FR2641536A1 - 3-Alkanoyloxy-5-[2-[N-(2-aryl-2-oxoethyl)methylamino]ethyl]-2-(4-m ethoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepin-4-one derivatives, their preparation and their therapeutic application - Google Patents

Abstract

Compound of general formula: in which R represents either a phenyl group optionally substituted by one or two halogen atoms, by one or two (C1-C4)alkyl, (C1-C4)alkoxy or trifluoromethyl groups, or by a methylenedioxy or ethylenedioxy group, or a naphthyl group, and R' represents a (C1-C4)alkyl group. Application in therapeutics.

Description

The present invention relates to 3-alkanoyloxy [tN- (aryl-2-oxo-2-ethyl) methylamino] -2-ethyl) -5 (4-methoxyphenyl) -2,5-dihydro-5H-benzothiazepine-1 derivatives. , 5 one-4, their preparation and their therapeutic application.

The compounds of the invention correspond to the general formula (I) of the scheme given below, in which formula
R represents either a phenyl group optionally substituted with one or two halogen atoms, with one or two linear or branched (C1-C4) alkyl groups, linear or branched (C1-C4) alkoxy or trifluoromethyl groups, or with a methylenedioxy group; or ethylenedioxy, a naphthyl group, and
R 'represents a linear or branched (C1-C4) alkyl group.

The compounds of the invention may be in the form of free bases or addition salts with acids,
They contain in their molecule two chiral carbon atoms (positions 2 and 3 of the heterocycle), and can therefore have various optical isomers. The optical isomers, pure or mixed together, are of course part of the invention.

The compounds of general formula (I) can be prepared according to a process illustrated by the scheme below.

This process consists in reacting a benzothiazepinone of general formula (II) (in which R 'is as defined above) with a halo-2-ethanone of general formula (III) (in which X represents a halogen atom and R is as defined above), under conditions suitable for the condensation of a secondary amine and a halogenated derivative. Thus, for example, the reaction may be carried out in an aprotic solvent, for example a ketone such as acetone or butanone-2, in the presence of a base, for example a mineral base such as potassium carbonate or of sodium, at a temperature ranging from ambient to the reflux temperature of the solvent.

Diagram

The starting compounds of general formula (II) are described in patent applications EP-0158339 and 0158340.

The starting compounds of general formula (III), or at least their process of preparation, are described in patent applications EP-0109317 and 0202164.

The examples which follow illustrate in detail the preparation of some compounds according to the invention.

The elemental microanalyses and the IR and NMR spectra confirm the structures of the products obtained.

The numbers given in the titles of the examples correspond to those in the table given below.

EXAMPLE 1 (Compound No. 6) (+) - cis-2S, 3S-Acetyloxy-3 (4-methoxyphenyl) -2 ([3-N- (3-propyloxyphenyl) -2-oxoethyl] methylamino] -2 ethyl] -2,5-dihydro-5H-benzothiazepine-1,5-one-4 oxalate.

1.1. 3-Phenyloxyphenyl) -1 ethanone.

25 g (124 mmol) of (3-hydroxyphenyl) -1-ethanone in solution in 100 ml of ethanol and 22.1 ml (131 mmol) of 5.9M sodium methoxide are introduced into a 250 ml flask. The mixture is heated at 40 ° C. for 15 minutes, then 33.4 ml (343 mmol) of iodo-propane are introduced and the mixture is heated at 700 ° C. for 6 hours. The solvents are evaporated, the oily residue is taken up in dichloromethane, the solution is washed twice with a cold solution of 1N sodium hydroxide, the organic phase is dried over magnesium sulphate, evaporated and the residue is distilled. at 1020C at about 53 Pa (0.4 mmHg). 16.7 g of product are obtained.

1.2. 2-Bromo-3- (3-propyloxyphenyl) ethanone.

In a flask of 250 ml, 7.1 g (40 mmol) of (3-propyloxyphenyl) -1-ethanone dissolved in 70 ml of dichloromethane are added, 2.25 ml (44 mmol) of bromine in solution in 20 ml of bromine are added. ml of dichloromethane and the mixture is stirred for 30 minutes. Ice is added and the solution is washed with bicarbonate water. The organic phase is dried over magnesium sulfate and the solvent is evaporated. 10.5 g of product are obtained which is used as it is in the next step.

1.3. (+) - cis-2S, 3S-3-acetyloxy-3- (4-methoxyphenyl) -2- [N- (3-propyloxy-phenyl) -2-oxoethyl] methylamino] -2-ethyl-dihydro-2,3-dihydro-5H benzothiazepine-1, 5-one-4, oxalate.

4.0 g (10 mmol) of (+) - cis-2S, 3S-acetyloxy-3 (4-methoxyphenyl) -2 (2-methylaminoethyl) dihydro-2 are introduced into a 250 ml flask, 5H-benzothiazepine-1,5-one-4, 2.9 g (11 mmol) of 2-bromo-3- (3-propyloxyphenyl) ethanone and 3.5 g (25 mmol) of potassium carbonate. The mixture is stirred for 30 minutes at room temperature and is then heated at 380 ° C. for 15 minutes. The mixture is filtered, the filtrate is evaporated, the residue is taken up in dichloromethane, washed with bicarbonate water, the organic phase is dried over magnesium sulphate, evaporated and the residue is purified by column chromatography. silica. 5.4 g of pure base are obtained, treated with 0.84 g of oxalic acid in ethanol. Finally, 3.5 g of oxalate are finally isolated.

