NOVEL BENZOXATHIIN DERIVATIVE, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITION

Abstract: A benzoxathiin derivative having the formula wherein R¹ represents hydrogen atom or a lower alkyl group, and R² represents a lower alkyl group or an aralkyl group, or a pharmaceutically acceptable acid addition salt thereof Phar­ maceutical compositions containing these compounds are extremely excellent as to anti-arrhythmic effect, while toxicity and side-effects are very low as compared to the conventional compounds, so that they can be used safely in the medical field, preferably as an ideal remedy for disorders of the car­ diovascular system such as arrhythmia, angina pectoris, hypertension and the like. Said benzoxathiin derivative can be produced economically and effectively by reacting an inter­ mediate compound having the general formula with an amine having the formula R¹R²NH, wherein R¹ and R² have the same meanings as defined above.

Description: Novel benzoxathiin derivative, process for preparing them and pharmaceutical composition This invention relates to a benzoxathiin derivative represented by the general formula EMI1.1 wherein R1 represents hydrogen atom or a lower alkyl group and R2 represents a lower alkyl group or an aralkyl group, or a pharmaceutically acceptable acid addition salt thereof. This invention also relates to the production process of the benzoxathiin derivative represented by the general formula (1) and to pharmaceutical compositions, preferably to combat diseases of the cardiovascular system. Since pronethalol emerged for the first time in 1962, a number of ss-adrenaline receptor blocking agents such as propranolol and the like have been developed. These ss-blockers reveal their activities by antagonizing the faction of catecholamines released from the peripheries of sympathetic nerve or adrenal medulla. The clinical effectiveness of these Blockers for arrythmia is considered to be due first of all to the blocking of the B-receptor and also to the participation of the quinidinelike actions. The effects of the ss-blockers on angina pectoris are supposedly due to the blocking of catecholamine action, thereby promoting a reduction of cardiac hyperergasia against constant motion loads, and the ss-blockers thus act defensively. The effects of the ss-blockers pn hypertension, thouth still remainillg ambiguous, are supposedly based on the suppression cE the release of renin, the suppression of the cardiac muscl B, the control of the central autonomic nerve and the like Thus,1 the ss-blockers are now widely used as remedies for arrhythmia, angina pectoris and hypertension. During the course of research which was conducted in order to develope a B-blocker superior to the currently available B-blockers in terms of such points as the ability to block the B-adrenaline receptor, the membrane stabilizing effect (local anesthetic and quinidine-like action) or the like, the present inventors have found a novel benzoxathiin derivative having every low toxicity and side-effects and a long dutetion, and have thereby accomplished his invention. - ?.at is, according to this invention, there are provided a benzoxathiin derivative having said general formula (1) or a pharmaceutically acceptable acid addition salt thereof, a production process for the same and its use as a remedy for diseases of the cardiovascular system such as the treatment of arrhythmia, angina pectoris and hypertension The compound represented by the general formula according to this invention is a novel compound described at the end of this literature, typical compounds of which include the following: EMI2.1 wherein -NR1R2 represents amino group, methylamino group, ethylamino group, n-propylamiro group, isopropylamino group, n-butylamino group, isobutylamino group, sec-butylamino group, t-butyfamino group; n-pentylamino group, isopentylamino group, neopentylamino group, t-pentylamino group, benzylamino group, phenethylamino group, 4-methoxyphenethylamino group, 2,3-dimethoxyphenethylamino group, 3,4-dimethoxyphenethylamino group, dimethylamino group, methylethylamino group, methylpropylamino group, methylisopropylamino group, methylbutylamino group, methylisobutylamino group, sec-butylmethylamino gorup, t-butylmethylamino group, pentylmethylamino group, isopentylmethylamino group, neopentylmethylamino group, t-penthymethylamino gorup, benzylmethylamino group, phenethylmethylamino group, 4-methoxyphenethylmethylamino