FR2626000A1 - Process for preparing 1,5-benzothiazepine derivatives - Google Patents

Abstract

The invention relates to a process for preparing 1,5-benzothiazepine derivatives of formula: in which R<1> to R<6> are defined, or one of their addition salts with pharmaceutically suitable acids, which have hypotensive, cerebral coronary vasodilatory and/or platelet aggregation inhibitory activities, which consist in subjecting a propionamide derivative of formula: in which X is a bromine or iodine atom, to an intramolecular cyclisation.

Description

dans laquelle R1 est un groupe alcoyle inférieur ou alcoxy inférieur ; R2 est un atome d'hydrogène ou un groupe alcanoyle inférieur ; un de R3 et R4 est un atome d'halogène ou un groupe alcoyle inférieur et l'autre est un atome d'hydrogène ; et chacun de it et R6 est un groupe alcoyle inférieur, et leurs sels d'addition d'acides convenant en pharmacie.PROCESS FOR PREPARING 1,5-BENZOTHIAZEPINE DERIVATIVES
The invention relates to a process for preparing 1,5-benzothiazepine derivatives. More particularly, it relates to a process for preparing 1,5-benzothiazepine derivatives of formula

wherein R1 is lower alkyl or lower alkoxy; R2 is a hydrogen atom or a lower alkanoyl group; one of R3 and R4 is a halogen atom or a lower alkyl group and the other is a hydrogen atom; and each of it and R6 is a lower alkyl group, and their pharmaceutically suitable acid addition salts.

1,5-Benzothiazepine (I) derivatives and their pharmaceutically suitable acid addition salts are useful pharmaceutical compounds having hypotensive activity, cerebral and coronary dilation activity and / or inhibitory activity. Excellent platelet aggregation, and among these compounds, compound (I) wherein R2 is hydrogen is also useful as an intermediate for the synthesis of other pharmaceutical compounds.

It is known to date that the above 1,5-benzothiazepine derivatives can be prepared by reacting the corresponding 1,5-benzothiazepine derivatives unsubstituted in nitrogen with a di (lower alkyl) aminoethyl halide [patent publications Japanese (not examined) Nos 225174/1984 and 20871/1985 J.

dans laquelle X est un atome de brome ou un atome d'iode, R1 à R4 sont comme défini ci-dessus, ou un dérivé réactif de celui-ci, et une N,N-di(alcoyl inférieur)éthylènediamine, pour obtenir un dérivé de propionanide de formule

dans laquelle R1 à R6 et X sont comme défini ci-dessus et soumettre le dérivé de propionamide à une cyclisation intramoléculaire.As a result of various researches, the Applicant has discovered a new industrial process for preparing 1,5-benzothiazepine derivatives (I). According to the invention, it is possible, in order to prepare the 1,5-benzothiazepine (I) derivatives or their addition salts of acids suitable in pharmacy, to condense a propionic acid derivative of formula

wherein X is a bromine atom or an iodine atom, R1 to R4 are as defined above, or a reactive derivative thereof, and an N, N-di (lower alkyl) ethylenediamine, to obtain a propionanide derivative of the formula

wherein R1 to R6 and X are as defined above and subjecting the propionamide derivative to intramolecular cyclization.

