GB2154577A - 1,5-benzothiazepines - Google Patents

Abstract

Compounds of the general formula: <IMAGE> (wherein R<1> is hydrogen or C2-4 alkanoyl, each of R<2> and R<3> is C1-4 alkyl, and each of R<4> and R<5> is C1-4 alkyl, C1-4 alkoxy or halogen) and their acid addition salts are hypotensive agents and/or cerebral or coronary vasodilators.

Description

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

wherein R1 is hydrogen or lower alkanoyl, each of R2 and R3 is lower alkyl, and each of R4 and R5 is lower alkyl, lower alkoxy or halogen, or a pharmaceutically acceptable acid addition salt thereof.

U.S. Patent 3,562,257 discloses various benzothiazepine derivatives such as 2-(4-methoxyphenyl)-3hydroxy (or acetoxy)-5-12-(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 compound (I) of the present invention or a pharmaceutically acceptable acid addition salt thereof has potent hypotensive and cerebral or coronary vasodilating activities. The compound (I) of the present invention is especially characteristic in that it shows a 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), (+)-cis-2-(4-methoxyphenyi)-3-acetoxy-5- 5- benzothiazepin-4(5H)-one (hydrochloride) at a dose of 30 mg/kg showed a decrease of about 92 mm Hg or 75 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 invention shows a potent platelet aggregation-inhibiting activity and is low in toxicity.

Representative examples of the compound of the present invention include those of the formula (I) in which R1 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 each of R4 and R5 is lower alkyl of one to 4 carbon atoms e.g. methyl, ethyl, propyl, or butyl, lower alkoxy of one to 4 carbon atoms e.g. methoxy, ethoxy propoxy or butoxy, or halogen e.g. chlorine, bromine or fluorine. Among the compounds of the present invention, a preferred subgenus is those of the formula (I) in which RI is hydrogen or acetyl, R2 and R3 are methyl, and R4 and R5 are methyl, methoxy or chlorine. More preferred subgenus is those of the formula (I) in which R1 is acetyl and R2, R3, R4 and R5 are methyl.

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., (+ )-cis, (-)-cis, (+)-trans and (-)-trans 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. Among said isomers, however, the cis isomer, especially the (+)-cis isomer, of the compound (I) is preferred for medicinal use.

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 X is halogen, or a salt thereof. Alternatively, the compound (I) in which R1 is lower alkanoyl can be prepared for example by acylating a

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 a 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). Exampies 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 solvents. It is preferred to carry out the reaction at a temperature of O" to 100"C, especially 20 to 70"C.

The acyiation 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: R6-OH (wherein R6 is the same as defined above) such as, for example, lower alkanoic acid anhydride (e.g.

acetic anhydride or propionic anhydride) and 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,N-diisopropylamine. Acetic acid, chloroform, dichloromethane, dimethylformamide and tetrahydrofuran are examples of a suitable solvent. 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"C to 140"C if the lower alkanoic anhydride is used as the acylating agent; or at a temperature of -10" to 10000 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) or (I-a) of the present invention involves four optical isomers (i.e., (+)-cis, (-)-cis, (+)-trans and (-)-trans isomers) due to the two asymmetric carbon atoms at the 2- and 3-positions of the benzothiazepine skeleton. However, since all of the above-mentioned reactions of the invention can be carried out without racemization, the compound (I) of the invention in an optically active form can be readily obtained by the use of the corresponding optically active isomer of the compound (II) or (I-a) as the starting material.

The starting compound (II) of the invention is a novei compound and may be prepared, for example, according to the methods shown by the following reaction schemes: (Method A)

(Method B)

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

The first step in the Method A, i.e., the reaction of the compound (IV) with the compound (V), can be accomplished by heating a mixture of the compound (IV) and the compound (V) at a temperature of 1 50" to 165"C either in a solvent (e.g., xylene, diphenyl ether or p-cymene) or without solvent. When the compound (Il-a) is obtained as a mixture of two stereoisomers (i.e., cis and trans isomers), they may be separated from each other by their difference in solubility in a solvent for example a lower alkanol (e.g. ethanol) or by column chromatography.

On the other hand, the first step in the Method B, i.e., the reaction of the compound (IV) with the compound (V), can be accomplished by heating a mixture of the compounds (1V) and (V) at a temperature of 25"C to 11000 in a solvent for example toluene, benzene, acetonitrile or dioxane. When the starting compound (V) is lower alkyltrans-3-(4-methoxyphenyl)glycidate, the threo isomer of the compound (Vl) is obtained.

The subsequent optional hydrolysis of the compound (Vl) can be conducted by treating said compound with an alkali (e.g., potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate) at a temperature of 0 to 100"C in a solvent (for example alkanol (e.g., methanol or ethanol or a mixture of water and said alkanol).

