CH492729A - (A) 3,1-Benzothiazines and 3,1-benzoxazines of gen. formula (I), where A = O or S R = H, alkyl, cycloalkyl, alkenyl, cycloalkenyl aryl, aralkyl, or - Google Patents

Abstract

(A) 3,1-Benzothiazines and 3,1-benzoxazines of gen. formula (I), where A = O or S R = H, alkyl, cycloalkyl, alkenyl, cycloalkenyl aryl, aralkyl, or lower dialkylaminoalkyl in which the dialkylamino group can also be cyclized via O, S, or methyl- or benzylimino, R1 = H, halogen, methoxy, CF3, NO2 R2 = alkyl, aralkyl, or aryl, in which the benzene rings of the last two can be substituted by halogen, methoxy, CF3, NO2. (B) Salts of I formed with organic and inorganic acids. Compounds (1) combine valuable pharmacological properties with very low toxicity. They are central depressants, as well as stimulants, sedatives, noradrenaline potentiators, analgesics and spasmolytics, and they prolong narcosis. They are useful in the treatment of mental diseases, e.g. depression, psychioneuroses, disturbances and anxiety states of neurotic and psychotic patients.

Description

  

  
 



  Process for the preparation of new 3,1-benzoxazine derivatives
The invention relates to a process for the preparation of new 3,1-benzoxazine derivatives with valuable pharmacological properties.



   It has been found that compounds of the formula
EMI1.1
 in which R is hydrogen, an alkyl group with 1-6 carbon atoms, a cycloalkyl group with 5-8 carbon atoms, an alkenyl group with 3-6 carbon atoms, a cycloalkenyl group with 5-6 carbon atoms, a phenyl group, a phenalkyl group with 1 - 3 carbon atoms in the alkylene radical or a dialkylaminoalkyl group with 1 - 4 carbon atoms in the alkyl radicals and 1 - 4 carbon atoms in the alkylene radical, the dialkylaminoalkyl group also optionally via an oxygen or sulfur atom or a methyl or .

  Benzyl-imino group can be closed to form the ring, Rl is hydrogen, halogen atoms, methoxy, trifluoromethyl or nitro groups, R2 is alkyl with 1-4 C atoms, phenalkyl with 1-3 C atoms in the alkylene radical or phenyl, the phenyl rings being through Halogen atoms, methoxy, trifluoromethyl or nitro groups can be substituted and their
Salts with inorganic and organic acids are obtained when compounds of the general formula
EMI1.2
 in which R1 and R2 have the above meaning and X is a chlorine or bromine atom, a hydroxyl, alkoxy or alkanoyloxy group, with compounds of the general formula O = C = Y in which Y is the groupings
EMI1.3
 and the two radicals R can be identical or different, optionally with the addition of acids and / or dehydrating agents,

   and, if appropriate, the basic compounds obtained are converted into their acid addition salts by treatment with inorganic or organic acids.



   For example, 2-amino-benzhydrols are suitable as starting materials of the general formula II for the reaction. Of these, the following may be mentioned: 2-aminobenzhydrol, 2-aminofluorobenzhydrols, 2-amino-chlorobenzhydrols, in particular 2-amino-5-chlorobenzhydrol, 2 aminobromobenzhydrols, 2-amino-methoxybenzhydrols, 2-aminotrifluoromethylbenzhydrols, 2-amino-nitrobenz.



  hydrols, in particular 2-amino-5-nitrobenzhydrol, 2-amino-methoxy-chlorobenzhydrols, 2-amino-nitrobromobenzhydrols, 2-amino-trifluoromethyl-nitrobenzhydrols, 2-amino-trifluoromethylchlorobenzhydrols, the substituents mentioned after 2-amino in the 3-, 4-, 5- or 6-position of one and / or in the 2'-, 3'- or 4'-position of the other benzene ring and 2 -amino-chloro-dimethoxybenzhydrole, 2-amino-nitrochlor- fluorobenzhydroles or 2-amino-methoxy-dichlorobenzhydrols, where of the substituents mentioned following 2-amino- one in each case in the 3-, 4-, 5- or 6-position of the benzene ring bearing the amino group and two in the 2'-, 3 '-, 4'-, 5'- or 6'-position of the other benzene ring can be.

