JPH01110679A - 1,5-benzothiazepine derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I {ring A is naphthalene ring condensing with benzene ring, heterocyclic ring or thiazepine ring to form naphtho[2,1-b][1,5]thiazepine ring; R<1> is (substituted) phenyl or (substituted) heterocyclic ring group; R<2> is H or alkanoyl; R<3> is H or (substituted) heterocyclic ring group, OH, halogen or (substituted) amino; Y is single bind, O or alkylene; Z is O, S or two H atoms} or acid addition salt thereof. EXAMPLE:(+ or -)-cis-2-(4-Methoxyphenyl)-3-hydroxy-5-[2-(N-methyl-N-benzylamino) ethyl]-2,3-dihydro-benzothiazepin-4(5H)-one.hydrochloride. USE:Having excellent hypotensive, cerebral coronary vasodilator, calmodulin and inhibitory action on blood platelet agglitination. PREPARATION:For example, a compound expressed by formula II is reacted with a compound expressed by the formula R<3>-Y-X<1> (X<1> is halogen) to afford the aimed compound expressed by formula I.

Description

Detailed Description of the Invention (Technical Field) The present invention provides a novel 1,5-benzothiazepine derivative, more specifically, a novel 1,5-benzothiazepine derivative, which has excellent antihypertensive action, cerebral and coronary vasodilatory action, anti-calmodulin action, and/or platelet aggregation inhibition. Concerning 1,5-benzothiazepine derivatives and pharmacologically acceptable acid addition salts thereof.

(Prior Art) U.S. Pat. No. 3,562.257 describes 2-(4-methoxyphenyl)-3-hydroxy (or acetoxy)-5
-[2-(dimethylamino)edyl]-7=chloro2
．． 3-dihydro-1,5-benzothiazepine-4 (51
Various benzothiazepine derivatives have been disclosed, including 7-chloro-15-benzothiazepine derivatives such as -1)-one, and these benzothiazepine derivatives have antidepressant, tranquilizing and /or It has been shown to have a coronary vasodilator effect.

(Objective of the Invention) The present invention provides 1,5-benzothiazepine derivatives and pharmacologically acceptable 1,5-benzothiazepine derivatives that contribute to excellent antihypertensive effects, cerebral and coronary vasodilatory effects, anti-calmodulin effects, and/or platelet aggregation inhibitory effects. The present invention aims to provide uroacid addition salts.

(Structure and Effects of the Invention) The novel 1,5-benzothiazepine derivative of the present invention is represented by the following general formula (1).

[In the formula, the ring represents a naphthalene ring that is fused with a benzene ring, a heterocycle, or a thiazepine ring that may be substituted with a halogen atom to form naphtho[2,l-b][1,5]thiazepine. , rtl represents a phenyl group or a heterocyclic group which may be substituted with a lower alkyl group, a lower alkoxy group or a lower alkylthio group, R1 represents a hydrogen atom or a lower alkanoyl group, and R3 represents (i)
Hydrogen atom, (ii) a heterocyclic group that may be substituted, (iii) a hydroxyl group, (iv) a halogen atom, (~・)
1 to 3 groups selected from a lower alkyl group, a lower alkanoyl group, a lower alkenyl group, a lower arginyl group, an aralkyl group that may be substituted with a phenyl nucleus, or an aryl group that may be substituted. Amino groups, which may be substituted, or (vi) -Y-13 and -R
2 together represents 10 00 H, -, Y
represents a single bond or a lower alkylene group which may be substituted with a hydroxyl group, and Z represents an oxygen atom, a sulfur atom or two hydrogen atoms. However, R3
is a mono- or di-lower alkylamino group, (
i) Ring A is a heterocycle or a naphthalene ring, or (i
i) R' is a heterocyclic group or lower alkylthiophenyl group, or (iii) Y is a branched lower alkylene group, or a straight or branched lower alkylene group substituted with a hydroxyl group, which seems to be an oxygen atom. is there or (i
v) Z is a sulfur atom or two hydrogen atoms] In the above formula (1), a lower alkyl group is a straight-chain or branched argyl group having 1 to 5 carbon atoms, for example,
medyl, edil, n-propyl, isopropyl, tar
Examples include t-butyl and pentyl.

Low-plate alkoxy group refers to a straight or branched alkoxy group having 1 to 5 carbon atoms, such as methquine, ethoxy,
Examples include brobogyshi, 5ec-butoxy, pendeloxo, and the like.

The lower alkanoyl group refers to a straight or branched alkanoyl group having 2 to G carbon atoms, and includes, for example, acedel, propionyl, butyryl, isobutyryl, hexanoyl, and the like.

Examples of halogen atoms include fluorine, chlorine, bromine, and iodine atoms.

The lower alkenyl group represents a straight chain or branched alkenyl group having 2 to G carbon atoms, and includes, for example, vinyl, allyl, isopropenyl, and 3-hexenyl.

The term "lower alkynyl group" refers to a straight or branched alkynyl group having 2 to 6 carbon atoms, such as ethynyl, 2-propynyl, 2-methyl-4-pentynyl, 3-hegicinyl, and the like.

Examples of the aralgyl group include benzyl, phenethyl, 3-phenylpropyl, and the like.

The lower alkylthio method refers to an alkylthio method in which the alkyl moiety is a linear or branched alkyl group having 1 to 5 carbon atoms, such as methylthio, methylthio, 5ec-butylthio, pentylthio, and the like.

A mono- or di-lower alkylamino group refers to a mono- or dialkylamino group in which the alkyl moiety is a linear or branched alkyl group having 1 to 5 carbon atoms, such as methylamino, isopropylamino, lert-butylamino,
Examples include dimethylamino, diethylamino, methyledylamino, methylpropylamino, noisopropylamino, and the like.

The lower alkylene group refers to a straight or branched alkylene group having 1 to 5 carbon atoms, such as methylene, ethylene,
Examples include trimethylene and tetramethylene.

IM a: Ring includes saturated or unsaturated 50-70 heterocycles and fused heterocycles, such as indolyl, quinolyl, isoquinolyl, pyrrolyl, pyrrolidyl, furyl, dienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, morpholyl. , diomorpholyl, piperidinyl, piperazinyl, thiazepinyl and the like.

Heterocyclic groups that may be substituted include, for example, lower alkyl groups and aryl groups that may be substituted with hydroxyl groups, aralkyl groups that may be substituted with halogen atoms, lower alkoxycarbonyl groups, and aralkyloxy groups. Represents a heterocyclic group that may be substituted with a carbonyl group, such as pyrrolidino, piperidino, morpholino, piperazino, 4-methylpiperazino, 4-(2-hydroxyethyl)piperazino, 4-phenylpiperazino, 4-benzyl Piperazino, 4-(4-chlorobenzyl)piperazino, 4-ethoxycarbonylpiperazino, 4
-benzyloxycarbonylpiperazino, 4-(diphenylmethyl)piperazino, and the like.

According to the present invention, the compound (1) is, for example, a compound of the general formula: [wherein rings A, R', R' and Z are compounds represented by the same J as above, and a salt thereof, and a general formula: % formula % ( ) [In the formula, R3 and Y are the same as above, and Xl does not represent a halogen atom] It can be produced by reacting with a compound represented by the following or a salt thereof.

The reaction of compound (ff) or a salt thereof with compound (III), preferably a salt thereof, can be carried out in a suitable solvent in the presence or absence of an alkaline reagent. When using compound (II) in free form, the condensation reaction is preferably carried out in the presence of an alkaline reagent. As the alkaline reagent, alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate), alkali metal hydride (e.g., sodium hydride), etc. are used. be able to. As the solvent, it is preferable to use, for example, acetone, ethyl acetate, dimethyl sulfoxide, dimethylformamide, dioxane, or the like. Further, the condensation reaction is preferably carried out at a temperature of 20 to 100°C, particularly 25 to 70°C.

Compounds of the present invention in which R2 is a lower alkanoyl group (D is a compound in which R2 is a hydrogen atom (D or a salt thereof and the general formula: % formula % () [wherein R2 does not represent a lower alkyl group] It can also be produced by reacting a compound represented by or a reactive derivative thereof.

The condensation reaction between compound (I) or a salt thereof in which It' is a hydrogen atom and compound (TV) can be carried out in a suitable solvent in the presence of a condensing agent. Examples of the condensing agent include dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, and N.

Examples include No-di-p-tolylcarbodiimide. As the solvent, for example, methylene chloride, chloroform, ether, benzene, acetonitrile, dimethylformamide, etc. are preferably used. This reaction was carried out at 0℃~3
Preferably it is carried out at 0°C.

The condensation reaction between compound (1) or a salt thereof in which R2 is a hydrogen atom and a reactive derivative of compound (IV) can be carried out in a suitable solvent. Reactive derivatives of compound ([V) include, for example, the corresponding acid halides (e.g., chloride, bromide), acid anhydrides, mixed acid anhydrides (e.g., ethoxycarbonyl ester, isopropoxycarbonyl ester, isobutoxycarbonyl ester)
, active esters (e.g. p-nitrophenyl ester, 2°4.5-)lichlorophenyl ester, 2,4
．． Examples include 6-dolychlorophenyl ester, N-hydroxysuccinimide ester, and -benzotriazole ester). As the solvent, for example, methylene chloride, ether, acetone, dioxane, ethyl acetate, benzene, chloroform, acetonitrile, dimethylformamide, etc. are preferably used. When carrying out the reaction, the temperature is 0°C to 30°C when compound (■) is used in the form of an acid halide, and when the compound (IV) is used in the form of an acid anhydride! 5°c-too°C, Compound (IV)
0°C to 30°C when compound (IV) is used in the form of a mixed acid anhydride, and 0°C to 30°C when compound (IV) is used in the form of an active ester.
Preferably it is carried out at 80°C. Furthermore, when compound (■) is used in the form of an acid halide, the reaction is preferably carried out in the presence of a deoxidizing agent. Examples of deoxidizers include pyridine, triethylamine, alkali metal carbonates (e.g., sodium carbonate, potassium carbonate), alkali metal bicarbonates (e.g., sodium bicarbonate, potassium bicarbonate), alkali metal hydroxides (e.g., sodium hydroxide). , potassium hydroxide) and the like.

