NO163275B - HALF-SUBMITTED PLATFORM. - Google Patents

Description

Analogy methods for producing therapeutic effect

some 4H-3,1-benzothiazine derivatives and 4H-3,1-benzoxazine-

derivatives.

The invention relates to analogous methods for the production of 3,1-benzothiazine and 3,1-benzoxazine derivatives with valuable pharmacological properties.

The invention therefore relates to analogous methods for the preparation of therapeutically effective 4H-3,1-benzothiazine derivatives and 4H-3,1-benzoxazine derivatives of the general formula I in which A means oxygen or sulphur, R means hydrogen, a lower alkyl-, cycloalkyl- with 5- 7 C atoms, phenyl, phenyl-lower alkyl, low molecular weight dialkylaminoalkyl, piperidino-lower alkyl or pyrrolidino-lower alkyl group, means hydrogen, halogen, trifluoromethyl or methoxy, and R~ means alkyl, phenyl-lower alkyl or phenyl residues, wherein the phenyl ring may be substituted with halogen atoms, methoxy or trifluoromethyl groups, as well as their acid addition salts with inorganic or organic acids, and the method is characterized by either

a) reacts with compounds of the general formula II

in which R 1 and R 2 have the meaning given above, and X means a chlorine or bromine atom, a hydroxyl, sulfhydryl, alkoxy, alkylthio or alkanoyloxy group with thiourea of the general formula Illa in which R has the meaning given above, and the two residues R can be the same or different, or with isothiocyanates of the general formula IIIb in which R has the above meaning, resp. corresponding isothiocyanate formers, optionally with the addition of acids and/or water-splitting agents, or reacts compounds of formula II, in which X means a chlorine or bromine atom, a hydroxyl, alkoxy or alkanoyloxy group with the isocyanate of the general formula Ille

in which R has the above meaning, or corresponding isocyanate formers, optionally with the addition of acids and/or water-splitting agents, or

b) treats compounds of the general formula IV

in which A, X, R, R^ and R^ have the above meaning, resp. corresponding functional derivatives of these ureas and thioureas, possibly ur..<:>?r simultaneous or subsequent acid treatment, with hydrogen sulphide, inorganic sulphides or water splitting agents when A means an oxygen atom, or reacting with sulfur splitting agents when A means a sulfur atom, or

c) reacts with compounds of the general formula V

in which R-^ and R^ have the meaning given above, and R^ means a chlorine or bromine atom, a sulfhydryl or S-alkyl group with amines of the general formula VI or their salts in which R' has the meaning of R with the exception of hydrogen . , which within the scope of the meaning of R can also be ring-closed, with complex metal hydrides, and if R^ means a haloalkyl radical react the obtained compounds with dialkylamines, which within the meaning of R can also be ring-closed, or e) react compounds with the general formula II, in which X means a chlorine or bromine atom, a hydroxyl, alkoxy or alkanoyloxy group, and and has the meaning given above, with halocyanos of the general formula VIII in which Y means a chlorine, bromine or iodine atom, optionally during subsequent acid treatment, or f) reacts compounds with the general formula I, in which A means an oxygen atom, and R, R-^ and R 2 have the meaning indicated above,

with hydrogen sulfide or inorganic sulfides,

and if desired reacts process products in which R means hydrogen with amines or reactive. derivatives of alcohols to such compounds in which R has one of the other meanings mentioned above, and/or if desired transfer the formed basic compounds by treatment with inorganic or organic acids in their acid addition salts.

For the reaction according to a), 2-amino-benzhydrols come into consideration as starting substances with the general formula II, for example. These include: 2-aminobenzhydrol, 2-amino-fluorobenzhydrol, 2-amino-chlorobenzhydrol, especially 2-amino-5~ chlorobenzhydrol, 2-aminobromobenzhydrol, 2-amino-methoxybenzhydrol, 2-amino-trifluoromethylbenzhydrol, 2- amino-methoxy-chlorobenzhydrols, 2-amino-trifluoromethyl-chlorobenzhydrols, in that the substituents mentioned in connection with "2-amino-" can be in 3-,

4-, 5- or 6-position of one and/or in the 2'-, 3'- or 4'-position of the other benzene ring, as well as 2-amino-chloro-dimethoxy-benzhydrols or 2-amino-methoxy -dichlorobenzhydrols, each of the substituents mentioned in connection with "2-amino-" can be in the 3-, <*>*-, 5- or 6-position of the benzol ring, which has the amino group and two in the 2'-, 3 '-, 4'-, 5'- or 6'-position of the second benzene ring. Furthermore, the corresponding lower O-alkyl ethers such as 2-amino-benzhydryl methyl ether, -ethyl ether, or the corresponding esters with lower aliphatic carboxylic acids can be used for the above-mentioned benzhydrols, e.g. the acetates or propionates of the aforementioned benzhydrols. The corresponding halides, such as 2-aminophenyl-phenyl-chloro- (resp. -bromo)-methane as well as the corresponding substituted compounds in the phenyl residue, for the preparation of benzothiazines also the corresponding mercaptans and lower alkyl thioethers such as 2-amino-phenyl- phenyl-methyl mercaptan or the corresponding lower alkyl thioethers can also be used.

Furthermore, α-alkyl-2-aminobenzyl alcohols and also α-aralkyl-2-aminobenzyl alcohols come into consideration as starting materials of the general formula II. These include: α-methyl-2-aminobenzyl alcohol, α-methyl-2-aminofluorobenzyl alcohols, α-methyl-2-aminochlorobenzyl alcohols, α-methyl-2-aminobromobenzyl alcohols, α-methyl-2-aminomethoxybenzyl alcohols, α-methyl-2- aminotrifluoromethylbenzyl alcohols, α-ethyl-2-aminobenzyl alcohols, α-ethyl-2-aminochlorobenzyl alcohols, α-ethyl-2-aminomethoxybenzyl alcohols, α-ethyl-2-amino-trifluoromethylbenzyl alcohols, α-propyl-2-aminobenzyl alcohol, a-propyl-2-aminochlorobenzyl alcohols, a-isopropyl-2-aminobenzyl alcohol, o-isopropyl-2-aminobromobenzyl alcohols, a-isopropyl-2-amino-methoxybenzyl alcohols, a-butyl-2-aminobenzyl alcohol, a-butyl-2- aminochlorobenzyl alcohol, α-isobutyl-2-aminobenzyl alcohol, α-isobutyl-2-aminochlorobenzyl alcohols, α-benzyl-2-amino-benzyl alcohol, α-benzyl-2-aminochlorobenzyl alcohols, α-benzyl-2-aminomethoxy-benzyl alcohol, where appropriate those in attachment to "2-amino-" said substituents can be in the 3-, 4-, 5~ or 6-position of the benzene ring.

Furthermore, the corresponding lower O-alkyl ethers or the corresponding esters with lower aliphatic carboxylic acids can be used for the mentioned benzyl alcohols, e.g. the acetates or propionates of the aforementioned benzyl alcohols.

The corresponding halides such as methyl-2-aminophenylchloro-(resp. -bromo)-methane as well as the corresponding substituted compounds in the phenyl residue for the preparation of benzothiazines also the corresponding mercaptans and lower alkyl thioethers such as α-methyl-2-amino-benzyl- mercaptan or the corresponding lower alkyl thioethers can likewise be used.

The salts derived from the aforementioned basic compounds

with strong acids such as hydrohalic acids, sulfuric acids as well as benzene or toluene sulphonic acids are also suitable as starting materials.

As starting materials of the general formula IIIa, thiourea and its N-mono- and N,N'-disubstituted derivatives such as N-methyl-, N-ethyl-, N-propyl-, N-isopropyl-, N-butyl -, N-isobutyl-, N-hexyl-, N-cyclohexyl-, N-allyl-, N-cyclohexenyl-, N-phenyl-, N-benzyl-, N-diethylaminoethyl-, N-dimethylaminopropyl-, N,N '-dimethyl-, N,N<*->diethyl-thiourea, while isothiocyanates such as methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, hexyl-, cyclohexyl, allyl, cyclopentenyl, phenyl, benzyl, dimethylaminoethyl, piperidinoethyl, diethylaminopropyl, pyrrolidinopropyl isothiocyanate. Furthermore, it replaces the isothiocyanates as well

considering isothiocyanate formers such as the corresponding thiourethanes or dithiocarbamic acid esters.

Isocyanic acid and isocyanates such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, hexyl, cyclohexyl, allyl, cyclohexenyl, phenyl, benzyl, dimethylaminopropyl isocyanate, further isocyanate formers are taken into account (compare Houben Weyl "Methoden der organischen Chemie" 4th edition, volume 8, pages 119-127) such as the corresponding carbamic acid chlorides and urethanes.

The reaction of the compounds of the general formula II, as well as their acid addition salts with the thioureas of the general formula IIa according to a) takes place at temperatures from 20-250°C, preferably 80-180°C.

You work in the presence of inorganic or organic acids, e.g. halogenated acids, such as hydrochloric acid, hydrobromic acid and hydroiodic acid, further sulfuric acid, phosphoric acid, lower aliphatic carboxylic acids such as formic acid and acetic acid, halogenated carboxylic acids such as chloroacetic acid, trifluoroacetic acid as well as benzene and toluenesulfonic acid or their mixtures. One can also possibly work in the presence of water-splitting agents, e.g. inorganic acid halides and

-anhydrides such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, thionyl chloride or phosphorus pentoxide, further zinc chloride and boron fluoride. The isothioronium salts of the general formula II, in which X represents the radical -S-CtNH^)^^ appearing in the reaction of compounds of the general formula II with thioureas of the formula IIIa, are not usually isolated, as under the reaction conditions they easily pass into the process products.

