CA1312077C - Process for preparing 1,5-benzothiazepine derivatives - Google Patents
Process for preparing 1,5-benzothiazepine derivativesInfo
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- CA1312077C CA1312077C CA000571434A CA571434A CA1312077C CA 1312077 C CA1312077 C CA 1312077C CA 000571434 A CA000571434 A CA 000571434A CA 571434 A CA571434 A CA 571434A CA 1312077 C CA1312077 C CA 1312077C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
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Abstract
Abstract:
Process for preparing 1,5-benzothiazepine derivatives There is disclosed a process for preparing 1,5-benzothiaze-pine derivatives represented by the formula:
(I) wherein R1 is a lower alkyl group or a lower alkoxy group, R2 is hydrogen or a lower alkanoyl group, one of R3 and R4 is a lower alkyl group or halogen atom, and the other is hydrogen, and each of R5 and R6 is a lower alkyl group, or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting a compound represented by the formula:
(II) wherein R1, R2, R3 and R4 have the same meanings as defined above, with an aminoethanol represented by the formula:
Process for preparing 1,5-benzothiazepine derivatives There is disclosed a process for preparing 1,5-benzothiaze-pine derivatives represented by the formula:
(I) wherein R1 is a lower alkyl group or a lower alkoxy group, R2 is hydrogen or a lower alkanoyl group, one of R3 and R4 is a lower alkyl group or halogen atom, and the other is hydrogen, and each of R5 and R6 is a lower alkyl group, or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting a compound represented by the formula:
(II) wherein R1, R2, R3 and R4 have the same meanings as defined above, with an aminoethanol represented by the formula:
Description
Process for preparinq 1,5-benzothiazepine derivatives SUMMARY OF THE INVENTION
This invention relates to a process for preparing 1,5- :
benzothiazepine derivatives and a pharmaceutically accept- - ~ : able salt thereof which is useful as a pharmaceutical compound and represented by the formula:
R4 ~ Rl ~ ~ -OR2 (I) N
¦ R5 CH2CH2N\ 6 wherein R is a lower alkyl group or a lower alkoxy group, R is hydrogen or a lower alkanoyl group, one -of R3 and R4 is a lower alkyl group or halogen atom, and the other is hydrogen, and each of R5 and R6 is a .
lower alkyl group. .
- ~:
The 1,5-benzothiazepine derivatives (I) and a pharmaceuti- -~
cally acceptable acid addition salt thereof are useful 25 pharmaceutical compounds having an excellent hypotensive~- -~ ~~ , . ~ , ~. r~
- 1312~77 activity, cerebral or coronary vasodilating activity and/or platelet aggregation-inhibiting activity, and among the compound (I), a compound wherein R2 is hydrogen atom is also useful of as an intermediate for synthesis of pharmaceuticals.
DESCRIPTION OF TH~ PREFERRED EMBODIMENTS
Examples of the compound (I) of the present invention may include compounds in which R is a lower alkyl group, or a lower alkoxy group, R2 is hydrogen or a lower alkanoyl ;
group, either one of R3 or R is a lower alkyl group or halogen atom, and the other is hydrogen atom, and each of R5 and R6 is a lower alkyl group.
-In the above-mentioned examples of the 1,5-benzothiazepine derivative (I), the lower alkoxy group, the lower alkyl group and the lower alkanoyl group include an alkoxy group --~
of one to six carbon atoms, an alkyl group of one to six carbon atoms and an alkanoyl group of two to six carbon atoms, respectively. Preferred examples of these group ~ -are an alkyl group of one to four carbon atoms and an alkanoyl group of two to five carbon atoms. ; -~
According to the present invention, the compound (I) or a pharmaceutically acceptable salt thereof can be prepared ; -by reacting a compound represented by the formula~
.:: .. . :. :
H~
wherein Rl, R2, R3 and R4 have the same meanings as ~ : -defined above, ' '.-.' ':
1312~77 with an aminoethanol represented by the formula: -R \
N-CH -CH -OZ (III) R
wherein R5 and R6 have the same meanings as defined above, and Z is hydrogen, a lower alkylsulfonyl group, an arylsulfonyl group or sulfo group, to condensation reaction and, if necessary, convert it to a salt thereof according to a conventional method.
The above condensation reaction, when the starting compound (III) wherein Z is hydrogen is employed, can be practiced - ~
15 suitably in the presence of a dehydrating agent. As the -dehydrating agent, for example, a mixture of triphenylphos-phine and diethylazodicarboxylate, a mixture of triphenyl-phosphine and dimethylazodicarboxylate, a mixture of sulfuryldiimidazole and sodium hydride can be suitably 20 used. This condensation reaction may be preferably prac- -ticed in a suitable solvent (e.g., chloroform, dichloro-ethane, dichloromethane, acetone, diethyl ketone, methyl -ethyl ketone, ethyl acetate, methyl acetate, ethyl propion- -ate, methyl propionate, dimethylformamide, diethylformate, 25 dimethylacetamide, N-formylmorpholine, N-acetylmorpholine, dioxane, tetrahydrofuran, ether, dimethoxyethane, diglyme, -toluene, benzene, xylene, etc.) at 0 C to 150 C.
