KR800000493B1 - Process for preparing 4-hydroxy-2h-naphto(2,1-e)-1,2-thiazine-3-carboxamide-1,1-dioxides - Google Patents

Abstract

4-Hydroxy-2H-naphtho[2,1-e -1,2-thiazine-3-carboxamide-1,1-dioxides(I, R1 = methyl, ethyl; Ar = phenyl, 3-chlorophenyl, 3-bromophenyl, 2-methoxyphenyl, 2-pyridyl, 2-pyrazinyl, 2-thiazolyl, 5-methyl-3-isoxazolyl), useful as antiphlogistic, blood platelet aggregation inhibitor, were prepd. by hydrolyzing enaminic carboxamide(IIa, R4 and R5 are C1-3 alkyl; R1 and Ar are given) obtained by reaction of enaminic chloride(II, Hal = halogen) and aromatic amine(III) at -40-80≰C in the presence of inert organic solvent.

Description

Method for producing 4-hydroxy-2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1-dioxide

The present invention provides 4-hydroxy-2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1- of the following structural formula (I) useful as an anti-inflammatory and platelet aggregation inhibitor. It relates to a method for producing a dioxide.

In the above structural formula (I)

R ₁ is methyl or ethyl group

Ar is phenyl, 3-chlorophenyl, 3-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-tolyl, 2-methoxyphenyl, 3-methoxyphenyl, 2 -Pyridyl, 4-methyl-2-pyridyl, 6-methyl-2-pyridyl, 3-hydroxy-2-pyridyl, 3-pyridyl, 4-pyridyl, 6-chloro-3-pyrida Genyl, 2-pyrazinyl, 6-chloro-2-pyrazinyl, 6-chloro-4-pyrimidinyl, 2-thiazolyl, 4-methyl-2-thiazolyl, 4-ethyl-2-thiazolyl, 5 -Methyl-2-thiazolyl, 5-ethyl-2-thiazolyl, 4,5-dimethyl-2-thiazolyl, 4-ethyl-5-methyl-2-thiazolyl, 5-ethyl-4-methyl-2 -Thiazolyl, 2-benzothiazolyl, 4,5,6,7-tetrahydro-2-benzothiazolyl, 5,6-dihydro-7H-thiopyrano [4,3-d] thiazole-2 -Yl, 3-methyl-5-isothiazolyl, 1,3,4-thiadiazolyl, 5-methyl-1,3,4-thiadiazol-2-yl or 5-methyl-3-isoxazolyl Represents a group.

The compound of formula (I) of the present invention reacts the enamine acid chloride of formula (II) with the aromatic amine of formula (III), and then acid hydrolyzes the enamine carboxamide of formula (IIa), the product of the above. Prepared by conversion to the desired end product by the process.

In the above structural formula

R ₁ is methyl or ethyl group

Hal is halogen

R ₄ and R ₅ may be an alkyl group having 1 to 3 carbon atoms or may be bonded together with a nitrogen atom to form a piperidino, pyrrolidino, morpholino or N-methyl piperazino group.

The reaction of the enamine acid chloride of formula (II) with the amine of formula (III) is carried out in the presence of an inert organic solvent such as an aromatic hydrocarbon or an ether at a temperature of -40 ° C to + 80 ° C and a tertiary such as triethylamine. It is also carried out in the presence of an organic base.

For subsequent hydrolysis reactions, the enaminecarboxamide of formula (IIa) may be used as an aqueous solution of a strong acid or moderately strong acid, such as hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, P-toluenesulfonic acid, trifluoroacetic acid, etc. Or an aqueous-alcoholic solution or a strong or moderately strong acid, such as hydrofluoric acid, is heated together with a solution dissolved in a glacial acetic acid or glacial acetic acid-water mixture. The compound of formula (I) can be converted into physiologically toxic salts with inorganic or organic bases by known methods. Suitable bases include alkali alcohols, alkali metal hydroxides, alkaline earth metal hydroxides, trialkylammonium hydroxides, alkylamines and the like.

