NOVEL BENZOTHIAZINE DERIVATIVES

Abstract: Novel benzothiazine derivatives represented by the fol­ lowing general formula (I), process for their preparation, and agents for treating diseases of circulatory organs containing these compounds as effective ingredients: wherein R¹ repre­ sents one or more groups selected from among a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a hydroxy group, a lower alkoxy group, a lower alkanoyloxy group, an amino group, a lower alkylamino group and a lower alkoxycarbonyloxy group, R² represents a hydrogen atom, a lower alkyl group or a (C₃ - C₆) cycloalkyl group, R³ represents one or more of a hydrogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a halogen atom, a nitro group, a lower alkylenedioxy group, a lower alkanoyloxy group, a lower alkanoyl group, an amino group, a lower alkylamino group, a lower alkanoylamino group and a lower alkoxycarbonyloxy group, or (CH₂) n , R⁴ represents a hydrogen atom or a lower alkyl group, A and B which may be the same or different and each represents a lower alkylene group containing 1 to 6 carbon atoms, and n represents 3 or 4.

Description: FIELD OF THE ART This invention relates to benzothiazine derivatives which possess anti-platelet aggregation and calcium antagonism effects and are useful for treatment of circulatory diseases. BACKGROUND OF THE INVENTION There have been few studies on benzothiazine derivatives useful as therapeutic drugs. Especially, there is only one prior publication, Japanese Unexamined Patent Publication 148771/84 filed by the same inventors of this invention, disclosing the compounds useful for treatment of circulatory diseases of the present object. The inventors further advanced the previous study to find out novel and useful compounds. The characteristic of the chemical structure of the compounds of this invention is that the phenyl group substituted at the 2-position of the benzothiazine ring has a side chain which has a substituted or unsubstituted phenyloxy group. Such structural characteristic has not been disclosed in the above Japanese Unexamined Patent Publication 148771/84. As other prior art concerning compounds having a benzothiazine ring, there exist publications by J. Krapcho ( U.S. Pat. No. 3166554), Stearns et al. ( U.S. Pat. No. 3555155) and Stanley O. et al. ( Can. Pat. No. 717979). The chemical structures of the compounds disclosed in the respective patents are different from those of this invention and the objects thereof are also different. The object of the patent of J. Krapcho is a treatment of Parkinsonism, the patent of Stearns et al. is on herbicides, and the patent of Stanley et al. is on medicines having anticholinergic activity and antihistaminic activity. The object of this invention is to search and find more useful drugs for circulatory diseases based on the prior art. DISCLOSURE OF THE INVENTION This invention relates to benzothiazine derivatives of the formula [I] and salts thereof, processes for preparing them, and their use in the manufacture of therapeutic drugs for circulatory diseases, wherein R¹ is one or more groups selected from hydrogen, lower alkyl, halogen, nitro, hydroxy, lower alkoxy, lower alkanoyloxy and lower alkoxycarbonyloxy; R² is hydrogen, lower alkyl or (C₃-C₆)cycloalkyl; R³ is one or more groups selected from hydrogen , lower alkyl, hydroxy, lower alkoxy, halogen, nitro, lower alkylenedioxy, lower alkanoyloxy, lower alkanoyl and lower alkoxycarbonyloxy or R⁴ is hydrogen or lower alkyl; A and B are the same or different and are lower alkylene having 1 to 6 carbon atoms; and n is 3 to 4. The same shall be applied hereinafter. The groups defined above are explained below more in detail: Lower alkyl is an alkyl group having 1 to 6 carbon atoms exemplified by methyl, ethyl, propyl and hexyl; halogen is exemplified by fluorine, chlorine and bromine; lower alkoxy is an alkoxy group having 1 to 6 carbon atoms exemplified by methoxy, ethoxy, propoxy and hexyloxy; lower alkanoyloxy is an alkanoyloxy group having 1 to 6 carbon atoms exemplified by acetyloxy, propionyloxy and hexanoyloxy; (C₃-C₆) cycloalkyl is a cycloalkyl group having 3 to 6 carbon atoms exemplified by cyclopropyl and cyclohexyl; lower alkylenedioxy is a group which have (C₁-C₆) alkylene between two oxygen atoms exemplified by methylenedioxy and ethylenedioxy; lower alkanoyl is an alkanoyl group having 1 to 6 carbon atoms exemplified by acetyl, propionyl and hexanoyl. The compounds of this invention can be prepared by the following methods. 