group, 2, 3-dimethoxyphenethylmethylamino group, 2,3-dimethoxyphenethylmethylamino group and 3,4dimethoxyphenethylmethylamino group. The compound (1) of this invention is a basic om- pound and forms a salt with a pharmaceutically acceptable acid. The acid in this case includes, for example, mineral acids such as hydrogen chloride, hydrobromic acid, hydroiodic acid, phosphoric acid and sufluric acid, and appropriate organic carboxylic acids or sulfuric acis such as trifluoroacetic acid, acetic acid, p-toluenesulfonic acid, benzenesulfonic acid, maleic acid, citric acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid and malic acid. The compound (1) of this invention is obtained by treating 8-(2',3'-epoxypropoxy)-3,4-dihydro-1,2-benzo- xathiin-2,2-dioxide (2),. which is a novel compound described at the end of this literature, with various amino compounds. That is, the compound (1) of this invention is obtained by reacting at room temperature or heating 8 (2',3'-epoxypropoxy)-3,4-dihydro-1,2-benzoxathiin-2,2- dioxide (2) with an amine, for example, an alkyl amine such as aqueous ammonia, methylamine, ethylamine, propylamine, butylamine, pentylamine or the like; a dialkylamine such as dimethylamine, diethylamine, methylethylamine, methylpropylamine, methylbutylamine, methylpentylamine or the like; or an aralkylamine or a lower alkoxyaralkylamine such as benzylamine, benzylmethylamine, phenethylamine, phenethylmethylamine, 4'-methoxyphenethylamine, 4 '-methoxyphenethyl- methylamine, 2',3'-methoxyphenethylamine, 2' , 3' -methoxy- phenethylmethylamine, 3' '4' -methoxyphenethylamine, 3' '4' - methoxyphenethylmethylamine or the like in an alcoholic solvent. The solvent used is preferably water or an alcohol. The compounds thus obtained from corresponding salts by treating with pharmaceutically acceptable acids. The above-mentioned 8-(2',3'-epoxypropoxy)-3,4 dihydro-l,2-benzoxathiin-2,2-dioxide (2) is a novel compound and can be produced from o-vanillin as a raw material. o-Vanillin and methanesulfonyl chloride are condensed in the presence of a base to form 3-methoxy-2-methanesulfonyloxybenzaldehyde (3). The base used is preferably trimethylamine or the like. 3-Methoxy-2-methanesulfonyloxybenzaldehyde (3) is cyclized by a base, for example, a strong base such as potassium hydroxide, sodium hydroxide or the like to form 4-hydroxy-8-methoxy-3,4-dihydro-1,2-benzoxathiin-2,2-dioxide (4). This compound (4), on treating with a dehydrating agent such as thionyl chloride, phosphrus oxychloride or the like, forms a dehydrated product 8-methoxy-1,2-benzoxathiin2,2-dioxide (5). When 8-methoxy-l, 2-benzoxathiin-2, 2-dioxide (5) is reduced with a catalyst, 8-methoxy-3,4-dihydro-1,2-benzoxathiin-2,2-dioxide (6) which is a reduction product of the double bonding of the compound (5) is obtained in a good yield. As the catalyst used in this reduction, there can be mentioned Raney nickel, palladium on carbon, palladium, platinum and the like. Subsequently, 8-methoxy-3,4-dihydro-1,2-benzoxathiin2,2-dioxide (6) is treated with hydrobromic acid, hydroiodic acid, aluminium chloride, hydrogen chloride, boron tribromide or the like to form 8-hydroxy-3,4-dihydro-l,2- benzoxathiin-2,2-dioxide (7). When 8-hydroxy-3 , 4-dihydro-l, 2-benzoxathiin-2 , 2- dioxide (7) thus obtained and epichlorohydrin are reacted by heating in the presence of a base, 8-(2',3'-epoxypropoxy) 3,4-dihydro-l,2-benzoxathiin-2,2-dioxide (2) is obtianed as the raw material of this invention. The base used in this reaction is preferably potassium carbonate, sodium carbonate, lithium carbonate or the like. The above-mentioned processes are shown in the following reaction formulae: EMI4.1 EMI5.1 wherein R1 and R2 have the same meanings as defined above. The test methods of the compound of this invention for various pharmacological effects on the cardiovascular system and the results thereof are described below. Pharmacological Experiments (1) Test of the blocking effect Preparation of a membrane specimen Spraque-Dawley male rats having 150 - 200 g body weight were decapitated, and the brains were quickly taken out and, after decortication, frozen at -700C. After freezing overnight at -700C, the thawed brain was homogenized with a buffer [0.25 mole sucrose, 5 mmole tris (hydroxymethyl) aminomethane hydrochloride, 1 mmole magnesium chloride, pH 7.4] in an amount of 8 times the weight of the brain. The homogenate was centrifuged at 800 x g for 20 