1,5-BENZOTHIAZEPINE COMPOUNDS AND PROCESS FOR PREPARING THE SAME

COMPOSES DE 1,5-BENZOTHIAZEPINE ET PROCEDE DE PREPARATION

English Abstract

M-12
ABSTRACT OF THE DISCLOSURE
Cis or trans-1,5-benzothiazepine compounds represented
by the formula (I):
(I)
<IMG>
wherein R1 represents a hydrogen atom, a halogen atom, an
alkyl group or an alkoxy group and R2 represents a hydrogen atom,
an alkyl group or a hydroxyalkyl group and the pharmaceutically
acceptable acid addition salts and quaternary ammonium salts
thereof which exhibit anticholinergic activity and are useful
as anti-ulcer, gastric secretion inhibiting and antispasmodic
agents in mammals, and a process for preparing the same.

Claims

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. A process for the preparation of novel cis and trans-
1,5-benzothiazepine compounds represented by the general
formula (I):
(I)
<IMG>
wherein R1 is selected from the group consisting of a hydrogen
atom, a halogen atom, selected from the group con-
sisting of chlorine and bromine, a straight or branched
chain alkyl group having 1 to 4 carbon atoms, and a
C1-4 alkoxy group;
R2 is selected from the group consisting of a hydrogen
atom, an alkyl group and a C2-4 hydroxyalkyl group;
and pharmaceutically acceptable acid addition salts and
quaternary ammonium salts thereof; said process comprising:
(a) reacting a compound selected from the group consisting
of:
(i) compounds of the general formula (II):
(II)
<IMG>
29

Claim 1 continued....
wherein R1 is defined hereinbefore; and
(ii) compounds of the general formula (III):
(III)
<IMG>
wherein R1 is defined hereinbefore and
R3 represents a methyl group or a p-tolyl group;
with a piperazine compound in an amount from an equimolar amount
to a large excess at a temperature from about 80° to about
100°C for about 30 minutes to about 10 hours.
2. A process as claimed in claim 1 wherein compounds of
the general formula (III) as defined in claim 1(a)(ii) are
produced by reacting a compound of the general formula (IV):
(IV)
<IMG>
wherein R1 is defined in claim 1, with a substituted sulfonyl
chloride or bromide in a tertiary amine.
3. A process as claimed in claim 2 wherein said tertiary
amine is selected from the group consisting of pyridine, triethyl-
amine, and mixtures thereof.

4. A process as claimed in claim 3 wherein said reaction
is carried out in an inert organic solvent at room temperature
for a period of from about 1 hour to about 3 hours.
5. A process as claimed in claim 2 wherein said tertiary
amine is selected from the group consisting of pyridine, triethyl-
amine, and mixtures thereof; said reaction is carried out in an
inert organic solvent at room temperature for a period of from
about 1 hour to about 3 hours; and about 1 to about 3 mols of
said substituted sulfonyl chloride or bromide per mol of said
compound of the general formula (IV) as defined in claim 2 are
used.
6. A process as claimed in claim 1 wherein compounds of
the general formula (II) as defined in claim 1(a)(i) are
produced by reacting a compound of the general formula (IV):
(IV)
<IMG>
wherein R1 is defined in claim 1, with a chlorinating agent.
7. A process as claimed in claim 6 wherein said
chlorinating agent is selected from the group consisting of
thionyl chloride and phosphorus oxychloride.
8. A process as claimed in claim 7 wherein said reaction
is carried out in an inert organic solvent at a temperature of
about 60°C to about 100°C for a period of about 30 minutes to
about 2 hours.
31

9. A process as claimed in claim 6 wherein said chlori-
nating agent is selected from the group consisting of thionyl
chloride and phosphorus oxychloride; said reaction is carried
out in an inert organic solvent at a temperature of about 60°C
to about 100°C for a period of about 30 minutes to about 2 hours;
and about l to about 2 mols of the chlorinating agent per mol
of the compound of the general formula (IV) as defined in claim
6 are used.
10. A process as claimed in claim 9 which is conducted in
the presence of a catalyst selected from the group consisting of
hydrochloric acid and tertiary amine hydrochlorides.
11. A process as claimed in claim 2 wherein the compound
of the general formula (IV) as defined in claim 2 is produced
by reducing a compound of the general formula (V):
(V)
<IMG>
wherein R1 is selected from the group consisting of a hydrogen
atom, a hologen atom, selected from the group consisting of
chlorine and bromine, a straight or branched chain alkyl group
having 1 to 4 carbon atoms, and a C1-4 alkoxy group; and
pharmaceutically acceptable acid addition salts and quaternary
ammonium salts thereof.
12. A process as claimed in claim 11 wherein said reduction
is carried out using a reducing agent which is selected from the
group consisting of lithium aluminum hydride and calcium
borohydride.
32

13. A process as claimed in claim 12 wherein said reduction
is carried out at a temperature at about 20°C to about 100°C
in an inert organic solvent.
14. A process as claimed in claim 6 wherein the compound
of the general formula (IV) as defined in claim 6 is produced
by reducing a compound of the general formula (V):
(V)
<IMG>
wherein R1 is selected from the group consisting of a hydrogen
atom, a halogen atom, selected from the group consisting of
chlorine and bromine, a straight or branched chain alkyl group
having 1 to 4 carbon atoms, and a C1-4 alkoxy group; and
pharamaceutically acceptable acid addition salts and quaternary
ammonium salts thereof.
15. A process as claimed in claim 14 wherein said reduction
is carried out using a reducing agent which is selected from
the group consisting of lithium aluminum hydride and calcium
borohydride.
16. A process as claimed in claim 15 wherein said reduction
is carried out at a temperature of about 20°C to about 100°C in
an inert organic solvent.
17. A process as claimed in claim 11 wherein the compound
of the general formula (V) as defined in claim 11 is produced by
heating a compound of the general formula (VI):
33

Claim 17 condinued....
(VI)
<IMG>
wherein R1 is defined in claim 11 at a temperature of about
160°C to about 180°C in the presence of a catalyst selected
from the group consisting of hydrochloric acid and tertiary amine
hydrochlorides.
18. A process as claimed in claim 14 wherein the compound
of the general formula (V) as defined in claim 14 is produced
by heating a compound of the general formula (VI):
(VI)
<IMG>
wherein R1 is defined in claim 14 at a temperature of about
160°C to about 180°C in the presence of a catalyst selected from
the group consisting of hydrochloric acid and tertiary amine
hydrochlorides.
19. A process as claimed in claim 17 wherein the compound
of the general formula (VI) is produced by reacting a compound
of the general formula (VIII):
<IMG> (VIII)
34

