DE1545820B - 3, 1-Benzothiazines and processes for their preparation - Google Patents

Description

It has been found that 4H-3,1-Benzothiazines of the general formula I

NHR

(D

Sulphides or dehydrating agents, optionally with the addition of acids, or

c) a compound of the general formula V.

, N

r r

^R i ~ TI c (V)

IO

where R denotes a hydrogen atom or a lower alkyl group, and R ₁ and R _{2 are} identical or different and denote hydrogen or halogen atoms, and their salts with physiologically acceptable acids have valuable pharmacological properties, in particular both centrally depressive and stimulating, tranquilizing, thymoleptic noradrenaline-potentiating, have analgesic and spasmolytic effectiveness with extremely low toxicity and a central apomorphine synergism. These compounds are produced in a manner known per se by either
a) a compound of the general formula II

wherein R ₃ denotes a chlorine or bromine atom, an amino, sulfhydryl or S-alkyl group, with amines of the general formula VI or salts thereof

R '- NH ₂

(VI)

NH,

(H)

wherein X is a chlorine or bromine atom, a hydroxyl, sulfhydryl, alkoxy, alkylthio or alkanoyloxy group means with thioureas of the general formula IHa

(III a)

NHR
.o - ρ

NHR

or isothiocyanates of the general formula IIIb S = C = NR (TIIb)

or corresponding isothiocyanate formers, optionally with the addition of acids and / or dehydrating agents Means, implements or

b) a compound of the general formula IV

(IV)

or corresponding functional derivatives of these ureas with hydrogen sulfide or inorganic ones wherein R 'has the meaning of R with the exception of a hydrogen atom, converts or

d) a compound of the general formula V, in which R ₃ denotes the amino group, with a reactive derivative of an alcohol of the general formula VII

R'-OH

(VII)

converts and optionally the basic compounds obtained according to a) to d) by treatment converted into their acid addition salts with inorganic or organic acids.

The following 2-aminobenzhydrols are used as starting materials of the general formula II for the reaction according to a) into consideration: 2-aminobenzhydrol, 2-aminofluorobenzhydroles, 2-amino-chlorobenzhydroles, in particular 2-amino-5-chlorobenzhydrol and 2-aminobromobenzhydrols, the halogen atoms in the 3-, 4-, 5- or 6-position of one and / or in the 2'-, 3'-, or 4'-position of the other benzene ring can be.

Furthermore, the lower O-alkyl ethers corresponding to the above-mentioned benzhydrols, such as 2-aminobenzhydrol methyl ether, ethyl ether, or the corresponding esters with lower aliphatic carboxylic acids, z. B. the acetates or propionates of the benzhydrols mentioned can be used. The corresponding Halides, such as 2-aminophenyl-phenyl-chloro- (or. -brotn-) methane and the compounds correspondingly substituted in the phenyl radicals, the corresponding Mercaptans and lower alkyl thioethers such as 2-aminophenyl-phenyl-methyl mercaptan or the corresponding lower alkyl thioethers or those derived from the basic compounds mentioned Salts with strong acids, such as hydrohalic acids, sulfuric acid and benzene and toluene sulfonic acid, are also suitable as starting materials. The abovementioned benzhydrols can be found in can be produced in a known manner by reducing the corresponding benzophenones (e.g. in analogy to J. org. Chemistry 27, 1929-1930 [1962]). As starting materials of the general formula III a come Thiourea and N-methyl-, N-ethyl-, N-propyl-, N-isopropyl-, N-butyl-, N-isobutyl-, N, N'-dimethyl-, N, N'-diethyl-thio-urea in question, while as starting substances of the general formein IUb isothiocyanates, such as methyl, ethyl, propyl, Isopropyl, butyl, isobutyl isothiocyanate can be used. Continue to come in place of isothiocyanates also isothiocyanate formers, such as

corresponding thiourethanes or dithiocarbamic acid esters. into consideration.

The reaction of compounds of the general formula II as well as their acid addition salts with the compounds of the general formulas IIIa and IIIb according to a) takes place at temperatures of 20 to 25O ⁰ C, preferably 80 to 180 ⁰ C, in the presence of inorganic or organic acids, eg. B. hydrohalic acids such as hydrochloric acid, hydrobromic and hydroiodic acid, also sulfuric acid, phosphoric acid, lower aliphatic carboxylic acids such as formic acid and acetic acid, halocarboxylic acids. such as chloroacetic acid, trifluoroacetic acid, and benzene and toluenesulphonic acid or mixtures thereof. You can also, optionally in the presence of dehydrating agents such. B. inorganic acid halides and anhydrides, such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, thionyl chloride or phosphorus pentoxide, also zinc chloride or boron fluoride, work.