minutes, and the supernatant was centrifuged at 14,000 x g for 14 minutes, the deposit of which was washed three times with the above-mentioned buffer. The deposit finally obtained was suspended again in a buffer of 75 mmole tris(hydroxymethyl)aminomethane and 25 mmole magnesium chloride (pH 7.4) to form a membrane specimen. Test method To 50 1 of the membrane specimen were added 50 1 of 3H-dihydroalprenolol (3H-OHA) and 50 1 of the mixture of the test frug and the buffer, such that the total volume was adjusted to 150 1, and the mixture was incubated at 370C for 10 minutes. The reaction was stopped by adding an ice-cooled mixture of 50 mmole tris(hydroxymethyl)aminomethane hydrochloride and 17 mmole magnesium chloride (pH 7.4), and the mixture was filtered under reduced pressure through a Whatman GF/B glassfiber. The filter was washed three times and dried, and a toluene type scintillator was added to measure the radioactivity. In the measurement, the amount obtained by subtracting the bondings obtained in the presence of 10-5 mole propranolol from the total bondings was considered to represent the specific bondings of the S-receptor. In addition, the determination of protein was carried out according to the method of Lowry et al. [Lowry, O.H. et al., J. Biol. Chem., 193, 265-275 (1951)]. The results are shown in Table 1. Table 1 Test Result 6-Receptor blockign effect of the synaptosome membrane of rat brain EMI7.1 EMI7.2 <tb> Example <SEP> R1 <SEP> ss-Receptor <SEP> blocking <tb> code <SEP> of <SEP> -N <SEP> effect <SEP> Inhibition <SEP> (%) <tb> test <SEP> \Rê <SEP> 10-6 <SEP> <SEP> mole <SEP> ¯ <SEP> mole <tb> compound <tb> <SEP> 1 <SEP> methylamino <SEP> group, <SEP> 35.4 <SEP> 73.9 <tb> <SEP> fumarate <SEP> 73 <tb> <SEP> 2 <SEP> dimethylamino <SEP> group, <SEP> 17.1 <SEP> 62.6 <SEP> <tb> <SEP> fumarate <tb> <SEP> 3 <SEP> isopropylamino <SEP> group, <SEP> 97.6 <SEP> 91.6 <SEP> <tb> <SEP> hydrochloride <tb> <SEP> 4 <SEP> t-butylamino <SEP> group, <SEP> 96.3 <SEP> 91.4 <SEP> <tb> <SEP> hydrochloride <SEP> <tb> <SEP> 5 <SEP> sec-butylamino <SEP> group, <SEP> 83.0 <SEP> 95.3 <SEP> <tb> <SEP> hydrochloride <tb> <SEP> 6 <SEP> isobutylamino <SEP> group, <SEP> 41.7 <SEP> 81.9 <tb> <SEP> hydrochloride <tb> <SEP> 7 <SEP> 3'4'-dimethoxyphenethyl <SEP> 75.2 <SEP> 90.1 <tb> <SEP> group, <SEP> hydrochloride <tb> (2) Test of anti-arrhythmic effect Referring to the method described by J W. Lawson (Journal of Pharmacology and Experimental Therapeutics, 160, 22, 1968), a ddy male mouse was subjected to the inhalation of chloroform, and when respiration stopped, an electrocardiogram was recorded and the ventricular flutter and fibrillation were observed. When a compound showing an anti-arrhythmic effect is previously administered, such an irregular ventricular appearance is prevented. The compound of this invention was intraperioneally administered in various dosages to the groups of 29 - 40 mice. After 30 minutes the mice were subjected to the inhalation of chloroform, and the preventive ratios of the venticular flutter and fibrillation were measured for respective dosages. Then, according to the method of Litchfield and Wilcvxon (Journal of Pharmacology and Experimental Therapeutics, 96, 99, 1949), the 50% effective dose (ED50) and 95% confidence limit thereof were calculated and shown in Table 3. As is apparent from Table 3, the compound of this invention had an excellent anti-arrhythmic effect in a half amount or even in an extremely low dosage as compared to the conventional compounds, and showed a property of retaining the anti-arrhythmic effect even after 24 hours. (3) Effects on the blood pressure and heart rate in SI{R In order to measure the blood pressure of a SHR (spontaneous hypertensive rat), a polyethylene tube was inserted into an artery to a level of the abdominal aorta through the crural artery, and the other end of the tube was tightly stoppered by a metal rod, extended subcutaneously and exposed out of the body at the posterior of the neck and fixed by suturation to the surrounding skin. The tube was filled with 500 U of heparin. On the day subsequent to the operation, the blood pressure was measured without anesthetization or restriction using a pressure transducer and continously recorded on a thermal recording system together with the heart rate which was measured by driving a tachometer with the pulse wave of blood pressure. The test drugs were dissolved in physiological saline and