NO170541B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1,5-BENZOTIAZEPINE DERIVATIVES - Google Patents

Description

The present invention relates to an analogous process for the production of 1,5-benzothiazepine derivatives and pharmaceutically acceptable salts thereof which are suitable as a pharmaceutical compound and indicated by the formula:

where R<1> is a Q-Q alkyl group, R<2> is hydrogen or a C2-C6 alkanoyl group, R<3> is a C1-C6 alkyl group, and each of R5 and R<6> is a CVC6 alkyl group.

Compounds of a similar type are described in NO explanatory notes 162518 and 163488, where the R<1-> group is an alkoxy group and where the R<3-> group is represented by a halogen. However, these compounds show no measurable inhibitory effect against platelet aggregation.

The purpose of the present invention is to provide a compound which exhibits improved activity, with regard to inhibition of platelet aggregation and/or improved hypotensive activity, cerebral or coronary vasodilating activity.

This purpose is achieved according to the characterizing part of the patent claim.

The 1,5-benzothiazepine derivative (I) and a pharmaceutically acceptable salt thereof prepared by the addition of acid are suitable pharmaceutical compounds with an excellent hypotensive activity, cerebral or coronary vasodilatory activity and/or platelet aggregation inhibitory activity.

Description of the preferred embodiments

Examples of the compound (I) may include compounds in which R<1> is a lower alkyl group, R<2> is hydrogen or a lower alkanoyl group, R3 is a lower alkyl group, and each of R<5> and R<6> is a lower alkyl group.

In the above-mentioned examples of the 1,5-benzothiazepine derivative (I), the lower alkyl group and the lower alkanoyl group include an alkyl group having from 1 to 6 carbon atoms and an alkanoyl group having from 2 to 6 carbon atoms, respectively. Preferred examples of these groups are an alkyl group with from 1 to 4 carbon atoms, and an alkanoyl group with from 2 to 5 carbon atoms.

The compound (I) or a pharmaceutically acceptable salt thereof can be prepared by allowing a compound represented by the formula:

where R<1>, R<2> and R<3> have the same meaning as defined above,

react with an amine ethanol given by the formula:

where R<5> and R<6> have the same meaning as stated above, and Z is hydrogen, one lower

alkylsulfonyl group, an arylsulfonyl group or sulfo group,

by a condensation reaction, and if necessary convert it to a salt thereof according to a conventional procedure.

The above condensation reaction, when the starting compound (III) where Z is hydrogen is used, can be carried out in the presence of a dehydrating agent. As a dehydrating agent, it can e.g. a mixture of triphenylphosphine and diethylazodicarboxylate is used, a mixture of triphenylphosphine and dimethylazodicarboxylate, a mixture of sulphuryldiimidazole and sodium hydride. This condensation reaction can preferably be carried out in a suitable solvent, (eg, chloroform, dichloroethane, dichloromethane, acetone, diethyl ketone, methyl ethyl ketone, ethyl acetate, methyl acetate, ethyl propionate, methyl propionate, dimethylformamide, diethyl formate, dimethylacetamide, N-formylmorpholine, N-acetylmorpholine, dioxane, tetrahydrofuran, ether, dimethoxyethane, diglyme, toluene, benzene, xylene, etc.) at 0 to 150°C.

On the other hand, when the compound (III) where Z is a lower alkylsulfonyl group (e.g., methylsulfonyl group, ethylsulfonyl group), an arylsulfonyl group, (e.g., benzenesulfonyl group, tosyl group) or sulfo group, the condensation reaction of said compound and the compound (2) preferably carried out in the presence of an alkaline reagent. Examples of the alkaline reagent may include alkali metal hydroxides (e.g. potassium hydroxide, etc), 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 preferably be carried out in a suitable solvent (e.g. methyl ethyl ketone, diethyl ketone, acetone, dimethyl sulfoxide, dimethyl formamide, ethyl acetate, methyl propionate, ethyl propionate, tetrahydrofuran, dioxane, ether, dimethoxyethane, diglyme, toluene, benzene, xylene, acetonitrile, dimethyl acetamide, diethylformamide, N-formylmorpholine, N-acetylmorpholine, etc.) at 0 to 150°C.