1) Reaction of a compound of the formula [II) with an amine derivative of the formula [III], wherein R¹, R², R³, R⁴, A and B are as defined as above and X is halogen or methanesulfonyloxy. The same shall be applied hereinafter. 2) Reaction of a compound of the formula [IV] with a compound of the formula [V]. 3) Reaction of a compound of the formula [VI] with a compound of the formula [VII]. The above reactions are usually carried out under basic conditions. Examples of a preferable base is inorganic or organic base such as sodium hydride, potassium carbonate, sodium carbonate, sodium hydoxide, sodium alcholate, triethylamine, pyridine or N,N-dimethylaniline. The reactions can be carried out using an excess amount of amine reactant without adding a base. The compounds of this invention have stereoisomers, and such isomers are included in the scope of this invention. Optically active compounds of the formula [I] can be obtained from racemic compounds of the formula [I] by known methods such as an optical resolution method using an optically active organic acid exemplified by mandelic acid and a separation method using a cellulose triacetate column as a separator. Optically active compounds of the formula [I] can be also prepared by using an optically active starting material in the processes for preparing the compounds of the formula[I]. An example for preparing an optically active starting material is shown below. wherein R⁵ is a residual group of carboxylic acid derivatives having one or more asymmetic carbon atoms. A mixture of diastereomers of the formula [IX] is prepared by a reaction of a racemic compound of the formula[IV] with a carboxylic acid of the formula [VIII] having an asymetric carbon atom using a condensing agent such as DCC. The mixture of diastereomers is separated and followed by removal of the R⁵CO-group by a method such as hydrolysis and reduction to give the desired optically active compound of the formula [IV]. Using the optically active compound of the formula [IV], the optically active compounds of the formula [I] can be prepared. The conditions such as solvent and reaction temperature are not necessarily limited and can be selected depending on a kind of base, solubility of a reactant, etc. The compounds of this invention can be converted into pharmaceutically acceptable salts. Examples of the salts are hydrochloric acid salt, sulfuric acid salt, phosphoric acid salt, lactic acid salt, maleic acid salt, fumaric acid salt, oxalic acid salt methanesulfonic acid salt and p-toluenesulfonic acid salt. The compounds of this invention can be administered either orally or parenterally. Examples of the dosage forms are tablet, capsule, granule, powder, suppository, injection, etc. The dosage is adjusted depending on symptom, dosage form, etc., but usual daily dosage is 1 to 5,000mg, preferably 10 to 1,000mg, in one or a few divided doses. The compounds of this invention have platelet antiagrregation activity and calcium-antagonism activity, and they are useful for treatment of circulatory diseases such as hypertension, thrombosis and arrhythmia. As the pharmacological test to prove the effects of the compounds of this invention, a test on calcium-antagonism activity is is shown as follows. As typical compounds of this invention, 3,4-dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate (defined as Compound A for short hereinafter), 3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl] amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate (defined as Compound B for short hereinafter) and 3,4-dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-[(3,4-dimethoxy)phenoxy]ethyl]amino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate (defined as Compound C for short hereinafter) were tested. As a reference compound (see Japanese Unexamined Patent Publication No. 166674/1985), 3,4-dihydro-2-[5-methoxy-2-[4-[N-methyl-(3,4-dimethoxy)phenetylamino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate(mp 145-147 °C) was used. The structure of the reference compound resembles to compound of this invention, but it does not have the characteristic structure of the compound of this invention, ie the presence of a phenyloxy group in the side chain. Pharmacological Test (Method for measurement of