If required, the compound (VII) thus-obtained may be optically resolved by using an optically active resolving agent to give the corresponding optically active compound (VII). For example, the optical resolution of (j )-threo-2-hydroxy-3-(2-amino-4,5-dimethyl phenylthio)-3-(4methoxyphenyl)-prnpionic acid can be accomplished by the steps of reacting said compound with an optically active p-hydroxyphenylglycine methyl ester to form the diastereoisomeric salts thereof, and separating the diastereoisomeric salts from each other by selective crystallization. Selective crystallization is carried out by recrystallizing the diastereoisomeric salts from a solvent for example a lower alkanol (e.g. methanol or ethanol).After the optical resolution, the optically active compound (VII) in free form can be recovered by treating the thus-obtained diastereoisomeric salt with an acid (e.g., hydrochloric acid) or an ion-exchange resin.

The intramolecular cyclization of the thus-obtained racemic or optically active compound (VI) or (VII) can be carried out by heating at 110 to 16000 either in a solvent (e.g., xylene, toluene, diphenyl ether, p-cymene or acetic acid) or without solvent. The intramolecular cyclization of the compound (VI) may also be carried out at 0 to 50"C in the presence of methylsulfinylcarbanion (CH3SOCH2-) (prepared from dimethylsufomide and sodium hydride) in dimethylsulfoxide.Alternatively, the intramolecular cyclization of the compound (VII) may be carried out at .100 two 70"C in a solvent (e.g., chloroform, dimethylformamide, carbon tetrachloride, dichloromethane, ethylene dichloride, ethyl acetate, tetrahydrofuran or dioxane) in the presence of a condensing agent.Dicyclohexylcarbodiimide is used alone as the condensing agent or in combination with N-hydroxybenzotriazole, 4-dimethylaminopyridine, N-hydroxyphthalimide, N-hydroxysuccinimide, trichlorophenol, p-nitrophenol, 1 -hydroxybenzotriazole or 3-hydroxy-4-oxo-3,4-dihydro-1 ,2,3-benzotriazine. Carbonyldiimidazole, ethoxyacetylene and 1-methyl-2-halopyridinium halide (e.g., 1-methyl-2-chloropyridinium iodide or 1-methyl-2-bromopyridinium iodide) may also be used as the condensing agent. 1-Methyl-2halopyridinium halide, the condensing agent, may be used in combination with a base for example triethylamine ortributylamine.

The acylation of the racemic or optically active compound (Il-a) obtained above can be accomplished by reacting said compound with an acylating agent for example a lower alkanoic acid 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).

All of the aforementioned reactions can be carried out without racemization.

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 for example cerebral vasospasm or cerebral infarction; and heart diseases for example 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 particuiar 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 parenteral administration (e.g., intravenous injection).

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

Throughout the specification and claims, the terms "lower alkyl", "lower alkoxy", "lower alkanoyl", "lower alkanoic acid" and "lower alkanoic acid anhydride" should be interpreted as referring to alkyl of one to 4 carbon atoms, alkoxy of one to four 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) Atest 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 plethysmographictechnique (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 resuits are shown in the following Table 1.

TABLE 1 Hypotensive activity Test Dose Decrease in blood pressure Compounds* rmglkg (mmHg) lhr 4hr 1. 100 -50.1 -53.8 30 -92.3 -75.0 2. 100 -108.4 -120.0 Note: *: Compound 1 (+ )-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-7,8-dimethyl-2,3 dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride Compound 2 ( +)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-7,8-dimethyl-2,3- dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride Experiment2 (Cerebral vasodilating activity) Male dogs weighing about 15 kg were anesthetized with sodium pentobarbital (30 mg/kg, 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. As a result, the cerebral vasodilating activity of (+ )-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-7,8-dimethyl.2,3- dihydro-1,5-benzothiazepin-4(5H)-one oxalate was 6.4 times stronger than that of papaverine.

Experiment 3 {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 106mm3.Then, a mixture of 200 Fl of said diluted PRP and 25 Fl of a test compound solution (final concentration: 100 ug/ml) was introduced into a glass cell of an aggregometer. After the mixture was stirred for 2 minutes at 37"C, 25 I of a collagen solution which was prepared by the method of Holmsen et al. [Biochem. Biophys. Act, 186, page 245(1969)1 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)1.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 that of acetylsalicyclic acid (100 Fg/ml); or (+ +) if the test compound showed the platelet aggregation-inhibiting activity at least as strong as that of acetylsalicylic acid (100,ag/ml).

The results are shown in the following Table 2.