The compound (I) prepared in this way can easily be converted into a pharmaceutically acceptable salt, for example by treatment with an acid, if necessary. Examples of such pharmaceutically acceptable salts may include salts prepared with inorganic acids such as hydrochloric acid, bromic acid, iodic acid, perchlorate, sulfate, phosphate, etc.; and salts prepared with organic acids such as oxalate, maleate, tartrate, methanesulfonate, etc

Since the reaction as mentioned above proceeds without accompanying racemization, the compound (I) can be prepared as an optically active compound using an optically active compound (II) as starting material.

The 1,5-benzothiazepine derivative (I) or pharmaceutically acceptable salt thereof has excellent hypotensive activity, cerebral or coronary vasodilating activity and/or platelet aggregation inhibitory activity as mentioned above, and can be used for therapy and preventive measures against brain diseases such as cerebrovascular contraction, cerebral ischemia , cerebral infarction, etc, or heart diseases such as stenocardia, heart attack, etc. Also, among the compounds (I), the compound wherein R<2> is hydrogen is also useful as a synthetic intermediate, since this compound can be converted by acylation into a compound (I) where R<2> is a lower alkanoyl group.

The starting compound (II) can be prepared according to the procedures described in Japanese Patent Document No. 202871/1985 (corresponding to U.S. Patent Document 4,590,188).

The compound (I) and the compound (II) also include either two kinds of stereoisomers (that is, cis and trans isomers) or 4 kinds of optical isomers (that is, (+)-cis, (-)-cis, (+ )-trans and (r)-trans isomers) and mixtures thereof based on asymmetric carbon atoms (2) in the molecule.

Example 1:

To 82 ml of dichloromethane solution of 2.8 g of (+)-cis-2-(4-methylphenyl)-3-acetoxy-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 2.38 g of triphenylphosphine, 15 ml of a dichloromethane solution of 805 mg of 2-(dimethylamino)ethanol were added over the course of 20 minutes, then 15 ml of a dichloromethane solution of 1.57 g of diethyl azodicarboxylate at room temperature over the course of 20 minutes. The mixture was stirred for 20 hours at room temperature, followed by evaporation under reduced pressure. The residue was dissolved in ethyl acetate and insoluble substances were removed by filtration. The filtrate was extracted with a 10% hydrochloric acid, and the aqueous phase 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 recrystallization from ethanol gave 3.52 g of (+)-cis-2(4-methylphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-methyl-2,3-dihydro- 1,5-benzothiazepin-4(5H)-one maleate.

Yield: 81.2%.

Melting point 194 to 197°C. (decomposed)

[ a]* >D + 83.7° (c=0.362, methanol)

Example 2:

To 50 ml of dimethyl sulfoxide solution of 3.00 g of (+)-cis-2-(4-methylphenyl)-3-hydroxy-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was 1.40 g of potassium hydroxide was added under ice cooling and, after stirring at room temperature, 2.43 g of 2-(dimethylamino)ethyl methanesulfonate hydrochloride was added, followed by stirring at room temperature for 16 hours. After the reaction had gone to completion, the mixture was poured into ice water and the mixture was extracted with a 1:1 mixture of chloroform and ether. The extract was washed with water, dried and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate gave 2.87 g (+)-cis-2-(4-methylphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-methyl-2,3-dihydro-1,5 -benzothiazepin-4(5H)-one.

Yield: 77.4%

Melting point: 142 to 143 °C.

(2) (+)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepine-4( 5H)-one hydrochloride.

Melting point 184 to 186°C (recrystallized from a solvent mixture of isopropanol and ether).

This product, when recrystallized from a solvent mixture of acetone and isopropyl ether, exhibits a melting point of 190 to 192°C.

Fumarate of this product:

Melting point 196.5 to 198.5°C (recrystallized from isopropanol).

Maleate of this product:

Melting point 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 polymorphic crystal properties.

