FI93009B - Process for the preparation of 1,5-benzothiazepine derivatives - Google Patents

Description

93009

METHOD. FOR THE PREPARATION OF 1,5-BENZOTIACEPI INI Derivatives

The invention relates to a process for the preparation of 1,5-benzothiazepine derivatives and their pharmaceutically acceptable salts which are useful as pharmaceutical compounds and which correspond to the formula: R 4 / Or 10 R 5 CH 2 CH 2 N (, R 6 wherein R 1 is a lower alkyl group or a lower alkoxy group, R 2 is hydrogen or a lower alkoyl group) , one of R 3 or R 4 is a lower alkyl group or a halogen atom and the other is a hydrogen atom, and each of R 5 and R 6 is a lower alkyl group.

The 1,5-benzothiazepine derivatives (I) and their pharmaceutically acceptable salts are useful pharmaceutical compounds having excellent hypotensive activity, vasodilating effect on cerebrovascular and coronary arteries and / or inhibiting platelet aggregation, and, wherein the compound (I) is a compound of formula (I), hydrogen atom, is also useful as an intermediate in pharmaceutical manufacturing.

EP applications 127882 and 154838 disclose a process for the preparation of 8- or 9-halogen or lower alkyl-1,5-benzothiazepine derivatives. These methods use a hydroxyl-containing alkylating agent which is first converted to a halide to make it more reactive.

It appears from the Merck Index, 10 (1983), ONR-61, that alcohols of the formula RzOH can be used as alkylating agents for acidic starting materials of the formula HX. Reaction 93009 2 uses diethyl azocarboxylate and triphenylphosphine. as a dehydrating agent. Examples of acidic starting materials are phosphorus mono- and diesters, carboxylic acids, phenols, imides, oximes and active methylene compounds.

In the Journal of the American Chero. Soc. 94 (1972) No. 2, pp. 679-80, also discloses a reaction which avoids the conversion of an alcohol to a reactive group. The starting material for the process is phthalimide or succinimide, both of which have acidic hydrogen in the cyclic amine.

It can be said that there is a need to develop methods in which alkylation can be performed without converting the alkylating agent to a halide, thus avoiding the problems associated with the handling and storage of the halide. In addition, the considerable advantage of avoiding a single reaction step is achieved.

The problem when carrying out N-alkylation using alkylating agents containing less reactive groups is that the reaction does not proceed as easily as when using halogenated alkylating agents.

Following research, the present inventors have succeeded in developing a reaction system using a very weakly acidic starting material, i.e., a 1,5-benzothiazepine compound, as the starting material, while avoiding the disadvantages of prior art methods, i.e., the use of a halogenated alkylating agent. The invention is characterized by what is set forth in the characterizing part of the claims.

Production Process

According to the invention, a 1,5-benzothiazepine derivative of the formula (I) or a pharmaceutically acceptable salt thereof is prepared by administering a compound represented by the formula:

Il: 93009 3 r4 J \ 'V ^ 1 R vVS “\ 2

VoR (II) H ° wherein R 1, R 2, R 3 and R * are as defined above, react with an aminoethanol corresponding to the formula: R 5 n -ch 2 -ch 2 -oh (III) R 6 wherein R 5 and R 6 are as defined above in a condensation reaction and, if desired, converting the compound to its salt by conventional methods.

In the 1,5-benzothiazepine derivatives prepared by the process of the present invention, the lower alkyl, lower alkoxy and lower alkanoyl groups include alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, and alkanoyl groups having 2 to 6 carbon atoms. carbon atoms, respectively. Preferred examples of these groups are alkyl groups having 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms and alkanoyl groups having 2 to 5 carbon atoms.

The above condensation reaction, may conveniently be carried out in the presence of a dehydrating agent. As the dehydrating agent, for example, a mixture of triphenylphosphine and diethyl azodicarboxylate, a mixture of triphenylphosphine and dimethylazodicarboxylate or a mixture of sulfuryldiimidazole and sodium hydride can be used. This condensation reaction is preferably carried out in a suitable solvent (examples include chloroform, dichloroethane, dichloromethane, acetone, diethyl ketone, methyl ethyl ketone, ethyl acetate, methyl acetate, ethyl propionate, methyl propionate, dimethylformamide, dimethylformamide, diethylformamide, diethylformamide, diethylformamide, acetylmorpholine, dioxane, tetrahydrofuran, ether, dimethoxyethane, diglyme, 93009 4 toluene, benzene, xylene, etc.) at a temperature between 0 and 150 ° C.