Further, the compound (1) of the present invention in which R2 is a lower alkanoyl group can be used to combine compound (If) or a salt thereof and compound (I
V) or a reactive derivative thereof, and then the obtained compound [OH7!1 (OC
It can also be produced by reacting a compound (II) or a salt thereof with a compound (II) or a salt thereof and a compound (■) or a reactive derivative thereof. The reaction with the compound (■) in which R2 is a hydrogen atom or a salt thereof and the compound (IV) or a reactive derivative thereof is carried out in the same manner as in the reaction of the compound (■) in which R2 is a hydrogen atom or a salt thereof with the compound (IV) or a reactive derivative thereof.
(It seems to be a compound substituted with "°", its salt and compound (I
The reaction with II) or its salt can be carried out in the same manner as the reaction of compound (1) with its salt and compound ([[) or its salt.

Compound (I) of the present invention, in which Y is a lower alkylene group substituted with an oxygen atom, can be obtained by, for example, reacting compound (II) with chloroacetic acid to obtain the corresponding acetic acid derivative, and then reacting this compound with a suitable amine. Compound (1) of the present invention, in which Y is a lower alkylene group substituted by a hydroxyl method, can be prepared by reacting with, for example, compound (II).
Each can be produced by reacting U. with epichlorohydrin and then reacting the obtained compound with a suitable amine.

-Y-R' and -R" are iso-shon"C-COCHt
The compound (1) of the present invention which does not represent - is, for example, the compound (n
) and chloroacedel chloride to obtain a compound (1) in which -Y-R'a<-GOCI-1,C(l), and then intramolecular condensation of this compound in the presence of an acid deoxidizing agent. It can be manufactured by

Compounds of the present invention in which Z is 2 hydrogen atoms or sulfur atoms (0 may be produced using the above compound (n) in which Z is 2 g of hydrogen atoms or sulfur atoms as a starting material, but corresponding They can also be produced by treating compound (I) in which Z is an oxygen atom by a conventional method to reduce the oxygen atom or to substitute it with sulfur.

Moreover, the compound (1) of the present invention contains many types of groups as R3 groups, and by further subjecting the R3 group of these compounds to substitution reactions, hydrolysis, etc., other compounds of the present invention (1) can be obtained. ). For example, (i)
Compound (1) in which R3 is a mono- or di-substituted amino group can be obtained by reacting compound (1) in which R3 is a halogen atom with a corresponding amine, or R3 is an unsubstituted amino group or a mono-substituted amino group. By reacting compound (1) with a suitable alkylating agent or acylating agent, (ii) a compound in which R3 is a 4-substituted piperazinyl group (D is a compound (1) in which R3 is an unsubstituted piperazinyl group). By introducing a substituent at the 4-position by a conventional method, and (iii) Compound (1) in which R3 is an unsubstituted piperazinyl group, a compound (1) in which R3 is a 4-alkyl (or aralkyl)oxycarbonylpiperazinyl group ( By hydrolyzing 1), further (iv)
Compound (1) in which R3 is a mono-lower alkylamino group
can be produced by reacting the compound (1) in which R3 is a di-lower alkylamino group with a reactive derivative of halogenoformic acid, followed by heating with water.

Since the compound (1) of the present invention has two asymmetric carbon atoms at the 2 and 3 positions of the benzothiazepine skeleton, it has four types of isomers [
That is, (+)-cis, (-)-cis, (+)-trans and (-)-)-lance isomers], but all the above reactions proceed without racemization, so If the optically active form of compound (II) is used as a raw material compound, the optically active form of compound (1) of the present invention can be easily obtained.

The starting compound (Il) of the present invention, in which Z is an oxygen atom, has, for example, the general formula: [wherein, the ring is represented by the same compound as above and the general formula: [wherein R represents an ester residue] , R1 can be produced by reacting the above with the same β-substituted glycidic acid ester. According to another method, a compound of formula (V) in which the amino group is substituted with a nitro group is used as a starting material, and after reacting this nitro compound with compound (Vl), the nitro group is removed by a conventional method. It can also be produced by reduction.

A compound ('') in which Z is two hydrogen atoms can be obtained by reducing compound (II) in which Z is an oxygen atom by a conventional method, and a compound (■) in which Z is a sulfur atom can be obtained by reducing compound (II) in which Z is an oxygen atom. Each can be produced by substituting the atom of compound (II) with sulfur using a conventional method.

When compound (1) of the present invention is used as a medicament, it can be used as a free compound or as a pharmacologically acceptable acid addition salt thereof. Such pharmacologically acceptable acid addition salts include, for example, inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, and phosphate; Examples include organic acid addition salts such as acid salts, maleates, fumarates, tartrates, methanesulfonates, and succinates. These salts can be easily obtained, for example, by treating compound (1) with an acid. Compound (1) or a pharmacologically acceptable acid addition salt thereof can be administered either orally or parenterally.

Compound (1) of the present invention and its pharmacologically acceptable acid addition salts have excellent antihypertensive effects and cerebral/coronary vasodilatory effects.

As a vasodilator, for example, 5-[(3,4-dimethoxyphenyl)methylamino]-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile (-ship name: verapamil) is already commercially available. However, such vasodilators suppress the atrioventricular conduction time and prolong the atrioventricular conduction time, and such conduction disturbances are said to sometimes cause arrhythmia. However, the compound (1) of the present invention and its salts, unlike such known vasodilators, exhibit almost no side effects (eg, atrioventricular conduction suppressing effect, heart rate decreasing effect) and have low toxicity.

For this reason, compound (1) and its salts have a high therapeutic coefficient of cerebral or coronary vasodilatory action against side effects (atrioventricular conduction suppressing action), and are said to be highly safe when used as cerebral or coronary vasodilators. It has characteristics. Therefore, compound (1) and its salts are useful for the treatment and prevention of brain diseases such as cerebral vasospasm, cerebral ischemia, and cerebral infarction; and heart diseases such as angina pectoris and myocardial infarction.

Furthermore, the compound (1) of the present invention and its salts have an excellent platelet aggregation inhibiting effect. The platelet aggregation inhibitory effect, combined with the cerebral vasodilator effect, is useful for the treatment of brain diseases such as cerebral vasospasm, cerebral ischemia, and cerebral infarction.

Furthermore, the compound (1) of the present invention and its salts also have an excellent anti-calmodulin effect. Calmodulin antagonists have vasorelaxant effects [see The Journal on Pharmacology and Experimental Therapeutics, Vol. 256, pp. 8-15 (1978)]
and platelet aggregation inhibitory effect [The Journal on Biological Chemistry, Vol. 256, No. 1252]
3-12528 pages (1981): Nature, No. 28
Volume 7.

863-865 (1980).

When the compound (I) of the present invention or a pharmacologically acceptable acid addition salt thereof is used as a medicine, the compound (1)
or a salt thereof can be used as a pharmaceutical preparation mixed with a pharmaceutical excipient suitable for oral or parenteral administration. In addition, suitable excipients include, for example, starch, lactose, glucose, potassium phosphate, corn starch, gum arabic, stearic acid, and other conventional pharmaceutical excipients. The pharmaceutical preparation may be a solid preparation such as a tablet, gunpowder, capsule, or active ingredient, 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 solution.

The daily dosage of the compound (1) of the present invention or a pharmacologically acceptable salt thereof is determined by the administration method, patient's age, body weight,
Although it varies depending on the condition and type of disease, the daily dosage is usually preferably about 0.05 to ICJt9/kg, particularly about 0.5 to IO, Wg/kg for oral administration.
For parenteral administration (e.g. intravenous injection) about 0.05-2
txg/kg is preferred.

The present invention will be explained in more detail below with reference to Examples and Production Examples, but the present invention is not limited thereto.

Experimental Example 1 Antihypertensive effect (method) Specimen dissolved or suspended in water (administration: 30ff9/k
g)! Spontaneous hypertensive rat 1- (Sr-
IR). After administration, the systolic blood pressure of the rats was measured by the plethysmograph method (The Journal of Laboratories and Clinical Medicine, Vol. 78, p. 957 (1971)). The hypotensive effect of the sample is calculated by the “blood pressure lowering value (ΔizHg)” using the formula below.
It was evaluated by

Blood pressure drop value (Δytm I-1g) = [Blood pressure immediately before administration of sample] - [Blood pressure after administration of sample] (Results) The results are shown in Table 1 below.

*) Chemical name of test compound: (±)-cis-2-(4-methoxyphenyl)-3
-acetoxy-5-[2-dimethylamino)ethyl]-
2,3-dihydro-naphtho[2,1-bl[+,5]
Thiazepine-4(5H)-one fumarate Example 1 (±)-cis-2-(4-methoxyphenyl)-3
10 g of -hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is dissolved in 80 ml of dimethyl sulfoxide (DMSO), 4.2 g of potassium hydroxide is added, and the mixture is stirred for about 1 hour. Then 2-(N-
Methyl-N-benzylamino)ethyl chloride hydrochloride 8.41! ? Add and stir at room temperature.

After the reaction is completed, the reaction solution is poured into ice water and extracted with benzene. The extract was washed with water, dried, converted to hydrochloride, and recrystallized from aqueous ethanol to give (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-
Methyl-N-benzylamino) (blank below) 14.5 g (90%
).

M, p,: 157-159°C Mass (m/e): 448 In (Nujol, cm-1): 2700-2300
．． 1660.1605 Example 2 (±)-cis-2-(4-methoxyphenyl)-3
-Hydroxy-2,3-dihydro-naphtho[2,1-b
][1,5]Diazepin-4(51-I)-one 3.5
2g, 2-(dimethylamino)ethyl chloride・■(C
Ql, 17g, K v C0,3, 249 is refluxed in acetone 135J112. After the reaction is complete, inorganic substances are removed and the filtrate is concentrated under reduced pressure. The residue is dissolved in chloroform, washed with water, dried, concentrated, and separated by silica gel chromatography.