Additional solvents or diluents that can optionally be used are water, lower alcohols, such as ""> Methanol, ethanol, isopropanol, ethers, such as diethyl ether, Tetrahydrofuran, dioxane, also glycol, glycol monomethyl and ethyl ether, di- and triethylene glycol such as . aromatic hydrocarbons such as benzene, toluene, xylene, or chlorinated hydrocarbons, such as chlorobenzene, chloroform, trichlorethylene or tetrachloroethane can be used, the choice being made of the suitable solvent or diluent through the stability and reactivity of the respective reaction components is determined.

For the implementation of the benzhydryl halides of the general formula II (X = Cl, Br) or their acid addition salts with the compounds of general formula IIIa and IHb is the presence of acids or water-releasing agents are not required. These reactions can preferably be carried out in the Carry out melt or by heating in a suitable inert solvent.

The reaction times vary from 30 minutes to 30 hours. For work-up, they can usually be saved as Salts of the reaction products of the general formula I, if appropriate after concentrating the solution, ; / isolated directly and, if desired, converted into the free bases by subsequent treatment with alkali will. You can also make the reaction mixture alkaline before isolation, whereby the process products can be isolated in the customary manner in the form of the free bases.

The reaction of compounds of the general formula II with thioureas of the general Formula IHa occurring isothiuronium salts, those of the general formula II, in which X is the remainder

e

-SC (NH ₂ ) = NH ₂

represents, correspond, are generally not isolated, since they are easily under the reaction conditions pass into the process products.

If the implementation of the above-mentioned aminobenzhydrols of the general formula II or their Ethers and esters or the corresponding mercaptans and thioethers with the isothiocyanates of the general Formula IIIb made in the absence of acids or dehydrating agents, so leave The corresponding thioureas isolate themselves as intermediate products, which are then isolated by heating can be converted into the process products with acids or water-releasing agents.

The starting materials of the general formula IV required for the reaction according to b) are obtained by z. B. Compounds of general formula II in which X is a halogen atom, an alkoxy, Alkanoyloxy or alkylthio group, with isocyanates of the general formula

R-N = C = O

where R has the meaning defined above. Furthermore, compounds of the formula IV, in which X is a hydroxyl group, for example by degradation of appropriately substituted derivatives of o-carboxy-benzophenones according to Hoffmann or Curtius and implementation of the so formed o-Isocyanato-benzophenones with amines of the general formula VI and subsequent reduction receive. Instead of compounds of the general formula IV can also be used in the reaction according to b) functional derivatives of these ureas, d. H. Compounds that instead of the urea grouping their Precursors such as the carbodiimide group or the chloroformic acid amidine group are converted into process products.

The reaction of the compounds of the general formula IV with hydrogen sulfide or inorganic sulfides, such as alkali metal sulfides or phosphorus pentasulfide or mixtures thereof, is carried out at temperatures of 50 to 200 ⁰ C, preferably 80 to 160 ⁰ C, optionally with the addition of acid and the use of an organic solvent, for example one aromatic hydrocarbon such as benzene, toluene or xylene or an aliphatic or aromatic chlorinated hydrocarbon such as carbon tetrachloride, tetrachloroethane or chlorobenzene, carried out. Depending on the boiling point of the solvent used and the necessary reaction temperature, especially when using hydrogen sulfide, the reaction may be carried out under pressure.

Compounds of the general formula IV, in which X stands for the sulfhydryl group, can also by Implementation with dehydrating agents, such as inorganic acid halides and anhydrides, in the process products are transferred.

Compounds of the general formula V, as required as starting materials for the reaction with the amines of the formula VI or their salts according to c), can be prepared, for example, by reacting compounds of the formula II according to a) with thiourea. This gives compounds of the formula V in which R _{3 is} the amino group. If compounds of the general formula II, in which X is a halogen atom, the hydroxyl, sulfhydryl or an alkanoyloxy group, are reacted with carbon disulfide or alkali metal oxanthates in the presence of bases such as alkali metal hydroxides (e.g. in analogy to J. pharmaz. Soc. Japan, 57, 54 [1937]; C. 1937 II, 2840), compounds of the general formula V arise in which R ₃ denotes the sulfhydryl group. The mercapto compounds obtained can optionally be alkylated, R ₃ having the meaning of the S-alkyl group. The compounds of general formula V in which R _{3 is} a chlorine or bromine atom are, for. B. by reacting the aminobenzhydryl halides of the general formula II (X = Cl, Br) with thiophosgene or from Ver

bonds of the general formula V, in which R ₃ denotes the amino group, are accessible with the aid of the Sandmeyer reaction (e.g. in analogy to HeIv. Chim. Acta, 32, pp. 63 to 68 [1949]).

