CA1238635A - 1,5-benzothiazepine derivatives and processes for preparing the same - Google Patents

Abstract

ABSTRACT OF DISCLOSURE

This invention provides novel 1,5-benzothiazepine derivatives of the formula:

(I) wherein R1 is lower alkyl or lower alkoxy, R2 is hydrogen atom or lower alkanoyl, Ring A is a substituted benzene ring of the formula:

or

Description

~2;~ 35 Novel 1,5-benzothiazepine derivatives and processes for preparinq the same This invention relates to novel 1,5-benzothiazepine derivatives and processes for preparing the same.
U.S. Patent 3,562,257 discloses various benzothiazepine derivatives such as 2-(4-methoxyphenyl)-3-hydroxy (or S acetoxy)-5-[2-dimethylamino)ethyll-7-chloro-2,3-dihydro-1,5-benzothiazepine-4(5H)-one. The U.S. Patent also dlscloses that these benzothiazepine derivatives show an antidepressive activity, tranquilizer activity and/or coronary vasodilating activity.
As a result of various investiqations, the inventors have no~ found that the novel compounds of the present invention or the salts thereof are useful as an intermediate in the synthesis of novel 5-alkyl-1,5-benzothiazepine derivatives which show potent hypotensive activity and potent cerebral or coronary vasodilating activity, and which are claimed in our related patent application serial no. 474,421, of which the present application is a division.
The present invention provides a compound of the formula:

:

~:

,., -- ~

s ~Rl ~ N = ~ OR (I) wherein Rl is lower alkyl or lower alkoxy, R2 is hydrogen atom or lower alkanoyl, Ring A is a sub-stituted benzene ring of the formula:

S ~a ~ R ~ ~e ~

Ra is lower alkyl, lower alkoxy, lower alkylthio or benzyloxy, each one o~ Rb and Rc is lower alkyl, lower alkoxy or halogen atom, and either one o~ Rd and R is fluorine atom and the other one is hydrogen atom, or a salt thereof.
Representative examples of the compounds of the present invention include those of the formula (I) in which R1 is : lower alkyl of one to 4 carbon atoms such as methyl, ethyl, propyl or butyl, or lower alkoxy of one to 4 carbon atoms such as:methoxy, ethoxy, propoxy or butoxy; R2 is hydrogen atom or lower alkanoyl of 2 to 4 carbon atoms such as acetyl, propionyl or butyryl; Ring A is a substituted benzene ring : of the formula:
: ~ :

:
:

~" : :: `

, ~231~3S

R ~ R ~ Re ~

Ra is lower alkyl of one to 4 carbon atoms such as methyl, ethyl, propyl or butyl, lower alkoxy of one to 4 carbon atoms such methoxy, ethoxy, propoxy or butoxy, lower alkyl-S thio of one to 4 carbon atoms such as methylthio, ethylthio,propylthio or butylthio, or benzyloxy; each one of Rb and Rc is lower alkyl of one to 4 carbon atoms such as methyl, ethyl, propyl or butyl, lower alkoxy of one to 4 carbon atoms such as methoxy, ethoxy, propoxy or butoxy, or halogen atom such as chlorine atom, bromine atom or fluorine atom;
and either one of Rd and Re is fluorine atom and the other one is hydrogen atom.
A preferred subgenus consists of those compounds o~ the formula (I) in which Rl is methyl or methoxy. Another preferred subgenus consists of those compounds of formula (I) in which R is methyl or methoxy, Ring A is a substituted ben~ene ring of formula:
~ , ., ~,~. .
:
.
:~ . :
.. : . : :

lZ;~1!3S3S

~a ~ R ~

R is methyl or methoxy, and Rb and Rc are methyl, methoxy or a chlorine atom. A further preferred subgenus consists of those compounds of formul~ (I) in which Rl is methyl or methoxy, R is hydrogen or lower alkanoyl, Ring A is a substituted benzene ring of the formula:

Ra~ RC)~

R is methyl or methoxy, and Rb and R are methyl. Still further preferred subgenus consists of those compounds of formula (I) in which Rl is methyl or methoxy~ R2 is hydrogen or acetyl, Ring A is a substituted benzene ring of the Eormula:

R ,~

Ra is methyl or methoxy, and Rb and Rc are methyl.
On the other ~hand, suitable examples of the salt of the compound (Ij include, for example, alkali metal salts (e.g., sodium salt or potassium~salt~and~alkaline~earth ~, ~
.

' ~

~2:~363S

metal salts (e.g., calcium salt or barium salt). Such salts are readily obtained by treating the compound (I) with, for example, alkali metal hydroxide or alkaline earth metal hydroxide in a solvent.
While the compound (I) of the present invention can exist in the form of two stereoisomers (i.e., cis and trans isomers) or four optical isomers (i.e., (+)-cis, (-)-cis, (+)-trans and (-)-trans isomers) due to the two asymmetric carbon atoms involved therein, all of these isomers or mixtures thereof are included within the scope of the invention.
According to the present invention, the compound (I) of the invention is a novel compound and may be prepared, for example, according to the method shown by the follow-ing reaction schem~:

:

:~ : : :

~, : ' , , ~ , 123~63S

Step (II) ~ R
+ R -~-CH -CH-COOR ~ ~ COOR 4 (II) (III) / (IV) Step ~I) Step (III ~Step (IV) ~

\ ~ R ~ ~ R

N ~ OH , Step (V) ~ S ~
H COOH

(I-a) (V) Step (VI) R

~ ~R
: : H
~::
(I-b) wherein R1 and Ring A are the same as defined above, R3 is ; lower alkanoyl and R4 is lower alkyl.
Step (I) in the above-mentioned reaction scheme can be accomplished by heating a~mixture of the compound (II) and III) at 150 to 165C either in a solvent (e.g., xylene, di~
phenyl ether, p-cymene)~ or without solvent. It is preferred : . ~ ^~, :

, .~ , ~Z3~3S

to carry it out in an inert gas (e.g., argon). When the compound (I-a) is obtained as a rnixture of two stereoisomers (i.e., cis and trans isomers), they may be separated from each other by their difference in solubility in a solvent ~ such as lower alkanol (e.g., ethanol) or by column chromato-graphy.
The reaction of the compound (II) with the compound (III), i.e., Step (II), can be accomplished by heating a mixture of the compounds (II) and ~III) in a solvent (e.g.
toluene, acetonitrile, ben~ene, dioxane) or without solvent.
It is preferred to carry out the reaction at 25 to 110C.
When the trans isomer of the compound (III~ is used as the starting compound, the threo lsomer of the compound(IV) is obtained.
The subsequent optional hydrolysls of the compound (IV), i.e., Step (IV), can be conducted by treating it with an alkali metal hydroxide ~e.g., potassium hydroxide, sodium hydroxide) or an alkali metal carbonate ~e.g., potassium ~ carbonate, sodium carbonate~) at O to 100C in a solvent (e.g., `~ ~ 20 aqueous methanol, aqueous~ ethanol).
If required, the compound ~V) thus-obtained may be resolved into each optical isomers~ by using a resolving agent such as p-hydroxyphenylglycine esters. For~example, the optical resolution of;(+)-threo-2-hydroxy-3-(2-amin methylphenylthio)-3-(4-methoxyp~enyl)~propionic acid or , (+)-threo-2-hydroxy-3-~(2-amino-4,5-dimethylphenylthio)-3-:~ :
~: :
:

:. , : :

~.
: : .,. . : ,: ,. ..

3l~231~;3S

(4-methoxyphenyl)propionic acid can be accomplished by the steps of reacting said compound with an optically active p-hydroxyphenylglycine methyl ester to form the diastereo-isomeric salts thereof, and separating the diastereoisomeric salts from each other by selective crystallization. Selective crystallization is carried out by recrystallizing the diastereo-isomeric salts from a solvent (e.g., methanol, ethanol).
After the optical resolution, the optically active compound (VJ in free form can be recovered by treating the thus-1~ obtained diastereoisomeric salt with an acid (e.g., hydro-chloric acidJ or an ion-exchange resin.
The intramolecular cyclization of the thus-obtained racemic or optically active compound (IV~ or (V), i.e., Step (III) or (V), can be carried out by heating at 110 to l_ 160C either in a solvent (e.g., xylene) or wlthout solvent.
The intramolecular cyclization of the compound (IV) may also be carried out at 0 to 50C in the presence of ~ethyl-sulfinylcarbanion (CH3SOCH2~) (prepared from dimethylsulfoxide and sodium hydride) in dimethylsulfoxide. Alternatively, the intramolecular cyclization of the compound (V) may be carried out at -10 to 70C in a solvent (e.g., dimethyl-formamide, dichloromethane, tetrahydrofuran or a mixture thereof) in the presence of a condensing agent such as dicyclohexylcarbodiimide or a mixture of dicyclohexylcarbo- !
I
diimide and N-hydroxybenzotriazole.