On the other hand, when the compound (III) wherein Z is a 30 lower alkylsulfonyl group (e.g., methylsulfonyl group, ethylsulfonyl group), an arylsulfonyl group (e.g., benzene-sulfonyl group, tosyl group) or sulfo group, the condensa-tion reaction of said compound and the compound (II) can be practiced preferably in the presence of an alkali y 35 reagent. Examples of the alkali reagent may include alkali metal hydroxides (e.g., potassium hydroxide, etc.), :
, , , ~312~77 alkali metal carbonates (e.g., potassium carbonate, etc.), alkali metal hydrogen carbonates (e.g., potassium hydrogen -carbonate, etc.), alkali metal hydrides (e.g., sodium ~-hydride, etc.). This condensation reaction should prefer-ably be practiced in a suitable solvent (e.g., methyl -ethyl ketone, diethyl ketone, acetone, dimethylsulfoxide, dimethylformamide, ethyl acetate, methyl propionate, ethyl -~ -propionate, tetrahydrofuran, dioxane, ether, dimethoxy-ethane, diglyme, toluene, benzene, xylene, acetonitrile, -10 dimethylacetamide, diethylforma~lide, N-formylmorpholine, ~ -N-acetylmorpholine, etc.) at 0 C to 150 C. ~ ~
The compound (I) thus obtained can be easily converted - - -into a pharmaceutically acceptable acid addition salt, for -~
15 example, by treating with an acid, if necessary. Examples -of such pharmaceutically acceptable acid addition salts ;~
may include inorganic acid addition salts such as hydro-chloride, hydrobromide, hydroiodide, perchlorate, sulfate, phosphate, etc.; and organic acid addition salts such as : -~
20 oxalate, maleate, fumarate, tartrate, methanesulfonate, etc. -~
Since the reaction of the present invention as mentioned :
above can proceed without accompanying any racemization, by using an optically active compound (II) as the starting ~
25 material, the compound (I) can be obtained as an optically i-~ :
active compound. ';
The 1,5-benzothiazapine derivatives (I) or pharmaceuti- ~-cally acceptable acid addition salts thereof of the pre- ;
sent invention have excellent hypotensive activity, cere-bral or coronary vasodilating activity and/or platelet aggregation-inhibiting activity as mentioned above, and -can be used for therapy and prevention of brain diseases -~
such as cerebrovascular contraction, cerebral ischemia, : :
35 cerebral infarction, etc., or cardiac diseases such as ~ - -stenocardia, cardiac infarction, etc. Also, among the - . ' .
- .: .
` 1312~77 compound (I), the compound wherein R2 is hydrogen is also useful as a synthetic intermediate, since this compound can be converted by acylation to a compound (I) wherein R2 is a lower alkanoyl group.
The starting compound (II) to be used in the present invention can be prepared according to the methods as described in U.S. Patents No. 4,567,175, No. 4,590,188 and No. 4,665,068, respectively.
Also, the compound (I) of the present invention and the compound (II) include either two kinds of stereoisomers (that -~
is, cis and trans-isomers) or four kinds of optical isomers (that is, (+)-cis, (-)-cis, (+)-trans and (-)-trans isomers) and mixtures thereof based on asymmetric carbon atoms (two) in the molecule.
Example 1 To 80 ml dichloromethane solution of 3 g of (+)-cis-2-(4- -methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1,5-benzo-thiazepin-4(5H)-one and 2.3 g of triphenylphosphine were added 15 ml dichloromethane solution of 779 mg of 2-(di-methylamino) ethanol over 20 minutes, then 15 ml dichloro-methane solution of 1.52 g of diethylazodicarboxylate at room temperature over 20 minutes. The mixture was stirred for 20 .
1312~77 - 5a -hours at room temperature, followed by condensation under reduced pressure. The residue was dissolved in ethyl acetate ~
and insolubles were removed by filtration. The filtrate was --extracted with a 10 % hydrochloric acid, and the aqueous layer was made alkaline with potassium carbonate and extracted with chloroform. The extract was washed with ~-water, dried and evaporated under reduced pressure. The residue was converted to maleate and re- ~
''':
1312~77 crystallization from ethanol gave 3.55 g of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.maleate.
Yield: 79.2 %.
mp. 158 to 160 C.
Example 2 - -After stirring a mixture of 354 mg of 2-(dimethylamino)-ethanol and 159 mg of a 60 ~ sodium hydride in 14 ml of ~ -dimethylformamide at room temperature for 20 minutes, 787 mg of sulfuryldiimidazole was added at - 40 ~C to the mixture and the mixture was stirred at the same tempera-ture for one hour. Subsequently, 5 ml dimethyl sulfoxide solution of 1.0 g of (+)-cis-2-(4-methoxyphenyl)-3-acet-oxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was added at - 40 C and after gradual warming, the reaction mixture was stirred at room temperature for 20 hours.