  Furthermore, the lower alkyl ethers corresponding to the abovementioned benzhydrols, such as 2-amino-benzhydryl methyl ether, -ethyl ether, or the corresponding esters with lower aliphatic carboxylic acids, e.g. the acetates or propionates of the benzhydrols mentioned are used. The corresponding halides such as 2-aminophenyl-phenyl-chloro- (or -bromo) -methane and the compounds correspondingly substituted in the phenyl radicals can also be used.



   Also suitable as starting materials of the general formula II are z-alkyl-2-aminobenzyl alcohols and α- aralkyl-2-aminobenzyl alcohols. Of these, there may be mentioned: α-methyl-2-aminobenzyl alcohol, α-methyl -2-aminofluorobenzyl alcohols, z-methyl-2-aminochlorobenzyl alcohols, 1-methyl-2-aminobromobenzyl alcohols,, oc-methyl-2-aminomethoxybenzyl alcohols, oc - methyl 2-aminotrifluoromethylbenzyl alcohols, oc - methyl-2-aminonitrobenzyl alcohols, G-ethyl-2-aminobenzyl alcohol, oc- -ethyl - 2-aminochlorobenzyl alcohols, sc - ethyl -2-

   amino methoxybenzyl alcohols, 5s - ethyl-2-aminotrifluoromethylbenzyl alcohols, Z-ethyl-2-aminonitrobenzyl alcohols, oc- -propyl-2-aminobenzyl alcohol, 5s - propyl -2- aminochlorobenzyl alcohols, X - propyl-2-zyl-aminopropyl alcohols, X-propyl-2-zyl-aminopropole -2-aminobenzyl alcohol.

   a-Isopropyl-2-amino-bromobenzyl alcohols, r, -Isopropyl-2-aminomethoxybenzyl alcohols, X-butyl -2-aminobenzyl alcohol, z-butyl-2- aminochlorobenzyl alcohols, sc-isobutyl-2-aminobenzyl alcohol, z-isobutyl 2-aminochlorobenzyl alcohols, sc-benzyl- -2-aminobenzyl alcohol, z- - benzyl-2-aminochlorobenzyl alcohols, r, -benzyl-2-aminomethoxybenzyl alcohols, whereby the substituents mentioned after 2-amino- in 3-, 4 -, 5- or 6-position of the benzene ring can be.



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



   The corresponding halides such as methyl-2-aminophenylchloro- (or -bromo) -methane and the compounds correspondingly substituted in the phenyl radical can also be used.



   The salts with strong acids such as hydrohalic acids, sulfuric acid and benzene and toluenesulphonic acid, derived from the basic compounds mentioned, are also suitable as starting materials.



   As starting materials of the general formula III isocyanic acid and isocyanates such as methyl, ethyl, propyl. Isopropyl. Butyl, isobutyl, hexyl, cyclohexyl, allyl, cyclohexenyl, phenyl, benzyl, dimethylaminopropyl isocyanate can be used, as well as isocyanate formers (cf. Houben Weyl Methods of Organic Chemistry 4th ed. Vol. 8, p. 119-127) as well as the corresponding carbamic acid chlorides and urethanes.



   The reaction of the compounds of the general formula II with the compounds of the general formula III takes place in a manner known per se. Urea derivatives formed as intermediates, which can be isolated as intermediates if desired, are then expediently converted into the process products by treating the reaction mixture or the isolated intermediate compounds with inorganic or organic acids or with dehydrating agents, with increased temperatures being advantageous depending on the reaction rate .



  If appropriate, the reaction can be carried out in an additional solvent or diluent, the selection of the suitable solvent or diluent being determined by the stability and reactivity of the respective reaction components.



   For the reaction of the benzhydryl halides of the general formula II (X = Cl, Br) or their acid addition salts with the compounds of the general formula III, the presence of acids or dehydrating agents for cyclizing the urea derivatives formed as intermediates is generally not necessary. These reactions can preferably be carried out in the melt or by heating in a suitable solvent.