~ ~ '''' : , :
;

:' ~ `
':

1~3~;35 If required, the racemic modification of the compound (I-a) thus-obtained may be resolved into each optical enantiomers thereof by using (S)-1-(2-naphthylsulfonyl)-pyrrolidine-2-carbonyl chloride as a resolving agent, i.e., by the steps of reacting the compound (I-a) with said pyrrolidinecarbonyl chloride to give a pair of dia-stereoisomers, and then separating said diastereoisomers Erom each other by selective crystallizatin or by column chromatography. Hydrolysis of each diastereoisomers gives the optically active compound (I-a).
The subsequent optional acylation of the compound (I-a), i.e. Step (VI~, can be accomplished by reacting said compound with a compound of the formula: R3-oH
(R3 is the same as defined above) (VI) or a reactive derivative thereof.
The condensation of the compound (I-a) or a salt thereof with a reactive derivative of the compound (VI) can be conducted in a solvent in the presence or absence of an acid acceptor. The reactive derivative of the compound (VI) include, for example, lower alkanoic acid anhydride (e.g., acetic anhydride, propionic anhydride) and lower alkanoyl halide (e.g., acetyl chloride, pro-pionyl chloride, butyryl chloride). The acid acceptor includes, for example, pyridine, triethylamine, N-methyl-piperidine, N-methylmorpholine, N-methylpyrrolidine and N-ethyl-N,N-diisopropylamine. Acetic acid, chloroform, :

.

~. ' ' , ~3~$~3S

dichloromethane, dimethylformamide and tetrahydrofuran are suitable as the solvent. When an excess amount of acetic anhydride is used as the reactive derivative of the com-pound (VI), it is not always necessary to use the solvent because said acetic anhydride serves as the solvent. It is preferred to carry out the reaction at a temperature of -10 to 140C, especially at a temperature of 20 to 140C
if the lower alkanoic acid anhydride is used as the reac-tive derivative of the compound (VI); or at a temperature of -10 to 100C if the lower alkanoyl halide is used as the reactive derivative of the compound (VI).
On the other hand, when the compound (VI) is used in the form of free acid, the condensation thereof with the compound (I-a) or a salt thereof may be carried out in a solvent in the presence of a condensing agent. The con-densing agent includes, for example, dicyclohexylcarbodi-imide, N,W'-carbonyldiimidazole, l-methyl-2-halopyridinium iodide (e.g., l-methyl-2-bromopyridinium iodide), methoxy-acetylene and (C6H5)3P-CC14. Methylene chloride, 1,2-dichloroethane, chloroform, benzene, toluene, tetra-~; hydrofuran and dioxane are suitable as the solvent. It is preferred to carry out the reaction at a temperature of 0 to 50C, especially at 0 to 25C.~

Alternatively, the compound (I) may be prepared by reacting a compound of the ~ormula:

~: : :

- : ':
- ,. , ~2;38~;35 SH

2 (VII) wherein Ring A is the same as def:ined above, with the compound (III), reducing the resu:Ltant compound of the formula:

~ ~ OH (VIII) c ooR4 wherein Rl, R4 and Ring A are the same as defined above, to give the compound (rv3~ and th~n treating said compound in the same manner as described in Step (III) to (VI) of the above-mentioned reaction scheme.
The reaction of the compound~(VII) with the compound (III) can be accompllshed by heating a mixture of said ~: compounds at 20 to 80C in a solvent (eOg., acetonitrile, toluene, benzene).; The reduction of the compound (VIII) can be accomplished~by reacting:it with a~reducing agent (e.g., stannous chloride ln hydrochlorio~acid) at 0 to 50C in a solvent (e.g. aoetic acid).~ The reduction of the compound tVI:II) may be~also accomplished by catalyt;ic hydrogenation.

The compound (IV), (V) or (VIII) of the presen~t ~ :
invention:involves four optical isomers due to the two : ::
:: : : : ~ :: : :

.

,. ;-, : ::
~ : : `.: ., , ~L23863S

asymmetric carbon atoms at 2- and 3-positions o the propionic acid compound (IV), (V) or (VIII). However, since the above-mentioned reactions according to the invention can be carried out without racemization, the compound (I) of the present invention in an opticall~
active form can be readily obtained from the corres-ponding optically active isomer of the compound (IV), (V) or (VIII).

The compound (I) of the present invention is useful as an inter~ediate in the synthesis of novel 5-alkyl-1,5-benzothiazepine derivative of the following for~ula:

/~Rl i ~ RS (IX) 2 2 ~ R6 wherein each one of R and~R is lower alkyl and R1, R2 and Ring A are the sa~e as defined above.
The compound (IX) may be prepared from the compound (I) of the present invention, for example, by condensing the compound (I) or a salt thereof with amino alkyl compound of the for~ula: :
:
: j R 5 X-CH2C-'12N ~ (X~

.

:, ~, .

; .

38~i35 ~herein X is halogen atom, and R and R are the same as defined a~ove, or a salt thereof (e.g., hydrochloride or hydrobro~ide)in the presence or absence of an alkali agent such as alkali metal hydroxide (e.g., potassium hydroxide or sodium hydroxide), alkali metal carbonate (e.g., potassium carbonate or sodium carbonate) and alkali metal hydride (e.g., sodium hydride) in a solvent (e.g., acetone, ethyl acetate, dimethylsulfoxide, dimethylformamide, acetonitrile, tetrahydrofuran and dioxane) and, ~rhen R2 is hydrogen, if lo required, condensing the resulting product with the compound (VI) or a reactive derivative thereof in the same manner as the condensation of the compound (I-a) with the compound (VI) or a reactive derivati~e thereof.
As mentioned hereinbefore, the thus-obtained compound (IX) has a potent hypotensive activity, a potent cerebral or coronary vasodilating activity and a potent platelet aggregation-inhibiting activity. Therefore, the compoun~
(IX) is useful for the treatment, amelioration or prophy-laxis of hypertension; cerebral diseases such as cerebral vasospasm or cerebral infarction; and heart diseases such as angina pectoris, arrhythmias or coronary or cardiac infarction.
Practical and presently preferred embodiments of the present invention are lllustratively shown in the following lines. Throughout the specification and claims, the term : :: : : : :

~: ' ~LZ3~i3S

"lower alkyl n~ 1l lower alkoxy", "lower alkanoyl", "lower alkanoic acid anhydride" and "lower alkylthio" should be interpreted as referring to alkyl of one to 4 carbon atoms, alkoxy of one to 4 carbon atoms, alkanoyl of 2 to 4 carbon atoms, alkanoic acid anhydride of 4 to 8 carbon atoms and alkylthio of one to 4 carbon atoms, respectively.
Concomitantly, throughout t:he specification and claims, the term "threo" means that the hydroxy and substituted-phenylthio groups substituted at the 2- and 3-positions of propionic acid have threo-type configuration (i.e., said two groups are placed on opposite side of the central bond in the Fisher's projection formula).

Example l A mixture of 13 g of 2-amino-4-methoxy-thiophenol and 17.6 g of methyl (+)-trans-3-(4-methoxyphenyl)glycidate is heated at 160C for 16 hours under argon atmosphere. After cooling, ethanol is added to the mixture. The precipitated crystals are collected by filtration and recrystallized from chloroform. 4.52 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-2~ 7-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.
M.p. 220 - 222C
The mother liquors (The ethanol and chloroform solutions) are comblned and evaporated to remove solvent. The residue is purified by silica gel chromatography (Solvent: chloroform).