The reaction according to c) takes place at temperatures between 20 and 250 ⁰ C, preferably between 80 and 200 ° C, for a reaction time of 15 minutes to 24 hours, with the choice of reaction conditions on the reactivity of the compound of general formula V employed is dependent. The use of a solvent or diluent is useful here, but not absolutely necessary. Suitable solvents are mainly aromatic hydrocarbons, such as benzene, tuluene and the xylenes, aliphatic and aromatic chlorohydrocarbons such as chloroform, tetrachloroethane, chlorobenzene, and ethers, such as tetrahydrofuran, dioxane, glycol dimethyl and diethylene glycol diethyl ether, and an excess of the amine used can also be used as the solvent Solvents can be used. Depending on the boiling point of the amine and the solvent used and the required reaction temperature, the reaction may have to be carried out in a closed vessel.

For the reaction of compounds of the general formula V, in which R ₃ denotes the amino group, according to d) with reactive derivatives of alcohols of the general formula VII, alcohol derivatives in particular include their halides, such as chlorides, bromides, iodides, and also the corresponding sulfates, carbonates and Alkyl or aryl sulfonates are suitable, for example methyl iodide, dimethyl sulfate, ethyl iodide, ethyl toluene sulfonate. The alkylation is carried out in the customary manner in the presence of basic condensing agents, such as alkali metal carbonates and hydroxides, alkali metal alcoholates, alkali metal and alkaline earth metal amides and hydrides.

The process products can be used as basic compounds with the aid of inorganic or organic Acids are converted into the corresponding salts. Examples of inorganic acids are into consideration: hydrohalic acids, such as hydrochloric acid and hydrobromic acid, as well as Sulfuric acid, phosphoric acid and sulfamic acid. Examples of organic acids are: 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, emboxylic acid, naphthalenedisulfonic acid or toluenesulfonic acid.

The compounds prepared according to the method are in animal experiments with low toxicity with respect to their central depressive effect of the comparison substance 7 - chloro - 2 - methylamine - 5 - phenyl - 3 H-1,4-benzodiazepine-4-oxide consider how by registering the spontaneous and provoked motility in the mouse and in the somnolence test (N i e s c h u 1 z, O. et al, Arzneimittelforschg., 6, 651 [1956]) would.

Dilute sodium hydroxide solution made alkaline and extracted several times with ether. The ether solution, washed with water and dried over sodium sulfate, is evaporated and the solid residue that remains is recrystallized from benzene-petroleum ether. Obtained in this manner 40.8 g (85% of theory) of 2-amino-4-phenyl-4H-3, l-benzothiazine as colorless crystals of melting point 148-149 ⁰ C.

Example 2

2-methylamino-4-phenyl-4H-3, l-benzothiazine

30 g of 2-aminobenzhydrol are dissolved in 450 ml of ether and refluxed with 11 g of methyl mustard oil for 1 hour. The ether is then evaporated off and the residue is refluxed with 10 ml of concentrated hydrochloric acid for 30 minutes. The reaction mixture is diluted with water, made alkaline with dilute sodium hydroxide solution and extracted several times with benzene. The benzene solution, washed with water and dried over sodium sulfate, gives 2-methylamine-4-phenyl-4H-3, l-benzothiazine as a yellowish oil which soon solidifies in crystalline form after the solvent has been stripped off in vacuo. Recrystallization from benzene-petroleum ether gives 29.5 g (78% of theory) of colorless crystals of melting point 99 to 100 ⁰ C.

Example 3

2-Amino-4-phenyl-6-chloro-4H-3, l-benzothiazine

46.7 g of 5-chloro-2-aminobenzhydrol and 15.2 g of thiourea are dissolved in 100 ml of 48% strength hydrobromic acid Heated to reflux with stirring for 1 hour. After the initial solution begins soon the hydrobromide of 2-amino-4-phenyl-6-chloro-4H-3, l-benzothiazine to be deposited as a crystalline precipitate, which after cooling by suction isolated, washed with acetone and recrystallized from ethanol. 60.2 g (84% of the Theory) colorless crystals with a melting point of 277 to 278 ° C (decomposition).

The above hydrobromide does not need to be isolated for the preparation of the free base. Man in this case dilutes the reaction mixture with the amount sufficient to dissolve the salt Water and makes alkaline with dilute sodium hydroxide solution. After the precipitate has been filtered off with suction and recrystallized 48.5 g (88% of theory) of 2-amino-4-phenyl-6-chloro-4H-3, l-benzothiazine are obtained from benzene-petroleum ether or from ethanol from a melting point of 170 to 171 ° C.

Example 4 example 1

2-Amino-4-phenyl-4 H-3, l-benzothiazine benzhydrol with 7.6 g of thiourea in 50 ml of 48%

39.8 g of 2-aminobenzhydrol and 15.2 g of thiouric hydrobromic acid analogous to Example 3 are 26 g

2-Amino-4-phenyl-6-bromo-4H-3, l-benzothiazine
By reacting 27.8 g of 5-bromo-2-amino

substance are refluxed for 1 1/2 hours with stirring in 100 ml of 48% hydrobromic acid. After cooling, the reaction mixture is mixed with (81% of theory) 2-amino-4-phenyl-6-bromo-4H-3, l-benzothiazine from melting point 198 to 199 ° C receive.