calcium-antagonistic activity) Isolated guinea-pig taenia coli was suspended in a 20ml organ bath filled with Krebs solution at 32°C and bubbled with 5% carbon dioxide in oxygen. After equilibration, the muscule was suspended in Ca⁺⁺-free Krebs solution. The muscle was then exposed to the test compound for 5 minutes before the addition of CaCl₂, and the contraction induced by CaCl₂( 3 X 10⁻⁴M) was recorded isotonically. The calcium-antagonistic activity was represented by the concentration of the test compound which elicited 50% inhibition (IC₅₀ ) of Ca⁺⁺-induced contraction. Result) Compound IC₅₀ (M) Compound A 3.2 X 10⁻⁷ Compound B 2.4 X 10⁻⁷ Compound C 2.9 X 10⁻⁷ Reference Compound 3.2 X 10⁻⁶ REST MODE TO MAKE THE INVENTION Example 1 3,4-Dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate To a suspension of 50% sodium hydride (0.15g) in anhydrous dimethylformamide (5ml), a solution of 3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-3-oxo-2H-1,4-benzothiazine (0.9g) in anhydrous dimethylformamide (10ml) was added dropwise with stirring. After the addition, the mixture was stirred additionally for 15 minutes. To the mixture, a solution of 4-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]butoxy bromide (1.2g) in anhydrous dimethylformamide (10ml) was added dropwise with stirring. The mixture was then stirred for 2 hours at 50°C. The reaction mixture was poured into a mixture of chloroform (50ml) and 2 N hydrochloric acid (50ml). The organic layer was concentrated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with N sodium hydroxide and then with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography and the oily product was dissolved in ethyl acetate. To this solution, a solution of oxalic acid in ethyl acetate was added and the resulting crystals were filtered to give 1.4g (73%) of the titled compound. mp 160 - 162°C (ethanol - water) IR (KBr, cm⁻¹,the same shall be applied hereinafter unless specified) : 1655, 1584, 1499, 1475, 1400, 1356, 1277, 1238, 1205, 1185, 1132, 1034 The following compounds were prepared by the similar method as in Example 1. 3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate: mp 130 - 131°C (ethanol) IR : 1654, 1473, 1239, 1209, 1183, 1033 hydrochloride: mp 133 - 134.5°C (ethanol) IR : 2416, 1654, 1478, 1236, 1182, 1034 3,4-Dihydro-2-[2-[4-[N-[2-(4-methoxyphenoxy)ethyl]-N-methylamino]butoxy]-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate mp 149 - 150°C (ethanol - water) IR : 1674, 1473, 1238, 1218, 1037 3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4,5-trimethoxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate mp 137 - 139°C (ethanol - ethyl acetate) IR : 1715, 1653, 1589, 1489, 1457 3,4-Dihydro-2-[4-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy] ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate mp 146 - 148°C (ethanol) IR : 1648, 1582, 1473, 1399, 1356 3,4-Dihydro-2-[4-[2-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy] ethyl]amino]ethoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate mp 97 - 102°C (acetone) IR : 1647, 1478, 1398, 1237, 1182 3,4-Dihydro-2-[5-methoxy-2-[2-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]ethoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate mp 129 - 131.5°C (ethyl acetate - methanol) IR : 1645, 1474, 1399, 1236, 1183 3,4-Dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-[(3,4-dimethoxy)phenoxy]ethyl]amino]butoxy]phenyl]-3-oxo-2H-1,4-benzothiazine hydrochloride IR : 1653 (C=O) 2-[4-[4-[N-[2-(2-chlorophenoxy)ethyl]-N-ethylamino]butoxy]phenyl] 3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochloride IR : 1655 (C=O) 3,4-Dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]methylamino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR : 1654 (C=O) Example 2 3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate To a stirred solution of 2-[2-(3-bromopropoxy)-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine (1.2g) and sodium carbonate (0.4g) in dimethylformamide (5ml), N-methyl-2-[(3,4-methylenedioxy)phenoxy]ethylamine (0.8g) was added and the mixture was stirred for 2 hours at 80°C. The reaction mixture was poured into a mixture of chloroform (50ml) and 2 N hydrochloric acid (50ml). The following treatments were carried out by the similar procedures as in Example 1 to give 1.3g (70%) of the titled compound. mp 130 - 131°C (ethanol) IR : 1654, 1473, 1239, 1209, 1183, 1033 The following compounds were prepared by the similar method as in Example 2. 