KR960004829B1 - 1,2-benzothiazin-1,1-dioxide derivatives - Google Patents

Abstract

The derivatives of formula(I) is made by reaction with amino-hydanto derivatives in a high boiling point organic solvent in Soxhlet extractor. In formula(I), the one between X and Z can be OR5 and the other is fixed to formula (a) or (b). R1 is H or lower alkyl group and A is H or halogen. R2 is lower alkyl, lower alkenyl, cyclo-alkyl, replaced or non-replaced aryl, replaced or non-replaced ar-alkyl, or aroyl. R3 and R4 are independently hydrogen or lower alkyl. R5 is H and Y is sulfur or oxygen. The derivatives compounds are used for antiphologistic anodyne. They have a better effetiveness of anodyne than the known anodyne in using less quantity.

Description

1, 2-benzothiazine-1, 1-dioxide derivative

The present invention relates to novel 1, 2-benzothiazine-1, 1-dioxide derivatives, methods for their preparation and their use as anti-inflammatory analgesics.

Since the introduction of pyoxycamp (4-hydroxy-2H-1, 2-benzothiazine-3-carboxanilide-1, 1-dioxide) as a type of nonsteroidal anti-inflammatory agent (NSAIDS) in 1979, Pharmacological studies as anti-inflammatory drugs for 1, 2-benzothiazines having the same oxycamp structure as oxycam are actively underway and many studies have been reported. The anti-inflammatory analgesics of this series are mainly substituted with amide groups by reacting 3-carboxyl groups of benzothiazine with heterocyclic amine derivatives such as pyridine, thiazole and isoxazole, and representative examples thereof are sudoxicam and bisox. Cycam, tenoxycamp, doxycamp, ampicoxycamp and the like. However, the 1, 2-benzothiazine-1, 1-dioxide derivatives having an oxycam structure have the advantage of excellent efficacy as an anti-inflammatory analgesic agent and a long time to express the drug, whereas the side effect of stimulating the gastric mucosa upon prolonged administration The development of these formulations is subject to many limitations because they are difficult to absorb locally. Therefore, in order to overcome these side effects and develop a new drug having excellent efficacy, the synthesis and research on another compound of the oxycam system is constantly in progress.

The present inventors introduced a hydantoin ring, which has never been introduced until now, to 1, 2-benzothiazine-3-carboxamide, which is the basic skeleton of oxycam, to introduce novel 1,2-benzothiazine-1, 1- The present invention was completed by synthesizing the dioxide derivative and confirming its anti-inflammatory activity.

The present invention relates to novel 1, 2-benzothiazine-1, 1-dioxide derivatives of the general formula (I).

Wherein one of X and Z is OR ₅ , and the other is of general formula

R ₁ is hydrogen, lower alkyl group or lower alkenyl group, A is hydrogen or halogen, R ₂ is lower alkyl, lower alkenyl, cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted Aralkyl or aroyl, R ₃ and R ₄ are each independently hydrogen or lower alkyl, R ₅ is hydrogen, and Y is sulfur or oxygen.

Among the compounds of the general formula (I) according to the invention, preferred are X and OH.

Is a group of R ₁ is hydrogen, methyl or allyl, A is hydrogen, chloro or bromo and R ₂ is methyl, allyl, phenyl, benzyl, 4-chlorobenzyl, benzoyl, cyclohexyl or 4-chlorophenyl R ₃ and R ₄ are each independently hydrogen or methyl and Y is sulfur.

Particularly preferred compounds of formula (I) are those wherein X is OH and Z is Is a group wherein R ₁ is methyl, R ₂ is methyl, allyl, cyclohexyl or phenyl, A is hydrogen, R ₃ and R ₄ are hydrogen, and Y is sulfur.

According to the present invention, the novel 1, 2-benzothiazine-1, 1-dioxide derivatives of general formula (I) can be prepared by reacting a compound of general formula (II) with an amino hydantoin derivative of general formula (III). It has also been found that it is obtained.

Z'-NH ₂ (III)

Wherein one of B and D is OR ₅ , the other is an optionally esterified carboxylic acid group, and Z ′ is a general formula And R ₁ to R ₅ , Y, A, X and Z are as defined above.

Finally, according to the present invention, it was found that the novel 1, 2-benzothiazine-1, 1-dioxide derivatives of general formula (I) have very good anti-inflammatory analgesic action.

The reaction of the compounds of formula (II) and (III) to prepare the 1, 2-benzothiazine-1, 1-dioxide derivatives of general formula (I) according to the invention is preferably carried out in a suitable solvent. Suitable reaction solvents for this purpose are high boiling organic solvents, for example xylene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and the like.

The reaction of the general formula (II) compound and the general formula (III) compound is preferably carried out at 100 to 180 ° C over 10 hours to 3 days. The reaction is preferably carried out in the presence of molecular sieves under Soxhlet apparatus.

Some of the derivatives of general formula (III) used to prepare the new compounds of general formula (I) according to the invention are known compounds and some are new compounds which have not been known so far. Among the compounds of the general formula (III), novel compounds are represented by the following general formula (III-A), and these general formula (III-A) compounds are also the subject of the present invention.

Wherein R _2-a represents cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl or substituted or unsubstituted aroyl, and R ₃ and R ₄ are each independently hydrogen or lower alkyl group to be.

The novel 1-amino-2-thioxo-hydantoin derivatives of formula (III-A) can be prepared by methods analogous to the preparation of known compounds of general formula (III) compounds. For example, a compound of formula (III-A) can be prepared by reacting a thiocyanate derivative of formula (IV) with a hydrazine derivative of formula (V) in the presence of triethylamine. In this reaction, triethyl amine is used in a ratio of 2 equivalents or more to 1 equivalent of the derivative of general formula (IV). At this time, triethylamine may be used to directly prepare a compound of general formula (III-A) using 2 equivalents at one time, but using 1 equivalent to react to obtain a compound of general formula (VI) as an intermediate, followed by remaining 1 An equivalent of triethylamine can also be reacted to give the compound of formula (III-A).

The manufacturing process of the general formula (III-A) compound can be represented by the following scheme.

In the scheme, R _2-a 'R ₃ and R ₄ are as defined above.

Compounds of formula (II) used as starting materials in the process according to the invention are known compounds and can be prepared by known methods. For example, when B is OH and D is a carboxylic acid methyl ester (-COOCH ₃ ) group, the compound of formula (II) can be obtained from the method of Eckenroth and Koerppen from saccharin sodium (reference text). : Benzisothiazoline ester derivative (1) using Chem. Ber., 30, 1265 (1987)), isomerized with sodium methoxide in the presence of methol to give 1, 2-benzothiazine, derivative ( 2) can be prepared and then reacted with R ₁ X. This reaction is represented by the following scheme.

Wherein R ₁ is hydrogen, lower alkyl or lower alkenyl group and X is halogen.

Compounds of general formula (I) according to the invention exhibit potent anti-inflammatory and analgesic effects. The pharmacological effect of the compound (I) of the present invention is evidenced by the edema suppression effect in rats that caused edema with carrageenan and the analgesic effect in mice that caused torsion by acetic acid.

The active compound (I) according to the present invention showed an anti-inflammatory effect equivalent to or better than pyricampam or indomethacin in these experiments and an analgesic effect equivalent to or better than that of pyroxicam, indomethacin and aspirin. Therefore, the active compound (I) of the present invention can be effectively administered for the treatment of various inflammatory diseases and diseases involving pain.

The novel 1, 2-benzothiazine-1, 1-dioxide derivatives of general formula (I) according to the invention can be formulated into conventional pharmaceutical preparations with pharmaceutically acceptable carriers as required.

The invention is described in more detail below as examples.

