GB2154578A - Novel 1,5-benzothiazepine derivatives and processes for preparing the same - Google Patents

Abstract

Novel 1,5-benzothiazepine derivatives of the formula: <IMAGE> wherein R<1> is hydrogen or lower alkanoyl, each of R<2> and R<3> is lower alkyl, and either one of R<4> and R<5> is fluorine and the other one is hydrogen, and a pharmaceutically acceptable acid addition salt thereof, the derivative (I) and its salt being useful as a hypotensive agent and/or a cerebral or coronary vasodilator, and a 1,5 benzothiazepine derivative of the formula <IMAGE> wherein R<1> is hydrogen or lower alkanoyl, and either one of R<4> and R<5> is fluorine and the other one is hydrogen, or a salt thereof.

Description

SPECIFICATION Novel 1,5-benzothiazepine derivatives and processes for preparing the same This invention relates to novel 1,5-benzothiazepine derivatives and processes for preparing the same. More particularly, it relates to a compound of the formula:

wherein R1 is hydrogen or lower alkanoyl, each of R2 and R3 is lower alkyl, and either one of R4 and R5 is fluorine and the other is hydrogen, or a pharmaceuticaliy acceptable acid addition salt thereof.

U.S. Patent 3,562,257 discloses various benzothiazepine derivatives such as 2-(4-methoxyphenyl)-3hydroxy (or acetoxy)-5-[2-(dimethylamino)ethyl]-7-chloro-2,3-dihydro-1 ,5-benzothiazepin-4(5H )-one. Said U.S. Patent also discloses that these benzothiazepine derivatives show antidepressive, tranquilizing and/or coronary vasodilating activities.

As a result of various investigations, we have now found that the novel compound (I) of the present invention or a pharmaceutically acceptable acid addition salt thereof has potent hypotensive and cerebral or coronary vasodilator activities. The compound (I) of the invention is epsecially characteristic in that it shows long-lasting therapeutic effects (e.g., long-lasting hypotensive activity for example showing activity even 4 hours after administration). For example, when administered orally to spontaneously hypertensive rats (SHR), (i)-cis-2.(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-84luoro-2,3-dihydro-1 ,5benzothiazepin-4(5H)-one (hydrochloride) at a dose of 30 mg;kg showed a decrease of about 64 mm Hg or 50 mm Hg in blood pressure of said SHR one or 4 hours after administration of the test compound.

In addition, the compound (I) of the present invention shows a potent platelet aggregation-inhibiting activity and is low in toxicity.

Representative examples of the compound of the present invention are those of the formula (I) in which R' is hydrogen or lower alkanoyl of 2 to 4 carbon atoms e.g. acetyl, propionyl or butyryl; each of R2 and R3 is lower alkyl of one to 4 carbon atoms e.g. methyl, ethyl, propyl or butyl; and either one of R4 and R5 is fluorine and the other one is hydrogen. Among the compounds of the present invention, a preferred subgenus is those of the formula (I) in which R1 is acetyl, R2 and R3 are methyl and either one of R4 and R5 is fluorine and the other one is hydrogen.

While the compound (I) of the present invention can exist in the form of two stereoisomers (i.e., cis and trans isomers) or four optical isomers (i.e., (el-cis, (-)-cis, (-)-trans and (-)4rans isomers) due to the two asymmetric carbon atoms involved therein, all of these isomers or a mixture thereof are included within the scope of the invention.

According to the present invention, the compound (I) can be prepared for example by condensing a compound oftheformula:

wherein R1, R4 and R5 are the same as defined above, or a salt thereof with a compound of the formula:

wherein R2 and R3 are the same as defined above and Xis halogen, or a salt thereof.

Alternatively, the compound (I) in which R1 is lower alkanoyl can be prepared for example by acylating a compound of the formula:

wherein R2, R3, R4 and R5 are the same as defined above, or a salt thereof to give a compound of the formula:

wherein R2, R3, R4 and R5 are the same as defined above and R6 is lower alkanoyl.