Claim 19 continued.....
with a compound of the general formula (VII):
<IMG> (VII)
wherein R1 is defined in claim 17.
20. A process as claimed in claim 19 wherein an approximate
equimolar amount of the compounds of the general formulae (VIII)
and (VII) are reacted at a temperature of from about room
temperature to about 90°C for a time of from about 3 hours to
about 6 hours.
21. A process as claimed in claim 20 wherein said reaction
is conducted in the absence of a solvent.
22. A process as claimed in claim 18 wherein the compound
of the general formula (VI) is produced by reacting a compound
of the general formula (VIII)
(VIII)
<IMG>
with a compound of the general formula (VII)
(VII)
<IMG>

Claim 22 continued...
wherein R1 is the same as defined in claim 18.
23. A process as claimed in claim 22 wherein an approxi-
mately equimolar amount of the compound of the general formulae
(VIII) and (VII) are reacted at a temperature of from about room
temperature to about 90°C for a time of from about 3 hours to
6 hours.
24. A process as claimed in claim 11 wherein the compound
of the general formula (V) as defined in claim 11 is prepared
by reacting a compound of the general formula (VIII):
<IMG>
(VIII)
with a compound of the general formula (VII)
<IMG> (VII)
in the presence of a catalyst selected from the group consisting
of hydrochloric acid and tertiary amine hydrochlorides.
25. A compound of the general formula (I) as defined in
claim 1 whenever prepared by the process as claimed in claims 1,
2 or 3.
26. A compound of the general formula (I) as defined in
claim 1 whenever prepared by the process as claimed in claims 4
or 5.
27. A compound of the general formula (I) as defined in
claim 1 whenever prepared by the process as claimed in claims 6
or 7.
36

28. A compound of the general formula (I) as defined in
claim 1 whenever prepared by the process as claimed in claims 8
or 9.
29. A compound of the general formula (I) as defined in
claim 1 whenever prepared by the process as claimed in claims 10
or 11.
30. A compound of the general formula (I) as defined in
claim 1 whenever prepared by the process as claimed in claims 12
or 13.
31. A compound of the general formula (I) as defined in
claim 1 whenever prepared by the process as dlaimed in claims 14
or 15.
32. A compound of the general formula (I) as defined in
claim 1 whenever prepared by the process as claimed in claims 16
or 17.
33. A compound of the general formula (I) as defined in
claim 1 whenever prepared by the process as claimed in claims 18
or 19.
34. A compound of the general formula (I) as defined in
claim 1 whenever prepared by the process as claimed in claims 20
or 21.
35. A compound of the general formula (I) as defined in
claim 1 whenever prepared by the process as claimed in claims 22
or 23.
36. A compound of the general formula (I) as defined in
claim 1 whenever prepared by the process as claimed in claim 24.
37

37. A process as claimed in claim 1 wherein 3-chloromethyl-
2,3-dihydro-2-phenyl-1,5-benzothiazepin-4(5H)-one is reacted
with N-methyl piperazine.
38. (?)-Cis-2,3-dihydro-3-[(4-methylpiperazinyl)methyl]-2-
phenyl-1,5-benzothiazepin-4(5H)-one and the pharmaceutically
acceptable acid addition salts and quaternary ammonium salts
thereof whenever prepared by the process as claimed in claim 37.
39. A process as claimed in claim 1 wherein 3-chloromethyl-
2,3-dihydro-2-phenyl-1,5-benzothiazepin-4(5H)-one is reacted
with N-methyl piperazine, including optically resolving, with
a resolving agent, a compound produced represented by the general
formula (I) as defined in claim 1.
40. (-)-Cis-2,3-dihydro-3-[(4-methylpiperazinyl)methyl]-2-
phenyl-1,5-benzothiazepin-4(5H)-one and the pharmaceutically
acceptable acid addition salts and quaternary ammonium salts
thereof, whenever prepared by the process as claimed in claim 39.
38

Description

1 BACKGROUND OF T}IE INVENTION
1. Field of the Invention
This invention relates to novel cis and trans-1,5~
benzothiazepine compounds represented by the formula (I):
S
~` .
1 0 ~<R 1
wherein R1 represents a hydrogen atom, a halogen atom, an
alkyl group or an alkoxy group and R2 represents a hydrogen
atom, an alkyl group or a hydroxyalkyl group and pharmaceutically
acceptable acid addition salts and quaternary ammonium salts
thereof, and a process for preparing the same.
2. Description of the Prior Art
.
Hitherto, it is known that cis-(-)-3-acetyloxy-5-
(N,N-dimethylamino~ethyl-2-(p-methoxyphenyl)-1,5-benzothiazepin-
4(5H)-one hydrochloride is useful as a coronary vasodilator
as disclosed in Japanese Patent Publication No. 16988/71,
Arzneim.-Forsch. 21(9), 1338-1343 (1971) and Chem. Pharm. Bull.,
Japan, 21 (1), g2-97 (1973~. A~so, Journal of Medicinal
Chemistry, Vol. 11 (2), P 361, 1968 discloses 5-(N,N-
dimethylamino)ethyl-2-phenyl-1,5-benzothiazepin-4(5H)-one
hydrochloride as being useful as t~an~uilizer.
The above known compounds have a chemical structure
similar to the compounds of the present invention having the
formula (I) but they exhibit completely different pharmacological
activity from that of the present invention.
-- 1 --

1 DETAILED DESCRIPTION OF THE INVENTION
.. . . . _ . . . . .
The term "halogen" as used herein Eor Rl means a
chlorine a-tom or a bromine atom, preferably a chlorine atom.
The term "alkyl" as used herein for Rl means a straigh-t
or branched chain alkyl group having 1 to ~ carbon atoms, e.g.
a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or
tert-butyl group, preferably a methyl group.
The term "alkoxy" as used herein for Rl means an
alkoxy group having 1 to 4 carbon atoms, e.g., a methoxy, ethoxy,
propoxy or butoxy group, preferably a methoxy group.
The term "hydroxyalkyl" as used herein for ~2 means
a hydroxyalkyl group having 2 to ~ carbon atoms, e.g., a
hydroxyethyl, hydroxypropyl or hydroxybutyl group, preferably
a hydroxyethyl group.
As is apparent to one skilled in -the art, the 1,5-
benzothiazepin compounds of this invention represented by the
formula (I) above contain two asymmetric carbon atoms at the
2- and 3-positions of the 7-membered ring thereof and, therefore,
exist cis and trans forms and (+) and (-~ forms in each of the
steric isomer. It is to be understood that the present
invention includes, in the scope thereof, the optically active
cis and trans forms as well as cis and trans forms of the
compounds of $he formula (I), and pharmaceutically acceptable
acid addition salts and quaternary ammonium salts of these
compounds.
The 1,5-ben20thiazepin compounds represented by the
formula (I) can be prepared by the following reaction scheme:
~ ~ Rl ~ ~ CH=C(COOC2H5)2
(VIII) - 2 - (VII)