The starting material of formula (II) is 2H-naphtho [2,1-e] -1,2-thiazine-4 (3H) -one-1,1-dioxide of formula (IV), and the presence of an acidic catalyst Under reaction with a secondary aliphatic amine of formula (V) in an inert organic solvent such as benzene or toluene, and then the compound of formula (VI) obtained above is a tertiary freebase such as triethylamine Prepared by treatment with phosgene in an organic solvent such as tetrahydrofuran in the presence of

In the above structural formula

R ₁ , R ₄ and R ₅ are as described above.

The enamine acid chloride of formula (II) obtained above is further reacted directly without separation.

Starting materials of formula (IV) include alkali salts of 3-oxo-naphtho [2,1-d] isothiazoline-1,1-dioxide (HP Kaufmann and H. Zobel, Chem. Ber. 55 (B), 1499 [1922]) is reacted with halogen acetone such as chloroacetone in 120-150 ° C. dimethyl sulfoxide to 2-acetonyl-3-oxo-naphtho [2,1-d] isothiazoline-1,1- Dioxide is obtained and then prepared by rearrangement using a base as a catalyst in the presence of 2-3 molar amounts of alkali alcoholate.

After acidification, 3-acetyl-4-hydroxy-2H-naphtho [2,1-e] -1,2-thiazine-1,1-dioxide is separated. This product is treated with ethylene glycol in the presence of acid in a dehydrated state, and at the same time, acetyl groups are removed to obtain a ketal of formula (VII). As an example, 3-acetyl-4-hydroxy-2H-naphtho [2,1-e] -1,2-thiazine-1,1-dioxide was reacted for 5 days in the presence of a benzene solvent and a P-toluenesulfonic acid catalyst. After refluxing, the ketal of the structural formula (VII) was used with an equimolar amount of alkali metal hydroxide in an alcoholic or aqueous alcoholic solvent to obtain the structural formula (IV) compound in which R ₁ is a methyl group, and R ₁ is an ethyl group. To obtain a phosphorus (IV) compound, alkylated with ethyl iodide, and then using aqueous alcoholic hydrochloric acid, 2H-naphtho [2,1-e] -1,2-thiazine-4 (3H) of formula (IV) Convert to -on-1,1-dioxide.

As described above, the compound of formula (I) exhibits pharmacologically valuable properties, that is, effective against all kinds of rheumatism such as anti-inflammatory activity and platelet aggregation inhibitory ability and arthritis.

One example is 4-hydroxy-2-methyl-N- (2-thiazole) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1-dioxide (= A) was compared and tested with indomethacin (5-methoxy-2-methyl-1- (4-chlorobenzoyl) -3-indolacetic acid (= B) to examine kaolin-induced edema and carrageenin in rat hind paws. Acute antiexudative effects on induced edema and acute toxicity as a result of oral administration are measured.

a) kaolin edema of the hind paw of rats

Kaolin edema is induced by injecting 0.05 ml of a 10% suspension prepared by dissolving kaolin in 0.85% sodium chloride solution to the paw of the rat's foot according to the method of Hilbrecht [Arzneimittel-Forsh 4,607 (1954)]. The thickness of the foot is measured by the reefner and the serenity method [Int. Arch. Allergy Immunol. 12, 89 (1958). Thirty minutes before the induction of edema, the test substance is orally administered to the FW 49-rat (♂) with a body weight of 120-150 g via the esophagus. After 5 hours of induction of edema, the average size of the swelling of the rat treated with the control method and the rat treated with the present formulation is compared. By means of the indentation on the chart, the dosage (ED ₃₅ ) in which the swelling is reduced by 35% is calculated from the rate of reduction of the size of the swelling induced by administration in different amounts.

b) carrageenan edema of the hind paw of rats

0.05 ml of a 1% solution prepared by dissolving carrageenin in 0.85% sodium chloride solution was prepared in Winter et al. [Proc. Soc. Exp. Biol. Med. 111, 544 (1962), to induce carrageenan sarcoma by injection into the rat's foot. The test substance is administered 60 minutes before injection. After 3 hours of induction of edema, the size of the swelling is measured to calculate the reduction effect on edema. Other test methods are the same as in the kaolin edema test.

c) acute toxicity

LD ₅₀ is measured by oral administration of test substance to FW 49-mouse with a mean weight of 135g (male to female ratio 1: 1). The present compound is ground and fed to the tiles. Calculate the value of LD ₅₀ according to the method of Richfield & Wilcoxon, based on the percentage of animals that died within 14 days of receiving the other dose.