TABLE 2 Platelet Test compounds aggregation inhibiting actvity (+ )-cis-2-(4-methoxyphenyl)-3-acetoxy- 5-[2-(dimethylamino)ethyl]-7,8-dimethyl- ++ 2,3-dihydro-1,5-benzothiazepin-4(5H) one hydrochloride (+)-cis-2-(4-methoxyphenyl)-3-acetoxy- 5-[2-(dimethylamino)ethyl]-7,8-dimethyl- ++ 2,3-dihydro-1,5-benzothiazepin-4(5H) one oxalate (+ )-cis-2-(4-methoxyphenyl)-3-hydroxy- 5-[2-(dimethylamino)ethyl]-7,8-dimethoxy- ++ 2,3-dihydro-1,5-benzothiazepin 4(5H)-one oxalate (+ )-cis-2-(4-methoxyphenyl)-3-hydroxy-5- + + [2-(dimethylamino)ethyl]-6,7-dimethyl- 2,3-dihydro-1,5-benzothiazepin 4 (5H)-one hydrochloride (+ )-cis-2-(4-methoxyphenyl)-3-hydroxy- 5-[2-(dimethylamino)ethyl]-6,8-dimethyl- ++ 2,3-dihydro-1,5-benzothiazepin-4(5H) one hydrochloride (+)-cis-2-(4-methoxyphenyl)-3-hydroxy- 5-[2-(dimethylamino)ethyl]-7,9-dimethyl- ++ 2,3-dihydro-1,5-benzothiazepin-4(5H) one hydrochloride ( ~ )-cis-2-(4-methoxyphenyl)-3-acetoxy- 5-[2-(dimethylamino)ethyll-7,9-dimethyl- ++ 2,3-dihydro-1,5-benzothiazepin-4(5H) one hydrochloride Example 1 A mixture of 8.2 g of (~)-cis-2-(4-methoxyphenyl)-3-hydroxy-7,8-dimethyl-2,3-dihydro-1,5-benzothiazepin- 4(5H)-one, 3.1 g of potassium hydroxide and 100 ml of dimethylsulfoxide is stirred at room temperature for 30 minutes. Then, 4 g of 2-(dimethyiamino)ethyl chloride hydrochloride are added to the mixture, and said mixture is stirred at room temperature for 20 hours.After the reaction is completed, the mixture is poured into ice-water. The aqueous mixture is extracted with ethyl acetate, and the ethyl acetate layer is further extracted with 20 % hydrochloric acid. The hydrochloric acid layer is alkalized with conc. aqueous ammonia, and the precipitated crystals are collected by filtration, washed with water and then dried. 6.4 g of ()-cis-2-(4-methoxy-phenyl)-3-hydroxy-5[2-(dimethylamino)ethyl]-7,8-dimethyl-2,3-dihydro-1,5benzothiazepin-4(5H)-one are obtained.

M.p.179 - 181 C Hydrochloride: M.p. 248" - 250"C (decomp.) (recrystallized from a mixture of chloroform, ethanol and ether) Example 2 A mixture of one g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyll-7,8-dimethyl-2,3- dihydro-1 ,5-benzothiazepin-4(5H)-one and 10 ml of acetic anhydride is stirred at 11 00C for 4 hours. After the reaction is completed, the mixture is evaporated under reduced pressure to remove solvent. Benzene is added to the residue, and the mixture is evaporated under reduced pressure to remove solvent. The residue is converted to its hydrochloride and then recrystallized from a mixture of chloroform, ethanol and ether.

1.15 g of (+ )-cis-2-(4-methoxyphenyl )-3-acetoxy-5-[2-(dimethylamino)ethyl]-7,8-dimethyl-2,3-dihydro-1,5- benzothiazepin-4(5H)-one hydrochlorie are obtained.

M.p.209 - 211 C (decomp.) Example 3 A mixture of 4.4 g of (+ )-cis-2-(4-methoxyphenyl)-3-hydroxy-7,8-dimethyl-2,3-dihydro-1 ,5-benzothiazepin- 4(5H)-one, 2.12 g of 2-(dimethylamino)ethyl chloride hydrochloride, 4.06 g of potassium carbonate and 200 ml of acetone is refluxed for 20 hours under heating. After the reaction is completed, insoluble materials are removed by filtration and then washed with ethanol. The filtrate and the washing are combined and then evaporated to remove solvent.The residue is dissolved in ethyl acetate, and the solution is washed with water, dried and then evaporated to remove solvent The residue is recrystallized from a mixture of ethyl acetate and n-hexane. 4.85 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-7,8- dimethyl-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one are obtained.

M.p.117 - 118 C []2D0 + 149.70 (C=0.68, methanol) Example 4 A mixture of 4.75 g of (+ )-cis-2-(4-methoxyphenyl)-3-hydrnxy-5-[2-(dimethylamino)ethylj-7,8-dimethyl- 2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 50 ml of acetic anhydride and one ml of pyridine is heated at 110"C for 4 hours. After the reaction is completed, the mixture is evaporated under reduced pressure to remove solvent. Benzene is added to the residue, and the mixture is evaporated under reduced pressure.The residue is converted to its oxalate and then recrystallized from a mixture of chloroform and ethanol. 5.37 g of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-dimethylamino)ethyl]-7,8-dimethyl-2,3-dihydro-1 ,5- benzothiazepin-4(5H)- one oxalate 1/2 H2O are obtained.