The condensation reaction of the propionic acid derivative
(II) or a reactive derivative thereof and an N, N-di (lower alkyl) ethylenediamine can be carried out according to a conventional method of peptide synthesis. For example, when a reactive derivative of compound (11) is used as the starting compound, the condensation reaction can be carried out in the presence of a conventional acid acceptor (for example a di- or tri (lower alkyl) amine. , N- (lower alkyl) norpholine, di (lower alkyl) aminopyridine, alkali metal bicarbonate or alkali metal carbonate). Suitable examples of the reactive derivative of compound (II) include an acid halide (e.g. example a chloride or bromide), a mixed anhydride (for example a mixed anhydride of compound (II) with ethoxycarboxylic, tert-butoxycarboxylic or benzyloxycarboxylic acid) or a reactive ester (for example p-nitrophenyl, 2,4- dinitrophenyl
N-bydroxybenzotriazole, phthalimide, succinimide, piperidine, 2-pyridime, 2-pyrrolidone-1-yl and diethylchlorophos phinate), on the other hand, when a propionic acid derivative (II ) free as the starting compound, the condensation reaction can be carried out in the presence of a conventional condensing agent (such as dicyclohexylcarbodiimide, diethyl chlorophosphate, ethoxyacetylene, 1-methyl-2-halogenopyridinium halide and carbonyldiimidazole ). It is preferred to carry out the above reactions in an inert solvent (such as dichloromethane, dioxane, toluene, tetrahydrofuran, dimethylfornamide, etc.) between a cooling temperature and a heating temperature, in particular at a temperature of -20 to 1OO.c.

Intramolecular cyclization of the propionamide derivative
(III) thus obtained can be carried out in the presence of a catalyst and a base. Examples of the suitable catalyst include transition metal catalysts, such as copper powder, copper compounds (e.g. cuprous oxide, cupric oxide, cuprous chloride, cupric chloride, cuprous bromide, copper bromide, cuprous iodide, cupric iodide, copper carbonate and the like), palladium compounds (such as palladium acetate, tetrakis <triphenylphosphine complex) palladium and the like), nickel compounds such as nickel chloride, nickel bromide, tetrakis (triphenylphosphine) nickel complex and the like), rhodium compounds (such as rhodium chloride, rhodium acetate and the like) and platinum compounds (such as platinum chloride (IV), platinum bromide (IV1 and the like). Inorganic bases such as alkali metal bicarbonate, alkali metal carbonate and the like) and organic bases (cox eu tri (lower alkyl) amine, di (lower alkyl) arylasin, N- (lower alkyl) morpholine and the like). It is preferred to carry out the reaction in an inert solvent (such as cblorobenzene, toluene, dimethylsulfoxide and the like) with particular heating at a temperature of 50 to 200 ° C.

The 1,5-benzothiazepine derivative (I) of the invention thus obtained can be easily converted into a pharmaceutically suitable acid addition salt, for example by treating the compound with an acid. Examples of pharmacy suitable avid addition salts include mineral acid addition salts (such as hydrochlorides, hydrobromides, iodides, perchlorates, sulfates, phosphates), organic acid addition salts (such as oxalates, maleates, tartrates, methanesulfonates) etc.

Since the above reaction of the invention is carried out without racemization, the compound (I) can be obtained in optical form when an optically active propionic acid derivative (II) is used.

According to the invention, as mentioned above, the preferred examples of 1,5-benzothiazepine derivatives obtained in the invention comprise the compounds of formula (I) in which R1 is an alkyl or alkoxy group of 1 to 6 atoms of carbon; R2 is a hydrogen atom or an alkanoyl group of 2 to 6 carbon atoms; one of R3 and R4 is a halogen atom or an alkyl group of 1 to 6 carbon atoms and the other is a hydrogen atom; and R5 and R6 each is an alkyl group of 1 to 6 carbon atoms.

Particularly preferred examples include compounds of formula (I) in which R1 is an alkyl or alkoxy group of 1 to 4 carbon atoms; R2 is a hydrogen atom or an alkanoyl group of 2 to 4 carbon atoms; one of R3 and R4 is a chlorine atom or an alkyl group of 1 to 4 carbon atoms and the other is a hydrogen atom; and R5 and R6 each is an alkyl group of 1 to 4 carbon atoms.

