IL27245A - N-trifluoroethyl-1,4-benzodiazepin-2-one derivatives and process for their manufacture - Google Patents

Description

P.A. 272 5 II N-TRIFLUOROETHTL-L.4-BENZOPIAZEPIN—2-ONE-DERIVATIVES AND PROCESS FOR THEIR MANUFACTURE IK-re N- The invention relates to novel .-?-one eri vati P.κ pine eewpounai processes for their preparation and compositions containing these compounds.

The compounds of the invention are 1, ^benzodiazepines having the formula I independently selected from wherein X and Y areynydrogen, halogen, trifluoromethyl, and are nitro, alkyl &e- alkoxy; and, R]_ and R2I independently selected from offlgi hydrogen or one of and 2 is free hydroxy or alkanoyloxy o-r eotorifiod hydroxy and the other is hydrogen; I . J „ , J *- independently selected f om and the 4-oxides thereof when R-j_ and R2 a^iftydrogen and err alkyl. oyloxy group. The alkyl, alkoxy and alkanoyloxy substituents possibly present are preferably lower alkyl, lower alkoxy and lower alkanoyloxy respectively.

Tho term lower alkyl P.A. 272¾5 lII he term lower alkyl includes both straight and branched-chain hydrocarbon radicals. Preferably the lower alkyl group contains up to 6 carbon atoms* In like manner, lower alkoxy has a similar r ge of preferably up to 6 carbon atoms, including straight and branched—chain isomers. Lower alkanoyloxy preferably means hydrocarbon carboxylic acid radicals having up to 6 carbon atoms. Among these ares methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, methoxy, ethoxy, acetyl, propionoxy, isobutyroxy and capryloxy. The term halogen covers all four members. However, of particular value are those wherein X represents chloro or brotno and Ύ represents, fluoro or chloro. Of particular interest are these compounds in which Tt_^ is hydrogen, is hydrogen, alkyl, hydroxy or alkanoyloxy X is hal gen, preferably chloro attached to the 7-position, and Y is hydrogen or chloro or fluoro in the O-position.

The compounds of this invention exert an effect upon the central nervous system and as such are mseful as muscle relaxants, sedatives, anti-convulsa ts and anti-anxiety agents. 2H- 5-Phenyl-l, 4-benzodiassepine-2-ones and ^-oxides thereof similar to the new compounds are known in the art e.g. from Dutch patent application No .64 01 335» British patent specification 1 ,021 , 381 , Chemical Abstracts 62 (1965 ) , 5288b). This literature discloses benzodiazepines having hydrogen, alkyl, aralk l or alboyl in position 1. The said compounds are known to have anti-convulsive and muscle relaxant activity.

It has now been found that 1 ,%-benxodiazepin^-2-ones P.A. 272¾5/lII exert an effect on the central nervous system and as such are useful as muscle relaxants, sedatives, anticonvulsants, tranquilizers and anti-anxiety agents show important advantages above the compounds known from the literature cited above. In pharmacological testing there has been observed significant differentials between a tranquil!zing dose and one which causes neurological impairment. The therapeutic ratio (ratio of effective dose required to produce neurological impairment to the effective dose required to produce a tranquilizing e ect ) is signi icantly higher in the tangible embodiments than that observed in analogous compounds presently known in the art. In comparison with the known compounds the new compounds show higher an i-convulsive activity, low locomotor impairment and locomotor respiratory depression. By way of farther advantage, it has been found that test animals do not develop a tolerance to the tangible embodiments on repeated treatment in anti-convulsant evaluation.