20 After completion of the reaction, methanol and chloroform -were added. The mixture was washed with water and dried, followed by removal of the solvent, and the residue was separated by column chromatography. After removal of the -starting lactam by elution with chloroform-ethanol (20 :
1), the oily product subsequently eluted was converted to maleate and recrystallized from ethanol to give 777 mg of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)-ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.-maleate.
mp. 158 to 160 C.
Example 3 To 30 ml acetone solution of 1.86 9 of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1,5-benzo-" ~
, ' -thiazepin-4(5H)-one were added 2.4 g of powdery potassium carbonate and 1.1 g of 2-(dimethylamino)ethyl methane-sulfonate-hydrochloride, and the mixture was refluxed under stirring for 10 hours. After completion of the reaction, inorganic materials were removed by filtration, to the residue were added a 10 % hydrochloric acid and -ethyl acetate, and extracted with a 10 % hydrochloric -~ -acid. The extract was washed with water, dried and then - :-condensed under reduced pressure. The residue was con-verted into hydrochloride and recrystallized from a mix-ture of acetone-ethanol to give 2.10 g of (+)-cis-2-(4- -~
methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8- -chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.hydro-chloride. Yield: 86.5 %. -:
mp. 127 to 131 C (decomposed). --Example 4 :~
. ~, To 50 ml dimethylsulfoxide solution of 3.36 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was added 1.35 g of potassium hydroxide under ice-cooling and, after stirring at room temperature, 244 mg of 2-(dimethylamino)ethyl methanesul-fonate hydrochloride was added, followed by stirring at room temperature for 16 hours. After completion of the -reaction, the mixture was poured into ice-water and the ;
mixture was extracted with a 1 : 1 mixture of chloroform and ethanol. The extract was washed with water, dried and then evaporated under reduced pressure. Recrystallization of 3.48 g of the residue from a mixed solvent of ethyl acetate and hexane gave 3.06 g of (+)-cis-2-(4-methoxy- -phenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. Yield: 75.2 %. --mp. 122 to 124 C.
'' ~, ' .,-..~
: ~' ' 1312~77 Example 5 To 30 ml acetone-0.5 ml water solution of 1.68 9 of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one were added 2.40 9 of potas-sium carbonate and 1.09 9 of 2-(dimethylamino)ethyl methanesulfonate-hydrochloride, followed by refluxing for 20 hours. After completion of the reaction, inorganic - --materials were removed by filtration, to the residue were added a 10 ~ hydrochloric acid and ethyl acetate and the organic layer was extracted with a 10 % hydrochloric acid.
The hydrochloric acid layers were combined and made alka-line with potassium carbonate and then extracted with ethyl acetate. The extract was washed with water, dried, and evaporated under reduced pressure. Recrystallization of the residue from a mixture of ethyl acetate-n-hexane gave 1.40 9 of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiaze- ~
pin-4(5H)-one. Yield: 68.8 ~i. -mp. 123 to 125 C.
Example 6 In Example 3, by use of 2-(dimethylamino)ethyl benzene-sulfonate.hydrochloride in place of 2-(dimethylamino)ethyl methanesulfonate, (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzo-thiazepin-4(5H)-one.hydrochloride was obtained.
This product had the same physical data as the product in Example 3. -~-Example 7 - -In Example 3, by use of 2-(dimethylamino)ethyl toluene-1312~77 ~
g sulfonate.hydrochloride in place of 2-(dimethylamino)ethyl methanesulfonate, (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-l2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzo-thiazepin-4(5H)-one.hydrochloride was obtained.
This product had the same physical data as the product in Example 3.
:. . .
Example 8 ': ':
In Example 3, by use of 2-(dimethylamino)ethyl sulfate in place of 2-(dimethylamino)ethyl methanesulfonate.hydro- ; -chloride, (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(di-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.hydrochloride was obtained.
This product had the same physical data as the product in :
Example 3.
20 Examples 9 to 14 -"'. ' .
By treating the corresponding starting materials in the same manner as in Examples 1 to 5, the following compounds - -were obtained.
(9) (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-12-(dimethyl- ~- -amino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.perchlorate ~hydrate ~ "'' .- ' mp. 190 to 192 C. ~
: .,:' ~, (10) (~)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethyl-amino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5~1)-one.hydrochloride monohydrate -mp. 140 to 143 C.
1312~77 (11) (+)-cis-2-(4-methylphenyl)-3-hydroxy-5-~2-(dimethyl-amino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one mp. 142 to 143 C (recrystalli7ed from ethyl acetate).
(12) (+)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethyl-amino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.hydrochloride mp. 184 to 186 C (recrystallized from a mixed solvent of isopropanol and ether).
This product, when recrystallized from a mixed solvent of acetone and isopropanol exhibits a melting point of 190 to 192 C.