The condensation of the compound (II) or a salt thereof with the compound (III) or a salt thereof can be carried out for example in a solvent. Suitable salts of the compound (II) are, for example, alkali metal salts e.g. sodium or potassium salts. When the compound (II) is used in free form, it is preferred to carry out the reaction in the presence of an alkali. The alkali may be, for example, alkali metal hydroxide (e.g. potassium hydroxide, or sodium hydroxide), alkali metal carbonate (e.g., potassium carbonate) or alkali metal hydride (e.g., sodium hydride). Examples of the salt of the compound (ill) are acid addition salts thereof e.g.

hydrochloride or hydrobromide. Acetone, ethyl acetate, dimethylsulfoxide, dimethylformamide, acetonitrile, tetrahydrofuran and dioxane are examples of suitable solvents. It is preferred to carry out the reaction at a temperature of 0 to 1 00 C, especially 20" to 70"C.

The acylation of the compound (I-a) can be accomplished for example by reacting said compound with an acylating agent in a solvent in the presence or absence of an acid acceptor. The acylating agent may be, for example, a reactive derivative of the carboxylic acid compound: Rs-OH (wherein R6 is the same as defined above) such as, for example, lower alkanoic acid anhydride (e.g., acetic an hydride or propionic an hydride) or lower alkanoyl halide (e.g., acetyl chloride or propionyl chloride). The acid acceptor may be, for example, pyridine, triethylamine, methylpiperidine, methylmorpholine, methylpyrrolidine or N-ethyl-N,Ndiisopropylamine. Acetic acid, chloroform, dichloromethane, dimethylformamide and tetrahydrofuran are examples of suitable solvents.When an excess amount of acetic anhydride is used as the acylating agent, it is not always necessary to use the solvent because said acetic anhydride serves as the solvent. It is preferred to carry out the reaction at a temperature of 50 to 140 C if the lower alkanoic anhydride is used as the acylating agent; or at a temperature of - 10 to 100"C if the lower alkanoic acid halide is used as the acylating agent. The compound (I-a) may be used for the above-mentioned reaction in the form of either a free base or an acid addition salt thereof (e.g., hydrochloride, or hydrobromide).

The starting compound (II) of the invention is a novel compound and may be prepared, for example, according to the method by the following reaction scheme:

wherein R4, R5 and R6 are the same as defined above and R7 is lower alkyl.

Thus, the compound (II) can be prepared for example by reacting 2-amino-5- or 6-fluoro-thiophenol (IV) with the 3-(p-methoxyphenyl)glycidate (V) to give the compound (Il-a) and, if required, further acylating the compound (Il-a) to give the compound (Il-b). Alternatively, the compound (Il-a) can be prepared by reacting 2-amino-5- or 6-thiophenol (IV) with the 3-(p-methoxyphenyl)glycidate (V) to give the propionate compound (VI) and then the subjecting the compound (Vl) to intramolecular cyclization to give the compound (Il-a).

The reaction of the compound (IV) with the compound (V) can be accomplished for example by heating a mixture of the compound (IV) and the compound (V) at a temperature of 150 to 1 60"C. The reaction may be carried out either in a solvent (e.g., xylene, diphenyl ether, or p-cymene) or without solvent. When the reaction product thus obtained is a mixture of the compound (Il-a) and the compound (VI) or a mixture of two stereoisomers (i.e., cis and trans isomers) of the compound (Il-a), they can be separated from each other by their difference in solubility in a solvent (e.g., ethanol or ethyl acetate) or by column chromatography.The compound (VI) may be prepared as the main product when the reaction of the compound (lV) with the compound (V) is carried out at a temperature of 25 to 11 0 C, especially 600 to 1 00 C, in a solvent (e.g., toluene, xylene, acetonitrile, or dioxane).

The intramolecular cyclization of the thus-obtained compound (VI) can be carried out in the presence of methyl-sulfinylcarbanion (CH3SOCH2-) prepared from dimethylsulfoxide and sodium hydride) in di methyl- sulfoxide. It is preferred to carry out the reaction at a temperature of 0 to 50"C, especially 20 to 30"C.

Alternatively, the intramolecular cyclization of the compound (VI) may be carried out by heating it either in a solvent or without solvent. Xylene, toluene, diphenyl ether, p-cymene and acetic acid are examples of suitable solvents. It is preferred to carry out the reaction at a temperature of 1100 to 1 60"C, especially under refluxing.