The present N-triflyoroethylated 1,4-benzodiazepines and 4-oxides may be prepared in any convenient way, such as by methods suitable for the preparation of the corresponding compounds without the 1-tritluoroethyl subs ituent, preferably the corresponding 1-mnsubstituted or methyl-eubstituted compounds. They may be very advantageously prepared from intermediates already bearing the desired triflueroethyl radical, or by tri luo oothylation of the corresponding l-unsubstituted compounds. When i' is desired tc prepare the present - trif luoroeth lated compounds from the corresponding l-unsubstituted compounds several tri luoroethylation procedures may be utilized, such as methods making use of a compound of the formula CF_-CH - , wherein A is a reactive grouping, such as a reactive organic or inorganic ester grouping. Alternatively, for example,, a grouping C (Hal)_-CH2- . with Hal representing a halogen other than fluoro3 rnaj first be introduced., whereupon Hal is replaced by fluoro, such as by reaction with silver fluoride. In a preferred instance the said l-unsubstituted compound is subjected to alkylation with a sulfonate ester of tri~ fluoroethanol of the general formula CF^CH^OSO^ wherein Z is a member of the group consisting of alkyl, aryl, aralkyl and polyhaloalkyl . Among the sulfonate esters which may be used are 2,2,2-trifluoroethyl-methylsulfonate, 2, 2, - trifluoroethyl phenylsuifonate, 2, 2, 2-trifluoroethyl-benzylsulfonat and 2, 2, 2-tri luoroethyl- trichloro-methylsul onate . In effecting this alkylation reaction, the reactant are usually heated together in an anhydrous solvent system at reflux temperatures in the presence of an inorganic base such as potassium carbonate. Among the solvents useful for this reaction are diphenylet digl^me and tetralin. In another convenient embodi ment the appropriately X and Y substituted benzo- diaz&pine starting materials are alkylated with 2, 2, 2-trifluoroethyl bromide, chloride or preferably iodide. The trifluoroethylation reaction with these halides is preferably effected in non reactive organic solvents such as dimethyl- ormamide or aromatic hydrocarbons like benzene, toluene or xylene in the presence of a basic condensing agent according to standard techniques. Among the basic condensing agents which may be used are sodium methoxide, sodium hydride, potassium t-butoxide, and sodium amide.

The reaction is usually conducted at temperatures in the range from about 20 to about 110°C, preferably around 65°C, and for a period of time ranging from 1 to 2h hours, preferably about 7 hours, followed by the further addition of trifluoroethyl halide and further reaction for approximately l6 hours .

The trifluoroethylated benzodiazepine products may be isolated by filtration of the insoluble salts, evaporation of the filtrate, further isolated by selective solvent extraction techniques, and purified by chromatographic techniques such as by elution from an alumina adsorption column.

When it is desired to prepare the 1- tri luoroethylated 1, -benzodiazepines according to the invention from intermediates already bearing the trifluoroethyl radical, several routes of synthesis are applicable.

Usually, the several routes of synthesis ultimately employ an N-trifluoroethyl-substituted aminobenzo-phenone of the general partial formula: wherein X and Y are as previously defined, which aminobenzophenone through condensation reactions may be transformed into the desired 1, -benzodiaze-pine, which, if desired, may be converted into o e of the previously defined -oxide^. aminobenzophenone of the general formula (ID IK-re wherein X and Y are as previously defined may be condensed, preferably by heating in the presence of a solvent, such as pyridine, with a compound having the ormula III : wherein and R^ are as previously defined, and R' is hydrogen or alkyl, preferably ethyl. Instead of the free acid or the ester, other reactive derivatives such as the halides may be used. The condensation may lead directly to the desired end product, or an intermediate (IV) may first be formed which undergoes further reaction to give the 1,4- benzodiazepine . Reaction scheme A illustrates this condensation: (II) (i ) , IK- e 908 Israel (I) In the above described reaction the amino group preferably is protected, either by substitution or by forming an addition salt. The preferred protecting substituents are acyl groups, such as the phthaloyl carbobenzoxy or the phthalimido group. Among the addition salts which may be used, the hydrochloride is preferred.

Instead of the aforementioned aminoace ic acid or acid derivatives (III) one can also use the corresponding halo compounds wherein the NH^-group is replaced by chloro, iodo or preferably bromo (III' ) In the first step the condensation using such a haL compound yields a 2- [N-(2, 2, 2-trifluoroethyl) -a-halo acetamido ]-benzophenone (IV' ) which is then reacted with ammonia to yield the corresponding 2- [N- ,(2,2,2 trifluoroethyl ) -a-amino-acetami^do ] -benzophenone, which simultaneously undergoes intramolecular condensation to give a compound of formula I, as illustrated in reaction scheme (IV) (I) The compounds of formula (IV) may also be used as starting compounds. By intramolecular condensation the desired end product is formed.