The reaction of the compounds of the general formula II with the compounds of the general formulas Illb and Ille takes place at temperatures of 0-200°C, preferably 20-130°C. Intermediately formed urea resp. thiourea derivatives, which if desired can be isolated as intermediates, are conveniently transferred in connection with treatment of the reaction mixture or the isolated intermediate compound with inorganic or organic acids or with water-splitting agents in the process products where the degree of the reaction rate elevated temperatures can be advantageous.

As additional solvents or diluents may

water, lower alcohols such as methanol, ethanol,

isopropanol, ether such as diethyl ether, tetrahydrofuran, dioxane, further glycol, glycol monomethyl- and -ethyl ether, di- and triethylene glycol as well as aromatic hydrocarbons such as benzene, toluene, xylol or chlorohydrocarbons, such as chlorobenzene, chloroform, trichloroethylene or tetrachloroethane, the selection of the suitable solvent or diluent is determined by the stability and reactivity of any reaction components.

Por the reaction of benzhydryl halides of the general formula II (<v>" = Cl, Br) or their acid addition salts with the compound of the general formulas IIa, IIb and IIe is usually the presence of acids or water splitting agents for cyclization of the intermediates formed urea or thiourea derivatives not necessary These reactions can preferably be carried out in a melt or by heating in a suitable solvent.

The reaction times are variable within wide limits, depending on the reactivity of the components and the chosen temperatures. For processing, the reaction products with the general formula I, which are mostly formed as salts, can be isolated directly after evaporation of the solution and, if desired, transferred into the free bases by subsequent treatment with alkali. You can also make the reaction mixture alkaline before isolation, whereby the process products can be isolated in the usual way in the form of the free bases.

The starting substances with the general formula IV, in which A means an oxygen atom, which are necessary for the reaction according to b), are reached by e.g. reacts compounds of the general formula II, in which X means a halogen atom, a hydroxyl, alkoxy, alkanoyloxy or alkylthio group, with isocyanates of the general formula R-N=C=0, where R has the above meaning.

Instead of compounds with the general formula IV, in the reaction according to b), functional derivatives of these urea substances can also be reacted to process products, e.g. compounds, which instead of the urea group contain its advantages, such as the carbodiimide group, the guanidino or chloroformic amidine group.

While the treatment of the aforementioned compounds with formula

IV with acids or water-splitting agents leads to benzoxazines, with hydrogen sulphide or inorganic sulphides such as alkali sulphides or phosphorus pentasulphide or their mixtures the corresponding benzothiazines are obtained. This reaction is carried out at temperatures of 50 to 200°C, preferably 80 to 160°C, optionally with the addition of acid and the use of an organic solvent, for example an aromatic hydrocarbon such as benzene, toluene or xylol or an aliphatic or aromatic chlorohydrocarbon such as tetrachlorocarbon3 tetrachloroethane or chlorobenzene . Particularly advantageous, however, is the use of pyridine as solvent. Depending on the boiling point of the solvent used, as well as the required reaction temperature, especially when hydrogen sulphide is used, the reaction can possibly be carried out under pressure.

Ureas of the general formula IV, in which X means the sulfhydryl group, can also be transferred into the process products by reaction with water-splitting agents such as inorganic acid halides and anhydrides.

The starting materials f required for the reaction according to b) are of the general formula IV, in which A means a sulfur atom, one arrives by e.g. reacts compounds of the general formula II with isothiocyanates of the general formula R-N=C=S, R having the above meaning. For this, isothiocyanates such as methyl-, ethyl-, propyl-, .isopropyl-, butyl-, isobutyl-, hexyl-, cyclohexyl-, allyl-, cyclopentenyl-, phenyl-, benzyl-, dimethylaminoethyl-, piperidinoethyl-, N -methylpiperazinoethyl-, diethylaminopropyl-, pyrrolidinopropyl. Furthermore, instead of isothiocyanates, isothiocyanate formers are also considered (compare Houben-Weyl "Methoden der organischen Chemie, H. edition, volume 9, pages 867-878) such as the corresponding thiourethanes or dithiocarbamic acid esters.

The desulfurization of the thioureas with the general

formula IV takes place by reaction with sulphur-decomposing agents such as heavy metal oxides or heavy metal salts, e.g. mercuric oxide, silver oxide, lead oxide, arsenic trioxide, lead acetate, silver nitrate, mercuric chloride or with oxidising agents such as sodium hypochlorite. In this way, intermediately formed carbodiimides are usually not isolated,

they go e.g. in the case of the compound of the general formula IV, in which X represents the hydroxy group, under the reaction conditions easily into the process products, while in the case of the compounds of the general formula IV, in which X represents an alkoxy or alkanoyloxy group, treatment with inorganic or organic acids.

The reaction is carried out at temperatures of 20-200°C, preferably 50-120°C, reaction times vary between 15 minutes

and 30 hours.

The reaction medium used is water, lower alcohols such as methanol, ethanol, isopropanol, ethers such as diethyl ether, tetrahydrofuran, dioxane, further glycol, glycol monomethyl- and -ethyl ether, aromatic hydrocarbons such as benzol, toluene, xylol, chlorinated hydrocarbons such as methylene chloride, chloroform, dichloroethane, trichloroethylene as well such as acetone or carbon disulfide or their mixtures, the choice of the suitable solvent being determined by the stability and reactivity of any reaction components and products.

Compounds of the general formula V, as they are required for starting materials for the reactions with the amines of formula VI or their salts according to c) can be prepared, for example, by bringing compounds of formula II, in which X means a halogen atom, hydroxyl, sulfhydryl or an alkanoyloxy group, to react in the presence of bases such as alkali hydroxides with carbon disulfide or alkali xanthogenates (eg, analogous to J.pharmac.Soc. Japan 57, 54 (1937), C 1937 II, 2840). This results in compounds of the general formula V, in which FU means the sulfhydryl group. The formed mercapto compounds can optionally be alkylated, with R 1 taking on the meaning of the S-alkyl group. The compounds of the general formula V, in which Rj means a chlorine or bromine atom, are e.g. available from compounds of the general formula V in which R 1 denotes the amino group by means of the Sandmeyer reaction (e.g. in analogy to Helv.chim. acta 32, 63-68 (1949)).

The turnover according to c) which leads to the production of

■ 3,1-benzothiazine derivatives, takes place at temperatures between 20 and 250°C, preferably between 80 and 200°C, with a reaction duration of 15 minutes to 24 hours, the choice of reaction conditions depending on the reactivity of the compounds with the general formula used V. The use of a dissolving or diluting agent is, however, expediently not absolutely necessary here.

As a solvent, aromatic hydrocarbons such as benzene, toluene and xylenes, aliphatic and aromatic chlorohydrocarbons, such as chloroform, tetrachloroethane, chlorobenzene, further ethers, such as tetrahydrofuran, dioxane, glycoldimethyl and diethylene glycol diethyl ethers are mainly taken into account. Depending on the boiling point of the solvent used, as well as the required reaction temperature, the reaction may need to be carried out in a closed vessel.

The Por reaction according to d) is used as starting materials optionally with the residues R and R^ substituted 2-acylaminobenzothiazine (resp. -benoxazine) derivatives, for example the corresponding aliphatic acylamino derivatives such as 2-acetylamino-, 2-propionylamino-, 2-butyrylamino-, 2 -crotonoylamino or aromatic acylamino derivatives such as 2-benzoylamino-it-phenyl-4H-3,1-benzothiazine (or -benzoxazine) derivatives. Halogenated aliphatic acyl compounds can also be used as starting materials, for example 2-chloroacetyl-, 2-chloro-propionyl-, 2-chlorobutyryl-4-phenyl-4H-3,1-benzothiazine- (resp.

-benzoxazine) derivatives.

These acyl compounds are produced in the usual way by acylation of 2-aminobenzothiazine (or oxazine) derivatives, for example by the action of acid chlorides such as acetyl chloride, propionyl chloride, crotonyl chloride or the corresponding anhydrides such as acetic anhydride, propionic anhydride on optionally with R and R 1 substituted 2-amino-4-phenyl-4H-3,1-benzothiazines (resp. -benzoxazines). The acyl compounds, especially the halogenated acyl compounds, can also be obtained by reacting these 2-aminobenzothiazines (or oxazines) derivatives with the corresponding carboxylic acids in the presence of a water-splitting agent, for example dicyclohexylcarbodiimide.

Furthermore, basic substituted acyl compounds such as 2-dialkylaminoacetylaminox 2-dialkylaminopropionyl-amine-4-phenyl-4H-3,1-benzothiazine-(resp.-oxazine)-derivatives can be used as starting materials, with dialkylamino radical being understood as low-molecular-weight dialkylamino groups , preferably dimethyl or diethyl-amino groups^ and the corresponding piperidino- and pyrrolidino-acylamino-4-phenyl-4H-3,1-benzothiazine (or -oxazine) derivatives.

The reduction of the acyl derivatives takes place in the method according to the invention in the usual way with complex metal hydrides, especially lithium aluminum hydride, in indifferent solvents, preferably ethers such as dioxane, ether, tetrahydrofuran, optionally in a mixture with aromatic hydrocarbons at temperatures from 0 to the boiling point of the solvent used.

If halogen-acyl compounds are used, these can either be first reacted with the corresponding amines such as dimethylamine, diethylamine, dipropylamine or the corresponding heterocyclic amines such as piperidine or pyrrolidine, or it is first reduced in the manner mentioned and then the formed haloalkyl compounds are reacted with the aforementioned amines in a regular way. Hereby, there is an advantage with an excess of amine for binding liberated halogen hydrogen.

The turnover of the compounds with the general formula

II with halogen cyans according to e) which exclusively leads to benzoxazines, is preferably carried out in the presence of weak bases, e.g. alkali

and alkaline earth salts of fatty acids such as sodium acetate, alkali and alkaline earth carbonates, bicarbonates and hydroxides at temperatures from -20 to 100°C and reaction times from 30 minutes to 30 hours.