Example 1

Synthesis of 4-chloro-2-chlorosulfonyl toluene

1.97 mol (230 g) of chlorosulfonic acid was introduced into a three neck round bottom flask, cooled to 0 ° C., and 1.58 mol (200 g) of p-chlorotoluene was slowly added while maintaining 5 ° C. After the dropwise addition, the mixture was stirred for 1 hour at 20 ° C and the reaction solution was added to ice. The resulting precipitate is dissolved in methylene chloride, washed with water, the aqueous layer is extracted with methylene chloride, the methylene chloride layer is dried over sodium sulfate and then dried under reduced pressure to give the desired compound; Yield 55.0%; Melting point = 24 ° C .; Chemical formula C ₇ H ₆ Cl ₂ O ₂ S (molecular weight 225); IR (NaCl, cm ⁻¹ ): 2940 (CH), 2750 (CH), 1385, 1150 (SO ₂ ); NMR (CDCl ₃ , δ): 4.80 (s, 3H, CH ₃ , 7.55 (m, 3H, ClC ₆ H ₃ )

Example 2

Synthesis of 4-chloro-2-aminosulfonyl toluene

To 0.48 mole (130 g) of 4-chloro-2-chlorosulfonyl toluene, 284 ml of ammonia water (2 moles as ammonia) were slowly added dropwise while keeping the temperature below 10 ° C. After the dropwise addition, the temperature was raised to 70 ° C. and methylene chloride was added as a solvent while stirring for another hour. The resulting precipitate is left to stand until room temperature is filtered off and washed with a small amount of cold water to give the title compound as a white crystalline powder; Yield 92.3%; Melting point = 142 ° C .; Chemical formula C ₇ H ₈ ClNO ₂ S (molecular weight 205.5); NMR (CDCl ₃ + DMSO-d ₆ ): 2.45 (s, 3H, CH ₃ ), 6.71 (s, 2H, NH ₂ ), 7.15-7.62 (m, 3H, ClC ₆ H ₃ ); IR (NaCl, cm ⁻¹ ): 3200 (NH), 3050 (NH ₂ ), 2380 (CH), 1355, 1160 (SO ₂ )

Example 3

Synthesis of 6-chlorosaccharin

To 0.82 mol (170 g) of 4-chloro-2-chlorosulfonyl toluene, 700 ml of water was added, and 120 ml of 30% -NaOH solution was added to dissolve. 2.36 mol (370 g) of potassium permanganate is added in small portions at a temperature while maintaining the temperature at 30 to 40 ° C. After stirring for 2 hours while maintaining the same temperature, the mixture is filtered and saturated sodium hydrogen sulfite solution is added to the filtrate to adjust the liquidity to neutrality. The resulting dark brown precipitate is filtered off and the pH is adjusted to 2-3 by adding c-HCl to the filtrate. Filtration to obtain the desired compound as a white fine powder; Yield 80%; Melting point = 216 to 218 ° C; Chemical formula C ₇ H ₄ ClNO ₃ S (molecular weight 217.57); NMR (CDCl ₃ + DMSO-d ₆ ): 7.55-8.31 (m, 3H, ClC ₆ H ₃ ), 9.53 (s, 1H, NH); IR (KBr, cm ^-1 ): 3395 (NH), 2280 (CH), 1375, 1140 (SO ₂ )

Example 4

Synthesis of Sodium-6-chlorosaccharin

50 ml of water is added to 0.55 mole (120 g) of 6-chlorosaccharin, and the pH is adjusted to 7 by adding a small amount of 30% -NaOH solution. After complete dissolution, 1.5 times of ethanol was added to the resulting solution to give the desired compound by white precipitation; Yield 80%; Fusion = 300 degreeC or more; Chemical formula C ₇ H ₃ ClNNaO ₃ S (molecular weight 239.5); NMR (CDCl ₃ + DMSO-d ₆ ): 7.24-7.71 (m, 3H, ClC ₆ H ₃ ); IR (KBr, cm ^-1 ): 3585, 3145 (CH), 1355, 1155 (SO ₂ )

Example 5

Synthesis of 6-chloro-3-oxo-1, 2-benzothiazoline-3-acetic acid-1, 1-dioxide methyl ester

0.096 mol (1.23 g) of methyl chloroacetate was added to 20 ml of dimethylformamide, and 0.096 mol (23 g) of sodium 6-chlorosaccharin was added with good stirring, followed by reaction under reflux for 3 hours. After cooling the reaction solution, about twice the amount of water is added and the resulting crystals are solidified while stirring well in an ice bath. After the crystals were completely precipitated, the mixture was filtered under reduced pressure and washed sufficiently with water to obtain a white crystalline target compound; Yield 95%; Melting point = 132 to 133 ° C; Chemical formula C ₁₀ H ₈ ClNO ₅ S (molecular weight 289.65); NMR (DMSO-d ₆ ) 4.10 (s, 3H, OCH ₃ ), 4.92 (s, 2H, NCH ₂ ), 8.18-8.99 (m, 3H, C ₆ H ₃ ); IR (KBr, cm ^-1 ): 3045 (CH), 1730, 1690 (CO), 1330, 1170 (SO ₂ )

Example 6

Synthesis of 7-chloro-4-hydroxy-2H-1, 2-benzothiazine-3-carboxylic acid-1, 1-dioxide methyl ester

Sodium methoxide solution was cooled by adding a small amount of 0.36 mole (8.47 g) of sodium to 79.4 ml of methanol dried with 4 μg of molecular sieve, and then cooled, and then 7-chloro-3-oxo-1, 2-benzothia 0.046 mol (13.5 g) of zolin-3-acetic acid-1 and 1-dioxide methyl ester are added in a dry powder state at once. The mixture is allowed to react while warming to reflux for 1 hour, and the reaction solution is poured into a beaker containing 100 ml of cold c-HCl at once and cooled in an ice bath. The resulting crystals were filtered under reduced pressure and washed with cold water to give the title compound as white powder; Yield 85%; Melting point = 242 to 245 ° C; Chemical formula C ₁₀ H ₈ ClNO ₅ S (molecular weight 289.65); NMR (DMSO-d ₆ ): 3.40 (s, 3H, OCH ₃ ), 4.15 (s, 3H, NCH ₃ ), 7.91-8.2 (m, 3H, ClC ₆ H ₃ ), 14.5 (s, 1H, NH) ; IR (KBr, cm ^-1 ): 3200 (CH), 1670, 1620 (CO), 1380 (SO ₂ )

Example 7

Synthesis of 7-bromo-4-hydroxy-2-methyl-1, 2-benzothiazine-3-carboxylic acid-1, 1-dioxide methyl ester

30 ml of 1N-NaOH and 65 ml of ethanol were added and mixed with 17.5 ml of water, and 6.25 ml (0.1 mol) of methyl iodide was added with stirring, followed by 7-bromo-4-hydroxy-2H-1, 2-benzothiazine- 8.35 g (0.025 mol) of 3-carboxylic acid methyl ester-1, 1-dioxide are added to dissolve to give a clear yellow urine. Stirring for further 24 hours, the precipitated crystals are filtered under reduced pressure and washed with a small amount of cold methanol to obtain the title compound as white powder; Yield 90.4%; Melting point 186 to 188 ° C; Chemical formula C ₁₁ H ₁₀ BrNO ₅ S (molecular weight 348.17); NMR (DMSO-d ₆ ): 4.25 (s, 3H, OCH ₃ ), 5.5 (s, 3H, NCH ₃ ), 8.31-8.52 (m, 3H, BrC ₆ H ₃ ); IR (KBr, cm ^-1 ): 2970 (CH), 1700, 1590 (CO), 1330, 1160 (SO ₂ )

Example 8

Synthesis of 7-bromo-4-hydroxy-2-allyl-1, 2-benzothiazine-3-carboxylic acid-1, 1-dioxide methyl ester

To 35 ml of water, 133 ml of ethanol and 60 ml of 1N-NaOH solution were added, and 17 ml (0.2 mol) of allyl bromide was added to the mixed solution with stirring, followed by 7-bromo-4-hydroxy-2H-1, 2-benzothiazine-3 16.7 g (0.05 mol) of -carboxylic acid-1, 1-dioxide methyl ester was added to dissolve to give a clear brown color. The mixture was stirred for further 48 hours, and the precipitated crystals were filtered under reduced pressure, washed with a small amount of cold methanol to obtain a white powdery target compound; Yield 81.8%; Melting point = 152 to 154 ° C; Chemical formula C ₁₃ H ₁₂ BrNO ₅ S (molecular weight 374.2); NMR (DMDO-d ₆ ): 4.25 (s, 3H, OCH ₃ ), 4.35 (s, 3H, = CH ₂ ), 5.30 (m, 1H, CH), 5.50 (d, 2H, NCH ₂ ), 8.30- 8.53 (m, 3H, BrC ₆ H ₃ ); IR (KBr, cm ^-1 ): 2950 (CH), 1650, 1600 (CO), 1320, 1150 (SO ₂ ), 1240 (CH ₃ )

Example 9

Synthesis of 1-amino-2-thioxo-3-methyl-4-imidazolone

To 80 ml of methylene chloride 14 ml (20 mmol) methyl isothiocyanate and 8.3 g (60 mmol) triethylamine are added slowly with stirring. 3.11 g (20 mmol) of ethyl hydrazine acetate and HCl are gradually added to this solution, and the solution is left for 4 days after complete dissolution. The reaction solution is concentrated under reduced pressure and washed with a small amount of cold water, followed by ether removal to remove the dendritic material. Cooled crystals were dissolved by adding a small amount of boiling methanol to remove the reaction intermediate N-amino-N-ethoxycarbonylmethyl-N'-methylthiourea, cooled to -20 ° C, and cooled to a pale peach. The target compound of light columnar crystals is obtained; Yield 69.5%; Melting point = 117 to 118 ° C; Chemical formula C ₄ H ₇ N ₃ OS (molecular weight 145); NMR (CDCl ₃ + DMSO-d ₆ ): 3.17 (s, 3H, CH ₃ ) 4.26 (s, 2H, CH ₂ ), 4.99 (s, 2H, NH ₂ ); IR (KBr, cm ^-1 ): 3444 (NH ₂ ), 3316 (NH), 2939 (CH), 1740, 1627 (CO), 937 (CS)

By the similar method, the following compounds (a) to (h) are prepared using the corresponding starting compounds.