M.p.191 - 192 C (decomp.) [0L12D0 + 101.9 (C=0.736, dimethylformamide) Example5 A mixture of 1.8 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-7,8-dimethyl-2,3-dihydro-1,5-benzothiazepin- 4(5H)-one, 0.87 g of 2-(dimethylamino)ethyl chloride hydrochloride, 1.66 g of potassium carbonate and 100 ml of acetone is treated in the same manner as described in Example 3. The crude product thus obtained is recrystallized from a mixture of ethyl acetate and n-hexane. 1.84 g of (-)-cis-2-(4-methoxyphenyl)-3hydroxy-5-[2-(dimethylamino)ethyl-7,8-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.

M.p.117 - 119 C [a]20 - 141.10 (C=0.792, methanol) Example 6 A mixture of 1.76 g of (- )-cis-2-(4-methoxyphenyl )-3-hydroxy-5-[2-(dimethylamino)ethyl]-7,8-dimethyl- 2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 20 ml of acetic anhydride and 0.5 ml of pyridine is treated in the same manner as described in Example 4. The crude product thus obtained is converted to its oxalate and then recrystallized from a mixture of chloroform and ethanol. 1.96 g of (-)-cis-2-(4-methoxyphenyl)-3 acetoxy-5-[2-(dimethylamino)ethyl]-7,8-dimethyl-2,3-dihydro-1 ,5-benzothiazepin-4(5H )-one oxalate. 1/2 H2O are obtained.

M.p. 18 - 1910C (decomp.) [a]2D0 -99.5 (C=0.79, dimethylformamide) Example 7 A mixture of 1.81 g of (j )-cis-2-(4-methoxyphenyl )-3-hydroxy-7,8-dimethoxy-2,3-dihydro-1 ,5- benzothiazepin-4(5H)-one, 0.79 g of 2-(dimethylamino)ethyl chloride hydrochloride, 2.07 g of potassium carbonate and 35 ml of acetone is treated in the same manner as described in Example 3. The crude product thus obtained is recrystallized from methanol.

1.64 g of (+ )-cis-2-(4-methoxyphenyl )-3-hydroxy-5-[2-(dimethylamino)ethyll-7,8-dimethoxy-2,3-dihydro-1 ,5- benzothiazepin-4(5H)-one are obtained.

M.p.154.5 - 156 C Oxalate H20 M.p. 192"- 194"C (decomp.) (recrystallized from methanol) Example 8 A mixture of 0.56 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-7,8-dimethoxy- 2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 6 ml of acetic anhydride and 0.3 ml of pyridine is treated in the same manner as described in Example 4. The crude product thus obtained is converted to its hydrochloride and then recrystallized from ethanol.

0.591 9 of (j)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-7,8-dimethoxy-2,3-dihydro- 1,5-benzothiazepin-4(5H)-one hydrochloride is obtained.

M.p. 241.5"- 243"C (decomp.) Example 9 A mixture of 1.05 g of (j )-cis-2-(4-methoxyphenyl)-3-hydroxy-6,7-dimethyl-2,3-dihydro-1 ,5- benzothiazepin-4(5H)-one, 0.6 g of 2-(dimethylamino)ethyl chloride hydrochloride, 1.02 g of potassium carbonate and 26 ml of acetone is treated in the same manner as described in Example 3. The crude product thus obtained is converted to its hydrochloride and then recrystallized from a mixture of ethanol and ether.

1.164 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-6,7-dimethyl-2,3-dihydro-1,5- benzothiazepin-4(5H)-one hydrochloride .H2O are obtained.

M.p. 117'- 1190C (decomp.) Example 10 A mixture of 0.618 g of ( )-cis-2-(4-methoxyphenyl)-3-hydrnxy-5-[2-(dimethylamino)ethyl]-6,7-dimethyl- 2,3-dihydro1 ,5-benzothiazepin-4 (5H)-one hydrochloride, 6 ml of acetic anhydride and 6 ml of acetic acid is heated at 105 "C for 18 hours. After the reaction is completed, the mixture is evaporated under reduced pressure to remove solvent. Benzene is added to the residue, and the mixture is evaporated under reduced pressure to remove solvent. The residue is recystallized from a mixture of ethanol and ether. 0.44 g of ()-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-dimethylamino)-ethyl]-6,7-dimethyl-2,3-dihydro-1,5benzothiazepin-4(5H)-one hydrochloride 3/2 H2O is obtained.