3,4-Dihydro-2-[2-[4-[N-[2-[(2,6-dimethoxy)phenoxy]ethyl-N-methyl]amino]butoxy]-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochloride IR : 1652, 1473, 1238, 1207, 1104 3,4-Dihydro-2-[5-chloro-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate mp 116 - 118°C (ethanol) IR : 1654, 1474, 1357, 1265, 1240 3,4-Dihydro-2[2-[4-[N-[2-[(5-indanyloxy)ethyl]-N-methylamino]butoxy]-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate mp 145 - 146°C (ethanol - water) IR : 1673, 1474, 1239, 1217 3,4-Dihydro-2-[4-[4-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate mp 105 - 108°C (ethanol) IR : 1646, 1582, 1476, 1399, 1357 3,4-Dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-(phenoxy)ethyl]amino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR : 1655 (C=O) 3,4-Dihydro-2-[5-methoxy-2-[5-[N-methyl-N-[2-(3,4,5-trimethoxy)phenoxy]ethyl]amino]pentyloxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR : 1655 (C=O) 3,4-Dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-(3,4-methylenedioxy)phenoxy]ethyl]amino]butoxy]phenyl]-3-oxo-2H-1,4-benzothiazine hydrochloride IR : 1655 (C=O) 3,4-Dihydro-2-[5-chloro-2-[3-[N-methyl-N-[2-(3,4-dimethoxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochloride IR : 1655 (C=O) 3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-(4-methoxyphenoxy)ethyl]amino]propoxy]phenyl]-3-oxo-2H-1,4-benzothiazine fumarate IR : 1656 (C=O) 3,4-Dihydro-2-[2-[3-[N-[2-(2-fluorophenoxy)ethyl-N-methyl]amino]propoxy]-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochloride IR : 1656 (C=O) 2,[4-[4-[N-Cyclopropyl-N-[2-(4-nitrophenoxy)ethyl]amino]butoxy]phenyl]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR : 1656 (C=O) 3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-dimethoxy)phenoxy]ethyl]amino]propoxy]-4-nitrophenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR : 1654 (C=O) 3,4-Dihydro-2-[2-[4-[N-ethyl-N-[2-[(2,3,4-trimethoxy)phenoxy]ethyl]amino]butoxy]-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR : 1653 (C=O) 3,4-Dihydro-2-[5-methoxy-N-[2-[3-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochloride IR : 1656 (C=O) 3,4-Dihydro-2-[2-[4-[N-[2-(4-chlorophenoxy)ethyl]-N-cyclohexylamino]butoxy]-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR : 1655 (C=O) 3,4-Dihydro-4-methyl-2-[4-[3-[N-[2-[(3,4,5-trimethoxy)phenoxy]ethyl]amino]propoxy]phenyl]-3-oxo-2H-1,4-benzothiazine hydrochloride IR : 1657 (C=O) 3,4-Dihydro-2-[4-[5-[N-cyclohexyl-N-[2-[(4-methylphenoxy)ethyl]amino]pentyloxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochloride IR : 1658 (C=O) 3,4-Dihydro-2-[4-[5-[N-methyl-N-[(2,3,4-trimethoxy)phenoxy]methylamino]pentyloxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochloride IR : 1655 (C=O) Example 3 3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate To a solution of 3,4-dihydro-2-[5-methoxy-2-[3-(methylamino)propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine (1.2g) and triethylamine (0.4g) in ethanol (10ml), 2-[(3,4-methylenedioxy)phenoxy]ethyl methanesulfonate (1.0g) was added and the mixture was refluxed for 2 hours. The reaction mixture was concentrated in vacuo and the residue was poured into a mixture of chloroform (50ml) and 2 N hydrochloric acid (50ml). The following treatments were carried out by the similar procedures in Example 1 to give 1.3g (65%) of the titled compound. The melting point and IR data of the compound were identical with the crystals prepared in Example 2. The following compounds were prepared by the similar method as in Example 3. 3,4-Dihydro-2-[2-[4-[N-[2-[(3,4-dimethoxy)phenoxy]ethyl-N-methyl]amino]butoxy]-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate mp 167 - 168°C (ethanol - water) IR : 1653, 1500, 1458, 1217, 1198 3,4-Dihydro-2-[5-methyl-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate mp 114 - 116°C (ethanol) IR : 1652, 1582, 1466, 1355, 1304 3,4-Dihydro-2-[4-[3-[N-[2-[(5-indanyloxy)ethyl-N-methyl]amino]propoxy]-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate mp 107 - 109°C (ethyl acetate) IR : 1661, 1472, 1240, 1214, 1041 3,4-Dihydro-2-[5-methoxy-2-[2-[N-methyl-N-[3-[(3,4-methylenedioxy)phenoxy]propyl]amino]ethoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate mp 121 - 126°C (ethanol) IR : 1627, 1464, 1354, 1276, 1181 