As solvents and diluents, e.g. lower alcohols such as methanol, ethanol, isopropanol, ethers such as diethyl ether, tetrahydrofuran, dioxane, aromatic hydrocarbons such as benzene, toluene, xylol, chlorohydrocarbons such as methylene chloride, chloroform, dichloroethane, chlorobenzene, further acetone and pyridine or their mixtures. The intermediately formed cyanamide derivatives pass either spontaneously or by treatment with the acid during ring closure into the process products.

For the production of benzothiazines with formula I, the method mentioned under f) is also suitable. As starting substances with formula I, in which A means an oxygen atom, it comes up, for example

speech: 2-amino-4-phenyl-4H-3,1-benzoxazine, 2-amino-4-phenyl-6-chloro-4H-3,1-benzoxazine-2-methylamino-4-pheny1-4H-3, 1-benzoxazine, 2-ethylamino-4-phenyl-6-chloro-4H-3,1-benzoxazine ^2-benzylamino-4-phenyl-6-chloro-4H-3,1-benzoxazine, 2-ethylamino-4- phenyl~5-chloro-4H-3,1-benzoxazine, 2-methylamino-4-phenyl-6-bromo-4H-3,1-benzoxazine, 2-ethylamino-4-(p-methoxyphenyl)-6-chloro- 4-H-3,1-benzoxazine, 2-ethylamino-4-(p-chlorophenyl)-6-chloro-4H-3,1-benzoxazine, 2-ethylamino-4-(o-fluorophenyl)-6-chloro- 4H-3,1-benzoxazine, 2-ethylamino-4-phenyl-7-chloro-4H-3,1-benzoxazine, 2-benzylamino-4-phenyl-6-methoxy-4H-3,1-benzoxazine, 2- amino-4-methyl-4H-3,1-benzoxazine, 2-ethylamino-4-methyl-4H-3,1-benzoxazine, 2-methylamino-4-ethyl-4H-3,1-benzoxazine, 2-ethylamino- 4-methyl-6-chloro-4H-3,1-benzoxazine, 2-cyclohexylamino-4-methyl-6-methoxy-4H-3,1-benzoxazine.

The reaction of these compounds with hydrogen sulphide or inorganic sulphides such as alkali sulphides or phosphorus sulphides, preferably phosphorus (V) sulphide, or their mixtures is carried out at temperatures from 50 to 200°C, preferably 80 to 160°C, possibly using an organic solvent such as pyridine, an aromatic hydrocarbon such as benzene, toluene or xylol, or an aliphatic or aromatic chlorohydrocarbon such as tetrachlorocarbon, tetrachloroethane or chlorobenzene. Depending on the boiling point of the solvent used, as well as the required reaction temperature, especially when using hydrogen sulphide, the reaction may need to be carried out under pressure.

Por the reaction which may be carried out by compounds of the general formula I, in which R means hydrogen,

with reactive derivatives of alcohols, alcohol derivatives in particular include their halides, such as chlorides, bromides, iodides, - further the corresponding sulfates, carbonates and alkyl or aryl sulfonates, for example methyl iodide, dimethyl sulfate, ethyl iodide, benzyl bromide, allyl bromide, dimethylaminoethyl chloride , piperidinopropyl chloride, bis-(ethylamino-ethyl carbonate), ethyl toluene sulphonate. The alkylation is carried out in the usual way in the presence of basic condensation agents such as alkali carbonates and hydroxides, alkali alcoholates, alkali and alkaline earth amides and hydrides.

The reaction of compounds of formula I formed in the first method step, in which R means hydrogen, with amines is carried out in a manner known per se, for example as discussed under point c). In this way, you can also use an excess of the amine used as a solvent and, if necessary, carry out the reaction in a closed vessel.

The process products can be transferred as basic compounds by means of inorganic or organic acids in the corresponding salts. Examples of inorganic acids that come into consideration are: halogenated acids such as hydrochloric acid and hydrobromic acid as well as sulfuric acid, phosphoric acid and amidesulphonic acid. Examples of organic acids include: acetic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, fumaric acid, maleic acid, oxalic acid, succinic acid, tartaric acid, benzoic acid, salicylic acid, citric acid, aceturic acid, oxyethanesulfonic acid and ethylenediaminetetraacetic acid, embonic acid, naphthalene disulfonic acid or toluenesulfonic acid.

The process products have, in part, very little toxicity, valuable pharmacological properties, in particular they are both centrally depressant as well as energizing, tranquillising, norepinephrine-enhancing and narcosis-prolonging and furthermore, e.g. analgesic and spasmolytic effect.

The process products, especially the benzothiazine derivatives such as e.g. 2-ethylamino-4-phenyl-6-chloro-4H-3,1-benzothiazine (LD 50: ^6 g/kg in mice per os) is clearly superior to structurally similar known compounds with regard to their central depressant effect, for example 2-ethylamino-4H-3,1-benzothiazine (LD 50: 800 mg/kg). They also have a remarkable central late effect. The additional qualities of action, with which the process products are distinguished, include narcosis-prolonging properties and strengthening of the physiological effect of catabolamines as well as an anti-cataleptic effect, which corresponds to the thymoleptic effect in humans. The latter properties are particularly clearly pronounced with benzoxazine derivatives, for example 2-ethylamino-4-phenyl-6-chloro-4H~3,1-benzoxazine, (LD 50: 600 mg/kg in mice per os) while they e.g. completely lacking in the known 2-ethylamino-4H-3,1-benzoxazine (LD 50: 320 mg/kg).

The central depressant effect was investigated by recording the spontaneous and provoked motility in mice and in the Somnolenz test (Nieschulz, 0. et al., Arzneimittelforschung 6,

651 (1956)), the anesthetic effect in the usual way. Breakthrough or abolition of it by 2-oxo-3-isobutyl-9,10-dimethoxy-1>2,3,4,6,7-hexahydro-llb-H-benzo/_ a/-quinolizine (tetrabenazine) out- resolved catalepsy in mice was tested according to a modification of that by von Sulser et al. (Ped. Proe. 19, 268 (1960) and Ann. N.Y. Acad. Sei. 96, 279 (1962)) described experimental device. The investigation into noradrenaline potentiating effect took place on the blood pressure of cats.

The process products can be applied as such or in the form of corresponding salts, possibly with the addition of pharmaceutically common carriers.

The process products are used for the treatment of mental illnesses, e.g. depressions, psychoneuroses, depression and anxiety states of neurotic and psychotic origin.

In the following Table I, a number of additional compounds obtained according to the invention are compared with regard to their central depressant effects and their toxicity with known compounds. The central depressant effect was determined in the somnolence test. In this way, it was observed how mice treated with the process products behave on a 35° inclined smooth surface. The percentage of the mice that on this crooked plane slid down instead of going down is a measure of the products' central depressant properties.

Compounds 1 and 2 are known from Chemische Berichte

22, 1671 (1889), compounds 3 and 4 of US Patent No. 3,168,517. Compounds 5 to 21 are prepared according to the invention.

The comparison shows that, with equal or lesser toxicity, the process products already in considerably lower dosages produce a stronger central depressant effect than the comparison compounds.

The anticataleptic effect of benzoxazines prepared according to the invention was investigated on two compounds prepared according to the invention in comparison with compound 1 in Table I according to a modification of the method by Sulser et al. (Ped. Proe. 19, 268 (1960)). The result is shown in the following table.

Example 1.

2- amino- 4- phenyl- 4H~ 3, 1- benzothiazine.

39.8 g of 2-aminobenzhydrol and 15.2 g of thiourea are boiled

in 100 ml of 48% hydrobromic acid for 1 hour under stirring and reflux. After cooling, the reaction mixture is made alkaline with dilute caustic soda and extracted several times with ether. The ether solution washed with water and dried over sodium sulfate is evaporated and the remaining solid residue recrystallized from benzene/petroleum ether. In this way, 40.8 g (85% of the theoretical) of 2-amino-4-phenyl-4H-3,1-benzothiazine are obtained as colorless crystals with a melting point of 148-149°C -

Example 2.

2- methylamino- 4- phenyl- 4H- 3, 1- benzothiazine.

30 g of 2-aminobenzhydrol are dissolved in 450 ml of ether and heated with 11 g of methyl mustard oil for 1 hour under reflux. The ether is then evaporated and the residue is boiled with 10 ml of concentrated hydrochloric acid for 30 minutes under reflux. The reaction mixture is diluted with water, made alkaline with dilute caustic soda and extracted several times with benzene. From the benzene solution washed with water and dried over sodium sulfate, after removal of the solvent in vacuo, 2-methylamino-4-phenyl-4H-3,1-benzothiazine is obtained as a yellowish oil, which rapidly solidifies crystalline. Recrystallization from benzene/petroleum ether gives 29.5 g (78$ of the theoretical) colorless crystals of m.p. 99-100°C.

Example 3.

2- amino- 4- phenyl- 6- chloro- 4H- 3, 1- benzothiazine.

46.7 g of 5-chloro-2-aminobenzhydrol and 15.2 g of thiourea are heated in 100 ml of 48% hydrobromic acid for 1 hour while stirring to reflux. After initial dissolution, the hydrobromide of 2-amino-4-phenyl-6-chloro-4H-3,1-benzothiazine rapidly begins to separate as a crystalline precipitate, which, after cooling, is isolated by suction, washed with acetone and recrystallized from ethanol. 60.2 g (84% of the theoretical value) of colorless crystals with m.p. 277-278°C during decomposition.

For the preparation of the free base, the above-mentioned hydrobromide need not be isolated. In this case, the reaction mixture is diluted with the amount of water sufficient to dissolve the salt and made alkaline with diluted caustic soda. After suctioning off the precipitate and recrystallization from benzene/petroleum ether or from ethanol, 48.5 g (88% of the theoretical) of 2-amino-4-phenyl-6-chloro-4H-3,1-benzothiazine with m.p..170- 171°C.

Example 4.

