CS207762B2 - Method of making the new 3,4-dihydro-2h-1,2-benzothiazin-1,1-dioxides - Google Patents

Description

(54) A process for the preparation of the novel 3,4-dihydro-2H-1,2-benzothennazine-1,1-dioxide

The present invention relates to a process for the preparation of novel azathianaphthalene derivatives, in particular substituted 3,4-dihydro-2H-1,2-benzothiazine-1,1-dioxides of the general formula I

in which

R is a benzopyron radical optionally substituted by a lower alkyl group having 1 to 4 carbon atoms, a lower alkylene group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a halogen and / or a trifluoromethyl group,

R 1 is hydrogen, C 1 -C 4 lower alkyl, C 1 -C 4 lower alkenyl, C 1 -C 4 hydroxy (C 1 -C 4) alkyl or C 1 -C 4 lower alkoxy (C 1 -C 4) alkyl alkoxy and alkyl moieties, and salts thereof.

An optionally substituted benzopyron radical R may be attached at any position and is, for example, as indicated or optionally substituted, at the 4, poloze position or, in particular at the 3 or 7 position, a 2-oxo-2H-1-benzopyronyl radical or at the 3-position or, in the second row at the 6 or 7, a 4-oxo-4H-1-benzopyranyl radical bonded.

Lower alkylene as R is a 3- or 4-membered lower alkylene group bonded at the 5, 6, 6, 7 or 7, 8 position or the 3,4-position of the 2-oxo-2H-1-benzopyran-7-yl radical .

In the section below, the general terms have the following meanings:

The lower radicals contain 1 to 4 carbon atoms.

Lower alkyl is, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

Lower alkylene is, for example, 1,3-propylene.

Lower alkoxy is, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy or n-butyloxy.

Lower alkoxy (lower) alkyl is, for example

2-methoxyethyl or 2-ethoxyethyl, while the hydroxy (lower) alkyl is in particular 2-hydroxyethyl or 3-hydroxypropyl.

The compounds of formula I may exist in free form or in the form of their salts, in particular in the form of their pharmaceutically usable, non-toxic salts.

Thus, the compounds of formula I may form salts with bases such as salts with metals I and II. groups of the Periodic Table of the Elements, for example alkali metal or alkaline earth metal salts, in particular sodium, potassium, magnesium or calcium salts, copper or zinc salts, ammonium salts and salts with organic bases such as suitable amines, e.g. ethylamine, triethylamine, diethylaminoethanol, ethylenediamine, benzylamine, procaine, pyrrolidine, piperidine, morpholine, 1-ethylpiperidine or 2-piperidinoethanol.

The compounds of formula I may exist in several tautomeric forms. The most important of these tautomeric forms corresponds to the general formula Ia

The compounds of the present invention may further exist in the form of mixtures of isomers, as racemates, or in the form of pure isomers, for example as antipodes.

The azathianaphthalene derivatives according to the invention, in particular the compounds of formula I, have valuable pharmacological properties, in particular anti-inflammatory properties. These properties can be demonstrated, for example, by carrageenan edema on the paw of an oral paw at an oral dose of from about 30 to about 100 mg / kg, as well as by kaolin edema on the paw of an oral paw at an oral dose of about 100 to about 300 mg / kg. arthritis in the rat at an oral dose of from about 30 to 100 mg / kg. The novel 3,4-dihydro-2H-1,2-benzothiazine-1,1-dioxides can therefore be used as antiinflammatory agents in inflammatory processes of various causes, in particular rheumatic forms.

In particular, the invention relates to compounds of the formula I in which R represents an optionally lower alkyl, lower alkoxy or halogen substituted one or more times or on two adjacent carbon atoms a 2-oxo-2H-1-benzopyranyl radical or a 4-oxo-substituted lower alkylene group 2H-1-benzopyranyl, and R 1 is hydrogen, lower alkyl or lower alkenyl and their base salts.

In particular, the invention relates to compounds of formula I wherein R is in the position

A 3, 4, 6 or 7 bonded 2-oxo-2H-1-benzopyranyl residue or in the 3-position or, in the second row, a 6-bonded 4-oxo-2H-1-benzopyranyl residue which is unsubstituted or optionally substituted lower alkyl of up to 4 carbon atoms, such as methyl, lower alkoxy of up to 4 carbon atoms, such as methoxy or halogen of up to 35, such as chlorine, one or more times or two adjacent carbon atoms with lower alkylene of up to 4 atoms carbon, such as a 1,3-propylene group; or

And R 1 represents hydrogen or a lower alkyl group of up to 4 carbon atoms, such as methyl or ethyl, and their base salts.

More particularly, the invention relates to compounds of formula (1b)

R2 represents hydrogen or, in particular, a lower alkyl group having 1 to 4 carbon atoms, for example a methyl group or an ethyl group,

R 3 and R 6 independently represent hydrogen, lower alkyl of up to 4 carbon atoms, for example methyl or lower alkoxy of up to 4 carbon atoms, for example methoxy, or together represent a 3- or 4-membered lower alkylene group bonded to adjacent carbon atoms , for example, a 1,3-propylene group or a 1,4-butylene group, and their base salts.

In particular, the invention relates to compounds of formula (1b) wherein:

R 2 represents a lower alkyl group having 1 to 4 carbon atoms, such as a methyl group,

R 3 and R a independently represent hydrogen, a lower alkyl group or a lower alkoxy group of up to 4 carbon atoms, such as a methyl group or a methoxy group, or together are preferably a 3- to 4-membered lower alkylene group of up to 4 carbon atoms , such as a 1,3-propylene group, and their base salts.

The invention further relates to the compounds of the formula I, notably those mentioned in the examples, in particular the compounds of the formula 1b, and their salts with bases.

