IL87026A - Preparation of 1,5-benzothiazepine derivatives by reacting 2-phenyl-3-hydroxy n-unsubstituted benzothiazepinone with n,n-dialkyl amino ethanol derivatives - Google Patents

Description

87026/2 > pi-rT>n-?> .2-2 rmn >"y ) >2ΤΝ>ηη.α-5,1 ?ν> ηη ιη ruon η>αΝ >ρρχ>-τ-Ν,Ν ?ν> ηπ ιη ον οηια-Ν } ι J >orN>nn .α-Ν Preparation of 1 ,5-benzothiazepine derivatives by reacting 2-phenyl-3-hydroxy N-unsubstituted benzothiazepinone with Ν,Ν-dialkyl amino ethanol derivatives TANABE SEIYAKU CO . , LTD C: 75213 Process for preparing 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: wherein R is a lower alkyl group or a lower alkoxy 2 group, R is hydrogen or a lower alkanoyl group, one 3 4 of R and R is a lower alkyl group or halogen atom, and the other is hydrogen, and each of R^ and R^ is a lower alkyl group.

The 1 , 5-benzothiazepine derivatives (I) and a pharmaceutically acceptable acid addition salt thereof are useful pharmaceutical compounds having an excellent hypotensive activity, cerebral or coronary vasodilating activity and/or platelet aggregation-inhibiting activity, and among 2 the compound (I), a compound wherein R is hydrogen atom is also useful of as an intermediate for synthesis of pharmaceuticals .

The Japanese Patent. o. 61/225,175, described preparation of 1,5-benzothiazepine derivatives of formula (I): wherein A represents an aryl residure which may have a lower alkoxy group, R , R and R represent a lower alkyl group, and X represents a lower alkylene group, by reacting compounds of formulae (III) and (IV): T r, h e , w t i DESCRIPTION OF THE PREFERRED EMBODIMENTS Examples of the compound (Γ) of the present invention may 1 include compounds in which R is a lower alkyl group,, or a 2 lower alkoxy group, R is hydrogen or a lower alkanoyl group, either one of R3 or R4 is a lower alkyl group or halogen atom, and the other is hydrogen atom, and each of R^* and R^ is a lower alkyl group. - 2a - 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: wherein R , R , R and R have the same meanings as defined above, ·· . - 3 - with an aminoethanol represented by the formula: wherein R and R 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 (Ill) wherein Z is hydrogen is employed, can be practiced suitably in the presence of a dehydrating agent. As the dehydrating agent, for example, a mixture of tr iphenylphos phine and diethylazodicarboxyla te , a mixture of triphenyl-phosphine and dimethylazodicarboxyla te , a mixture of sulfuryldi imidazole and sodium hydride can be suitably used. This condensation. reaction may be preferably practiced in a suitable solvent (e.g., chloroform, dichloro-ethane, dichloromethane , acetone, diethyl ketone, methyl ethyl ketone, ethyl acetate, methyl acetate, ethyl propionate, methyl propionate, dimethylformamide , diethylforma te , 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 lower alkylsulfonyl group (e.g., methylsulfonyl group, ethylsulfonyl group), an arylsulfonyl group (e.g., benzene- sulfonyl group, tosyl group) or sulfo group, the condensation reaction of said compound and the compound (II) can be practiced preferably in the presence of an alkali reagent. Examples of the alkali reagent may include alkali metal hydroxides (e.g., potassium hydroxide, etc.), . - 4 - 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, dimethylacetamide , diethylformamide , 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 example, by treating with an acid, if necessary. Examples of such pharmaceutically acceptable acid addition salts may include inorganic acid addition salts such as hydrochloride, hydrobromide , hydroiodide, perchlorate, sulfate, phosphate, etc.; and organic acid addition salts such as 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 material, the compound (I) can be obtained as an optically active compound.

The 1 , 5-benzothiazapine derivatives (I) or pharmaceutically acceptable acid addition salts thereof of the pre-sent invention have excellent hypotensive activity, cerebral 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, cerebral infarction, etc., or cardiac diseases such as stenocardia, cardiac infarction, etc. Also, among the - 5 - compound (I), the compound wherein R is hydrogen is also useful as a synthetic intermediate, since this compound can be converted by acylation to a compound (I) wherein R 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 Japanese Provisional Patent Publications No. 225174/1984, No. 202871/1985 and No. 122281/1986 (which correspond to 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 stereoiso- mers (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-l , 5-benzo- thiazepin-4 ( 5H ) -one and 2.3 g of tr iphenylphosphine were added 15 ml dichloromethane solution of 779 mg of 2-(di- methylamino) ethanol over 20 minutes, then 15 ml dichloromethane solution of 1.52 g of diethylazodicarboxylate at room temperature over 20 minutes. The mixture was stirred for 20 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- - 6 - crystallization from ethanol gave 3.55 g of ( + ) -cis-2- ( 4-methoxyphenyl) -3-acetoxy-5- [ 2- ( dimethyl amino) ethyl ] - 8-chloro-2 , 3-dihydro-l , 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-l , 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.