(a) 1-amino-2-thioxo-3-cyclohexyl-4-imidazolone

Yield 70.5%; Melting point = 162 to 166 ° C; Chemical formula C ₉ H ₁₅ N ₃ OS; NMR (CDCl ₃ + DMSO-D ₆ ), δ (ppm): 1.67 (m, 10H, C ₆ H ₁₀ ), 3.26 (s, 1H, CH); IR (KBr, cm ^-1 ): 1742 (C = O)

(b) 1-amino-2-thioxo-3-cyclohexyl-5-methyl-4-imidazolone

Yield 66.0%; Melting point = 79 to 81 ° C; Chemical formula C ₁₀ H ₁₇ N ₃ OS; NMR (CDCl ₃ + DMSO-d ₆ ), δ (ppm): 1.69 (m, 10H, C ₆ H ₁₀ ), 3.89 (m, 1H, —CH—); IR (KBr, cm ^-1 ): 1742 (C = 0)

(c) 1-amino-2-thioxo-3-phenyl-5-methyl-4-imidazolone

Yield 53.8%; Melting point = 151 to 153 ° C; Chemical formula C ₁₀ H ₁₁ N ₃ OS; NMR (CDCl ₃ + DMSO-d ₆ ), δ (ppm): 7.32 (m, 5H, C ₆ H ₅ ); IR (KBr, cm ^-1 ): 1744 (C = O)

(d) 1-amino-2-thioxo-3-benzyl-5-methyl-4-imidazolone

Yield 66.8%; Melting point = 101 to 103 ° C; Formula C ₁₁ H ₁₃ N ₃ OS; NMR (CDCl ₃ + DMSO-d ₆ ), δ (ppm): 4.87 (m, 2H, -CH ₂ ), 7.25 (m, 5H, C ₆ H ₅ ): IR (KBr, cm ^-1 ): 1727 (C = O)

(e) 1-amino-2-thioxo-3- (4-chlorobenzyl) -5-methyl-4-imidazolone

Yield 73.1%; Melting point = 106 to 108 ° C; Formula C ₁₁ H ₁₂ ClN ₃ OS; NMR (CDCl ₃ + DMSO-d ₆ ), δ (ppm): 4.85 (m, 2H, —CH ₂ ), 7.25 (m, 4H, C ₆ H ₅ ); IR (KBr, cm ^-1 ): 1745 (C = O)

(f) 1-amino-2-thioxo-3-benzoyl-4-imidazolone

Yield 29.5%; Melting point = 217 to 218 ° C; Formula C ₁₀ H ₉ N ₃ O ₂ S; NMR (CDCl ₃ + DMSO-d ₆ ), δ (ppm): 7.65-7.84 (m, 5H, C ₆ H ₅ ); IR (KBr, cm): 1760 (C = O)

(g) 1-amino-2-thioxo-3-(-4-nitrobenzoyl) -4-imidazolone

Yield 24.5%; Melting point = 200 to 202 ° C; Chemical formula C ₁₀ H ₉ N ₃ OS; NMR (CDCl ₃ + DMSO-d ₆ ), δ (ppm): 7.47 (AB-system, 4H, C ₆ H ₄ ); IR (KBr, cm ^-1 ): 1740 (C = O)

(h) 1-amino-2-thioxo-3- (2-naphthyl) -4-imidazolone

Yield 45.3%; Melting point = 185 to 187 ° C; Chemical formula C ₁₃ H ₁₁ N ₃ OS; NMR (CDCl ₃ + DMSO-d ₆ ), δ (ppm): 7.5-7.85 (m, 7H, C ₁₀ H ₇ ); IR (KBr, cm ^-1 ): 1740 (C = O)

Example 10

Synthesis of 4-hydroxy-2H-N- (3-methyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

5.2 g (0.02 mol) of 4-hydroxy-2H-1, 2-benzothiazine-3-carboxylic acid-1, 1-dioxide methyl ester, and 1-amino-2-thio-3-methyl-4- in 300 ml of xylene 4.06 g (0.0028 mole) of imidazolone is added and reacted under reflux for about 24 hours in a Soxhlet apparatus containing 15 g of molecular sieve of 4 kPa in a cylindrical space. TLC confirms the progress of the reaction and, upon completion of the reaction, is filtered under reduced pressure, washed with a small amount of cold ether and cooled to afford the desired compound; Yield 97.3%; Melting point = 264 to 268 ° C (decomposition); Chemical formula C ₁₃ H ₁₂ N ₄ O ₅ S ₂ (molecular weight 368); NMR (DMSO-d ₆ ), δ (ppm): 31.6 (s, 3H, CH ₃ ), 4.26 (s, 2H, CH), 7.89 (m, 4H, C ₆ H ₄ ); IR (KBr, cm ^-1 ): 3345, 3034 (NH), 1722, 1648 (CO), 1334, 1174 (SO ₂ )

The compounds of the following Examples 11-59 are prepared according to methods equivalent to those of Example 10 using the corresponding starting compounds and reactants.

Example 11

4-hydroxy-2H-N- (3-allyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 12.8%; Melting point 249-250 ° C .; Chemical formula C ₁₅ H ₁₄ N ₄ O ₅ S ₂ (molecular weight 394); NMR (DMSO-d ₆ , δ): 3.45 (m, 1H, NH), 4.34 (d, 2H, = CH ₂ ), 4.47 (s, 2H, CH ₂ ), 5.11 (m, 1H, CH), 5.29 (s, 2H, NCH ₂ ), 7.92 (m, 4H, C ₆ H ₄ ); IR (KBr, cm ^-1 : 3297 (NH), 3069 (NH), 1721 (C = O), 1659 (C = O), 1509 (C = O), 1349 (SO ₂ ), 1178 (SO ₂ )

Example 12

4-hydroxy-2H-N- (3-cyclohexyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 80.2%; Melting point 233-236 ° C .; Chemical formula C ₁₈ H ₂₀ N ₄ O ₅ S ₂ (molecular weight 436); NMR (DMSO-d ₆ , δ), 1.76 (m, 10H, C ₆ H ₁₀ ), 2.56 (m, 1H, CH), 4.35 (s, 2H, CH ₂ ), 7.92 (m, 4H, C ₆ H ₄ ); IR (KBr, cm ^-1 ) 3301 (NH), 3055 (NH), 2921 (CH), 2852 (CH), 1740 (C = O), 1652 (C = O), 1558 (C = O), 1343 (SO ₂ )

Example 13

4-hydroxy-2H-N- (3-phenyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 79.7%; Melting point 271 to 272 ° C; Chemical formula C ₁₈ H ₁₄ N ₄ O ₅ S ₂ (molecular weight 430); NMR (DMSO-d ₆ , δ), 4.65 (s, 2H, CH ₂ ), 7.49 (m, 5H, NC ₆ H ₅ ), 7.92 (m, 4H, C ₆ H ₄ ); IR (KBr, cm ^-1 ) 3316 (NH), 3170 (CH), 2970 (CH), 1740 (C = O), 1610 (C = O), 1560 (C = O), 1330 (SO ₂ ), 1170 (SO ₂ )

Example 14

4-hydroxy-2H-N- (3- (4-chlorophenyl) -2-thio-1-hydantoinyl) -1,2-benzo thiazine-3-carboxamide-1, 1-dioxide

Yield 54.3%; Melting point 280 to 282 ° C; Chemical formula C ₁₈ H ₁₃ ClN ₄ O ₅ S ₂ (molecular weight 464.5); NMR (DMSO-d ₆ , δ) 4.66 (s, 2H, CH ₂ ), 7.51 (q, 4H, ClC ₆ H ₄ ), 7.93 (m, 4H, C ₆ H ₄ ); IR (KBr, cm ^-1 ) 3365 (NH), 2954 (CH), 1729 (C = O), 1497 (C-N), 1322 (SO ₂ ), 1099 (C = S)