The novel compounds of the formula (I) can be prepared by methods known per se, for example by starting in a compound of the formula (II)

in which

R 'represents a residue which is cyclizable to an optionally substituted benzopyrone residue R, or a salt thereof, cyclizes the residue R' to a residue R, whereupon the compound thus obtained is converted to another compound of formula I and / or the free compound obtained is converted to a salt or converting the obtained salt into the free compound or another salt.

The R R radicals which are cyclizable to the benzopyrone R radicals are, for example, to the R radicals

in which

Ph is optionally substituted 1,2-phenyl, cyclizable radicals of formulas Hal, IIa2, IIa3 or IIa4 —CH2 — C (= O) —Ph — O — C (= O) —Re (Hal) —CH (CORg) - C (= O) —Ph — Rg (IIa2) - (C = O) —CH (Rg) —C (= O) —Ph — Rg (IIa3) or —C (R <J) = C (Rg) —O — Ph — H (IIa4), further to the radicals R of formula IIb

cyclisable residues of formulas IIb1, IIb2 and IIb3, respectively

C (= Oj - CH 2 R e)

Z —Ph (Ilbl) \

O — C (= O) —Rz

C (= O) —CH (R0) —C (= O) -R 7 z

-Ph (IIb2) \

Rg optionally

H

From —Ph (IIb3), \

O-C (R 7) = C (R 6) -R 9 further on to the radicals R of formula IIc

cyclizable radicals of formulas IIc4 and IIc4, respectively IIc2, IIc3 -C (Rg) = C (R ₇₎ -Ph-R (Hel), - C (PhR 8) - C (R 7) - R 9 (IIc2) —CH2 — C (= O) —O — Ph — Rg (Ilc3), optionally —CH (Rg) —C (= O) —Ph — Rg (IIc4) or to the radicals R of formula IId l ^! _and (people) cyclisable radicals of formulas IId4 IId2, IId3 -Ph (Rg) -C (R7) = C (R ₆₎ -rg (people) —Ph (Rg) —O — C (= O) —CHaRe (IId2), —Ph (R3) —C (= O) —CH (Re) —Rg (IId3) optionally —Ph (O — R8) —C (= O) —CH 2 R 6 (Hd4),

whereas

Ph represents a 1,2-phenylene group optionally substituted by a lower alkyl group, a lower alkylene group, a lower alkoxy group, a halogen and / or a trifluoromethyl group,

R e and R 7 are each independently hydrogen or lower alkyl, or together are lower alkylene,

Re represents halogen or lower alkoxy and

R 9 is an optionally esterified or anhydride carboxy group.

Divalent aliphatic radicals R @ 6 + R @ 7 in particular include 3- to 4-membered alkylene radicals, such as 1,3-propylene and 1,4-butylene. Lower alkoxy is, for example, methoxy. Esterified carboxy is, for example, lower alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, or optionally substituted phenoxycarbonyl. An anhydride carboxy group is, for example, a lower alkanoyloxycarbonyl group, such as a formyl or acstoxycarbonyl group, or a halogen- such as a chlorocarbonyl group.

The cyclization of the compounds of formula II is carried out in a conventional manner, for example by a method known from the chemical literature for analogous reactions, preferably in the presence of a basic or acidic condensing agent and in a solvent inert to the reactants, optionally with removal of the volatile compounds formed, for example by azeotropic distillation. cooling or with heating, for example in a temperature range of about 0 to about 200 ° C, under an inert gas such as nitrogen, and / or in a closed vessel.

Basic condensing agents are, for example, hydroxides, alkoxides such as lower alkoxides, carbonates or carboxylates, such as carboxylates derived from a lower alkanecarboxylic acid, alkali metals such as sodium or potassium hydroxide, sodium or potassium methoxide or sodium or potassium ethoxide, potassium carbonate or sodium acetate or potassium acetate. Acidic condensing agents are, for example, protonic acids or their anhydrides, such as sulfuric acid, phosphoric acid, hydrohalic acid, for example hydrochloric acid, hydrobromic acid or hydroiodic acid, phosphorus pentoxide or acetyl chloride or acetic anhydride, and Lewis acids such as aluminum chloride.

Suitable solvents are, for example, hydrocarbons such as benzene, toluene or xylene, alcohols such as lower alkanols or lower alkanediols such as ethanol, methanol or ethylene glycol, di (lower) alkyl ketones such as acetone, aliphatic or cycloaliphatic ethers such as tetrahydrofuran or dibutyl ether, carboxylic acids , such as acetic acid, or anhydrides thereof, such as acetic anhydride or tertiary amides of lower alkanoic acids, such as dimethylformamide or N-methylpyrrolidone, or mixtures, for example, aqueous mixtures of these compounds. For cyclization of compounds of formula II wherein R 'is a radical of formula IIa2, IIa3, IIa4, IIb2, IIb3, cheek, IIc2, IIc4, human or IId3, acidic condensing agents such as strong, for example at least 20% aqueous hydroiodic acid are preferably used. or hydrobromic acid in acetic acid, in the case of R 'residues of formulas IIc4 or IId3, for example concentrated, ie at least 50%, sulfuric acid, and in the case of R' residues of formulas IIa4 or IIb3, for example also sulfuric acid or acid anhydrides, e.g. phosphorus or acetyl chloride.

When starting materials of compounds of formula (II) in which R * is a radical of formula (IIa), (IIb1), (IIc3), (IIc4), (IId3) or (IId4) are used as starting materials, for example, potassium carbonate in acetone or a sodium or potassium salt of an organic carboxylic acid in the presence of a volatile anhydride thereof, or in the case of R 'residues of formulas IIc3, IIc4, IId3 or IId4 in the presence of sodium or an alkali metal alkoxide, preferably sodium alkoxide in the alcohol concerned.