The subsequent acylation of the compound (Il-a) may be accomplished by reacting said compound with an acylating agent e.g. a lower alkanoic acid anhydride or lower alkanoyl halide in the presence or absence of an acid acceptor. This acylation reaction is carried out under the same conditions as used in acylation of the compound (I-a).

The compound (I) of the invention can be used for pharmaceutical use either as the free base or as an acid addition salt thereof. Pharmaceutically acceptable acid addition salts of the compound (I) are, for example, inorganic acid addition salts e.g. hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate or phosphate, or organic acid addition salts e.g. oxalate, maleate, fumarate or methanesulfonate. These salts may be prepared, for example, by neutralizing the compound (I) with an acid. The compound (I) or a pharmaceutically acceptable acid addition salt thereof can be administered either orally or parenterally.

Further, the compound (I) or its salt may be used in the form of a pharmaceutical preparation containing the same compound in conjunction or admixture with a pharmaceutical excipient suitable for oral or parenteral administration. Suitable excipients are, for example, starch, lactose, glucose, potassium phosphate, corn starch, gum arabic, stearic acid and other known medicinal excipients. The pharmaceutical preparations may be in solid form e.g. tablets, pills, capsules or suppositories, or in liquid form e.g. solutions, suspensions or emulsions. Further, when administered parenterally, the pharmaceutical preparation may be used in the form of injections.

As mentioned hereinbefore, the compound (I) of the present invention has a potent hypotensive activity, a potent cerebral or coronary vasodilating activity and a potent platelet aggregation-inhibiting activity.

Therefore, the compound (I) is useful for the treatment, amelioration or prophylaxis of hypertension; cerebral diseases e.g. cerebral vasospasm or cerebral infarction; heart diseases e.g. angina pectoris, arrhythmias or coronary or cardiac infarction.

The therapeutic dose of the compound (I) or its salt depends on the route of administration, the age, weight and conditions of patients, and particular diseases to be treated. In general, however, it may be used at a dose of 0.05 to 10 mg/kg/day, especially at a dose of 0.2 to 10 mg/kg/day in the case of oral administration or at a dose of 0.05 to 5 mg/kg/day in the case of parental administration (e.g., intravenous injection).

Practical and presently preferred embodiments of the present invention are illustratively shown below.

Throughout the specification and claims, the terms "lower alkyl", "lower alkanoyl", "lower alkanoic acid" and "lower alkanoic acid anhydride" should be interpreted as referring to alkyl of one to 4 carbon atoms, alkanoyl of 2 to 4 carbon atoms, alkanoic acid of 2 to 4 carbon atoms and alkanoic acid anhydride of 4 to 8 carbon atoms respectively.

Experiment 1 (hypotensive activity) A test compound (dose: 100 or 30 mg/kg) dissolved in water was administered orally to spontaneously hypertensive rats (SHR) (one group: 3 rats) fasted overnight). The systolic blood pressure of the rats was measured by the tail plethysmographic technique (The Journal of Laboratory and Clinical Medicine 78 (1971), page 957). The hypotensive activity of the test compound was estimated one or 4 hours after dosing.

The results are shown in the following Table 1.

TABLE 1 Hypotensive activity Test Dose Decrease in blood pressure (mm Hg) compounds* (mg/kg) 1 hr 4 hr 30 -63.7 -50.0 1.

100 -66.9 -72.9 2. 100 -39.0 -60.3 Note: *: Compound 1 (+ )-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl ]-8- fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride Compound 2 (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-9- fluoro-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one hydrochloride Experiment 2 (Cerebral vasodilating activity) Male dogs weighing about 15 kg were anesthetized with sodium pentobarbital (30 mglkg, intravenous injection). The blood flow in vertebral artery was measured continuously by means of an electromagnetic flowmeter under artificial respiration. A test compound was injected into vertebral artery.The cerebral vasodilating activity of the test compound was estimated in terms of the potency ratio of said compound to papaverine, which was calculated from the dose-response curves thereof.

The results are shown in the following Table 2.