   The reaction times can be varied within wide limits depending on the reactivity of the components and the selected temperature. For work-up, the reaction products of the general formula I, which are usually obtained as salts, can be isolated directly, if appropriate after concentration of the solution, and, if desired, converted into the free bases by subsequent treatment with alkali. The reaction mixture can also be made alkaline before isolation, whereby the process products can be isolated in the customary manner in the form of the free bases.



   The products of the process can be converted into the corresponding salts as basic compounds with the aid of inorganic or organic acids.



  Examples of inorganic acids are: hydrohalic acids, such as hydrochloric acid and hydrobromic acid, and also 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, oxyethanesulphonic acid and ethylenediaminetetraacetic acid or toluenesulphonic acid, naphthalenesulphonic acid.

 

   The compounds prepared according to the method show good central damping properties with low toxicity even in low doses, with a remarkable delayed effect being observed in addition.



  In addition, an interesting anticataleptic effect can be demonstrated in the tetrabenzazine test described below.



   The products of the process are clearly superior to the well-known 2-ethylamino-4H-3,1-benzoxazine in every respect. E.g. the 2-ethylamino-4-phenyl-6-chloro-4H-3, 1-benzoxazine produced according to the process is much less toxic than the comparison substance, but has a stronger sedative effect. Furthermore, 2-ethylamino-4-phenyl-6-chloro-4H-3, 1 -benzoxazine has anticataleptic properties, as well as muscle-relaxing and anesthetic-prolonging effects, which the comparison substance lacks. The central depressive effect expressed in the sedative effect mentioned above was determined by recording the spontaneous and provoked motility in the mouse and in the somnolence test [Nieschulz, O. et al .: Arzneimittelforschg. 6,651 (1956)], the anesthesia prolongation in the usual way.

  The breakthrough or reversal of the mouse catalepsy caused by 2-oxo-3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11 b H-benzo (quinoflzin (tetrahenazine)) was achieved in a modification of that described by Sulser et al [Fed. Proc. 19, 268 (1960) and Ann. NY



  Acad. Sci. 96, 279 (1962)] tested test arrangement described.



   The products of the process can be applied as such or in the form of corresponding salts, optionally with admixture of customary pharmaceutically acceptable carriers. The pharmaceutical preparations can be in the form of tablets, coated tablets, capsules or suppositories; they can also be in liquid form as solutions.



  Suspensions or emulsions are administered. Substances that do not react with the process products, such as e.g. Water, gelatine, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols and the like. They can be sterilized and / or treated with stabilizers. The pharmaceutical preparations can also contain other therapeutically valuable substances.



   The products of the process are used to treat mental illnesses, e.g. Depression, psychoneuroses, moods and anxiety states of neurotic and psychotic origin.



   The temperatures in the following examples are given in OC.



   Example I 2-Amino-4-phenyl-6-chlor4fl-3, 1-henzoxazine a) In a solution of 10.2 g of 5-chloro-2-aminobenzhydrol in 300 ml of glacial acetic acid, 30 g of potassium cyanate are added in portions while stirring and cooling entered about 15 minutes. After a further 10 minutes, the reaction mixture is heated on the steam bath for a quarter of an hour and, after cooling, diluted with water. The precipitated N- [4-chloro-2 - (- hydrnxy-benzyl)] - phenylurea is filtered off with suction after 2-3 hours, washed with water, dried and recrystallized from ethyl acetate / petroleum ether. 61.5 g (74% of theory) of colorless crystals with a melting point of 157 to 1590 are then obtained.



   b) 14 g of the urea prepared according to a) are heated with 50 ml of 48% hydrobromic acid for 5-10 minutes while stirring on the steam bath and then rapidly cooled. It is diluted with water and decanted, the semi-solid residue is taken up in methylene chloride and shaken with dilute sodium hydroxide solution.



  The methylene 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 converted into the oxalate, which crystallizes from ethanol / ether in colorless crystals with a melting point of 167-1680. Yield: 12 g (69% of theory). By shaking the oxalate with methylene chloride and dilute sodium hydroxide solution and concentrating the organic phase, the free base can be obtained, which melts at 133-1340 after recrystallization from benzene / petroleum ether.