Elution with chloroform:methanol (30:l) gives
Initially (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-naphtho[2,1-b][1
,5] diazepine-4(5H)-one 2.01y is obtained.

This is treated with fumaric acid and recrystallized from ethanol to give the corresponding fumarate salt.

M, p,: 216-218℃ (decomposition) Mass (m/z) + 422 (M"") I R (N
ujol, cm-li:3460.3050.1730,
IO+30 Elemental analysis value (as CzaHzaNtOaS-C4H+Oa) CHN S Calculated value: 62.44.5.61. 5.20.5.9
5 Actual measurements: 62.29.5.66, 5.24.6.
05 Then, (±)-cis-2-(
4-methoxyphenyl)-3-[2-(dimethylamino)ethyl]oxy-2,3-dihydro-naphtho[2,1
-b] [1,5] diazebi: / -4(5H)-off
Obtain 4 oOmg.

M, p,: 136-138°C (recrystallization solvent diethanol
Mass (m/z): 422 (M”) I R (Nu
jol, cm-t:3340.331O13270,3
11O13060, 1660 Example 3 (±)-cis-2-(4-methoxyphenyl)-3
-Hydroxy-5-[2-(piperazino)ethyl]-2
,3-dihydro-1,5-benzothiazepine-4 (5H
)-one 827319.2-bromoethanol 500
Stir a+y and sodium bicarbonate 504yt9 in dimethylformamide (DMF) 15x at 50°C overnight. After cooling, concentrate under reduced pressure and add ethyl acetate to the residue. After filtering off the inorganic matter, the solvent was distilled off and the residue was recrystallized from isopropanol diisopropyl ether to give (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-(2-[4 -(2-hydroxyethyl)piperazino]ethyl)-2,3-dihydro-
1,5-benzothiazepine-4(51-1)-one 58
0gy (63.4%) is obtained.

M, p, +99-101'C Mass (m/e): 457 I R (Nujol, am-'): 3200.1665
, +610, l 580 Example 4 (±)-cis-2-(4-methoxyphenyl)-3
-Hydroxy-5-[2-(4-benzylpiperazino)
ethyl]-2,3-dihydro-1,5-benzothiazepin-4(51-1)-one (5.39 g) in benzene (60 liters) under reflux, benzyloxycarbonyl chloride (5.39 g.)
A benzene 5xQ solution of No. 49 was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. After the reaction, the reaction solution was concentrated under reduced pressure, the residue was converted to hydrochloride, and recrystallized from aqueous methanol to give (±)-c.
is -2-(4-methoxyphenyl)-3-hydroxy-5-(2-[4-(benzyloxycarbonyl)piperazinocoethyl)-2,3-dihydro-1,5-benzothiazepine-4( 51-1)-one hydrochloride 1/2
H105,89C93%) is obtained.

M, p, :l B B-189℃ (decomposition) Mass (m
/e): 547 I R (Nujol, cm-li: 3640.3400.
2700-2000.1695.1655, Kankankoi i (±)-cis-2-(4-methoxyphenyl)-3
-hydroxy-5-(2-[4-(benzyloxycarbonyl)piperazinocoethyl)-2,3-dihydro-■
, 5-benzothiazepine-4(51-1)-one hydrochloride, l/2H102,339, was catalytically reduced in 50 g of methanol and 3 g of water in the presence of 1 g of 10% palladium-carbon catalyst at 40 psi. do. After filtering off the catalyst, it was concentrated, and the residue was converted into hydrochloride and recrystallized from aqueous methanol to give (±)-cis-2-(4-methoxyphenyl)-
3-Hydroxy-5-[2-(piperazino)ethyl]-
2,3-dihydro-1゜5-benzothiazepine-4 (5
H)-one dihydrochloride 1.89 (92%) is obtained.

M, p,: 264-265°C (decomposition) Mass (n+/e): 413 I R (Nujol, am-ri: 3450.3100.
2750-2250.1660.1600 Example 6 (±)-cis-2-(4-methoxyphenyl)-3
-acetoxy5-(2-[4-(benzyloxycarbonyl)piperazino]ethyl)-2,3-dihydro-1
,5-benzothiazepin-4(5H)-one 1.189
of acetic acid 1.5JII2 solution with 25% H
Add 4 sides of B r-acetic acid. This mixture was heated at room temperature to 1.5
After reacting for an hour, it was diluted with diethyl ether, and the precipitated crystals were recrystallized from aqueous isopropanol (±)-
cis -2-(4-methoxyphenyl)-3-acetoxy-5-[2-(piperazino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one dibromide Hydrogen salt・1/2l-1tO1,1'1F(8
9.1%).

M, p,: 202-203°C (decomposition) Mass (m/e): 455 I R (Nujol, am-1): 3450.280
0-2300.1750.1735, l680, forked plate L (±)-cis-2-(4-methoxyphenyl)-3
-Hydroxy-5-(3-chloropropyl)-2゜3-
Dihydro-li, 5-benzothiazepin-4(5H)-one 1.4 g, triethylamine 1, 5 J! +!
.

■ A mixture of 830 iy of -(2-hydroxyethyl)piperazine and DMF l O is heated at 50-60° C. for 5 hours. The mixture is then poured into water, made alkaline with potassium carbonate and extracted with ethyl acetate. The extract was washed with water, dried, concentrated, and subjected to silica gel column chromatography (eluent: chloroform/methanol/
When purified with ammonia water = 180/2010.5), (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-(3-[4-(2-hydroxyethyl)pipe radinocopropyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one
1.1y (65%) is obtained.

This is treated with hydrochloric acid and re-crystallized from aqueous ethanol to obtain the corresponding dihydrochloride.l/2H,O.

M, p,: 23B-241°C (decomposition) Mass (m/e): 471 1 R (Nujol, cm-'): 3430.3150
．． 2750-2200.1685.161O Example 8 (±)-cis-2-(4-methoxyphenyl)-3
-Hydroxy-2,3-dihydro-1,5-benzothiazepin-4(51■)-one 1.59, potassium carbonate T, ee9, shrimp chlorohydrin 1.111F and acetone 40aQ were mixed at 50°C. Heat and stir overnight. Next, insoluble materials were filtered off, and the solvent was distilled off. 30 txQ of benzene and 5 m of diethylamine were added to the residual oil.
Add 12 and react at room temperature. After the reaction is completed, the mixture is concentrated under pressure and the residue is dissolved in 10% hydrochloric acid. The solution is washed with ethyl acetate, made alkaline with potassium carbonate, and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated to give (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[3-(diethylamino)=2-hydroxypropyl]-2 as an oil. ,3-dihydro-1,5-benzothiazepin-4(51-1)-one
Obtain Ig (46%).

This is treated with maleic acid and recrystallized from acetone-diisopropyl ether to give the corresponding maleate salt.

M, p,: 125-127°C Mas++ (m/e): 430 [R(Nujol, cm-li: 3350.2700-2
150.1660.1645.1610 Example 9 (±)-cis-2-(4-methoxyphenyl)-3
-Hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5M)-one 1.09 DMF 15
112 solution, 60% sodium hydride (dispersion in oil)
140 H1 then 2-chloroethyl bromide 5.2
Add 0 mg and stir at room temperature for 1 day. This mixture is then poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried, purified by silica gel column chromatography (eluent: chloroform), and recrystallized from ethanol to yield (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-( 2-chloroethyl)-2
,3-dihydro-i,s-benzothiazepine-4 (5H
)-on 460 m9 (38%) are obtained.

M,p,:I 29-130℃ Mass(IIl/e):365.363I R(Nu
jol, cm-1): 3460.1665, Example 10 (±)-cis, -2-(4-methoxyphenyl)-3
-Hydroxy-2,3-dihydro-1,5-benzothiazepin-4(51-1)-one 309.65% sodium hydride (dispersion in oil) 4 g, 2-(tetrahydropyranyloxy)ethyl chloride 209 and DMF300
A mixture of (±) -cis -2-(4-methoxyphenyl)-3-hydroxy-5-[2-(tetrahydropyranyl) oxy)ethyl]-2,3-dihydro=1
．． 5-benzothiazepine-4(5H)-one 399(9
1%).

Mass (m/e): 429 Add 50011112 of ethanol and 20 of water to this oil.
Add and dissolve 0J112, and add 2x (l) concentrated hydrochloric acid to this solution.
and hydrolyzed at 40°C. Concentrate the reaction solution under reduced pressure,
When the residue is recrystallized from aqueous ethanol, (±)-cis
-2-(4-methoxyphenyl)-3-hydroxy-5
-(2-hydroxyethyl)-2,3-dihydro-1,
5-benzothiazepine-4(51-I)-one 249(
70%) is obtained.

M, p,: 142.5-144°C Mass (m/e): 345 I R (Nujol, am-'): 3470.1655
．． 1640.1600 Example 11 (±) -trans -2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-pyrido[2°3-bl[1,5]thiazepine-4(5H)- on 1
゜09 (3,32 mmol) was dissolved in DMSO4,5i12, 3901 g (7,031 mol) of potassium hydroxide,
Next, 5001 g of 2-(dimethylamino)ethyl chloride hydrochloride is added. This mixture was heated at room temperature for 4 hours at 50°C.
After stirring at -60°C for 40 minutes, the mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried, concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane (±
) -trans -2-(4-methoxyphenyl)-
3-Hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-pyrido[2,3-bco[1,5
] Thiazepin-4(5H)-one 506 mg (40,
6%).

M, p,: 133-134°C -dihydro-pyrido [2゜3
-bl[1,5]thiazepine-4(5H)-one 2°0
Stir f (4.80 mmol) with 20zQ of 10% hydrochloric acid at room temperature overnight. Next, the reaction solution is made alkaline with potassium carbonate, and then extracted with chloroform. After washing the extract with water and drying, it was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-hegizan to give (±)-trans-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino) ethyl]-2,3-dihydro-pyrido[2,3-
bco[1,5]thiazehin-4(51'l)-one 1
/41-1.0 1.53g (84°5%) is obtained.

