CH549585A - 1 4-benzodiazepine derivatives - Google Patents

Abstract

1,4-Benzodiazepine derivatives of the general formula (I), and N-trifluoroethyl substituted amino-benzophenones and anilines used as intermediates for the preparation of (I) (see "Preparation"). - where X and Y = H, halogen, trifluoromethyl, nitro, alkyl or alkoxy. R1 and R2 = H, alkyl or free or esterified hydroxy, pref. an alkanoyloxy group. If R1 or R2 is a free or esterified hydroxy, the other is a hydrogen atom and the compound exists as the 4-oxide if R1 or R2 independently of each other are hydrogen or alkyl. - The compounds have CNS activity, acting as tranquillisers and are not so toxic at the active dose as previously used medicines in this filed.

Description

  

  The invention relates to a process for the preparation of new 1,4-benzodiazepines of the formula
EMI0001.0000
    or their 4-oxides, in which X and Y are hydrogen, halogen, trifluoromethyl, nitro, alkyl or alkoxy and and R2 is hydrogen or alkyl. R alkyl and alkoxy substituents The ducks that may be present are preferably lower alkyl or lower alkoxy. The term alkyl preferably denotes lower aliphatic, saturated hydrocarbon radicals with up to 6 carbon atoms including the straight-chain and branched isomers.

   In the same way, the lower alkoxy radical has a similar range of preferably up to 6 carbon atoms, saturated, straight-chain and branched isomers being included.



  The term halogen includes fluorine, chlorine, bromine and iodine. However, compounds in which X is chlorine or bromine and Y is fluorine or chlorine are of particular value.



  The compounds prepared according to the invention have an effect on the central nervous system and as such are valuable muscle relaxants, sedatives and valuable agents against convulsions and anxiety.



  The process for the preparation of the new 1,4-benzodiazepines of the formula (I) is based on the fact that a compound of the formula in which R 1, R2, X and Y have the meaning given above
EMI0001.0007
    and Q2 and L are radicals reacting with one another to form the bridge = N-, are subjected to an intramolecular condensation.



  If appropriate, a 1,4-benzodiazepine of the formula (I) obtained in this way is oxidized to its 4-oxide.



  To produce the desired product one can e.g. start from a benzophenone of the general formula (Ih) given below, in which X and Y have the meanings given above. This is combined with the general formula
EMI0001.0011
    wherein R1, R2 and L have the meaning given above, or a reactive derivative thereof condensed. For example, by condensing the benzophenone (III) with a compound of the formula (III) in which L is an amino group (III), the desired end product can be obtained according to the following reaction scheme:
EMI0002.0000
    The reaction can be carried out in stages, with first acylation of the benzophenone and then cyclization by intramolecular condensation.



  of an addition salt The reaction can, however, also take place without isolating the intermediate product.



  In the above reaction scheme, R 'denotes a lower alkyl group, preferably an ethyl group, and R1, R2, X and Y have the above meanings. Instead of the ester, however, another reactive derivative, e.g. a halide, or the free acid can also be used. It is particularly advantageous for the first stage of reaction t1 to protect the amino group of the amino acid. This can e.g. by the formation of an addition salt or by substitution with a removable group. The halides, especially the chlorides, are particularly suitable as addition salts. The protective group can be, for example, an acyl group, such as the carbobenzoxy or phthalimide group.



  Instead of the ester (IIP), e.g. the following connections can be used:
EMI0002.0006
    
EMI0003.0000
    In order to produce the 4-oxides of the 1,4-benzodiazepines, the compounds of the formula (I) obtained are oxidized. Particularly suitable oxidizing agents are peroxyacids, e.g. the peracetic acid. The condensation reactions are preferably carried out by heating in an inert solvent.



  The starting compounds of the formula (II) can be obtained by known processes for the preparation of the corresponding compounds without the trifluoroethyl group.



  So you can e.g. produce the desired benzophenone by reacting a trifluoroethylated aniline with benzoyl chloride: ran
EMI0003.0001
  
EMI0003.0002
    X and Y have the meaning given above.



  Further reaction of the benzophenone (II) with a compound of the formula (III) or a reactive derivative thereof leads to the starting compounds of the formula (II).



  Of course, the order of the reactions can also be reversed: reaction of the aniline mentioned with the compound of formula (III) or a reactive derivative thereof and then the preparation of the benzophenone (II) analogously to reaction scheme B.



  The starting compounds of the formula (II) can also be obtained by first preparing the corresponding compounds without the trifluoroethyl group and subsequently trifluoroethylating them, e.g .:
EMI0003.0003
    X, Y and Qz have the meanings given above.



  The compounds prepared according to the invention exert an influence on the central nervous system, determined by standard pharmacological methods, and as such are valuable sedatives or agents for eliminating states of anxiety. In addition, the new compounds are valuable agents against convulsions and have muscle slackening properties. In the pharmacological under-booking, significant differences were found between a calming dose and a dose that causes neurological impairment.