:
` : . , i .' ; ~ ~ :

123!3i3S

2.9 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-7-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5~)-one and 1.1 g of (+)-trans-2-(4-methoxyphenyl)-3-hydroxy-7-methoxy-2,3-dihydro-1,5-benzo-thiazepin-4(5H)-one are further obtained from the eluates.
(+)-Trans-isomer:
M.p. 189 190C (recrysta:Llized from a mixture of ethyl acetate and n-hexane~
Examples 2 to 10 The following compounds are obtained from the corres-ponding starting materials in the same manner as descxibedin Ex,,ample l.

a ~ SH Rl ~ CH-CH-COOCH3 S ~ R
R ~ ~ R ~ ~ OH

(II) (I-a) ~ ~ 1 :

;:: ~ : :
:: :

: ~

:

, `
:

1;~ ;3S

_ _ . .. .
Compound (I-a) Example ~- a Nos. ~ R M.p., etc.
_ . . ~ _ _ . . . _ . _ _ . . _ . . _ Cis-isomer: 204 - 206C
2 OC~3 8-OCH3 (recrystallized from ethyl acetate) Trans-isomer: 150 - 152C
(recrystallized from a mixture of ethyl acetate and n-hexane~
. ~
Cis-isomer: 225 - 227 5C

3* OCH3 6 CH3 trecrystallized from a mixture of dimethylformamide and ethanol) Trans-isomer: 231 - 233C
(recrystallized from a mixture of dimethylformamide and ethanol) __ I
Cis-isomer: 182. 5 - 184. 5C

4 CH3 8-CH3 (recrystallized from a mixture of dimethylformamide and ethanol) . . _ _ . _ _ _ . _ _ . _ .
Cis-isomer-hemi hydrate: 208 - 210C

5 OCH3 6-OCH (recrystallized from a mixture of 3 chloroform and n-hexane) ~Cis-isomer: 202 - 206C

6 CH3 8-OCH3 (recrystallized from ethanol) Trans-isomer: 185 - 188C
(recrystallized from ethanol) _ , ., Cis-isomer: 172 - 174C

7 OCH3 8- Irecrystallized from a mixture of OCH C H~ dimethylformamide and ethanol) -- -- ------ -- -- -- -- . -- -- ~ _ . _ . _ _ _ _ _ : : Cis-isomer: 219 - 221C

8 OCH3 8-CH3 (recrystallized from dimethyl-formamide) Cis-isomer: 218 - 22IC
: 9 OCH3 7-CH3 (recrystallized from dimethyl-: formamide) 10 CH3 ~- Cis-isomer: 164 - 165C
OCH C H (recrystallized from ethanol) _ _ ?~6 5 ~ _ _ _ :

::

'` ' ~ ' ~ ~';' ' ;
:.
:

;
;
:

~23~;35 Note: The compounds listed in the Table are all racemic compounds.
* : Methyl (+)-threo-2-hydroxy-3-(4-methoxyphenyl)-3-(2-amino-3-methylphenylthio)propionate is obtained in addition to the compounds listed above.
M.p. 98 - 110C kecrystallized from ethanol) Example 11 (a) A mixture of 29.1 g of 2-amino-5-methyl-thiophenol, 47.8 g of methyl (+)-trans-3-(4-methoxyphenyl)glycidate and lO300 ml of toluene is heated at 60 - 65C for 3 days and then at 70 - 80C for 2 days. The mixture is evaporated under reduced pressure to remove solvent. Benzene is added to the residue and the mixture is extracted with conc.

hydrochloric acid-water (1:1). The extract is neutralized with potassium carbonate, and the aqueous solution is extracted with benzene. The extract is washed with water, dried and then evaporated to remove benzene. The residue is chromatographed on silica gel (Solvent: benzene-ethyl acetate = 10:1). The crude product thus obtained is recrystallized from a mixture of ethanol and isopropyl ether. 15.8 g of methyl (~) threo-2-.
~; ~hydroxy-3-(2-amino-5-methylphenylthio)-3-(4-methoxypnenyl)-propionate are obtained~
M.p. 110 - 112~C
~;The following compounds are obtained from the ~ 25 corresponding startlng materials in the same manner as~
above.

, ~
~,_ , - : :
: ` ` :
.
: :

.

~Z~3S

SH Rl ~ CH-CH-COOCH3 ~ R
Ra ~ (III) __~ ~a ~ ~ OH

(II) (IV) Compound (IV) Nos.
R1Ra Reaction M.p., etc.
conditions -i OCH34-CH3 60 - 70C, (recrystallized from 4 days ethanol-isopropyl ehter) 60C, 4 days 114 - 114.5C
ii CH35-CH3 + (recrystallized from 100C, 8 days isopropyl ether) 90C, 114 - 116C
iii* OCH5-SCH 20 hours (recrystallized from 3 3 ethanol) : 90C, 130 132C
iv OCH4-SCH 20 hours lrecrystallized ~rom 3 3 ethanol) 70 - 75C, 99.5 - 102.5C:~
V OCH 5-OCH3 5 days ~ (recrystallized from 3 isopropanol) Note: The compounds listed in the Table are all (+)-threo isomers.~
* : (+)-Cis-2-( 4-methoxyphenyl)-3-hydroxy-8-methyl-thio-2;3-dihydro-lt5-benzothiazepin-4(5H)~one is obtained , in addition to the compound Iisted above.
M.p. 183 - 184C (recrystallized from a mixture of dlmethylformamlde and ethano1~ ~

:

: : , :
: ~ ~ .: . ' ~;2313~35 (b) A mixture of S g of methyl (~)-threo-2-hydroxy-3-(2-amino-5-methylphenylthio)-3-(4-methoxyphenyl)propionate, 50 ml of an aqueous 5 ~ sodium hyclroxide solution and 50 ml of methanol is stirred at room temperature for 2 hours.
After the reaction is completed, the mixture is adjusted to pH 3 to 5 with 10 % hydrochloric acid under ice-cooling. The precipitated crystals are collected by filtration, washed with water, dried and then recrystallized from methanol.
4.3 g of (+)-threo-2-hydroxy-3-~2-amino-5-methylphenylthio)-3-(4-methoxyphenyl)propionic acid are obtained.
M.p. 190 - 193C
The following compounds are obtained from the corresponding starting materials in the same manner as above.

~Rl > ~Rl ~NH2 ~ ~ NH2 ~ OH

(IV) (V) . ..
., ~.

:: .~.

~23~3~

Compound (V~
No - 1 ~~~---~- --------- __ R R Solvent M.p., etc.
.. . . . ~

i OCH3 4-CH3 Methanol (recrystallized from methanol) ii CH 5-CH Ethanol 168 - 172C
~ 3 S iii OCH 5-oCH Ethanol 210 - 212C (decomp.) Note`: The compounds listed in the Table are all (+)-threo isomers.

(c) 45.3 g L-lp-hydroxyphenyl)glyclne methyl ester hydrochloride are dissolved in 1000 ml of methanol. A
solution of 11.7 g of potassium hydroxide in 100 ml of methanol is added to the solution under ice-cooling, and the precipitates (potassium chloride) are removed by filtration.
37.8 g of (+~-threo-2-hydroxy-3-(2-amino-5-methylphenyl-thio)-3-(4-methoxyphenyl)propionic acid are added to the filtrate. The mixture~ ~s warmed to about 50~C, and then 900 ml of methanol are added thereto to make a clear solution : I
The clear solution is evaporated under reduced pressure at a temperature of below 50C. 200 ml of ethanol are added to the resldue, and the mixture is allowed to stand ln a refrigerator overnight. ~The precipitated crystals are colleated by filtration~(The mothe~r liquor lS referred as "Mother liquor I".), and then recrystallized from ethanol ~ : !

~: , . . . ,~

, . .
- ` : ` .

(The mother liquor is referred as "Mother liquor II".).
The crude products thus obtained is further recrystallized from ethanol. 20.7 g of (+)-threo-2-hydroxy-3-(2-amino-5-methylphenylthio)-3-(4-methoxyphenyl)propionic acid~L-(p-hydroxyphenyl)glycine methyl este-, salt (M.p. 164 - 167C, ~ 20 +255.8(c=0.655, methanol)) are obtained.
15.3 g of the product thus obtained are suspended in a mixture of 240 ml of methanol and 200 ml of water, and 27 ml of cation exchange resins are added thereto. The mixture is stirred at room temperature overnight. The resins are removed by filtration and washed with methanol. The filtrate and the washing are combined and evaporated under reduced pressure to remove solvent. Water is added to the residue.
The precipitated crystals are collected by filtration and then recrystallized from ethanol. 7 g of (~)-threo-2-hydroxy-3-(2-amino-5-methylphenylthio)-3-(4-methoxyphenyl)-propionic acid are obtained.
M.p. 158 - 160C
~D +296.0(c=0.290, methanol) Mother liquors I and II are combined, and 13 ml of conc. hydrochloric acid are added thereto. The mixture is evaporated under reduced pressure to remove solvent. Water is added to the residue, and the precipitated crystals are collected by iltratin. Then, the crystals (lS.5 g) thus obtained, 20.3 g of D-(p-hydroxyphenyl)glycine methyl ester hydrochloride and 5.2 g o potassium hydroxide are treated ' ' .