Although compounds (I) may exist as a cis or trans isomer or an optical isomer [e.g. (+) - cis, (-) - cis, (+) - trans and (-) - transj as a result of the two asymmetric carbon atoms which they comprise, all these isomers and their mixtures come within the scope of the invention. However, among these isomers, preferred for medical use are the cis isomers of compounds (I).

dans laquelle les symboles R3, R4 et X sont comme défini ci-dessus avec un glycidate de formule :

dans, laquelle R8 est un groupe alcoyle inférieur et R1 est comme défini ci-dessus, hydrolyse du produit et, au besoin, acylation du groupe hydroxy du produit obtenu de façon classique.The starting compounds (II) of the present invention are prepared for example by reaction of a thiophenol derivative of formula

in which the symbols R3, R4 and X are as defined above with a glycidate of formula:

wherein R8 is a lower alkyl group and R1 is as defined above, hydrolyzing the product and, if necessary, acylating the hydroxy group of the product obtained in a conventional manner.

In addition, when the starting compound (II) is a racemic mixture, an optically active form can be obtained therefrom, for example according to the stages consisting in (A) reacting the compound (II) in which R2 is an atom of hydrogen with a reactive derivative of an optically active acid (such as 1- (2-naphthylsulfonyl) pyrrolidine-2-carbonyl chloride) or form diastereomeric salts of compound (II) with an optically active base (e.g. l (p-hydroxyphenyl) glycine methyl ester, cinchonidine, ephedrine, l &alpha;; - ethylbenzylauine, various amino acids or esters thereof and the like), (B) separate the two kinds of diastereomers of the product, conventionally (for example by column chromatography, fractional crystallization) or both types of diastereomeric salts, by fractional crystallization, (C) hydrolyze the diastereomer or recover the optically active compound (II) from diastereomeric salts and (B) if necessary, acylate the hydroxy group in position 2.

Example 1
(1) A mixture of 10 g of sodium 5-chloro-2-iodobenzenesulfonate, 10 g of phosphorus pentachloride and 5 ml of phosphorus oxychloride is stirred at room temperature for 1 hour and refluxed for 1 hour. . After the reaction, the mixture is concentrated under reduced pressure and the residue is recrystallized from N-hexane to obtain 8.66 g of 5-chloro-2-iodobenzenesulfonyl chloride.

Mp 66-68 ° C.

8.56 g of the product obtained above is added to a mixture of ice and 9.47 ml of concentrated sulfuric acid and 8.45 g of zinc powder is added while cooling with ice. The mixture is stirred for 1 hour, gradually heated for 2 hours and brought to reflux. 3 g of zinc powder are added and the mixture is left to stand at room temperature to cool.

The mixture was extracted with toluene, the extract was washed, dried and concentrated under reduced pressure to obtain 3.4 g of 5-chloro-2-iodothiophenol as a colorless oil.

(2) A toluene solution containing 1.7 g of the product obtained above, 1.5 g of methyl trans-3- (4-methoxyphenyl) glycidate and 2 drops of tin (II) 2-ethylhexanoate is stirred. ).

After the reaction, the mixture is concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel [solvent: toluene / ethyl acetate = 20 / 1d and recrystallized from diethyl ether and n-hexane to obtain 1.8 g of (+) - Methyl threo-3- (4-sethoxyphenyl) -3- (2-iodo-5-chlorophenyl) thio-2-hydroxypropionate.

Pf. 66 to 68-C.

IR vNujol (cm: 3,480, 1,740, 1,605.

max
1.8 g of the product obtained above is added to a mixture of 30 ml of methanol and 15 ml of 10% aqueous sodium hydroxide and the mixture is stirred at room temperature for 3 hours. The mixture is acidified and extracted with ether. The extract is washed with water, dried and evaporated to remove the solvent and the residue is recrystallized from ethyl acetate and isopropyl ether to obtain 1.07 g of (+) - threo acid. -3- (4-ethoxyphenyl) -3- (2-iodo-5-chlorophenyl) thio-2-hydroxypropionic.

P. 168 to 169-C.

IR #Nujol (cm) 3470, 3200 to 2100, 1700, 1600.

max
(3) A mixture of 2.0 g of the product obtained above and 10 ml of acetic anhydride is stirred at 60 ° C. for 2 hours. After the reaction, 200 ml of water and 100 ml of tetrahydrofuran are added to the mixture and further stirred at room temperature for 1 hour. The reaction mixture was basified with potassium carbonate to completely decompose acetic anhydride, acidified with hydrochloric acid, then extracted with ethyl acetate. The extract is washed with water, dried and concentrated under reduced pressure to obtain 2.18 g of (+) - threo-3- (4-methoxyphenyl) -3- (2-iodo-5 acid. -chlorophenyl) thio-2-acetoxypropionic in the form of an oil in quantitative yield.