Fumarate of this product:
mp. 196.5 to 198.5 C (recrystallized from isopropanol).
Maleate of this product: ~ -mp. 173.5 to 175.5 oc (recrystallized from ethanol).
'~-:
This product, when recrystallized from methanol exhibits a melting point of 172.5 to 174 oc and, when recrystallized from water, gives crystals exhibiting a melting point of -191.9 C, thus having the properties of crystals polymor-phism.
., Methanesulfonate of this product:
mp. 124 to 128 C (recrystalllzed from isopropanol).
(13) (+)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethyl-amino)ethyl~-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.maleate . .
1312~77 mp. 194 to 197 C (decomposed) (recrystallized from ethanol).
¦~]20 + 83.7 (c=0.362, methanol).
Oxalate of this product:
mp. 179 to 180 C (recrystallized from ethanol).
[~]20 + 88.2O (c=0.288, methanol).
(14) (-)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethyl-amino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.oxalate mp. 179.5 to 181 C (decomposed) (recrystallized from ethanol).
[~]D ~ 83.8 (c=0.333, methanol).
Maleate of this product: -mp. 195 to 197.5 C (decomposed) (recrystallized from ethanol).
[~]20 _ 83.6 (c=0.50, methanol). - :
Fumarate of this product:
mp. 210.5 to 212.5 C (decomposed) (recrystallized from ethanol).
[~20 _ 91.3 (c=0.323, methanol).
L-(+)-tartrate of this product:
mp. 140 to 143 C (recrystallized from a mixed solvent of ethanol and ether).
. .,, . , " ~ , " . , ~. , , - . .
This invention relates to a process for preparing 1,5- :
benzothiazepine derivatives and a pharmaceutically accept- - ~ : able salt thereof which is useful as a pharmaceutical compound and represented by the formula:
R4 ~ Rl ~ ~ -OR2 (I) N
¦ R5 CH2CH2N\ 6 wherein R is a lower alkyl group or a lower alkoxy group, R is hydrogen or a lower alkanoyl group, one -of R3 and R4 is a lower alkyl group or halogen atom, and the other is hydrogen, and each of R5 and R6 is a .
lower alkyl group. .
- ~:
The 1,5-benzothiazepine derivatives (I) and a pharmaceuti- -~
cally acceptable acid addition salt thereof are useful 25 pharmaceutical compounds having an excellent hypotensive~- -~ ~~ , . ~ , ~. r~
- 1312~77 activity, cerebral or coronary vasodilating activity and/or platelet aggregation-inhibiting activity, and among the compound (I), a compound wherein R2 is hydrogen atom is also useful of as an intermediate for synthesis of pharmaceuticals.
DESCRIPTION OF TH~ PREFERRED EMBODIMENTS
Examples of the compound (I) of the present invention may include compounds in which R is a lower alkyl group, or a lower alkoxy group, R2 is hydrogen or a lower alkanoyl ;
group, either one of R3 or R is a lower alkyl group or halogen atom, and the other is hydrogen atom, and each of R5 and R6 is a lower alkyl group.
-In the above-mentioned examples of the 1,5-benzothiazepine derivative (I), the lower alkoxy group, the lower alkyl group and the lower alkanoyl group include an alkoxy group --~
of one to six carbon atoms, an alkyl group of one to six carbon atoms and an alkanoyl group of two to six carbon atoms, respectively. Preferred examples of these group ~ -are an alkyl group of one to four carbon atoms and an alkanoyl group of two to five carbon atoms. ; -~
According to the present invention, the compound (I) or a pharmaceutically acceptable salt thereof can be prepared ; -by reacting a compound represented by the formula~
.:: .. . :. :
H~
wherein Rl, R2, R3 and R4 have the same meanings as ~ : -defined above, ' '.-.' ':
1312~77 with an aminoethanol represented by the formula: -R \
N-CH -CH -OZ (III) R
wherein R5 and R6 have the same meanings as defined above, and Z is hydrogen, a lower alkylsulfonyl group, an arylsulfonyl group or sulfo group, to condensation reaction and, if necessary, convert it to a salt thereof according to a conventional method.
The above condensation reaction, when the starting compound (III) wherein Z is hydrogen is employed, can be practiced - ~
15 suitably in the presence of a dehydrating agent. As the -dehydrating agent, for example, a mixture of triphenylphos-phine and diethylazodicarboxylate, a mixture of triphenyl-phosphine and dimethylazodicarboxylate, a mixture of sulfuryldiimidazole and sodium hydride can be suitably 20 used. This condensation reaction may be preferably prac- -ticed in a suitable solvent (e.g., chloroform, dichloro-ethane, dichloromethane, acetone, diethyl ketone, methyl -ethyl ketone, ethyl acetate, methyl acetate, ethyl propion- -ate, methyl propionate, dimethylformamide, diethylformate, 25 dimethylacetamide, N-formylmorpholine, N-acetylmorpholine, dioxane, tetrahydrofuran, ether, dimethoxyethane, diglyme, -toluene, benzene, xylene, etc.) at 0 C to 150 C.