administered using a sound (p.o.) Before administration of drugs the blood pressures and heart rates of SHR showed no significant difference as between the control group, to which the physiological saline was administered, and groups treated with SUN3479 (the product in Example 4) or carteolol. The blood pressure and heart rate increased only slightly, probably as a result of being handled during the administration of the physiological saline (5 ml/kg), from the time immediately after the administration until 1 hour after the administration, but thereafter they started to show the tendency to decrease. The changes of blood pressure with the passage of time after the administration of drugs in the three groups is shown in Table 2. Table 2 Effects of product in Example 4 (SUN 3479) and carteolol on mean blood pressure in conscious spontaneously hypertensive rats. EMI10.1 <SEP> Control <SEP> SUN <SEP> 3479 <SEP> Carteolol <tb> <SEP> (saline) <SEP> 0.1 <SEP> mg\kg <SEP> p.o. <SEP> 0.1 <SEP> mg\kg <SEP> p.o. <SEP> 0.1 <SEP> mg\kg <SEP> p.o. <SEP> 0.1 <SEP> mg\kg <SEP> p.o. <tb> <SEP> Time <SEP> (n=4) <SEP> (n=4) <SEP> (n=5) <SEP> (n=4) <SEP> (n=5) <tb> <SEP> Basal <SEP> value(mmHg) <SEP> 145.2+-3.2 <SEP> 154.5+-14.6 <SEP> 166.4+-4.5 <SEP> 149.0+-7.9 <SEP> 159.0+-6.7 <tb> % <SEP> 10 <SEP> min <SEP> 4.1+-2.3 <SEP> 6.4+-3.5 <SEP> 1.4+-1.2 <SEP> 1.4+-2.1 <SEP> 2.5+-3.2 <tb> E <SEP> 20 <SEP> min <SEP> 3.1+-1.3 <SEP> 4.6+-3.2 <SEP> -0.3+-1.7 <SEP> -9.2+-4.0 <SEP> -1.4+-2.6 <tb> x <SEP> 30 <SEP> min <SEP> 2.0+-1.3 <SEP> 4.1+-2.6 <SEP> -8.1+-2.9* <SEP> -11.3+-3.9* <SEP> -5.1+-3.6 <tb> c <SEP> 60 <SEP> min <SEP> -0.3+-1.5 <SEP> -4.2+-3.8 <SEP> -12.0+-4.3* <SEP> -.7.3.+-2.7* <SEP> -11.7+-3.3** <tb> h <SEP> 90 <SEP> min <SEP> -4.2+-2.8 <SEP> -6.5+-3.2 <SEP> -10.9+-2.8** <SEP> 18.1+-3.7** <SEP> -14.7+-3.6** <tb> a <SEP> 120 <SEP> min <SEP> -6.3+-3.4 <SEP> -7.3+-5.9 <SEP> -14.5+-4.3** <SEP> -12.7+-6.5 <SEP> -23.8+-3.0*** <tb> n <SEP> 3 <SEP> hr <SEP> -5.8+-3.3 <SEP> -8.9+-3.0 <SEP> -16.3+-4.1** <SEP> -15.4+-3.3** <SEP> -23.1+-4.8** <tb> g <SEP> 4 <SEP> hr <SEP> -3.9+-5.0 <SEP> -13.0+-2.5** <SEP> -20.0+-3.7*** <SEP> -15.1+-3.7** <SEP> -24.4+-4.2*** <tb> e <SEP> 5 <SEP> hr <SEP> -7.8+-0.8 <SEP> -14.7+-2.5*** <SEP> -24.5+-4.0*** <SEP> -18.8+-1.3*** <SEP> -24.7+-4.7*** <tb> <SEP> 6 <SEP> hr <SEP> -6.7+-3.8 <SEP> -14.8+-2.4*** <SEP> -24.1+-3.3*** <SEP> -20.8+-1.7*** <SEP> -21.3+-4.2*** <tb> <SEP> 24 <SEP> hr <SEP> -2.8+-4.2 <SEP> -11.5+-6.2 <SEP> -2.1+-2.5 <SEP> -2.1+-4.5 <tb> Each value represents the mean #SEM. Significantly different from control, * p < 0.05 ** p < 0.01 *** p < 0.001 As apparent from Table 2, the compound in Example 4 has an excellent hypotensive effect at almost the same level as carteolol, and it remains effective even after 24 hours with no significant difference being recognized. (4) Acute toxicity The test compounds were administered in the caudal rein or stomach of ddy male mice having 18-22 g body weight, and the LD50 was calculated from the mortality occurring within 1 week after administration, using the up and down method (Edited by Takagi and Ozawa; YAKUBUTSUGAKU JIKKEN, p. 204, Nanzando, 1972). The results are shown in Table 3. Table 3 Anti-arrhythmic effect and acute toxicity of the compound of this invention EMI11.1 EMI11.2 <tb> <SEP> Anti-arrhythmic <SEP> Acute <SEP> toxicity <tb> Example <SEP> R1 <SEP> effect <tb> code <SEP> of <SEP> - <SEP> (EDso) <SEP> mg/kg <SEP> (LDso) <SEP> mg/kg <tb> test <SEP> -N <SEP> R2 <SEP> 95% <SEP> con- <SEP> intra- <SEP> in <tb> <SEP> limit <SEP> venous <SEP> stomach <tb> <SEP> imit <SEP> venous <SEP> stomach <tb> <SEP> isopropylamino <SEP> 0.10 <SEP> 68.2 <SEP> > 500 <tb> <SEP> 3 <SEP> group, <SEP> 0.23 <SEP> 0 <SEP> 54 <SEP> 0.54 <tb> <SEP> hydrochloride <tb> <SEP> t-butylamino <SEP> 0.01 <SEP> <tb> <SEP> 4 <SEP> group, <SEP> 0.03 <SEP> 0.07 <SEP> 59.2 <SEP> > 500 <tb> <SEP> hydrochloride <tb> <SEP> se-butylamino <SEP> 0.45 <SEP> <tb> <SEP> 5 <SEP> group, <SEP> 1.30 <SEP> 3.72 <SEP> - <SEP> 68.2 <SEP> > 500 <tb> <SEP> hydrochloride <tb> <SEP> 1.03 <SEP> <tb> <SEP> propranolol <SEP> 2.20 <SEP> 1.03 <SEP> - <SEP> 21.9 <SEP> <tb> <SEP> 4. <SEP> - <SEP> 38.0 <SEP> <tb> <SEP> carteolol <SEP> 400.00 <SEP> 816.00 <tb> <SEP> acebutolol <SEP> 47.00 <SEP> 20.8022 <SEP> 40.2 <SEP> <tb> <SEP> 106.22 <tb> As is apparent from Table 3, the compound of this invention showed very high stabilities in both intravenous and oral administrations. Particularly in oral