~/ /CH~COOC2}15)
~VI
~ ~ $CH2
(V) 1 H ~ ~Rl
~ ~H20502R3 ~ ~ L~12CQ
~III) \~ 1 (II) 1
1~ ~-CH21~N_R2
-- 3 --

1 wherein Rl and R2 are as defined above and R3 represents a
methyl group or a p-tolyl group.
The process of this invention will be described in
greater detail according to the above reaction scheme.
The reaction between o-aminothiophenol (VIII) and an
ethyl benzalmalonate (VII) can be carried out using an
approximately equimolar amount of these compounds at a tem-
perature of from room temperature (about 15-30C) to about 90C,
preferably 20 to 50C, for a periocl of about 3 to 6 hours,
1~ generally in the absence of a solvent to obtain an adduct of the
formula (VI).
The resulting adduct of the formula (VI) is then heated
at a tempera*ure of about 160 to about 180C in the presence
of a catalyst such as concentrated hydrochloric acid, a
tertiary amine hydrochloride, for example, triethylamine
hydrochloride, pyridine hydrochloride and the like until no
further ethanol formed during cyclization reaction is distilled
out from the reaction system to form the corresponding 3-
ethoxycarbonyl compound of the formula (V) which is then reduced
with a reducing agent, for example, lithium aluminum hydride,
calcium borohydride, etc. at a temperature of about 20C to
about 100C in an inert organic solvent such as tetrahydrofuran,
dioxane and the like to obtain the corresponding 3-hydroxymethyl
compound of the formula (IV).
Alternatively, the reaction between o-aminothiophenol
5VIII) and the ethyl benzalmalonate (VII) can be carried out in
the presence of the catalyst described above whereby the 3-
ethoxycarbonyl compound of the formula (V) can be produced
without isolating the adduct of the formula (VI).
The resulting 3-hydroxymethyl compounds of the formula
(IV) obtained above are novel compounds and are useful
-- 4 --

1 intermediates for the prepara-tion of the desir~d compounds of
the formula (I) v.ia alternati~e rou-tes through the corresponding
3-chloromethyl compounds of the formula (II) or the
corresponding 3-substituted-sulfony:Loxymethyl compounds of the
formula (III~.
The conversion of the 3-hydroxymethyl compound of the
formula (IV) into the corresponding 3-chloromethyl compound
of the formula (II) can be conducted by reacting the 3-
hydroxymethyl compound (IV) with a chlorinating agen~ such as
thionyl chloride, phosphorus oxychloride and the like in an
inert organic solvent such as benzene, toluene, chloroform and thelike at a temperature of about 60C to about 100C for a period
of about 30 minutes to about 2 hours, using about l to about 2
mols of the chlorinating agent per mol of the 3-hydroxymethyl
compound (IV). Alternatively, the above convention is
preferably conducted in the presence of a catalyst such as a
tertiary amine, for example, pyridine, triethylamine and the
like whereby the reaction proceeds smoothly.
In an alternative route, the conversion of the 3-
hydroxymethyl compound of the formula (IV). into the corresponding
3-substituted-sulfonyloxymethyl compound of the formula (III)
can be conducted by reacting the 3-hydroxymethyl compound (IV)
with a substituted sulfonyl chloride or bromide in a tertiary
amine such as pyridine, triethylamine and the like or a
mixture thereof with an inert organic solvent such as benzene,
toluene, chloroform and the like at room temperature for a
period of from about l to about 3 hours, using about l to about
2 mols of the substituted sulfonyl chloride or bromide per
mol of the 3-hydroxymethyl compound (IV).
The substitution reaction of the compound of the formula

B
(II) or the formula (I~I) to the desired compound of the
formula (I) generally proceeds by reac-t.ing the compound (II) or
(III) with a piperazine compound in an equimolar amount to a
large excess amount which serves as a reactant as well as a
reaction solvent at a temperature of about 80 to about 100C
for about 30 minutes to about 10 hours. A solvent such as
dioxane, benzene, toluene and the like can also be used in the
reaction. After completion of the reaction, the reaction
mixture can be concentrated, if necessary, and poured into water
to obtain the desired pxoduct of the formula (I) as a mixture
of cis and trans forms.
As set forth previously, the compounds of the present
i.nvention of the formula (I) have two asymmetric carbon atoms
and, therefore, four optically active steric isomers and (-)-cis-
and (+)-trans forms exist which have the same chemical structure
but are different in the IR absorption spectrum and the
melting point. The present inventors studied on the nuclear
magnetic resonance spectra of these compounds in order to
determine the chemical structure of the compounds and found that
one of these isomers showed the coupling constant (J 2 3) f
about 6Hz, whereas the other isomer showed the coupling
constant (J 2 3) f about 12Hz, which correspond to the cis
and trans forms, respectively.
~ s a result of further studies on the pharmaceutical
activities of the optically active compounds of the formula (I),
it was found that the compound in (-) form generally exhibits
higher anticholinergic and anti-ulcer activities in comparison
with the corresponding racemate. For example, in (-)-cis-
2,3-dihydro-3-[(4-methylpiperazinyl)methyl]-2-phenyl-1,5-
benzothiazepin-4(5H)-one which has been found to have potent
-- 6 --

1 gastric secretion inhibitory activity and anti-ulcer activity in
comparison with known anticholinergic agents, the (-) form
exhibited an anticholinergic activity and anti-ulcer activity
of 2 and ~ times the activities of the corresponding racemate,
respectively. In addition, the ~-) form exhibited a lower
desalivation activity as a side-effect to a degree o~ about 1/2
and a lower acute toxicity to a degree of 3/4 by oral adminis-
tration and 2/5 by intravenous administration, in comparison with
the corresponding racemate [(-)-cis form] as shown below.
Racemic Mi~ture (~) Form
Anticholinergic Activity 1 2
Anti-ulcer Activity (Stress) 1 4
Desalivation Activity 1 0.6
Acute Toxicity (LD50 mg/kg)
Oral in Mice 650 870
Intravenous in Mice 65 160
The optical resolution of the racemate of the com-
pounds (I) can be achieved by a conventional procedure, for
example, using an optically active acid as a resoluting agent
such as (+) or (-) tartaric acid or a derivative thereof, e.g.,
(+) or (-) diacetyltartaric acid, (+) or (-) monomethyl
tartarate, (+)-camphor-sulfonic acid, etc. which are well known
in the art.
In a typical procedure for the optical resolution, a
racemate of the compound of the formula (I) is reacted with an
optically active acid as described above in an equimolar amount
in a solvent and the resulting crystalline two optically active
acid salts are separated by taking advantage of their different
solubility. Any types of solvents can be used in the above
reaction as long as these solvents have remarkable difference in