Moreover an intermediate of formula (IV' ) is a very convenient starting material and can be transformed into the corresponding 1, 4-benzodiazepine by treatment according to the two last steps of reaction scheme B.

By subjecting the trifluoroethylated products, wherein R^ and R^ represent hydrogen or alkyl to an oxidative treatment, the claimed 4-oxides are obtained. N-oxidation of an intermediate of the formula wherein R^ and R^ represent hydrogen or alkyl, followed by trifluoroethylation as described supra is another way for the preparation of these 4-oxides The oxidative treatment can be conveniently carried out by means of a peroxy acid like peracetic acid. The inventive wherein R. or R is or alkanoyloxy , , free or- oe ai'iffiodi'-hydroxy (may he prepared by heating the corresponding 1-tri luoroethylated or 1-unsubstituted -oxide with an anhydride such as acetic anhydride, followed, if desired, by hydrolysis of the esterified hydroxy group =h¾-to the free hydroxy group and, if necessary, introduction of a trifluoroeth l substituent in position 1.

An example of this transformation is given in reaction scheme C C: with alkali. (v ) (VI) (VII) 908 Israel 3fc/cm The hydroxyl group thus introduced can be converted in the usual manner into other esters, such as with acid chlorides or anhydrides of propionic acid, butyric acid, and valeric acid. 1 , -benzodiazepines The] tangible embodiments of this invention exert an effect on the central nervous system as determined by standard pharmacological evaluation and as such are useful as tranquillizer or antianxiety agents. In addition the novel compounds exhibit valuable anti-convulsant and muscle relaxant properties. In pharmacological testing there has been observed significant differentials between a tranquillizing dose and one which causes neurological impairment. The therapeutic ratio (ratioi'.of effective dose required to produce neurological impairment to the effective dose required to produce a tranquillizing effect) is significantly 1, ^-be ing to the invention higher in the than that observed in analogous compounds presently known in the art. In particular, 7-chloro-l,^-dihydro- 5-phenyl-l- (2,2, 2- trif luoroethyl ) -2H-1, -benzodiaz-e ^pine 2-one has a therapeutic ratio of about 1 which indicates that the neurological impairment dose is about 13 times greater than that dose required to produce a tranquillizing effect according to . -accepted pharmacological testing methods. By way of further advantage, it has been found that IK-re test animals do not develop a tolerance to the 1, -benzodiazepines according to the invention tangible embodim«a-fe-& on repeated treatment in anti convulsant evaluation.

The taii|i¾¾¾z¾te¾ ¾¾¾¾¾ of this invention are preferably administered via the oral route and for such are compounded into pharmaceutical dosage forms such as tablets, capsules, elixirs, and solutions. In the compounding, a dosage unit may contain the usual excipients like starches, gums and alcohol bases commonly employed. In 1, ^-benzodiazepines of this invention addition, the tangible embodiments may be incorporated into a dosage unit together with another active therapeutic agent. The dose depends upon the patient and severity of condition being treated. Normally a dose of about 0.1 to 1.0 mg. per kg. body weight per day, given in three or four divided doses is sufficient to elicit a therapeutic effect.

The following examples are illustrative of the production of 1, 4-benzodiazepines according to the preparation of ropreoentationo of tho tangiblo embodimentc of thio invention: Exam le 1 7^C loro-l,3-dihydro-5-phen ^ Prepare a solution of sodium methylate by dissolving 3· 9 grams of sodium metal in 500 ml. of methanol. Add 39*0 grams of 7-chloro-l,3-dihydro-5-phenyl-2H-l, -benzo-diazepinj£-2-one. Evaporate the reaction mixture to a residue and dissolve the residue in 170 ml. of dimethyl-formamide. Add 0 grams of 2, 2, 2-trifluoroethyl iodide and stir at room temperature for l/2 hour,, then heat to 60° - 70°C for an additional 7 hours. Add 19 grams of 2, 2, 2-trifluoroethyl iodide and resume the heating and stirring at 60° - 70°C for an additional l6 hours.