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-l , 5-benzothiazepin-4 ( 5H) -one. -maleate. mp. 158 to 160 °C.

Example 3 To 30 ml acetone solution of 1.86 g of ( + ) -cis-2- ( 4- methoxyphenyl ) -3-acetoxy-8-chlo o-2 , 3-dihydro-l , 5-benzo- - 7 - thiazepin-4 ( 5H ) -one were added 2.4 g of powdery potassium carbonate and 1.1 g of 2- ( dimethylamino ) ethy 1 methane-sulfona te · hydrochlo ide , 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 converted into hydrochlo ide and recrystallized from a mixture of acetone-ethanol to give 2.10 g of ( + ) -cis-2- ( 4-methoxyphenyl) -3-acetoxy-5- [ 2- (dimethylamino) ethyl ] -8-chloro-2 , 3-dihydro-l , 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 -hyd oxy-8-chloro-2 , 3-dihydro-l , 5- benzothiazepin- ( 5H ) -one was added 1.35 g of potassium hydroxide under ice-cooling and, after stirring at room temperature, 2.44 g 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 diethyl ether. 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- ( -methoxy- pheny 1) -3 -hydroxy-5- [ 2- (dimethylamino ) ethyl ] -8 -chloro-2 , 3- d ihydro- 1 , 5-benzothiazepin-4 ( 5H ) -one . Yield: 75.2 %. 122 to 124 °C. - 8 - Example 5 To 30 ml acetone-0.5 ml water solution of 1.68 g of (+)-cis-2- ( 4 -methox phenyl ) -3-hyd oxy-8-chloro-2 ,3-dihydro-"1 , 5-benzothiazepin-4 ( 5H ) -one were added 2.40 g of potassium carbonate and 1.09 g of 2- ( dimethylamino ) ethy 1 methanesulfonate · hydrochloride , followed by refluxing for 20 hours. After completion of the reaction, inorganic materials were removed by filtration and the filtrate was concentrated 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 alkaline with potassium carbonate and then extracted with ethyl acetate. The extract was washed with water, dried, and evaporated under reduced pressure. Recrys tallization of the residue from a mixture of ethyl aceta te-n-hexane gave 1.40 g of (+) -cis-2- ( -methoxypheny 1 ) -3-hydroxy-5- [ 2- ( dimethylamino) ethyl ]-8-chloro-2, 3-dihydro-l , 5-benzothiaze-pin-4 (5H)-one. Yield: 68 /8 % . 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.hydrochloride(+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5- [ 2- (dimethylamino ) ethyl] -8 -chloro-2, 3-dihyd o-l, 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- ( d ime thy lam ino ) e thy 1 toluene- - 9 - sulfonate . hydrochloride in place of 2- (dimethylamino)ethyl methanesulfonaT-er { +) -cis-2- (4-methoxyphenyl ) -3-acetoxy-5-[ 2- (dimeth lamino) ethyl ] -8-chloro-2 , 3-dihydro-l , 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 . hydrochloride, ( +) -cis-2-.( 4-methoxyphenyl) -3-acetoxy-5- [ 2- (dimethylamino) ethyl ] -8-chloro-2 , 3-dihydro-l , 5-benzothiazepin-4 (5H) -one. hydrochloride was obtained.

This product had the same physical data as the product in Example 3.

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- [ 2- ( dimethylamino) ethyl ] -9-chloro-2 , 3-dihydro-l , 5-benzothiazepin-4 (5H) -one . perchlorate ^hydrate mp. 190 to 192 °C. ( 10 ) (+) -cis-2- (4-methoxyphenyl ) -3-acetoxy-5- [ 2- (dimethylamino) ethyl ] -9-chloro-2 , 3-dihydro-l , 5-benzothiazepin-4 ( 5H ) -one . hydrochlor ide monohydrate mp. 140 to 14.3 - 10 - (11) (±) -cis-2- (4^methylphenyl ) -3-hydroxy-5- [ 2- (dimethy1-amino ) ethyl ] -8-methy1-2 , 3-dihydro-l , 5-benzothiazepin-4 ( 5H ) one mp. 142 to 143 °C (recrystallized from ethyl acetate). (12) (±).-cis-2- ( 4-methylphenyl) -3-acetoxy-5- [ 2- (dimethy1-amino) ethyl] -8-methy1-2 , 3-dihydro-l , 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 °C (recrystallized from ethanol).