The compound (I) thus obtained can be easily converted into a pharmaceutically acceptable acid addition salt, if necessary, by treatment with an acid. Examples of such pharmaceutically acceptable acid addition salts 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, methane.

Since the reaction of the present invention can be carried out as described above without the formation of racemic mixtures, by using the optically active compound (II) as a starting material, the compound (I) can be obtained as an optically active compound.

The 1,5-benzothiazepine compounds or pharmaceutically acceptable acid addition salts thereof prepared by the process of the invention have excellent hypotensive activity, vasodilating effect on cerebrovascular and coronary arteries and / or inhibition of platelet aggregation as mentioned above, and can be used in the treatment and inhibition of platelet aggregation. contraction, cerebral ischemia, cerebral infarction, etc., or heart diseases such as myocardial infarction, myocardial infarction, etc. Also, of compounds (I), a compound in which R 2 is hydrogen is also useful as a synthetic intermediate because the compound can be converted by acylation to compound (I) in which R 2 is lower alkanoyl group.

The starting material (II) used in the invention can be prepared by the methods described in JP Preliminary Patent Publications 225174/1984, 202871/1985 and 122281/1986 (corresponding to U.S. Patents 4,567,175, 4,590,188 and 4,665,068, respectively).

Also, the compounds (I) and (II) of the invention each include two types of stereoisomers (i.e., cis and li 93009 5 trans isomers) or four types of optical isomers (i.e., (+) - cis-, (-) - cis- , (+) - trans and (-) - trans isomers) and mixtures thereof due to the asymmetric carbon atoms of the molecule (two).

Example 1 80 ml of a dichloromethane solution containing 3 g of (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H ) -one and 2/3 g of triphenylphosphine, 15 ml of a dichloromethane solution of 779 mg of 2- (dimethylamino) ethanol were added over 20 minutes and then 15 ml of dichloromethane containing 1/52 g of diethyl azodicarboxylate at room temperature over 20 minutes were added. . The solution was stirred at room temperature for 20 h, and condensed under reduced pressure. The residue was dissolved in ethyl acetate, and insoluble matters were removed by filtration. The filtrate was extracted with 10% hydrochloric acid, and the aqueous phase was basified with potassium carbonate and extracted with chloroform. The extract was washed with water, dried and evaporated under reduced pressure. The residue was converted into maleate and recrystallized from ethanol to give 3.55 g of (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- (2- (dimethylamino) ethyl] -8-chloro-2 1,3-dihydro-1,5-benzothiazepin-4 (5H) -one maleate Yield: 79.2%, mp 158-160 ° C.

EXAMPLE 2

A mixture of 354 mg of 2- (dimethylamino) ethanol and 159 mg of potassium hydride in 14 ml of dimethylformamide was stirred at room temperature for 20 minutes, and 787 mg of sulfuryldiimidazole was added at -40 ° C, and the mixture was stirred at this temperature for 1 hour. Then, 5 ml of a dimethyl sulfoxide solution containing 1.0 g of (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-8-chloro-2,3-dihydro-1,5-benzothiazide was added to the mixture. pin-4 (5H) -one at -40 ° C and after gradual heating, the mixture was stirred at room temperature for 20 h. After the reaction was complete, methanol and 93009 6 chloroform were added to the mixture. The mixture was washed with water, dried, the solvent was distilled off, and the residue was separated by column chromatography. After the starting lactam was separated by elution with chloroform / ethanol = 20/1), the eluted oily product was then converted to a maleate and recrystallized from ethanol to give 777 mg of (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5 - [2- (dimethyl-amino) ethyl] -8-chloro-2,3-dihydro-l, 5-benzothiazepin-4 (5H) -oni.maleaattia. mp: 158-160 ° C.