On the other hand, when the compound (III) wherein Z is a 30 lower alkylsulfonyl group (e.g., methylsulfonyl group, ethylsulfonyl group), an arylsulfonyl group (e.g., benzene-sulfonyl group, tosyl group) or sulfo group, the condensa-tion reaction of said compound and the compound (II) can be practiced preferably in the presence of an alkali y 35 reagent. Examples of the alkali reagent may include alkali metal hydroxides (e.g., potassium hydroxide, etc.), :
, , , ~312~77 alkali metal carbonates (e.g., potassium carbonate, etc.), alkali metal hydrogen carbonates (e.g., potassium hydrogen -carbonate, etc.), alkali metal hydrides (e.g., sodium ~-hydride, etc.). This condensation reaction should prefer-ably be practiced in a suitable solvent (e.g., methyl -ethyl ketone, diethyl ketone, acetone, dimethylsulfoxide, dimethylformamide, ethyl acetate, methyl propionate, ethyl -~ -propionate, tetrahydrofuran, dioxane, ether, dimethoxy-ethane, diglyme, toluene, benzene, xylene, acetonitrile, -10 dimethylacetamide, diethylforma~lide, N-formylmorpholine, ~ -N-acetylmorpholine, etc.) at 0 C to 150 C. ~ ~
The compound (I) thus obtained can be easily converted - - -into a pharmaceutically acceptable acid addition salt, for -~
15 example, by treating with an acid, if necessary. Examples -of such pharmaceutically acceptable acid addition salts ;~
may include inorganic acid addition salts such as hydro-chloride, hydrobromide, hydroiodide, perchlorate, sulfate, phosphate, etc.; and organic acid addition salts such as : -~
20 oxalate, maleate, fumarate, tartrate, methanesulfonate, etc. -~
Since the reaction of the present invention as mentioned :
above can proceed without accompanying any racemization, by using an optically active compound (II) as the starting ~
25 material, the compound (I) can be obtained as an optically i-~ :
active compound. ';
The 1,5-benzothiazapine derivatives (I) or pharmaceuti- ~-cally acceptable acid addition salts thereof of the pre- ;
sent invention have excellent hypotensive activity, cere-bral or coronary vasodilating activity and/or platelet aggregation-inhibiting activity as mentioned above, and -can be used for therapy and prevention of brain diseases -~
such as cerebrovascular contraction, cerebral ischemia, : :
35 cerebral infarction, etc., or cardiac diseases such as ~ - -stenocardia, cardiac infarction, etc. Also, among the - . ' .
- .: .
` 1312~77 compound (I), the compound wherein R2 is hydrogen is also useful as a synthetic intermediate, since this compound can be converted by acylation to a compound (I) wherein R2 is a lower alkanoyl group.
The starting compound (II) to be used in the present invention can be prepared according to the methods as described in U.S. Patents No. 4,567,175, No. 4,590,188 and No. 4,665,068, respectively.
Also, the compound (I) of the present invention and the compound (II) include either two kinds of stereoisomers (that -~
is, cis and trans-isomers) or four kinds of optical isomers (that is, (+)-cis, (-)-cis, (+)-trans and (-)-trans isomers) and mixtures thereof based on asymmetric carbon atoms (two) in the molecule.
Example 1 To 80 ml dichloromethane solution of 3 g of (+)-cis-2-(4- -methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1,5-benzo-thiazepin-4(5H)-one and 2.3 g of triphenylphosphine were added 15 ml dichloromethane solution of 779 mg of 2-(di-methylamino) ethanol over 20 minutes, then 15 ml dichloro-methane solution of 1.52 g of diethylazodicarboxylate at room temperature over 20 minutes. The mixture was stirred for 20 .
1312~77 - 5a -hours at room temperature, followed by condensation under reduced pressure. The residue was dissolved in ethyl acetate ~
and insolubles were removed by filtration. The filtrate was --extracted with a 10 % hydrochloric acid, and the aqueous layer was made alkaline with potassium carbonate and extracted with chloroform. The extract was washed with ~-water, dried and evaporated under reduced pressure. The residue was converted to maleate and re- ~
''':
1312~77 crystallization from ethanol gave 3.55 g of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.maleate.
Yield: 79.2 %.
mp. 158 to 160 C.
Example 2 - -After stirring a mixture of 354 mg of 2-(dimethylamino)-ethanol and 159 mg of a 60 ~ sodium hydride in 14 ml of ~ -dimethylformamide at room temperature for 20 minutes, 787 mg of sulfuryldiimidazole was added at - 40 ~C to the mixture and the mixture was stirred at the same tempera-ture for one hour. Subsequently, 5 ml dimethyl sulfoxide solution of 1.0 g of (+)-cis-2-(4-methoxyphenyl)-3-acet-oxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was added at - 40 C and after gradual warming, the reaction mixture was stirred at room temperature for 20 hours.