The starting materials of the formula II can, if new, be prepared by methods known per se, for example by reacting to an ester such as the lower alkyl ester of the acid of the formula III

OH

(lil) in which

Ph and R 1 are as defined above, with an amine of formula

R ‘- NH2 in which

R * is as defined above, preferably as in the reaction of esters of formula II with amines of formula

R‘ = NH2

Compounds of formula II in which R R is a radical of formula IIa2 can be further obtained by, for example, compounds of formula IV

in which

Ph and R 1 are as defined above, in the presence of a mixed formic anhydride and acetic acid react with a salt, for example with the sodium salt of an acid of formula V

Z2-COOH (V) wherein one of Z1 and Z2 is R6 and the other is -PhR5.

In an analogous manner, compounds of formula (II) wherein R @ 1 is a radical of formula (IIb2) may be obtained by reacting

OH

PL · \

O

NH-PMi-COOH or, preferably, a salt thereof or an ester thereof, such as a lower alkyl ester.

Compounds of formula VII containing a human group R‘ as the radical R @ 1 may further be obtained by a conventional reaction of a compound of formula X

with a compound of formula XI

R6CH2R9 (XI),

The starting materials of the formula II in which R R represents the radical of the formulas Hal, IIb1, IIc3, IIc4, IId3 or IId4 are preferably produced under in situ reaction conditions and cyclized without isolation. Thus, for example, a compound of formula XII (VI) or an ester, for example a lower alkyl ester, or a salt, for example a sodium salt thereof, can be reacted with a compound of the formula V

OH sA2-NH-CHrC (= O) -Phr OH, (XII)

R ₆ CH ₂ (= O] -R 7 (V), optionally with an ester and / or a salt thereof, for example a sodium salt, for example as described above or in the presence of sodium in xylene or sodium methoxide in methanol.

Compounds of formula II wherein R R is a radical of formula IIb3 can be further obtained by reacting a compound of formula VIII with an acid anhydride of formula XIII

R 5 COOH (XIII), preferably in the presence of an alkali metal salt, for example sodium salt, to form intermediately a compound of formula II wherein R ‘represents a residue of formula Hal.

Analogously, the compound of formula XIV can be used

The C-NH-Pk (OH) -C (* O) -CH _of R ₆ 'fy (XIV) derived alkali metal phenoxide, such as sodium phenoxide, reacts with a compound of formula IX to give an intermediate of formula II in which R 'represents a group of formula IIb1, reacted with an anhydride of a compound of formula XV

Hal — C (R 7) = C (R 6j - R 8 (IX),

R7COOH (XV) wherein

R 7 is different from hydroxy.

in which

Hal means halogen, such as chlorine or bromine,

Further, compounds of formulas XVI can be reacted in the presence of strong throws, for example sodium or alkali metal alkoxides, for example sodium alkoxides.

(XVI) optionally an ester, or a salt of these compounds and a compound of formula XVII

HO — PhRs (XVII), or a salt of these compounds to give an intermediate R‘ of formula IIc3, or a compound of formulas XVIII

OH o

C-NH-Ph. (Ry) -OH

Pb

O 0 (XVIII) optionally an ester and / or salt thereof and a compound of formula XXIII

R6CH2R9 (XXIII), or an ester or a salt of these compounds, to form an intermediate R * of formula IId3.

Further, a compound of formula XXIV and a compound of formula XIX can be reacted optionally or ester and / or salt thereof

R 6 CH 2 COOH (XIX), optionally an ester or a salt of these compounds, to form an intermediate residue of the R 1 formula

IId2,

OH 0'-NH-PI 1 (H) OH or a compound of formula XX

On 'R.

(XXI v)

optionally an ester and / or salt thereof and a compound of formula XXI

Re — Ph — COOH (XXI), optionally an ester or a salt of these compounds to give an intermediate R R of formula IIc4, or a compound of formula XXII with a compound of formula XXV

R 7 - C (= O) - CH (R 6) R 9 (XXV), in the presence of an acidic agent such as a protonic acid such as sulfuric acid or an acid anhydride such as phosphorous pentoxide.

In this reaction, which directly yields the corresponding benzopyrone derivatives of formula I as the first isolable reaction product as the first isolable reaction product, the ratio of the resulting 2H-1-benzopyrone derivative to the 4H-1-benzopyrone derivative is determined by the specificity of the starting materials and reaction conditions. In general, however, the use of phospho207762 as the condensing agent yields predominantly 4H-1-benzopyrone derivatives, and using more or less concentrated sulfuric acid, in contrast, predominantly obtains 2H-1-benzopyran derivatives.

The compound of formula I obtained by the process of the invention can be converted in a conventional manner into another compound of formula I.

For example, a lower alkyl radical, a lower alkenyl radical, a hydroxy (lower jalkyl radical or (loweralkoxy) radical (lower alkyl radical R 1) can be introduced into a compound of formula I obtained by the process of the invention in which R 1 is hydrogen, for example by reaction with a introducing agent. this residue, such as a reactive ester, for example an ester of the alcohol concerned with a mineral acid or a sulfonic acid or an epoxide derived therefrom.

The esters of mineral acids are in particular esters derived from hydrohalic acid, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, and esters derived from sulfuric acid and sulphonic acid, in particular esters with aromatic or aliphatic sulphonic acids, such as esters with methane, ethane -, ethene, benzene, p-bromobenzene or p-toluenesulfonic acid. For example, epoxides are epoxides derived from lower alkyl radicals R 1 with at least two carbon atoms in the alkyl moiety. In an analogous manner, the hydroxy group R can also be etherified with a lower alkyl radical.

The above reactions are carried out in a conventional manner, optionally in the presence of a basic condensing agent, such as a basic metal compound, for example an alkali metal or alkaline earth metal hydroxide, an alkali metal or alkaline earth metal carbonate, an alkali metal or alkaline earth metal hydride or a hydrocarbon compound. an alkali metal, a nitrogenous base, for example a tertiary amine, optionally in an inert solvent and / or with cooling or heating, for example in a temperature range of from about -10 ° C to about 105 ° C.