2- amino- 4- phenyl- 6- bromo- 4H- 331- benzothiazine.

By reacting 27.8 g of 5-bromo-2-aminobenzhydrol with 7.6 g of thiourea in .50 ml of 48% hydrobromic acid analogously to example 3, 26 g (8l# of the theoretical) of 2-amino-4-phenyl- 6-bromo-4H-3,1-benzothiazine with melting point 198-199°C

Example 5.

2- methylamino- 4- phenyl- 6- chloro- 4H- 3, 1- benzothiazine.

a) A solution of 46.7 g of 5-chloro-2-amino-benzhydrol i

500 ml of ether is mixed with 18.3 g of methyl mustard oil and kept for 24

hours at room temperature. You then distill approx. 2/3

of the solvent in vacuo and isolates the crystalline precipitate by suction. In this way, 50.5 g (83% of the theoretical) of pure N-methyl-N'-£~4-chloro-2-(α-hydroxybenzylVZ-phenylthiourea) with m.p. 164-165°C are obtained

b) 30.6 g of the thiourea formed according to a) is boiled in 100 ml of 48% hydrobromic acid for 1 hour while stirring, under reflux

run. The cooled reaction mixture is made alkaline with dilute caustic soda and extracted several times with vinegar. After the solvent evaporates in a vacuum, a yellowish oil remains, which solidifies crystalline after some time. After recrystallization from benzene/petroleum ether, 25.6 g (89% of the theoretical) of 2-methylamino-4-phenyl-6-chloro-4H-3,1-benzothiazine are obtained as colorless crystals with m.p. 109.5-110.5°C.

c) 23.4 g of 5-chloro-2-aminobenzhydrol and 7.3 g of methyl mustard

oil is boiled in 50 ml of 48% hydrobromic acid for 2 hours while stirring

and backflow. The reaction mixture is then worked up as described above under point b) and the reaction product formed is chromatographed for purification on basic alumina, activity III, using benzene as eluent. The 2-methylamino-4-phenyl-6-chloro-4H-3,1-benzothiazine produced in this way melts at 109.5-HO.5°C

and is identical to the compound described under b). The yield amounts to 20.7 g (72% of the theoretical).

Example 6.

2- ethylamino- 4- phenyl- 6- chloro- 4H- 3, 1- benzothiazine.

a) 35 g of 5-chloro-2-aminobenzhydrol are heated together with 26 g of ethyl mustard oil for 5 min. in a steam bath, and then stored

overnight at room temperature. The resulting crystal slurry is boiled with 75 ml of benzene to remove excess mustard oil. 43 g (89% of the theoretical) of N-ethyl-N'-(4-chloro-2-(2a-hydroxybenzyl)-7-phenylthiourea are thus obtained as colorless crystals with m.p. 147-148°C, which also remains constant on recrystallization from acetic ester/petroleum ether.

b) 32 g of the thiourea formed according to point a)

heated as in example 5 b) with hydrobromic acid, obtaining 25.6 g

(85% of theory) 2-ethylamino-4-phenyl-6-chloro-4H-3,1-benzothiazine with m.p. 118-120°C.

c) Analogously to example 5c), the reaction of 23.4 g of 5-chloro-2-aminobenzhydrol with 9.0 g of ethyl mustard oil gives 20.5 g (68% of the theoretical) 2-ethylamino-4-phenyl-6-chloro- 4H-3,1-benzothiazine with m.p. ll8-120°C.

Example 7«

2- be' nzyla~ mino- 4- f enyI- 6- chloro- 4H- 3, 1- benzothiazine.

13.7 g of 2-amino-4-phenyl-6-chloro-1H-3,1-benzothiazine prepared according to Example 3 is boiled in 25 ml of benzylamine for 2 hours under reflux. After cooling, the reaction mixture is diluted with petroleum ether, with 2-benzylamino-4-phenyl-6-chloro-4H-3,1-benzothiazine first separating as an oil. After chromatography on alumina of activity III using benzene/petroleum ether 1:1

as an eluent, 12.7 g (70% of the theoretical) of colorless crystals with m.p. 107-109°C.

Example 8.

2- phenylamino- 4- phenyl- 6- chloro- 4H- 3, 1- benzothiazine.

a) By reacting 23.4 g of 5-chloro-2-aminobenzhydrol with 13.5 g of phenyl mustard oil analogously to example 5 c) 26.5 g is produced

(76% of theory) 2-phenylamino-4-phenyl-6-chloro-4H-3,1-berisothiazine with m.p. 148-T50°C (from benzene/petroleum ether).

b) 5.5 g of the 2-amino-4-phenyl-6-chloro-4H-3,1-benzdiazine prepared according to example 3 is boiled in 15 ml of aniline for 5 hours under

backflow. The largest part of excess aniline is then distilled off in a vacuum and the oily residue is chromatographed as indicated in example 7 on aluminum oxide. Thus, 5.0 g (72% of the theoretical) of 2-phenylamino-4-phenyl-6-chloro-4H-3,1-benzothiazine with m.p. 148-150°C, which is identical to the compound described under a).

Example 9 -

2-(2t- diethylaminoethyl)- amino- 4- phenyl- 6- chloro- 4H- 3, 1- benzothiazine. 35 g of 5-chloro-2-aminobenzhydrol and 25 g of diethylamino-ethyl mustard oil are boiled in 100 ml of 48% hydrobromic acid for 2 hours while stirring under reflux. After cooling, the reaction mixture is made alkaline with dilute caustic soda while cooling and extracted with benzene. The oily residue remaining after evaporation of the solvent is chromatographed on the basis of aluminum oxide of activity III with benzene as eluent, obtaining 44 g (79% of the theoretical) 2-(2'-diethylamino-ethyl)-amino-4-phenyl-6 -chloro-4H-3,1-benzothiazine as pale yellow oils. The oxalate melts at 150-152°C.

Example 10. 2-(3'-diethylaminopropyl)-amino-4-phenyl-6-chloro-4H-3,1-benzothiazine.

a) 7 g of 5-chloro-2-amino-benzhydrol and 9.5 g of 3-diethylaminopropyl-thiourea are heated in 30 ml of 48% hydrobromic acid

1J hour under reflux. The usual work-up gives 1350 g (67% of the theoretical) of oily 2-(3'-diethylaminopropyl)-amino-4-phenyl-6-chloro-4H-3,1-benzothiazine, whose oxalate melts at 160-162°C . b) The same compound is obtained analogously to the prescription given in example 9 from 23.4 g of 5-chloro-2-aminobenzhydrol and 17.0 g of 3-diethylaminopropyl mustard oil in a 73% yield. The oxalate's melting point 160-162°C.

Example 11/

2- amino- 4- phenyl- 5- chloro- 4H- 3, 1- benzothiazine.

23.4 g 6-chloro-2-aminobenzhydrol (m.p. 139-141°C)

(from ethanol) prepared by reduction of 6-chloro-2-aminobenzophenone with sodium borohydride) and 7.6 g of thiourea are heated in 75 ml of 48% hydrobromic acid for 2 hours with stirring and reflux. After diluting the cooled reaction mixture with water, the precipitate that has formed is suctioned off and shaken with methylene chloride and diluted caustic soda. Evaporation of the methylene chloride solution washed with water and dried over sodium sulfate gives 20.6 g (75% of the theoretical) 2-amino-4-phenyl-5-chloro-4H-3,1-benzothiazine as approximately colorless crystals, which after recrystallization from benzene/petroleum ether melts at 207-209°C

Example 12.

2-amino-4-(p-chloro(resp. methoxy)phenyl)-6-chloro-4H-3,1-benzothiazine.

26.8 g 5,4'-dichloro-2-aminobenzhydrol (m.p. 130-131°C)

(from methanol/water), prepared from 5,4'-dichloro-2-aminobenzophenone by reduction with sodium borohydride, and 7.6 g of thiourea are heated with stirring and reflux in a solution of 37>7 g of p-toluenesulfonic acid in 60 ml of water for 2 hours. After cooling, the reaction mixture is made alkaline with dilute caustic soda and extracted with benzene. By evaporation of the dried benzene solution and recrystallization of the residue from benzene/petroleum ether, 26 g (84% of the theoretical) of 2-amino-4-(p-chlorophenyl)-6-chloro-4H-3,1-benzothiazine are obtained as colorless crystals with m.p. 189-191°C.

In the same way, from 26.4 g of 2-amino-5-chloro-4'-methoxy-benzhydrol, 20.4 g (67% of the theoretical) of 2-amino-4-(p-methoxyphenyl)-6-chloro is obtained -4H-3,1-benzothiazine with m.p. l66-l68°C (from benzene/petroleum ether).

Example 13. •

2- ethylamino- 4- phenyl- 4H- 3, 1- benzothiazine.

a) 20 g of 2-aminobenzhydrol and 13 g of ethyl mustard oil are heated for 10 min. at 90°C and then cooled rapidly. Mon

digest the reaction mixture with ether, filter off the formed crystal slurry after washing with a little ether and in this way obtain 23 g (80% of the theoretical) N-ethyl-N'-_/~2-(α-hydroxybenzyl_)_7-phenylthiourea in colorless crystals with m.p. 120-122°C. b) 28.6 g of the thiourea formed according to a) is boiled in 200 ml of concentrated hydrochloric acid for 30 minutes with stirring and reflux. After cooling, the largest part of the hydrochloric acid is removed by careful decantation and the oily residue is shaken with ether and diluted caustic soda. Evaporation of the ether phase washed with water and dried over sodium sulfate leaves 2-ethylamino-4-phenyl-4H-3,1-benzothiazine as a yellowish oil, on redissolution from cyclohexane 19.5 g of colorless crystals are obtained (73% of the theoretical) with m.p. 76-78°C.

Example 14.

2-ethylamino-4-(p-methoxyphenyl)-6-chloro-4H-3,1-benzothiazine.