20 After completion of the reaction, methanol and chloroform -were added. The mixture was washed with water and dried, followed by removal of the solvent, and the residue was separated by column chromatography. After removal of the -starting lactam by elution with chloroform-ethanol (20 :
1), the oily product subsequently eluted was converted to maleate and recrystallized from ethanol to give 777 mg of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)-ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.-maleate.
mp. 158 to 160 C.
Example 3 To 30 ml acetone solution of 1.86 9 of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1,5-benzo-" ~
, ' -thiazepin-4(5H)-one were added 2.4 g of powdery potassium carbonate and 1.1 g of 2-(dimethylamino)ethyl methane-sulfonate-hydrochloride, and the mixture was refluxed under stirring for 10 hours. After completion of the reaction, inorganic materials were removed by filtration, to the residue were added a 10 % hydrochloric acid and -ethyl acetate, and extracted with a 10 % hydrochloric -~ -acid. The extract was washed with water, dried and then - :-condensed under reduced pressure. The residue was con-verted into hydrochloride and recrystallized from a mix-ture of acetone-ethanol to give 2.10 g of (+)-cis-2-(4- -~
methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8- -chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.hydro-chloride. Yield: 86.5 %. -:
mp. 127 to 131 C (decomposed). --Example 4 :~
. ~, To 50 ml dimethylsulfoxide solution of 3.36 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was added 1.35 g of potassium hydroxide under ice-cooling and, after stirring at room temperature, 244 mg of 2-(dimethylamino)ethyl methanesul-fonate hydrochloride was added, followed by stirring at room temperature for 16 hours. After completion of the -reaction, the mixture was poured into ice-water and the ;
mixture was extracted with a 1 : 1 mixture of chloroform and ethanol. The extract was washed with water, dried and then evaporated under reduced pressure. Recrystallization of 3.48 g of the residue from a mixed solvent of ethyl acetate and hexane gave 3.06 g of (+)-cis-2-(4-methoxy- -phenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. Yield: 75.2 %. --mp. 122 to 124 C.
'' ~, ' .,-..~
: ~' ' 1312~77 Example 5 To 30 ml acetone-0.5 ml water solution of 1.68 9 of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one were added 2.40 9 of potas-sium carbonate and 1.09 9 of 2-(dimethylamino)ethyl methanesulfonate-hydrochloride, followed by refluxing for 20 hours. After completion of the reaction, inorganic - --materials were removed by filtration, to the residue were added a 10 ~ hydrochloric acid and ethyl acetate and the organic layer was extracted with a 10 % hydrochloric acid.
The hydrochloric acid layers were combined and made alka-line with potassium carbonate and then extracted with ethyl acetate. The extract was washed with water, dried, and evaporated under reduced pressure. Recrystallization of the residue from a mixture of ethyl acetate-n-hexane gave 1.40 9 of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiaze- ~
pin-4(5H)-one. Yield: 68.8 ~i. -mp. 123 to 125 C.
Example 6 In Example 3, by use of 2-(dimethylamino)ethyl benzene-sulfonate.hydrochloride in place of 2-(dimethylamino)ethyl methanesulfonate, (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzo-thiazepin-4(5H)-one.hydrochloride was obtained.
This product had the same physical data as the product in Example 3. -~-Example 7 - -In Example 3, by use of 2-(dimethylamino)ethyl toluene-1312~77 ~
g sulfonate.hydrochloride in place of 2-(dimethylamino)ethyl methanesulfonate, (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-l2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzo-thiazepin-4(5H)-one.hydrochloride was obtained.
This product had the same physical data as the product in Example 3.
:. . .
Example 8 ': ':
In Example 3, by use of 2-(dimethylamino)ethyl sulfate in place of 2-(dimethylamino)ethyl methanesulfonate.hydro- ; -chloride, (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(di-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.hydrochloride was obtained.
This product had the same physical data as the product in :
Example 3.
20 Examples 9 to 14 -"'. ' .
By treating the corresponding starting materials in the same manner as in Examples 1 to 5, the following compounds - -were obtained.
(9) (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-12-(dimethyl- ~- -amino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.perchlorate ~hydrate ~ "'' .- ' mp. 190 to 192 C. ~
: .,:' ~, (10) (~)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethyl-amino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5~1)-one.hydrochloride monohydrate -mp. 140 to 143 C.
1312~77 (11) (+)-cis-2-(4-methylphenyl)-3-hydroxy-5-~2-(dimethyl-amino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one mp. 142 to 143 C (recrystalli7ed from ethyl acetate).
(12) (+)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethyl-amino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.hydrochloride mp. 184 to 186 C (recrystallized from a mixed solvent of isopropanol and ether).
This product, when recrystallized from a mixed solvent of acetone and isopropanol exhibits a melting point of 190 to 192 C.
Fumarate of this product:
mp. 196.5 to 198.5 C (recrystallized from isopropanol).
Maleate of this product: ~ -mp. 173.5 to 175.5 oc (recrystallized from ethanol).