Melting point: 1020C. Ec0D20 = + 76.60 (c = 1, MeOH).

 Example 2 (Compound NO10) (+) - cis-2S, 3S-Acetyloxy-3E- [3,4-dimethoxy-phenyl] -2-oxo-ethyl-ethylamino] -2-ethyl-5 (4-methoxyphenyl) 2,3-dihydro-5H-benzothiazepine-1,5-one-4 oxalate.

A mixture of 4 g (9.1 mmol) of (+) - cis-2S, 3S-acetyloxy-3 (4-methoxyphenyl) -2 (2-methylaminoethyl) dihydro is refluxed for 2 hours. -2,3-H -benzothiazepine-1,5-one, 4.3 g (11.8 mmol) bromo-2- (3,4-dimethoxyphenyl) -1 ethanone and 9.6 g (70 mmol) potassium in 80 ml of butanone-2. The mixture is filtered, the filtrate is evaporated, the residue is taken up in 80 ml of chloroform, it is washed with 50 ml of water, the organic phase is dried over magnesium sulphate, evaporated and the oil is purified. residual by chromatography on a silica column. The pure base is taken up in ethanol, treated with 0.5 g of oxalic acid, the precipitate is filtered and recrystallized from ethanol. Finally, 1.9 g of oxalate are finally isolated.

Melting point: 1180C. Ea020 = + 80, 40 (c = 0.5, MeOH).

The following table illustrates the chemical structures and the physical properties of some compounds according to the invention.
Board

<tb> N <SEP> R <SEP> R '<SEP> Salt <SEP>[&alpha;] D20 <SEP><SEP> (c, <SEP> MeOH) <SEP> PF
<tb><SEP> 1 <SEP> Phenyl <SEP> CH3 <SEP> Ox <SEP> +86.40 <SEP> (0.5) <SEP> 140
<tb><SEP> 2 <SEP> Methoxy-3 <SEP> phenyl <SEP> CH3 <SEP> Mal <SEP> +123.80 <SEP> (0.5) <SEP> 95
<tb><SEP> 3 <SEP> Methyl-3 <SEP> Phenyl <SEP> CH3 <SEP> Ox <SEP> +86.60 <SEP> (0.5) <SEP> 110
<tb><SEP> 4 <SEP> Trifluoromethyl-3 <SEP> phenyl <SEP> -CH3 <SEP> Ox <SEP> +800 <SEP> (0.5) <SEP> 136
<tb><SEP> 5 <SEP> Ethoxy-3 <SEP> phenyl <SEP> CH3 <SEP> HC1 <SEP> +83.20 <SEP> (1) <SEP> 152
<tb><SEP> 6 <SEP> n-Propyloxy-3 <SEP> phenyl <SEP> CH3 <SEP> Ox <SEP> +76.60 <SEP> (1) <SEP> 102
<tb><SEP> 7 <SEP> i-Propyloxy-3 <SEP> phenyl <SEP> CH3 <SEP> HC1 <SEP> +79.80 <SEP> (1) <SEP> 146
<tb><SEP> 8 <SEP> 4-Fluoro <SEP> phenyl <SEP> CH3 <SEP> Ox <SEP> +920 <SEP> (0.5) <SEP> 154
<tb><SEP> 9 <SEP> 9 <SEP> Methoxy-4 <SEP> phenyl <SEP> CH3 <SEP> Ox <SEP> +85.30 <SEP> (0.5) <SEP> 116
<tb> 10 <SEP> 3,4-Dimethoxy <SEP> phenyl <SEP> CH3 <SEP> Ox <SEP> +80.40 <SEP> (0.5) <SEP> 118
<tb> 11 <SEP> 3,4-Dichloro [SEP] phenyl <SEP> CH3 <SEP> Ox <SEP> +91.10 <SEP> (0.5) <SEP> 160
<tb> 12 <SEP> 3,4-Methylenedioxy <SEP> phenyl <SEP> CH3 <SEP> Ox <SEP> +83.10 <SEP> (0.5) <SEP> 120
<tb> 13 <SEP> 3,4-Etylenedioxy <SEP> Phenyl <SEP> CH3 <SEP> Ox <SEP> +89.20 <SEP> (0.5) <SEP> 110
<tb> 14 <SEP> Naphtyl-2 <SEP> CH3 <SEP> Ox <SEP> +77.60 <SEP> (0.5) <SEP> 120
<Tb>
In the "Salt" column, "Ox" denotes an oxalate, "Mal" denotes a maleate and "HCl" denotes a hydrochloride.

The compounds of the invention have been the subject of a series of pharmacological tests which have demonstrated their interest as therapeutic substances of the cardiovascular system.