M, Ri: 133-134°C This is treated with oxalic acid and recrystallized from methanol to obtain the corresponding oxalate salt 1/41-1.0.

M, p,: 115-116°C Mass (m/e): 373 I R (Nujol, cm”): l 675.160
0 elemental analysis value (G +sHtsNso 5S-CtHt
o As 4 1/4 HIO) CHN S Calculated value: 53.89.5.49. 8.98.6.8
5 Actual measurement value: 53.87.5.40. 8.81.6.
95 Example 13 In the same manner as in Example 12, (±)-cis -2-(4-
methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-pyrido[
2,3-b3[1,5]thiazepin-4(5H)-one is obtained with a yield of 80%.

M, p,: 85-87°C (recrystallization solvent: ethyl acetate-diisopropyl ether) Mass (m/c): 374.2211 R(N
ujol, am-'): 1680 elemental analysis value (Cto
(as l-1t3NaOsS) CHN S Calculated value: 61.10.6.21.11.25.8.5
9 Actual measurement value: 60.97.6.26.11.06.8.
37 Example 14 i) (±)-cis-2-(4-methoxyphenyl)
-3-Hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 52.60% sodium hydride (dispersion in oil) t, 69, 2.3 g of chloroacetic acid and 30 mg of DMF The obtained crystals were recrystallized from aqueous ethanol to give (±)-cis-2-(4-methoxyphenyl)-
2.5 g (40%) of 3-hydroxy-2,3-dihydro-1,5-benzothiazepine-4(51-1)-one-5-acetic acid/1/3 ethanol is obtained.

M, p,: 214-215°C Mass (m/e): 359.330.222.149
, +21 ii) 1.529 of the acetic acid derivative obtained in i) was dissolved in 30 ml of chloroform, triethylamine was added, and 20 minutes later, 580 mg of 1-(2-hydroxyethyl)piperazine was added.
and 1.23 g of diphenylphosphoryl azide were added,
Stir for 2 days. The reaction solution was mixed with a 10% potassium carbonate aqueous solution,
It is then washed with water and extracted with 10% hydrochloric acid. This 10%
The hydrochloric acid extract is made alkaline with potassium carbonate and extracted with chloroform. After washing the extract with water and drying, it was concentrated and
The residue was recrystallized from ethanol-diethyl ether (
±)-cis-2-(4-methoxyphenyl)-3-
Hydroxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one-5-acetic acid 4-(2-hydroxyethyl)piperazinamide 860iy (45%)
get.

M, p,: Treat the compound at 147-149° with hydrochloric acid to obtain the corresponding hydrochloride 1/2H,
Get O.

M, p,: 236-239°C (recrystallization solvent: 0% ethanol-water) Mass (m/e): 471 1 R (Nujol, cm-li: 3300.3200.
1670,! 650.1605 Example 15 (±)-cis-2-(4-methoxyphenyl)-3
-Hydroxy-5-[2-(dimethylamino)ethyl]
-2,3-dihydro-naphtho[2,1-b][,■,5
] Thiazepine-4 (51-D-one 2.329 is refluxed in acetic acid-acetic anhydride (1:I) 70112. After the reaction is completed, it is concentrated under reduced pressure, and the residue is dissolved in a small amount of ethanol.
When fumaric acid is added to this solution and the precipitated crystals are recrystallized from ethanol, (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-2, 3-dihydro-naphtho[2,1
-b][1,5]thiazepine-/1(51-1)-one fumarate salt 2.09 is obtained.

M, p,: 21 G-218, 5℃ (decomposition) Mass (
n/z): 464 (M”) I R (Nujol, a
m-ri:3060.3040.2600-2300.1
740.1690 elemental analysis value (CtJ(t++N to
4S-C4tl 404) HN Calculated value: 62.06.5.5B, 4.82 Actual value: 62.01.5.59. 4.87 Example +6 (±)-cis-2-(4-methoxyphenyl)-3
-Hydroxy5-(2-[4-(benzyloxycarbonyl)piperazinocoethyl)-2,3-dihydro-!
, 5-benzothiazepine-4 (5H)-one 1.08
A mixture of 9, pyridine 7zQ and acetic anhydride 1,5 m (1) is left overnight, then diluted with benzene and washed with dilute ammonium hydroxide and then with water. After drying the solution, it is concentrated and the residue is Recrystallization from diisopropyl ether-isopropanol gave (±)-cis-2-(4
-methoxyphenyl)-3-acetoxy-5-(2-[
4-(benzyloxycarbonyl)piperazinocoethyl)-Z, a->hydro-1,5-benzothiazepine-4
(51-1)-one 960i9 (82.8%) is obtained.

M, p,: 161-162°C Mass (m/e): 589 I R (Nujol, am-1): 1760,! 69
0.1675.1G10 Example I7 (±)-cis-2-(4-methoxyphenyl)-3
-Hydroxy-5-[2-(morpholino)ethyl]-2
,3-dihydro-1,5-benzothiazepine-4 (5H
)-one 1.09 is dissolved in pyridine 5112, acetyl chloride 0,5 zQ is added under water cooling, and the mixture is stirred at room temperature. After the reaction is complete, dilute with benzene and add ice cubes. The benzene layer is separated, washed with aqueous sodium bicarbonate solution and water, dried and concentrated. The residue was converted into hydrochloride and recrystallized from ethanol to give (±)-cis-2
-(4-methoxyphenyl)-3-acetoxy-5-(
2-morpholinoethyl)-2,3-dihydro-1,5-
Benzothiazepine-4(511)-one hydrochloride 1.
07 g (90%) are obtained.

M, p,: 222°C Mass (m/e): 456 I R (Nujol, am-ri: 3470.3420.
2430,! 735.1680.1605 Example 18 i) (±)-cia-2(4-methoxyphenyl)-3
-Hydroxy-5-[2-(piperazino)ethyl/I/]
-2,3-dihydro-1,5-benzothiazepine-4 (
5H)-one 1.359, sodium bicarbonate 700
*y and 2-(2-tetrahydropyranyl)oxyethyl bromide 870R9 were reacted and worked up in the same manner as in Example 3 to form (±)-cis-2- as an oil.
(4-methoxyphenyl)-3-hydroxy-5-(2
1.7 g of -[4-(2-tetrahydropyranyloxyethyl)piperazinocoethyl)-2,3-dihydro-1,5-benzothiazepin-4(5I-1)-one are obtained.

ii) Acetic anhydride (,5iσ and pyridine 1OIlo2
The compound obtained in i) was acetylated in the same manner as in Example 1G using (±)-cis-2-(4
-methoxyphenyl)-3-acetoxy-5-(2-4
1.6 g of 4-(2-tetrahydropyranyloxyethyl)piperazinocoethyl)-2,3-dihydro-1,5-benzothiazepin-4(514)-one are obtained.

1ii) ii) The obtained compound was mixed with 0. IN-Hydrochloric acid 15
x (1 and after stirring for 5 hours in 3 mQ of methanol,
Add ethyl acetate and concentrated aqueous ammonia. The ethyl acetate layer was then separated, washed with water, dried, and concentrated. The residue was purified by preparative TLC [silica gel:chloroform-methanol (10:1)] to give an oil (±
)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-[4-(2-hydroxyethyl)
piperazinocoethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 1 g (77,9%
) is obtained.

This is treated with hydrochloric acid and recrystallized from methanol to give the corresponding dihydrochloride.

M, p,: 249-250°C (decomposition) MassQ++/e): 500 I R (Nujol, cm-'): 3400.2750
-2300.1740.1670.1605 Example 19 (±)-cis-2-(4-methoxyphenyl)-3
-acetoxy-2,3-dihydro-1,5-benzothiazepin-4(5I-1)-one 3.439.2-(N-
Methyl J%, -N-benzylamino)ethyl chloride.
2.429 of the hydrochloride, 3.459 of potassium carbonate, and 40 ml of acetone were reacted in the same manner as in Example 2, converted to the hydrochloride, and then recrystallized from ethanol-diethyl ether to give (±)-cis- 2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-methyl-N-
benzylamino)ethyl]-2,3-dihydro-1,5
-Benzothiazepine-4(5H)-one hydrochloride 4.9
59 (90%).

M, p,: 182-184℃ Mass (m/
c): 490 I R (Nujol, cm-1): 3380.2600
-2100,! 735, ■685, +605 Example 20 (±)-cis-2-(4-methoxyphenyl)-3
-Hydroxy-5-[2-(dimethylamino)ethyl]
-2,3-dihydro-1,5-benzothiazepine-4 (
5H)-one 600iy, benzyl chloride 1,
A mixture of 5 rxQ and acetone 5zQ is heated to reflux. After the reaction, it was concentrated under reduced pressure, and the residue was recrystallized from aqueous isopropanol to give (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2, 3-dihydro-1,5-benzothiazepine-4(5H)-one benzyl chloride 6
83ztC85%).

M, p,: 205-210'C Mass (m/e): 448 I R (Nujol, co+-ri: 3370, 3150
゜1665.1600 Example 21 i) (±)-cis-2-(2-thienyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 2,5y (9.03 g mol), 2
-(N-benzyl-N-methylamino)ethyl chloride hydrochloride 2.181F (9.93 g mol), potassium carbonate 3.12 g (22.6 g mol) and acetone 50
The mixture is heated to reflux overnight. After the reaction is complete, inorganic substances are filtered off and concentrated under reduced pressure to obtain (±) -ci as an oily substance.
s -2-(2-thienyl)-3-hydroxy-5-[
2-(N-benzyl-N-methylamino)ethylco2
,3-dihydro-1,5-benzothiazepine-4 (5H
)-one 4.08 g are obtained.

This is treated with hydrochloric acid to obtain the corresponding hydrochloride.