'~-:
This product, when recrystallized from methanol exhibits a melting point of 172.5 to 174 oc and, when recrystallized from water, gives crystals exhibiting a melting point of -191.9 C, thus having the properties of crystals polymor-phism.
., Methanesulfonate of this product:
mp. 124 to 128 C (recrystalllzed from isopropanol).
(13) (+)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethyl-amino)ethyl~-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.maleate . .
1312~77 mp. 194 to 197 C (decomposed) (recrystallized from ethanol).
¦~]20 + 83.7 (c=0.362, methanol).
Oxalate of this product:
mp. 179 to 180 C (recrystallized from ethanol).
[~]20 + 88.2O (c=0.288, methanol).
(14) (-)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethyl-amino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.oxalate mp. 179.5 to 181 C (decomposed) (recrystallized from ethanol).
[~]D ~ 83.8 (c=0.333, methanol).
Maleate of this product: -mp. 195 to 197.5 C (decomposed) (recrystallized from ethanol).
[~]20 _ 83.6 (c=0.50, methanol). - :
Fumarate of this product:
mp. 210.5 to 212.5 C (decomposed) (recrystallized from ethanol).
[~20 _ 91.3 (c=0.323, methanol).
L-(+)-tartrate of this product:
mp. 140 to 143 C (recrystallized from a mixed solvent of ethanol and ether).
. .,, . , " ~ , " . , ~. , , - . .
Claims (7)
1. A process for preparing 1,5-benzothiazepine derivatives represented by the formula:
(I) wherein R1 is a lower alkyl group or a lower alkoxy group, R2 is hydrogen or a lower alkanoyl group, one of R3 and R4 is a lower alkyl group or halogen atom, and the other is hydrogen, and each of R5 and R6 is a lower alkyl group, or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting a compound represented by the formula:
(II) wherein R1, R2, R3 and R4 have the same meanings as defined above, with an aminoethanol represented by the formula:
(III) wherein R5 and R6 have the same meanings as defined above, and Z is hydrogen, a lower alkylsulfonyl group, an arylsulfonyl group or sulfo group, to condensation reaction and, if necessary, convert it to a pharmaceutacally acceptable acid addition salt thereof.
(I) wherein R1 is a lower alkyl group or a lower alkoxy group, R2 is hydrogen or a lower alkanoyl group, one of R3 and R4 is a lower alkyl group or halogen atom, and the other is hydrogen, and each of R5 and R6 is a lower alkyl group, or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting a compound represented by the formula:
(II) wherein R1, R2, R3 and R4 have the same meanings as defined above, with an aminoethanol represented by the formula:
(III) wherein R5 and R6 have the same meanings as defined above, and Z is hydrogen, a lower alkylsulfonyl group, an arylsulfonyl group or sulfo group, to condensation reaction and, if necessary, convert it to a pharmaceutacally acceptable acid addition salt thereof.
2. A process for preparing 1,5-benzothiazepine deriva-tives according to Claim 1, wherein the condensation reaction is carried out in a solvent at 0 °C to 150 °C.
3. A process for preparing 1,5-benzothiazepine deriva-tives according to Claim 2, wherein the condensation reaction is carried out in the presence of a dehydrating agent when Z in the compound of the formula (III) is hydrogen.
4. A process for preparing 1,5-benzothiazepine deriva-tives according to Claim 3, wherein the dehydrating agent is a mixture of triphenylphosphine and diethylazodicarbo-xylate, a mixture of triphenylphosphine and dimethylazo-dicarboxylate, or a mixture of sulfuryldiimidazole and sodium hydride.
5. A process for preparing 1,5-benzothiazepine deriva-tives according to Claim 2, wherein the condensation reaction is carried out in the presence of an alkali reagent when Z in the compound of the formula (III) is a lower alkylsulfonyl group, an arylsulfonyl group or a sulfo group.
6. A process for preparing 1,5-benzothiazepine deriva-tives according to Claim 5, wherein the alkali reagent is an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogen carbonate or an alkali metal hydr-ide.
