NO904470L - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE BENZOTIAZEPINE DERIVATIVES. - Google Patents

Description

The present invention relates to a method for the production of therapeutically active 5-{2-[[2-amino-2-oxoethyl]-methylamino]ethyl}-2,3-dihydro-3-hydroxy-2-(4-methoxy-phenyl) -1,5(5H)benzothiazepin-4-one derivatives.

The compounds that can be prepared by the invention correspond to the general formula (I)

in which RI stands for a hydrogen atom or a C2-C4 alkanoyl group

R 2 stands for a hydrogen atom or a C 1 -C 4 alkyl group

n stands for an integer 0-3, and

R3 stands for either a phenyl group containing 1-3 substituents selected from halogen atoms and trifluoromethyl, methyl,

C1-C4 alkoxy or C1-C4 alkylthio, nitro, cyano, carbamoyl, acetamido, methanesulfonamido, methoxycarbonyl or phenylcarbonyl, or an aromatic heterocyclic group such as e.g. a pyridinyl group or imidazolyl group.

The compounds with a general formula (I) can exist in the form of free bases or addition salts with acids. As the carbon atoms in the 2-position and 3-position are asymmetric, the compound can also occur in different diastereoisomers, racemic or optically pure forms. Production of these forms forms part of the invention.

In accordance with the invention, the compounds of the general formula (I) can be prepared according to the following reaction sequence.

A first method consists in reacting a benzothiazepinone of formula (V) (where RI is as indicated above) with a halogenated amine of general formula (IV) (where R 2 and R 3 have the above meaning and Y is a halogen atom such as chlorine or bromine).

The second method consists in reacting a benzothiazepinone of general formula (VI) (where RI has the above meaning) with a halogenated derivative of general formula (II) (where R 2 and R 3 have the above meaning and Y is a halogen atom such as chlorine or bromine).

These two reactions, either between a benzothiazepinone (V) or an amine (VI) (in the form of a free base or acid addition salt) and a halogenated derivative are of the classical type and consequently take place under conditions well known to the person skilled in the art, i.e. for example in an aprotic solvent, such as acetone, butanone-2 or ethyl acetate, at the reflux temperature, in the presence of a base to bind the released acid (and in the individual case to release the base in the starting compound), for example potassium carbonate, and optionally in the presence of a phase transfer catalyst such as tetra-n-butylammonium iodide or benzyltriethylammonium chloride.

It follows that one can convert a compound of formula (I) in which RI stands for a hydrogen atom into a compound of formula (I) in which RI stands for an alkanoyl group by means of an acylation of a known type, as the reverse conversion is also possible by hydrolysis. The benzothiazepinones of formula (V) are described in US patent document 3,562,257. The compounds of formula (VI) are described in European patent applications 158,339 and 158,340.

The halogenated amine of formula (IV) can be prepared, for example, from the alcohol of formula (III) by the action of a halogenating agent such as thionyl chloride. The amino alcohol of formula (III) can itself be prepared using any known method, for example from a halogenated derivative of formula (II) and 2-methylaminoethanol. The compounds of formula (II) can be obtained from chloroacetyl chloride and amines of general formula R 2 -HN-(CH 2 )-R 3 (in which R 2 , n and R 3 are as indicated above) which are described in the literature.

The following examples illustrate in detail the preparation of some compounds in accordance with the invention. Elemental microanalyses and IR and NMR spectra confirm the structures of the products obtained. The figures in parentheses for each example correspond to the figures in the following table which illustrate the structures and physical properties of some of the compounds produced by the invention.

Example 1 (compound no. 1)

(+)-cis-(2S,3S)-3-acetyloxy-2,3-dihydro-5-{2-[[2-(3,4-dimethoxyphenyl)amino-2-oxoethyl]methylamino]ethyl} -2-(4-methoxy-phenyl)-1,5(5H)-benzothiazepin-4-one.