Filter off the solids and evaporate the filtrate to a residue in vacuo. Triturate the residue with water and extract with ethyl ether. Wash the ethereal extract with water^ dry over anhydrous sodium sulfate and evaporate the solvent to a residue. Extract the residue with ethyl ether and filter. Concentrate the ethereal extract to a residue. Dissolve the residue in benzene and chromatograph on 300 grams of alumina contained in a glass column 1.5 inches in diameter to give the curde product. Elute with benzene. Crystallize this product from acetone-petroleum ether to obtain the product of this example.

Alternatively, the compound of this example is prepared as follows: Dissolve 29. 5 grams of 2- ( 2, , 2-trifluoroethyl)-amino-5-chlorobenzophenone and 21. 0 grams of glycine ethyl ester hydrochloride in 200 ml. of pyridine. Heat the solution to reflux and maintain the reflux with stirring for 15 hours. During the first 4 hours remove approximately 0 ml. of solvent and replace with dry pyridine. Concentrate the solution in vacuo to a residue. Triturate the residue in water and extract with ether. Filter off any remaining solids and separate the solvent layers. Adjust the pH of the aqueous solution to 8. 0 - 8. 5 and re-extract with ether. Combine the ethereal extracts and wash them with water and dry them over anhydrous sodium sulfate. Chromatograph as described above.

Example 2 Zr9^i2$:ii2r ihyd o- =phen l-l-(2, 2, 2-trifluoroethyl)- 2H-1, 4-benzodiazepine^-2-one-4-oxide Dissolve 50.0 grams of 7-chloro-l, j5-dihydro-5-phenyl-2H-l,4-benzodiazepin -2-one in 1250 ml. of acetic acid. Cool the solution slightly and with agitation add 50 ml. of 40 peracetic acid. Maintain this solution at room temperature for 24 hours and precipitate by the addition of 10 liters of water with agitation. Neutralize the suspension with sodium carbonate and filter. Wash the precipitate with water and crystallize 7-chloro-l, 3-dihydro-5-phenyl-2H-l, 4-benzodiazepiry£-2-one-4-oxide from alcohol for use in the next step.

Prepare a solution of sodium methylate by dissolving 3.9 g. sodium metal in 500 ml. methanol. Add 39,8 g. of 7-chloro-l, 3-dihydro-5-phenyl-2H-l, 4-benzodiazepin^-2-one-4-oxide with stirring. Evaporate the methanol and dissolve the residue in 170 ml. dimethylformamide. Add 0 grams of 2, 2, -trifluoroethyl iodide and stir at room temperature for l/2 hour. Heat the mixture to 60° - 70°C with stirring for 7 hours. Add 19 grams of 2, 2, 2-trifluoroethyl iodide and heat with stirring at 60° - 70°C for a further l6 hours. Filter off the in-solubles and evaporate the filtrate to a residue in vacuo. Triturate the residue with water, extract with ether, wash the ethereal solution with water, dry the solution over anhydrous sodium sulfate and evaporate to a residue. Triturate the residue with ether and filter. Evaporate the ether to a residue, dissolve the residue in benzene and chromatograph on 00 grams of alumina contained in a glass column 1.5 inches in diameter. Elute with benzen to give the product. Crystalli ze this product from acetone-petroleum ether to give the purified product.

Example 3 ^-Acetoxy-T^chloro-l^-dihydro^ fluoroethyl) -2E-1, -benzodiazepin^-2-one Suspend 10 grams of 7-chloro-l, 3-dihydro-5-phenyl-l-( 2,2, 2-trifluoroethyl) -2H-1, -benzodiazepine'-2-one- -oxide in 100 ml. of acetic anhydride. Heat the mixture on the steam bath for 30 minutes with agitation. Cool and collect the product by filtration. Crystallize from acetone petroleum ether obtaining the product of this example.