M.p. 1500 - 1 520C [245 C (decomp)] Example 11 A mixture of 1.5 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-6,8-dimethyl-2,3-dihydro-1,5-benzothiazepin- 4(5H)-one, 0.98 g of 2-(dimethylamino)ethyl chloride hydrochloride, 1.45 g of potassium carbonate and 40 ml of acetone is treated in the same manner as described in Example 3. The crude product thus obtained is converted to its hydrochloride and then recrystallized from ethanol. 1.689 g of )-cis-2-(4-methoxyphenyl)- 3-hydroxy-5-[2-(dimethylamino)ethylj-6,8-dimethyl-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one hydrochloride H2O are obtained.

M.p. 1240 - 1480C (decomp.) Example 12 A mixture of 0.703 g of ()-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-6,8-dimethyl- 2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one hydrochloride, 7 ml of acetic anhydride and 7 ml of acetic acid is treated in the same manner as described in Example 10. The crude product thus obtained is recrystallized from a mixture of ethanol and ether. 0.628 (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2- (dimethylamino)ethyl]-6,8-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H )-one hydrochloride .C2H5OH is obtained.

M.p.218 - 221 C Example 13 A mixture of 1.5 g of l+)-cis-2-(4-methoxyphenyl)-3-hydroxy-7,9-dimethyl-2,3-dihydro-1,5-benzothiazepin- 4(5H)-one, 0,98 g of 2-(dimethylamino)ethyl chloride hydrochioride, 1,45 g of potassium carbonate and 40 ml of acetone is treated in the same manner as described in Example 3. The crude product thus obtained is converted to its hydrochloride and then recrystallized from a mixture of ethanol and ether.

1.72 g of ( )-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethylj-7,9-dimethyl-2,3-dihydro-1 ,5- benzothiazepin-4(5H)-one hydrochloride are obtained.

M.p. 224' - 225"C (decomp.) Example 14 A mixture of 0.7 g of (l)-cis-2-(4-methoxyphenyl)-3-hydrnxy-5-[2-(dimethylamino)ethylj-7,9-dimethyl-2,3- dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride, 10 ml of acetic anhydride and 10 ml of acetic acid is treated in the same manner as described in Example 10. The crude product thus obtained is recrystallized from a mixture of ethanol and ether. 0.66 g of (t)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2- (dimethylamino)ethyl]-7,9-dimethyl-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one hydrochloride is obtained.

M.p. 240"- 242"C (decomp.) Example 15 A mixture of 1.48 g of ()-cis-2-(4-methoxyphenyl)-3-hydroxy-7,8-dichlorn-2,3-dihydrn-1 ,5- benzothiazepin-4(5H)-one, 0.64 g of 2-(dimethylamino)ethyl chloride hydrochloride, 1.66 g of potassium carbonate, 45 ml of acetone and 0.5 ml of water is refluxed for 22 hours. After the reaction is completed, insoluble materials are removed by filtration. The filtrate is evaporated to remove solvent, and diisopropyl ether is added to the residue.The precipitated crystals are collected by filtration and then recrystallized from ethyl acetate. 1.189 of (~)-cis-2-(4-methoxphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-7,8-dichloro-2,3- dihydro-1 ,5-benzothiazepin-4(5H)-one are obtained.

M.p.178 - 179.5 C Hydrochloride: M.p. 232.5" - 234"C (decomp.) (recrystallized from methanol) Example 16 A mixture of 0.57 g of ( )-cis-2-(4-methoxyphenyl )-3-hydroxy-5-[2-(dimethylamino)ethyl]-7,8-dichloro-2,3- dihydro-1,5-benzothiazepin-4(5H)-one, 6 ml of acetic anhydride and 3 drops of pyridine is treated in the same manner as described in Example 4. The crude product thus obtained is converted to its hydrochloride and then recrystallized from methanol. 0.58 g of (t)-cis-2-(4methoxyphenyl)-3-acetoxy-5-[2- (dimethylamino)ethyl]-7,8-dichloro-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one hydrochloride is obtained.

M.p. 189'- 192'C (decomp.) Example 17 A mixture of 1.67 g of ()-cis-2-(4-methoxyphenyl)-3-hydroxy-8,9-dichloro-2,3-dihydro-1,5- benzothiazepin-4(5H)-one, 0.71 g of 2-(dimethylamino)ethyl chloride hydrochloride, 1.87 g of potassium carbonate, 50 ml of acetone and 0.5 ml of water is treated in the same manner as described in Example 15.

The crude product is recrystallized from ethyl acetate. 0.91 g of (~)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2- (dimethylamino)ethyl]-8,9-dichloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained.

M.p. 175.5"- 176.5 C Hydrochloride 3/2 H2O: M.p. 172" - 175"C (recrystallized from a mixture of methanol and ether.