M, p,: 19B-200°C (decomposition) Mass (m/e): 424.333 I R (Nujol, c+s-'): I G 50i
i) A mixture of 3.759 of this N-benzyl compound, 6.009 (35.2 w mol) of benzyloxycarbonyl chloride and 50xQ of benzene is refluxed for 4 hours, concentrated under pressure, and the residue is washed with n-hexane. Obtained (±)
-cis-2-(2-thienyl)-3-hydroxy-
To 5.14 g of 5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-2,3-dihydro-1,5-benzothiazepine-,1(5H)-one was added 1O of acetic anhydride. Add e and 1 molecule of pyridine and heat at 100℃ for 2 hours.
Heat for an hour. The reaction solution was then concentrated under reduced pressure to give (±)-cis-2-(2-thienyl)-3-acetoxy-5-[2-(N-benzyloxycarbonyl-
N-methylamino)ethylco-2,3-dihydro-1,
5-benzothiazepine-4(51-I)-one 6.23
9 is obtained.

1ii) Dissolve the compound obtained in ii) in acetic acid 6112,
Add 25% I-IBr-acetic acid GtxQ at room temperature, and stir at the same temperature for 3.5 hours. The reaction solution is then diluted with diethyl ether, and the resulting precipitate is collected by filtration and washed with diethyl ether. Dissolve this HBr salt in water, add benzene and make alkaline with sodium bicarbonate. The benzene layer was separated, washed with water, dried, and concentrated to obtain residue 2.
゜83g was replaced with oxalate, and DMr-1.Isobu(J
(±)-cis-2-(2-thienyl)-3-acetoxy-5-[2-(methylamino)ethyl]-2,3-dihydro-1°5-benzothiazepine- 4(5H)-one oxalate 1.859 is obtained.

M, p,: 195-197℃ (decomposed) Mass (m/e): 377 I R (Nujol, cm-li: 1740, !680 elemental analysis value (as C2゜Ht t N t Oa S *) CI- I N S Calculated value: 51.49.4.75. 6.00.13.
34 Actual value: 51.31.4.83. 6.1:(,
13,05 Example 22 (±) -cis -2-(2-thienyl)-3-acetoxy-5-[2-(methylamino)ethyl]-2,3
-dihydro-1,5-benzothiazepine-4(5H)-
Add 1.0 g of oxalate to a solution of 2°09 potassium carbonate in 10 mQ of water and 10xQ of methanol, and stir at room temperature.
Stir for an hour. Next, ethyl acetate is added to this solution for extraction, and the extract is washed with water, dried, and concentrated. When this residue is converted into hydrochloride and recrystallized from ethanol, (±)−
cis -2-(2-thienyl)-3-hydroxy-5
-[2-(methylamino)ethyl]-2,3-dihydro-1,5-benzothiazepine-4(5r-1)-one.
650 x g of hydrochloride are obtained.

M, p,: 225-230°C (decomposition) Mass (n/e): 335 I R (Nujol, ca+-ri: 3470.2680
, elemental analysis value (C+sl (+5NtOtSxC12) CHN S CQ calculated value: 51.81.5.16. 7.55.17.
29.9.56 Actual value 252.05.5.25. 7.
42.17.24.9.53 123 (±)-cis-2-(4-methoxyphenyl)-3
-Hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 309 in dioxane 360M
The I2 solution is added dropwise to a solution of 11.4y of lithium aluminum hydride in dioxane 4003!12 at 95-100 DEG C. and the solution is then refluxed for 30 minutes. After the reaction is complete, aqueous T I-I F is added to decompose the complex, inorganic substances are filtered off, and the filtrate is concentrated under reduced pressure. Recrystallization of the residue from ethyl acetate yields 25.89 of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-2°3.4.5-tetrahydro-1,5-benzothiazepine. .

M, p,: 166-168° C. This is treated with hydrochloric acid and recrystallized from methanol-diisopropyl ether to obtain the corresponding hydrochloride.

M, p,: 223-224°C (decomposition) Mass (m/e): 287 I R (Nujol, am-ri: 3160.2580.
2520.2450.1605 In the same manner as above, (±)-trans -2-(4-methoxyphenyl)-3-hydroxy-2,3,4,5-
Tetrahydro-1,5-benzothiazepine is obtained.

M,p,:I 17-118.5°C (recrystallization solvent: isopropanol) This compound is also treated with methanesulfonic acid to obtain the corresponding methanesulfonate.

M, p,: 199.5-201.5°C (decomposition) (recrystallization solvent: methanol) Mass (m/e): 2 B? I R (Nujol, cm-li: 3280.2720.
2520.2450.1610 Example 24 (±)-cis-2-(4-methoxyphenyl)-3
-hydroxy-5-(3-chloropropionyl)-2,
After refluxing a mixture of 3,4,5-tetrahydro=L,S-benzothiazepine 2.2 g, l-phenylpiperazine 1.049, triethylamine 5 ml and ethanol 50112 overnight, the precipitated crystals were collected by filtration, Recrystallization from ethyl acetate gives (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[3-(4-phenylpiperazino)propionyl]-2゜3.4.5-
2.459 of tetrahydro-1,5-benzothiazepine are obtained.

M,p,:l 54-155.5℃ This was treated with hydrochloric acid and recrystallized from ethanol-diisopropyl ether to give the corresponding dihydrochloride 1/21-1
10 2.89 is obtained.

M, p, :l G G -168,5℃ (decomposition) Mas
s (m/a): 503 I IN (Nujol, am-ri: 3400.2700
-2000.1670.1605 Example 25 (±)-cis-2-(4-methoxyphenyl)-3
-Hydroxy-5-chloroacetyl-2,3,4゜5-
A mixture of 3.5 g of tetrahydro-1,5-benzothiazepine, 4.19 piperidine and 50.times.Q of ethanol is refluxed for 1 hour and then concentrated under pressure. The residue was extracted with a 5% aqueous sodium bicarbonate solution and ethyl acetate, the ethyl acetate layer was separated, washed with water, dried, and concentrated, and the residue was recrystallized from benzene-diisopropyl ether.
±)-ais-2-(4-methoxyphenyl)-3-hydroxy-5-(piperidino)acetyl-2,3,4,
5-tetrahydro-1,5-benzothiazepine 3.67
g (93%) is obtained.

M, p,: 122.5-124.5 DEG C. This is treated with hydrochloric acid and recrystallized from isopropanol diisopropyl ether to give the corresponding hydrochloride 3.719.

M, p, :I 91.5-194℃ (decomposition) Mass (
IIl/e): 412 I R (Nujol, cm-li: 3260.2740-
2500! 640.161O11580 Example 26 (±)-trans-2-(4-methoxyphenyl)
-3-Hydroxy-5-chloroacetyl-2,3,4°5-tetrahydro-1,5-benzothiazepine l.

1 g and 1.649 of 2-(3,4-dimethoxyphenyl)ethylamine are stirred in DMFGyxQ. After the reaction, the mixture was submerged in ice water, the precipitated crystals were collected by filtration, and recrystallized from ethanol to give (±)-trans
-2-(4-methoxyphenyl)-3-hydroxy-5
-[2-(3,4-dimethoxyphenyl)ethylamino]acetyl-2,3,4,5-tetrahydro-1,5-
1.36 g (89%) of benzothiazepine are obtained.

M, p,: 159-160 DEG C. This is treated with maleic acid and recrystallized from isopropanol-methanol to obtain 1.52 g of the corresponding maleate salt.

M, p,: 187-189°C (decomposition) Mass (m/e): 508 I R (Nujol, am-'): 3320.3140
．． 1680.1610 Example 27 (±)-cis-2-(4-methoxyphenyl)-3
-To a solution of 9 g of hydroxy-5-(4-benzylpiperazino)acetyl-2,3,4,5-tetrahydro-1,5-benzothiazepine in 703112 benzene, 9.159 g of benzyloxycarbonyl chloride was added under reflux. Drip. The mixture was refluxed for an additional 20 minutes, then concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography [eluent:
Purification with chloroform-methanol (40:I)] and recrystallization from benzene-diisopropyl ether (±
)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[4-(benzyloxycarbonyl)piperazinocoacetyl-2,3,4,5-tetrahydro-
9.11 g (93%) of 1,5-benzothiazepine are obtained.

M, p,: 143-144°C IR (Nujol, cm”): 3250. f 7
00°1680, l605 Example 28 (±)-cis-2-(4-methoxyphenyl)-3
-Hydroxy-5-[4-(benzyloxycarbonyl)piperazinocoacetyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 830mg, 25%H
A mixture of Br-acetic acid 3zQ and acetic acid 2mQ was reacted and treated in the same manner as in Example 6, and the resulting 2HBr salt was recrystallized from aqueous ethanol to give (±)-cis-2-
(4-methoxyphenyl)-3-hydroxy-5-(piperazino)acetyl-2,3,4゜5-tetrahydro-
1,5-benzothiazepine dihydrobromide 750+1
F (86%) is obtained.

M,p,:239-241'C(decomposition)Mass(m
/c):413 Irl(Nujol, am-'):3110.269
0.2560.2490.1670.1605 Example 2
9 (±)-cis-2-(4-methoxyphenyl)-3
-Hydroxy-5-[2-(dimethylamino)upperyl]
-2,3-dihydro-1,5-benzothiazepine-4 (
51-1)-one 2g, sodium borohydride 2.0
59 and dioxane 40 shoulder Q, acetic acid 3.24
g of dioxane 1011Q solution is added dropwise at room temperature, and the mixture is then heated under reflux for 2 hours and then concentrated. The residue is dissolved in acetic acid, washed with water, dried and concentrated, and the residue is heated at 100° C. in dioxane 50×(j) and acetic acid 5×12 to decompose the −N BHs.

When this solution is concentrated under reduced pressure and left to stand, (±)-cis-2
-(4-methoxyphenyl)-3-hydroxy-5-[
2-(dimethylamino)ethyl]-2,3,4゜5-tetrahydro-1,5-benzothiazepine 1゜739 (
89%) is obtained.

M,p,:I 89.5-192°C This is treated with hydrochloric acid and recrystallized from acetone-ethyl acetate to give the corresponding hydrochloride salt 1.869.