7. A process for preparing 1,5-benzothiazepine deriva-tives according to Claim 1, wherein the compound obtained is treated with an acid to convert it to a pharmaceuti-cally acceptable acid addition salt.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62208482A JPS6450872A (en) | 1987-08-21 | 1987-08-21 | Production of 1,5-benzothiazepine derivative |
| JP208482/1987 | 1987-08-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1312077C true CA1312077C (en) | 1992-12-29 |
Family
ID=16556895
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000571434A Expired - Fee Related CA1312077C (en) | 1987-08-21 | 1988-07-07 | Process for preparing 1,5-benzothiazepine derivatives |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS6450872A (en) |
| KR (1) | KR890003723A (en) |
| CN (1) | CN1031374A (en) |
| AT (1) | AT395424B (en) |
| BG (1) | BG49047A3 (en) |
| CA (1) | CA1312077C (en) |
| ES (1) | ES2007993A6 (en) |
| FI (1) | FI93009C (en) |
| GR (1) | GR1000452B (en) |
| IE (1) | IE61169B1 (en) |
| IL (1) | IL87026A (en) |
| NO (1) | NO170541C (en) |
| PT (1) | PT88300B (en) |
| RU (1) | RU1784041C (en) |
| TW (1) | TW207536B (en) |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1236467A (en) * | 1967-10-28 | 1971-06-23 | Tanabe Seiyaku Co | Benzothiazepine derivatives |
| SE449611B (en) * | 1982-07-09 | 1987-05-11 | Tanabe Seiyaku Co | SET TO MAKE 1,5-BENZOTIAZEPINE DERIVATIVES |
| US4564612A (en) * | 1983-04-22 | 1986-01-14 | Takeda Chemical Industries, Ltd. | Condensed, seven-membered ring compounds and their use |
| US4567175A (en) * | 1983-06-03 | 1986-01-28 | Tanabe Seiyaku Co., Ltd. | 8-Chloro-1,5-benzothiazepine derivatives |
| GB8315364D0 (en) * | 1983-06-03 | 1983-07-06 | Tanabe Seiyaku Co | 8-chloro-1 5-benzothiazepine derivatives |
| GB8406318D0 (en) * | 1984-03-10 | 1984-04-11 | Tanabe Seiyaku Co | 1 5-benzothiazepine derivatives |
| JPS61103877A (en) * | 1984-10-24 | 1986-05-22 | Tanabe Seiyaku Co Ltd | Benzothiazepine derivative and its preparation |
| GB2167063A (en) * | 1984-11-17 | 1986-05-21 | Tanabe Seiyaku Co | 6 or 9-chloro-1, 5-benzothiazepine derivatives |
| JPS61225175A (en) * | 1985-03-28 | 1986-10-06 | Sawai Seiyaku Kk | Production of 1,5-benzothiazepine derivative |
| HU195795B (en) * | 1985-11-06 | 1988-07-28 | Richter Gedeon Vegyeszet | Process for preparing (2s,3s)-3-acetoxy-5-(n,n-dimethyl-amino-ethyl)-2-(h-methoxy-phenyl)-2,3-dihydro-1,5-benzothiazepin-h(5h)-one |
-
1987
- 1987-08-21 JP JP62208482A patent/JPS6450872A/en active Pending
-
1988
- 1988-06-27 IE IE195088A patent/IE61169B1/en not_active IP Right Cessation
- 1988-06-29 FI FI883116A patent/FI93009C/en not_active IP Right Cessation
- 1988-07-07 CA CA000571434A patent/CA1312077C/en not_active Expired - Fee Related
- 1988-07-07 IL IL8702688A patent/IL87026A/en not_active IP Right Cessation
- 1988-07-16 CN CN88104429A patent/CN1031374A/en active Pending
- 1988-08-02 BG BG85117A patent/BG49047A3/en unknown
- 1988-08-04 GR GR880100516A patent/GR1000452B/en unknown
- 1988-08-09 NO NO883526A patent/NO170541C/en unknown
- 1988-08-12 ES ES8802539A patent/ES2007993A6/en not_active Expired
- 1988-08-18 PT PT88300A patent/PT88300B/en not_active IP Right Cessation
- 1988-08-19 RU SU884356329A patent/RU1784041C/en active
- 1988-08-19 AT AT0206388A patent/AT395424B/en not_active IP Right Cessation
- 1988-08-20 KR KR1019880010577A patent/KR890003723A/en not_active Application Discontinuation
-
1990
- 1990-05-07 TW TW079103691A patent/TW207536B/zh active
Also Published As
| Publication number | Publication date |
|---|---|
| BG49047A3 (en) | 1991-07-15 |
| CN1031374A (en) | 1989-03-01 |
| ATA206388A (en) | 1992-05-15 |
| RU1784041C (en) | 1992-12-23 |
| PT88300A (en) | 1989-06-30 |
| TW207536B (en) | 1993-06-11 |
| FI883116A0 (en) | 1988-06-29 |
| FI93009B (en) | 1994-10-31 |
| IE61169B1 (en) | 1994-10-05 |
| IE881950L (en) | 1989-02-21 |
| IL87026A (en) | 1995-01-24 |
| PT88300B (en) | 1995-03-31 |
| NO170541B (en) | 1992-07-20 |
| NO170541C (en) | 1992-10-28 |
| ES2007993A6 (en) | 1989-07-01 |
| NO883526L (en) | 1989-02-22 |
| JPS6450872A (en) | 1989-02-27 |
| IL87026A0 (en) | 1988-12-30 |
| GR880100516A (en) | 1989-05-25 |
| GR1000452B (en) | 1992-07-30 |
| NO883526D0 (en) | 1988-08-09 |
| FI883116A (en) | 1989-02-22 |
| AT395424B (en) | 1992-12-28 |
| FI93009C (en) | 1995-02-10 |
| KR890003723A (en) | 1989-04-17 |
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