Treatment rate (measurement of therapeutic utility) is calculated as an index of the values of LD ₅₀ and ED ₅₀ derived from the test to determine antiexudative activity against kaolin- and carrageenan-induced edema.

The results are shown in the following table.

This compound has twice the therapeutic rate of known indomethacin.

In addition, compound A and 4-hydroxy-2-methyl-N- (2-pyridyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1 -Dioxide (= C) is compared to phenylbutazone (= 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazoline = D) to determine the effect on arthritis aids.

d) rat arthritis aids

Rat arthritis adjuvant testing was conducted by Rosentale and Nagra [Proc. Soc. Exp. Biol. Med. 125, 149 (1967).

0.1 ml of a 1% suspension prepared by dissolving M, butyricum in viscous paraffin wax is injected into the sole of the FW 49-male rat. M. Begin injecting butyricum and administer the test substance to the esophagus tube once every 20 days.

21 days after the induction of arthritis, the volume of the right foot (non-specific primary response at the injection site) and the left foot (immune-specific secondary response induced by the injection) of the rat treated with the test substance are compared with the rat treated with the control compound. . ED ₅₀ is determined graphically from the rate of reduction of swelling induced by administration in different amounts. The results of this experiment are as follows.

As shown in the table, Compounds A and C have surprising effects on arthritis supplements, which were unexpected in the results of foot edema testing. The two compounds A and C have several times the effect of known anti-inflammatory phenylbutazone.

Compound A was also treated with 4-hydroxy-2-methyl-N- (2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide to determine the inhibitory effect on platelet aggregation and coagulation. -1,1-dioxide (sudoxicam = E) compared with [German Offenlegungsschrift 2,208,351]. The test is carried out in two ways:

a) Morris-test

t”von Erythrozyten und Thrombozyten, I. Int, Sympositum in Wien, 1968, 6, 17-22, 게오르그 티메, 스투트가르트].The principle of the Morris-test is described in the literature [Stoffwechsel und Membranpermeabilit

t ”von Erythrozyten und Thrombozyten, I. Int, Sympositum in Wien, 1968, 6, 17-22, Georg Timme, Stuttgart].

Pipette 1 ml of citrate-blood into a small amount of test tube, then add the test substance to the desired concentration and warm at 37 ° C for 10 minutes. 2g glass beads are placed in half of the whole test tube, and the plastic stopper is completely rotated from end to end for 45 seconds in the vertical direction. The test tube is then left to stand at ambient temperature for 1 hour to precipitate erythrocytes and glass beads. Remove 0.01 ml of supernatant plasma, dilute to 1: 800 with cell scope solution, and read platelet count in the cell scope. The percentage of platelets remaining in the precipitate (attached or agglomerated to glass beads) is calculated from the difference in platelet counts when the glass beads are not in contact with the glass beads.

The following table shows the rate of reduction of adhesion compared to the control (no test substance administered).

b) born-test

Platelet aggregation is measured by the method of Born and Cross (J. Physiol 170,397 [1974]) in platelet-rich plasma collected from healthy people.

The extent of decrease in optical density of the platelet suspension is measured and recorded by photometry after colloid addition. The aggregation speed can be measured from the inclination angle of the density curve, and the optical density is expressed as a point on the curve through which most of the light passes. Colloids are selected in such amount that an irreversible control curve is obtained.

The numbers shown are for optical density and represent the rate of change in the passage of light by administering the test substance compared to the control.

Messrs at this time. Use a commodity colloid from Hormon Chemie Munich. The following two test results are shown in the following table.

As can be seen from the table, Compound A has a much stronger platelet aggregation inhibitory effect than Compound E, and it has already been shown to reduce the aggregation phenomenon by 50% at a concentration 10 times lower than the concentration of Compound E.