~ . . .
:

,. .

~3~ S

in the same manner as above. 12.9 g of (-)-threo-2-hydroxy-3-(2-amino-5-methylphenylthio~-3-(4-methoxyphenyl)propionic acid.D-(p-hydroxyphenyl)glycine methyl ester salt (M.p. 164 -167C (recrystallized from ethanol, (lX)20 -254.8 (c=0.949, methanol)) are obtained.
The product (15.3 g) thus obtained are then converted into its free acid in the same manner as above. 6.5 g of (-)-threo-2-hydroxy-3-(2-amino-5-methylphenylthio)-3-(4-methoxyphenyl)propionic acid are obtained.
~o M.p. 158 - 160C (recrystallized from ethanol) ~t)~)D -265.3 (c=0.331, methanol) The following compounds are obtained from (+)-threo-2-hydroxy-3-(2-amino-4-methylphenylthio)-3-(4-methoxyphenyl)-propionic acid in the same manner as above.
lS (+)-Threo-2-hydroxy-3-(2-amino-4-methylphenylthio)-3-(4-methoxyphenyl)propionic acid:
M.p. 168 - 170C trecrystallized from ethanol) D +360.3 (c=0.342, methanol) (-)-Threo-2-hydroxy-3-12-amino-4-methylphenylthio)-3-(4-methoxyphenyl)propionic acid:
M.p. 173 - 176C (recrystallized from ethanol) ~D -360.5 lc~0.352, methanol) (d) A mixture of 9 g of (+)-threo-2-hydroxy-3-(2-amino-S-methylphenylthio)-3-(4-methoxyphenyl)propionic acid Zs and 350 ml of xylene is refluxed for 24 hours. The resulting water i~ removed during the reaction. After the reaction, ' - ~23~`~35 - 23 _ ( the mixture is evaporated to remove xylene, and the residue is recrystallized from ethyl acetate. 7.8 g of (~)-cis-2-(4-methoxyphenyl)-3-nydroxy-8-methyl-2,3-dihydro-1,5-benzothiazepin-~(5H)-one are obtained.
M~p. 223 - 226C (decomp.) ~CX~0 +123.8 (c=0.707, dimethylformamide) The following compounds are obtained from the corresponding starting materials in the same manner as above.

R ~5 ~ ~ R
COOH H O

(V) (I-a) :

:

: :

:; ~ : : :

. .
: ~ : -, ~ - ~ .-, ;
.'' ' ' '' ~
., : .

;3S

_ Compound tI-a Nos.
Rl Ra optical M.p., etc.
isomer 224 - 226C ~decomp., i OCH8-CH3 - recrystallized from ethyl 3 ace~ate) ~ a3~u _ 123.7 (c=0.414, clim8thylformamide) -213 - 216C (decomp., ii OCH7-CH3 + recrystallized from ethyl 3 ace~te) L~u + 123.0 (c=û,246, dim~thylformamide) 212 - 215C (decomp., iii OCH 7-CH - recrystallized from ethyl 3 3 ace~te) t~l U -123.7 (c=û.358, dim~thylformamide) 182 - 184C (recrystallized iv CH 8-CH + from dimethylformamide-3 3 ~ ethanol) Note: The compounds listed in the Table are all cis isomers.

Example 12 A mixture of l.S g of sodium hydride (63 ~ oil disper-sion) and 25 ml of~dimethylsulfoxide is heated at 7ûC for 50 minutes in argon atmosphere. A solution of-7 g o~ methyl (+)-threo-2-hydroxy-3-~2 amino-5-methylthiophenylthlo)-3-(4-methoxyphenyl)propionate in 12 ml of dimethylsulfoxide is added dropwise to the mixture under cooling. The mlxture ~

is stirred at room temperature for 2û minutes. After the ~ -~: : :

--., . . ~ , : ,, . - ;
.
-` . .. ., ~ .
- .
.. : : ., .. . .

~;23&~63~

!
reaction is completed, the mixture is poured into ice-water.
The precipitated crystals are collected by filtration, washed with water, dried and then recrystallized from a mixture of dimethylformamide and ethanol. 6.7 g of (~)-cis-2-(4-methoxyphenyl)-3 hydroxy-8-methylthio-2,3-dihydro-1,5-benzothiazepin-4(5H) one are obta:ined.
M.p. 183 - 184C
The following compound is obtained from the corres-ponding starting material in the same manner as above.

~N~l~Rl ~N~Rl ~COOCH3 H O

(IV) (I-a) :

Compound (I-a) Nos.
R Ra optical M.p., etc.
isomer 211 - 214C (recrystallized i OCH 7-SCH3 + from dimethylformamide-3 ethanol) Note: The compound listed in the Table is cis isomer.

:
:

- :
,,, ,., ., .

,~

:.

~31~;3S

!
Example 13 A mixture of 0.54 g of (+)-threo-2-hydroxy-3-(2-amino-S-methoxyphenylthio)-3-(4-methoxyphenyl)propionic aid, 0.048 g of N-hydroxybenzotriazole monohydrate and 10 ml of dimethyl-S formamide is cooled to 0 to 3C, and 0.442 g of N,N'-dicyclo-hyxylcarbodiimide is added thereto. The mixture is stirred at the same temperature for 8 hours, and then further stirred at room temperature for 24 hours. After the reaction is completed, the precipitated crystals are collected by filtra-tion and washed with ethyl acetate. The filtrate and the washing are combined and washed with an aqueous S ~ sodium bicarbonate solution and water, successively. The solution is dried and then evaporated to remo~e solvent. The crystals and residue obtained above are combined and recrystallized from acetone. 0.382 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy~8-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained.
M.p. 204 - 206 Example 14 ~20 (a) A mixture of 4 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-methoxy-2,3-dlhydro-1,5-benzothiazepin-4(SH)-one, 13 ml of pyridine and 5 ml of methylene chloride is cooled with ice-water, and 4 g o~ (S)-1-(2-naphthylsulfonyl)pyrrolldine-~; 2-carbonyl chloride (prepared from (S)-1-(2-naphthylsulfonyl)-pyrrolidine-2-carboxylic acid and oxalyl chloride in anhydrous benzene) are added therF~o. The mixture is stirred at room ~, , ~123~3~35 _ 27 -( temperature for 3 hours. After the reaction is completed, water and a mixture of ethyl acetate and chloroform (1:1) are added to the mixture. The organic layer is collected therefrom and washed with 10 ~ hydrochloric acid, water, an aqueous 5 % sodium bicarbonate so:Lution and water, successively.
The solution is dried and then evaporated. The residue is dissolved in benzene, and the precipitated crystals (3.7 g, M.p. 148 - 150C (recrystallized from ethyl acetate), ~]D
-28.5 (c=0.75S,chloroform)) are collected by filtration (The mother liquor is referred as "Mother liquor I".).
A mixture of 3.6 g of the crystals obtained above, 5 ml of chloroform, 50 ml of ethanol and 50 ml of an aqueous 5 ~ sodium hydroxide is stirred at room temperature for 1 hour. After the reaction is completed, the mixture is washed with water, dried and then evaporated. The residue is recrystallized from ethyl acetate. 1.46 g of ~ cis-2-(4-methoxyphenyl)-3-hydroxy-8-methoxy-2,3-dihydro-1,5-benzo-thiazepin-4(5H)-one are obtained.
M.p. 187 - 189C
~D0 -98.7 (c=0~.290, dimethylformamide) (b) Mother liquor I (benzene solution) is evaporated and the residue is chromatographed on silica gel, whereby 3.4 g of the product (oil,~CX~20 -68.5 (c=0.539, chloroform)) are obtained.
; 25 3.3 g of the product obtained above, 5 ml of chloroform, ~ ~ 50 ml of ethanol and 50 ml of an aqueous 5 % sodium hydroxide .
- :
. ~ . .
-: ' " . :
.. ~ :' ;
' ~ '' , ' ~23~i35 ( are treated in the same manner as described in Paragraph (a). 1.3 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-methoxy-2,3-dihydro-i,5-benzothiazepin-4(5H)-one are obtained.
M.p. 187 - 190C (recrystallized from ethyl acetate) ~D +99~0 (c=0.257, dimethylformamide) Examples 15 to-21 The following compounds are obtained from the corresponding starting materials in the same manner as described in Example 1. , Rb SH 3 ~ Cd-Cd-COOCH3 ,S- ~ ~ OCH3 R Nd2 R ~ N
(II) (I-a) -Compound ~I a) Example Nos. Rb, R M.p., etc.
Cis-isomer: 221 - 224C (decomp., 7,8-(CH ) (recrystallized from a mlxture of 3 2 chloroform and dimethylformamide) Trans-isomer: 235 - 237C (decomp, recrystallized from a mixture of ethyl acetate and n-hexane~
Cis-isomer: 240 - 241.5C (decomp., 16 7,8-(CH 0) recrystallized from a mixture of 3 2 dimethylformamide and ethanol) :
' :: :
:

-:
::

~23~;3S
_ 29 -( -Compound (I-a) -Example Nos. Rb, R M.p., etc.
_ Cis-isomer: 235 - 238C trecrysta-17* 6,7-(CH )2 llized from ethyl acetate~
3 Trans-isomer: 270 - 271C
-Cis-iso~ler: 208 - 210C (recrys-18** 6,8-~CH3)2 tallized from ethyl acetate) Trans-isomer: 161 - 163C
*** Cis-isomer: 246 - 249C
19 7,9-~CH3)2 Trans-isomer: 227 - 230C
Cis-isomer: 239 - 243C Idecomp., 7,8-Cl recrystallized from a mixture o~
2 chloroform and ethanol) (turbid melt at 210C) Cis-isomer: 207 - 20gC (recrysta-21 8,9-Cl2 llied from a mixture of chloroform and ethanol) Trans-isomer: 244 - 249C
Note: The compounds listed in the Table are all racemic compounds.
* : Methyl (+)-threo-2-hydroxy-3-(2-amino-3,4-dimethyl-phenylthio)-3-(4-methoxyphenyl~propionate is obtained in addition to the compounds listed abve.
M.p. 109 - 111.5C (recrystallized from isopropanol) ** : Methyl (+)-threo-2-hydroxy-3-(2-amino-3,5-dimethyl-phenylthio)-3-(4-methoxyphenyl)propionate is obained in addition to the cmpounds listed above.
M.p. 109 - 113C (recrystallized from isopropyl ether) *** : Methyl (+)-threo-2-hydroxy-3-(2-amino-4,6-dimethyl-phenylthio)-3-t4~methoxyphenyl)propionate i5 obtained in addition to the compound listed above.
M.p.~130 - 133C
:

:: :
:

31 ;~3863S

( Example 22 (a) A mixture of 49.52 g of 2-amino-4,5-dimethyl-thiophenol, 47.49 g of methyl t+)-trans-3 (4-methoxyphenyl)-glycidate and S00 ml of toluene is heated at 95 - 100C for 23 hours. After cooling, the precipitated crystals (Cyrstals I) are collected by filtration, and the filtrate is evaporated to remove solvent. The residue is digested with diisopropyl ether, and the crystals thus obtained (Crystals II) are collected by filtration. Crystals I and Crystals II are combined and then recrystallized from a mixture of ethyl acetate and n-hexane. 58.95 g of methyl (+)-threo-2-hydroxy-3-(2-amino-4,5-dimethylphenylthio)-3-(4-methoxyphenyllpropionate are obtained.
M.p. 111 - 114C
(b) A mixture of 58.9 g of methyl ~+)-threo-2-hydroxy-3-(2-amino-4,5-dimethylphenylthio)-3-~4-methoxyphenyl)propionate, S90 ml of an aqueous 5 ~ sodium hydroxide solution and 590 ml of ethanol is stirred at room temperature for 2 hours.
After the reaction is completed, the mixture is adjusted to ; 20 pH 3 with 10 % hydrochloric acid. The precipitated crystals are collected by filtration, washed with water and then dried. 54.2 g of (+)-threo-2-hydroxy-3-(2-amino-4,5-dimethyl-phenylthio)-3-(4-methoxyphenyl)propionic acid are obtained.
~ M.p. L63 - 168C
2~5 (c) 31.3 g of L- (p-hydro~yphenyl)glycine methyl ester hydrochloride are dissolved in 750 ml of methanol. A

:: ::

.
:~ : :

~, ~ . .

lZ3B~;35 ( solution of 8.08 g of potassium hydroxide in 375 ml of methanol is added to the solution, and the precipitates (inorganic materials) are removed by filtration. 25 g of (+)-threo-2-hydroxy-3-~2-amino-4,5-dimethylphenylthio)-3-(4-methoxyphenyl)propionic acid are added to the filtrate, and 375 ml of methanol are added thereto to make a clear solution. The clear solution is evaporated under reduced pressure to remove solvent. The residue is recrystallized three times from ethanol (the mother liquor is referred to as "Mother liquor I"), whereby 10.2 g of (~)-threo-2-hydroxy-3-(2-amino-4,5-dimethylphenylthio)-3-(4-methoxyphenyl)propionic acid-L-~p-hydroxyphenyl)glycine methyl ester salt are obtained.
M.p. 173 - 175C (decomp.) ~)20 + 290.8 (C= 0.410, dimethylformamide) lS The product obtained above is dissolved in 10 %
hydrochloric acid, and the solution is adjusted to pH 4 with potassium carbonate. The precipitated crystals are collected by filtration, washed with water and then dried. 4.7 g of (+)-threo-2-hydroxy-3-(2-amino-4,5-dimethylphenylthio)-3-(4-methoxyphenyl)propionic~acid are obtained.
M.p. 167 - 169C (decomp.) 2 ~ 361.2 (C=0.556, N-NaOH) Mother liquor I (ethanol solution) is evaporated under reduced pressure to remove solvent. The residue is dissolved in 10 ~ hydrochloric acld, and the solution lS
adjusted to pH 4 with potassium carbonate. The precipltated :;

3L;~3~3~;35 ( crystals are collected by filtration. Then, a mixture of the crystals tl3.3 g) thus obtained, 16.7 g of D-(p-hydroxy-phenyl)glycine methyl ester hydrochloride and 4.3 g of potassium hydroxide is treated in the same manner as above.
The crude product thus obtained is recrystallized from ethanol, whereby 8.97 g of (-~-threo-2-hydroxy-3-(2-amino-4,5-dimethylphenylthio)-3-(4-methoxyphenyl)propionic acid-D-(p-hydroxyphenyl)glycine methyl ester salt are obtained.
M.p. 170 - 174C (decomp.) ~20 - 222.1 (C=0.664, dimethylformamide) The product obtained above are converted to its free acid in the same manner as above, whereby 2.66 g of (-)-threo-2-hydroxy-3-(2-amino-4,5-dimethylphenylthio)-3-(4-methoxy-phenyl)propionic acid are obtained.
M.p. 154 - 157C (decomp.) ~20 -316.8 (C=0.512, N-NaO~1 (d-1) A mixture of 4.7 g of (+)-threo-2-hydroxy-3-(2-amino-4,5-dimethylphenylthio)-3-(4-methoxyphenyl)propionic acid and 80 ml of xylene is refluxed for 24 hours. The resulting water is removed during the reactlon. After the reaction is completed,~ the mixture is evaporated to remove solvent. 3.95 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-7,3-dimethyl-2,3-~ihydro-1,5-benzothiazepin-4(5H)-one are obtained.
`~ 25 M.p. 232 - 234C (decomp.) 2 + 131 4 (C=0.778, dimethylformamide) :
: ~:
: : :
:: ; :

:, -, , -:. ~
` . : .

':

~;2 3~3~3S

( (d-2) A mixture of 2.6 g of (-)-threo-2-hydroxy-3-12-amino-4,5-dimethylphenylthio)-3-(4-methoxvphenyl)propionic acid and 45 ml of xylenen is treated in the same manner as described in paragraph (d-1~. 1.98 g of l-)-cis-2-(4-methoxy-phenyl)-3-hydroxy-7,8-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)~one are obtained.
M.p. 225 - 227C (decomp.) ~D -127.2 (C=0.66, dimethylformamide) Examples 23 ~o 24 The following compounds are obtained from the corres-ponding starting materials in the same manner as described in Example 1.

R j~ S H C H 3 0~C~-C H-COOc H3 R ~ ~OC H 3 (II) (I-a) :
:
,.

~ ~ .

lZ3863S
_ 34 _ Compound (I-a) Example Nos. R Re M.p., etc.