This product, when recrystallized from methanol exhibits a melting point of 172.5 to 174 °C and, when recrystallized from- water, gives crystals exhibiting a melting point of 191.9 °C, thus having the properties of crystals polymorphism.

Methanesulfonate of this product: mp. 124 to 128 °C (recrystallized from isopropanol). ( 13 ) (+) -cis-2- (4-methylphenyl ) -3-acetoxy-5- [ 2- (dimethy1- amino) ethyl ] -8-methy1-2 , 3-dihydro-l , 5-benzothiazepin-4 ( 5H ) one. maleate mp. 194 to 197 °C (decomposed) (recrystallized from ethanol) . [α]2°·+ 83.7° (c=0.362, methanol).

Oxalate of this product: mp. 179 to 180 °C (recrystallized from ethanol). [a]2° + 88.2° (c=0.288, methanol). ( 1 ) (-) -cis-2- ( 4-methylphenyl) -3-acetoxy-5- [ 2- (dimethy1-amino) ethyl ] -8-methy1-2 , 3-dihydro-l , 5-benzothiazepin- ( 5H) -one. oxalate mp. 179.5 to 181 °C (decomposed) (recrystallized from ethanol ) . [a]^° - 83.8° (c=0.333, methanol).

Maleate of this product: mp. 195 to 197.5 °C (decomposed) (recrystallized from ethanol) . [a]^° - 83.6° (c=0.50, methanol).

Fumarate of this product: mp. 210.5 to 212.5 °C (decomposed) (recrystallized from ethanol) . [a] - 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)

- 12 - Claims :

1. A process for preparing 1 , 5-benzothiazepine derivatives represented by the formula: wherein R is a lower alkyl group or a lower alkoxy 2 group, R is hydrogen or a lower alkanoyl group, one 3 of R and R is a lower alkyl group or halogen atom, 5 6 and the other is hydrogen, and each of R and R is a lower alkyl group, or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting a compound represented by the formula: wherein R , R , R and R have the same meanings as defined above, with an aminoethanol represented by the formula: R \ -CH--CH--OZ (III 87026/2 -13- wherein R and R have the same meanings as defined above, and Z is hydrogen, a lower a 1 k y lsu 1 fony 1 group, an arylsulfonyl group or sulfo group, and, if necessary, convert the product to a pharmaceutically acceptable acid addition salt thereof.

2. A process for preparing 1.5-benzothiazepine derivatives according to Claim 1, wherein one of R3 and R4 is a halogen atom, and the other is hydrogen.

3. A process for preparing 1.5-benzothiazepine derivatives according to Claim 1, wherein one of R3 and R4 is a lower, alkyl group, and the other is hydrogen.

4. . A process for preparing 1 , 5-benzothiazepine derivatives represented by the formula: wherein R is a lower alkyl group or a lower alkoxy 2 group, R is hydrogen or a lower alkanoyl group, one 3 of R and R 4 is a lower alkyl group or halogen atom, and the other is hydrogen, and each of R^ and R^ is a lower alkyl group, or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting a compound represented by the formula: (ID 87026/ 2 -14- 1 2 3 4 wherein R , R , R and R have the same meanings as defined above, with an aminoethanoi represented by the formula: wherein R5 and R6 have the same meaning as defined above, and Z is hydrogen, in the presence of a basic dehydrating agent such as a mixture of sulfurylimidazole and sodium hydride or, b) with an aminoethanoi represented by the formula: wherein R^ and ^ have the same meanings as defined above, and Z is a lower alkylsulfonyl group, an arylsulfonyl group or sulfo group, and if necessary convert the product to a pharmaceutically acceptable acid addition salt thereof.

5. A process for preparing 1 , 5-benzothiazepine derivatives according to Claim 1, wherein the condensation reaction is carried out in a solvent at 0 °C to 150 °C

6. A process for preparing 1 , 5-benzothiazepine derivatives according to Claim 5, 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.

7. A process for preparing 1 , 5-benzothiazepine derivatives according to Claim 6, wherein the alkali reagent is an alkali metal hydroxide, an alkali metal carbonate an alkali metal hydrogen carbonate or an alkali metal hydr- ide . - 1 5 - g A process for preparing 1 , 5-benzoth ia zep ine derivatives according to Claim 1, wherein the compound obtained is treated with an acid to convert it to a pharmaceutically acceptable acid addition salt. For the Applicants, DR REI ED COHN AND PARTNERS