In the Morris test, the fact that compound E inhibits adhesion by only 3% means that compound E is not as effective as compound A. Moreover, compound A is less toxic than compound.

Other compounds are tested in comparison with acetylsalicylic acid (= N) to determine platelet aggregation inhibitory effect (Born test, colloid-aggregation).

N- (3-chlorophenyl) -4-hydroxy-2-methyl-2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1-dioxide = F

4-hydroxy-2-methyl-N- (3-tolyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1-dioxide = G

4-hydroxy-2-methyl-N- (4-methyl-2-pyridyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1 -Dioxide-sodium salt = H

N- (6-chloro-2-pyrazinyl) -4-hydroxy-2-methyl-2H-naphtho- [2,1-e] -1,2-thiazine-3-carboxamide-1, 1-dioxide = I

4-hydroxy-2-methyl-N- (4-methyl-2-thiazolyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1 Dioxide = J

4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1 Dioxide = K

N- (4,5-dimethyl-2-thiazolyl) -2-hydroxy-4-methyl-2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1 , 1-dioxide = L

And

N- (4-ethyl-5-methyl-2-thiazolyl) -4-hydroxy-2-methyl-2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide -1,1-dioxide = M

The results are shown in the following table.

Comparative compound N (acetyl salicylic acid) shows a 50% reduction in aggregation when the concentration is only 4 × 10 ⁻⁵ mol / l and H, I, J, L and M show a 50% reduction when diluted at least 100 times F, G, and K show a 50% reduction at 20-fold dilute concentrations.

The present invention is explained in detail in the following examples.

Example 1

N- (3-chlorophenyl) -4-hydroxy-2-methyl-2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1-dioxide

A solution of 0.51 g (44 mmol) of 3-chloroaniline in 8 ml of anhydrous tetrahydrofuran was dissolved in 2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1. To a solution of, 2-thiazine-3-carboxylic acid chloride-1,1-dioxide in tetrahydrofuran was added dropwise at -40 ° C.

The reaction product is 0.63 g of 2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-1,1-dioxide in 16 ml of anhydrous tetrahydro. Obtained by reacting 0.25 g (2.5 mmol) of phosgene with 0.25 g (2.5 mmol) of triethylamine in furan.

The reaction mixture is heated at room temperature for 6 hours and then stirred at this temperature for 24 hours. Ice water is added and extracted twice with methylene chloride. The organic layer is washed twice with water, dehydrated over sodium sulfate and then evaporated in vacuo. Petroleum ether was added to the residue to form crystalline crude product N- (3-chlorophenyl) -2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2 -Thiazine-3-carboxamide-1,1-dioxide [melting point 163-167 degreeC (decomposition)] is obtained. The compound was dissolved in 6 ml of acetic acid, 2N hydrochloric acid was added, heated at 100 ° C. for 30 minutes, and then 50 ml of ice water was added thereto. The product is filtered, dried and recrystallized in ethylene chloride / petroleum ether to give 410 mg (49% of theory) of the title compound. Melting point is 247-248 degreeC (decomposition).

Starting materials are synthesized as follows.

a) 2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-1,1-dioxide

6.6 g (0.025 moles) of 2-methyl-2H-naphtho [2,1-e] -1,2-thiazine-4 (3H) -one-1,1-dioxide, 3.6 g (0.050 moles) of Pyrrolidine and 0.1 g of P-toluenesulfonic acid were dissolved in 150 ml of benzol and refluxed for 72 hours in a water separatory funnel. The cooled solution is neutralized with water, dried, evaporated and recrystallized to yield 5.8 g (74% of theory) of the title compound. Melting Point: 176 ~ 178 ℃

b) 2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide

0.63 g (2 mmol) of 2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-1,1-dioxide and 0.25 g (2.5 Millimol) triethylamine dissolved in 12 ml anhydrous tetrahydrofuran -40 ℃ solution, 0.25g (2.5 mmol) phosgene (using 1.5 ml of 20% solution dissolved in toluene) 4ml anhydrous tetrahydrofuran Is added to a solution cooled to -40 ° C. After raising to room temperature within 1 hour, it is allowed to stand still at room temperature for 2 hours. The enamine acid chloride obtained in the form of a tetrahydrofuran solution is used directly in the next reaction.