Cis-isomer: 215 - 218C (recrysta-23 H F llized from a mixture of dimethyl-formamide and ethanol3 Cis-isomer: 218 - 222C (recrysta-24* F H llized from a mixture of dimethyl-formamide and ethanol1 (turbid melt at 208C) Trans-isomer: 231 - 235C (recrysta-llized from a mixture of dimethyl-formamide and ethanol) (turbid melt at 215C) Note: The compounds listed in the Table are all racemic compounds.
* : Methyl (+)-threo-2-hydroxy-3-(2-amino-6-fluorophenyl-thio)-3-~4-methoxyphenyl)propionate is obtained in addition to the compounds listed above.
M.p.~110 - 112C (recrystallized from ethanol) Example 25 A mixture of 0.683 g of sodium hydride (63 ~ oil dispersion) and 12 ml of dimethylsulfoxide is stirred at 70C for 45 minutes~. After cooling, a solution of 3 g of methyl (~)-threo-2-hydroxy-3-(2-amino-6-fluorophenylthio)-3-(4-methoxyphenyl)propionate in 7 ml of dlmethylsulfoxide is added dropwise to the mixture, and said mixture is stirred at room temperature for 5 minutes. After the reaction is ~
completed, the mixture is poured into ice-water. The aqueous mixture is adjusted to a pH of about 7 with acetic acid, and the precipitated crystals are collected by filtration. Said ~ :

:' . ~ ''~ .,, . , : ' :: : : .: '; ' ~ -. .
:

~3~35 ( crystals are washed with water and n-hexane and then dried.
2.39 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-9-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5~)-one are obtained.
The physico-chemical properties of this product are identical with those of the product obtained in Example 24.

Example 26 A solution of 500 mg of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 358 mg of pyridine in 8 ml of dimethylformamide is ice-cooled, and a solution of 130 mg of acetyl chloride in 2 ml of dimethylformamide is dropwise added thereto. The mixture is stirred at room temperature for one hour. After the reaction is completed, the mixture is poured into ice-water.
The aqueous mixture is extracted with chloroform, and the lS extract is washed with 10 % hydrochloric acid and water, successively. Then, the extract is dried and evaporated under reduced pressure to remove solvent. The residue is recrystallized from a mixture of dimethylformamide and ethanol. 465 mg of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-methoxy-2,3-dihydro-1,5-benzothiazepin-4t5H)-one 1/3 hydrate are obtained.
; M.p. 21B -219C
Example 27 226 mg of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-1,8-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(s~)-one are suspended :: ::

~ . :

`~

1;~3~3~;35 ( in 2 ml of pyridine, and 59 mg of acetyl chloride are added thereto under ice-cooling. The mi~ture is stirred at room temperature for 2 hours. After the reaction is completed, ethyl acetate-chloroform (1 : 1) is added to the reaction mixture. The mixture is washed with 10 ~ hydrochlric acid and water, successively. Then, the mixture is dried and evaporated under reduced pressure to remove solvent. 219 mg of (+)-cis-2-(4-methoxyphenyl~-3-acetoxy-7,8-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(SH)-one are obtained.

Mop~ 227 - 229C

' :
~' :

::

.~ .
'`' ' ''''- '~

s Reference example 1 tl) A mixture of O.R28 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-7-methoxy-2,3-dihydro-l,S-benzothiazepin-4(5H)-one, 0.307 g of potassium hydroxide and 15 ml of dimethylsulfoxide S is stirred at room temperature for 2 hours, and then 0.396 g of 2-(dimethylamino)ethyl chloride hydrochloride is added thereto.
The mixture is stirred at room temperature for 16 hours.
After the reaction is completed, the mixture is poured into ice-water, and the aqueous solution is extracted with ethyl acetate. The ethyl acetate solution is extracted with a 10 ~ hydrochloric acid solutiGn. The extract is adjusted to about pH 10 with potassium c~rbonate. The alkaline solution is extracted witn ethyl acetate, and the extract is washed with water, dried and then evaporated to remove solvent.
The residue is recrystallized from a mixture of ethyl acetate and n-hexane. 0.82 g of (-,)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-~2-(dimethylamino)ethyl)-7-methoxy-2,3-dihydro-1,5-benzothiazepin-4(SH)-one is obtained.

M.p. 127 - 129C
Hydrochloride:

M.p. 212 - 214C (recrystallized from a mixture of chloroform, ethanol and ether) :

:: :: :
, :; , , ,,: ~ ' . , -. .
, ~ 2) A mixture of 1 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-~2-tdimethylamino)ethyl)-7-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride, 1.5 ml of acetic anhydride and 1.5 ml of acetic acid is stirred at 110C for 4 hours. After the reaction is completed, the mixture is evaporated under reduced pressure to remove aeetie anhydride and aeetie aeid. Benzeneis added to the residue, and the mixture is evaporated under redueed ~ressure to remove aeetie anhydride and aeetie aeid. The residue thus obtained is recrystallized from a mixture of ethanol and ether. 0.87 g of (+~-eis-2-(4-~ethoxyphenyl)-3-ae2toxy-5-~2-~dimethylamino)-ethyl)-7-methoxy-2,3-dihydro-l,S-benzothiazepin-4(5H)-one hydrochloride 1/2 hydrate is obtained.
M.p. 216 - 218C

Reference examDles 2 - 56 The following compounds are obtained from the corresponding starting compounds in the same manner as described ln Refe~ence exelDple 1-(1) or 1-(2~.

- ~, .: ;: :- :
~, :,~': ' , .

-` ~IL23~3~;3S

R
N ~ ~ OH ~ R ~ ~ OH

H I O
(CH2)2N(C 3t2 (I ) (IX) Reference Compound (IX) Nos. 1 a Optical R R isomer M.p., etc.
2 CH 8-CH + Free base: 142 - 143C
3 3 (recrystallized from ethyl acetate) Hydrochloride: 168 - 169C
(decomp., recrystallized from a mixtuxe of ethanol and ether) : ~ :
3 OCH3 6-OCH3 + Hydrochloride: 199 - 202C
: ~ (decomp. recrystallized ~: : from a mixture of ethanol and ether).

4 CH3 8-OCH3 : - Free base: 127 - 130C, : Hydrochloride-hemi hydrate:
153 - 155C (recrystallized from a mixture of ethanol and ether) ~
-: S OCH 8~ Hydrochloride-mono hydrate:~ :
3 OCH C H : 138 - 140C (recrystallized 2 6 5 from a mixture of ethanol and ether) ~: :
::

,. :

: : :: : :: :

, .. :
. .

~38~3S

-R + Compound (IX) p e Nos. 1 a Optical R R isomer M.p., etc.
6 OCH3 8-CH3 + Free base : 157 - 158C
(recrystallized from ethyl acetate) Hydrochloride: 232 - 234C
(recrystallized from a mixture of ethanol and ether) 7 OCH 7-CH + Free base: 125 - 129C
3 3 ~ (recrystallized from ethyl acetate) Hydrochloride: 235.5 - 236C
~decomp., recrystallized from ethanol~

8 OCH3 8-CH3 + Free base: 120 - 122C
(recrystallized from ethyl ace~te).
~)n fl55-0 (c=0.465, metnanol) '~

-9 OCH3 8-CH3 - Free base: 121 - 123C
recrystallized from ethyl ace2.~te ) ~D -153.1(c=0.40, methanol) ..... _ _ .

10 OCH 7-CH + Free base: 94 - 95C
3 3 (recrystallized from ethyl ace~te) D +159.8(c=0.43, methanol) ll OCH3 7-CH3 - Free base: 94 - 95C
: (recrystallized from ethyl ace~te) D -160.8(c=0.325, methanol) 12 CH3 8- + Free base-hemi hydrate: 118 -2 6 5 120C (recrystallized from a : mi.~ture of ethyl acetate:and isopropyl ether) : ~ :
:: :
. ~:

-- ~.23~363S

.
Reference Compound (IX) Nos. Optical Rl Ra isomer M.p., etc.
.. . _ . . . . .
13 OCH3 8-OCH + Free base: 139 - 141C
- 3 (recrystallized from ethyl ace~te), Yield: 96 %
~D +129.9(c=0.465, methanol) l-~ OCH 8-OCH - Free base: 139 - 141C
3 3 (recrystallized from ethyl ace~te), Yield: 93 %
~D -127.8¦c=0.385, methanol) .
OCH3 8-SCH + Free base: 153 - 154C, 3 Yield: 86 %
Hydrochloride: 247 - 251C
(decomp., recrystallized from ethanol) 16 OCH 7-SC~ , Free base:~167 - 168C, 3 3 ~ Yield: 70 %
Hydrochloride: 239 - 240C
(decomp., recrystallized from ethanol3 ___~
Hydrochloride 3/4 hydrate:
17 OCH3 6-CH + 112 - 115~C (recrystal-3 lized from ethanol and ether) Hydrochloride-mono ethanol:
18 OCH 8-OCH + 130 - 132C (recrystallized from 3 3 ~ a mixture of chloroform, ethanol and ether), Yield: 77 ~ ~

, .. -- : ~ -- -- --- :

Note: The compounds listed in the Table are all CiS--isQmers.