IR ilq. (cm-1): 3,600 to 2,200, 1,750, 1,605, 1580.

iax
The product obtained is dissolved in 10 ml of dichloromethane, 4 ml of thionyl chloride are added, then the mixture is refluxed for 2 hours. The reaction mixture is concentrated under reduced pressure to obtain 2.27 g of (+) - threo-3 (4-methoxyphenyl) -3- (2-iodo-5-chlorophenyl) thio-2-acetoxypropionyl chloride in quantitative yield. .IR #liq (cm 1): 1795, 1760, 1610.

max
(4) A solution of 2.27 g of the product obtained above in 100 ml of dichloromethane is added to a solution of 480 mg of
N, N-dimethyl ethylenediamine and 570 ng of triethylamine in 70 ml of dichloronethane. The mixture is stirred at the same temperature for 1 hour. After the reaction, the mixture was diluted with ethyl acetate, washed with 5% sodium bicarbonate and water, dried and concentrated under reduced pressure to obtain 2.48 g of () - threo-N- [2- (dimethylamino) ethyl] -3- (4-methoxyphenyl) -3- (2-iodo-5-chlorophenyl) thio-2-acetoxypropionamide as an oil in quantitative yield.

IR #liq. (cm-1): 3,330, 3,070, 2,820, 2,770, 1,750, 1,670, 1,610,
max
1,530, 1,515.

(5) A mixture of 2.3 g of the product obtained above, 50 mg of cuprous iodide and 1.21 g of potassium carbonate in 20 ml of chlorobenzene is refluxed for 2 hours. After the reaction, the mixture is diluted with ethyl acetate. Insoluble inorganic matter is filtered off, washed with ethyl acetate, the filtrate and washings are combined and concentrated under reduced pressure. The residual oil is purified by chromatography on a gel column. silica solvent: chloroform / ethanol = 20/1] and the product is converted into its hydrochloride, then recrystallized from ethanol-diethyl ether to obtain 1.53 g of (+) - cis-2- (4- hydrochloride) methoxyphenyl) - 3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one with a yield of 79.4%.

Mp 159-161 ° C.

Example 2
25 mg of cuprous iodide and 520 mg of potassium carbonate are added to a solution of 1.0 g of (+) - threo-N) - [2- (dimethylamino) ethyl] -3- (4-methoxyphenyl). ) -3- (2-iodo-5-chlorophenyl) thio-2-acetoxypropionamide in 10 ml of dimethylsulfoxide and 10 ml of toluene and the mixture is stirred at 110 ° C for 2 hours. After the reaction, the mixture is diluted with ethyl acetate. The insoluble mineral matters are separated by filtration and the filtrate is washed with water, dried and concentrated under reduced pressure. The residual oil is purified by chromatography on a column of silica gel [solvent: chloroform / ethanol = 20/1] and the product is converted to its hydrochloride, then recrystallized from chloroform-ethanol-diethyl ether to obtain 410 mg of (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5 hydrochloride. -t2- (dimathylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one in a yield of 48.7 *.

The physicochemical properties of the product are identical to those of the product obtained in Example 1- (5).

Example 3
(1) 6.7 g of t +) - threo-3- (4-methoxyphenyl) - 3- (2-iodo-5-chlorophenyl) thio-2-hydroxypropionic acid are dissolved in 30 ml of pyridine. 4.95 g of (S) -1- (2-naphthylsulfonyl) pyrrolidine-2-carbonyl chloride was added to the solution while cooling with ice, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate and water are added to the reaction mixture and the mixture is acidified with dilute hydrochloric acid. The organic layer is separated and washed with 10% hydrochloric acid and water, dried and evaporated to remove the solvent. The residue is separated by chromatography on a column of silica gel solvent: chloroform / ethyl acetate / acetic acid / water / ethanol = 1430/1 170/12/8/1201 to obtain 4.45 g of (2S, 3S) -3- (4-methoxyphenyl) -3- (2 -iodo-5-chloro-phenyl) thio-2 - [(S) -1- (2-naphthylsulfonyl) pyrrolidine-2-carbonyl] oxypropionic.