Example 2

4-hydroxy-2-methyl-N-phenyl-2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1-dioxide

Similar to Example 1, 2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide From aniline a product having a melting point of 273 to 274 ° C (decomposition) is obtained. Similar to Example 1, the following compounds were prepared.

a) N- (3-bromophenyl) -4-hydroxy-2-methyl-2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1- Dioxide

From 2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 3-bromoaniline A product having a melting point of 268 to 269 ° C. (decomposition) is obtained.

b) N- (2-fluorophenyl) -4-hydroxy-2-methyl-2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1- Dioxide

From 2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 2-fluoroaniline A product having a melting point of 240 to 243 ° C. (decomposition) (recrystallized from xylene) is obtained.

c) N- (3-fluorophenyl) -4-hydroxy-2-methyl-2H-naphtho- [2,1-e] -1,2-thiazine-3-carboxamide-1,1 -Dioxide

From 2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 3-fluoroaniline , A product having a melting point of 278 to 279 ° C. (decomposition) upon recrystallization in xylene.

d) N- (4-fluorophenyl) -4-hydroxy-2-methyl-2H-naphtho- [2,1-e] -1,2-thiazine-3-carboxamide-1,1 -Dioxide

From 2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 4-fluoroaniline A product having a melting point of 284 to 285 ° C. (decomposition) (when recrystallized from xylene) is obtained.

e) 4-hydroxy-2-methyl-N- (3-tolyl) -2H-naphtho- [2,1-e] -1,2-thiazine-3-carboxamide-1,1-dioxide

Melting point from 2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and m-toluidine A product is obtained which is 240 to 242 ° C. (decomposition) (when recrystallized from xylene).

f) 4-hydroxy-N- (2-dimethoxyphenyl) -2-methyl-2H-naphtho- [2,1-e] -1,2-thiazine-3-carboxamide-1,1 -Dioxide

From 2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 2-methoxyaniline The product has a melting point of 198 to 200 ° C. upon recrystallization in ethylene chloride / petroleum ether.

g) 4-hydroxy-N- (3-methoxyphenyl) -2-methyl-2H-naphtho- [2,1-e] -1,2-thiazine-3-carboxamide-1,1 -Dioxide

From 2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 3-methoxyaniline A product having a melting point of 242 to 244 ° C. (decomposition) (when recrystallized from xylene) is obtained.

h) 4-hydroxy-2-methyl-N- (2-pyridyl) -2H-naphtho- [2,1-e] -1,2-thiazine-3-carboxamide-1,1- Dioxide

Melting point from 2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 2-aminopyridine The product which is this 237-238 degreeC (decomposition) is obtained.

i) 4-hydroxy-2-methyl-N- (4-methyl-2-pyridyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1 , 1-dioxide

2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 2-amino-4- From methyl-pyridine a product having a melting point of 221 ° C. (decomposition) is obtained.

j) 4-hydroxy-2-methyl-N- (6-methyl-2-pyridyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1 , 1-dioxide

2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 2-amino-6- From methyl-pyridine a product having a melting point of 221 to 223 ° C. (decomposition) (when recrystallized from ethyl acetate) is obtained.

k) 4-hydroxy-N- (3-hydroxy-2-pyridyl) -2-methyl-2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide- 1,1-dioxide

2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 2-amino-3- From hydroxy pyridine a product having a melting point of 255 ° C. (decomposition) is obtained.

l) 4-hydroxy-2-methyl-N- (3-pyridyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1-dioxide

From 2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 3-amino-pyridine A product having a melting point of 254 ° C. (decomposition) (when recrystallized from ethanol / ethyl acetate) is obtained.

m) 4-hydroxy-2-methyl-N- (4-pyridyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1-dioxide

Melting point from 2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 4-aminopyridine This product is 257 DEG C (decomposition) (when ethanol is recrystallized).

n) N- (6-chloro-3-pyridazinyl) -4-hydroxy-2-methyl-2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide- 1,1-dioxide