Example 15

4-hydroxy-2H-N- (3-benzyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 18.4%; Melting point 232-234 ° C; Chemical formula C ₁₉ H ₁₆ N ₄ O ₅ S ₂ (molecular weight 444); _{NMR (DMSO-d 6, δ} ) 4.67 (s, 2H, CH 2), 5.13 (m, 2H, NCH 2), 7.49 (m, 5H, C 6 H 5 -), 7.94 (m, 4H, C 6 H ₄ ); IR (KBR, cm ⁻¹ ) 3314 (NH), 2961 (CH), 2842 (CH), 1735 (C = O), 1623 (C = O), 1548 (C = O), 1335 (SO ₂ ), 1120 (SO ₂ )

Example 16

4-hydroxy-2H-N- (3-benzoyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 15.5%; Melting point 288-290 ° C; Chemical formula C ₁₉ H ₁₄ N ₄ O ₆ S ₂ (molecular weight 458); NMR (DMSO-d ₆ , δ) 4.69 (s, 2H, CH ₂ ), 7.51 (m, 5H, C ₆ H ₅ ), 8.02 (m, 4H, C ₆ H ₄ ); IR (KBr, cm ^-1 ) 3321 (NH), 2948 (CH), 1761 (C = O), 1670 (C = O), 1556 (C = O), 1347 (SO ₂ ), 1124 (SO ₂ )

Example 17

4-hydroxy-2-methyl-N- (3-methyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 57.1%; Melting point 261 to 262 ° C; Chemical formula C ₁₄ H ₁₄ N ₄ O ₅ S ₂ (molecular weight 382); NMR (DMSO-d ₆ , δ) 2.51 (m, 1H, NH), 2.93 (s, 3H, NCH ₃ ), 3.25 (s, 2H, NCH ₃ ), 4.47 (s, 2H, CH ₂ ), 7.94 ( m, 4H, C ₆ H ₄ ); IR (KBr, cm ^-1 ) 3190 (NH), 2910 (CH), 1750 (C = O), 1640 (C = O), 1340 (SO ₂ ), 1160 (SO ₂ ), 9.30 (C = S)

Example 18

4-hydroxy-2-methyl-N- (3-allyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 70.7%; Melting point 226 to 228 ° C; Chemical formula C ₁₆ H ₁₆ N ₄ O ₅ S ₂ (molecular weight 408); NMR (DMSO-d ₆ , δ) 2.09 (s, 1H, NH), 2.95 (s, 3H, NCH ₃ ), 4.42 (d, 2H, = CH ₂ ), 4.49 (s, 2H, CH ₂ ), 5.08 (m, 1H, CH), 5.30 (s, 2H, NCH ₂ ), 7.93 (m, 4H, C ₆ H ₄ ); IR (KBr, cm ^-1 ) 3180 (NH), 2930 (CH), 2870 (CH), 1715 (C = O), 1630 (C = O), 1575 (C = O), 1330 (SO ₂ ), 1130 (SO ₂ )

Example 19

4-hydroxy-2-methyl-N- (3-cyclohexyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 31.3%; Melting point 262 to 265 ° C; Chemical formula C ₁₉ H ₂₂ N ₄ O ₅ S ₂ (molecular weight 450); NMR (CDCl ₃ + DMSO-d ₆ , δ) 1.75 (m, 1OH, C ₆ H ₁₀ ), 2.26 (m, 1H, NH), 2.98 (s, 3H, NCH ₃ ), 2.99 (s, 1H, CH) , 4.33 (s, 2H, CH ₂ ), 4.35 (m, 1H, NH), 7.92 (M, 4H, C ₆ H ₄ ); IR (KBr, cm ^-1 ) 3232 (NH), 2929 (CH), 2869 (CH), 1741 (C = O), 1653 (C = O), 1563 (C = O), 1339 (SO ₂ ), 1169 (SO ₂ )

Example 20

4-hydroxy-2-methyl-N- (3-cyclohexyl-5-methyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1- Dioxide

Yield 54.5%; Melting point 264-265 ° C. (decomposition); Chemical formula C ₂₀ H ₂₄ N ₄ O ₅ S ₂ (molecular weight 464); NMR (DMSO-d ₆ , δ), 0.61-2.40 (m, 1OH, C ₆ H ₁₀ ), 1.17 (d, 3H, CH-CH ₃ ), 2.80 (s, 3H, N-CH ₃ ), 4.20 ( m, 1H, -CH-), 4.23 (q, 1H, CH-CH ₃ ), 7.69 (m, 4H, C ₆ H ₄ ); IR (KBr, cm ^-1 ) 3254 (NH), 2932 (CH), 2854 (CH), 1736 (C = O), 1613 (C = O), 1353 (SO ₂ ), 1157 (SO ₂ ), 1035 (C = S)

Example 21

4-hydroxy-2-methyl-N- (3-phenyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 75.8%; Melting point 275-276 ° C. (decomposition); Chemical formula C ₁₉ H ₁₆ N ₄ O ₅ S ₂ (molecular weight 444); NMR (CDCl ₃ + DMSO-d ₆ , δ) 2.99 (s, 3H, NCH ₃ ), 4.60 (s, 2H, CH ₂ ); 7.48 (s, 5H, C ₆ H ₅ ), 7.92 (s, 4H, C ₆ H ₄ ), 11.3 (s, 1H, OH); IR (KBr, cm ^-1 ) 3280 (NH), 2900 (CH), 1755 (C = O), 1600 (C = O), 1590 (C = O), 1350 (SO ₂ ), 1115 (SO ₂ )

Example 22

4-hydroxy-2-methyl-N- (3-phenyl-5-methyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 52.4%; Melting point 239-240 ° C. (decomposition); Chemical formula C ₂₀ H ₁₈ N ₄ O ₅ S ₂ (molecular weight 458); NMR (DMSO-d ₆ , δ) 1.34 (d, 3H, CH-CH ₃ ), 2.74 (s, 3H, N-CH ₃ ), 4.55 (q, 1H, CH-CH ₃ ), 7.22 (m, 5H , C ₆ H ₅ ), 7.80 (m, 4H, C ₆ H ₄ ); IR (KBr, cm ^-1 ) 3297 (NH), 1759 (C = O), 1621 (C = O), 1337 (SO ₂ ), 1175 (SO ₂ ), 933 (C = S)

Example 23

4-hydroxy-2-methyl-N- (3- (4-chlorophenyl) -2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1- Dioxide

Yield 70.8%; Melting point 282-284 ° C. (decomposition); Chemical formula C ₁₉ H ₁₅ ClN ₄ O ₅ S ₂ (molecular weight 478.5); NMR (DMSO-d ₆ , δ) 2.93 (s, 3H, NCH ₃ ), 3.51 (m, 1H, NH), 4.65 (s, 2H, CH ₂ ), 7.50 (q, 4H, ClC ₆ H ₄ ), 7.93 (m, 4H, C ₆ H ₄ ); IR (KBr, cm ^-1 ) 3286 (NH), 2920 (CH), 1763 (C = O), 1643 (C = O), 1514 (C = O), 1409 (SO ₂ ), 1198 (SO ₂ )

Example 24

4-hydroxy-2-methyl-N- (3-benzyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 86.9%; Melting point 256-258 ° C; Chemical formula C ₂₀ H ₁₈ N ₄ O ₅ S ₂ (molecular weight 458); NMR (DMSO-d ₆ , δ) 2.94 (s, 3H, NCH ₃ ), 4.56 (s, 2H, CH ₂ ); 4.99 (s, 2H, NCH ₂ ), 7.34 (s, 5H, C ₆ H ₅ ), 7.94 (m, 4H, C ₆ H ₄ ); IR (KBr, cm ^-1 ) 3224 (NH), 2950 (CH), 2855 (CH), 1749 (C = O), 1632 (C = O), 1562 (C = O), 1320 (SO ₂ ), 1040 (SO ₂ )

Example 25

4-hydroxy-2-methyl-N- (3-benzyl-5-methyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 67.8%; Melting point 195-199 ° C .; Chemical formula C ₂₁ H ₂₀ N ₄ O ₅ S ₂ (molecular weight 472); NMR (DMSO-d ₆ , δ) 1.24 (d, 3H, CH-CH ₃ ), 2.72 (s, 3H, N-CH ₃ ); 4.51 (q, 1H, CH-CH ₃ ), 4.75 (s, 2H, -CH _2- ), 7.07 (m, 5H, C ₆ H ₅ ); 7.68 (m, 4H, C ₆ H ₄ ); IR (KBr, cm ⁻¹ ) 3321 (NH), 1756 (C═O), 1645 (C═O), 1353 (SO ₂ ), 1172 (SO ₂ ), 1121 (C = S).