Under reflux, a mixture of 4 g (9.15 mmol) of (+)-cis-(2S,3S)-3-acetyloxy-2,3-dihydro-2-(4-methoxy-phenyl)-5 is heated for 9 hours -(2-methylaminoethyl)-1,5(5H)-benzothiazepin-4-one hydrochloride, 2.4 g (10 mmol) 1-chloro-N-(3,4-dimethoxyphenyl)acetamide and 9.9 g potassium carbonate in 50 ml butanone-2. The mixture is filtered and the filtrate is evaporated and the residue is purified by chromatography on a silica column. In this way, 5.3 g of oil is obtained, which is taken up in 60 ml of ethanol and which is treated with 0.81 g of oxalic acid. The precipitate obtained by adding ether is filtered off and recrystallized from ethanol. 4 g of oxalate is isolated.

M.p.: 144°C [α]D<20>=+59.5° (c=0.5; MeOH).

Example 2 (compound no. 11)

(+)-cis-(2S,3S)-3-acetyloxy-2,3-dihydro-5-{2-[[2-(4-methyl-phenyl)methyl]methylamino-2-oxoethyl]methylamino]ethyl} -2-(4-methoxy-phenyl)-1,5(5H)-benzothiazepin-4-one.

For 9 hours, a mixture of 4 g (9.15 mmol) of (+)-cis-(2S,3S)-3-acetyloxy-2,3-dihydro-2-(4-methoxy-phenyl)-5 is heated under reflux -(2-methylaminoethyl)-1,5(5H)-benzothiazepin-4-one hydrochloride, 1.85 g (8.73 mmol) 1-chloro-N-methyl-N-(4-methylphenyl)- methyl]acetamide and 6.05 g of potassium carbonate in 50 ml of butanone-2. The mixture is filtered, the filtrate is evaporated and the residue is purified by chromatography on a silica column. In this way, 3.5 g of oil is obtained, which is taken up in ethanol and which is treated with 1 equivalent of oxalic acid. The precipitate obtained by adding ether is filtered off and recrystallized from ethanol. 2.5 g of oxalate is isolated.

Mp: 108.3 - 109.2°C [α]D<20>=+71.4° (c=0.3; MeOH).

Example 3 (compound no. 18)

(_+)-cis-(2S,3S)-3-acetyloxy-2,3-dihydro-5-{2- [[2-(2-(3,4-dimethoxyphenyl)ethyl]methylamino-2- oxoethyl]methylamino]ethyl}-2-(4-methoxyphenyl)-1,5(5H)-benzothiazepin-4-one.

Under reflux, a mixture of 3 g (6.7 mmol) of (+)-cis-(2S,3S)-3-acetyloxy-2,3-dihydro-2-(4-methoxy-phenyl)-5 is heated for 8 hours -(2-methylaminoethyl)-1,5(5H)-benzothiazepin-4-one hydrochloride, 2.4 g (8.9 mmol) 1-chloro-N-methyl-N-[2-(3, 4-dimethoxy-phenyl)ethylacetamis and 7 g of potassium carbonate in 50 ml of butanone-2. The mixture is filtered, the filtrate is evaporated and the residue is purified by chromatography on a silica column. An oil is obtained which is taken up in ethanol and which is treated with 1 equivalent of oxalic acid. The precipitate obtained by adding ether from is filtered and recrystallized from ethanol. 2 g of oxalate is isolated.

Mp: 90°C [α]D<20>=+52.8° (c=0.5; MeOH).

Example 4 (compound no. 20)

(+)-cis-(2S,3S)-3-acetyloxy-2,3-dihydro-5-{2-[[2-[3-(1-imidazolyl)propyl]amino-2-oxoethyl]methylamino ]ethyl}-2-(4-methoxy-phenyl)-1,5(5H)-benzothiazepin-4-one.

Under reflux, a mixture of 4 g (9.15 mmol) of (+)-cis-(2S,3S)-3-acetyloxy-2,3-dihydro-2-(4-methoxy-phenyl)-5 is heated for 10 hours -(2-methylaminoethyl)-1,5(5H)-benzothiazepin-4-one hydrochloride, 4 g (19.8 mmol) 1-chloro-N-[3-(1-imidazolyl)propyl]-acetamide and 3.6 g of potassium carbonate in 60 ml of butanone-2. The mixture is filtered, the filtrate is evaporated and the residue is purified by chromatography on a silica column. In this way, 2 g of oil is obtained, which is taken up in 12 ml of ethanol and which is treated with 0.32 g of oxalic acid. The precipitate obtained by adding ether is filtered off and recrystallized from ethanol. 1.1 g of oxalate is isolated.