2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 3-amino-6- From chloro-pyridazine a product having a melting point of 235 to 237 ° C. (decomposition) is obtained.

o) 4-hydroxy-2-methyl-N-pyrazinyl-2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1-dioxide

Melting point 245 from 2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and aminopyrazine Obtain a product that is deg. C (decomposition).

p) N- (6-chloro-2-pyrazinyl) -4-hydroxy-2-methyl-2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1 , 1-dioxide

2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 2-amino-6- From chloro pyrazine a product having a melting point of 209-210 ° C. (when ethanol recrystallization) is obtained.

q) N- (6-chloro-4-pyrimidinyl) -4-hydroxy-2-methyl-2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide- 1,1-dioxide

2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 4-amino-6- From chloro-pyrimidine a product having a melting point of 263 ° C. (decomposition) (when recrystallized from xylene) is obtained.

Example 3

4-hydroxy-2-methyl-N- (2-thiazolyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1-dioxide

A solution of 0.9 g (9 mmol) of 2-aminothiazole and 0.78 g (7.7 mmol) of triethylamine in 8 ml of tetrahydrofuran was dissolved at -40 ° C. to 6.4 mmol of 2-methyl-4- (1- Pyrrolidineri) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide solution [2 g (6.4 mmol) 2-methyl-4- (1 Pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-1,1-dioxide was dissolved in 80 ml of tetrahydrofuran 0.78 g (7.7 mmol) triethylamine. Obtained by reacting with 4 ml of a 20% solution of phosgene dissolved in 7.7 mmol of toluene in the presence of a solution. Within 2 hours the reaction mixture is allowed to warm to room temperature and stirred for 36 hours. After adding ice water and extracting several times with ethylene chloride, the organic layer was evaporated and the residue was refluxed with 2-normal hydrochloric acid for 2 hours. After cooling, extraction with ethylene chloride and evaporation is followed by purification of the residue by chromatography on silica gel, with eluent chloroform-methanol (10: 1). As a result, 0.9 g (35% of theory) of the title compound were obtained. Melting point 248-249 ° C (decomposition)

The following compounds are similarly prepared.

a) 4-hydroxy-2-methyl-N- (4-methyl 2-thiazolyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1, 1-dioxide

2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 2-amino-4- From methyl-thiazole a product having a melting point of 177 ° C is obtained.

b) N- (4-ethyl-2-thiazolyl) -4-hydroxy-2-methyl-2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1 , 1-dioxide

2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 2-amino-4- From ethylthiazole a product having a melting point of 194 to 195 ° C is obtained.

c) 4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-naphtho- [2,1-e] -1,2-thiazine-3-carboxamide- 1,1-dioxide

2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 2-amino-5- From methyl-thiazole a product having a melting point of 249 to 250 ° C. (decomposition) (recrystallized from xylene) is obtained.

d) N- (5-ethyl-2-thiazolyl) -4-hydroxy-2-methyl-2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1 , 1-dioxide

2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 2-amino-5- From ethylthiazole a product having a melting point of 230 ° C. (decomposition) (when recrystallized from xylene) is obtained.

e) N- (4,5-dimethyl-2-thiazolyl) -4-hydroxy-2-methyl-2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide -1,1-dioxide

2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 2-amino-4, From 5-dimethyl-thiazole a product having a melting point of 264 to 265 ° C. (decomposition) (when recrystallized from ethylene chloride) is obtained.

f) N- (4-ethyl-5-methyl-2-thiazolyl) -4-hydroxy-2-methyl-2H-naphtho [2,1-e] -1,2-thiazine-3-car Copyamide-1,1-dioxide

2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 2-amino-4- From ethyl-5-methyl-thiazole a product having a melting point of 233 to 234 ° C. (decomposition) (when recrystallized from xylene) is obtained.

g) N- (5-ethyl-4-methyl-2-thiazolyl) -4-hydroxy-2-methyl-2H-naphtho [2,1-e] -1,2-thiazine-3-car Copyamide-1,1-dioxide

2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 2-amino-5- From ethyl-4-methyl-thiazole a product having a melting point of 253 to 255 ° C. (decomposition) (when recrystallized from ethanol) is obtained.