TABLE 2 Cerebral Test compounds vasodilating activity (potency ratio) (The compounds of the present invention) (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2- 4.5 (dimethylamino)ethyl]-8-fluoro-2,3-dihydro-1 5- benzothiazepin-4(5H)-one hydrochloride ( + )-cis-2-(4-methoxyphenyl )-3-hydroxy-5-[2- 4.2 (dimethylamino)ethyl]-8-fluoro-2,3-dihydro-1,5- benzothiazepin-4(5H)-one hydrochloride (Positive control) Papaverine 1.0 Experiment 3 (Coronary vasodilating activity) Langendorff's method was used for testing the effect of a test compound on the coronary blood flow of the isolated heart of guinea pig (about 280 g).The isolated heart was perfused with Locke-Ringer solution containing 2% of defibrinated rabbit blood, which had been saturated with a mixed gas of 95% 2 and 5% CO2 (30"C). Perfusion pressure was kept at 40 cm H2O. A solution of a test compound in an aqueous 5% glucose solution was injected into the perfusate at a volume of 0.1 ml per heart. The outflow of the perfusate was measured by means of a drop counter.

The coronary vasodilating activity of the test compound was expressed as (+) if the increase in coronary blood flow is not less than 0.5 ml/minute at a dose of 30g/heart.

The results are shown in the following Table 3.

TABLE 3 Coronary vaso dilating activity ( + )-cis-2-(4-methoxyphenyl )-3-hydroxy-5-[2- + (dimethylamino)ethyl]-84l uoro-2,3-dihydro-1 5- benzothiazepin-4(5H)-one hydrochloride (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2- + (dimethylamino)ethyl]-8-fluoro-2,3-dihydro-1 ,5- benzothiazepin-4(5H)-one hydrochloride ( + )-cis-2-(4-methoxyphenyl )-3-hydroxy-5-[2- + (dimethylamino)ethyl]-9-fluoro-2,3-dihydro-1,5- benzothiazepin-4(5H)-one hydrochloride (- )-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2- + (dimethylamino)ethyl]-9-fluoro-2,3-dihydro-1 ,5- benzothiazepin-4(5H)-one hydrochloride Experiment 4 (Platelet aggregation-inhibiting activity) Blood was collected from the abdominal aorta of male Sprague-Dawley rats (body weight: 200 - 250 g) which were anesthetized with ether. Nine volumes of said blood were mixed with one volume of an aqueous 3.8% trisodium citrate solution, and the mixture was centrifuged at 250 X g for 5 minutes to give platelet-rich plasma (hereinafter referred to as "PRP") as the supernatant solution. The bottom layer was further centrifuged at 750 X g for 10 minutes to give platelet-poor plasma (hereinafter referred to as "PPP") as the supernatant solution. PRP was diluted with PPP so that the blood platelet count was 0.8 - 1 x 1061mum3. Then, a mixture of 200 Fl of said diluted PRP and 25 l of a test compound solution (final concentration: 100 llg/ml) was introduced into a glass cell of an aggregometer.After the mixture was stirred for 2 minutes at 370C, 25iÌ of a collagen solution which was prepared by the method of Holmsen et al. [Biochem, Biophys. Acta, 186, page 254(1969)] were added thereto, and the percentage inhibition of platelet aggregation was calculated from the degree of platelet aggregation which was estimated by Born's method [Nature, 194, page 927(1962)].Further, on the basis of said percentage inhibition calculated above, the platelet aggregationinhibiting activity of the test compound was expressed as (-) if the test compound showed less than 10% inhibition of platelet aggregation; (+) if the test compound showed not less than 10% inhibition of platelet aggregation but said percentage inhibition was lower than the of acetylsalicyclic acid (100 g/ml); or (+ +) if the test compound showed the platelet aggregation-inhibiting activity at least as strong as that of acetylsalicyclic acid (100Agfml).

The results are shown in the following Table 4.