Example 26

4-hydroxy-2-methyl-N- {3-benzyl-5- (4-chlorobenzyl) -2-thio-1-hydantoinyl} -1,2-benzothiazine-3-carboxamide- 1, 1-dioxide

Yield 89.5%; Melting point 175-177 ° C .; Chemical formula C ₂₁ H ₁₉ ClN ₄ O ₅ S ₂ (molecular weight 506.5); NMR (DMSO-d ₆ , δ) 1.16 (d, 3H, CH-CH ₃ ), 2.61 (s, 3H, N-CH ₃ ); 4.38 (q, 1H, CH-CH ₃ ), 4.71 (s, 2H, -CH _2- ), 7.12 (m, 4H, C ₆ H ₄ ), 7.68 (m, 4H, C ₆ H ₄ ); IR (KBr, cm ⁻¹ ) 3298 (NH), 1758 (C═O), 1620 (C═O), 1355 (SO ₂ ), 1171 (SO ₂ ), 1090 (C = S).

Example 27

4-hydroxy-2-methyl-N- (3-benzoyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 22.3%; Melting point 284-287 ° C; Chemical formula C ₂₀ H ₁₆ N ₄ O ₆ S ₂ (molecular weight 472); NMR (DMSO-d ₆ , δ) 3.02 (d, 3H, NCH ₃ ), 4.81 (s, 2H, CH ₂ ), 7.48 (s, 5H, C ₆ H ₅ ), 7.98 (m, 4H, C ₆ H ₄ ); IR (KBr, cm ^-1 ) 3250 (NH), 2928 (CH), 1771 (C = O), 1683 (C = O), 1580 (C = O), 1342 (SO ₂ ), 1125 (S0 ₂ ) .

Example 28

4-hydroxy-2-allyl-N- (3-methyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 38.5%; Melting point 164-166 ° C .; Chemical formula C ₁₆ H ₁₆ N ₄ O ₅ S ₂ (molecular weight 398); NMR (DMSO-d ₆ , δ) 3.19 (s, 3H, CH ₃ ), 4.20 (d, 2H, = CH ₂ ), 4.50 (s, 2H, CH ₂ ), 5.08 (m, 1H, CH), 5.18 (m, 2H, NCH ₂ ), 7.98 (m, 4H, C ₆ H ₄ ); IR (KBr, cm ^-1 ) (NH), 3213 (NH), 2959 (CH), 1762 (C = O), 1647 (C = O), 1561 (C = O), 1343 (SO ₂ ), 1119 (S0 ₂ )

Example 29

4-hydroxy-2-allyl-N- (3-allyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 64.7%; Melting point 220-221 ° C; Chemical formula C ₁₈ H ₁₈ N ₄ O ₅ S ₂ (molecular weight 424); NMR (DMSO-d ₆ , δ) 2.51 (m, 1H, NH), 4.18 (d, 2H, = CH ₂ ), 4.38 (d, 2H, = CH ₂ ), 4.51 (s, 2H, CH ₂ ), 4.92 (m, 1H, CH), 4.98 (m, 1H, NCH), 5.15 (s, 2H, N-CH ₂ ), 5.31 (s, 2H, N-CH ₂ ), 7.94 (m, 4H, C ₆ H ₄ ); IR (KBr, cm ⁻¹ ) 3310 (NH), 2960 (CH), 1757 (C═O), 1630 (C═O), 1561 (C═O), 978 (C = S).

Example 30

4-hydroxy-2-allyl-N- (3-cyclohexyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 42.6%; Melting point 217-220 ° C .; Chemical formula C ₂₁ H ₂₄ N ₄ O ₅ S ₂ (molecular weight 466); NMR (DMSO-d ₆ , δ) 1.80 (m, 1OH, C ₅ H ₁₀ ), 2.50 (m, 1H, = NH), 3.38 (m, 1H, CH), 4.18 (d, 2H, = CH ₂ ) , 4.35 (m, 2H, CH ₂ ), 5.01 (m, 1H, -CH =), 5.16 (m, 1H, N-CH ₂ , 7.94 (m, 4H, C ₆ H ₄ ); IR (KBr, cm ^-1 ) 3316 (NH), 2961 (CH), 1764 (C = O), 1618 (C = O), 1567 (C = O), 1344 (SO ₂ ), 1121 (SO ₂ )

Example 31

4-hydroxy-2-allyl-N- (3-phenyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 80.7%; Melting point 225-227 ° C .; Chemical formula C ₂₁ H ₁₈ N ₄ O ₅ S ₂ (molecular weight 460); NMR (DMSO-d ₆ + CDCl ₃ , δ) 3.87 (s, 2H, = CH ₂ ), 4.35 (s, 2H, CH ₂ ), 5.09 (m, 1H, CH), 5.18 (m, 1H, = NCH ₂ ), 7.35 (m, 5H, C ₆ H ₅ ), 7.84 (m, 4H, C ₆ H ₄ ), 10.82 (s, 1H, OH),; IR (KBr, cm ^-1 ) 3309 (NH), 2948 (CH), 1757 (C = O), 1634 (C = O), 1560 (C = O), 1340 (SO ₂ ), 1119 (SO ₂ ) .

Example 32

4-hydroxy-2-allyl-N- (3- (4-chlorophenyl) -2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1- Dioxide

Yield 70.7%; Melting point 246-248 ° C .; Chemical formula C ₂₁ H ₁₇ N ₄ O ₅ S ₂ (molecular weight 494.5); NMR (DMSO-d ₆ , δ) 4.25 (m, 2H, = CH ₂ ), 4.66 (m, 2H, CH ₂ ), 4.98 (m, 1H, CH), 5.10 (m, 2H, NCH ₂ ), 7.52 (m, 4H, ClC ₆ H ₄ ), 7.96 (m, 4H, C ₆ H ₄ ); IR (KBr, cm ^-1 ) 3240 (NH), 2918 (CH), 1768 (C = O), 1649 (C = O), 1505 (C = O), 1332 (SO ₂ ), 1170 (SO ₂ )

Example 33

4-hydroxy-2-allyl-N- (3-benzyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 12.6%; Melting point 213-214 ° C; Chemical formula C ₂₂ H ₂₀ N ₄ O ₅ S ₂ (molecular weight 474); NMR (DMSO-d ₆ , δ) 4.17 (m, 2H, = CH ₃ ), 4.52 (s, 2H, CH ₂ CO), 4.85 (m, 1H, -CH =), 4.99 (m, 2H, NCH ₂ ), 5.13 (m, 2H, NCH ₂ ), 7.35 (s, 5H, C ₆ H ₅ ); IR (KBr, cm ^-1 ) 3218 (NH), 2963 (CH), 2855 (CH), 1755 (C = O), 1624 (C = O), 1559 (C = O), 1342 (SO ₂ ), 1170 (SO ₂ ).

Example 34

4-hydroxy-2-allyl-N- (3-benzoyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 13.8%; Melting point 250-254 ° C .; Chemical formula C ₂₂ H ₁₈ N ₄ O ₆ S ₂ (molecular weight 488); NMR (DMSO-d ₆ , δ) 4.18 (m, 2H, = CH ₂ ), 4.36 (s, 2H, CH ₂ CO), 4.88 (m, 1H, -CH =), 4.99 (m, 2H, NCH ₂ ), 7.54 (m, 5H, C ₆ H ₅ ), 7.98 (m, 4H, C ₆ H ₄ ); IR (KBr, cm ^-1 ) 3233 (NH), 2962 (CH), 1759 (C = O), 1643 (C = O), 1560 (C = O), 1343 (SO ₂ ), 1119 (SO ₂ )

Example 35

7-bromo-4-hydroxy-2H-N- (3-methyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 68.8%; Melting point = 271-273 ° C. (decomposition); Chemical formula C ₁₃ H ₁₁ BrN ₄ O ₅ S ₂ (molecular weight 447.11); NMR (DMSO-d ₆ ) 2.36 (s, 1H, NH), 3.03 (s, 3H, CH ₃ ), 4.27 (s, 2H, CH ₂ ), 7.63-7.93 (m, 3H, BrC ₆ H ₃ ); IR (KBr, cm ⁻¹ ) 3517 (OH), 3319, 3080 (NH), 2813 (CH), 1744, 1646 (CO), 1337, 1176 (SO ₂ ), 1085 (CS), 1020 (CBr).

Example 36

7-chloro-4-hydroxy-2H-N- (3-methyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 68.8%; Melting point = 243-245 ° C. (decomposition); Chemical formula C ₁₃ H ₁₁ ClN ₄ O ₅ S ₂ (molecular weight 415); NMR (DMSO-d ₆ ) 3.45 (s, 3H, CH ₃ ), 4.55 (s, 2H, CH), 7.72-8.43 (m, 3H, ClC ₆ H ₃ ); IR (KBr, cm ⁻¹ ) 3500 (OH), 3210, 3060 (NH), 2720 (CH), 1740, 1640 (CO), 1330, 1180 (SO ₂ ), 1040 (CS), 945 (CCl).