1 the solubility between the above salts, but methanol, ethanol
or a mixture thereof (e.g., 50:50 by volume) is preferably used.
Eaeh of the optically active salts thus separated is
then dissolved in water and the aqueous solution is rendered
neutral with an alkali such as ~ium carbonate, potassium
earbonate and the like to obtain th~ corresponding free eompound
in the form of either (+) or (-).
The pharmaeeutieally aeeeptable aeid addition salts and
quaternary ammonium salts of the resulting (~) or (-) eompound
1~ ean be easily obtained by the reaetion of the eompound with a
non-toxic pharmaeeutieally aeeeptable inorganic or organic aeid
such as hydroehloric acid, hydrobromic acid, sulfuric acid,
oxalie acid, fumaric acid, maleie aeid, succinie aeid, eitrie aeid,
malie acid and the like or by the reaetion with an alkyl halide
sueh as methyl bromide, butyl bromide and the like, in a
usual manner as well known in the art.
The aeute toxieity and the antieholinergie activity of
the typieal eompound of this invention having the formula (I)
in eomparison with eommereially available typieal eompounds
having a similar aetivity are set forth below.
Test Compounds
A: Cis~2,3-dihydro-3-[4-methylpiperazinyl)methyl~-2-
phenyl-1,5-benzothiazepin-4(5H)-one-2HCl-H20
(prepared in Example 1 of this invention)
B: Glyeopyrrolate (Merek Index, 8th Ed.) (anti-peptie
uleer agent having an excellent aetivity whieh has
reeently been eommereially available)
C: Atropin Sulfate (a well-known anti-eholinergie agent)
-- 8 --

1 LD50 (in mice)
, .
Compounds Oral (mg/kg) Intravenous (mg/kg)
A 650 65
B 860 20
C 500 90
Anti~ulcer Activity
Administ- %Inhibi-tory
Type of Ulcer Animal ration Dose
10 Induced _ (Number) Route* (mg/kg) A B C
Stress Mice (6)p.o. 5 91.6 81.9 82.3
Aspirin Rats (5)s.c. 5 100.0100.0 79.3
Indomethacin Rats (6) p.o. A: 5 99.0 88.6
B:20
Aspirin- Mice (6)s.c. 5 51.8 47.6 48.0
Stress
Pylorus Rats (5)s.c. 20 100.0 100.0 , 13.0
Ligature
* p.o. : Oral Administration
s.c. : Subcutaneous Adminis-tration
Gastric Secretion Inhibitory Activity
The gastric secretion inhibitory activity of the test
compounds were observed simultaneously in the above anti-ulcer
activity test using aspirin and the results are as follows.
Test Compounds ~Inhibitory
....
A 90
B 90
C 70
The corecliastasis which is considered as one of serious
side effects frequently observed in administering anticholinergic
agents was found to be 0.31 mg/kg (Compound A)~ 0.037 mg/kg
(Compound B) and 0.076 mg/kg (Compound C) in terms of ED20 by
~ g _

1 intraperitoneal adm.inistration.
As is apparent from the above pharmacological data,
Compound A of the present invention shows approximately the
same degree of acute toxicity as Glycopyrrolate, but exhibits
an equal or higher anti-ulcer activlty and further about 1/10
degree of core~astasis as side effect. This fact indicates that
the Compound A is very useful as anticholinergic agent in
comparison with known compounds which are now commercially
available. Similar activities are also expected in other com-
pounds of the present invention having the formula (I).
The present invention is further illustrated in greater
detail by the following ~eference Examples and Examples, but
these Examples are given for illustrated purpose only and
are not to be construed as limiting the scope of the present
invention. Unless otherwise indicated, all parts, percents,
ratios and the like are by weight.
Reference Example 1
(a) A mixture of 32 g of o-aminothiophenol and 62 g of
ethyl benzalmalonate was heated at 90C for 5 hours and then
allowed to stand to crystallize. ~he resulting crystals were
then recrystallized from diethyl ether-petroleum ether to
obtain 90 g of diethyl 2-(o-aminophenylthio~-2-phenylethane-
ll-dicarboxylate as colourless needles having a melting point
of 71C.
Elementary Analysis:
Calc'd for C20H23N04S ~M.W. 373.475):
C, 64.32; H, 6.21; M, 3.75 (%)
Found: C, 64.25; H, 6.26; N, 3.72 (~)
tb) 74.6 g of the product obtained in (a) above was mixed
-- 10 --

~~
1 with 1.~ g oE triethylamine hydrochloride and the mixture was
heated at about 1~0C until no further ethanol was diskilled out
(for about 2 hours). After allowing the reaction mixture to
cool, a mixture of benzene-petroleum ether was added thereto
and the mixture was then thoroughly stirred and filtered. The
resulting filter cake was recrystallized from a mixture of
chloroform-petroleum ether to obtain 35 g of 2,3-dihydro-3-
ethoxycarbonyl-2-phenyl-1,5-benzthiazepin-4(5H)-one as colourless
needles having a melting point of 199C.
Elementary Analysis:
18 17 O3S (M-W. 327.405)
C, 66.04; Ht 5.23; N, ~.28 (%)
Foùnd: C, 66.17; H, 5.29; N, 4.21 (%)
(c) 32.7 g of the product obtained in ~b) above was added in
small portions to a mixture of 150 ml of tetrahydrofuran
and 35 g of lithium aluminum hydride with stirring, followed
by heating under refluxing for 3 hours. After cooling, methanol
was added to the reaction mixture to decompose any excess of
the remaining lithium aluminum hydride. The resulting solution
was poured into ice water which had been rendered acidic with
hydrochloric acid, and the precipitated crystals were filtered
and recrystallized from a mixture of dimethylformamide-water to
obtain 23.2 g of 2,3-dihydro-3-hydroxymethyl-2-phenyl-1,5-
benzothiazepin~4(5H)-one having a melting point of 248C.
Elementary Analysis:
Calc'd for C16H15NO2S (M.W. 285.367~
C, 67.34; H, 5.30; N, 4.91 (%)
Found: C, 67.30; H, 5.24; N, 4.82 (%)
-- 11 --

Reference Example 2
(a) A mixture of 32 g of o-aminothiophenol, 70.7 g of p-
chlorobenzalmalonate and 1.4 g of pyridine hydrochloride
was heated at about 180C until no ~urther ethanol was distilled
out (for about 4 hours). After allowing the reaction mixture
to cool, a mixture of benzene-petroleum ether was added to the
reaction mixture which was then thoroughly stirred and filtered.
The resulting filter cake was recrystallized from chloroform-
petroleum ether to obtain 54.5 g of 2-(p-chlorophenyl)-2,3-
dihydro-3-ethoxycarbonyl-1,5-benzothiazepin-4(5H)-one as
colourless needles having a mel-ting point of 206C.
Elementary Analysis:
Caic'd for C18H16CQNO3S: (M.W. 361.850):
C, 59.75; H, 4.~6; N, 3.87 (%)
Found: C, 59.83; H, 4.40; N, 3.84 (%)
(b) 36.2 g of the product obtained in (a) above was added
in small portions to a mixture of 100 ml of dioxane and 2.5 g
of lithium aluminum hydride with stirring, followed by heating
at 80C for 3 hours. After cooling, methanol was added to the
reaction mixture to decompose any excess of the remaining lithium
aluminum hydride. The resulting solution was poured into ice
water which had been rendered acidic with hydrochloric acid,
and the pxecipitated cr~stals were filtered and recrystallized
from dimethyl~ormamide-water to obtain 19.8 g of 2-(p-chlorophenyl)-
2,3-dihydro-3-hydroxymethyl-1,5-benzothiazepin-4(5H)-one as
colourless prisms having a melting point of 23.9C.
Elementary Analysis:
Calc'd for Cl~H14CQNO2S (M.W. 319.812)
- 12 -