Example 7-Chloro-l 3-dihydro-3-hydroxy-5-phenyl-l-( 2, , 2-tri- fluoroethy -2H-l, -benzodiazepin^-2-one Suspend 5 · 0 grams of the product of Example 3 in 100 ml. of alcohol. Add one equivalent of a 5^ sodium hydroxide solution while stirring. Dilute the reaction mixture with water until the product is fully precipitated.

Collect the product by filtration, wash with water, air dry and recrystallize from hexane to yield the compound of this example.

IKr-e Example 5 3-Propionyloxy-7-chloro-l,3 ^ihy^r2z5zPhenyl-l- (2, 2, 2- trifluoroethyl) -2H-1, -benzodiazepin^-2-one Suspend 3. grams of 7-chloro-l, j5-dihydro-j?*-hydroxy-5-phenyl-lr-( 2, 2, 2-trifluoroethyl ) -2H-1, ^-benzodiazepine' 2-one in 25 ml. of benzene and add 1 ml. propionyl chlo ride. Heat the mixture to reflux and maintain for 2 hours. Cool the reaction mixture and dilute with hexane to incipient crystallization. Cool and filter obtaining the product of this example.

Example 6 fluroethyl) -2H-1 -benzodiazepin^-2-one Dissolve 2^-2 grams of 2-amino-5-chloro-benzophenone in 200 ml. of pyridine. Add 22.9 grams alanine ethyl ester hydrochloride and bring the mixture to reflux. Slowly distiLi from the reaction mixture approximately 40 ml. of solvent. Reflux the mixture for a total of about 15 hours, then cool slightly and concentrate the mixture under reduced pressure to a residue. Add water to the residue and extract with ether. If there are insolubles present, filter the mixture and separate the solvent layers. Adjust the pH of the aqueous layer to 8.0 - 8.5 and extract with ether. Combine the ether layers, water wash and dry. Filter and concentrate the layers to a crystalline slurry. There is obtained 7-chloro-l, 3-dihydro-j5-methyl-5-phenyl-2H-l, 4-benzo-diazpein^-2-one which is used in the next step.

Prepare a solution of sodium methylate by dissolving 1.0 grams of sodium metal in 125 ml. methanol. Add 9.Q g. of 7-chloro-l, 3-dihydro---methyl-5-phenyl-2H-l, 4-benzodiaze-pine-2-one and evaporate the solution to a residue.

Dissolve the residue in 5 ml. of dimethylformamide.

Add 8 g. of 2S 2, 2-trifluoroethyl iodide and stir at room temperature for l/2 hour, then heat to 60° - 70°C for an additional 7 hours. Add g- of 2, , 2-trifluoroethyl iodide and resume heating and stirring at 60° - 70°C for an additional l6 hours. Filter off- the residue and proceed as in Example 1, obtaining the compound of this example.

Example 7 benzodiazepine^-2-one Prepare a solution of sodium methylate by dissolving 2.4 grams of sodium metal in 400 ml. of methanol. Add 2 · 6 g. of 1, 3-dihydro-5-phenyl-2H-l, -benzodiazepin^- 2-one and evaporate the reaction mixture to a residue.

Dissolve the residue in 150 ml. of dimethylformamide and add 25. 0 g. of 2, 2, 2-trifluoroethyl iodide to the mixture. Stir the mixture at room temperature for l/2 hour, then heat to 60° - 70°C for an additional 7 hours. Add 15 g. of 2, 2S 2-trifluoroethyl iodide and resume the heating and stirring at 60° - 70°C for an additional 16 hours. Filter off the solids and evaporate the filtrate to a residue in vacuo. Triturate the residue with water and extract with ethyl ether. Wash the ethereal extract with water^ dry over anhydrous sodium solution sulfate and evaporate the solvent to a residue. Extract the residue with ethyl ether and filter off the solids. Concentrate the ethereal extract to a residue and dissolve the residue in benzene and chromatograph on j500 g. of alumina as described in previous examples obtaining the compound of this example.