h) N- (2-benzothiazolyl) -4-hydroxy-2-methyl-2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1- Dioxide

2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 2-amino-benzothia From the sol a product having a melting point of 262 ° C. (decomposition) (when recrystallized from xylene) is obtained.

i) 4-hydroxy-2-methyl-N- (4,5,6,7-tetrahydro-2-benzothiazolyl) -2H-naphtho- [2,1-e] -1,2-thia Gen-3-carboxamide-1,1-dioxide

2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 2-amino-4, From 5,6,7-tetrahydro-benzothiazole a product having a melting point of 255 to 257 ° C. (decomposition) (when recrystallized from ethylene chloride) is obtained.

j) N- (5,6-dihydro-7H-thiopyrano [4,3-d] thiazol-2-yl) -4-hydroxy-2-methyl-2H-naphtho [2,1- e] -1,2-thiazine-3-carboxamide-1,1-dioxide

2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 2-amino-5, From 6-dihydro-7H-thioparano [4,3-d] thiazole a product having a melting point of 255 ° C (decomposition) (when recrystallized from xylene) is obtained.

k) 4-hydroxy-2-methyl-N- (3-methyl-5-isothiazolyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide- 1,1-dioxide

2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 5-amino-3- From methyl-isothiazole a product having a melting point of 268 ° C. (decomposition) (when recrystallized from ethylene chloride) is obtained.

l) 4-hydroxy-2-methyl-N- (1,3,4-thiadiazolyl) -2H-naphtho- [2,1-e] -1,2-thiazine-3-carboxamide -1,1-dioxide

2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 2-amino-1, From 3,4-thiadiazole a product having a melting point of 217-219 ° C. (decomposition) (when recrystallized in ethylene chloride / ethyl acetate) is obtained.

m) 4-hydroxy-2-methyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) -2H-naphtho [2,1-e] -1,2-thia Gen-3-carboxamide-1,1-dioxide

2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 2-amino-5- From methyl-1,3,4-thiadiazole a product having a melting point of 252 to 255 ° C. (decomposition) (when recrystallized from ethanol) is obtained.

n) 4-hydroxy-2-methyl-N- (5-methyl-3-isoxazolyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide- 1,1-dioxide

2-methyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 3-amino-5- From methyl-isoxazole, a product having a melting point of 253 ° C is obtained.

Example 4

2-ethyl-4-hydroxy-N-phenyl-2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1-dioxide

Similar to Example 1, 2-ethyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide From aniline a product is obtained with a melting point of 245 to 247 ° C. (when recrystallized from ethylene chloride / petroleum ether). Yield: 46% of theory The starting material is prepared through the following intermediates.

a) 2-ethyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-1,1-dioxide

2 g (7.3 mmol) 2-ethyl-2H-naphtho [2,1-e] -1,2-thiazine-4 (3H) -one-1,1-dioxide, 1.04 g (14.6 mmol) of blood Lolidine and 200 mg of P-toluenesulfonic acid are refluxed for 24 hours with 100 ml of benzene in a water separation funnel. Subsequently, 1.04 g (14.6 mmol) of pyrrolidine and 200 mg of P-toluene sulfonic acid are added, heated for 24 hours, cooled, evaporated and extracted several times with ether. The ether extracts are combined, washed twice with water, dried and evaporated. Recrystallization in methanol yields 1.2 g (50% of theory) of the desired enamine. Melting Point: 115-117 ° C

b) 2-ethyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide

Similar to Example 1b, a solution of 2-ethyl-4- (1-pyrrolidinyl) -2H-naphtho [2,1-e] -1,2-thiazine-1,1-dioxide and tetrahydrofuran Prepared from phosgene in the form.