administration, there was no mortality even at a dose of 500 mg/kg. The compound of this invention, which shows clearly its effect as a 6-blocker, may be applied to angina pectoris and hypertension in addition to arrhythmia. The compound of this invention is used in the form of a free base, or in the form of a pharmaceutically acceptable salt such as the hydrochloride or the fumarate, as a remedy for arrhythmia. It may be administered orally or parenterally, alone or in combination with known non-toxic vehicles in an appropriate dosage form such as capsule, tablet, injection or the like, and these preparations may be prepared, for example, as follows. After the raw material is pulverized, it is mixed with a vehicle such as lactose, starch or a derivative thereof, a cellulose derivative or the like and is then charged into a gelatin capsule to form a capsule. In order to make a tablet, a bonding agent such as carboxymethylcellucose sodium, arginic acid or gum arabic and water are added in addition to the above-mentioned vehicle, mixed together and granulated with an extrusion granulator. To the granules obtained is added a lubricant such as talc or stearic acid, and tablets are prepared with a usual suppression tablet machine. For.parenteral administration by injection, a water-soluble salt of the compound is dissolved in sterilized distilled water or sterilized physiological saline and charged in an ampule to provide a preparation for injection. It may include a stabilizer and/or a buffer substance, if necessary. The effective amount of anti-arrhythmic agent varies depending on the kind and strength of arrhythmia or the physical condition of a patient, but it is usually dosed in an amount sufficient to make an irregular rhythm return to a sinus rhythm. As for the compound of this invention, it is orally administered in an amount of 10 - 30 mg per dosage for an adult, 2 - 3 times per day. This invention is specifically explained by referring to the following Examples, but it will be understood that this invention is not limited thereto. Example 1 8-(3-methylamino-2-hydroxypropoxy)-3,4 dihydro-1,2-benzoxathiin-2,2-dioxide EMI13.1 To 2.710 g (10.6 mmole) of 8-(2,3-epoxypropoxy) 3,4-dihydro-1,2-benzoxathiin-2,2-dioxide was added 60 ml of 30% methanolic solution of methylamine, and the mixture was stirred for 30 minutes at room temperature. Methylamine and methanol were removed by distillation under reduced pressure, and the residue was acidified by the addition of hydrochloric acid. The solution was extracted with chloroform, and the disused materials (including the raw material) were removed. Then, the hydrochloric acid layer was basified by the addition of dilute aqueous ammonia. The basic aqueous layer was extracted with chloroform (x 3), the extracts were dried over magnesium sulfate, and thereafter the solvent was removed by distillation under reduced pressure. To 1.95 g of the residue was added 0.39 g of fumaric acid, and the mixture was dissolved in methanol and then recrystallized to obtain quantitatively the fumaric acid salt of the entitled compound. Data of the fumarate Property: colorless prismatic crystal Melting point: 133.5 - 1370C IR spectrum (KBr, cm1) : 3400, 3080, 1590, 1380, 1160 Mass spectrum (m/z): 288(M++1), 243(b.p.) NMR spectrum (DMSO-d6, 6) 2.70-4.30(12H, m), 5.40-6.10(3H, m, OH, N¯2), 6.40(1H, s, fumaric acid), 6.60-7.20(3H, m) Elementary analysis: C (%) H (%) N (%) Calculated for C12H17NO5Sl/2C4H4O4l/2H2O: 47.45 5.69 3.95 Found: 47.59 5.77 3.86 Example 2 8- (3-dimethylamino-2-hydroxypropoxy) -3,4- dihydro-1,2-benzoxathiin-2,2-dioxide EMI14.1 To 2.312 g (9.0 mmole) of 8-(2,3-epoxypropoxy)- 3,4-dihydro-1,2-benzoxathiin-2,2-dioxide were added 30 ml of 50% aqueous dimethylamine solution and 30 ml of methanol, and the mixture was stirred for 30 minutes at room temperature. Treating in the same manner as in Example 1, 1.76 g (yield, 64%) of the entitled compound was obtained. To this compound was added 0.33 g of fumaric acid, and the mixture was dissolved in methanol and recrystallized to obtain 1.5 g of the fumarate. Data of the fumarate Property: colorless crystal Melting point: 144.9 - 145.70C Elementary analysis: C (%) H (z) N (%) Calculated for C13H19NO5S.l/2C4H4O4: 50.13 5.89 3.90 Found: 49.85 5.93 3.87 IR spectrum (KBr, cm1): 3200, 1590, 1360, 1155 Mass spectrum (m/z): 302(M++l), 257(b.p.) NMR spectrum (DMSO-d6, 6): 2.40(6H, s), 2.50-4.20 + (9H, m), 6.45-6.80(2H, m, OH, NH), 