Example 37

7-bromo-4-hydroxy-2H-N- (3-allyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 60.6%; Melting point = 255-257 ° C. (decomposition); Chemical formula C ₁₅ H ₁₃ BrN ₄ O ₅ S ₂ (molecular weight 473.11); NMR (DMSO-d ₆ ) 2.36 (s, 1H, NH), 4.28 (s, 2H, = CH ₂ ), 5.03 (s, 2H, CH ₂ ), 5.43 (1m, 1H, CH), 7.56-7.80 ( m, 3H, BrC ₆ H ₃ ); IR (KBr, cm ⁻¹ ) 3309, 3073, 2814 (CH), 1736, 1649 (CO), 1455 (CH), 1361, 1171 (SO ₂ ), 1086 (CS).

Example 38

7-chloro-4-hydroxy-2H-N- (3-allyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 95.34%; Melting point = 257-260 ° C. (decomposition); Chemical formula C ₁₅ H ₁₃ ClN ₄ O ₅ S ₂ (molecular weight 440.61); NMR (DMSO-d ₆ ) 2.91 (s, 1H, NH), 4.79 (s, 2H, = CH ₂ ), 4.80 (s, 2H, CH ₂ ), 5.18-5.75 (m, 1H, CH), 5.63 ( d, 2H, CH ₂ ), 7.92-8.68 (m, 3H, ClC ₆ H ₃ ); IR (KBr, cm ⁻¹ ) 3310, 3050, 1545 (NH), 2750, 1460 (CH), 1725, 1650 (CO), 1355, 1160 (SO ₂ ), 980 (CS).

Example 39

7-bromo-4-hydroxy-2H-N- (3-phenyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 98.7%; Melting point = 261-262 ° C. (decomposition); Chemical formula C ₁₈ H ₁₃ BrN ₄ O ₅ S ₂ (molecular weight 509.11); NMR (DMSO-d ₆ ) 2.35 (s, 1H, NH), 4.29 (s, 2H, CH ₂ ), 6.85-7.40 (m, 5H, NC ₆ H ₅ ); IR (KBr, cm ⁻¹ ) 3310 (NH), 2916, 1501 (CH), 1760, 1646 (CO), 1334, 1178 (SO ₂ ), 1084 (CS).

Example 40

7-chloro-4-hydroxy-2H-N- (3-phenyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 97.7%; Melting point = 284-286 ° C. (decomposition); Chemical formula C ₁₈ H ₁₃ ClN ₄ O ₅ S ₂ (molecular weight 476.61); NMR (DMSO-d ₆ ) 2.80 (s, 1H, NH), 4.87 (s, 2H, CH ₂ ), 7.45-8.49 (m, 5H, NC ₆ H ₅ ), 8.21 (m, 3H, ClC ₆ H ₃ ) 12.0 (s, 1H, OH); IR (KBr, cm ⁻¹ ) 3310 (NH), 2920, 1520 (CH), 1750, 1645 (CO), 1360, 1160 (SO ₂ ), 1100 (CS).

Example 41

7-chloro-4-hydroxy-2H-N- (3-phenyl-5-methyl-2-thio-1-hydantoinyl) -1, 2-benzothiazine-3-carboxamide-1, 1 -Dioxide

Yield 48.8%; Melting point = 273-275 ° C. (decomposition); Chemical formula C ₁₉ H ₁₅ ClN ₄ O ₅ S ₂ (molecular weight 478.5); NMR (DMSO-d ₆ ) 1.95 (d, 3H, CH ₃ ), 5.12 (q, 1H, CH), 7.38-8.51 (m, 5H, NC ₆ H ₅ ), 1040 (CS), 945 (CCl), 8.28 (m, 3H, ClC ₆ H ₃ ); IR (KBr, cm ⁻¹ ) 3250 (OH), 2920 (NH), 1755, 1620 (CO), 1450 (CH), 1350, 1155 (SO ₂ ), 1060 (CS).

Example 42

7-bromo-4-hydroxy-2H-N- (3- (4-chlorophenyl) -2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1 , 1-dioxide

Yield 61.3%; Melting point 279-280 ° C .; Chemical formula C ₁₈ H ₁₂ ClN ₄ O ₅ S ₂ (molecular weight 543.61); NMR (DMSO-d ₆ , δ) 2.35 (s, 1H, NH), 4.41 (s, 2H, CH ₂ ), 7.03-7.53 (m, 4H, ClC ₆ H ₄ ), 7.60-7.96 (m, 3H, C ₆ H ₃ ); IR (KBr, cm ⁻¹ ) 3548 (OH), 3129 (NH), 1763, 1646 (C═O), 1494 (CN), 1328, 1176 (SO ₂ ), 1087 (C = S).

Example 43

7-bromo-4-hydroxy-2H-N- (3-benzyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 71.4%; Melting point 241-242 ° C; Chemical formula C ₁₉ H ₁₅ BrN ₄ O ₅ S ₂ (molecular weight 523.11); NMR (DMSO-d ₆ , δ) 2.35 (s, 1H, NH), 4.25 (s, 2H, CH ₂ ), 4.60-4.83 (m, 2H, NCH ₂ ), 6.83-7.26 (m, 5H, C ₆ H _5- ), 7.51-7.89 (m, 3H, BrC ₆ H ₃ ); IR (KBr, cm ^-1 ) 3600 (OH), 3300 (NH), 2920 (CH), 1723 (C = O), 1650, 1603 (C = O), 1336 (SO ₂ ), 1176 (SO ₂ ) , 1082 (CS).

Example 44

7-chloro-4-hydroxy-2-methyl-N- (3-methyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 83.9%; Melting point = 260-261 ° C. (decomposition); Chemical formula C ₁₄ H ₁₃ BrN ₄ O ₅ S ₂ (molecular weight 461.13); NMR (DMSO-d ₆ ) 2.40 (s, 1H, NH), 3.0 (s, 3H, NCH ₃ ), 3.36 (s, 3H, NCH ₃ ), 4.30 (s, 2H, CH ₂ ), 7.60-8.0 ( m, 3H, BrC ₆ H ₃ ); IR (KBr, cm ⁻¹ ) 3500 (OH), 3078 (NH), 2985 (CH), 1761, 1643 (CO), 1179 (SO ₂ ), 1082 (CS), 1049 (CBr).

Example 45

7-chloro-4-hydroxy-2-methyl-N- (3-methyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 87.9%; Melting point = 274-277 ° C. (decomposition); Chemical formula C ₁₄ H ₁₃ BrN ₄ O ₅ S ₂ (molecular weight 428.63); NMR (DMSO-d ₆ ) 2.50 (s, 1H, NH), 3.38 (s, 3H, NCH ₃ ), 3.55 (s, 3H, NCH ₃ ), 4.92 (s, 2H, CH ₂ ), 8.41 (s, 3H, ClC ₆ H ₃ ); IR (KBr, cm ⁻¹ ) 3540 (OH), 3170, 1450 (NH), 3060 (CH), 1765, 1645, 1610 (CO), 1165 (SO ₂ ), 1075 (CS), 1035 (CCl).

Example 46

7-bromo-4-hydroxy-2-methyl-N- (3-allyl-2-thio-1-hydantoinyl) -1,2-benzothiazine-3-carboxamide-1, 1- Dioxide

Yield 70.5%; Melting point 274-275 ° C .; Chemical formula C ₁₆ H ₁₅ BrN ₄ O ₅ S ₂ (molecular weight 487.13); NMR (DMSO-d ₆ , δ) 2.40 (s, 1H, NH), 2.87 (s, 3H, NCH ₃ , 4.25 (d, 2H, = CH ₂ ), 4.31 (s, 2H, CH ₂ ), 4.96- 5.26 (m, 1H, CH), 5.52 (s, 2H, NCH ₂ ), 7.63-8.52 (m, 3H, BrC ₆ H ₃ ); IR (KBr, cm ^-1 ) 3294 (NH), 2933 (CH) , 1750 (C = O), 1645 (C = O), 1609 (C = O), 1170 (SO ₂ ), 1084 (CS, 1039 (SBr)).

Example 47

7-bromo-4-hydroxy-2-methyl-N- (3-phenyl-2-thio-1-hydantoinyl) -1, 2-benzothiazine-3-carboxamide-1, 1- Dioxide

Yield 62.5%; Melting point = 287-288 ° C. (decomposition); Chemical formula C ₁₉ H ₁₅ BrN ₄ O ₅ S ₂ (molecular weight 523.13); NMR (DMSO-d ₆ ) 2.30 (s, 1H, NH), 2.79 (s, 3H, NCH ₃ ), 4.36 (s, 2H, CH ₂ ), 6.96-7.40 (m, 5H, NC ₆ H ₅ ), 7.60-8.03 (m, 3H, BrC ₆ H ₃ ); IR (KBr, cm ⁻¹ ) 3330 (NH), 3061 (CH), 1757, 1645, 1611 (CO), 1163 (SO ₂ ), 1084 (CS), 1042 (CBr).