The basic metal compounds are, in particular, sodium and potassium hydroxide and / or potassium carbonate, sodium methoxide, sodium hydride, diisopropylamine lithium and phenyl as well as butyl lithium. Nitrogen bases are in particular pyridine, triethylamine or quinoline.

Conversely, in the compounds obtained according to the invention, the acylamino group can be hydrolyzed in a conventional manner to an amino and / or acyloxy group and / or an etherified hydroxy group to a hydroxy group, for example in the presence of acidic or basic hydrolyzing agents, optionally under gentle heating, e.g. The acid hydrolyzing agents are, in particular, mineral acids such as hydrochloric acid or sulfuric acid, or organic carboxylic or sulfonic acids such as acetic acid or p-toluenesulfonic acid. The basic hydrolyzing agents are, in particular, alkali such as sodium or potassium hydroxide or carbonate. In addition, hydrobromic acid in acetic acid, hydrochloric acid in pyridine or hydroiodic acid is used as the hydrolyzing agent containing mineral acid for the hydrolysis of the etherified hydroxy groups.

The above reactions are carried out in the usual manner in the presence or absence of diluents, condensing agents and / or catalysts, optionally at a reduced or elevated temperature, in a closed vessel and / or under an inert gas atmosphere.

Depending on the reaction conditions and the starting materials used, optionally salt-forming reaction products are obtained in free form or in the form of their salts, which can be converted into one another in the usual manner or can be converted into other salts. Thus, the compounds of formula I can be obtained in the form of their base salts; these salts can be reacted in a conventional manner, for example by reacting the free compound with a corresponding basic agent such as metal hydroxide I and II. groups of the periodic system of elements, for example with alkali or alkaline earth metal hydroxide, carbonate, bicarbonate, amide or hydride or with a suitable lower alkali metal alkoxide, with copper oxide or with zinc oxide, or with ammonia or amine, usable salt. The free salts of formula I can be liberated from the corresponding salts in a conventional manner, for example by reaction with acidic agents.

These and other salts may be used to purify the novel compounds, for example, by converting the free compounds into their salts, isolating them and converting them into the free compounds again. Due to the close relationship between the novel compounds in the free form and in the form of their salts, in the preceding and subsequent parts of the free compounds, the corresponding salts are meant, as appropriate, in the sense and purpose.

The mixtures of isomers obtained can be separated into the two stereoisomers, i.e. pure isomers, for example by chromatography and / or fractional crystallization, in a manner known per se, based on the physico-chemical differences of the components. Preferably, the more potent isomer is isolated.

The invention also relates to those embodiments of the process wherein the starting materials are compounds obtained as intermediates at any stage of the process and carrying out the missing reaction steps, or wherein the starting materials are formed under the reaction conditions or at which they are used in the form of their derivatives, as their salts and / or in the form of mixtures of isomers or isomers.

It is expedient to use for the reactions according to the invention starting materials which lead to groups of reaction products, especially mentioned at the beginning, and in particular to especially described or emphasized final materials.

Pharmaceutical compositions of the invention which contain compounds of formula I or pharmaceutically acceptable salts of such compounds with salt-forming groups are those for enteral administration such as oral or rectal, as well as parenteral administration to warm-blooded dogs which contain a pharmacologically active substance alone or together with a pharmaceutically acceptable carrier material.

The novel pharmaceutical preparations contain about 10% to about 95%, preferably from about 20% to about 90% of the active ingredient. The pharmaceutical preparations of the invention may be used in the form of dosage units such as dragees, tablets, capsules, suppositories or ampoules.

The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes. Thus, pharmaceutical preparations for oral administration can be obtained by combining the active ingredient with solid carriers, the resulting mixture optionally granulated and the mixture or granulate. optionally or after addition of suitable excipients, it is compressed into tablets or dragee cores.

Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example calcium phosphate or middle calcium phosphate or binders, such as greasy starches, for example corn, wheat, rice or potato starch. gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / or optionally disintegrants such as the above-mentioned starches, further carboxymethylated starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate, such as, for example, flow regulators and lubricants, for example silicic acid, talc, stearic acid or its salts, such as magnesium or calcium stearic acid and / or polyethylene glycol.

Dragee cores are provided with suitable coatings, optionally resistant to gastric juice, containing, inter alia, concentrated sugar solutions which optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide.

Furthermore, a solution of lacquers in suitable organic solvents or solvent mixtures, or for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, is used. The coated tablets or dragee cores may contain admixtures of dyes or pigments, for example to identify or distinguish different doses of the active ingredient.

Other orally administrable pharmaceutical formulations are gelatin insertable capsules as well as soft sealed gelatin capsules and a plasticizer such as glycerin or sorbitol. The push-fit capsules may contain the active ingredient in the form of a granulate, for example in admixture with fillers, such as lactose, binders, such as starches and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is dissolved or suspended preferably in suitable liquids such as fatty oils, paraffin oil or liquid polyethylene glycols, and stabilizers may also be added.

Particularly suitable for parenteral administration are aqueous solutions of the active compound in water-soluble form, for example in the form of a water-soluble salt, as well as suspensions of the active compound, such as corresponding oily injection suspensions, using suitable lipophilic solvents or other agents such as fatty oils. , for example, sesame oil or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injectable suspensions containing viscosity enhancers, for example sodium carboxymethylcellulose, sorbitol and / or dextran, and optionally also stabilizers.

The compounds of the formula I according to the invention or their pharmaceutically usable salts can be used as pharmacologically active substances, in particular as anti-inflammatory agents as well as analgesics, preferably in the form of pharmaceutical preparations. The dose of the effective dose depends on the species of warm-blooded individual, body weight and age and the individual condition as well as the mode of administration. On average, a warm-blooded individual weighing about 70 kg is administered a daily dose of from about 50 to about 200 mg, preferably from about 75 to about 150 milligrams of active ingredient.