3,4-Dihydro-4-methyl-2-[4-[4-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino)butoxy]phenyl]-3-oxo-2H-1,4-benzothiazine oxalate IR : 1654 (C=O) 3,4-Dihydro-2-[4-[4-[N-[2-(2-fluorophenoxy)ethyl]amino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochloride IR : 1660 (C=O) 3,4-Dihydro-2-[4-[4-[N-methyl-N-[2-(2-chlorophenoxy)ethyl]amino]butoxy]phenyl]-3-oxo-2H-1,4-benzothiazine fumarate IR : 1662 (C=O) 3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[(3,4-dimethoxy)phenoxy]methylamino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochloride IR : 1658 (C=O) Example 4 3,4-Dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-[(3,4,5-trimethoxy)phenoxy]ethyl]amino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate To a solution of 2-[2-(4-bromobutoxy)-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine (1.3g) and triethylamine (0.4g) in ethanol (10ml), N-methyl-2-[(3,4,5-trimethoxy)phenoxy]ethylamine(0.9g) was added and the mixture was refluxed for 2 hours. The reaction mixture was concentrated in vacuo and the residue was poured into a mixture of chloroform (50ml) and 2 N hydrochloric acid (50ml). The following treatments were carried out by the similar procedures as in Example 1 to give 1.5g (73%) of the titled compound. mp 149 - 151°C (ethanol - water) IR : 1653, 1591, 1499, 1458, 1234, 1217 The following compounds were prepared by the similar method as in Example 4. 3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(2,6-dimethoxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochloride mp 185 - 187°C (ethanol) IR : 1654, 1584, 1475, 1351, 1243 3,4-Dihydro-2-[[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]-5-nitrophenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate mp 135 - 137°C (ethanol) IR : 1654, 1584, 1477, 1388, 1260 3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[3-[(3,4-methylenedioxy)phenoxy]propyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate mp 146 - 148°C (ethanol) IR : 1659, 1583, 1472, 1355, 1238 3,4-Dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[3-[(3,4-methylenedioxy)phenoxy]propyl]amino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate mp 135 - 138°C (ethanol) IR : 1653, 1467, 1355, 1237 Example 5 Optical resolution of 3,4-dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine by a cellulose triacetate column chromatography. A solution of the racemic compound (4.0g) dissolved in chloroform was put into a column packed with fine crystalline cellulose triacetate (750g), which was prepared according to the method of Chromatographia, 6 , 277 (1973), and eluted with 95% ethanol to give (+)-compound and (-)-compound as free forms. The free compounds were converted into fumarates by a usual method. 1.62 Gram and 1.50g of fumarate of (+)- and (-)-compound were obtained respectively. fumarate of (+)-compound mp 148.5 - 149.5°C (ethyl acetate - ethanol) [ α ] 25 / D +195.4° ( c=1.0, dimethylsulfoxide) IR : 3392, 2912, 1653, 1473, 1353, 1239, 1204, 1184, 1033 fumarate of (-)-compound mp 149-150°C (ethyl acetate - ethanol) [ α ] 25 / D -195.5° ( c=1.0, dimethylsulfoxide) IR : 3380, 2910, 1653, 1473, 1353, 1239, 1202, 1184, 1033 The following compounds were prepared by the similar method as in Example 5. (+)-3,4-Dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-[(3,4,5-trimethoxy)phenoxy]ethyl]amino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate mp 133 - 135°C (ethanol) [ α ] 25 / D +177.0° ( c=1.0, dimethylsulfoxide) IR : 3400, 1664, 1465, 1220, 1125 (-)-3,4-Dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-[(3,4,5-trimethoxy)phenoxy]ethyl]amino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate mp 133 - 135°C (ethanol) [ α ] 25 / D -180.8° ( c=1.0, dimethylsulfoxide) IR : 3400, 1663, 1465, 1219, 1126 (+)-3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4,-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate mp 133 - 133.5°C (ethanol) [ α ] 25 / D +194.2° ( c=1.0, dimethylsulfoxide) IR : 1653, 1470, 1357, 1267, 1239, 1183, 1139, 1106, 1034, 980 (-)-3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4,5-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate mp 133 - 133.5°C (ethanol) [ α ] 25 / D -195.5° ( c=1.0, dimethylsulfoxide) IR : 1653, 1466, 1357, 1267, 1239, 1183, 1139, 1106, 1033, 980 Example 6 Optical resolution of 3,4-dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine by mandelic acid To a solution of the racemic compound (5.0g) in acetone (10ml), L-(+)-mandelic acid (0.59g) was added and made the mixture solution. The saparated crystals were collected by filtration and recrystallized with acetone to give 1.45g of L-(+)-mandelate of (+)-compound. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, concentrated in vacuo, and the residue was dissolved in acetone (10ml). To the solution D-(-)-mandelic acid (0.59g) was added and dissolved. Precipitated crystals were collected by filtration and recrystallized with acetone to give 1.52g of D-(-)-mandelate of (-)-compound. L-(+)-mandelate of (+)-compound mp 101 - 102.5°C [ α ] 25 / D +209.9° ( c=1.0, dimethylsulfoxide) IR : 3396, 1664, 1584, 1500, 1490, 1478, 1356, 1240, 1219, 1190, 1036, 755 D-(-)-mandelate of (-)-compound mp 98.5 - 100°C [ α ] 25 / D -205.9° ( c=1.0, dimethylsulfoxide) IR : 3392, 1663, 1583, 1500, 1487, 1477, 1355, 1239, 1218, 1188, 1035, 754 The mandelates can be made to free forms of (+)- and (-)- compound by a usual method and then converted into fumarates. The physical data of the fumarates were identical with the salts obtained in Example 5. The following compounds were prepared by the similar method as in Example 6. (+)- 3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine (+)-mandelate mp 113.5 - 114.5°C (acetone) [ α ] 25 / D +205.9° ( c=1.1, dimethylsulfoxide) IR : 1666, 1584, 1489, 1280, 1192, 1036 (-)- 3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine (-)-mandelate mp 114 - 115°C (acetone) [ α ] 25 / D -214.1° ( c=1.0, dimethylsulfoxide) IR : 1664, 1583, 1488, 1280, 1191, 1035 The mandelates can be made to free forms of (+)- and (-)- compound by a usual method and then converted into fumarates. The physical data of the fumarates were identical with the salts obtained in Example 5. Example 7 Synthesis of optically active 3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate by using optically active 3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (i) To a solution of 3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (24.1g) in anhydrous dimethylformamide (100ml), (2S,4S)-3-acetyl-5,5-dimethyl-2-(2-methoxyphenyl)-4-thiazolidinecarboxylic acid (37.1g), 4-dimethylaminopyridine (1.95g) and then dicyclohexylcarbodiimide (DCC) (24.8g) dissolved in anhydrous dimethylformamide (100ml) were added. The mixture was stirred for 3 hours at room temperature and then filtered. To the filtrate, water (500ml) was added and extracted with ethyl acetate (1ℓ). The organic layer was washed with saturated sodium bicarbonate solution, water and then saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was separated and purified by a silica gel column chromatography to give two kinds of diastereomer of 2-[2-[(2S,4S)-3-acetyl-5,5-dimethyl-2-(2-methoxyphenyl)thiazolidine-4- ylcarbonyloxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine-A (23.7g, 50%) and -B (22.7g, 48%), respectively. diastereomer-A : [ α ] 25 / D -108.6° ( c=1.0, chloroform) IR : 1755, 1646, 1457, 1376, 1328, 1279, 1242, 1189, 1136, 1105 diastereomer-B : mp : 165 - 166°C (benzene - n-hexane) [ α ] 25 / D -108.3° ( c=1.0, chloroform) IR : 1756, 1653, 1457, 1373, 1331, 1280, 1244, 1192, 1139, 1106 (ii) To a suspension of sodium borohydride (3.5g) in anhydrous ethanol (80ml), 2-[2-[(2S,4S)-3-acetyl-5,5-dimethyl-2-(2-methoxyphenyl)thiazolidine-4-ylcarbonyloxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine-A (12.0g), which was prepared by the process (i), dissolved in anhydrous tetrahydrofuran (40ml) was added under ice-cooling. The mixture was stirred for 24 hours at the same temperature and concentrated in vacuo. To the residue, water (150ml) was added and the product was extracted with ethyl acetate (250ml). The organic layer was washed with saturated sodium chloride solution, dried oved anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by the silica gel column chromatography to give 3.0g (50%) of (-)-3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine. mp 160.5 - 161.5°C (benzene - n-hexane) [ α ] 25 / D -30.6° ( c=0.51, chloroform) IR : 3224, 1625, 1582, 1429, 1366, 1264, 1218, 1201 By the similar method, (+)-3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine was obtained from 2-[2-[(2S,4S)-3-acetyl-5,5-dimethyl-2-(2-methoxyphenyl)thiazolidine-4-ylcarbonyloxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine-B. mp 161.5 - 162.5°C (benzene - n-hexane) [ α ] 25 / D +31.8° ( c=0.52, chloroform) IR : 3220, 1625, 1582, 