Their activity as calcium antagonists was shown by an isolated rabbit aortic test. The experimental protocol used is a variant of the one used by
Godfraind and Kaba (1969), (Blockade or reversal of the contraction induced by calcium and adrenaline in depolarized arterial smooth muscle, Br. J. Pharmac., 36, 549-560).

The details of the test are described in European patent N001 03500.

The molar concentration causing 50% relaxation of the calcium response (EC50) or its antilogarithm (chip50) is calculated
For the compounds of the invention the pCE50s are 5.5 to 7.0.

The compounds of the invention have also been subjected to a [3H] nitrendipine binding assay on the total rat cortex.

The details of the test are described in European patent application N00300865.

The IC50 concentrations of the compounds of the invention (concentrations which inhibit 50% of the specific binding of 3 [H] nitrendipine) are between 0.01 and 0.5 μM.

Endin the compounds of the invention were the subject of an inhibition test for the specific binding of "PAF", platelet activation factor.

The animals are rabbits weighing 2.5 to 3 kg, anesthetized with pentobarbital sodium (0.25 mg / kg intravenously) and maintained under artificial respiration by intubation. The blood is taken from the carotid artery and collected in tubes containing a citrate anticoagulant. The tubes were centrifuged at 100g for 15 min, and the platelet-rich plasma was diluted with 2 volumes of 10mM Tris-HCl buffer, pH 7.5, containing 150mM sodium chloride and 2mM d EDTA (buffer A). After centrifugation at 1000 g for 10 min at 40 ° C., the pellet is washed with 2 volumes of buffer A, and a new centrifugation is carried out.

The platelet-rich pellet is suspended in ice-cold buffer (10 mM Tris-HCl, pH 7.0, containing 5 mM magnesium chloride and 2 mM EDTA), homogenized and centrifuged at room temperature. 30000g and at 40C for 10 minutes. This procedure is repeated, the resulting pellet is collected in the same buffer, homogenized and the membrane suspension is frozen in liquid nitrogen. For the inhibition of binding assay, the suspension is de-geled and diluted with buffer to obtain a content of about 150 μg protein per milliliter.

Aliquots (30 μg of protein) of membranes are incubated in the presence of 10 mM Tris-HCl buffer, pH 7.0, containing 10 mM magnesium chloride and 0.25% (w / v). bovine serum albumin for 2 hours at 250C with 1 nM tritiated PAF ((3HJ 1-O-hexadecyl-2-acetylsn-glyceryl-3-phosphorylcholine) in a final volume of 1 ml. incubation by collecting the membranes and washing them rapidly with ice-cold buffer on filters
Whatman, using a Skatron cell collector connected to a vacuum pump. The filters are dried and measured by scintigraphic spectrometry. Specific binding is defined by the difference in membrane radioactivity observed in the absence and presence of 1 μM of tritiated PAF.

The inhibition of the binding tests are carried out under the conditions described, in the presence of different concentrations of test compounds. The IC50 concentration for each compound (concentration which inhibits the specific binding by 50%) is then determined by plotting the inhibition curve according to the least squares method.

The IC50's of the compounds of the invention in this test are between 0.1 and 1 M.

The results of the pharmacological tests show that the compounds of the invention are calcium antagonists and can, as such, be used for the treatment of various conditions for which this type of agent is indicated.

Thus, in particular, they can be used in cardiovascular medicine for the treatment of conditions requiring modulators of the transmembrane and intracellular movements of calcium, especially hyper- tension, angina and cardiac arrhythmia.

They also have antiatherogenic, antiplatelet, cardiac anti-ischemic, cerebral ischemic, antimigraine, antiepileptic, antiasthmatic and antiulcerous effects.

In the cardiovascular field they can be used alone or in combination with other known active substances such as diuretics, B-blockers, angiotensin converting enzyme inhibitors, α 1 -receptor antagonists, antiplatelet agents and acetylsalicylic acid.

Combined with agents intended to potentiate their effects or to reduce their toxicity, they may also be indicated for the treatment of cancer or in transplants.

The compounds of the invention may be presented in any form suitable for oral or parenteral administration, in combination with known excipients, for example in the form of tablets, capsules, dragees, capsules, solutions or suspensions drinkable or injectable.

The daily dosage may range, for example, from 30 to 300 mg orally and from 25 to 100 mg parenterally.

Claims (3)

claims 1. Compounds, in the form of pure optical isomers or mixtures thereof, having the general formula (I)

 in which R represents either a phenyl group optionally substituted with one or two halogen atoms, with one or two linear or branched (C1-C4) alkyl (C1-C4) alkyl groups, linear or branched alkoxy or trifluoromethyl groups, or with a methylenedioxy group; or ethylenedioxy, a naphthyl group, and R 'represents a linear or branched (C1-C4) alkyl group, as well as their addition salts with pharmaceutically acceptable acids. 2. Process for the preparation of the compounds according to claim 1, characterized in that a compound of general formula (II) is reacted

 (wherein R 'is as defined in claim 1) with a compound of the general formula (III)

 (wherein X represents a halogen atom and R is as defined in claim 1). 3. Pharmaceutical composition characterized in that it contains a compound according to claim 1, combined with a pharmaceutical excipient.