6.40-7.20(3H, m) Example 3 8- (3-isopropylamino-2-hydroxypropoxy) -3,4- dihydro-1,2-benzoxathiin-2,2-dioxide EMI14.2 To 2.008 g (7.8 mmole) of 8-(2,3-epoxypropoxy)-3,4- dihydro-1,2-benzoxathiin-2,2-dioxide were added 10 ml of isopropylamine and 50 ml of methanol, and the mixture was refluxed by heating for 1 hour. Proceeding in the same manner as in Example 1, the reaction residue was obtained. The residue obtained was dissolved in chloroform and reacted with a hydrochloric acid gas saturated ether to form a hydrochloride. The salt was recrystallized from a mixed solvent of isopropanol and ether, and 1.28 g of the hydrochloride of the entitled compound was obtained (yield, 57%). Data of the hydrochloride Property: colorless prismatic crystal Melting point: 168.0 - 170.00C Elementary analysis: C (%) H (%) N (%) Calculated for C14H2lNO5S HC1: 47.79 6.02 3.98 Found: 47.40 6.28 4.02 IR spectrum (KBr, cm 1): 3370, 2950, 1365, 1165 Mass spectrum (m/z): 316(M++1), 136(b.p.) -NMR spectrum (CDCl3, 6): 1.11(6H, d, J-6.75Hz), 2.50-3.10(3H, m), 3.00(2H, s, OH, NH), 3.80-4.30 (3H, m), 6.70-7.30(3H, m) Example 4 8- (3-t-butylamino-2-hydroxypropoxy) -3,4- dihydro-1,2-benzoxathiin-2,2-dioxide EMI15.1 To 2.04 g (8.0 mmole) of 8-(2,3-epoxypropoxy)-3,4dihydro-1,2-benzoxathiin-2,2-dioxide were added 10 ml of t-butylamine and 50 ml of methanol, and the mixture was refluxed by heating for 1 hour. The reaction mixture was treated in the same manner as in Example 1, and a reaction residue was obtained. The residue obtained was reacted with a hydrochloric gas saturated ether to form a hydrochloride. The hydrochloride obtained was recrystallized from a mixed solvent of methanol and ether and 1.52 g (yield, 52%) of the hydrochloride of the entitled compound was obtained. Data of the hydrochloride Property: colorless prismatic crystal Melting point: 248.0 - 250.00C Elementary analysis: C (%) H (%) N (%) Calculated for C15H23NO5S HC1: 49.24 6.61 3.83 Found: 49.05 6.62 3.80 IR spectrum (KBr, cml): 3320, 2975, 1380, 1160 Mass spectrum tm/z): 330(M++l), 314(b.p.) NMR spectrum (CDC13, 6): : 1.14(9H, s), 2.70-2.95(2H, m), 3.24(2H, s, OH, NH), 3.50(4H, s), 4.07(3H, m), 6.70-7.30(3H, m) Example 5 8-(3-sec-butylamino-2-hydroxypropoxy)-3,4 dihydro-1,2-benzoxathiin-2,2-dioxide EMI16.1 To 2.47 g (9.6 mmole) of 8-(2,3-epoxypropoxy)-3,4- dihydro-1,2-benzoxathiin-2,2-dioxide were added 10 ml of sec-butylamine and 50 ml of methanol, and the mixture was refluxed by heating for 30 minutes. The reaction mixture was treated in the same manner as in Example 1, whereby the reaction residue was obtained. The residue obtained was dissolved in chloroform and treated with a hydrochloric acid gas saturated ether to form a hydrochloride. Then, the salt was recrystallized to form a mixed solvent of methanol and isopropanol and 1.54 g of. the hydrochloride of the entitled compound was obtained (yield, 448). Data of the hydrochloride Property: colorless prismatic crystals Melting point: 169.5 - 170.00C Elementary analysis: C (%) H (%) N (%) Calculated for C15H23NO5SHCl: 49.24 6.61 3.83 Found: 49.11 6.73 3.75 IR spectrum (KBr, cm¯l): 3320, 2960, 1370, 1160 Mass spectrum (m/z): 330(M++1) NMR spectrum (CDC13, 6): : 0.70-1.80(8H, m), 2.20-3.00 (3H, m), 2.68(2H, m, OH, NH), 3.47(4H, s), 4.05 (3H, m), 6.70-7.20(3H, m) Example 6 8- (3-isobutylamino-2-hydroxypropoxy) -3,4- dihydro-1,2-benzoxathiin-2,2-dioxide EMI17.1 To 2.42 g (9.4 mmole) of 8-(2,3-epoxypropoxy)-3,4dihydro-1,2-benzoxathiin-2-,2-dioxide were added 10 ml of isobutylamine and 50 ml of methanol, and the mixture was refluxed by heating for 1.5 hours. The hydrochloride obtained by proceeding in the same manner as in Examples 1 and 3 was recrystallized from a mixed solvent of isopropanol and ether, and the hydrochloride of the entitled compound was obtained in an amount of 1.80 g (yield, 52%). Data of the hydrochloride Property: colorless prismatic crystals Melting point: 140.0 - 140.50C Elementary analysis: C (%) H (8) N (%) Calculated for C15H23NO5SHCl: 49.24 6.61 3.83 Found: 49.11 6.73 3.76 IR spectrum (KBr, cm1): 3280, 2960, 1368, 1158 Mass spectrum (m/z): 330(M++1), 286 (b.p.) NMR spectrum (CDC13, 6): 0.94(6H, d, J-6.75Hz), 1.40-2.10(1H, m), 2.38-2.95(4H, m), 3.48(4H, s), 3.95-4.28(3H, m), 6.70-7.20(3H, m) Example 7 8-13-(3,4-dimethoxyphenethylamino)-2-hydroxy- propoxyl-3,4-dihydro-1,2-benzoxathiin-2,2 dioxide EMI17.2 To 3.53 g (13.8 mmole) of 8-(2,3-epoxypropoxy)-3,4 