M, p, :l 54.5-156℃ (decomposition) Mass (
m/e) 23 5 B 1 R (Nujol, cm-'): 3400.3200
．． 3140.2730.1605 Example 30 (±)-cis-2-(4-methoxyphenyl)-3
-hydroxy-5-(dimethylamino)acetyl-2,
3,4,5-tetrahydro-1,5-benzothiazepine hydrochloride 2.09, acetic anhydride 4tttQ and acetic acid 41
After refluxing the mixture of 1Q for 1 hour, it was concentrated under reduced pressure and the residue was recrystallized from ethanol to give (±)-cis-2-(4
-methoxyphenyl)-3-acetoxy-5-(dimethylamino)acetyl-2,3,4,5-tetrahydro-
1,5-benzothiazepine hydrochloride 1.86y (84
%) is obtained.

M,p,22(31-262,5℃(decomposition)Mass(
m/e): 414 I R (Nujol, cm-'): 2630.1730
．． 1675.161O Example 3I (±) -cis -2-(4-methoxyphenyl)-
3-hydroxy-5-(piperidino)acetyl-2゜3
．． 4.5-tetrahydro-1,5-benzothiazepine 8
24JI9, pyridine 5x(2) and acetyl chloride 0.5Rσ were reacted and treated as in Example I7,
When the obtained hydrochloride is recrystallized from methanol-acetone, (±)-cis-2-(4-methoxyphenyl)-
3-acetoxy-5-(piperidino)acetyl-2,3
,4,5-tetrahydro-1,5-benzothiazepine.
The hydrochloride salt 835o (85%) is obtained.

M, p,: 242-243.5℃ (decomposition) Mass (m
/e): 454 I R (Nujol, cm-li: 2700-2200.
1730.1680.1605 Example 32 (+)-cis-2-(4-methoxyphenyl)-3
-acetoxy-5-[2-(dimethylamino)ethylco-2,3-dihydro-1,5-benzothiazepine-4(
Dissolve 5.4 g of 5H)-one hydrochloride in chloroform and make the free base by adding aqueous sodium bicarbonate solution.

After washing the chloroform layer with water and drying, the chloroform was distilled off, and the resulting free base was dissolved in 1,2-dimethoxyethane 1
303112 and Lowe Epson (Lawess
on) Add reagent 7.279 and reflux for 17 hours. Then, the reaction solution was concentrated under reduced pressure, and a small amount of methanol was added to the residue.
Add 10% potassium carbonate 50*Q and stir for 30 minutes. Methanol is distilled off under reduced pressure, ethyl acetate is added to the residual liquid, acidified with 10% hydrochloric acid, the aqueous layer is made alkaline with potassium carbonate, and extracted with ethyl acetate. Wash the extract with water,
After drying and concentrating, the obtained oil was subjected to silica gel column chromatography [eluent: 5% methanol-chloroform-concentrated aqueous ammonia (5003!12-5 drops)]
Separate and purify.

i) When the first eluting portion is recrystallized from ethanol-isopropanol, (+) -cis -2-(4-
methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-
Benzothiazepine-4(51-1)-thione l.

56 g (33%) are obtained.

M, p, :I 12-113°C [α]p: +444.5° (C= 1.0
6, C) [Cl23) This is treated with hydrochloric acid and recrystallized from ethyl acetate-methanol to give the corresponding hydrochloride.

M, p,: 197-199°C [α] Back: +474.4° (C = 1.04, CHC
Qa) Mass (m/e): 388 I R (Nujol, cm-ri: 3400.2420,
ii) Then (+)-c as an oil from the eluted portion
is-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2゜3-dihydro-1,5-benzothiazepine-4(5I-I)-
On 2.69 (58%) were recovered.

Example 33 (+)-cis-2-(4-methoxyphenyl)-3
-Hydroxy-5-(2-aminoethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 600JIIF, acetic acid 20d and acetic anhydride 0,5
The mixture of zQ was stirred at room temperature for 1 hour, then concentrated under reduced pressure,
The residue was recrystallized from isopropanol to (+)-cis
-2-(4-methoxyphenyl)-3-hydroxy-
5-[2-(acetamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 60
0119 (89%).

M, p: 243-245°C [α]p: +40.4° (C = 0, 23, MeO
I-1) Mal-1)/e):, 386 Example 34 i) (±)-cis-2-(4-methoxy, phenyl)-3-hydroxy-2,3,4,5-tetrahydro-
20g of 1,5-benzothiazepine and 380g of methylene chloride
A solution of chloroacetyl chloride 12.69 in methylene chloride 50J112 and a solution of sodium bicarbonate Il, 7v in water 901g were simultaneously added under water cooling for 15
Drop in minutes. After stirring at the same temperature for 0.5 hour, a 5% aqueous sodium hydrogen carbonate solution was added to the reaction mixture to make it alkaline. (After separating the inorganic layer, washing with water, drying, and concentrating, the residue was recrystallized from benzene to obtain (±)-cis
-2-(4-methoxyphenyl)-3-hydroxy-5
-chloroacedel-2,3,4,5-tetrahydro-1
, 23.09 (90.8%) of 5-benzothiazepine are obtained.

M,p,:I 59-160.5℃ ii) Convert this 5-chloroacetyl compound 3.63y to THF4
0g (dissolved in 60% sodium hydride (dispersion in oil)) and added dropwise to 480iy of 60% sodium hydride (dispersion in oil) suspended in THF30JI12 at room temperature. Then, add 20w (l) of isopropanol and heat under reflux for 1 hour. After the reaction is complete, reduce the pressure. Concentrate and extract by adding water and chloroform to the residue.The chloroform layer is separated, washed with water, dried, concentrated, and the residue is recrystallized from ethanol to give 3゜7-methano-2-(4-methoxyphenyl). -2゜3-dihydro-benzo[1,4,7]
Thioxazonin-6(5H)-one 2.09(61
, 1%) is obtained.

M, p,: 227.5-229.5°C Mass (m/e): 327 11i (Nujol, cm-li: 1675', 1605
Example 35 (+)-cis-2-(4-methoxyphenyl)-3
-Hydroxy-5-[2-(methylamino)ethyl]-
770Rg of 8-chloro2,3-dihydro-1,5-benzothiazepin-4(5I-1)-one was dissolved in DMF10
xQs potassium carbonate 1g and allylbromide 249
Stir with 319 at room temperature. After the reaction is completed, water and ethyl acetate are added for extraction. The ethyl acetate layer was separated, washed with water, dried, concentrated, and the residue was converted into fumarate and recrystallized from ethanol-diethyl ether to give (+)-
cis -2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-allyl-N-methylamino)ethyl]-8-chloro2,3-dihydro-1,5-benzothiazepine- 822 g (76.5%) of 4(5H)-one fumarate are obtained.

M, P, :l 36.5-138.5℃[α]F:+
9 7. 7° (C=1.00
, MeOH)I R(Nujol, am-'): 344
0.1680° Examples 36-145 In the same manner as in the above examples, the compounds shown in Table 2 below are obtained from the corresponding starting compounds. In addition, in the table, Me is methyl, Et
represents ethyl, Pr represents propyl, Bu represents butyl, ph represents phenyl and Ac represents acetyl.

Example 146 (±)-cis-2-(4-methoxyphenyl)-3
-acetoxy-5-[2-(dimethylamino)ethyl]
Naphtho[2,1-b][1,5]diazepine-4 (5H
)-one fumarate (78,811 g) was made alkaline by adding an aqueous CO3 solution, extracted with CHCl23, washed with water, dried, and then CHC(!s was distilled off. The resulting free base oil was dissolved in 10 ttt of toluene. (Dissolved in l, Et
3N 192R9 was added. Next, 403 Rg of trichloromethyl chloroformate (TCP) was added under water cooling, and the mixture was stirred at room temperature overnight. The reaction was concentrated under reduced pressure and the remaining oil was dissolved in a mixture of E two CHC123 (1:l) and washed with 10%) rc12 and then Ht2O to remove unreacted starting materials. After drying the organic layer, it was concentrated, and the remaining oil was dissolved in CH3CN1011Q, and I-I, 010x was added thereto, and the mixture was refluxed for 40 minutes.

After the reaction was completed, CH and CN were distilled off under reduced pressure, and the remaining aqueous solution was made alkaline with Na[(GO3) and extracted with CI-[CQ] under water cooling.The CHCQs layer was washed with water, dried, and then extracted with CI-[CQ. Concentrate, convert the remaining oil to the fumarate salt, and recrystallize from E t OI (±)-ci
s -2-(4-methoxyphenyl)-3-acetoxy-5-[2-(methylamino)ethyl]naphtho[2,i
bco[1,5]thiazepine-4(51-r)-one
63211 g (82%) of fumarate salt were obtained.

M, p,: 199-202°C (decomposition) I R (N ujol, cm-t: 3060.304
0.1740.1680.1660 Elemental analysis value CCzsHt*0<NtS-C4 Summer 440.
) C) I N Calculated value: 61.47. 5.34. 4.94 Actual value: 61.57. 5゜29. 4.97 manufacturing examples! (±)-cis-2-(4-methoxyphenyl)-3
-Hydroxy-2,3,4,5-tetrahydro-1゜5
- A solution of 20g of benzothiazepine in 380zQ of methylene chloride, a solution of 12.6y of chloroacedel chloride in 50% of methylene chloride, and 11.7g of sodium bicarbonate.
A 90xQ solution of water was simultaneously added dropwise over 15 minutes under water cooling. After stirring at the same temperature for 0.5 hour, a 5% aqueous sodium hydrogen carbonate solution was added to the reaction mixture to make it alkaline. The organic layer was separated, washed with water, dried, concentrated, and the residue was recrystallized from benzene to give (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-chloroacetyl-2゜3. .4.23.0 g (90%) of 5-tetrahydro-1,5-benzothiazepine are obtained.

M, p, 2 159-160.5°C The following compound is obtained in the same manner as above.