1429, 1366, 1264, 1218, 1201 (iii) To a solution of (-)-3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (6.3g), which was prepared by the process(ii), in anhydrous tetrahydrofuran (70ml), 3-bromo-1-propanol (8.8g), triphenylphosphine (16.6g) and then diethyl azodicarboxylate(10.0ml) were added. The mixture was stirred for 2 hours under nitrogen atomosphere and concentrated in vacuo. The residue was purified by the silica gel column chromatography to give 4.5g (51%) of (-)-3,4-dihydro-2-[2-(3-bromopropoxy)-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine. mp 77 - 78°C (ethanol) [ α ] 25 / D -195.9° ( c=1.0, chloroform) IR : 1643, 1584, 1491, 1464, 1359, 1271, 1239, 1201 By the similar method, (+)-3,4-dihydro-2-[2-(3-bromopropoxy)-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine was obtained from (+)-3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine. mp 78 - 79°C (ethanol) [ α ] 25 / D +197.7° ( c=1.0, chloroform) IR : 1647, 1584, 1492, 1465, 1357, 1271, 1240, 1201 (iv) Sodium iodide (4.3g) was added to a solution of (-)-3,4-dihydro-2-[2-(3-bromopropoxy)-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine (1.2g), which was prepared by the process (iii), in acetone (30ml). The mixture was refluxed for 12 hours and concentrated in vacuo. To the residue, water (30ml) was added and the product was extracted with ethyl acetate (50ml). The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. To the residue dissolved in anhydrous dimethylformamide (20ml), N-methyl-2-[(3,4-methylenedioxy)phenoxy]ethylamine (0.7g) and triethylamine (0.3g) were added and the mixture was stirred for 1.5 hours at 50°C. After cooling, water (50ml) was added to the mixture and the product was extracted with ethyl acetate (80ml). The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. To the residue fumaric acid (0.3g) dissolved in ethanol (9ml) was added. Precipitated crystals were collected by filtration to give 1.3g (70%) of (-)-3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy] ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate. The physical data of the compound was identical with the compound prepared in Example 5. By the similar method, (+)-3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate was obtained from (+)-3,4-dihydro-2-[2-(3-bromopropoxy)-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine. The physical data of the compound was identical with the compound prepared in Example 5. The following compounds were prepared by the similar method as in Example 7. (+)-3,4-dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-[(3,4,5-trimethoxy)phenoxy]ethyl]amino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate (-)-3,4-dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-[(3,4,5-trimethoxy)phenoxy]ethyl]amino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate (+)-3,4-dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate (-)-3,4-dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]butoxy]phenyl]-4-methyl-3-oxo-2H- 1,4-benzothiazine fumarate The physical data of the compound was identical with the compound prepared in Example 5. Example 8 (examples of formulations) As typical compounds of this invention, 3,4-dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate compound A) and 3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate were used. (i) tablet The following tablets were prepared by a direct compression of the compound A or B of this invention and excipients. (ii) capsule The following capsules were prepared using the compound A or B of this invention and lactose. By changing the ratio of the compound A or B of this invention and lactose, capsules which contain the compound of this invention 10mg, 30mg, 50mg, 100mg in each capsule were prepared. (iii) granule The following granules were prepared by a usual method mixing the compound A or B of this invention, lactose and starch and using methanol solution of hydroxypropylcellulose-L as a binding agent. The following coated granules were prepared as follows by a usual method. Granules were prepared first by a usual method mixing the compound A of this invention and mannitol and using aqueous polyvinylpyrrolidone K-30 solution as a binding agent and followed by coating with coating agent prepared by eudragid RL (trade name) and triacetine (plasticizer) by a usual method. Granules of the compound B were prepared by the similar method.