dihydro-1,2-benzoxathiin-2,2-dioxide were added 10 ml of 3,4-dimethoxyphenethylamine and 50 ml of methanol, and the mixture was refluxed by heating for 20 hours. After methanol and most of the 3,4-dimethoxyphenethylamine had been removed by distillation under reduced pressure, the residue was treated in the same manner as in Example 3 to form a hydrochloride. The hydrochloride was dissolved in methylene chloride, and isopropanol was added. Methylene chloride was removed by distillation, and the previpitated powder was collected by filtration and recrystallized from methylene chloride to obtain the hydrochloride of the entitled compound in an amount of 1.24 g (yeld, 20%). Data od the hydrochloride Property: colorless prismatic crystals Melting point: 193.0 - 194.50C Elementary analysis: C (%) H (%) N (%) Calculated for C21H27NO7S.HCl-l/4H2O: 52.71 6.00 2.92 Found: 52.62 5.92 2.90 IR spectrum (KBr, cm1): 3300, 2960, 1370, 1160 Mass spectrum (m/z): 438(M++1), 286(b.p.) NMR spectrum (DMSO-d6, 6): 2.70-4.30(13H, m), 3.35 (3H, m. OH, NH2), 3.76(3H, s), 3.80(3H, s), 6.70-7.30(6H, m) Preparation 1 3-methoxy-2-mesyloxybenzaldehyde EMI18.1 In 700 mol of acetone were dissolved 100 g (0.66 mole) of o-vanillin and 60 ml (0.78 mole) of methanesulfonyl chloride, and 200 ml (1.43 mole) of triethylamine was added dropwise with ice-cooling over a period of 2 hours. Precipitated triethylamine hydrochloride was collected by filtration and washed further with 300 ml of acetone, and the combined filtrate was concentrated. The concentrated residue was dissolved in chloroform, washed with a dilute aqueous hydrogen chloride and dried. Thereafter, chloroform was removed by distillation. By recrystallizing the residue from chloroform and ether, the entitled compound was obtained in an amount of 134.1 g (yield, 89%). Property: colorless prismatic crystals Melting point: 73.5 - 74.50C Elementary analysis: C (%) H (%) Calculated for CgH10SO5: 46.95 4.38 Found: 46.85 4.25 IR spectrum (KBr, cm1): 1690, 1360, 1280, 1150, 1060 Mass spectrum (m/z): 230(M+), 151 (b.p.) NMR spectrum (CDC13, 6): 3.39(3H, s), 4.00(3H, s), 7.25-7.70(3H, m), 10.38(1H, s) Preparation 2 4-hydroxy-8-methoxy-3,4-dihydro-1,2 benzoxathiin-2 , 2-dioxide EMI19.1 In 50 ml of pyridine was dissolved 8.00 g (34.7 mmole) of 3-methoxy-2-mesyloxybenzaldehyde, and 5 g of powdery potassium hydroxide was added to the solution with ice-cooling. The mixture was stirred for 1 hour. The reaction solution was poured into 5% aqueous hydrogen chloride and 300 g of crushed ice and extracted with ethyl acetate. The solvent was removed by distillation, and the residue was recrystallized from a mixed solvent of acetone and hexane. The entitled compound was obtained in an amount of 5.71 g (yield, 71%). Property: colorless needles Melting point: 108.5 - 110.00C Elementary analysis: C (%) H (%) Calculated for C9H10SO5: 46.95 4.38 Found: 46.74 4.34 IR spectrum (KBr, cm1): 3400, 1385, 1280, 1160, 1085 Mass spectrum (m/z): 230(M+), 212(b.p.) NMR spectrum (DMSO-d6, 6): 3.42(3H, s), 3.50-4,50 (3H, m, including OH), 4.95-5.35(1H, m), 7.10-7,85 (3H, m) Preparation 3 8-methoxy-1 , 2-benzoxathiin-2 , 2-dioxide EMI20.1 In 15 ml of pyridine was dissolved 3.35 g (14.6 mmole) of 4-hydroxy-8-methoxy-3,4-dihydro-1,2-benzoxathiin- 2,2-dioxide, and 2.60 g (21.8 mmole) of thionyl chloride was added with ice-cooling to the solution. Furthermore, heating was conducted to complete the reaction. Pyridine was removed by distillation under reduced pressure, and the residue was dissolved in chloroform and washed with water. The chloroform layer was dried and thereafter concentrated, and the residue was subjected to silica gel column chromatography (eluent; benzene). The crystals obtained were recrystallized from methylene chloride-hexane, and the entitled compound was obtained in an amount of 2.21 g (yield, 72%). Property: colorless prismatic crystals Melting point: 130.5 - 131.7eC Elementary analysis: C (%) H (%) Calculated for CgHgS04: 50.94 3.80 Found: 51.08 3.82 IR spectrum (KBr, cm 1) 1370, 1280, 1170, 1080 Mass spectrum (m/z): 212(M+) NMR spectrum (CDC13, 6): 3.96(3H, s), 6.80(1H, d, J=lOHz), 6.9O-7.25(3H, m), 7.24(1H, d, J=lOHz) Preparation 4 8-methoxy-3,4-dihydro-1,2-benzoxathiin 2,2-dioxide EMI20.2 9.58 g (45.1 mmole) of 8-methoxy-l,2-benzoxathiin- 2,2-dioxide and 2.0 g of palladium on carbon were suspended in 250 ml of methanol and 50 ml of dioxane, and the mixture was stirred under a hydrogen pressure of 