Example 5

2-methylamino-4-phenyl-6-chloro-4H-3, l-benzothiazine

a) A solution of 46.7 g of 5-chloro-2-aminobenzhydrol in 500 ml of ether is mixed with 18.3 g of methyl mustard oil and stored for 24 hours at room temperature. About two thirds of the solvent is then distilled off in vacuo and the crystalline precipitate is isolated by suction. Obtained in this manner 50.5 g (83% of theory) of pure N-methyl-N '- [4-chloro-2- (uhydroxybenzyl)] - phenyl - thiourea melting point of 164-165 ⁰ C.

b) 30.6 g of the thiourea obtained according to a) are dissolved in 100 ml of 48% hydrobromic acid Boiled under reflux with stirring for 1 hour. The cooled reaction mixture is diluted with Sodium hydroxide solution made alkaline and extracted several times with ethyl acetate. After evaporation of the solvent remains behind in vacuo

■ yellowish oil that solidifies in crystalline form after a while. Recrystallization from benzene petroleum ether gives 25.6 g (89% of theory) of 2-methyl-amino-4-phenyl-6-chloro-4 H-3,1-benzothiazine as colorless crystals with a melting point of 109.5 to 110 , 5 ⁰ C.

c) 23.4 g of 5-chloro-2-aminobenzhydrol and 7.3 g of methyl mustard oil are in 50 ml of 48% hydrobromic acid for 2 hours with stirring and reflux cooked. The reaction mixture is then worked up as described under b) and the reaction product obtained for purification on basic aluminum oxide, activity III, chromatographed using benzene as the eluant. That won in this way 2 - methyl - amino - 4 - phenyl - 6 - chloro-4 H-3,1 -benzothiazine melts at 109.5 to 110.5 ° C and is identical to the compound described under b). The yield is 20.7 g (72% theory).

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

40

45

a) 35 g of 5-chloro-2-aminobenzhydrol are together with 26 g of ethyl mustard oil for 5 minutes on the Steam bath heated and then stored overnight at room temperature. The resulting Crystal pulp is boiled with 75 ml of benzene to remove excess mustard oil. This gives 43 g (89% of theory) of N-ethyl-N '- [4 - chloro - 2 - (α - hydroxybenzyl)] - phenyl - thiourea as colorless crystals with a melting point of 147 to 148 ° C, which also occurs during recrystallization from ethyl acetate-petroleum ether remains constant.

b) 32 g of the thiourea obtained according to a) are heated with hydrobromic acid as in Example 5 b), 25.6 g (85% of theory) of 2-ethylamino-4-phenyl-6-chloro-4 H -3, 1 benzothiazine of melting point 118-120 ⁰ C.

c) In analogy to Example 5 c), 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 theory) of 2-ethylamino - 4 - phenyl - 6 - chloro - 4 H - 3,1 - benzothiazine melting point of 118-120 ⁰ C.

Claims (2)

Patent claims:
1. 4H-3,1-Benzothiazines of the general For NO wherein R denotes a hydrogen atom or a lower alkyl group, and R ₁ and R _{2 are} identical or different and denote hydrogen or halogen atoms, and their salts with inorganic and organic acids. 2. Process for the preparation of 4H-3,1-benzothiazines according to claim 1, characterized in that either in a known manner a) a compound of the general formula II wherein X is a chlorine or bromine atom, a hydroxyl. Sulfhydryl, alkoxy, alkylthio or alkanoyloxy group means with thioureas of the general formula IHa NHR (HIa) NHR or isothiocyanates of the general formula III I-S = C = N-R (HIb) or corresponding isothiocyanate formers, if necessary with the addition of acids and / or odc dehydrating agents, or. b) a compound of the general formula I \ Il / N-C-NHR X (IV) R, or corresponding functional derivatives this ureas with hydrogen sulfide or anorti 109 529 /: niche sulfides or dehydrating agents, optionally with the addition of acids, or c) a compound of the general formula V. wherein R _{3 is} a chlorine or bromine atom, an amino, sulfhydryl or S-alkyl group, with Amines of the general formula VI or their salts R '- NH, (VI) where R 'is the meaning of R with the exception of a water atom, or
d) ^ eJfIe ₇ compound of the general formula V onn R ₃ denotes the amino lip, with a reactive derivative of an alcohol of the general Formula VII R'-OH (VII) converts and optionally the basic compounds obtained according to a) to d) by treatment converted into their acid addition salts with inorganic or organic acids.