(±)-cis-5-(3-chloropropionyl) form M, l), :10 s, s-to, s°C (recrystallization solvent: ethyl acetate-hexane) (±)-1rans-5- Chloroacetyl body M, p,:
I 96.5-198.5℃ (iT) Material solvent: ethyl acetate) (±) -trans-5-(3-chloropropionyl) compound M, p: 141.0-142.5℃ (recrystallization Solvent: edyl acetate hexane) Production example 2 2-amino-5-chlorodiophenol 11°351F
(7,5,3 mmol) and 13.541+ (1 mol of 64I) methyl 3-(4-methylthiophenyl)glycidate are heated at 150-160° C. overnight under a stream of argon. The reaction mixture is then dissolved in ethanol and left to stand (
±)-cis-2-(4-methylthiophenyl)-3
-Hydroxy-8-chloro-2,3-dihydro-1,5
-Benzothiazepin-4(51-1)-one is precipitated. This is recrystallized from DMF=ethanol [4.56
9C20,3%)].

M, p,: 215-217℃ Mass (m/e): 351.333.322I
R (Nujol, cm-ri: 3420.3370°16
80, 1640 Elemental analysis value (C,0I-I,,NO!SIC(l
) CI-I N S C & calculated value: 54.62.4.01.3.98.1g, 22.1
0.07 Actual value: 54.5g, 3,88.4.00
．． 1g, 39. 9.97 Similarly as above, (±)-c
is -2-(3-pyridyl)-3-hydroxy-2,
3-dihydro-1,5-benzothiazepine-4(5I(
) - get on.

M, p,: 250-252°C (decomposition) (recrystallization solvent: ethanol-chloroform) Mass (m/e): 272 I R (Nujol, cn+-'): 3220.315
0゜Production Example 3 2-Nitrodiophenol (purity 285%) 1.0f (
5,4 g mol) and 1.231 F (5,481 mol) of methyl 3-(4-methylthiophenyl)glycidate are reacted in acetonitrile under a nitrogen stream at 80° C. for 20 hours. After the reaction, the solution was concentrated under reduced pressure and the residue was chromatographed on silica gel column 1 [eluent: benzene-ethyl acetate (15:I)] to give 3-(2-nitrophenylthio)-3 as a yellow solid. -(4-Methylthiophenyl)-2-hydroxypropionate 973 mg (4
6.8%) is obtained.

933 mg of this yellow solid was recrystallized from methanol to obtain 525 mg (2G, 4%) of methyl threo-3-(2-nitrophenylthio)-3-(4-methylthiophenyl)-2-hydroxypropionate.

M, p,: 131-132℃ Mass (m/e): 379.290.225I n(
Nujol, cm-'): 3500.1725.159
0.1510.1330 Elemental analysis value (as C+JI tvN OsS t)C
HNS calculated value: 53.81.4.52.3.69.16.9
0 actual measurement value: 53.64.4.46.3. gt, 17
．． 10 Next, an erythro body is obtained.

M, p,: I I I-115°C (recrystallization solvent: methanol) Mass (m/e): 379.290.225I R
(Nujol, am-li:3550.3320.174
0.1590.1510.1340 element Ft value (C,
,, ■4 r t N Oa S t) CI-I
N S Calculated value: 53.81.4.52.3.69.16.9
0 actual measurement value: 53.81.4.43.3.67, 16.
86 The following compound is obtained in the same manner as above.

3-(2-nitrophenylthio)-3-(2-furyl)
-2-hydroxypropionate methylthreo form; M, p,: 148-151°C (recrystallization solvent: ethanol) Mass (m/e): 323 1 [1 (Nujol, cm-'): 3450.172
0.1560.1330 Elemental analysis value (C+48, sN C)+S) CI
-INS Calculated value: 52.01.4.05.4,33. 9.9
2 Actual measurement value: 52.01.4.02.4.26.10.
303-(2-nitrophenylthio)-3-(2-thienyl)-2-hydroxypropionate methylthreo form; M, p,: 137-141"C (recrystallization solvent: ethanol) Mass (m/e): 339.250 I R (Nujol, cm-'): 3480.1730
Elemental analysis value (as C,,1-[,,N01S,)CH
NS Calculated value: 49.55.3.86.4.13.18.8
9 actual measurements: 49.38.3.76, 4.13.19.
12N lithium; M, p,: 140-143℃ (recrystallization solvent; ethanol) Mass (m/e): 339.250 I R (Nujol, cm"): 3480.1730 Elemental analysis value (C + JI + CoN As Os S z)C)
I N S Calculated value: 49.55.3.86.4.13.18.8
9 Actual measurement value: 49.30.3.74.4.14.19.
153-(2-nitrophenylthio")-3-(2-methoxyphenyl)-2-hydroxypropionate methylthreo form; M, p,: 153-159°C (recrystallization solvent: ethanol) I R (Nujol, cIll- '): 3450.17
30 elemental analysis values (CI?I-1+tNOs
S) CHN S Calculated value: 56.19.4.72.3.85.8.82
Actual value: 56.19.4.75.3.83.8.85
Engineering cell; M, p,: 146i50℃ (recrystallization solvent: ethanol) I R (Nujol, cs-li: 3490.1740 elemental analysis value (as C1-Ht?NO@S) CI (N
S Calculated value: 56.19.4.72.3.85.8.82
Actual value 256.24.4.66, 3.81.9.00 Production Example 4 1) Threo-3-(2-nitrophenylthio)-3-(4-methylthiophenyl) obtained in Production Example 3 above Methyl-2-hydroxypropionate 6.0y (15.83w mol) was added to 5nC(lt・2Ht0 12.84f(57
x mol) to a solution of concentrated hydrochloric acid 9.48119 and acetic acid 48*Q while cooling with water, return to room temperature, and add 1.
Stir for 5 hours. The mixture is then stirred at 38-40°C for 3 hours and then poured into a mixture of 2.056M aqueous sodium hydroxide, water and chloroform. The chloroform layer was separated, washed with water, dried, concentrated, and the residue was washed with diisopropyl ether and recrystallized from ethanol to give threo-3-(2-aminophenylthio)-3-(
4.119 (74.4%) of methyl 4-methylthiophenyl)-2-hydroxypropionate is obtained.

M,p,: 125-127℃ The following compounds are obtained in the same manner as above.

3-(2-aminophenylthio)-3-(2-furyl)
-2-hydroxypropionate methylthreo form: M, p,: 80-84°C (recrystallization solvent: isopropanol) Mass (m/e): 293 I R (C1-1c12s, cm-') 23 5
0 0, 1745, erythro body: M ass (m/e): 293 1 rj (CI-IC+!3.cm-'): 3500.
1745, 3-(2-aminophenylthio)-3-(2
-thienyl)-2-hydroxypropionate methylthreo form; M, p, near 9-81°C (recrystallization solvent: isopropanol) Mass (m/e): 309 I R (Nujol, cm-li: 3490.3410°3280 , +715, !600 Elemental analysis value (as C+4H+5NO1St) CI-I
N Calculated value: 54.35. C89, 4, 53 actual measurement value:
54.20.4.79.4.54 engineering litho body; Mass (m/e): 309.291.220.184
I R (Iiq,, cm-1): 3470.17403
-(2-aminophenylthio)-3-(2-methoxyphenyl)-2-hydroquine propionate methylthreo form; IR (Nujol, am"): 3390.3380.
331O11740,1730 Erythro form; I R (N ujol, c: 3460.336
0ii) 4.0 g of crystals of methyl threo-3-(2-aminophenylthio)-3-(4-methylthiophenyl)-2-hydroxybropionate obtained in i) above in DMSO
12 shoulder Q solution prepared from 60% sodium hydride (dispersion) 963319 and DMSO27JI (!
It was added dropwise to a solution of I-1s SOCI (tNa) at 15°C, and then stirred at room temperature for 30 minutes. The reaction solution was submerged in ice water containing 1.5 g of acetic acid, and the precipitated crystals were collected by filtration. , after washing it with water and then hexane, DM
F- Recrystallized from ethanol as needle-shaped crystals (±)-c
is -2-(4-methylthiophenyl)-3-hydroxy-2,3-dihydro-■.

5-benzothiazepine-4(51-1)-one 3.14
g (86,4%).

M, p,: 226-228℃ Mass (m/e): 317.299.288I R(
Nujol, cm-1): 3370, l685, elemental analysis value (C, as sHlsN Ots t) CHN
S Calculated value: 60.54.4.76, 4.41.20.2
0 actual measurement value: 60.61.4.71.4.34.20.
44 The following compound is obtained in the same manner as above.

(±)-2-(2-furyl)-3-hydroxy-2゜3
-dihydro-1,5-benzothiazepine-4 (51-1
)-one cis form; M, p,: 224-226°C (decomposition) (recrystallization solvent: D
MF-ethanol) Mass (m/e): 261, 232I R(
Nujol, cm-li: 3310.1685, elemental analysis value (as Cl31-1 + + N O3S) CI-
INS calculated value: 59.7
6, 4.24.5.36.12.27 Actual value: 59.
46.4.19.5.43.12.12(±)-2-(
2-thienyl)-3-hydroxy-2,3-dihydro-
1,5-benzothiazepine-4(5H)-one cis form; M, p,: 203.5-206°C (recrystallization solvent: ethanol) Mass (+n/c): 277 I n (Nujol, cm -'): 3400.322
0, elemental analysis value (as C+JI++N0tS*) CI
-INS Calculated value: 56.30.4.00.5.05.23.1
2 Actual measurement value: 56.44.3.89.5.06.23.
32 trans body; M, p,: 158-160°C (recrystallization solvent: ethanol) Mass (m/e): 277 I R (Nujol, co+-li: 3480.3200
, elemental analysis value (C+ a Hr IN Ot S t・
(as EtOH) CI-IN Calculated value: 55.70.5.30.4.33 Actual value:
55.90.5.22.4.36(±)-2-(2-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one cis form ; M, p, :I 68.5-169.5°C (recrystallization solvent: ethanol) Mass (m/e): 301 1 R (Nujol, am”): 3400.3200.
1670.1640 trans body; M, p,: 217-2206C (recrystallization solvent: ethanol) Mass (m/c): 301 1 n (Nujol, cm-'): 3500.3I90
．． 3150.3100.1675 (±)-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-pyrido[2,3-bl[+.