1 C, 60.09; H, 4.41; N, 4.38 (~)
Found: C, 60.16; H, 4.37; N, 4.45 (~)
Reference Example 3
(a) A mixture o~ 32 g of o-aminothiophenol, 65.6 g of
p-methylbenzalmalonate and 1.4 g of triethylamine hydrochloride
was heated at about 180C until no further ethanol was distilled
out (for about 3 hours). The resulting reaction mixture was
worked up in the same manner as described in Reference Example 2
(a) and the crystals thus obtained was recrystallized from
chloroform~petroleum ether to obtain 34 g of 2,3-dihydro-3-
ethoxycarbonyl~2-(p-tolyl)-1,5-benzothiazepin-4(5H)-one as light
yellow needles having a melting point of 185C.
Elementary analysis:
Calc'd for ClgHlgNO3S (M.W. 341-~32)
C, 66.84; H, 5.61; N, 4.10 (~)
Found: C, 66.70, H, 5.53; N, 4.00 (%~
(b) 34 g of the product obtained in (a) above was added
in small portions to a mixture of 200 ml of tetrahydrofuran
and 3.5 g of lithium aluminum hydride with stirring, followed
by heating under refluxing for 3 hours. The resulting reaction
mixture was then worked up in the same manner as described in
Reference Example 1 (c) and the crystals thus obtained were
recrystallized from dimethylformamide-water to obtain 16.8 g of
2,3-dihydro-3-hydroxymethyl-2-(p-tolyl)-1,5-benzo-thiazepin-
415H)-one as colourless prisms having a melting point of
229C.
Elementary Analysis:
Calc'd for C17H17NO2S (M.W. 299.395)
- 13 -

-
1 C, 68.20; H, 5.72; N, 4.68 (%)
Found: C, 68.12; H, 5.78; N, 4.53 (~)
Reference Example 4
(a) A mixture of 32 g of o-aminothiophenol, 69.6 g of
ethyl p-methoxybenzalmalonate and 1.6 g of triethylamine
hydrochloride was heated at about 180C until no further ethanol
was distilled out (for about 4 hours). The resulting mixture
was then worked up in the same manner as described in Reference
Example 2 (a) and the crystals thus obtained were recrystallized
lû
from chloroform-petroleum ether to obtain 25 g of 2,3-dihydro-3-
ethoxycarbonyl-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-
one as colourless needles having a melting point of 192C.
Elementary Analysis:
Calc'd for ClgHlgN04S (M.W. 357.432)
C, 63.85; H, 5.36; N, 3.92 (~)
Found: C, 63.69; H, 5.42; N, 3.86 (~)
(b) 18 g of the product obtained in (a) above was added in
small portions to a mixture of 70 ml of tetrahydrofuran and
1.3 g of lithium aluminum hydride with stirring, followed by
heating under refluxing for 3 hours. The resulting reackion
mixture was then worked up in the same manner as described in
Reference Example 1 (c) to obtain 9.8 g of 2,3-dihydro-3-
hydroxymethyl-2-(p-methoxyphenyl)-1,5-benzothiazepin-4~5H)-
one as colourless needles having a melting point of 217~C.
Elementary Analysis:
Calc'd for C17H17N03S (M.W. 315.394)
C, 64.74; H, 5.43; N, 4.44 (%)
Found: C, 64.63; H, 5.40; N, 4~47 (~)
- 14 -

1 ' EXA.~IPLE 1
(a) 5.7 g of 2,3-dihydro-3-hydroxymethyl-2-phenyl-1,5-
benzothiazepin-4(SH)-one prepared as described in Reference
Example 1 and 1.6 g of pyridine were dissolved in 30 ml of
benzene, and 3.6 g of thiony~ chloride was added to the
solution, followed by heating under refluxing for 1 hour. The
solvent was then distilled off and water was added to the residue.
The precipitated crystals were filtered, washed with methanol
and recrystallized from benzene to obtain 5.1 g of 3-chloromethyl-
~0
2,3-dihydro-2-phenyl-1,5-benzothiazepin-4(SH)~one as colourless
needles having a melting point of 233C (with decomposition).
Elementary Analysis:
Calc'd for C16H14CQNOS (M.W. 303.813)
C, 63.26; H, ~.64; N, 4.61 (%)
Found: C, 63.35; H, 4.60; N, ~.53 (~)
(b) 4.5 g of the product obtained in (a~ above was added
to 10 ml of N-methylpiperazine with stirring, and the
mixture was heated under refluxing for 2 hours. After allowing
the mixture to cool, water was added to the mixture and the
precipitated crystals were separated by filtration. The
filter cake was added to 20 ml of methanol and the solution was
heated and then cooled. The methanol-insoluble substance (a
product in a trans form) was separated by filtration and set
aside. The filtrate was concentrated and he resulting residue
was recrystallized from a mixture of benzene-diethyl ether to
obtain cis-2,3-dihyaro-3-[(4-methylpiperazinyl)methyl]-2-
phenyl-1,5-benzothiazepin-4(5H)-one as colourless prisms haviny
a melting point of 198C.
- 15 -

1 Elementary Analysis:
Calc'd for C21H25N3S (~.W. 367.517)
C, 68.63; ~I, 6.86; N, 11.~3 (%)
Found: C, 68.52; H, 6.85; N, 11.39 (~)
EXAMPLE 2
. . _
(a) 3 g of 2,3-dihydro-3-hydroxymethyl-2-(p-tolyl)-1,5-
benzothiazepin-4(5H)-one prepared as described in Reference
Example 3 was dissolved in 15 ml of pyrldine. 1.3 g of methane-
sulfonyl chloride was added to the solution and the mixture wasstirred at room temperature for 2 hours. Water was added to the
reaction mixture and the precipitated crystals were separated
by filtration and recrystallized from dichloromethane-n-hexane
to obtain 3.3 g of 2,3-dihydro-3-[~methylsulfonyloxy)methyl]-
2-(p-tolyl)-1,5-benzothiazepin-4(5H)-one as colourless needles
having a melting point of 207C.
Elementary Analysis:
Calc'd for ClgHlgN04S2 ~M.W. 377.48~)
C, 57.27; H, 5.07; N, 3.71 (%)
Found: C, 57.42; ~, 5.14; N, 3.5~ (%)
(b) 1.8 g of the product obtained in (a) above was added
to S ml of N-methylpiperazine and the mixture was heated at
90C for 30 ~inutes while stirring. After allowing the mixture
to cool, water was added to the mixture and the precipitated
crystals were separated by filtration. The filter cake was
extracted with dichloromethane and most of the solvent was
distilled off and diethyl ether was added to the residue. The
mixture was allowecl to stand and the precipitated crystals (a
product in a trans form) was separated by filtration. The
filtrate was concentrated under reduced pressure and the resulting
- 16 -