EXAMPLES 3-8 Treatment of the corresponding starting materials according to Examples 1-2 gave the following compounds (3) (+) - cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (dimethylamino) ethyl] -9 -Chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one perchlorate.1 / 4-hydrate m.p. 190-192 ° C.

(4) (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -9-chloro-2,3-dihydro-1,5-benzothiazepine 4 (5H) -one hydrochloride monohydrate m.p. 140-143 ° C.

(5) (+) - cis-2- (4-methylphenyl) -3-hydroxy-5- [2- (dimethylamino) ethyl] -8-methyl-2,3-dihydro-1,5-benzothiazepine 4 (5H) -one m.p. 142-143 ° C (recrystallized from ethyl acetate).

(6) (+) - cis-2- (4-methylphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-methyl-2,3-dihydro-1,5-benzothiazepine 4 (5H) -one hydrochloride m.p. 184-186 ° C (recrystallized from a mixture of isopropanol and ether).

The melting point of this product when crystallized from a mixture of acetone and isopropyl ether is 190-192 ° C.

93009 7 The fumarate of this product: m.p. 196.5-198.5 ° C (recrystallized from isopropanol) The maleate of this product: m.p. 173.5-175.5 ° C (recrystallized from ethanol) This product has a melting point of 172.5-174 ° C when crystallized from methanol and 191.9 ° C when recrystallized from water due to crystal polymorphism.

Methanesulfonate of this product: m.p. 124-128 ° C (recrystallized from isopropanol) (7) (+) - cis-2- (4-methylphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-methyl-2, 3-Dihydro-1,5-benzothiazepin-4 (5H) -one maleate m.p. 194-197 ° C (decomposes) (recrystallized from ethanol) [α] 20 D + 83.7 ° (c = 0.362, methanol) The oxalate of this product m.p. 179-180 ° C (recrystallized from ethanol) [α] 20 D + 88.2 ° (c = 0.288, methanol) (8) (-) - cis-2- (4-methylphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-methyl-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one oxalate m.p. 179.5-181 ° C (decomposes) (recrystallized from ethanol) [α] 20 D -83.8 ° (c = 0.333, methanol) The maleate of this product: m.p. 195-197.5 ° C (decomposes) (recrystallized from ethanol) [α] 20 D -83.6 ° (c = 0.50, methanol) The fumarate of this product: m.p. 210.5-212.5 ° C (decomposes) (recrystallized from ethanol) [<*] 20d -91.3 ° (c = 0.323, methanol)

Claims (5)

8 93009 L - (+) - tartrate of this product: a.p. 140-143 ° C (recrystallized from a mixture of ethanol and ether). A process for the preparation of 1,5-benzothiazepine derivatives of the following formula; R4 ^ | (R) 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 a halogen atom and the other is hydrogen, and each of R5 and R6 is a lower alkyl group, or for the preparation of their pharmaceutically acceptable acid addition salts, characterized in that a compound of the following formula is administered: wherein H 0 wherein R 1, R 2, R 3 and R 4 are as defined above, is reacted with an aminoethanol of the formula: li. 93009 9 R 5 -ΟΗ -, - ΟΗ -, - ΟΗ (III) r6 / wherein R5 and R6 are as defined above, in a condensation reaction, and if necessary converting the product into a pharmaceutically acceptable acid addition salt. Process for the preparation of 1,5-benzothiazepine derivatives according to Claim 1, characterized in that the condensation reaction is carried out in a solvent at a temperature of 0 ° C to 150 ° C. Process for the preparation of 1,5-benzothiazepine derivatives according to Claim 2, characterized in that the condensation reaction is carried out in the presence of a dehydrating agent. Process for the preparation of 1,5-benzothiazepine derivatives according to Claim 3, characterized in that the dehydrating agent is a mixture of triphenylphosphine and diethyl azodicarboxylate, a mixture of triphenylphosphine and dimethyl azodicarboxylate, or a mixture of sulfuryldiimidazole and sodium hydride. Process for the preparation of 1,5-benzothiazepine derivatives according to Claim 1, characterized in that the compound obtained is treated with an acid to convert it into a pharmaceutically acceptable acid addition salt. 93009 10