(2) 4.45 g of the product obtained above is added to a solution of 6.6 g of potassium carbonate in 36 ml of water and 66 ml of methanol, and the mixture is stirred at room temperature for a period of time. night. The reaction mixture is acidified and extracted with chloroform. The extract is washed with water, dried and evaporated to remove the solvent and the residue is purified by chromatography on a silica gel column [solvent chloroform / ethanol / acetic acid = 600/48/5] to obtain obtain 2.32 g of (+) - threo-3- (4-methoxyphenyl) -3- (2-iodo-5-chlorophenyl) thio-2-hydroxypropiomic acid in the form of an oil with a yield of 84, 4 t.

[&alpha;] 24: +94.5 '(C = 0.40; tetrahydrofuran).

IR Sluj61 (cm-): 3,300 (wide), 1,710, 1,610, 1,580.

max
(3) A mixture of 1.9 g of the product obtained above and 10 ml of acetic anhydride is stirred at 60 ° C. for 2 hours. The reaction mixture is worked up in the same manner as described in Example 1- (3) to obtain 2.07 g of (+) - threo-3- (4-methoxyphenyl) -3- (2-iodo- 5-chlorophenyl) thio-2-acetoxypropionic.

23 [&alpha;] D: +69.7 (C = 0.83; chloroform).

IR #chloroform (c-1): i 750, 1715, 1640, 1600.

The product obtained above is dissolved in 10 ml of dichlorometham, 4 ml of thionyl chloride are added and the mixture is refluxed for 2 hours. The reaction mixture is concentrated under reduced pressure to obtain 2.15 g of sodium chloride.
(+) - threo-3- (4-methoxyphenyl) -3- (2-iodo-5-chlorophenyl) thio-2-acetoxypropionyl as an oil in quantitative yield.

(4) A solution of the product obtained above in 100 ml of dichioronethane is added to a solution of 480 mg of N, N-dimethylethylenediamine and 570 mg of triethylamine in 60 ml of dichloronethane and the mixture is treated in the same way as described in Example 1- (4) to obtain 2.35 g of (+) - threo-N- [2
(dimethylamino) ethyl] -3- (2-iodo-5-chlorophenyl) thio-3- (4-methoxy-phenyl) -2-acetoxypropionamide as an oil in quantitative yield.

21 [&alpha;] D: +80.2 (C = 0.41; chloroform)
IR liq. (cm-1): 3,320, 3,070, 2,930, 2,850, 2,830, 2,760, 1,740,
max
1,660, 1,600, 1,575, 1505.

(5) A mixture of 4.1 g of the product obtained above, 100 mg of cuprous iodide, 2.6 g of potassium carbonate and 50 ml of chlorobenzene is refluxed for 3 hours. The reaction mixture is treated in the same way as described in Example 1- (5) and the product is converted into the maleate, then recrystallized from methanol to obtain 3.35 g of (+) - cis-2 maleate. - (4methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3- dihydro-1,5-benzothiazepine-4 (5H) -one with a yield of 83.4 t .

Pf. 158-160-C.

Examples 4 to 10
The corresponding starting compounds are treated in the same way as described in one of Examples 1 to 3 to obtain the following compounds [4] (+) - cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2 - (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one.

Mp 123-125 ° C.

[5] (+) - cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (dimethylamino) ethyl] -9-chloro-2,3-dihydro-1,5-benzothiazepine- perchlorate 4 (5H) -one 1/4 hydrated.

Pf. 190 to 192 C.