1 residue was recrystallized from benzene-diethyl ether to ob-tain
cis-2,3-dihydro 3-[(4-methylpiperazinyl)methyl~-2-(p-tolyl)-1,5-
benzothiazepin-4(5H)-one as colourless prisms having a melting
point of 196C.
Elementary Analysis:
Calc'd for C22H27N3OS ~M.W. 381.544)
C, 69.26; H, 7.13; N, 11.01 (%)
Found: C, 69.45; H, 7.18; N, 10.88 (%)
EXAMPLE 3
(a) 5.7 g of 2,3-dihydro-3-hydroxymethyl-2-phenyl-1,5-
benzothiazepin-4(5H)-one prepared as described in Reference
Example 1 was dissolved in 20 ml of triethylamine. 3.8 g of
p-toluenesulfonyl chloride was added to the solution while
stirring and the mixture was stirred at room temperature for
2 hours. Water was added to the reaction mixture and the pre-
cipitated crystals were separated by filtration and recrystallized
from a mixture of dichloromethane-n-hexane to o~tain 8 g of
2,3-dihydro-2-phenyl-3-[(p-toluene-sulfonyloxy)methyl]-1,5-
benzothiazepin-4(5H)-one as colourless prisms having a melting
point of 215C.
Elementary Analysis:
Calc'd for C23H21N4S2
C, 62.85; H, 4.82; N, 3.19 (%)
Found: C, 62.74; H, 4.78; N, 3.10 (%)
(b) 2.2 g of the product obtained in (a) above was added
to 6 ml of piperazinoethanol and the mixture was heated at
100C for 5 hours. After allowing the mixture to cool, water
was added to the mixture and the precipitated crystals were
- separated by filtration. 10 ml of methanol was added to the
- 17 -

1 crystals thus obtained and the mixture was heated for 30
minutes under refluxing. After allowing the mixture to cool,
the insoluble substance (a product in a trans form) was separated
by filtration and the filtrate was concentrated under reduced
pressure. The resulting residue was recrystallized from a
mixture of benzene-diethyl ether to obtain cis-2,3-dihydro-4-
[(4-hydroxyethyl~piperazinyl)methylJ-2-phenyl-1,5-benzothiazepin--
4(5H)-one as colourless prisms having a melting point of 106 C.
Elementary Analysis:
10Calc'd for C22H27N32S (M-W- 397-543)
C, 66.47; H, 6.85; N, 10.57 (%)
Found: C, 66.59; H, 6.90; N, 10.57 (~)
EXA~PLE 4
(a) 3.6 g of cis-2,3-dihydro-3-[~4-methylpiperazinyl)-
methyl]-2-phenyl-1,5-benzothiazepin-4(5H)-one was dissolved in
10 ml of ethanol, and 2.5 ml of concentrated hydrochloric acid
was added to the solution while stirring. The precipitated
crystals were filtered and recrystall.ized from aqueous methanol
to obtain cis-2,3-dihydro-3-~(4-methylpiperazinyl)mèthyl]-2-
phenyl-1,5-benzothiazepin-4(5H)-one dihydrochloride monohydrate
as colourless needles having a melting point of 212C (with
decomposition).
Elementary Analysis:
Calc'd for C2lH25N3os-2HcQ~H2o (M.W. 458.454)
C, 55.02; H, 6.38; N, 9.17 (%)
Found: C, 55.20; H, 6.52; Nr 9.10 (%)
EXAMPLES 5 - 14
30According to the procedures as described in Examples 1
to 4, the following 1,5-benzothiazepine compounds and the salts
- 18 -

~iL$~
1 thereof were prepared.
~ffH 2~ R2
~Rl
- 19 -

~ ~ ~r~ Ln
o v~ r~ Ln,~
o r~ r~oo o t_co ,
z l
~ r~ ot~ oo co ~1
a> t~ u,
U~ r.~ n r~ ~ r~ ~o
td ~ ~ ~ Ln Ln ~0 ~ Lr~
r~ n ~ n n ~ ~ ~D ~D
t~
r~ ~DO t~
~ O o~ OO O C~
n~ tLn co GO n r~ oo r~
r~Lnu~ .r~ O
.
tn
~n ~ ~n tn ln
r - z ~ - o ~ - o - ~ o
t~ u~ h
~ , Z ~ ~ ~ r~ z ~ ~D z ~ ~ ;~
.,~ ~ U ~~r~ o ~ n o ~D r~
h :~ ~v.~: ~ ~ , r~
X ~
~ h o ~,/ ~ ~ cr~ ~ o co ~ ~ r~ o
E~ O ~ v ~ ~ Ln ~ ~ ~ ~ W r~ t~ t~l
~4
P~
o ~ O O ~ f~ O ~ e O ~ Ei O
- rJ ~Ln ~ ) r-l ~ O u~ J o co ~ O c~
rV O o ~ rv r~r~ o O0
,~ v ~ ~ ~v ~1
o
.~
to
: o
t-d ` L~ L~)
~1r-l ~V Lt~ V O tv~ rv VlVl O fV U~ tV
d O ~ ~ ~1 Ll)O r-l rv5 ~ r-l tV
r~ 1 0 ~ V
In~d O ~1 ~ ,~ O LqttJ O ~tV ~ O ~S
S ~I rv rV ~ ~1 rl~: ~I rv S ~ ~ ~ ~
rV O ~ ~ o tVt~ tV O 5--~ O tV 0~ tV O tV tV
~ ) Z ¢ ~ ) z¢ ~ ~ z ,~:q
rv a~
rV ~ tV
~ ~ - h ~'I rv :~
-1 t~S tV ~ O ~ ~)
~d tV ~/ ~ ~ a) h
tJ) ~1 ~r~ ~ ~ ~ S~ ~
td ,~ ~3 0 td ~ O O tV
Ei ~ O ~ v
fV h o ~ o ~,~
t~ ~ ~ t~
~:
t~
~ ~: X
C~ I I i tJ
q
~ ~ tO Lq td V~ Lq
~ O E~ c~
,~
Ei Ln ~ r~ t~o cJ~
~d ~
O
~L~z
-- 20 --