Example 8 benzodiazepine- 2-one-4-oxide Dissolve 5 - 0 g. of the product of Example 7 in 125 nil. of acetic acid. Cool the solution slightly and add 5 · 0 ml. peracetic of 0 T:e3C¾-2t]2 acid. Maintain this solution at room temperature for 2 hours and precipitate the product - by the addition of 1.0 liter of cold water followed by neutralization with sodium carbonate solution. Filter and wash the precipitate with water. Crystallize from alcohol obtaining the N-oxide of this example.

Example 9 7-Chloro-l-(2, 2, 2-trifluoroethyl)-5-phenyl-l, 3-dihydro 2H-1, -benzodiazeping-2-one Dissolve 52 gms. of 2- [N- ( 2, 2, 2-^'rxfluoroethyl) -2- brtiqacetamido ] -5-chlorobenzophenone in 1.0 liter of chloroform and bubble ammonia gas through the solution at room temperature for l8 hours. Evaporate the chloroform under reduced pressure, wash the residue with water, extract the residue with ether and wash the ethereal solution with water. Dry the solution over anhydrous sodium sulfate and evaporate the solution to a residue. Crystallize the residue from an acetone-petroleum ether mixture to yield 30 gms. of 7-chloro-l-( 2, 2, 2-trifluoroethyl)-5-phenyl-l,3-dihydro-2H-l, -benzo diazepin/½-2-one melting 164 - 166 C.

By following the process of this example using as a star ting compound 2- [N-( 2, 2, -trifluoroethyl-a-bromaceta-mido ] -5-chlorobenzophenone the 7-chloro-l- (2, , 2-tri-fluoroethyl-5-phenyl-l, 3-dihydro-2H-l:, 4-benzodiazepin^-2-one is obtained, m.p. = 164° - l66°C.

Example 10 7-Chloro-l-(2s 2 S 2-trifluoroethyl) -5-phenyl-l, 3-dihydro 2H-1, -benzodiazepin -2-one- -oxide Dissolve 27 gms. of 2- [ 2- (N-acetoxyacetamido ) -N- ( 2, 2, 2-tri luoroethyl ) -acetamido ] -5-chlorobenzophenone in 100 ml. of ethyl alcohol. Add 10 ml. of 15# hydro-, chloric acid and reflux for 15 minutes. Dilute with water and chill the mixture. Collect the solids by filtration. Wash the solids with mother liquor and with water and dry at 50°C. Crystallize the solids from alcohol to yield the product of this example.

Claims (6)

1. 9θ8 Israel WHAT WE CLAIM IS: 1. 1, 4-Benzodiazepines having the general formula I wherein X and Y are independently selected from hydrogen, halogen, trifluoromethyl, nitro, alkyl and alkoxy; R1 and 2 R are independently selected from hydrogen and alkyl, or one is hydrogen and the other free hydroxy or alkanoyloxy 1 2 and the -oxides thereof when R and R are independently selected from hydrogen and alkyl.

2. Compounds as claimed in Claim 1 in which the alkyl, up alkoxy and alkanoyloxy substitents have £6$Χ£ to 6 carbon atoms. · Compounds as claimed in any preceding claim in which X is halogen and Y is hydrogen or fluoro or chloro. 4. Compounds as claimed in any preceding claim in which 1 2 R is hydrogen and R is hydrogen, alkyl, hydroxy or alkanoyloxy. 908 Israel January 22, IK-re 5. Compounds as claimed in any preceding claim in which X is chloro in the 7-position. 6. Compounds as claimed in any preceding claim in which Y is fluoro or chloro in the o-posit n. 7. 7-Chloro-li3-dhydro-5-phenyl-l-(2,2,2-trifluoroethyi)-2H-1, 4-benzodiazepin -2-one and the 4-oxide thereof. 8. 3-Acetoxy-7-chloro-l,3-dihydro-5-phenyl-l-(2,2J2-trifluoroethyl) -2H-1, 4-benzodiazepin^-2-one. 9. 7-Chloro-l,3-dihydro-3-hydroxy-5-phenyl-l- ( 2, 2, 2-t ifluoroethyl) -2H-1, -benzodiazepin^-2-one. 10. ]3-Propionyloxy-7-chloro-l, J-dihydro-5-phenyl-l-(2, 2, 2-trifluoroethyl) -2H-1, 4-benzodiazepin|-2-one. 11. 7-Chloro-l,3-dihydro- -methyl-5-phenyl-l-( 2,2,2-trifluoroethyl) - 2H-1, 4-benzodiazepin -2-one. 12. 1, -Dihydro-5-phenyl-l-( 2,2, -trifluoroethyl) -2H-1, -benzodiazepin|§-2-on^ and the 4-oxide thereof. 908 Israel January 22, 1971 IK-re 1