35 g 2-(α-ethylthioureido)-5~chloro-4'-methoxybenzhydrol (m.p. 132-134°C (from ethanol/water), prepared from 2-amino-5-chloro-4'-methoxybenzhydrol and ethyl mustard oil) is boiled analogously to example 13 with 150 ml of concentrated hydrochloric acid for 1 hour with reflux. 28.5 g (85% of the theoretical) of 2-ethylamino-4-(p-rnetoxy-phenyl)-6-chloro-4H-3,1-benzothiazine are thus obtained as colorless crystals with m.p. 107-109°C (from ethanol/water).

Example 15.

a) One dissolves 35 g of 5-chloro-2-amino-benzhydrol in the just sufficient amount of ether, adds 30 g of isopropyl mustard oil and stores the reaction mixture at room temperature for several days. Afterwards, approx. 2/3 of the solvent in vacuum and isolate the crystalline precipitate by suction while washing with a little ether. In this way, it is possible to prepare 40 g (80% of the theoretical) of pure N-isopropyl-N'-_/4-chloro-2-(α-hydroxybenzyl)/-phenylthiourea with m.p. 127-129°C. b) 33.5 g of the thiourea substance prepared according to a) is boiled in 100 ml of 48% hydrobromic acid for 1 hour with stirring and reflux. The reaction mixture is then made alkaline with caustic soda while cooling and extracted with benzene or ethylene chloride. On evaporation of the organic phase washed with water and dried over sodium sulfate, 2-isopropylamino-4-phenyl-6-chloro-4H-3,1-benzothiazine remains as a yellowish oil, the compound is formed by redissolution from benzene/petroleum ether in fragmentless crystals of m.p. 114-116°C. Yield: 26 g (82% of the theoretical).

In an analogous way as described above, the following compounds can be obtained:

N-butyl-N' -/~4-chloro-2-(α-hydroxybenzyl_)7-phenylthiourea f,

m.p. 116-118°C.

2-butylamino-4-phenyl-6-chloro-4H-3,1-benzothiazine, m.p. 88-90°C. N-cyclohexyl-N'-_/-4-chloro-2-(ct-hydroxybenzyl_)7-phenylthiourea f, m.p. 143-145°C

2-cyclohexylamino-4-phenyl-6-chloro-4H-3,1-benzothiazine, m.p. 160-162°C. N-ethyl-N' -/_ 3-brom-2-(α-hydroxybenzyl_)_/~phenylthiourea f,

m.p. 147-149°C

2-ethylamino-4-phenyl-6-bromo-4H-3,1-benzothiazine, m.p. 99-101°C. Example 16.

a) 23 g of 5-chloro-2-amino-benzhydrol are heated together with 20 g of propylene mustard oil for 15 min. on a steam bath and then cooled

quickly to room temperature. The crystal slurry formed after keeping the reaction mixture overnight is filtered off while washing with some ether/petroleum ether (1:1) and 28.5 g (85% of the theoretical) of N-propyl-N*-/_4-chloro-2- (α-Hydroxybenzyl_)_7-phenylthiourin substance f as colorless crystals of m.p. 96-98°C.

b) 33.5 g of the thiourea produced according to a) is heated analogously to example 16 b) with hydrobromic acid, thereby obtaining 28 g (88% of the theoretical) 2-propylamino-4-phenyl-6-chloro-4H-3,1 -benzothiazine as colorless needles of m.p. 105-106°C (from benzene/petroleum ether).

In an analogous manner to that described above, the following compounds can be prepared: 2-((io-ethylthioureido)-5,4'-dichlorobenzhydrol, m.p. 136-138°C, 2-ethylamino-4-(p-chlorophenyl)-6 -chloro-4H-3,1-benzothiazine, mp 126-127°C (from ethanol/water).

Example 17.

a) A solution of 25 g of 2-amino~5-chloro-2'-fluorobenzhydrol (melting point 99-100°C, prepared from 2-amino~5-chloro-2'-fluorobenzo-phenone by reduction with sodium brohydride) in 250 ml of ether is mixed with 13 g of ethyl mustard oil and the reaction mixture is stored for several days at room temperature. The solvent is finally removed by vacuum distillation, the oily residue is digested with cyclohexane and the resulting crystalline precipitate of 2-(o)-ethylthioureido)-5-chloro-2'-fluorobenzhydrol is filtered off with suction while washing with cyclohexane. Recrystallization from benzene/cyclohexane yields 26 g (77% of the theoretical) colorless crystals with m.p. 129-130°C. b) 17 g of the compound formed according to point a) is boiled with 100 ml of 48% hydrobromic acid with vigorous stirring for 5 min.

during reflux. The cooled reaction mixture is diluted with

■\ann, after some time carefully decant off and shake the residue with methylene chloride and dilute caustic soda. After distilling off the solvent, 16 g of 2-ethylamino-4-(o-fluorophenyl)-6-chloro-4H-3,1-benzothiazine are obtained from the water-washed, dried over sodium sulfate organic phase as a viscous, colorless oil.

Analogously, as described above, it allows . the following compounds are prepared: 2-amino-5-chloro-3'-fluorobenzhydrol, m.p. 122-124°C. 2-((jj-ethylthioureido)-5-chloro-3'-fluorobenzhydrol, m.p. 144-145°C. 2-ethylamino-4-(m-fluorophenyl)-6-chloro-4H-3,1-benzothiazine,

m.p. 124-125°C.

2-amino-5-chloro-4'-fluorobenzhydrol, m.p. 125-126°C.

2-(w-ethylthioureido)-5-chloro-4'-fluorobenzhydrol, m.p. 141-142°C. 2-ethylamino-4-(p-fluorophenyl)-6-chloro-4R*-3,1-benzothiazine,

m.p. 133-134°C.

Example 18. ■

2- ethylamino- 4- phenyl- 4H- 3, 1- benzothiazine.

a) A solution of 20 g of 2-aminobenzhydrol in 175 ml of chloroform is added while stirring and cooling 7.5 g freshly distilled

ethyl isocyanate in 25 ml of chloroform. The reaction mixture is stirred for a further 30 minutes at room temperature, the solvent is distilled off in vacuo and the remaining brownish oil is taken up in hot benzene. After careful addition of petroleum ether, 20 g (74% of the theoretical) of N-ethyl-N'-/<->2-(a-hydroxybenzyljy-phenylurea) separates out as colorless crystals with mp 132-134°C. •

b) 13.5 g of the urea formed according to a) is boiled with 25 g of finely grated phosphorus pentasulphide in 75 ml of pyridine for 2 hours under

agitation and reflux. The reaction mixture is mixed while cooling with 250 ml of 2-n NaOH, stirred for 30 min. at room temperature and

is extracted after further water dilution with ether. After evaporation of the ether solution dried over sodium sulfate in vacuum, a brownish oil remains, from which 7.6 g of 2-ethylamino-4-phenyl-411-3,1-benzothiazine can be extracted with hot petroleum ether.

On recrystallization from petroleum ether, colorless crystals are obtained which melt at 76-78°C and with the compound prepared according to example 1'1 no melting point depression is obtained.

Example 19.

2- cyclohexylamino- 4- phenyl- 6- chloro- 4H- 3, 1- benzothiazine.

a) To a solution of 60 g potassium hydroxide in 300 ml abs. 70 g of 5-chloro-2-aminobenzhydrol and 90 ml of carbon disulfide are added to ethanol

and heats the mixture for 5 hours on a steam bath under reflux. The residue formed after evaporation of the solvent is dissolved in diluted caustic soda, filtered from some smaller amounts of insoluble matter and acidified with diluted hydrochloric acid. Extraction with benzene gives 69 g (79% of the theoretical) of 2-mercapto-it-phenyl-6-chloro-411-3,1-benzothiazine, which crystallizes from ethanol in slightly yellowish needles of m.p. 158-160°C.

b) 14.6 g of the compound formed according to a) is boiled in 25 ml of cyclohexylamine for 6 hours under reflux. After removal of

excess cyclohexylamine in a rotary evaporator, the residue is chromatographed on basic alumina, activity stage II, using benzene as eluent, obtaining 12.3 g (69/' of the theoretical) 2-cyclohexylamino-4-phenyl-6-chloro-4H-3 ,1-benzothiazine. The compound melts after recrystallization from benzene/petroleum ether at 160-162°C and, with a sample prepared according to example 16, gives no melting point depression.

Example 20.

2- benzylamino- 4- phenyl- 6- chloro- 4H- 3, I- benzothiazine.

a) 15 g of 2-methylmercapto-4-phenyl-6-chloro-4H-3,1-benzothiazine (produced by methylation of 2-mercapto-4-phenyl-6-chloro-4H-3,1-benzothiazine with methyl iodide, m.p. 114-116°C) is boiled in 30 ml of benzylamine for 9 hours under reflux. After the main amount of excess benzylamine has been removed by vacuum distillation, the residue is chromatographed on basic aluminum oxide of activity stage II with benzene as eluent, thereby obtaining 12 g of 2-benzylamino-4-phenyl-6-chloro-<J>4H-3,1-benzothiazine as pale yellow oil. The compound crystallizes from benzo/petroleum ether in colorless needles of m.p. 107-109°C and is identical to the compound described in example 7.

Example 21.

2-Ethylamino-4-phenyl-6-chloro-4H-3,1-benzothiazine.

14 g of 2-ethylamino-4-phenyl-6-chloro-4H-3,1-benzoxazine in

100 ml of pyridine is boiled with twice the growth amount of phosphorus pentasulphide for 2 hours while stirring and refluxing. After cooling, add 500 ml of diluted caustic soda and continue stirring for 1 hour at room temperature. The colorless precipitate is then filtered off with suction, washed thoroughly with water, dried and recrystallized from benzene/petroleum ether. In this way, 11 g (73% of the theoretical) of 2-ethylamino-4-phenyl-6-chloro-4H-3,1-benzothiazine are obtained as colorless crystals with m.p. 118-120~C (mixture melting point with a comparative preparation prepared according to example 6 b): no depression).