Example 48

7-chloro-4-hydroxy-2-methyl-N- (3-phenyl-2-thio-1-hydantoinyl) -1, 2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 94.5%; Melting point = 280-283 ° C. (decomposition); Chemical formula C ₁₉ H ₁₅ ClN ₄ O ₅ S ₂ (molecular weight 490.5); NMR (DMSO-d ₆ ) 2.80 (s, 1H, NH), 3.25 (s, 3H, NCH ₃ ), 4.95 (s, 2H, CH ₂ ), 7.34-8.47 (m, 5H, NC ₆ H ₅ ), 8.25 (m, 3H, ClC ₆ H ₃ ); IR (KBr, cm ⁻¹ ) 3320 (NH), 3155 (CH), 1765, 1640, 1595 (CO), 1140 (SO ₂ ), 1075 (CS), 1040 (CCl).

Example 49

7-chloro-4-hydroxy-2-methyl-N- (3-phenyl-5-methyl-2-thio-1-hydantoinyl) -1, 2-benzothiazine-3-carboxamide-1 , 1-dioxide

Yield 60.9%; Melting point = 282-285 ° C. (decomposition); Chemical formula C ₂₀ H ₁₇ ClN ₄ O ₅ S ₂ (molecular weight 492.5); NMR (DMSO-d ₆ ) 1.85 (d, 3H, CH ₃ ), 3.25 (s, 3H, NCH ₃ ), 5.11 (q, 2H, CH), 7.42-8.32 (m, 5H, C ₆ H ₅ ), 8.25 (m, 3H, ClC ₆ H ₃ ),; IR (KBr, cm ⁻¹ ) 3265 (NH), 3075 (CH), 1750, 1365, 1610 (CO), 1140 (SO ₂ ), 1015 (CS), 1020 (CCl).

Example 50

7-bromo-4-hydroxy-2-methyl-N- (3- (4-chlorophenyl) -2-thio-1-hydantoinyl) -1, 2-benzothiazine-3-carboxamide -1, 1-dioxide

Yield 73.0%; Melting point 288-289 ° C .; Chemical formula C ₁₉ H ₁₄ BrClN ₄ O ₅ S ₂ (molecular weight 557.63); NMR (DMSO-d ₆ , δ) 2.37 (s, 1H, NH), 2.82 (s, 3H, NCH ₃ ), 4.5 (s, 2H, CH ₂ ), 7.0-7.56 (m, 4H, ClC ₆ H ₄ ), 7.56-8.03 (m, 3H, BrC ₆ H ₃ ); IR (KBr, cm ⁻¹ ) 3313 (NH), 2929 (CH), 1760, 1646, 1610 (C═O), 1171 (SO ₂ ), 1085 (C = S), 1041 (CBr).

Example 51

7-bromo-4-hydroxy-2-methyl-N- (3-benzyl-2-thio-1-hydantoinyl) -1, 2-benzothiazine-3-carboxamide-1, 1- Dioxide

Yield 67.0%; Melting point 235-236 ° C .; Chemical formula C ₂₀ H ₁₇ BrN ₄ O ₅ S ₂ (molecular weight 537.13); NMR (DMSO-d ₆ , δ) 2.40 (s, 1H, NH), 2.79 (s, 3H, NCH ₃ ), 4.35 (s, 2H, CH ₂ ), 4.81 (m, 2H, NCH ₂ ), 6.97- 7.27 (m, 5H, C ₆ H _5- ), 7.66-8.0 (m, 3H, BrC ₆ H ₃ ); IR (KBr, cm ^-1 ) 3500 (OH), 3227 (NH), 2946, 2857 (CH), 1754 (C = O), 1646, 1609 (C = O), 1365 (SO ₂ ), 1167 (SO ₂ ), 1083 (CS), 1042 (CBr).

Example 52

7-bromo-4-hydroxy-2-allyl-N- (3-methyl-2-thio-1-hydantoinyl) -1, 2-benzothiazine-3-carboxamide-1, 1- Dioxide

Yield 57.5%; Melting point 243-245 ° C. (decomposition); Chemical formula C ₁₆ H ₁₅ BrN ₄ O ₅ S ₂ (molecular weight 487.16); NMR (DMSO-d ₆ ) 2.93 (s, 3H, NCH ₃ ), 3.85 (d, 2H, = CH ₂ ), 4.10 (s, 2H, CH ₂ ), 4.63 (m, 1H, CH), 4.90 (d , 2H, NCH ₂ ), 7.40-8.07 (m, 3H, BrC ₆ H ₃ ); IR (KBr, cm ⁻¹ ) 3510 (OH), 3335 (NH), 2950 (CH), 1754, 1637, 1612 (CO), 1174 (SO ₂ ), 1118 (CS), 1019 (CBr).

Example 53

7-chloro-4-hydroxy-2-allyl-N- (3-methyl-2-thio-1-hydantoinyl) -1, 2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 60.2%; Melting point 276-278 ° C. (decomposition); Chemical formula C ₁₆ H ₁₅ ClN ₄ O ₅ S ₂ (molecular weight 454.66); NMR (DMSO -d ₆ ) 3.50 (s, 3H, NCH ₃ ), 4.00 (d, 2H, = CH ₂ ), 4.50 (s, 2H, CH ₂ ), 4.32-5.01 (m, 2H, NCH ₂ ), 4.80 (s, 2H, CH ₂ ), 5.01-5.81 (m, 1H, CH), 7.85-8.52 (m, 3H, ClC ₆ H ₃ ); IR (KBr, cm ⁻¹ ) 3200 (NH), 2950 (CH), 1765, 1640, 1590 (CO), 1160 (SO ₂ ), 1130 (CS), 1020 (CCl).

Example 54

7-bromo-4-hydroxy-2-allyl-N- (3-allyl-2-thio-1-hydantoinyl) -1, 2-benzothiazine-3-carboxamide-1, 1- Dioxide

Yield 78.9%; Melting point 220-221 ° C; Chemical formula C ₁₈ H ₁₇ BrN ₄ O ₅ S ₂ (molecular weight 513.16); NMR (DMSO-d ₆ , δ) 2.34 (s, 1H, NH), 3.35 (d, 2H, = CH ₂ ), 4.0 (d, 2H, = CH ₂ ), 4.33 (s, 2H, CH ₂ ), 4.83 (m, 1H, CH), 4.90 (m, 1H, CH), 5.06 (d, 2H, NCH ₂ ), 5.43 (d, 2H, NCH ₂ ), 7.46-7.93 (m, 3H, BrC ₆ H ₃ ); IR (KBr, cm ⁻¹ ) 3306 (NH), 2963 (CH), 1794, 1643, 1607 (CO), 1359, 1177 (SO ₂ ), 1083 (CS).

Example 55

7-chloro-4-hydroxy-2-allyl-N- (3-allyl-2-thio-1-hydantoinyl) -1, 2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 46.1%; Melting point 242-246 ° C .; Chemical formula C ₁₈ H ₁₇ ClN ₄ O ₅ S ₂ (molecular weight 480.66); NMR (DMSO-d ₆ , δ) 2.75 (s, 1H, NH), 4.12-4.92 (m, 5H, = CH ₂ ), 4.80 (s, 2H, CH ₂ ), 5.04-5.68 (m, 5H, allyl ), 7.42-8.42 (m, 3H, ClC ₆ H ₃ ; IR (KBr, cm ^-1 ) 3310 (NH), 2925 (CH), 1740, 1645, 1610 (CO), 1355, 1180 (SO ₂ ), 1105 (CS).

Example 56

7-bromo-4-hydroxy-2-allyl-N- (3-phenyl-2-thio-1-hydantoinyl) -1, 2-benzothiazine-3-carboxamide-1, 1- Dioxide

Yield 46.8%; Melting point 260-261 ° C. (decomposition); Chemical formula C ₂₁ H ₁₇ BrN ₄ O ₅ S ₂ (molecular weight 549.16); NMR (DMSO-d ₆ , δ) 2.33 (s, 1H, NH), 4.0 (d, 2H, -CH ₂ ), 4.46 (s, 2H, CH ₂ ), 4.82 (m, 1H, CH), 4.85- 5.13 (m, 2H, NCH ₂ ), 6.97-7.53 (m, 5H, C ₆ H ₅ ), 7.67-8.0 (m, 3H, BrC ₆ H ₃ ); IR (KBr, cm ⁻¹ ) 3111 (NH), 2968 (CH), 1763, 1637, 1602 (CO), 1384, 1180 (SO ₂ ), 1083 (CS).