100/cm2 at room temperature for 3 days. The catalyst was collected by filtration and washed with acetone, and the organic layer was then concentrated. The condensed residue was recrystallized from a mixed solvent of chloroform and methylene chloride, and the entitled compound was obtained in an amount of 8.96 g (yield, 93%). Property: colorless needles Melting point: 130.0 - 131.00C Elementary analysis: C (%) H (%) Calculated for C9H10SO4: 50.46 4.71 Found: 50.24 4.70 IR spectrum (KBr, cm1): 1370, 1270, 1150, 1080 Mass spectrum (m/z): 214(M+), 106(b.p.) Preparation 5 8-Hydroxy-3,4-dihydro-1,2-benzoxathiin 2,2-dioxide EMI21.1 To 8.96 g (41.8 mmole) of 8-methoxy-3,4-dihydro-1,2- benzoxathiin-2,2-dioxide was added 100 ml of 47% hydrobromic acid, and the mixture was dissolved by heating and refluxed by heating for a further 1.5 hours. After cooling the mixture, precipitated crystals were collected by filtration and washed with water. The aqueous solution was extracted with ether, and the ethereal extract was dried. Then, the solvent was removed by distillation, and crystals obtained were combined and dried (yield, quantitatively). Property: colorless crystals Melting point: 146.5 - 148.00C Elementary analysis: C (%) H (%) Calculated for C8H8SO4: 47.99 4.03 Found: 47.93 4.23 IR spectrum (KBr, cm-1): 3520, 1375, 1150 Mail spectrum (m/z): 200(M+), 136(b.p.) Preparation 6 8-(2,3-epoxypropoxy)-3,4-dihydro-1,2- benzoxathiin-2, 2-dioxide EMI22.1 In 50 ml of acetone were dissolved 3.30 g (16.5 mmole) of 8-hydroxy-3,4-dihydro-1,2-benzoxathiin-2,2-dioxide and 6 ml (76 mmole) of epichlorohydrin, 3 g of potassium carbonate was added to the solution, and the mixture was heated under reflux for 38 hours. After removal of acetone by distillation, the residue was extracted with chloroform, and the extract was dried and concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of chloroform and hexane, and the entitled compound was obtained in an amount of 3.87 g (yield, 92%). Property: colorless prismatic crystals Melting point: 103.5 - 104.2 C Elementary analysis: C (%) H (%) Calculated for C11H12SO5: 51.55 4.71 Found: 51.29 4.84 IR spectrum (KBr, cm-1): 1370, 1280, 1160, 1080, 920, 770 Mass spectrum (m/z): 256(M+); 136(b.p.) NMR spectrum (CDCl3, 6 2.70-3.05(2H, m), 3.20-3.50 (1H, m), 3.50(4H, s), 3.88-4.50(2E, m), 6.70-7.30 (3H,m)

Claims: Claims: 1. A benzoxathiin derivative having the general formula EMI23.1 wherein 1 represents hydrogen atom or a lower alkyl. grouP1 and R2 represents a lower alkyl group or an aralkyl group, or a pharmaceutically acceptable acid addition salt thereof. 2. A benzoxathiin derivative according to Claim 1, wherein when R1 represents hydrogen atom or methyl group, R2 represents methyl group, ethyl group, isopropyl group, isobutyl group, t-butyl group, sec-butyl group, n-propyl group or n-butyl group. 3. A benzoxathiin derivative according to Claim 1, wherein when R1 represents hydrogen atom or methyl group, R2 represents phenethyl group, 3',4'-dimethoxyphenethyl group, 2',3'-dimethoxyphenethyl group or 4'-methoxyphenethyl group. 4. A pharmaceutical composition comprising a benzoxa-thiin derivative having the general formula EMI23.2 wherein R1 represents hydrogen atom or a lower alkyl group, and R2 represents a lower alkyl group or an aralkyl group, or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier. 5. A composition according to Claim 4, wherein when R1 represents hydrogen atom or methyl group, R2 represents methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group or t-butyl group. 6. A composition according to Claim 4, wherein when R represents hydrogen atom or methyl group, R2 represents phenethyl group, 3' , 4' -dimethoxyphenethyl group, 2',3'dimethoxyphenethyl group or 4'-methoxyphenethyl group. 7. A process for producing a benzoxathiin derivative having the general formula EMI24.1 wherein R1 represents hydrogen atom or a lower alkyl group, and R2 represents a lower alkyl group or an aralkyl group, and a pharmaceutically acceptable acid addition salt there of, characterized by reacting a compound having the general formula EMI24.2 with a compound having the formula R1R2NH wherein R1 and R2 have the same meanings as defined above, and, if necessary, further treating the product with a pharmaceutically acceptable acid.

Inventors: HORI, MIKIO
Applicants: SUNTORY LIMITED
Application year: 1985
Main classification: C07D327
IPC codes: A61P9, C07D411, A61K31, C07D327