The following examples illustrate the invention described above. However, these examples are not intended to limit the scope of the invention in any way. Temperatures are given in degrees Celsius.

Example 1

To 4.0 g of 2-methyl-N - [(2-hydroxybenzoylmethyl) -3,4-dihydro-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide and 1,4 g of sodium formate, 10 ml of mixed formic anhydride and acetic anhydride are added under stirring at room temperature, the mixture is allowed to stir for 1 hour and then heated at 100 DEG C. for 3 hours, then cooled to room temperature and 200 ml of cold water are added. methyl 4-oxo-N- (4-oxo207762)

-4H-1-benzopyran-3-yl) -3,4-dihydro-2H-1,2-benzothiazine-1,1-dioxide was separated and purified. Finally chromatography on silica gel. The product melts at 280 °.

For example, the starting material can be prepared from α-amino-2-hydroxyacetophenone and 2-methyl-4-oxo-3,4-dihydro-1,2-benzothiazine-3-carboxylic acid methyl ester 1,1-dioxide (m.p. 258 DEG, from dimethylformamide / ethanol = 1: 10.

Example 2

The following compounds can also be prepared by the procedure of Example 1:

2-Methyl-3,4-dihydro-4-oxo-N- (4,6,7,8-tetrahydro-4-oxocyclopenta [g] -1-benzopyran-3-yl) -2H-1,2- benzothiazine-3-carboxamide-1,1-dioxide, m.p. 293-295 °,

2-methyl-3,4-dihydro-4-oxo-N- (4-oxo-6-methyl-4H-1-benzopyran-3-yl) -2H-1,2-benzothiazine-3-carboxamide-1; 1-dioxide, m.p. 272-275 °,

2-methyl-3,4-dihydro-4-oxo-N- (4-oxo-8-methyl-4H-1-benzopyran-3-yl) -2H-1,2-benzothiazine-3-carboxamide-1; 1-dioxide, m.p. 303-305 ° C;

2-Methyl-3,4-dihydro-4-oxo-N- (2-oxo-4-hydroxy-6-methyl-2 H -1-benzopyran-3-yl) -2H-1,2-benzothiazin-3- carboxamide-1,1-dioxide, melting point 279 ° (decomposition),

2-Methyl-3,4-dihydro-4-oxo-N- (4-oxo-6-chloro-8-methyl-4H-1-benzopyran-3-yl) -2H-1,2-benzothiazin-3 -carboxamide 1,1-dioxide, m.p. 292-295 °,

2-methyl-3,4-dihydro-4-oxo-N- (4-oxo-6,7-dimethyl-4H-1-benzopyran-3-yl) -2H-1,2-benzothiazine-3-carboxamide- 1-dioxide, m.p. 292-297 °,

2-methyl-3,4-dihydro-4-oxo-N- (4-oxo-6-methoxy-4H-1-benzopyran-3-yl) -2H-1,2-benzothiazine-3-carboxamide-1; 1-dioxide, m.p. 272-276 °;

2-Methyl-3,4-dihydro-4-oxo-N- (4-oxo-5,7-dimethyl-4H-1-benzopyran-3-yl) -2H-1,2-benzothiazine-3-carboxamide- 1,1-dioxide, m.p. 286-291 ° (dec.),

2-Methyl-3,4-dihydro-4-oxo-N- (2-oxo-4-hydroxy-6-chloro-2H-1-benzopyran-3-yl) -2H-1,2-benzothiazine-3- Carhoxamide 1,1-dioxide

2-Methyl-3,4-dihydro-3-oxo-N- (2-oxo-4-hydroxy-6,8-dichloro-2H-1-benzopyran-3-yl) -2H-1,2-benzothiazine- 3-carboxamide-1,1-dioxide,

2-methyl-3,4-dihydro-4-oxo-N- (2-oxo-4-hydroxy-4,6,7,8-tetrahydro-cyclopenta [g] -2H-1-benzopyran-3-yl) -2H -1,2-benzothiazine-3-carboxamide-1,1-dioxide a

2-Methyl-3,4-dihydro-4-oxo-N- (2-oxo-4-hydroxy-8-methyl-2H-1-benzopyran-3-yl) -2H-1,2-benzothiazine-3-carboxamide- 1,1-dioxide,

2-methyl-3,4-dihydro-4-oxo-N- (2-oxo-4-methyl-2H-1-benzopyran-7-yl) -2H-1,2-benzothlazine-3-carboxamide-1; l-dioxide, melting point above 285 °,

4-oxo-N- (4-oxo-4H-1,4-benzopyran-3-yl) -3,4-dihydro-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, m.p. 288-290 ° C,

2-ethyl-4-oxo-N- (4-oxo-1,4-benzopyran-3-yl) -3,4-dihydro-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide,

2-allyl-4-oxo-N- (4-oxo-4H-1,4-benzopyran-3-yl) -3,4-dihydro-2H-1,2-benzothiazine-3-carboxamide-1,1- dioxide, m.p. 200 ° C.

Example 3 g 2-methyl-4-oxo (N-4-oxo-4H-1,4-benzopyran-3-yl) -3,4-dihydro-2H-1,2-benzothiazine-3-carboxamide-1,1 -dioxide is dissolved in a mixture of 125 ml of 0.1 N sodium hydroxide solution and 100 ml of methanol at 50 DEG C. The solution is cooled to 5 DEG C. and the yellow crystals of sodium salt of 2-methyl-4-oxo-N- (4- oxo-4H-1,4-benzopyran-3-yl) -3,4-dihydro-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, m.p. 240 DEG-245 DEG C. (dec.); isolate.

EXAMPLE 4 g 2-Methyl-4-oxo-N- (4-oxo-4H-1,4-benzopyran-3-yl) -3,4-dihydro-2H-1,2-sodium salt monohydrate -benzothiazine-3-carboxamide-1,1-dioxide is dissolved in 900 ml of methanol and 400 ml of water and a solution of 1.65 g of zinc sulphate dihydrate in 50 ml of water is added. 2-Methyl-4-oxo-N- (4-oxo-4H-1,4-benzopyran-3-yl) -3,4-dihydro-2H-1,2-benzothiazine-3-carboxamide- m.p. 280 DEG C. (decomposition).