3. Process for the production of a compound of the general formula I set forth in claim 1, wherein and R 2 are independently selected from hydrogen and alkyl, ■which comprises condensing a compound of the general formula II CH2CP3 wherein X and Y are as defined in Claim 1 with a compound of the general formula VIII or with a reactive derivative thereof, wherein R and R 2 are as above defined and L is a free or protected amino group. l . A process as claimed in claim 13 in which the reactive derivative of the compound of formula VIII is an alkyl ester. 908 Israel 22nd January, 1971 · IK-re 15. A process as claimed in claim 14, in which the alkyl ester is the ethyl ester. 16. A process as claimed in any one of claims 1 to 15 in which L is an amino group protected by the formation of an addition salt. 17. A process as claimed in claim l6, in which the addition salt is the hydrochloride. 18. Process for the production of a compound of the 1 2 general formula I, set forth in claim 1, wherein R , R , X and Y are as defined in claim 13, which comprises condensing the compound of the general formula II, set forth in claim 1 with a compound of the general formula IX wherein R and R are as above defined and Hal is chloro, bromo or iodo and reacting the so obtained compound of the general formula XI 908 Israel 22nd January 1971 1 2 wherein R , R , X and Y and Hal as above defined with ammonia. 19. A process for the production of a compound of the general formula I, set forth in claim 1, or a 4-oxide thereof, which comprises trifluoroethylating a compound of the general for mula or a 4-oxide Y are as defined in claim 1 by reaction with a compound of the general formula C(Hal)^CH2—A wherein A is a reactive organic or inorganic ester group, and Hal represents halogen, followed, if necessary, by replacement of Hal with fluoro. 20. A process as claimed in claim 19, in which A is chloro, bromo or iodo. 21. A process as claimed in claim 19, in which A is OSO^Z, wherein Z is aryl, alkyl, aralkyl or polyhaloalkyl. 22. A process for the production of a 4-oxide, set forth in claim 1, which comprises reacting a compound of the general I 1 2 formula I, set forth in claim/L, wherein R and R are independently selected from hydrogen and alkyl with a peroxy acid. 9θ8 Israel January 22, IK-re 23. A process as claimed in claim 22 in which the peroxy acid is peracetic acid. 2

4. A process for the production of a compound of formula I, 1 2 set forth in claim 1, wherein of R and R one is hydrogen and the other free hydroxy or alkanoyloxy, which comprises heating a compound of the general formula wherein X and Y are as defined in claim 1 and D is hydrogen car o-cylic or trifluoroethyl, with an acid anhydride, followed, if necessary, by conversion of D into tri luoroethyl and, if desired, of the alkanoyloxy group into a free hydroxy group, and if desired, by subsequent re-esterification. 2

5. A process for the production of a compound claimed in claim 1 substantially as hereinbefore described and exemplified. 2

6. A compound when produced by a process according to any one of claims 1 to 2¾. 27- Pharmaceutical preparation containing as active ingredient a compound according to any one of claims 1 to 12 and 26 in admixture with a pharmaceutically acceptable carrier or excipient. i-i 908 Israel 28. A process for the production of a pharmaceutical preparation, which comprises bringing a compound claimed in any one of claims 1 to 12 and 26 into a form suitable for pharmaceutical administration, preferably by mixing it with a pharmaceutic lly acceptable ess excipient ifiFarrier 29. Pharmaceutical preparations containing as active ingredient a compound according to any one of claims 1 to 12 and 26 whenever produced by a process as claimed in claim 28. P 0. Box 33116 , Att rney cs f toorr A «pFPHl l c a n l