Example 22.

2- amino- 4- methyl- 4H- 3, 1- benzothiazine.

27.4 g of 2-amino-o-methyl-benzyl alcohol (prepared by catalytic hydrogenation of 2-nitro-o-methyl-benzyl alcohol in ethanol at room temperature and 20 ato H? in the presence of palladium, m.p. 58-59°C

from benzene/petroleum ether) and 15.2 g of thiourea are boiled in 100 ml of 48% hydrobromic acid for one hour with stirring and reflux. After cooling, the reaction mixture is made alkaline with dilute caustic soda and extracted several times with methylene chloride. By evaporating the methylene chloride solution washed with water and dried over sodium sulfate, 2-amino-4-methyl-4H-3,1-benzothiazine is obtained as a brownish oil, which solidifies crystalline after several hours. Recrystallization from benzo/petroleum ether gives 32.3 g (91% of theory) of colorless crystals of m.p. 128-129°C

Example 23-

2- methylamino- 4- methyl- 4H- 3, 1- benzothiazine.

a) 27 g of 2-amino-α-methyl-benzyl alcohol and 22 g of methyl mustard oil are heated for 5-10 minutes at 100°C and then cooled rapidly.

It is digested with benzol, sucked off and the precipitate is then boiled off again with a little benzol. 39 g (93% of the theoretical) of N-methyl-N'-[2-(c-hydroxyethyl_)7-phenylthiourea with m.p. 121-122°C/ A sample recrystallized for analysis from acetic acid/petroleum ether shows no increase in melting point.

b) 21 g of the thiourea formed according to a) is boiled in 100 ml of 48% hydrobromic acid for 1 hour with stirring and reflux. It

the cooled reaction mixture is made alkaline with dilute caustic soda and extracted several times with benzene. After evaporating it with

water washed and benzene solution dried over sodium sulfate, 2-methylamino-4-methyl-4H-3,1-benzothiazine remains as colorless oils, which crystallize on expulsion. Recrystallization from ethanol/water gives 14.5 g (76% of the theoretical) colorless crystals with m.p. 83-84°C. From benzene/petroleum ether, a higher-melting modification with m.p. 92-93°C.

Example 24. 2-Ethylamino-4-methyl-4H-3,1-benzothiazine.

a) Analogous example 23 a) is obtained by reacting 27 g of 2-amino-α-methyl-benzyl alcohol with 35 g of ethyl mustard oil 41 g (92% of

the theoretical) N-ethyl-N' -/~2-(α-hydroxyethyl_)7-phenylthiourea f with m.p. 108-110°C (from benzene).

b) 22.4 g of the thiourea formed according to a) is heated as in example 26 b) with hydrobromic acid, obtaining 16.3 g

(79% of theory) 2-ethylamino-4-methyl-4H-3,1-benzothiazine as colorless crystals with m.p. 90-92°C (from ethanol/water).

Example 25.

2- cyclohexylamino- 4- methyl- 4H- 3, 1- benzothiazine.

27.8 g of the analogous example 23 a) by reacting 2-amino-α-methyl-benzyl alcohol with cyclohexyl, mustard oil in 83% yield prepared N-cyclohexyl-N'- £~ 2-{α-hydroxyethyl)7- phenylthiourea f (m.p. 143-145°C from acetic ester/petroleum ether) is heated in 100 ml of 48% hydrobromic acid for 45 minutes with stirring and reflux. After working up as in example 26 b) you get 22.0 g (85%

of the theoretical) 2-cyclohexylamino-4-methyl-4H-3,1-benzothiazine as colorless crystals with melting point 128-130°C (from petroleum ether). Example 26.

2- ethylamino- 4- methyl- 4H- 3, 1- benzothiazine.

19 g of 2-ethylamino-4-methyl-4H-3,1-benzoxazine are heated together with 40 g of phosphorus pentasulphide in 200 ml of toluene for 3 hours with stirring and reflux. After cooling, the solvent is decanted off and removed under vacuum. The remaining residue gives after recrystallization from benzene/petroleum ether resp. ethanol/water 13.5 g (65% of the theoretical) 2-ethylamino-4-methyl-4H-3,1-benzothiazine with m.p. 91-92°C.

Example 27.

2- isopropylamino- 4- methyl- 4H- 3, 1- benzothiazine.

a) 54 g of 2-amino-a-methyl-benzyl alcohol and 80 g of isopropyl mustard oil are heated for 10 min. at 100°C. On cooling, the crystalline solidified reaction product is purified by recrystallization from acetic acid/petroleum ether and 76 g (81% of the theoretical) of N-isopropyl-N'-1_ 2-(α-hydroxyethyl_)_/-phenylthiourea with m.p. . 98-100°C. b) 30 g of the thiourea formed according to a) is heated as in example 28 with hydrobromic acid. Then with diluted

caustic soda while cooling the alkaline-adjusted reaction mixture is extracted with methylene chloride. After washing, drying and evaporation of the methylene chloride solution, 2-isopropylamino-4-methyl-4H-3,1-benzothiazine remains as a yellowish oil. On redissolution from ethanol/water, 19.5 g (7% of the theoretical) colorless crystals of m.p. 78-80°C.

Example 28.

2- ethylamino- 4- phenyl- 6- chloro- 4H- 3, 1- benzothiazine.

a) Preparation of the starting material:

Dissolve 27.5 g of 2-amino-4-phenyl-6-chloro-4H-3,1-benzothiazine in 150 ml of acetic anhydride. During spontaneous heating, the rapidly separated crystalline precipitate is filtered off with suction after a few hours and washed with ether. By recrystallization from ethyl acetate/petroleum ether, 25.6 g (81% of the theoretical) of 2-acetylamino-4-phenyl-6-chloro-4H-3,1-benzothiazine are obtained as colorless crystals with m.p. 229-230°C.

b) 27.5 g of 2-amino-4-phenyl-6-chloro-4lI-3,1-benzothiazine in 100 ml of pyridine are mixed dropwise with stirring and ice-cooling

8.5 ml of acetyl chloride. You continue to stir for 30 minutes. at 0°C and 30 minutes at room temperature and precipitates the acetyl compound on dilution with water as colorless precipitates, which are sucked off, washed with water, dried and recrystallized from acetic acid/petroleum ether. The yield amounts to 29.2 g (92% of the theoretical) of 2-acetylamino-4-phenyl-6-chloro-4H-3,1-benzothiazine with m.p. 228-229°C.

c) To a solution of 2.4 g of glacial acetic acid in 20 ml of acetone, add 4.2 g of triethylamine slowly while stirring and ice-cooling

followed by 4.4 g of chloroformate ethyl ester. After 30 min. a solution of 11.0 g of 2-amino-4-phenyl-6-chloro-benzothiazine in 80 ml of acetone is also added dropwise under ice-cooling and further stirring for 1 hour at 0°C and 2 hours at room temperature. The crystalline residue remaining after evaporation of the solvent in vacuum is extracted several times with water and recrystallized after drying from acetic acid/petroleum ether. 9.5 g (75% of the theoretical) of 2-acetylamino-4-phenyl-6-chloro-4H-3,1-benzothiazine with mp. 228-229°C.

d) Reduction:

31.7 g of the compound formed according to a) - c).

is reduced by 4.0 g of lithium aluminum hydride in 500 ml of absolute ether. After 2 hours of boiling with stirring and reflux, it is carefully split with water and the precipitated aluminum hydroxide is filtered off. The filtrate is washed with water, dried over sodium sulphate and evaporated. After recrystallization from the residue from benzene/petroleum ether,

man 25.0 g (83% of the theoretical) 2-ethylamino-4-phenyl-6-chloro-4H-3,1-benzothiazine as colorless crystals with m.p. 118-120°C. Example 29.

2- ethylamino- 4- phenyl- 5~ chloro- 4H- 3, 1- benzothiazine.

a) Preparation of the starting material:

27.5 g 2-amino-4-phenyl-5-chloro-4H-3,1-benzothiazine

poured over with 150 ml of acetic anhydride and dissolved by careful heating on a steam bath. The reaction mixture is allowed to stand overnight at room temperature and the crystalline precipitate is filtered off with suction. By recrystallization from benzene, 29.0 g (92% of the theoretical) of 2-acetylamino-4-phenyl-5-chloro-4H-3,1-benzothiazine are obtained as colorless crystals with m.p. 197-198°C.

b) Reduction:

25.4 g of the compound prepared according to a) is reduced

with 6.0 g of lithium aluminum hydride in a mixture of 300 ml of absolute ether and 150 ml of absolute benzene. After 4 hours of boiling under reflux, it is worked up as in example 28 d). After recrystallization from benzene/petroleum ether, 18.5 g of 2-ethylamino-4-phenyl-5-chloro-4H-3,1-benzothiazine with m.p. 108-110°C.

Example 30»

2- benzylamino- 4- phenyl- 6- chloro- 4H- 3, 1- benzothiazine.

a) Preparation of the starting material:

27.5 g of 2-amino-4-phenyl-6-chloro-4H-3,1-benzothiazine about is added in the manner described in example 28 d) with 13.5 ml of benzoyl chloride, thereby obtaining 30.0 g (79% of the theoretical) of 2-benzoylamino- 4-phenyl-6-chloro-4H-3,1-benzothiazine as colorless crystals with m.p. 184-186°C (from acetic acid/petroleum ether).

b) Reduction:

19.0 g of the compound formed according to a) is reduced

with 3.0 g lithium aluminum hydride in 500 ml abs. ether by heating under reflux for 3 hours. After work-up analogous to example 31 d) and recrystallization of crude products from petroleum ether, one obtains

13.0 g (70% of the theoretical) 2-benzylamino-4-phenyl-6-chloro-4H-3,1-benzothiazine in the form of colorless crystals with m.p. 107-109°C. Example 31.