Example 5 g of 2-methyl-4-oxo-N- (4-oxo-4H-1,4-benzopyran-3-yl) -3,4-dihydro-2H-1,2-benzothiazine-3- sodium salt monohydrate of carboxamide 1,1-dioxide are dissolved in 1000 ml of methano2D7762

2 ml of water and 200 ml of water and a solution of 1.2 g of copper (II) acetate is added to this solution. The copper salt of 2-methyl-4-oxo-N - (+ ηχ-4Η-β, 4-benzopyrah-3-yl) -3,4-dihydro-2H-1,2-benzothiazine-3-carboxamide is obtained. 1,1-dioxide having a melting point above 300 ° C.

Examples' Η I · -: PI 1 N 'i \ f:' - ‘i o i. : i '·. · I ’.} ''

Tablets containing 25 mg of 2-methyl-3 ', 4-dl-hydro-4-oxo-N- (4H-1-benzopyran-3-yl) -2H-1,2-biphazole-thiazine-3-carboxamide- l, l-dio ^, ions; ⁱ can be produced, for example, as follows: ^{11 (}

Ingredients (for 10,000 tablets)

2-methyl-3,4-dihydro-4-OKo ¹ -N- (4H-1-benzopyran-3-yl) -2H-1,2- '

-benzothiazine-S-carboxamide-4-di-. ,,.

oxide (active látkaj ^{Υ, Γ χβ IHL} Ž'5Íí ^b '^ lactose.. ", 460 g of corn throttled,' ¹⁶⁵⁰ g polyvinyrpýřFřjlídóii ^'H · ^{β' 1} 'magnesium salt' ^J ^ tíý§éftiiy you BVA ^{1 !, I} g '' kol kol kol ig ig ig ig ig ^ ^ ^ ^ _{W W W W W} , _{W W W} b b b b b b Tis Tis

Active substance; ^One log of starch is mixed and the mixture is moistened with an aqueous solution of polyvinylpyrrolidine. The graft is zeroed, the granulate is dried, and the magnesium stearate salt, colloidal silicon dioxide and the rest of corn are added to the granules.

bjnnis udίβ i-ll ni ;; 1, U Η cS ;. btóiitt: ίίΠ UU L li miltothot ')'.

sv flaufιχόί; -ih nbixo

P ^! R Ϊ k'V s VU ^from D ¹ - ^'! to η: rioísoS, ίΓ 06 riq iiioríBíílmn of dbéip úákď ^^ ^ ^^ O ^ is Ah ^[y ^ BC AII ^^^ W ^ iii ^ he ^ if & ýýrptíiť tábíety contents ^ RE + vžcfý -tíg ^ ^{'! ! 'Ar} ^ ^ .07 (01,000 UF-oj -noí I: UhlXf.iiD-l., X-u i híffífiftOtbiBá .iXoid ÍOXHtíd' S-iŮMhýF ^{JJs-tifH-dihydro-I-B-b-RFi! J 'RII' d} - (4,6,7,8-tetrahydro-4-oxocyklopenta- [g] -l-benzopyran-3-yl) -2H-l, 2-Ben & ^{8 '8' 8} zothiazin-3-carboxamide -1,1-dioxide, '^no;·'Gibraltar;

í: ^v . G 1 jb ^! / <, ib :. _; , i i i .: - ,, · -, ^L1 ->'/<, š - j j kj i.! 77 '

2-methyl-3,4-dihydro-4-oxo-N- (4-oxo-6-methyl-4H-1-benzopyran-

3-yl) -2H-l, ^2-and 3--tie'nzothiazm carnauba ⁱ '· -carboxamide-L, 1-dioxide, ¹ ...... ^{.. ·!}

2-methyl-3,4'-dih ^, ydro-4m'Xt) ⁱⁿ N- ¹ '- ¹ '

- (4-t-DXO (-théthýÍ-4PI-i-behžůpýťáh-3-yl) -2H-1,2-benzothiazine-3-car- ^'' -carboxamide-l, l-dioxide, ';' -pyran 3-yl-2H-1,2-beiisothiazine-3-carboxamide dioxidium,

2-methyl-3,4-dihydro-4-oxo-Nd (4-tíxĎ6miěthbxy-'l-4H-benzopyran-3-yl) -2H-.l, ^{2-benzotbiazln-3-car-; about} :; : -1-boxamide, 1,1-dioxide, --....- h, -o '24-phthyl-3,4-dihydro-4-oxo-N-' ···

- ^{(4-oxo-5,7-dimethyl-4H -ld3eitíí0-:!} · Pyran-3-yl j -2H-l, 2-benzothiazine-3-carboxamide-l, l-dioxide, - ^Í! · ' · I 7 i 1 '

Z-Methyl-S-α-diltydro-4-oxo-N- ¹ -molar

- (2-oxo-4-6 hydřtíXý ^{j i} r dhló 2H'-x L ^{i -; 1>} 1 ^{1 '1} 1 ^1>

benzopyran-3-yl] -2H-1,2-benzothiazine-5-carboxamide-11-dioxide; 0 / :, 0.0!