   Example 2 2-Ethylansino-4-phenyl-4H-39 erezoxazine a) 7.1 g of freshly distilled ethyl isocyanate in 30 ml of chloroform are added dropwise to a solution of 20 g of 2-aminobenzhydrol in 200 ml of chloroform while stirring and cooling with ice. The mixture is stirred for a further 30 minutes at room temperature and then the solvent is removed in vacuo. The brownish oil that remains is taken up in hot benzene and petroleum ether is carefully added to the benzene solution. On cooling, 19 g (70 SO of the theory) of N-ethyl-N '- [2- (la-hydroxybenzyl)] - phenylurea with a melting point of 132-1340 crystallize out.



   b) A suspension of 13.5 g of the urea prepared according to a) in 100 ml of ethanol is mixed with 17.5 g of p-toluenesulfonic acid with stirring and then refluxed for 45 minutes. After cooling, it is made alkaline with sodium hydroxide solution, diluted with water and extracted with ether. From the ether solution washed with water and dried over sodium sulfate, after evaporation of the solvent, 2-ethylamino-4-phenyl-4H-3,1-benzoxazine is obtained as a yellowish oil. Redissolving in hexane gives 7.2 g (57% of theory) of colorless crystals with a melting point of 76-780.



   Example 3 24sobutylainino-4-phenyl-6-chloro-4H-3, 1 -benzoxazine
16.6 g of N-isobutyl-N'-C4-chloro-2- (α-hydroxybenzyl) 1-phenylurea [mp. 152-1540 (from benzene / petroleum ether), represented by the reaction of 2-amino-5-chlorobenzhydrol with isobutyl isocyanate in ether analogous to Example 2 a), are heated with hydrobromic acid as described in Example 1 b). Appropriate work-up gives 14.3 g (91% of theory) of 2-isobutylamino-4-phenyl-6-chloro-4H-3.1-benzoxazine as colorless crystals with a melting point of 117-1180 (from petroleum ether).

 

   Example 4
15 g of N-ethyl-N '- [4-chloro-2- (c -hydroxybenzyl)] - phenylurea melting point 130-1320 (shown analogously to Example 3 are mixed with 50 ml of 48% HBr for 5-10 minutes Stirring heated on the steam bath and then rapidly cooled. After working up as in Example 1 b), 12.5 g (88% of theory) of 2-ethylamino-4-phenyl-6-chloro-4H-3,1-benzoxazine are obtained from mp. 124-1250.

 

Claims (1)

PATENT CLAIM Process for the preparation of compounds of the formula EMI3.1 in which R is hydrogen, an alkyl group with 1 - 6 C atoms, a cycloalkyl group with 5 - 8 C atoms, an alkenyl group with 3 - 6 C atoms, a cycloalkenyl group with 5 - 6 C atoms, a phenyl group, a phenalkyl group with 1 - 3 C atoms in the alkylene radical or a dialkylaminoalkyl group with 1 - 4 C atoms in the alkyl radicals and 1-4 C atoms in the alkylene radical, the dialkylaminoalkyl group also optionally via an oxygen or sulfur atom or a methyl or . Benzyl-imino group can be closed to the ring, R1 hydrogen, halogen atoms, methoxy, trifluoromethyl or nitro groups, R alkyl with 1-4 carbon atoms, phenalkyl with 1-3 carbon atoms in the alkylene radical or phenyl, the phenyl rings through Halogen atoms, methoxy, trifluoromethyl or nitro groups can be substituted, characterized in that a compound of the formula EMI4.1 in which X is a chlorine or bromine atom, a hydroxyl, alkoxy or alkanoyloxy group, with a compound of the formula O = C = Y where Y is the grouping EMI4.2 means and the two radicals R can be identical or different. SUBCLAIMS 1. The method according to claim, characterized in that the reaction is carried out with the addition of acids and / or dehydrating agents. 2. The method according to claim, characterized in that the basic compounds obtained are converted into their acid addition salts by treatment with inorganic or organic acids.