: ~

: : :

~-: ~ :
:

_ ~2 --R ~ Rl 'S ~ OH , R ~ l O

(C~2)2N(C~3)2 (CH2)2N(CH3)2 (IX-b) (IX-a) Reference Compound (IX-a~
Example 1 a Nos. R R M.p., etc.
l9 OCH 8-OCH Hydrochloride-mono ethanol:
3 3 192 - 194C (recrystallized from a mixture of chloroform, ethanol and etherl _ . ~
OCH 6-OCH Oxalate-hemi hydrate: 212 --20-- 3 3 213C (decomp., recrystallized from a mixture of ethanol, chloroform and ether) Ox21ate:
21 CH3 8-OCH3 209 - 211 C (decomp., rec.ystal-lized ~rom chloroform, eth~nol and ether) . _ _ . , . __ 22 OCH 6-CH Hydrochloride: 208 - 210C
3 3 (recrystallized from ethanol) 23 CH 8-CH Hydrochloride: L84 - }86C
3 3 (recrys~allized from a mi~ture of isopropanol and ether) _ OCH 8-CH Hydrochloride-mono ethanol-24 3 ~ 3 183.5 - 185~5C (recrystaliized from ethanoll 25- OCH 7-CH Hydrochloride: 157.5 - 159.5C
~ 3 3 (recrystallized from ethanol) ;~ Note: The comcounds listed in the Table are all (~)-cis isomers.

.:,,: :: : :
:

' .
.- . :
:

~Z3863S

~ OCH3 ~ OCH3 a ~ ~S ~ OH_ ~ R ~ ~ OCOC~3 CH2CH2N(CH3)2 CH2CH2N(CH3)2 (IX-b) (IX-a) -ReferenceCompound (IX-a) Example a Nos. R Optical M.p., etc.
isomer 2 6 5 Hydrochloride-mono isopropanol:
26 171 - 174C (recrystallized from isopropanol) ~ -27 8-CH3 - Hydrobromide: 151 - 154C (decomp., recrystallized from a mixture of eth~ol and ether) t~l D -82.1 (c=0.42, methanol) :
28 7-CH 1 Hydrobromide-1/4 hydrate:
3 157 - 160C (recrystallized from a mixture of ethanol and2~ther) t~] ~87.8 (c=0.303, metRanol) 29 7-CH} - Hydrobromide-lt4 hydrate:
157 - 160C (recrystallized from a mixture of ethanol and2~ther) [~3 -88.7 (c=0.549, metRanol) 8-OCH - Hydrochloride: 164 - 166C
3 (recrystallized from a mixture of ethanol and e~er),~
~ -79.9 (c=0.344, methanB1) :

,-. :
.
:

, .

-` ~IL23~63S
- 4~ -Reference Com~ound (IX-a) Example a Nos. R Optical M.p., etc.

31 8-OCH3 + Hydrochloride: 164 - 166C
(recrystallized from a mixture of ethanol and e~er)~
L~ ~ 79.4 (c=0.389, methan~l) 32 8-SCH ~ Hydrochloride-mono ethanol:
3 179 - 182C (recrystallized from ethanol), Hydrobromide: 151 - 152C
(decomp., recrystallized from 33 3-CH + ethanol and ether) [~j20 + 82.5 (c=0.308, methanol) _ .
34 7-SCH3 ~ Hydrochloride-mono isopropanol:
198 - 200~C (recr~stallized from isopropanol) .. . . _ . . _ Note: The compounds llsted in the Table are all cis isomers.

:~ :

~:
::
~:

:

.
:., :

3~35 _ 45 _ -o b / ~ ~ 3 (CH2)2N(CH3)2 (I) (IX) Reference Compound (IX) Example Nos. Optical R , R isomer M.p., etc.
_ . _ _ . . _ . . . . _ Free ~as~: 117 - 119C (recrys-7,8-(CH3)2 - tallized from a mixture of eth~ acetate and n-he~ane) ~ -lal.1 (c=0.792, methanol) Free basa: 154.5 ~ 156C
36 7,8-(OCH3)2 , (recrystallized from methanol) O~alate monohydrate: 192 -194C (decomp., recrystallized from methanol) .. _ _ _ . . , .. _ , _ . . _ _ _ _ ... . _ . . _ Hydrochloride monoAydrate:
37 6,7-(C'~3)2 + 1}7 - 119C (decomp., recrys-tallized from a mixture of ethanol and ether~

Hydrochloride monohydrate:
38 6,8-(CH )2 + 124 - 148C (decomp., rec~s-3 - tallized from ethanoL) (turbid melt at ll9~C) . _ _ . . . . .
Hydrochloride: 224 - 225C
39 7~9-(C~3)2 ~ tdecomp., recrystallized from a mixture of ethanol and ether) (turbid melt at 145~C) ;

- ::

:
:
: ...
~':

'~

.

;3S
- ~6 -Reference Compound (IX) Examp1e Nos. Optic~1 R , R isomer ,~.p., etc.
Free base: 179 - 181C
Hydrochloride: 248 - 250 C
407,8-(CH3)2 -+ (decomp., recrystallized from ch]oro~orm, ethanol and ether) . . . _ . . _ Free base: 117 - 118C
(recrystallized from ethyl acetate 417,8-(CH3)2 ~ and n-hexane) [~]D + 149.7 (c= 0.6B, methanol) _ .

42 Free base: 178 - 179.5 C (recrystl-7,8-Cl2 ~ liæed from ethyl acetate) Hydrochloride: 232.5 - 234 C
(decomp., recrystallized from methanol) . ... . _ _ Free base: 175.5 - 176.5 C
43 8,9-Cl + (recrystallized from ethyl acetate) 2 - Hydrochloride 3/2 hydrate: 172 -175 C (recrystallized from methanol and ether) [230 - 233 C (decomp.) (turbid melt at 156 C)]

Note: The compoundslisted in the Table are all cis-isomers.

`:

.~ :

, . ~ '' : : .

..

--` lZ3~3635 Rb /~;~OCH3 Rb ~-OCH3 ~5 ~OH ~ ~3~ ~OCOCH3 (CH2)2N(CH3)2 (CH2)2N~CH~)2 (IX-b) (IX-a) Reference Compound (IX-a) Example Nos. Optical R, R isomer M.p., etc.
. . ~
4ds Oxalate hemihydxate;
7,8-(CH3)2 - 189 - 191C (decomp.,recrys-tallized from a mixture of chl~!6ofonn and ethanol) ~0~)D ~99-5 (c=0.79, dimethyl-formamide) Hydrochloride: 241.5 - 243C
7,8-(OCH )2 + (decomp., recrystallized from 3 ethanol) .
Hydrochloride: 189 - 192C
46 7,8-Cl2 + (recrystallized from methanol) ; (turbid melt at 182C) ~ ' Hydrochloride hemihydrate:
47 8,9~Cl + 233 - 235C (decomp., re-2 crystallized from a mixture of methanol and ether), Hydrochloide mono-ethanoI-48 6,8~(CH3)2 + 218 - 221C ~recrystallized - t from a mixture of ethanol and ether) Hydrochloride: 240 - 242C
49 7,9-(CH3)2 (decomp., recrystalli~ed from + a mixture of ethanol and ether), `

:
. , :
: `~``' ~ ~ :

:
,', :.

`-`` l.Z3~3~3S
_ 48 -Reference ExamDle Compound (IX-a) Nos Optical R , R isomer M p., etc.
~ .
Hydrochloride: 209 - 211C(decomp.) (recrystallized from ether, 7,8-(CH3)2 + chloroform and ethanol) Oxalate 1/2 hydrate: 191 192 C
(decomp., recrystallized from 51 7,8-(CH3)2 + chloroform and ethanol) ~d]D + 101.9 (c= 0.736, dimethylformamide) 52 ~,7-(CH ) ~ Hydrochloride 3/2 hydrate: 245C
3 2 - (decomp., turbid melt at 150 -152 C) (recrystallized from ethanol and ether) Note: The compounds listed in the Table are all cis-isomers.

.
: :, ~: :

: ~ , :

: ~ : :

. ~ ., ~ : . ,: .