2-methylphenyl] -3,4 dihydro ^for <3 PXO ¹¹ N - ^(2-OXB! - ^ - h ⁱ YD-t (! RxY ^{i-6-S-díéíl} LDR-Ž.Hh! - ^{i? 1} »benzopyran-3-yl) -2H-l, 2-benzothiazine ¹ '-3-carboxamide-l, l-dioxide,

- if υ x 11 Í-- (; ii í - v i!.: t j - ø, c -1 '([.1 .i o 11 i - S

2-méťhyh3, ^ ^'d®BýSř! the ^{L-4-átíO'-! Ni} - ^{i J l!} · ^F - 0 - <xo - i - i

- (2-oxa-4rhýď! Íldxý ^IL _{4y617; T-8} TBTT ^S ·· ahýd ^i! 'I id íý.1 Is rocyklopentafg) ^and l- -§H- ^b: běiižiíípyřá'ň! - ^f i' i 1 ', 3'-3'-yl-2H-1,2-benzothiazine-3-carboxamide-11'-dioxide, ¹ ' - ¹ '- 1'-nitro-,-ϋ dioxidΓϋίίϋ-ο

J in G7y'Qu (id. Ks--7Π kil Π · Β-UXD-1: | | ^^ thf thf--Q Qhydhydhydhydhydhydhydhydhydhydhydhydhydihihihihihihihih 2 2 2 2 2 2 2 2 2 2 oxo-4-hydroxy-8-2H-měfhýl - L ^{'-; Η1 | ΐΐ} ojoliio: benzopyran-3-yl] -2H-l, 2-3-b3nzothiazin karhdíkai®rdýl ^|, Tjdltík? Importan and ΐ ροοί! i ioiíioií US- t i / ([Ιοί! ι ί γκο'ΐίι knows about ί-R- / tk - oj ^2-L méllhýí 3Í4- ¹ dlhýdřb- ^{1-4H-'dxlD3N i} - ⁱ s - (L 'i of ^11'! P - ⁽ⁱ 2 ⁱ 4 ¹ bšld 'iiiéttíý -2H ¥ ⁱ l ^J Wéáiž0jyÍÉáHab U -bonn 7-y 1 j -2H-l, 2-benzothiazine-3-carboxamide-l Ditoxidabblybutylbutylbutylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylblue since the b, jt;,. s HO {iv bi ^{'1'., '1'} 0-1 irifí! i .mu.L (jt! Í JjjXlhti-n,.! analogous manner as described in Example 6, lÚbritrtř ^ ýyFtíbiť-tabáRWhlaty ObšáflŮjíS ^ UUG ⁰ '- · ίγίίόίί, οΟ t / rl-oxo PJI - i Ijl and BTL 0: 1; those i.e. - i - II i II i i II itiltí 1 - OI' Ο, ί -, ΗΗΗ-methyl N JŠiWíěr Hriéířtíyí ^ ^ O ³ - 'Jjnunh oxo-4H-benzopyran-3-yl) -4-oxo-3,4-dihjrdro-4H- ⁱ - ^B} ^ © iéf6p iíáiÍ 3iyl · ^t ) ^L '' ¹ ' ¹ ' ¹⁵ ' ^s -3-carbamoxamide-1,1-dTOxideH', '' dj-u <uu, 1-% d kilo <> dd i -He

2-methyl-5'-dihydro-6-oxo-4 '- (6' - 1 '⁾;

chloro-7-methyl-4-oxo-4H-benzopyran-3-yl) -2H-1,2 ^from benzo1! h'iázin-3 ';^; -kárbdxamid m-l, l-dioxide, · mottóhydráth sodium 2-4- mfitliyl - ^{'·: ::!} 1'-oxo-N- (4-oxo-4H-1,4-benzopyran-3-yl) -3,4-dihydro-2H-1,2-benzothiazole-3-carboxan-1-one; I ^dioxide;! - of ·;

2-Methyl-3,4-dihydro-4-oxo-N- (2-oxo-4-hydroxy-6-methyl-2H-1-benzopyran-3-yl) -2H-1,2-benzothiazine-3- carboxamide-l, l-dioxide, '''2-methyl-3,4-'hyl ^{L dlhydro--: 4boxo-N} - (4-oxo-6,7-dimethyl-4H-benzohydrátu sodium 2 ^{1-methyl-3,4-dihydro-4-oxo-N-} (4,6,7,8-tetrahydro- 4-oxo-cyclopent [g | -1-benzopyran-3-yl) -2H-l, 2-benzothiazine -3-car- '-carboxamide t-l / ^l-dioxide,! hydrate of the sodium salt of 2-methyl-3.4207762

2Ϊ 22

dihydro-4-oxo-N- (4-oxo-6,7-dimethyl-4H-1-benzopyran-3-yl) -2H-1,2-benzothiazine-3-carboxamide-1-dioxide sodium salt hydrate 2-methyl-3,4-n-dihydro-4-oxo-N- (4-oxo-6-methoxy-4H-1-benzopyran-3-yl) -2H-1,2-benzothiazine-carboxamide-1, 1-dioxid :; ^;

2-Methyl-3,4-dihydro-4-oxo-N- (4-oxo-5, 2-dimethyl- ^; 4H-1-benzopyran-3-yl) -2H1,2-benzothiazine- 3-carboxamide-1,1-dioxide, methyl 3,4-dihydro-4-oxo-N- (4-oxo-8-isolinyl-11,11-1-benzopyran-3-yl) -2H-1,2-benzothiazine- 3-carboxamide-1,1-dioxide, sodium salt of 2-methyl-3,4-dihydro-4-oxo-N- (4-oxo-8-methyl-1H-1-benzopyran-3-yl) 2-methyl-3,4-dihydro-4-oxo-N-4-oxo-6-methyl-2-methyl-2-benzothiazine-3-carboxamide-1,1-dioxide; - + - ^ H ^ lAběnžopyrániS ýrj-zh ^ i ^ · Ben 'Zoth i and ^yn -3-k i d rboxami -1,1 -di ^oxide:?