TABLE 4 Platelet Test compounds aggregation inhibiting activity ( c ()-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2- + + (dimethylamino)ethyl]-8-fluoro-2,3-dihydro-1,5- benzothiazepin-4(5H)-one hydrochloride ()-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2- + + (dimethylamino)ethyl]-8-fl uoro-2,3-dihydro-1 ,5- benzothiazepin-4(5H)-one hydrochloride ( + )-cis-2-(4-methoxyphenyl )-3-hydroxy-5-[2- + + (dimethylamino)ethyl]-9-fluoro-2,3-dihydro-1,5- benzothiazepin-4(5H)-one hydrochloride ()-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2- + + (dimethylamino)ethyl]-9-fluoro-2,3-dihydro-1,5- benzothiazepin-4(5H)-one hydrochloride Example 1 A mixture of 4 g of (+) cis-2-(4-methoxyphenyl)-3-hydroxy-8-fiuorn-2,3-dihydro-1,5-benzothiazepin-4(5H)- one, 1.99 g of 2-(dimethylamino)ethyl chloride hydrochloride, 4.3 g of potassium carbonate and 50 ml of acetone is refluxed for 18 hours. After the reaction is completed, insoluble materials are removed by filtration and washed with hot acetone. The filtrate and the washings are combined and then evaporated to remove solvent. The residue is converted to its hydrochloride and recrystallized from a mixture of isopropanol, ethanol and ether. 4 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8- fluoro-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one hydrochloride are obtained.

M.p. 197- 1980C Example 2 A mixture of 0.7 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-fluoro-2,3- dihydro-1 ,5-benzothiazepin-4(5H)-one hydrochloride and 8 ml of acetic anhydride is heated at 100 C for 4 hours. After the reaction is completed, the mixture is evaporated under reduced pressure to remove solvent.

Toluene is added to the residue, and the mixture is evaporated under reduced pressure to remove solvent.

The residue is recrystallized from a mixture of ethanol and ether. 0.68 g of ()-cis-2-(4-methoxyphenyI)-3- acetoxy-5-[2-(dimethylamino)ethyl]-8-fluoro-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one hydrochloride1/3 H2O is obtained.

M.p. 137- 1410C Example 3 A mixture of 1.2 g of ( )-cis-2-(4-methoxyphenyl)-3-hydroxy-94luoro-2,3-dihydro-1 ,5-benzothiazepin- 4(5H)-one, 0.65 g of 2-(dimethylamino)ethyl chloride hydrochloride, 1.3 g of potassium carbonate and 50 ml of acetone is treated in the same manner as described in Example 1. The crude product thus obtained is converted to its hydrochloride and recrystallized from isopropanol. 1.7 g of (+)-cis-2-(4-methoxyphenyl)-3- hydroxy-5-[2-(dimethylamino)ethyl]-94luoro-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one hydrochloride are obtained.

M.p. 202"- 205 Example 4 A mixture of 1 g of (~)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-9-fluoro-2,3- dihydro-1,5-benzothiazepin-4(5H)-one and 10 ml of acetic anhydride is treated in the same manner as described in Example 2. The crude product is converted to its hydrochloride and recrystallized from a mixture of isopropanol and ether. 0.729 g of (~)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)- ethylj-9-fluoro-2,3-dihydro-1 ,5-benzothiazepin-4(5H )-one hydrochloride is obtained.

M.p. 200"- 204"C (decomp.) [Preparation of Starting Compound] Preparation 1 A mixture of 20.17 g of 2-amino-5-fluoro-thiophenol and 28.8 g of methyl (-c)-trans-3-(4 methoxyphenyl)glycidate is heated at 1500 - 1 600C for 15 hours. After the reaction is completed, ethanol is added to the reaction mixture. The precipitated crystals are collected by filtration and washed with ethanol and then recrystallized from a mixture of dimethylformamide and ethanol. 6.92 g of (t)-cis-2-(4 methoxyphenyl)-3-hydroxy-8-fluoro-2,3-dihydro-1 ,5-benzothiazepin-4(5H )-one are obtained.

M.p. 215"C - 218"C Preparation 2 (1) A mixture of 9.3 g of 2-amino-6-fluoro-thiophenol and 14.88 g of methyl (')-trans-3-(4- methoxyphenyl)glycidate is heated at 150 - 160"C for 17 hours in argon atmosphere. After cooling, the reaction mixture is subjected to silica gel chromatography (Solvent: benzene-ethyl acetate (5:1)), whereby the following compounds are obtained.