[This product decomposes at 230 - 233"C].

Example 18 A mixture of 0.56 g of (c)-cis-2-(4-m )-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8,9-dichloro-2,3- dihydro-1,5-benzothiazepin-4(5H)-one, 6 ml of acetic anhydride and 4 drops of pyridine is treated in the same manner as described in Example 4. The crude product thus obtained is converted to its hydrochloride and then recrystallized from a mixture of methanol and ether. 0.57 g of (i)-cis-2-(4-methoxyphenyl)-3-acetoxy-5- [2-(dimethylamino)ethyl]-8,9-dichloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride.1/2 H2O is obtained.

M.p. 233' - 235"C (decomp.) (Preparation of Starting Compounds) Preparation 1 A mixture of 23.4 g of 2-amino-4,5-dimethyl-thiophenol and 31.8 g of methyl (+)trans-3-(4- methoxyphenyl)glycidate is heated at 160"C for 16 hours under argon atmosphere. After cooling, hot ethanol is added to the mixture, and said mixture is filtered to collect crystalline precipitates. The crystals thus obtained are recrystallized from a mixture of chloroform and dimethylformamide. 15.7 g of (+)-cis-2-(4- methoxyphenyl)-3-hydroxy-7,8-dimethyl-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one are obtained.

M.p. 2210 - 2240C (decomp.) The mother liquor (ethanol solution) is evaporated to remove solvent. The residue is dissolved in ethyl acetate, and the solution is washed with 10 % hydrochloric acid and an aqueous saturated sodium bicarbonate solution, successively. The washed solution is dried and evaporated to remove solvent. Then, the residue is purified by silica gel chromatography (Solvent: chloroform), whereby 1.4 g of (+)-cis-2-(4- methoxyphenyl)-3-hydroxy-7,8-dimethyl-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one and 0.66 g of (r)-trans- 2-(4-methoxyphenyl)-3-hydroxy-7,8-dimethyl-2,3-dihydro-1 ,5-benzothiazepin-4(5H-one is obtained, respectively.

Trans isomer: M.p. 235" - 237"C (decomp.) (recrystallized from a mixture of ethyl acetate and n-hexane) Preparation 2 (1 ) Synthesis of Compound (VI) A mixture of 49.52 g of 2-amino-4,5-dimethylthiophenol, 47.49 g of methyl (i)4rans-3-(4-methoxyphenyl) glycidate and 500 ml of toluene is heated at 95" - 1 OO"C for 23 hours. After cooling, the precipitated crystals (Crystais I) are collected by filtration, and the filtrate is evaporated to remove solvent. The residue is digested with diisopropyl ether, and the crystals thus obtained (Crystals II) are collected by filtration.Crystals I and Crystals II are combined and then recrystallized from a mixture of ethyl acetate and n-hexane. 58.95 g of methyl ( + )-threo-2-hydroxy-3-(2-amino-4,5-dimethyl phenylthio)-3-(4-methoxyphenyl)propionate are obtained.

M.p. 114 C (2) Synthesis of Compound (VIZ) A mixture of 58.9 g of methyl (j )-threo-2-hydroxy-3-(2-amino-4,5-dimethylphenylthio)-3-(4- methoxyphenyl)propionate, 590 ml of an aqueous 5 % sodium hydroxide solution and 590 ml of ethanol is stirred at room temperature for 2 hours. After the reaction is completed, the mixture is adjusted to pH 3 with 10 % hydrochloric acid. The precipitated crystals are collected by filtration, washed with water and then dried. 54.2 g of (+)-threo-2-hydroxy-3-(2-amino-4,5-dimethylphenylthio)-3-(4-methoxyphenyl)propionic acid are obtained.

M.p.163"-168"C (3) Optical Resolution of Compound (VIZ) 31.3 g of L-(p-hydroxyphenyl)glycine methyl ester hydrochloride are dissolved in 750 ml of methanol. A solution of 8.08 g of potassium hydroxide in 375 ml of methanol is added to the solution, and the precipitates (inorganic materials) are removed by filtration. 25 g of (t)-threo-2-hydroxy-3-(2-amino-4,5- dimethylphenylthio)-3-(4-methoxyphenyl)propionic acid are added to the filtrate, and 375 ml of methanol are added thereto to make a clear solution. The clear solution is evaporated under reduced pressure to remove solvent.The residue is recrystallized three times from ethanol (the mother liquor is referred to as "Mother liquor I"), whereby 10.2 g of (+ )-threo-2-hydroxy-3-(2-amino-4,5-dimethylphenylthio)-3-(4- methoxyphenyl)propionic acid.L-(p-hydroxyphenyl)glycine methyl ester salt are obtained.