4-οχο · · Ν (4-oxo-4H-l / l-bunzopyran-3-one] LT, td il! Yd; 'o ^2H-Y) 2 -bcnzo- ^-'-:; thiaziiix-1-carboxamide-1,1-dioxide, ^-H- 1-ethylbenzene N-11-ol-11H-11-benzo [d] Tau-3-yl) -3,4-diliydro-2H-1,2-, + • bcnzotliiazinO 1boxamid-ka-1,1-di - oxides and ''^{'! i7} - ++ from ·· - ·· ++ ¹ 2-allyl-4-oxo-N- (4-oxo-4H- 1,3-bonzopyran-3-yl) -3-, 4-dibydrul-2 H -1,2,2-behzothiazine-3-carboxamide-1,1-dioxide.

Example 11 + '·'

The following compounds can be prepared in an analogous manner to that described in Example 3: 2-methyl-3,4-dlhydro-4-oxo-N- (4-oxo-6-methoxy-4H-1-benzopyran-) sodium salt hydrate 3-yl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, m.p. 235-239 ° C, 2-methyl-3,4-dihydro-4-oxo-N sodium salt hydrate (4-oxo-5,7-dimethyl-4H-1-benzopyran-3-yl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, m.p. 234-238 ° C; !

sodium 2-methyl-3,4-diliydro-4-oxo-N- (4-oxo-8-methyl-4H-1-benzopyran-3-yl) -2H-1,2-benzothiazine-3-carbohydrate ^: -carboxamide-l, l-dioxide, mp 239-241 ° C, sodium salt hydrate, 2-mcíhyl dihýdFO-3,4-4-oXO-N! - (4-oxo-6-fflethyl- - ^4H- 1-benzopyran-3-yl} -2H-1,2,2-benzoethyl-3-carboxamide-11-di-oxide, m.p. 235-233 ° C, ^1- sodium monohydrate 2-methyl · -3,4-dihydro-4-oxo-N- (4-oxo-4,6,7,8 + ^1);

-tetrahydroeyklopentaj g] ·! -benzo · -pýřaft-3-yl) -2 - l 2 + benzoíliiazirů3- - '-carboxylic Box η id i -1, l-diolidui, ^1:;! ' ^! - ^;! mp 240-241 ° C, sodium salt hydrate 2 ^; Methyl-3,4-dihydro-4-oxo-N - (4-oxo-6,7 + dimethyl-4H-1-benzopyran-3-yl) -2H-1,2-benzothiazine-3-carboxamide-1 260 DEG-261 DEG C. 2-methyl-N- (6-chloro-7-methyl-4-oxo-4H-1-benzopyran-3-yl) -4-oxo-sodium monohydrate M.p. 239-241 A1; 3,4- + - (3-methyl-4H-menopyrari-3-yl) -3-carboxamide-1,1-dioxide.

Claims (6)

SUBJECT A process for the preparation of the novel 3,4-dihydro-2H-1,2-benzothiazine-1,1-dioxides of the general formula I wherein: R is a benzopyrone radical optionally substituted by one or more C1-C4 lower alkyl, C1-C4 lower alkylene, C1-C4 lower alkoxy, halogen and / or trifluoromethyl groups, and R 1 is hydrogen, C 1 -C 4 lower alkyl, C 1 -C 4 lower alkenyl, C 1 -C 4 hydroxy (C 1 -C 4) alkyl or (C 1 -C 4 lower) alkoxy (C 1 -C 4 alkyl) carbon in the alkoxy and alkyl moieties, and salts thereof, characterized in that in a compound of formula II R ‘represents a residue which is cyclizable to an optionally substituted benzopyrone radical R a R 1 is as hereinbefore defined, or in its salts cycles the radical R 1 to the radical R, whereupon optionally the salt obtained by the process of the invention is converted into a free compound or another salt or the salt obtained by the process of the invention is converted into a free compound. 2. A process according to claim 1, wherein the compound of formula (II) wherein: R 'is a radical of the formula Hal -CEZ- C ^(=! Oj- Ph-O-C ™ (= O) -R ₆ (Hal) OF THE INVENTION where R 6 represents hydrogen or a lower alkyl group having 1 to 4 carbon atoms and Ph is optionally lower alkyl having 1 to 4 carbon atoms, lower alkylene having 1 to 4 carbon atoms, lower alkoxy having 1 to 4 carbon atoms, halogen and / or trifluoromethyl substituted 1,2-phenylene or pyridyl, R1 is as defined in point 1, or in its salts, cyclizes the radical R @ 1 under basic conditions to the radical of formula Ha (Ha) wherein: Ph and R 6 are as defined above. 3. Process according to claim 1 or 2, characterized in that the compounds of the general formula (II) are used as starting materials R ‘represents a radical of formula Hal in which R 5 represents hydrogen or a lower alkyl group having 1 to 4 carbon atoms and Ph is unsubstituted or lower alkyl having 1 to 4 carbon atoms, lower alkoxy having 1 to 4 carbon atoms, or halogen having an atomic number of up to 35 substituted 1,2-phenylene, and R 1 represents hydrogen or a lower alkyl radical having 1 to 4 carbon atoms, or salts thereof. 4. The process according to claim 1 or 2, wherein the starting materials used are the compounds of the general formula IIb in which R2 represents hydrogen or a lower alkyl group having 1 to 4 carbon atoms, Re is hydrogen, R 1 and R 5 independently represent hydrogen, a lower alkyl group of up to 4 carbon atoms or a lower alkoxy group of 1 to 4 carbon atoms, or together represent a 3 or 4-membered lower alkylene group having up to 4 carbon atoms; 4 carbon atoms bonded to adjacent carbon atoms, or salts thereof. 5. A process according to claim 4, wherein the starting material is a compound of formula (IIb) in which R2 represents a lower alkyl group having 1 to 4 carbon atoms and R 1 and R 5 are each independently hydrogen, C 1 -C 4 lower alkyl or C 1 -C 4 lower alkoxy; and R e is as defined in point 4, or a salt thereof. 6. The process according to claim 4, wherein the starting material is a compound of formula IIb wherein: R2 is methyl and R 1, R 5 and R 6 represent hydrogen, or a salt thereof.