3~t;35 -- 01 ~ ~ N~`b (I-) (cH2)2N(cH3)2 (IX) . ~
Reference Example Compound (IX) Nos.
d e R , R M.p., etc.
Hydrochloride: 197 - 198C
53 8-F (recrystallized from ether, isopropanol and ethanol) . . _ _ . . . _ _ .
54 9-F Hydrochloride: 202 - 205 C tturbid melt at 198 C., recrystallized from isopropanol ) _ _ _ . . . _ .

Note: The compounds listed in the Table are all (~)-cis isomers.

:::
::

, , , ~, ,, : :

.: ~ . , :
:
: :; .
' . ~23~363S
so ' e R ~OC~3 e 2d /~OCH3 R ~ 5 ~ R ~[ 5 $

(CH2 ) 2N ( CH3 ) 2 (CH2 ) 2N (CH3 ) 2 (IX-b ) ( IX-â ) .
~eference ~ompound ~(IX-a) Nos.
R, Re M . p ., e tc .
Hydrochloride 1/3 hydrate: 137 - 141C
~55 8-F (recrystallized from ethanol and ether) : Hydrochloride: 200 - 204 C (turbid 56 9-F melt at 194 C., recrystallized from isopropanol and ether) Note: The compounds listed in the Table are all (+)-cis isomers.
:: :

, ~:` :

:

:
:

.,, ~:
:~ ~ ~ : .

~3863S
_ 5l Reference Example 57 A mixture of 406 mg of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-methoxy-1,5-benzothiazepin-4(5H)-one, 170 mg of 2-(dimethylamino)ethyl chloride hyclrochloride, 370 mg of potassium carbonate and 30 ml of acetone is refluxed for 20 hours. After the reaction is completed, insoluble materials are removed by filtration and washed with hot acetone. The filtrate and the washings are combined and then evaporated under reduced pressure to remove solvent. The residue is converted to its hydrochloride and recrystallized from a mixture of chloroform, ethanol and ether. 440 mg of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-~2-(dimethylamino)ethyl)-8-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride ethanol are obtained.
M.p. 192 - 194C

Reference Example 58 A mixture of 190 mg of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-7,8-dimethyl-2,3~dihydro-1,5-benzothiazepin-4(5H)-one, 81 mg of 2-(dimethylamino)ethyl chloride hydrochloride, 180 mg 20 of potassium carbonate and 15 ml of acetone is treated in the same manner as described in Example 57. The crude product is converted to its hydrochloride and recrystallized from a mixture of chloroform, ethanol and ether. 177 mg of (+)-cis-2-(4-methoxyphenyl)-3~acetoxy~5-[2-(dimethylamino3ethyl)-7,8-dimethyl-25 2,3~dihydro-1,5-benothiazepin-4(5H)-one hydrochloride are obtained.
M.p. 209 - 211C (decomp.3 .. ~

'

Claims (18)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a 1,5-benzothiazepine derivative of the formula:

(I) wherein R1 is lower alkyl or lower alkoxy, R2 is hydrogen atom or lower alkanoyl and Ring A is a substituted benzene ring of the formula:

or Ra is lower alkyl, lower alkoxy, lower alkylthio or benzyloxy, each one of Rb and Rc is lower alkyl, lower alkoxy or halogen atom, and either one of Rd and Re is fluorine atom and the other one is hydrogen atom, or a salt thereof; which process comprises the step(s) of:

[I] -a) reacting a compound of the formula:

(II) wherein Ring A is the same as defined above, with a compound of the formula:

(III) wherein R4 is lower alkyl and R1 is the same as defined above, to give a compound of the formula:

(I-a) wherein R1 and Ring A are the same as defined above, or -b ) subjecting a compound of the formula:

(IV) (V) wherein R1, R4 and Ring A are the same as defined above, to intramolecular cyclization to give the compound (I-a), [II] optionally condensing the compound (I-a) or a salt thereof with a compound of the formula:
R3-OH (VI) wherein R3 is lower alkanoyl, or a reactive derivative thereof, to give a compound of the formula:

(I-b) wherein R1, R3 and Ring A are the same as defined above, and [III] if required, further converting the resultant compound to a salt thereof.

2. A process according to claim 1 for produc-ing a compound of formula (I) in which R1 is methyl or methoxy, which comprises carrying out step [I] -a) or -b), step [II] or step [III] employing a starting material in which R1 is methyl or methoxy.

3. A process according to claim 1 for produc-ing a compound of formula (I) in which R1 is methyl or methoxy and Ring A is a substituted benzene ring of the formula:

or wherein Ra is methyl or methoxy, and Rb and Rc are methyl, methoxy or chlorine atom, which comprises carrying out step [I] -a) or -b), step [II] or step [III] employing a starting material in which R1 is methyl or methoxy, and Ring A is a substituted benzene ring of the formula:

wherein Ra is methyl or methoxy, and Rb and Rc are methyl, methoxy or chlorine atom.

4. A process according to claim 1 for producing a compound of formula (I) in which R1 is methyl or meth-oxy, R2 is hydrogen atom, and Ring A is a substituted benzene ring of the formula:

wherein Ra is methyl or methoxy, and Rb and Rc are methyl, which comprises carrying out step [I] -a) or -b), or step [III] employing a starting material in which R is methyl or methoxy, and Ring A is a substituted benzene ring of the formula:

wherein Ra is methyl or methoxy, and Rb and Rc are methyl.

5. A process according to claim 1 for producing a cis isomer of the compound of formula (I), which comprises carrying out step [I] -a) or -b), step [II] or step [III]
either employing an isomeric starting material which leads to a cis-isomer as the product, or by isolating the cis-isomer from a product mixture.

6. A process according to claim 1 for producing a (+)-cis isomer of the compound of formula (I), which comprises carrying out step [I] -a) or -b), step [II] or step [III] either employing an optically active starting material which leads to a (+)-cis isomer product or isolating the (+)-isomer from a product mixture.

7. A 1,5-benzothiazepine derivative of the formula:

(I) wherein R1 is lower alkyl or lower alkoxy, R2 is a hydrogen atom or a lower alkanoyl group, and Ring A is a substituted benzene ring of the formula:

Ra is lower alkyl, lower alkoxy, lower alkylthio or benzyloxy, each one of Rb and Rc is lower alkyl, lower alkoxy or halogen atom, and either one of Rd and Re is fluorine atom and the other one is hydrogen atom, or a salt thereof; whenever prepared by a process according to claim 1 or an obvious chemical equivalent.

8. A derivative according to claim 7 wherein R1 is methyl or methoxy; whenever prepared by a process accord-ing to claim 2 or an obvious chemical equivalent.

9. A derivative according to claim 7 wherein R1 is methyl or methoxy and Ring A is a substituted benzene ring of the formula:

or wherein Ra is methyl or methoxy, and Rb and Rc are methyl, methoxy or chlorine atom; whenever prepared by a process according to claim 3 or an obvious chemical equivalent.

10. A derivative according to claim 7 wherein R1 is methyl or methoxy, R2 is a hydrogen atom, Ring A is a substituted benzene ring of the formula:
or wherein Ra is methyl or methoxy, and Rb and Rc are methyl;
whenever prepared by a process according to claim 4 or an obvious chemical equivalent.

11. A cis isomer of the derivative of claim 7; whenever prepared by a process according to claim 5 or an obvious chemical equivalent.

12. A (+)-cis isomer of the derivative of claim 7; when-ever prepared by a process according to claim 6 or an obvious chemical equivalent.

13. A 1,5-benzothiazepine derivative of the formula:

(I) wherein R1 is lower alkyl or lower alkoxy, R2 is a hydrogen atom or a lower alkanoyl group, and Ring A is a substituted benzene ring of the formula:

Ra is lower alkyl, lower alkoxy, lower alkylthio or benzyloxy, each one of Rb and Rc is lower alkyl, lower alkoxy or halogen atom, and either one of Rd and Re is fluorine atom and the other is hydrogen atom, or a salt thereof.

14. A derivative according to claim 13 wherein R1 is methyl or methoxy.

15. A derivative according to claim 13 wherein R1 is methyl or methoxy and Ring A is a substituted benzene ring of the formula:

wherein Ra is methyl or methoxy, and Rb and Rc are methyl, methoxy or chlorine atom.

16. A derivative according to claim 13 wherein R1 is methyl or methoxy, R2 is a hydrogen atom, Ring A is a substituted benzene ring of the formula:

wherein Ra is methyl or methoxy, and R and Rc are methyl.

17. A cis isomer of the derivative of claim 13.

18. A (+)-cis isomer of the derivative of claim 13.