Example 5

Sodium of 4-hydroxy-2-methyl-N- (2-thiazolyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1-dioxide salt

A solution of 0.2 g (5 mmol) of sodium hydroxide in 20 ml of methanol was added to 1.94 g (5 mmol) of 4-hydroxy-2-methyl-N- (2-thiazolyl) -2H-naphtho in 30 ml of methanol. [2,1-e] -thiazine-3-carboxamide-1,1-dioxide is added to the dissolved suspension. After the mixture is left for 24 hours, ether is added and the semi-solution mixture is evaporated. The crystals are filtered and dried in vacuo to yield 1.9 g of the desired compound with a yield of 93%. Melting Point: 230 ℃ (Decomposition)

Example 6

4-hydroxy-2-methyl-N- (4-methyl-2-pyridyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1 Sodium salts of dioxide

1.9 g (4.8 mmol) of 4-hydroxy-2-methyl-N- (4-methyl-2-pyridyl) -2H-naphtho was dissolved in a solution of 0.192 g (4.8 mmol) of sodium hydroxide in 75 ml of methanol. To [2,1-e] -thiazine-3-carboxamide-1,1-dioxide. The reaction mixture is stirred at 30 ° C. for 3 hours, evaporated and ether is added thereto. The crystals were filtered and dried in vacuo to give 2 g of the target compound having a yield of 99.7%.

Melting Point: 218 to 220 ° C (Decomposition)

Example 7

Cyclo of 4-hydroxy-2-methyl-N- (2-thiazolyl) -2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1-dioxide Hexylamine salt

0.5 g (1.5 mmol) of 4-hydroxy-2-methyl-N- (2-thiazolyl) -2H-naphtho [2, suspended in 0.15 g (1.5 mmol) of cyclohexylamine in 10 ml of methanol 1-e] -thiazine-3-carboxamide-1,1-dioxide. The obtained solution was evaporated mostly in vacuo and the residue was treated with acetone, and the obtained crystals were suction filtered and washed with a small amount of acetone and ether to give 0.55 g of the desired compound with a yield of 76%.

Melting Point: 205-207 ° C

Compounds of the invention of formula (I) may be formulated into pharmaceutical compositions, optionally in combination with other active ingredients of formula (I), for pharmacological use. 10 to 250 mg (preferably 25 to 100 mg) in a single dose, 25 to 500 mg (preferably 50 to 250 mg) in a daily dose.

Claims (1)

The enamine acid chloride of the following formula (II) is reacted with the aromatic amine of the following formula (III) at a temperature of -40 to + 80 ° C. in the presence of an inert organic solvent to give the enamine acid carboxamide of the following formula (IIa) This compound is then hydrolyzed with acid to give the compound of formula (I), where necessary, the product is converted to its salt using an organic or inorganic base, characterized in that 4- Hydroxy-2H-naphtho [2,1-e] -1,2-thiazine-3-carboxamide-1,1-dioxide and a physiologically toxic salt thereof.

Wherein R ₁ is methyl or ethyl group and Ar is phenyl, 3-chlorophenyl, 3-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-tolyl, 2- Methoxyphenyl, 3-methoxyphenyl, 2-pyridyl, 4-methyl-2-pyridyl, 6-methyl-2-pyridyl, 3-hydroxy-2-pyridyl, 3-pyridyl, 4- Pyridyl, 6-chloro-3-pyridazinyl, 2-pyrazinyl, 6-chloro-2-pyrazinyl, 6-chloro-4-pyrimidinyl, 2-thiazolyl, 4-methyl-2-thiazolyl , 4-ethyl-2-thiazolyl, 5-methyl-2-thiazolyl, 5-ethyl-2-thiazolyl, 4,5-dimethyl-2-thiazolyl, 4-ethyl-5-methyl-2-thia Zolyl, 5-ethyl-4-methyl-2-thiazolyl, 2-benzothiazolyl, 4,5,6,7-tetrahydro-2-benzothiazolyl, 5,6-dihydro-7H-thiopyrano [4,3-d] thiazol-2-yl, 3-methyl-5-isothiazolyl, 1,3,4-thiadiazolyl, 5-methyl-1,3,4-thiadiazol-2- yl or 5-methyl-3-isoxazolyl represents a thiazolyl group, and Hal is halogen, R ₄ and R ₅ are burnt 1 to 3 or of an alkyl group, or, combined together with the nitrogen atom to piperidino, pyrrolidino, morpholino or N- to form a no-methyl piperazino group.