O u~ ~ o co~n o~ tv~ cn o
> tn~o t~~J t~ tn~ tnei
Zl
tl~ ,~, c~ oo o o ooo~c: o oo co
r~~r-l r-~r--~
~ o o ~ o~ t~t~tn ~ o
t~ ~ 0 ~ ~0~ 0 ~ 00t;O t~ ~
`D tn`D tn Ln~D ~ ~ ~D
r~ ~
~: u~ ~ h ~ o o~ tnco ~ ~ o
:~ U t~d Or~ ~ ~ ~ r~ ~ ~ t~
tntn ~ ~ tn tn~ ~Dtn tn
¢ '~ ,~ ~_
I
U~ O O Ct~ U~
~ ~ t~
,~ ~d O _`~ Z ~-- Z --~ O _~ O _~
,~ t~ Or~ ~ ,~ O ~ ~t~ ~ O
Z ~ J t~ Z~ Z
,~ ,~ u ~ t`3:: ~t~ an ~ X oo t`tn t~ X
:~ ~.C ~ . . ~ . t~J ~ ~
r~ C~ ~ X ~ t~. Xt~ X o~ oo
~ ~ O ,~ ~ ~ o ,~
E~ O ~: ~ ~:C ~tt`l eP '`' X ~t ~t~ ~ ~ ~t
~4 ,~
.~ ~ ~J ~ ~ ~ ~ P,
~ o ,C ~; o , :: ~3 ,~
,~ .,1 ~ cn ~ o oo ~ O t` ~ o '~ r~ ~ ~
Q~ O o e~ r~ U ~t ,~ u t~ r~ u a~ r~ r~ u
N~ (I> r~
S~ .
,~ ^ t~ t~ n ~ tn u~
~: r~ t~7o ^ U) r~ tt~ r~
o ~ ,~tn o a) ~n ~ ~ o o~ u) a) ,~
tl) r1 ~C~:l3 ~ r-1 (D O O r~l ~n 5 ~: r-~ tD S: ~r-l tn ~ ~ r~l n
(D ~O ~ r~lh ~ 5~ F: o ~ h r~ ~D ,C ~ E~ o ~
tn ~tD ~C O ~ O ~rJ O tntD,C O ~ N ~ O tn (VrC O tn
U t~ r~ ~ ~ r~ tV r~~ ~ r-~ r~3 ~) r~l ~V .C tV r-~ ~rt ~ ~ r-l ~r~
~D rl O ~: ~ O C~ ~D O ~DC ~ O ;-1 t~(V O tD tD ~rl O ~I t~ O
r-( U~ t~d C_) ~'~ ~ ~J Z ~) ~Ll ~ ~ ¢ ~ ~ Z ~:q Cl ~ ~ ¢
~V ~D IV
r l r~ ~r~
~ S-l ~
O ~D O ~V O ~V
r-~ ~ r_l ~ ,_1 ~
~C Cd rC ~
~) t~ ~ U 1-~ U
r-l 0~ 0~ 0
U ~ ~ ~ rC
~ O tV ~ O tD :~ O
rC ~ ~ rC ~: ~D .~ t
r l 0 5~ O $-i rl O
~ o
~ .
t~ t~ t~
I
r~ C~ t~
r~ ~ ~ ~ ~ 3
O O
tn
m ~d tn tn tn tn tn
~ o ~
~D
Ei O r~ t
~. ,~ ,~
X O
Z:
-- 21 --

r~,~,rj f~j
1 EX~MPLES 15 - 17
According to -the p~ocedures as described in Examples 1 to
4, the following 1,5-benzothiazepine intermedia-tes having the
formula (II) or (III) were prepared.
15. 3-chloromethyl-2,3-dihydro-2--(p-methoxyphenyl)-1,5-
benzothiazepin-4(5H)-one(II). Recrystallized from chloroform-
n-hexane. Colourless needles having a melting point 235C
(with decomposition).
Elementary Analysis:
Calc'd for C17H16CQNO2S ~M.W. 333.840)
C, 61.16; H, 4.83; N, 4.20 (%)
Found: C, 61.10; H, 4.88; N, 4.04 (%)
16. 3-chloromethyl-2-(p-chlorophenyl)--2,3-dihydro-1,5-
benzothiazepin-4(5H)-one (II). Recrystallized from chloroform-
n-hexane. Colourless prisms having a melting point of 241C
(with decomposition).
Elementary Analysis:
Calcd for C16H13CQ2NS (~-W- 338-258)
C, 56.81; H, 3.87; N, 4.14 (%)
Found: C, 56.93; H, 3.81; N, 4.12 (%)
17. 2,3-dihydro-3-methylsulfonyloxymethyl-2-phenyl-1,5-
benzothiazepin-4(5H)-one (III). Recrystallized from dichloro-
methane-n-hexane. Colourless needles having a melting point
of 215~C.
Elementary Analysis:
17 17 O4S2(M.W. 363.457)
C, 56.18; H, 4.71; N, 3.85 ~)
Found: C, 56.05; H, 4.78; N, 3.82 (%)
- 22 -

s~
EXAMPLE 1 ~
To a solution of 20 g of cis (~)~2,3-dihydro-3-
[(4-methyl piperazinyl)methyl]-2-phenyl-1,5-benzothiazepin-
4(5H)-one dissolved in 200 ml of methanol was added a solution
of 10 g of (+)-tartaric acid dissolved in 50 ml of methanol, and
the mixture was allowed to stand overnight at room tempera~ure.
The precipitated crystals were separated by filtration and re-
crystalliæed from a~ueous methanol to obtain g.7 g o~ a (~
tartarate of the compound in the (-~) form as colourless flake-
like crystals having a melting point of 192 C.
The resulting tartarate was dissolved in 200 ml of
water and the solution was rendered neutral with potassium carbo-
nate. The precipitated crystals were separated by filtration,
washed with water and recrystallized from dichloromethane -
petroleum ether to obtain 5.8 g of cis-~ )-2,3-dihydro-3~(4-
methylpiperazinyl)methyl]-2-phenyl-1,5-benzothiazepin-4(5H)-one
as colourless prisms having a melting point of 198 . []D
+ 46 ~C=2.4, chloroform)
Elementary Analysis:
2~
Calc'd for C21H25N3OS (M.W. 367.517)
C, 68.63; ~I, 6.86; N, 11.43 (%~
Found: ~, 68.58; ~, 6.92; N, 11.40 (%)
The filtrate which had been set aside when the above
crude (+) tartarate of (+) compound was filtered was con-
centrated under reduced pressure. The resulting oily substance
was dissolved in 200 ml of water and the solution was rendered
neutral with potassium carbonate. The precipitated crystals were
separated hy filtration and dissolved in 100 ml of methanol.
To the resulting solution was then added a solution of 4.5 g of
- 23 -