   The therapeutic ratio (ratio of the effective dose required to cause neurological impairment to the effective dose required to achieve a calming effect) is significantly higher in the compounds prepared according to the invention than that in z. Currently known analogous compounds observed ratio. In particular, 7-chloro-1,3-dihydro-5-phenyl-1- (2,2,2-trifluoroethyl) -2H-1,4-benzodiazepin-2-one has a therapeutic ratio of about 13.

   This means that the dose that causes a neurological impairment is about thirteen times greater than the dose that is required according to recognized pharmacological test methods to produce a sedative effect. As a further advantage it was found that test animals do not develop any tolerance to the compounds prepared according to the invention after repeated treatment for the evaluation of the effect as an anti-convulsive agent.



  <I> Example 1 </I> 7-chloro-1,3-dihydro-5-phenyl-1- (2,2,2-trifluoroethyl) -2H-1,4-benzodiazepin-2-one 38.6g N - (2-Benzoyl-4-chlorophenyl) -p-toluenesulfonamide and 5.4 g of sodium methoxide in 250 ml of benzene are refluxed for one hour. After adding 42 g of 2,2,2-trifluoroethyl iodide, the reaction mixture is refluxed with stirring for 12 hours. It is cooled, the solids are filtered off, the solvent is evaporated off, the residue is dissolved in 100 ml of concentrated sulfuric acid and the solution is heated on the steam bath for 25 minutes. The solution is cooled, poured into 1 liter of water, made basic with ammonia and extracted with chloroform.

   The chloroform extracts are washed with water, dried over anhydrous sodium sulfate and the chloroform is evaporated off, 2- (2,2,2-trifluoroethyl) -amino-5-chlorobenzophenone being obtained, which is used in the next stage. 29.5 g of 2- (2,2,2-trifluoroethyl) -amino-5-chlorobenzophenone, which was obtained in the manner described above, and 21.0 g of glycine ethyl ester hydrochloride are dissolved in 200 ml of pyridine. The solution is heated to the reflux temperature and the reflux is maintained for 15 hours with stirring. During the first hour, about 50 ml of solvent is removed, which is replaced by dry pyridine.

   The solution is concentrated to a residue under reduced pressure, the residue is triturated in water and extracted with ether, any remaining solids are filtered off and the solvent layers are separated off. The pH of the aqueous solution is adjusted to 8.0-8.5 and extracted again with ether. The ether extracts are combined, washed with water and dried over anhydrous sodium sulfate.



  The solvent is evaporated. The residue is extracted with ethyl ether and filtered. The ether extract is concentrated to a residue. The residue is dissolved in benzene and chromatographed on 300 g of aluminum oxide contained in a glass column 38 mm in diameter, the crude product being obtained. The column is eluted with benzene. The product is recrystallized from acetone-petroleum ether to give the desired product. Example 2 7-chloro-1,3-dihydro-5-phenyl-1- (2,2,2-trifluoroethyl) -2H-1,4-benzodiazepin-2-one-4-oxide. 5.0 g of the according to Example 1 obtained product in 125 ml of acetic acid. The solution is cooled slightly and 5.0 ml of 40% strength peracetic acid are added.

   The solution is kept at room temperature for 24 hours, the product is precipitated by adding 1.0 liter of cold water and subsequent neutralization with sodium carbonate solution, the precipitate is filtered and washed with water and recrystallized from alcohol to give the desired N-oxide .

 

Claims (1)

PATENT CLAIM Process for the production of new 1,4-benzodiazepines of the formula EMI0004.0022 i in which X and Y are hydrogen, halogen, trifluoromethyl, nitro, alkyl or alkoxy and R and R2 are independently hydrogen or alkyl, characterized in that a compound of the formula EMI0005.0000 where Q. and L are reacting radicals with each other to form the bridge = N-, subject to an intramolecular condensation. SUBClaims i 2 1. Process according to claim, characterized in that a compound of the formula II, in which Q2 = 0 and L is an amino group protected by means of hydrogen halide, preferably by means of hydrogen chloride, is condensed. ?. Process according to patent claim, characterized in that a compound of the formula (I1) in which Q2 = 0 and L is an acylated amino group and X, Y, R1 and R2 are as defined above, is condensed. 3. The method according to dependent claim 2, characterized in that L is a carbobenzoxyamino or phthalimido group. 4th Process according to dependent claim 1, characterized in that a compound of the formula II in which L is an amino group protected by means of hydrogen chloride, Q2 is oxygen, X is chlorine in position 5, Y, R1 and R2 is hydrogen, is condensed. 5. The method according to claim or one of the claims 1 to 4, characterized in that the condensation is carried out in an inert solvent. 6. The method according to claim or one of the claims 1 to 4, characterized in that a 1,4-benzodiazepine thus obtained is oxidized to its 4-oxide, preferably by means of a peroxy acid such as peracetic acid.