M.p. 173"- 175"C (decomp.) o,2D0 + 290.8 (C= 0.410, dimethylformamide) The product obtained above is dissolved in 10 % hydrochloric acid, and the solution is adjusted to pH 4 with potassium carbonate. The precipitated crystals are collected by filtration, washed with water and then dried. 4.7 g of (+ )-th reo-2-hydroxy-3-(2-amino-4,5-dimethylphenylthio)-3-(4-methoxyphenyl)propionic acid are obtained.

M.p. 167"-169"C (decomp.) [al20 + 361.2 (C=0.556, N-NaOH) Mother liquor I (ethanol solution) is evaporated under reduced pressure to remove solvent. The residue is dissolved in 10 % hydrochloric acidr and the solution is adjusted to pH 4 with potassium carbonate. The precipitated crystals are collected by filtration. Then, a mixture of the crystals (13.3 g) thus obtained, 16.7 g of D-(p-hydroxyphenyl)glycine methyl ester hydrochloride and 4.3 g of potassium hydroxide is treated in the same manner as above.The crude product thus obtained is recrystallized from ethanol, whereby 8.97 g of (-)-threo-2-hydroxy-3-(2-amino-4,5-dimethyl phenylthio)-3-(4-methoxyphenyl)propionic acid.D-(p- hydroxyphenyl)glycine methyl ester salt are obtained.

M.p.170 - 174"C (decomp.) [a]20 222.10 (C=0.664, dimethylformamide) The product obtained above are converted to its free acid in the same manner as above, whereby 2.66 g of (- )-threo-2-hydroxy-3-(2-amino-4,5-dimethyl phenylthio)-3-(4-methoxyphenyl)propionic acid are obtained.

M.p. 154"-157"C (decomp.) [a]20 -316.80 (C=0.512, N-NaOH) (4) Synthesis of Compound (11) (a) A mixture of 4.7 g of (+)-threo-2-hydroxy-3-(2-amino-4,5-dimethylphenylthio)-3-(4- methoxyphenyl)propionic acid and 80 ml of xylene is refluxed for 24 hours. The resulting water is removed during the reaction. After the reaction is completed, the mixture is evaporated to remove solvent. 3.95 g of (+ )-cis-2-(4-methxyphenyl)-3-hydrnxy-7,8-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.

M.p. 2320 - 234 C (decomp.) [cy]2oo + 131.40 (C=0.778, dimethylformamide) (b) A mixture of 2.6 g of (-)-threo-2-hydroxy-3-(2-amino-4,5-dimethylphenylthio)3-(4methoxyphenyl)propionic acid and 45 ml of xylene is treated in the same manner as described in paragraph (a). 1.98 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-7,8-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.

M.p. 2250 - 227 C (decomp.) ta]2c0 - 127.20 (C=0.66, dimethylformamide) Preparation 3 17.45 g of 2-amino-4,5-dimethoxy-thiophenol and 19.61 g of methyl (+)-trans-3-(4- methoxyphenyl)glycidate are treated in the same manner as described in Preparation 1, whereby 4.65 9 of ()-cis-2-(4-methoxyphenyl)-3-hydroxy-7,8-dimethoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.

M.p. 240" - 241.5"C (decomp.) (recrystallized from a mixture of dimethylformamide and ethanol) Preparation 4 4.4 g of 2-amino-3,4-dimethyl-thiophenol and 5.98 g of methyl (+ )-trans-3-(4-methoxyphenyl)glycidate are treated in the same manner as described in Preparation 1, whereby the following compounds are obtained.

()-Cis-2-(4-methoxyphenyl)-3-hydroxy-6,7-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one: 1.098g M.p. 235"- 2380C (recrystallized from ethyl acetate) (4 )-Trans-2-(4-methoxyphenyl)-3-hydroxy-6,7-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one: Yield: 0.156g M.p. 2700-2710C In this reaction, 2.724 g of methyl (i)-threo-2-hydroxy-3-(2-amino-3,4-dimethylphenylthio)-3-(4- methoxyphenyl)propionate are further obtained by silica gel chromatography.

M.p. 109.5"- 111.5"C (recrystallized from isopropanol) Preparation 5 3.936 g of 2-amino-3,5-dimethyl-thiophenol and 5.35 g of methyl (+)-trans-3-(4-methoxyphenyl)glycidate are treated in the same manner as described in Preparation 1, whereby the following compounds are obtained.

()-Cis-2-(4-methoxyphenyl-3-hydroxy-6,8-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one: Yield: 3.1 9 M.p. 2089 - 210 C (recrystallized from ethyl acetate) ()-Trans-2-(4-methoxyphenyl)3-hydroxy-6,8-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one: Yield: 0.282 g M.p. 1610-1630C In this reaction, 1.446 g of methyl (+)-threo-2-hydroxy-3-(2-amino-3,5-dimethylphenylthio)-3-(4- methoxyphenyl)propionate are further obtained by silica gel chromatography.