1 (-)-tartaric acid dissolved in 30 ml of methanol, and the
mixture was allowed to stand overnight at room temperature.
The precipitated crystals were Eiltered and recrystallized from
aqueous methanol to obtain 7.5 g of a (~)-tartarate of the
compound in the (-) form as colourless needles having a melting
point of 193Co
The resulting tartarate was dissolved in 200 ml of
water and the solution was rendered neutral with potassium
carbonate. The precipitated crystals were separated by fil-
1~ tration, washed with water and recrystallized from dichloro-
methane-petroleum ether to obtain 5.2 g of cis-(~)-2,3-
dihydro-3-[(4-methylpiperazinyl)methylJ-2-phenyl-1,5-benzo-
thiazepin-4(5H)-one as colourless prisms having a melting point
of 198 C. [aJD = -46 (c-2.4, chloroform)
Elementary Analysis:
21 25 3 ( .W. 367.517)
C, 68.63; H, 6.86; N, 11.~3 (%)
Found: C, 68.75; H, 6.95; N, 11.31 (%)
EXAMPLE 19
20 ~ of cis~(-)-2,3-dihydro-3-[(4-methylpiperazinyl)-
methyl]-2-phenyl-1,5-benzothiazepin-4(5H)-one was disso:Lved in
400 ml of a mixture of methanol-ethanol (50:50 by volume).
To the resulting solution was added a solution of 8.2 g of (-)-
tartaric acid dissolved in 100 ml of a mixture of methanol-
ethanol (50:50 by volume) and the resulting mixture was allowed
to stand overnight at room temperature. The precipitated
crystals were separated by filtration and recrystallized from
aqueous methanol to obtain 9 g of a (-)-tartarate of the (-)
form compound as colourless needles having a melting point of
- 24 -

1 193C. The crystals thus ohtained were dissolved in 200 ml
of water and the solu-tion was rendered neutral with sodium car-
bonate. The precipitated crystals were then separated by
filtration, washed with water and recrystallized from dichloro-
methane-petroleum ether to obtain 5.8 g of cis-(-)-2,3-
dihydro-3-[(4-methylpiperazinyl)methyl]-2~phenyl-1,5-benzo-
thiazepin-4(5H)-one as colourless prisms having a melting point
of 198C [a]20 = 46 ( 0 4 hl f
Elementary Analysis:
21 25 3 (M.W. 367.517)
C, 68.63; H, 6.~6; N, 11.43 (%)
Found: C, 68.70; H, 6.82; N, 11.45 (%)
EXAMPLE 20
5.2 g of cis-(-)-2,3-dihydro-3-[(4-methyLpiperazinyl)-
methyl]-2-phenyl-1,5-benzothiazepine prepared as described in
Example 18 or 19 was dissolved in 15 ml of ethanol and 3.6 ml
of concentrated hydrochloric acid was added to the solution
with stirring. The precipitated crystals were separated by
filtration and recrystallized from a~ueous methanol to obtain
cis-(-)-2,3-dihydro-3-[(4-methylpiperazinyl)methyl]-2-phenyl-
1,5-benzothiazepin-4(5H)-one dihydrochlorid as colourless
needles having a melting point of 231C (with decomposition).
[~]D0 = -56 (c=0.4, ~ater).
Elementary Analysis:
Calc'd for C21H25N3OS-2HCQ (M.W. 430.439)
C, 57.27; H, 6.18; N, 9.54 (~O)
Found: C, 57.40; H, 6.22; N, 9.46 (%)
EXAMPLE 21
7 g of cis-(-)-2,3-dihydro-3-[(4-methylpiperazinyl)-
methyl]-2-phenyl-1,5-benzothiazepin-4(5H)~one was dissolved in
- 25 -

a~
1 100 ml of c1ichlorometllane and the resu:Lting soLutlon was addedto 30 ml of a methanolic solution of 5 g of methyl bromide.
The mixture was then allowed to stand for 10 hours at room
temperature and the solven-t was distilled out. Dichloro-
methane and diethyl ether were addecl to the residue ancl the
precipitated crystals were separated by filtration and re-
crystallized from ethanol to obtain cis-(-~-2,3~dihydro-31(4-
methylpiperazinyl)methyl]--2-phenyl-1,5-benzothiazepin-4~5~1)-
one di(methyl bromide)monohydrate as a white crystalline powder
having a melting point of 259C (with decomposition).
[a]20 = -53 (c=0.4, water)
Elementary Analysis:
Calc'd for C23H31Br2N3S H2
C, 48.01; H, 5.78; N, 7.30 ~%)
Found: C, 48.07; H, 5.69; N, 7.49 (%)
EXAMPLES 22 to 26
The following optically active 1,5-benzothiazepine com-
pounds and salts thereof were prepared according to the procedure
as described in Examples 18 to 21.
22. Cis-(-j-2,3-dihydro-3-[(4-methylpiperazinyl)methyl]-2-
phenyl-1,5-benzothiazepin-4~5H)-one dimaleate. Recrystallized
from methanol-diethyl ether. White crystalline powder having a
melting point of 190C (with decomposition). [a]20 = -52
(c=0.4, water)
Flementary Analysis:
Calc~d for C21H25N3S 2C4~4O4 (
C, 58.09; H, 5.55; N, 7.01 (~)
Found: C, 57.74; H, 5.65; N, 6.72 (%)
- 26 -

1 23. Cis-(-)-2,3-dihydro-3-[(4-methylpiperazinyl)methyl]-2-
phenyl-1,5-benzothiazepin-4(5H)-one di(methyl sulfate).
Recrystallized from ethanol-diethyl ether. White crystalline
powder having a melting point of 287C (with decomposition).
[a]D = ~55 (c=0.4, water)
Elementary Analysis:
Calc~d for C23H31N3O5S2 t
C, 55.96; H, 6.33; N, 8.51 (%)
Found: C, 56.06; H, 6.39; N, 8.52 (%)
24. Cis-(-)-2,3-dihydro-3-[(4-methylpiperazinyl)methyl]-2-
phenyl-1,5-benzothiazepin-4(5H)-one di(methanesulfonate).
Recrystallized from ethanol. White crystalline power having a
melting point of 256C (with decomposition). la]20 = _47o
(c=0.4, water)
Elementary Analysis:
Calc d for C23H33N3o7s3 (M.W. 559.727)
C, 49.36; H, 5.94; N, 7.51 (%)
Found: C, 49.23; H, 5.98; N, 7.46 (%)
25. Cis-(-)-2,3-dihydro-3-[(4-methylpiperazinyl)methyl]-2-
phenyl-1,5-benzothiazepin-4(5H)~one butyl bromide monohydrate.
Recrystallized from acetone-diethyl ether. White crystalline
powder having a melting point of 254C (with decomposition).
[a32 = -55 (c=0.4, water)
Elementary Analysis:
Calc d for C25H34BrN3OS H2O (M-W- 522 558)
C, 57.46; H, 6.94; N, 8.04 (%)
Found: C, 57.55; H, 6.91; ~, 8.11 (~)
26. Cis-(+)-2,3-dihydro-3-[(4-methylpiperazinyl)methyl]-2-
~ .
phenyl-1,5-benzothiazepin-4(5H)-one dihydrochloride.

1 Recrystallized from aqueous methanol. Colourless needles having
a melting point of 231C (with decomposition). [a]D = +55
(c=0.4, water)
Elementary Analysis:
Calc d for C21H25N3os~2HcQ (M.W. 4~0.~39)
C, 57.27; H, 6.18; N, 9.54 (%)
Found: C, 57.33; H, 6.17; N, 9.49 (%)
- 28 - .