Methanesulfonate of this product:

Melting point 124 to 128°C (recrystallized from isopropanol).

(3) (+)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepine-4( 5H)-one oxalate.

Melting point 179 to 180°C (recrystallized from ethanol).

[α]xD + 88.2° (c = 0.288, methanol).

(4) (-)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepine-4( 5H)-one.oxalate.

Melting point 179.5 to 181 °C (decomposed) (recrystallized from ethanol).

[α<]>\ - 83.8° (c = 0.333, methanol).

Maleate of this product:

Melting point 195 to 197.5°C (decomposed) (recrystallized from ethanol).

[αj^u - 83.6° (c = 0.50, methanol).

Fumarate of this product:

Melting point 210.5 to 212.5°C (decomposed) (recrystallized from ethanol).

[ af°D - 91.3° (c = 0.323, methanol).

L-(+)-tartrate of this product:

Melting point 140 to 143°C (recrystallized from a solvent mixture of ethanol and ether).

Comparison test.

In these experiments, the inhibitory effects against platelet aggregation for the compounds according to the present invention and the compound described in NO disclosures 162518 and 163488 were investigated with regard to the inhibitory effect ex vivo on collagen-induced platelet aggregation or platelets from rats.

The toxicity of the compounds according to the present invention was estimated as maximum

tolerance dose.

Inhibitory effect ex vivo on collagen-induced platelet aggregation in rats.

A solution of the test compound (dose: 10 and 30 mg/kg) was administered orally to Sprague-Dawley rats (one group: 5 or 6 rats) fasted for about 20 hours. Three hours after allocation, blood was collected from the abdominal aorta of the rats. Nine volumes of blood were mixed with one volume of an aqueous solution of 3.8% by weight trisodium citrate, and the mixture was centrifuged to yield platelet-rich plasma ("PRP") as the supernatant solution. The bottom layer was further centrifuged to yield platelet-poor plasma ("PPP") as the supernatant solution. PRP was diluted with PPP so that the platelet count was 0.8-lxl0<6>/mm<3>. 25 of a collagen solution (Biochem. Biophys. Acta., 186. 254 (1969)) was added to 225 µl of diluted PEP to induce platelet aggregation. The degree of platelet aggregation was examined by Born's method (Nature., 19.4, 927 (1962)) and the percent inhibition of platelet aggregation was calculated from this. The results are shown in table 1.

Maximum tolerance dose

A test compound dissolved or suspended in a physiological salt solution or an aqueous solution containing a surface-active compound was administered orally to slc-ddy male mice (about 20g). The maximum tolerance dose of the test compound was estimated as the maximum dose that did not cause death during the 2-day observation period. The results are shown in the following table 2.

Claims (1)

1. Analogous process for the production of therapeutically active 1,5-benzothiazepine derivatives indicated by the formula: where R<1> is a C1-C6 alkyl group, R2 is hydrogen or a C2-C6 alkanoyl group, R<3> is a C1-C6 alkyl group, and each of R5 and R6 is a C1-C6 alkyl group, or a pharmaceutically acceptable salt thereof, characterized in that it comprises leaving a compound indicated by the formula: where R<1>, R<2> and R<3> have the same meaning as indicated above, react with an aminoethanol indicated by the formula: where R<5> and R<6> have the same meaning as stated above, and Z is hydrogen, a lower alkylsulfonyl group, an arylsulfonyl group or sulfo group, by a condensation reaction at a suitable temperature, preferably from 0 to 150°C, in the presence of a dehydrating agent, such as a mixture of triphenylphosphine and diethylazodicarboxylate, a mixture of triphenylphosphine and dimethylazodicarboxylate, or a mixture of sulfuryldiimidazole and sodium hydride, when Z in compound (III) is hydrogen; or in the presence of an alkaline reagent, such as an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogen carbonate or an alkali metal hydride, when Z in the compound (III) is a lower alkylsulfonyl group, an arylsulfonyl group or a sulfo group; and, if necessary, converting it to a pharmaceutically acceptable acid addition salt thereof.