Claims: Claims for the following Contracting States : BE, CH, DE, FR, IT, LI, NL, SE A compound of the formula [I] or a salt thereof, wherein R¹ is one or more groups selected from hydrogen, (C₁-C₆) alkyl, halogen, nitro, hydroxy, (C₁-C₆) alkoxy, (C₁-C₆) alkanoyloxy and (C₁-C₆) alkoxycarbonyloxy; R² is hydrogen, (C₁-C₆) alkyl or (C₃-C₆)cycloalkyl; R³ is one or more groups selected from hydrogen , (C₁-C₆) alkyl, hydroxy, (C₁-C₆) alkoxy, halogen, nitro, (C₁-C₆) alkylenedioxy, (C₁-C₆) alkanoyloxy, (C₁-C₆) alkanoyl and (C₁-C₆) alkoxycarbonyloxy or R⁴ is hydrogen or (C₁-C₆) akyl; A and B are same or different and are lower alkylene having 1 to 6 carbon atoms; and n is 3 to 4. A compound or salt thereof as claimed in claim 1, which is optically active. 3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine or a salt thereof. 3,4-Dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine or a salt thereof. 3,4-Dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-[(3,4-dimethoxy)phenoxy]ethyl]amino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine or a salt thereof. A compound as claimed in claim 3, which is optically active. A therapeutic agent for circulatory diseases containing a compound or pharmaceutically acceptable salt thereof as claimed in any preceding claim as an active ingredient. The use of a compound or pharmaceutically acceptable salt thereof as claimed in any preceding claim for the manufacture of a therapeutic agent for circulatory diseases. A process for preparing a compound of the formula [I] or a salt thereof as defined in claim 1, which comprises reacting a compound of the formula [II] with a compound of the formula [III], wherein R¹, R², R³, R⁴, A and B are as defined in claim 1 and X is halogen or methanesulfonyloxy; or reacting a compound of the formula [IV] with a compound of the formula [V], wherein R¹, R², R³, R⁴, A and B are as defined in claim 1 and X is halogen or methanesulfonyloxy; or reacting a compound of the formula [VI] with a compound of the formula [VII], wherein R¹, R², R³, R⁴, A and B are as defined in claim 1 and X is halogen or methanesulfonyloxy; and, if necessary, converting the compound of the formula [I] to a salt thereof and/or optically resolving the compound. Claims for the following Contracting State : AT A process for preparing a compound of the formula [I] or a salt thereof, wherein R¹ is one or more groups selected from hydrogen, (C₁-C₆) alkyl, halogen, nitro, hydroxy, (C₁-C₆) alkoxy, (C₁-C₆) alkanoyloxy and (C₁-C₆) alkoxycarbonyloxy; R² is hydrogen, (C₁-C₆) alkyl or (C₃-C₆)cycloalkyl; R³ is one or more groups selected from hydrogen , (C₁-C₆) alkyl, hydroxy, (C₁-C₆) alkoxy, halogen, nitro, (C₁-C₆) alkylenedioxy, (C₁-C₆) alkanoyloxy, (C₁-C₆) alkanoyl and (C₁-C₆) alkoxycarbonyloxy or R⁴ is hydrogen or (C₁-C₆) alkyl; A and B are same or different and are lower alkylene having 1 to 6 carbon atoms; and n is 3 to 4; which process comprises reacting a compound of the formula [III with a compound of the formula [III], wherein X is halogen or methanesulfonyloxy; or reacting a compound of the formula [IV] with a compound of the formula [V], or reacting a compound of the formula [VI] with a compound of the formula [VII], and if necessary, converting the compound of the formula [I] to a salt thereof and/or optically resolving the compound. A process as claimed in claim 1, wherein the compound is an optically active compound. A process as claimed in claim 1, wherein the compound is 3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine or a salt thereof. A process as claimed in claim 1, wherein the compound is 3,4-dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine or a salt thereof. A process as claimed in claim 1, wherein the compound is 3,4-dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-[(3,4-dimethoxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine or a salt thereof. A process as claimed in claim 3, wherein the compound is an optically active compound. A method of manufacturing a therapeutic agent for circulatory diseases, comprising the step of incorporating, as an active ingredient, a compound of the formula [I] or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴, A and B are as defined in claim 1.

Inventors: ISO, TADASHI, IWAO, JUN-ICHI, OYA, MASAYUKI
Applicants: SANTEN PHARMACEUTICAL CO., LTD.
Application year: 1986
Main classification: C07D279
IPC codes: C07D279