Methyl (t)-threo-2-hydrnxy-3-(2-amino-64luornphenylthio)-3-(4-methoxyphenyl)prnpionate: Yield: 3.39 9 M.p. 1100 - 112"C (recrystallized from ethanol) ()-Cis-2-(4-methoxyphenyl)-3-hydroxy-9-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one: Yield. 0.924 9 M.p. 218"- 222"C (r)-Trans-2-(4-methoxyphenyl )-3-hydroxy-9-fluoro-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one: Yield: 0.5g M.p. 231"- 235"C (2) A mixture of 0.683 g of sodium hydride (63% oil dispersion) and 12 ml of dimethylsulfoxide is stirred at 70"C for 45 minutes.After cooling, a solution of 3 g of methyl ( )-threo-2-hydroxy-3-(2-amino-6- fluorophenylthio)-3-(4-methoxyphenyl)propionate in 7 ml of dimethylsulfoxide is added dropwise to the mixture over 5 minutes, and said mixture is stirred at room temperature for 5 minutes. After the reaction is completed, the mixture is poured into ice-water. The aqueous mixture is adjusted to pH of about 7 with acetic acid, and the precipitated crystals are collected by filtration. Said crystals are washed with water and n-hexane, and then dried. 2.39 g of ()-cis-2-(4-methoxyphenyl)-3-hydroxy-94Iuorn-2,3-dihydro-1 ,5- benzothiazepin-4(5H)-one are obtained.

M.p. 205"- 2100C Recrystallization of the thus-obtained product from a mixture of dimethylformamide and ethanol gives crystals melting at 217"- 220"C.

Claims (14)

1. A 1 ,5-benzothiazepine derivative of the formula:

wherein R1 is hydrogen or lower alkanoyl, and each of R2 and R3 is lower alkyl, and either one of R4 and R5 is fluorine and the other one is hydrogen, or a pharmaceutically acceptable acid addition salt thereof.

2. A compound according to claim 1, in which R1 is hydrogen or acetyl.

3. A compound according to claim 1 or 2, in which R2 and R3 are methyl.

4. A compound according to claim 3, in which R1 is hydrogen.

5. A compound according to claim 3, in which R7 is acetyl.

6. A cis isomer of a compound as claimed in any of claims 1 to 5.

7. The compound of claim 5, which is (t)-cis-2-(4-methoxyphenyl)-3-acetoxy-5- (dimethylamino)ethyl]-84luoro-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one or a pharmaceutically acceptable acid addition salt thereof.

8. The compound of claim 5, which is (t)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2- (dimethylamino)ethyl]-94luoro-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one or a pharmaceutically acceptable acid addition salt thereof.

9. A 1 ,5-benzothiazepine derivative of the formula given in claim 1, or a pharmaceutically acceptable acid addition salt thereof, substantially as herein described with reference to and as illustrated in any of the Examples.

10. A process for preparing a 1,5-benzothiazepine derivative of the formula given in claim 1,which comprises condensing a compound of the formula:

ora saltthereofwith a compound oftheformula:

or a salt thereof, wherein R1, R2, R3, R4 and R5 have the meanings given in claim 1, and Xis halogen, and, if required, further converting the product to a pharmaceutically acceptable acid addition salt thereof.

11. A process for preparing 1 ,5-benzothiazepine derivative of the formula given in claim 1 which comprises acylating a compound of the formula:

wherein R2, R3, R4 and R5 have the meanings given in claim 1, or a salt thereof and, if required, further converting the product to a pharmaceutically acceptable acid addition salt thereof.

12. A pharmaceutical composition which comprises a therapeutically effective amount of a compound of the formula given in claim 1 or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier therefor.

13. A 1,5-benzothiazepine derivative of the formula given in claim 1, or a pharmaceutically acceptable acid addition salt thereof, for use as a hypotensive agent and/or a cerebral or coronary vasodilator.

14. A 1 ,5-benzothiazepine derivative of the formula:

wherein R' is hydrogen or lower alkanoyl, and either one of R4 and R5 is fluorine and the other one is hydrogen, or a salt thereof.