5] Thiazepine-4(5H)-one trans form; M, p,: 160-162°C (recrystallization solvent: chloroform-ethyl acetate) Mass (m/e): 302.273 I R (Nujol, c++-li: 3150,1670
゜Production Example 5 1) 45g of 2-mercapto-3-ditestone pyridine (0,
288 mol) and methyl 3-(4-methoxyphenyl)glycidate 65.99 (0,288x I.

1 mol) was dissolved in dioxane 700R12, 4 g of tin 2-ethylhexanoate (catalyst m) was added, and the mixture was reacted at 100°C for 2 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: benzene-ethyl acetate (10:I)] for 9 minutes to obtain (±)-3-
51.47 g of a threoerythro mixture of methyl (4-methoxyphenyl)-3-(3-nitro-2-pyridyl)thio-2-hydroxypropionate is obtained.

M, p,: 124-145℃ IR (Nujol, cm-1: 1750 elemental analysis value (
C+eHtsNtOsS) CI-I N
S Calculated value: 52.73.4.43.7.69.8.80
Actual value: 52.8? , 4.30.7.62.8.9
211) Add 160 ml of methisil to a solution of 30.99 of the ester obtained in 1) above in chloroform IGORQ, then add 26.09 of phosphorus pentoxide while cooling with water, and stir at room temperature for 1.5 hours. After the reaction is complete, the reaction solution is poured into ice water containing 1 kg of sodium bicarbonate and extracted with chloroform. The extract was washed with water, dried, concentrated, and purified by silica gel column chromatography [eluent: benzene-ethyl acetate (8:1) as an oil (±)-
3-(4-methoxyphenyl)-3-(3-nitro-2
-pyridyl)thio-2-methoxymethyloxypropionate 23.457 (6
8.1%) is obtained.

Mass (m/e): 408.287 I R (Liq, cm-Li: 17401-1) above i
1.54 g (3°771 mol) of the ester obtained in i)
50% ethanol, 10% palladium-carbon 450
Catalytic reduction is carried out using No. 319 at room temperature and normal pressure. After the reaction was completed, the catalyst and solvent were removed, and the remaining oil was separated by silica gel column chromatography [eluent: benzene-ethyl acetate (4:I)].

(±)-3-(4
604 mg of the threo isomer of methyl -meth21-diphenyl)-3-(3-amino-2-pyridyl)thio-2-methoxymethyloxypropionate is obtained.

I R (Liq, cm-1: 1740) Then, (±)-erythro form 413iy was obtained as an oily substance from the eluted portion.
is obtained.

I n(Liq,,cIll-ri:l740 Production Example 6 of methyl (±)-3-(4-methoxyphenyl)-3-(3-amino-2-pyridyl)thio-2-methoxymethyloxypropionate Threo body 4,224g (l 1.
16 g mol) of THFI5112 solution was added to a lithium diisopropylamide solution prepared from 1.139 (11,16 g mol) of diisopropylamine, n-butyllidium (10 w/v % hexane solution) 1 Lx (1) and TI-IFI5zQ at -60°C. The reaction solution was stirred at the same temperature for 2 hours, poured into ice water, and extracted with ethyl acetate.

The extract was washed with water, dried, concentrated, and the residue was recrystallized from ethyl acetate-hexane to obtain a prism product (±)-
cis -2-(4-methoxyphenyl)-3-methoxymethyloxy-2,3-dihyde(7-pyrido[2,3
-b][1,5]diazepine-4(51-1)-one 2
．． 39 (59,6%) is obtained.

M, p,: 173-174°C Mass (n+/e): 340.3011 R(Nu
jol, cm-li:l700 elemental analysis value (C+tl-I
+5NtOaS) CHN S Calculated value: 58.94.5.24.8.09.9.26
Actual measurements: 5g, 57.5.2g, 7.90.9.1
1 In the same way as above, (±) -Lrans body is set to 51.7
% yield.

M, p,: 184-186°C (recrystallization solvent: ethyl acetate-n-hexane) Mass (m/e): 346.301 1 R (Nujol, cm-li: 3200-2500,
Production Example 7 1) 2-Amino-5-chlorodiophenol 5, Og and methyl Lrans-3-(4-methyl)"-yl)grindate 8.31F are reacted at 100° C. in 60 ml of xylene. After the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in diisopropyl ether, and when left to stand, 3-(2-amino-5-chlorophenylthio)-3
6.89 g (58%) of the threo isomer of methyl -(4-methylphenyl)-2-hydroxypropionate is obtained.

M, p, :l 13-114°C 1υthreo-3-(2-amino-5-chlorophenylthio)-3-(4-methylphenyl)-2-hydroxypropionate methyl 11.479, potassium hydroxide 6
．． 469, water 1003112, methanol 100311
2 and '1-IP I O0txQ (D) The mixture is stirred at room temperature. After the reaction is completed, the reaction solution is concentrated, acidified with 10% hydrochloric acid, and extracted with ethyl acetate. The extract is washed with water,
After drying and concentrating, the residue is recrystallized from ethanol to obtain 9.979 g of threo-3-(2-amino-5-chlorophenylthio)-3-(4-methylphenyl)-2-hydroxybroionic acid. .

M,p,:I 84-185.5℃Mass(m/e): 337.339I R(
Nujol, am-li: 3280.2600.2080
．． 1620 iii) The carboxylic acid obtained in 11) above is refluxed in xylene 200d, and the crystals precipitated by cold leaching are collected by filtration and dried to yield (±)-cis-2-(4-methylphenyl).
-3-hydroxy-8-chloro-2,3-dihydro-!
, 5-benzothiazepine-4(51-1)-one 8.1
89 (yield from amino ester; 84%) is obtained.

M, p, :l 95-196.5℃ Mass (m/e): 319.321 1 R (Nujol, cs+-li: 3520.3470
．． 3180.3085.1670 Production example 8 (±)-cis-2-(4-methoxyphenyl)-3-
Methoxymethyloxy-2,3-dihydro-pyrido [2
,3-b][1,5]diazepine-4(51-1)-one! , 73y (5% mole), 730 mg of dimethylaminoethyl chloride hydrochloride, 2.09 g of potassium carbonate, and 30 JII2 of acetone was refluxed for 17 hours, the inorganic matter was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was dissolved in diisopropyl ether. When recrystallized from (±)-cis-2-
(4-methoxyphenyl)-3-methoxymethyloxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-pyrido[2,3-b]0.5]thiazepine-4
(5H)-one 1.78y (85°1%) is obtained.

M, p,: 102-104°C Production Example 9 1) 1-aminonaphthalene-2-thiol 7°867.
Methyl 3-(4-methoxyphenyl)glycidate 12
．． Heat 16f to 100°C in 80% toluene. After the reaction, the solution was concentrated under reduced pressure, diisopropyl ether was added to the residual oil, the precipitated crystals were collected by filtration, and il crystallization from methanol yielded (±)-3-(1-amino-
2-naphthyl)thio-3-(4-methoxyphenyl)-
Threo form of methyl 2-hydroxypropionate 6.4
9 g (38%) are obtained.

M, p,: 131.5-135°C Mass (m/z): 383 (M”)I R(Nu
jol, am-'): 3500.3 lI 20.31
20.1730 Elemental analysis value (as C!lHz IN Oa S) CI
-IN Calculated value: 65.78.5.52.3.65 Actual value:
65.74.5.42.3.59ii) Using the compound obtained in i) above, the following compound is obtained in the same manner as in Production Example 4.

(±)-threo-3-(l-amino-2-naphthyl)thio-3-(4-methoxyphenyl)-2-hydroxypropionic acid M, p: 164-165°C (decomposition) (recrystallization solvent: ethanol) Mass (m/z): 369 (M”) I R (Nu
jol, ca+-li: 3450.3400.3360.
3200, +800-1640 elemental analysis value (C!0HI
As SNO4S) CHN Calculated value: 65.02.5.18.3.79 Actual value:
65.00.5.09.3.76(±)-cis-2
-(4-methoxyphenyl)-3-hydroxy-2,3
-dihydro-naphtho[2,lb][1,5]thiazepin-4(5H)-one M, p,: 263-267°C (recrystallization solvent: chloroborum ethanol) Mass (m/'z) : 351 (M”)I R(
Nujol, c+s-tsu: 3520.3200.3■0
0.3080.3060.1660 Elemental analysis value (cm.

HI? As N03S) CHN

Claims (1)

[Claims] (1) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [In the formula, ring A is fused with a benzene ring, a heterocycle, or a thiazepine ring, which may be substituted with a halogen atom, to form a naphtho [ 2,1-b][1,5]represents a naphthalene ring forming thiazepine, R^1 represents a phenyl group or a heterocyclic group which may be substituted with a lower alkyl group, a lower alkoxy group or a lower alkylthio group. , R^2 represents a hydrogen atom or a lower alkanoyl group, and R^3 represents (i
) Hydrogen atom, (ii) Heterocyclic group which may be substituted, (iii) Hydroxyl group, (iv) Halogen atom, (v)
Substituted with 1 to 3 groups selected from lower alkyl groups, lower alkanoyl groups, lower alkenyl groups, lower alkynyl groups, aralkyl groups that may be substituted on the phenyl nucleus, and aryl groups that may be substituted. an amino group, or (vi) -Y-R^3 and -R
^2 together represent -COCH_2-, Y represents a single bond or a lower alkylene group which may be substituted with an oxygen atom or a hydroxyl group, Z is an oxygen atom,
Represents a sulfur atom or two hydrogen atoms. However, R^3
is a mono- or di-lower alkylamino group, (
i) Ring A is a heterocycle or a naphthalene ring, or (i
i) R^1 is a heterocyclic group or lower alkylthiophenyl group, or (iii) Y is a branched lower alkylene group, or a straight or branched lower alkylene group substituted with an oxygen atom or a hydroxyl group. There is or (
iv) Z is a sulfur atom or two hydrogen atoms] A 1,5-benzothiazepine derivative or a pharmacologically acceptable acid addition salt thereof.