2-(3'-piperidinopropyl)-amino-4-phenyl-6-chloro-4ii-3,1-benzothiazine.

a) = Preparation of the starting material:

To a solution of 27.5 g of 2-amino-4-phenyl-6-chloro-4H-3,1-benzothiazine and 14 g of B-chloropropionic acid in 200 ml of tetrahydrofuran, 27 g of dicyclohexylcarbodiimide in 100 ml of tetrahydrofuran are added dropwise while stirring. The reaction mixture is stirred overnight at room temperature and the precipitated dicyclohexylurea is removed by suction. After evaporation of the filtrate in a vacuum, the remaining residue is crystallized from benzene/petroleum ether and Mr thus 26.5 g of 2-(3-chloropropionyl)-amino-4-phenyl-6-chloro-4H-3,1-benzothiazine as colorless crystals with m.p. 147-149°C.

b) Reaction with piperidine:

22 g of the compound formed according to a) is boiled with 12 g

piperidine in 350 ml abs. toluene for 8 hours under stirring and reflux. After cooling, the filtered toluene solution is washed with water and dried over sodium sulfate. After removal of the solvent at 60°C in vacuo, 24 g of 2-(3'-piperidinopropionyl)-amino-4-phenyl-6-chloro-4H-3,1-benzothiazine remain as a pale yellow oil, the oxalate of which melts at 188 -189°C.

c) Reduction:

To a suspension of 3.5 g of lithium aluminum hydride i

175 ml abs. ether is added dropwise to 21 g of the compound formed according to b) dissolved in 175 ml abs. benzene with stirring and ice-cooling. After hours of heating the reaction mixture under reflux, it is worked up as described in example 28 d), obtaining 17.5 g (87%

of the theoretical) 2-(3'-piperidinopropyl)-amino-4-phenyl-6-chloro-4H-3,1-bcnzothiazine as an approximately colorless oil, the oxalate of which melts at 210-211°C.

Example 32.

2- ot ylamino- 4- met yl- 4 H- 3, 1- benzoxaz iri.

a) 13.7 g of ot-methyl-2-aminobenzyl alcohol are heated together with 13.0 g of ethyl mustard oil for 10 min. at 90-100°C. The reaction mixture, which crystallizes slowly on cooling, is expelled with petroleum ether and the crystalline precipitate is isolated by suction.

By recrystallization from benzene, 20.6 g (92% of the theoretical) N-ethyl-N'-/_ 2-(α-hydroxyethyl_)7-phenylthiourea is obtained as ['argoless crystals with m.p. 108-110°C.

b) 22.4 g of the thiourea coconut formed according to a) with 40 g of mercuric oxide in 200 ml of ethanol for 30 min. while stirring

and backflow. The reaction mixture is filtered hot and the solvent is evaporated in vacuo. This leaves 2-ethylamino-4-methyl-4H-3,1-benzoxazine as a colorless oil which rapidly solidifies crystalline. After recrystallization from petroleum ether, 16.5 g (87% of theory) of colorless crystals with m.p. 66-68°C. Example 33.

2- cyclohexylamino- 4- methyl- 4H- 3, 1- benzoxazine.

27.8 g of the analogous example 32 a) by reacting α-methyl-2-aminobenzyl alcohol with cyclohexyl mustard oil in 83% yield produced N-cyclohexyl-N' -/__2-(α-hydroxyethyl_)7-phenylthio-urea ( m.p. 143-145°C, from acetic ester/petroleum ether) is treated as in example 32 b) with mercuric oxide. After recrystallization of the crude product from petroleum ether, 18.5 g (76% of the theoretical) of 2-cyclohexylamino-4-methyl-4H-3,1-benzoxazine are obtained as colorless crystals with m.p. 107-109°C

Example 34.

2- ethylamino- 4- phenyl- 4H- 3, 1- benzoxazine.

a) A solution of 40 g of 2-aminobenzhydrol in 500 ml of ether is mixed with 35 g of ethyl mustard oil and kept for 48 hours at

room temperature. Approximately 2/3 of the solvent is then distilled off in a vacuum and the crystalline precipitate is isolated by suction. 51 g of pure N-ethyl-N"-/~2-(a-hydroxybenzyl)7-phenylthiourea with m.p. 119-121°C are obtained in this way. b) 28.6 g of the thiourea formed according to a) is heated with 40 g of mercuric oxide for 1 hour under stirring and reflux.

After the preparation of the reaction mixture as in example 32 b) obtains

one 2-ethylamino-4-phenyl-4H-3,1-benzoxazine as a pale yellow oJ'e, which after some time solidifies crystalline. For further purification, the compound is chromatographed on neutral alumina,

activity II, using benzene/petroleum ether 1:1 as well as benzene as eluent and obtain 17.5 g (69% of theoretical) colorless crystals of m.p. 76-78°C (from hexane).

Example 35.

2- ethylamino- 4- phenyl- 6- bromo- 4H- 3, 1- benzoxazine.

a) By reacting 28 g of 5-bromo-2-aminobenzhydrol with 17 g of ethyl mustard oil in 200 ml of ether analogous to example 34 a) is obtained

29 g (79% of theory) N-ethyl-N'-/~4-bromo-2-(α-hydroxybenzyl_)_/-

phenylthiourea with m.p. 148-150°C.

b) 18 g of the thiourea formed according to a) is heated with 22 g of mercuric oxide in 250 ml of ethanol for 30 minutes while stirring

and backflow. After processing as. in example 32 b) 13.5 g (82% of the theoretical) of 2-ethylamino-4-phenyl-6-bromo-4H-3,1-benzoxazine with m.p. 128-129°C (from benzene/petroleum ether).

Example 36.

2- methylamino- 4- phenyl- 6- chloro- 4H- 3, 1- benzoxazine.

Analogous to example 35 b), 21 g of N-methyl-N'-_/ 4-chloro-2-(o-hydroxybenzyl_)_/- phenylthiourea is obtained from 31 g according to example 5 a) (77% of the theoretical) 2-methylamino-4-phenyl-6-chloro-4lI-3,1-benzoxazine of m.p. 149-150°C (from benzene/petroleum ether). Example 37.

2- ethylamino- 4- phenyl- 6- chloro- 4H~ 3, 1- benzoxazine.

a) 32 g of the N-ethyl-N'-_/4-chloro-2-(o-hydroxybenzyl_)_/-phenylthiourea prepared according to example 6 a) are reacted as in

example 35 a) with mercuric oxide, obtaining 27 g (94% of the theoretical) of 2-ethylamino-4-phenyl-6-chloro-4lI-3,1-benzoxazine as colorless crystals with m.p. 124-125°C. b) 18 g of the thiourea mentioned under a) is boiled with 23 g of silver oxide in 250 ml of ethanol for 45 min. under stirring and reflux.

Filter hot and evaporate the solvent in a vacuum. By extracting the oily residue several times with hot petroleum ether, it is possible to prepare 1 g (77% of the theoretical) 2-ethylamino-4-phenyl-6-chloro-4H-3,1-benzoxazine with m.p. 124-125°C. Example 38.

2- amino- 4- phenyl- 6- chloro- 4H- 3, 1- benzoxazine.

a) In a solution of 70.2 g of 5-chloro-2-aminobenzhydrol in 300 ml of glacial acetic acid, 30 g of potassium cyanate are introduced in portions during approx. 15 min. After another 10 min. the reaction mixture is heated for fifteen minutes on a steam bath and, after cooling, diluted with water. The precipitated N-/4-chloro-2-(α-hydroxy-benzyl)/-phenylurea is suctioned off after 2-3 hours, washed with water, dried and recrystallized from ethyl acetate/petroleum ether. 61.5 g (74% of the theoretical) of colorless crystals with m.p. 157-159°C b) 14 g of the urea produced according to a) is heated with 50 ml of 48% hydrobromic acid for 5~10 min. while stirring on a steam bath and then cooled rapidly. Dilute with water, decant, take up half the residue with methyl chloride and shake with diluted caustic soda. The ethylene chloride solution is washed with water, dried over sodium sulfate and evaporated. The remaining crude 2-amino-4-phenyl-6-chloro-4H~3,1-benzoxazine is then transferred into the oxalate, which crystallizes from ethanol/ether in colorless crystals of m.p. 167-168°C. Yield 12 g (69% of theoretical). By shaking the oxalate with methylene chloride and diluted caustic soda and evaporating the organic phase, the free base can be produced which melts after recrystallization from benzene/petroleum ether at 133-134°C. Example 39-

2- ethylamino- 4- phenyl- 4H- 3, I- benzoxazine.

a) To a solution of 20 g of 2-aminobenzhydrol in 200 ml of chloroform, while stirring and ice-cooling, 7.1 g of freshly distilled

ethyl isocyanate in 30 ml chloroform during 30 min. You continue to stir for another 30 minutes. at room temperature and then remove the solvent in vacuo. The remaining brownish oil is taken up in hot benzene and the benzene solution is carefully mixed with petroleum ether. On cooling, 19 g (70% of the theoretical) of N-ethyl-N' -_/~2-(α-hydroxybenzyl_)7-phenylurea with m.p. 132-134°C. b) A suspension of 13.5 g of the urea produced according to a) in 100 ml of ethanol is mixed with stirring with 17.5 g of P-toluenesulfonic acid and then boiled for 45 minutes under reflux. After cooling, it is made alkaline with caustic soda, diluted with water and extracted with ether. From the ether solution washed with water and dried over sodium sulfate, 2-ethylamino-4-phenyl-4H-3,1-benzoxazine is obtained as a yellowish oil after evaporation of the solvent. When redissolving -ra hexane, 7.2 g (57% of the theoretical) of colorless crystals with m.p. 76-78°C, which with the compound prepared according to example 34 b) does not give any melting point depression.

Example 40.