L6] (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (divethylamino) ethyl] -9-chloro-2,3-dihydro-1,5-benzothiazepine- 4 hydrochloride (5H) -one monohydrate.

Pf. 140 to 143 C.

173 {+) - cis-2- (4-methylphenyl) -3-hydroxy-5- [2- (dimethylamino) thyl] -8-methyl-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one.

Mp 142-143 ° C (recrystallized from ethyl acetate).

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

Mp 190 to 192 C (recrystallized from acetone and isopropyl ether).

Mp 184-186 C (recrystallized from isopropyl alcohol and ether).

Fumarate:
Mp 196.5 to 198.5 C (decomposition, recrystallized from propanol)
Maleate: mp 172.5 to 174 C (recrystallized from methanol).

Mp 191.9 ° C (recrystallized from water).

Bethanesulfonate:
Mp 124 to 128 C (recrystallized from propanol).

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

Mp 194-197 ° C (decomp., Recrystallized from ethanol).

[&Alpha;] D: +83.7 (C = 0.362; methanol).

Oxalate:
Mp 179 at 180 C (recrystallized from ethanol).

20 [&alpha;] D: +88.2 (C = 0.288; methanol) [10] (-) - cis-2- (4-methylphenyl) -3-acetoxy-5- [2- (diXethylaXino) ethyl maleate -8-methyl-2,3-dihydro-1,5-benzothiazepine- 4 (5H) -one
Mp 195-197.5C (decomposition, recrystallized from ethanol).

[&Alpha;] D -83.6 (C = 0.50; methanol).

Oxalate
Mp 179.5 at 181 C (decomposition, recrystallized from ethanol)
[&Alpha;] D: -83.8 (C = 0.333; methanol).

Fumarate
Mp 210.5-212.5 ° C (decomp., Recrystallized from ethanol).

[&Alpha;] D: -91.3 (C = 0.323; methanol).

L - (+) - tartrate:
Mp 140-143 ° C (recrystallized from ethanol and diethyl ether).

Claims (6)

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

wherein R1 is lower alkyl or lower alkoxy; R2 is a hydrogen atom or a lower alkanoyl group; one of R3 and R4 is a halogen atom or a lower alkyl group and the other is a hydrogen atom; and each of R5 and R6 is a lower alkyl group, or one of its acid addition salts suitable for pharmacy, characterized in that it consists in subjecting to intramolecular cyclization a propionamide derivative of formula

wherein X is a bromine or iodine atom and R1 to R6 are known as defined above and, if necessary, further converting the compound to a pharmaceutically suitable acid addition salt thereof. 2. Process for preparing a 1,5-benzothiazepine derivative of the formula

wherein R1 is lower alkyl or lower alkoxy; R2 is a hydrogen atom or a lower alkanoyl group; one of R3 and R4 is a halogen atom or a lower alkyl group and the other is a hydrogen atom; and each of R5 and R6 is a lower alkyl group, or one of its acid addition salts suitable in pharmacy, characterized in that it consists in condensing a propionic acid derivative of formula

wherein X is a bromine or iodine atom and R1 to R4 are as defined above, or a reactive derivative thereof, and a N, N-di (lower alkyljethylenediamine, to form a propionamide derivative of the formula

wherein R1 to R6 and X are as defined above, subjecting the propionamide derivative to intramolecular cyclization and, if necessary, further converting the product to a pharmaceutically suitable acid addition salt thereof. 3. Method according to one of claims 1 or 2, characterized in that the intramolecular cyclization is carried out in the presence of a catalyst and a base. 4. Method according to claim 3, characterized in that the intramolecular cyclization is carried out in the presence of a transition metal catalyst and an inorganic or organic base at a temperature of 50 to 100 ° C. 5. Method according to any one of claims 1 to 4, characterized in that the 1,5-benzothiazepine derivative is 2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one, 6. Method according to any one of claims 1 to 4, characterized in that the 1,5-benzothiazepine derivative is 2- (4-methyiphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-methyl-2,3-dihydro-1,5-benzothiazepine-4 (5E) -one.