Mp: 55°C [α]D 2 O=+51.3° (c=0.5; MeOH).

The compounds that can be prepared by the invention were subjected to a number of pharmacological tests which show their interest as therapeutic substances in the cardiovascular system.

Their activity as calcium antagonists is demonstrated using a sample of isolated rabbit aorta. The trial protocol used is a variant of that 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). One calculates the molar concentration which produces 50% decontraction of the response to calcium (CE50) or better its antilogarithm (pCE50).

The pCE50 of the compounds that can be prepared by the invention is from 4.5 to 6.6.

Note: In the column for "salt" denotes ox. an oxalate and fum. denotes a fumarate.

The compounds that can be prepared by the invention were also subjected to an experiment with the binding of [<3>H]nitrendipine on total rat cortex.

The details of the experiment are described in European patent application 0300865.

The concentrations PCE50 of the compounds that can be prepared according to the invention (concentrations that inhibit the specific binding of [-^H] nitrendipene by 50% are between 0.001 and 10 µm.

The compounds that can be produced by the invention were further subjected to an experiment with inhibition of the specific binding of "PAF", platelet activation factor, with the experimental protocol described in European patent application 0320362.

CI50 (the concentrations that inhibit the specific binding by 50%) of the compounds that can be prepared by the invention in this experiment is between 0.5 and 5 µm.

Finally, the compounds that can be prepared by the invention were subjected to an experiment with the inhibition of aggregation of blood platelets induced with "PAF-aceter" (1-O-(c^-Ci-alkyl)_2-acetyl-sn-glyceryl-3-phosphorylcholine) with experimental protocol also described in European patent application 0320362.

The anti-aggregation effect of the compounds is expressed as concentration IC50, as the concentration which inhibits the aggregation produced by PAF-acetate by 50%.

CI50 of the compounds that can be prepared by the invention is between 2 and 20 µm in this experiment.

The results of the experiments show that the compounds that can be prepared by the invention are calcium antagonists and can therefore be used for the treatment of various disorders for which this type of agent is indicated. They can therefore be particularly used within cardiovascular medicine for the treatment of disorders that require modulators for transmembrane and intracellular movements of calcium, especially hypertension, heart pain and cardiac arrhythmia. They can also exhibit anti-athrogenic, cardiac anti-ischemic, cerebral anti-ischemic, anti-migraine, anti-epileptic, anti-asthmatic and anti-ulcer effects.

In the cardiovascular area, they can be used alone or in association with known active other substances such as diuretics, β-blocking agents, inhibitors of the enzyme for the conversion of angiotensin, and antagonists to α-β-receptors.

They are also indicated to potentiate the effect or to reduce the toxicity of agents used in the treatment of cancer or in organ transplants.

The compounds that can be prepared by the invention can be available in all suitable forms for oral or parenteral administration, in association with known excipients, for example in the form of tablets, gels, dragees, capsules, or drinkable or injectable solutions or suspensions.

The daily dose can be, for example, from 30 to 300 mg for oral administration and 25 to 100 mg for parenteral administration.

Claims (2)

1. Benzothiazepine derivatives in the form of pure diastereoisomers or their mixtures, characterized in that they have the general formula (I) in which RI stands for a hydrogen atom or a C2 - C4 alkanoyl group R2 stands for a hydrogen atom or a - C4 alkyl group n stands for an integer 0-3, and R 3 stands for a phenyl group bearing 1-3 substituents selected from halogen atoms and trifluoromethyl, C] - C 4 alkoxy or alkylthio group, nitro, cyano, carbamoyl, acetamido, methanesulfonamido, methoxycarbonyl or phenylcarbonyl group, or an aromatic heterocyclic group such as a pyridinyl group or imidazolyl group, as well as their addition salts with pharmacologically tolerable acids. 2. Procedure for the production of the derivatives specified in claim 1, characterized in that a benzothiazepinone of general formula (VI) (where RI has the above meaning, is reacted with a compound of general formula (II) (where R2 and R3 have the above meaning and Y stands for a halogen atom.