2- ethylamino- 4- phenyl- 6- chloro- 4H- 3, 1- benzoxazine.

a) 13 g of 2-amino-4-phenyl-6-chloro-4H-3,1-benzoxazine are introduced while stirring at room temperature into 100 ml of acetic anhydride. After

starting dissolution, the acetyl compound is rapidly separated as a crystalline precipitate. Cool for a further 1-2 hours in ice, suck off and wash the precipitate with a little ether. In this way it is possible to prepare 11 g (73% of the theoretical) of pure 2-acetylamino-4-phenyl-6-chloro-4H-3,1-benzoxazine with m.p. 147-148°C.

b) To a solution of 26 g of 2-amino-4-phenyl-6-chloro-4h-3,1-benzoxazine in 200 ml of pyridine is added dropwise while stirring and

ice cooling 9 ml acetyl chloride slowly. It is then stirred again

for 30 minutes at 0°C and 30 min. at room temperature, and the reaction mixture is finally poured into approx. 2 liters of water. As soon as initially some resin-like sediment has solidified, it is isolated by suction, washed with water and dried. By recrystallization from ethanol, 25.5 g (85% of the theoretical) of 2-acetylamino-4-phenyl-6-chloro-4lI-3,1-benzoxazine with m.p. 147-148°C.

c) 15 g of the compound formed according to a) or b) is reduced with 2 g of lithium aluminum hydride in 300 ml abs. ether. After

After boiling for 1 hour while stirring and refluxing, the reaction mixture is carefully mixed with water and the precipitated aluminum hydride is filtered off. The filtrate is washed with water, dried over sodium sulphate and evaporated. After recrystallization of the residue from benzene/petroleum ether, 11 g (76% of the theoretical) of 2-ethylamino-4-phenyl-6-chloro-4H-3,1-benzoxazine are obtained as colorless crystals of m.p. 122-123°C, which with the compound prepared according to example 40 does not cause melting point depression.

Example 41.

2- amino- 4- phenyl- 6- chloro- 4H- 3, 1- benzoxazine.

To a solution of 5.2 g of cyanogen bromide in 180 ml of methanol, 11.7 g of 2-amino-5-chlorobenzhydrol and 4 g of anhydrous sodium acetate in 180 ml of methanol are slowly added dropwise with stirring and ice-cooling. After the reaction mixture has been stored overnight at room temperature, the solvent is removed in vacuo and the residue is extracted with ether. The ether solution, washed with water and dried over sodium sulfate, yields a brown oil on evaporation, from which 5.1 g of 2-amino-4-phenyl-6-chloro-4H-3,1-benzoxazine can be prepared with oxalic acid in acetone as oxalate. The substance melts, recrystallized from ethanol/ether at 167-168°C during cleavage and is identical to the compound described in example 4.

Example 42.

2-isobutylamino-4-phenyl-6-chloro-4H-3,1-benzoxazine.

16.6 g of N-isobutyl-N' - 1_ 4-chloro-2-(α-hydroxybenzyl_)_/- phenylurea (m.p. 152-154°C (from benzene/petroleum ether) prepared by reaction of 2-amino-5 -chlorobenzhydrol with isobutylisocyanate in ether analogous to example 39 a) ) is heated as in example 38 b) with hydrobromic acid. After similar processing, 14.3 g is obtained

(91% of theory) 2-isobutylamino-4-phenyl-6-chloro-4H-3,1-benzoxazine as colorless crystals with m.p. 117-118°C (from petroleum ether).

Example 43.

24 g of the 2-(w-ethylthio-ureido)-5,4'-dichlorobenzhydrol described in example 16 is treated as in example 32 b) with mercuric oxide. After recrystallization of the crude product from benzol/petroleum ether, 12.5 g (60% of the theoretical) of 2-ethylamino-4-(p-chlorophenyl)-6-chloro-4H-3,1-benzoxazine with m.p. 144-145°C.

In an analogous manner, desulfurization of 17.5 g of 2-(w-ethyl-thioureido)-5-chloro-4'-methoxybenzhydrol (from Example 15) gives 9.4 g (59% of theory) of 2-ethylamino-4- (p-methoxyphenyl)-6-chloro-4H-3,1-benzoxazine with m.p. 106-108°C (from petroleum ether).

Example 44.

15 g of N-ethyl-N'-/~4-chloro-2-(α-hydroxybenzyl27-phenyl-urea, m.p. 130-132°C (prepared analogously to example 42) are heated with 50 ml of 48% HBr for 5-10 min . while stirring on a steam bath and then cooled rapidly. After preparation analogously to example 38 b), 12.5 g (88% of the theoretical) of 2-ethylamino-4-phenyl-6-chloro-4H-3,1-benzoxazine with m.p. 124-125°C.

Example 45.

2- ethylamino- 4- phenyl- 6- trifluoromethyl- 4H- 3, 1- benzothiazine.

a) 13 g of 2-amino-5-trifluoromethyl-benzhydrol (m.p. 86-88°C prepared by reducing 2-amino-5-trifluoromethyl-benzophenone with

sodium borohydride) is heated together with 6 g of ethyl mustard oil for 10 min. in a steam bath and then cooled rapidly. After overnight storage, the formed crystal slurry is digested with a little benzol and suctioned off. 13.5 g of N-ethyl-N'-(4-trifluoromethyl-2-(α-hydroxybenzyl)7-phenylthiourea are thus obtained as colorless crystals which, after recrystallization from benzene, melt at 166-168°C.

b) 9 g of the thiourea formed after a) is briefly heated analogously to example 17 b) with hydrobromic acid, thereby obtaining 7 g (82% of the theoretical) 2-ethylamino-4-phenyl-6-trifluoromethyl-4H-3,1- benzothiazine as colorless crystals with m.p. 84-85°C. Example 46.

2- ethylamino- 4- phenyl- 6- methoxy- 4H- 3, 1- benzothiazine.

a) 6.6 g of 2-amino-5-methoxy-benzhydrol (m.p. 95.5-96°C prepared by reduction of 2-amino-5-methoxy-benzophenone with

sodium borohydride) is heated with 3.2 g of ethyl mustard oil for 5 min. on

steam bath. The resin-like reaction product is dissolved hot in 75 ml of benzene. On slow cooling, crystallization occurs which can be completed by adding petroleum ether. 758 g of N-et<y>1-N'-_/ 4-methoxy-2-(a-hydroxybenzyl)-phenyl7-

thiourea with m.p. 133-134°C.

b) 7.8 g of the thiourea formed according to a) is boiled with 50 ml of concentrated hydrochloric acid for 30 min. under stirring and reflux.

After cooling, dilute with water, make alkaline with caustic soda

under ice-cooling, and the oily reaction product is taken up in methylene chloride. The methylene chloride solution is washed with water, dried with sodium sulfate and the solvent is removed. The residue is dissolved hot in 60 ml of cyclohexane. On cooling, 6.8 g (92.5% of the theoretical) of 2-ethylamino-4-phenyl-6-methoxy-4H-3,1-benzothiazine are obtained as colorless needles with m.p. 91-92.5°C.

Claims (1)

Analogous process for the preparation of therapeutically effective 4H-3,1-benzothiazine derivatives and 4H-3,1-benzoxazine derivatives of the general formula I wherein A means oxygen or sulphur, R means hydrogen, a lower alkyl, cycloalkyl of 5-7 C atoms, phenyl, phenyl lower alkyl, lower dialkylaminoalkyl, piperidino lower alkyl or pyrrolidino lower alkyl group, R means hydrogen, halogen, trifluoromethyl or methoxy, and R^ means alkyl, phenyl-lower alkyl or phenyl residues, the phenyl ring may be substituted with halogen atoms, methoxy or trifluoromethyl groups, as well as their acid addition salts with inorganic or organic acids, characterized by either a) reacts with compounds of the general formula II wherein R 1 and R 2 have the meaning given above, and X means a chlorine or bromine atom, a hydroxyl, sulfhydryl, alkoxy, alkylthio or alkanoyloxy group with thiourea of the general formula Illa in which R has the meaning given above, and the two residues R can be the same or different, or with isothiocyanates of the general formula IIIb in which R has the above meaning, resp. corresponding isothiocyanate formers, optionally with the addition of acids and/or water-splitting agents, or reacts compounds of formula II, in which X means a chlorine or bromine atom, a hydroxyl, alkoxy or alkanoyloxy group with the isocyanate of the general formula Ille in which R has the meaning stated above, or equivalent isocyanate formers, optionally with the addition of acids and/or water-splitting agents, or b) treats compounds of the general formula IV c) reacts compounds of the general formula V in which R and R? has the meaning given above, and R^ means a chlorine or bromine atom, a sulfhydryl or S-alkyl group with amines of the general formula VI or their salts in which R' has the meaning of R with the exception of hydrogen, or d) reduces a compound of the general formula VII in which A, R₂ and R₂ have the meaning given above, and R₂ means a lower alkyl, lower alkenyl, phenyl, phenyl-lower alkyl, halo-lower alkyl or lower dialkylamino group, which within -captured by the meaning of R can also be ring-closed, with complex metal hydrides, and if R^ means a haloalkyl radical react the obtained compounds with dialkylamines, which within the meaning of R can also be ring-closed, or e) react compounds of the general formula II , in which X means a chlorine or bromine atom, a hydroxyl, alkoxy or alkanoyloxy group, and R and R 2 have the meaning given above, with halocyanos of the general formula VIII in which Y means a chlorine, bromine or iodine atom, e optionally during subsequent acid treatment, or f) reacts compounds of the general formula I, in which A means an oxygen atom and R, R-^ and R2 have the meaning indicated above, with hydrogen sulphide or inorganic sulphides, and if desired reacts process products in which R means hydrogen with amines or reactive derivatives of alcohols to such compounds in which R has one of the other meanings mentioned above, and/or if desired transfer the formed basic compounds by treatment with inorganic or organic acids in their acid addition salts.