazepine derivative or a salt thereof represented by the general formula (wherein R2, R6 and R11 have the same meanings as above).