Example 57

7-chloro-4-hydroxy-2-allyl-N- (3-phenyl-2-thio-1-hydantoinyl) -1, 2-benzothiazine-3-carboxamide-1, 1-dioxide

Yield 88.7%; Melting point 253-258 ° C. (decomposition); Chemical formula C ₂₁ H ₁₇ ClN ₄ O ₅ S ₂ (molecular weight 516.66); NMR (DMSO-d ₆ , δ) 2.85 (s, 1H, NH), 4.55 (s, 2H, CH ₂ ), 5.00 (d, 2H, CH ₂ ), 5.30 (m, H, NCH ₂ ), 5.50 ( m, 2H, NCH ₂ ), 7.75 (m, 5H, C ₆ H ₅ ), 7.42-8.42 (m, 3H, ClC ₆ H ₃ ); IR (KBr, cm ⁻¹ ) 3100 (NH), 2960 (CH), 1760, 1637, 1600 (CO), 1360, 1175 (SO ₂ ), 1165 (CS).

Example 58

7-bromo-4-hydroxy-2-allyl-N- (3- (4-chlorophenyl) -2-thio-1-hydantoinyl) -1, 2-benzothiazine-3-carboxamide -1, 1-dioxide

Yield 45.1%; Melting point 255-256 ° C. (decomposition); Chemical formula C ₂₁ H ₁₆ BrClN ₄ O ₅ S ₂ (molecular weight 583.66); NMR (DMSO-d ₆ , δ) 2.35 (s, 1H, NH), 4.0 (d, 2H, = CH ₂ ), 4.51 (s, 2H, CH ₂ ), 4.85 (m, 1H, CH), 5.03 ( d, 2H, NCH ₂ ), 7.13-7.56 (m, 4H, ClC ₆ H ₅ ), 7.67-8.03 (m, 3H, BrC ₆ H ₃ ); IR (KBr, cm ⁻¹ ) 3650 (OH), 3190 (NH), 2961 (CH), 1764, 1645, 1608 (CO), 1318, 1175 (SO ₂ ), 1085 (CS), 1017 (CBr).

Example 59

7-bromo-4-hydroxy-2-allyl-N- (3-benzoyl-2-thio-1-hydantoinyl) -1, 2-benzothiazine-3-carboxamide-1, 1- Dioxide

Yield 20.1%; Melting point 248-249 ° C. (decomposition); Chemical formula C ₂₂ H ₁₉ BrN ₄ O ₅ S ₂ (molecular weight 563.16); NMR (DMSO-d ₆ , δ) 2.36 (s, 1H, NH), 3.97 (d, 2H, = CH ₂ ), 4.39 (s, 2H, CH ₂ ), 4.66 (m, 1H, CH), 4.80 ( d, 2H, NCH ₂ ), 4.93 (m, 2H, NCH ₂ ), 6.83-7.27 (m, 5H, C ₆ H ₅ ), 7.63-7.93 (m, 3H, BrC ₆ H ₃ ); IR (KBr, cm ⁻¹ ) 3334 (NH), 3081 (CH), 1748, 1631 (CO), 1369, 1175 (SO ₂ ), 1083 (CS), 1032 (CBr).

In order to demonstrate the pharmacological effects of the novel compound (I) according to the present invention, that is, anti-inflammatory and analgesic effects, experiments on carrageenan-induced edema inhibition and acetic acid-induced torsion inhibitory effects were carried out as follows.

Experiment 1: anti-inflammatory effect experiment (carrageenan induced edema inhibitory effect)

Experimental animals were tested according to the method of Winter et al. Using 6 male male rats of the Sprague Dawley system, each weighing 140 to 195 g. Drug administration was performed by orally administering the sample synthesized in the present invention in 0.5% CMC saline solution so that the test compound was administered at a dose of 3.3 mg / kg, respectively, in an amount of 10 ml / kg, and the control group was 0.5% CMC saline solution. Only was administered. Edema was caused by subcutaneous injection of 1% carrageenan (Sigma, Lambda type) at about 40 ° C. into the base and subcutaneous injection of 0.1 ml per rat into the sole of the right hind limb. Edema that occurred for 1 to 5 hours after injection was measured by volume measurement to the outside of the astragalus of the Fuji foot using a volumetric plethysmometer to calculate the carcinoma rate and edema inhibition rate according to the following equation.

Vn = volume of Fuji before carrageenan administration

Vt = volume of Fuji after carrageenan administration

Ec = average edema rate of control

Et = mean edema rate in the experimental group

The results are as described in Table 1 below.

TABLE 1

In the above experiments, the compounds of Examples 17, 18, 19, 21, 23, 37, and 58 had the same or better anti-inflammatory effect as compared to the pyroxicam used as a control drug and an excellent anti-inflammatory effect at a significantly lower dose than indomethacin. The effect was confirmed.

Experiment 2: Analgesic Effect Experiment (Acid Induced Torsion Inhibition Effect)

Experimental animals were tested according to the method of Wittle using 6 male mice each weighing 20-25 g. In the drug administration, the sample synthesized in the present invention was suspended in 0.5% CMC saline solution so that each test compound was administered at a dose of 16.5 mg / kg orally in an amount of 10 ml / kg, and the control group was 0.5% CMC saline solution. Only was administered. Intraperitoneally administer 0.7% acetic acid at a dose of 10ml / kg of body weight of mice 30 minutes after the administration of the sample, and measure the number of Writhing syndromes occurring 10 minutes after the injection and 10 minutes after the injection. Calculated.

The results are as described in Table 2 below.

TABLE 2

From the above experimental results, it was found that the compounds according to the present invention had a superior analgesic effect at a significantly lower dose than aspirin, and also had an excellent analgesic effect compared to pyroxicam and indomethacin.

Claims (10)

1, 2-benzothiazine-1, 1-dioxide derivative of the general formula (I) Wherein one of X and Z is OR ₅ , and the other is of general formula R ₁ is hydrogen, lower alkyl group or lower alkenyl group, A is hydrogen or halogen, R ₂ is lower alkyl, lower alkenyl, cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted Ring aralkyl or aroyl, R ₃ and R ₄ are each independently hydrogen or lower alkyl, R ₅ is hydrogen, and Y is sulfur or oxygen. The compound of claim 1 wherein X is OH and Z is a general formula R ₁ is hydrogen, methyl or allyl, A is hydrogen, chloro or bromo, R ₂ is methyl, allyl, phenyl, benzyl, 4-chlorobenzyl, benzoyl, cyclohexyl or 4-chlorophenyl , R ₃ and R ₄ are each independently hydrogen or methyl, Y is sulfur, the general formula (I) 1, 2-benzothiazine-1, 1-dioxide derivative. The compound of claim 2 wherein X is OH and Z is a general formula R ₁ is methyl, R ₂ is methyl, allyl, cyclohexyl or phenyl, A is hydrogen, R ₃ and R ₄ are hydrogen and Y is sulfur 1, 2- in general formula (I) Benzothiazine-1, 1-dioxide derivatives. A process for preparing 1, 2-benzothiazine-1, 1-dioxide derivatives of general formula (I), characterized by reacting a compound of general formula (II) with an aminohydantoin derivative of general formula (III): Wherein one of X and Z is OR ₅ , and the other is of general formula R ₁ is hydrogen, lower alkyl group or lower alkenyl group, A is hydrogen or halogen, R ₂ is lower alkyl, lower alkenyl, cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted Aralkyl or aroyl, R ₃ and R ₄ are each independently hydrogen or lower alkyl, R ₅ is hydrogen, Y is sulfur or oxygen, one of B and D is OR ₅ , and the other is Optionally esterified carboxyl group, Z 'is a general formula Is a group. The process according to claim 4, wherein the reaction is carried out in a high boiling organic solvent. 5. The method of claim 4, wherein the reaction is carried out in the presence of molecular sieves in a Soxhlet apparatus. 1-amino-2-thioxo-4-imidazolone derivatives of the general formula (III-A) Wherein R _2-a represents cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted aroyl, and R ₃ and R ₄ are each independently hydrogen or lower alkyl Group. 1-amino-thioxo-4-imide of formula (III-A) characterized by reacting a thiocyanate derivative of formula (IV) with a hydrazine derivative of formula (V) in the presence of triethylamine How to prepare dazolone derivatives: Wherein R _2-a represents cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted aroyl, and R ₃ and R ₄ are each independently hydrogen or lower alkyl Represents a group. 9. The process according to claim 8, wherein triethylamine is used in a ratio of 2 equivalents to 1 equivalent of thiocyanate derivative of general formula (IV). 10. The process according to claim 9, characterized in that the reaction is carried out first using 1 equivalent of triethylamine to obtain a compound of formula (VI) as an intermediate, followed by the reaction using 1 equivalent of triethylamine. Wherein R _2-a , R ₃ and R ₄ are as defined in claim 7.