M.p.109 - 113 C Preparation 6 2.97 g of 2-amino-4,6-dimethyl-thiophenol and 4.04 g of methyl ()-trans-3-(4-methoxyphenyl)glycidate are treated in the same manner as described in Preparation 1, whereby the following compounds are obtained.

(+)-Cis-2-(4-methoxyphenyl)-3-hydroxy-7,9-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one: Yield: 3.5719 M.p.246 - 249 C (+)-Trans-2-(4-methoxyphenyl )-3-hydroxy-7,9-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one: Yield: 0.336g M.p. 2270 - 2300C In this reaction, 0.027 g of methyl (+)-threo-2-hydroxy-3-(2-amino-4,6-dimethylphenylthio)-3-(4- methoxyphenyl)propionate is further obtained by silica gel chromatography.

M.p. 1300 - 1330C.

Preparation 7 A mixture of 19.3 g of 2-amino-4,5,dichloro-thiophenol and 20.7 g of methyl (+)-trans-3-(4methoxyphenyl)glycidate is heated at 165"C for 16 hours. After cooling, ethanol is added to the mixture. The precipitated crystals are collected by filtration, washed with ethanol and then recrystallized from a mixture of chloroform and ethanol. 7.2 g of ( + )-cis-2-(4-methoxyphenyl )-3-hydroxy-7,8-dichloro-2,3-dihyd ro- 1,5- benzothiazepin-4(5H)-one are obtained.

M.p. 2390 - 243"C (decomp.) [This product begins to moisten at 210 C].

Preparation 8 A mixture of 18.03 g of 2-amino-5,6-dichloro-thiophenol and 19.34 g of methyl (i)4rans-3-(4- methoxyphenyl)glycidate is heated at 165"C for 19 hours. Then a mixture of ethanol and diisopropyl ether is added to the mixture. Insoluble materials are removed by filtration and the filtrate is evaporated under reduced pressure to remove solvent. Ethanol is added to the residue, and the precipitated crystals are collected by filtration (The mother liquor is referred to as "Mother liquor I"). The crystals are recrystallized from a mixture of chloroform and ethanol. 2.47 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8,9-dichloro-2,3- dihydro-1,5-benzothiazepin-4(5H)-one are obtained.

M.p. 207 209"C The mother liquor I (ethanol solution) is evaporated to remove solvent. The residue is purified by silica gel chromatography (Solvent: chloroform-methanol (19:1)), whereby 2.47 g of (-+)-cis-2-(4-methoxyphenyl-3- hydroxy-8,9-dichloro-2,3-di hydro-1 ,5-benzothiazepin-4(5H)-one (M.p. 207 - 2090C) and 1.01 9 of (+)-trans-2- (4-methoxyphenyl)-3-hydroxy-8,9-dichloro-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one (M.p. 244 - 249"C) are obtained.

Claims (18)

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

wherein R1 is hydrogen or lower alkanoyl, each of R2 and R3 is lower alkyl, and each of R4 and R5 is lower alkyl, lower alkoxy or halogen, or a pharmaceutically acceptable acid addition salt thereof.

2. A compound according to claim 1 in which R4 and R5 are each methyl, methoxy or chlorine.

3. A compound according to claim 1 or 2 in which R1 is hydrogen or acetyl, and R2 and R3 are each methyl.

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

5. A compound according to claim 3 in which R1 is acetyl.

6. A compound according to claim 3 in which R4 and R5 are each methyl.

7. A compound according to claim 3 in which R4 and R5 are each methoxy.

8. A compound according to claim 3, in which R4 and Re are chlorine.

9. A cis isomer of a compound as claimed in any of claims 1 to 8.

10. A (+)-cis isomer of a compound as claimed in any of claims 1 to 8.

11. A compound according to claim 6 which is (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2- (dimethylamino)-ethyl]-7,8-dimethyl-2,3-dihydro-1,5-benzethiazepin-4(5H)-one or a pharmaceutically acceptable acid addition salt thereof.

12. A compound according to claim 6 which is (+ )-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2- (dimethylamino)-ethyl]-7,8-dimethyl-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one or a pharmaceutically acceptable acid addition salt thereof.

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

14. A process for preparing a 1,5-benzothiazepine derivative of the formula given in claim 1, which

or salt therof with a compound of the formula:

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

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

wherein R2, R3, R4 and Re are the same as defined above, or a salt thereof and, if required, further converting the product to a pharmaceutically acceptable acid addition salt thereof.

16. 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.

17. 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.

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

wherein R1 is a hydrogen or lower alkanoyl, and each of R4 and R5 is lower alkyl, lower alkoxy or halogen, or a salt thereof.