CH420201A - Process for the preparation of therapeutically effective ethers of benzhydrols substituted by a trifluoromethyl group - Google Patents

Description

  

  



  Process for the production of therapeutically effective ethers by a
Trifluoromethyl group substituted benzhydrols
The invention relates to a process for the preparation of therapeutically effective ethers of the formula
EMI1.1
 in which Y is a straight or branched hydrocarbon radical with a maximum of 6 carbon atoms, optionally interrupted by an oxygen atom, Z represents a dialkylamino group in which one or both alkyl groups together with the nitrogen atom and optionally with the hydrogen carbon radical Y is one or more heterocyclic rings can form, which in addition to this nitrogen atom can also contain a second hetero atom, which process is characterized by

   that one is a trifluoromethylbenzhydrol of the formula
EMI1.2
 or a functional derivative thereof with an alcohol of the formula
H-O-Y-Z or a functional derivative thereof.



  The reaction product can be converted into a salt or a quaternary ammonium compound.



   The hydrocarbon radical Y can, for. B. be an ethylene, propylene, isopropylene, butylene, pentylene, isopentylene or 3-oxapentylene radical.



   Suitable dialkylamino groups are e.g. B. the dimethylamino, diethylamino and dicyclohexylamino groups. Z can also be a piperidino, morpholino, pyridino, pyrrolidino or thiomorpholine radical. Groups in which Y and Z together form a heterocyclic nitrogen-containing ring are, for. B. the 2- or 3-pyrrolidylmethylene radical, the 2-, 3- or 4-piperidyl radical and the tropinyl radical.



   The salts can be of inorganic acids, e.g. B. hydrohalic acids, such as organic acids such. B. oxalic acid, fumaric acid, citric acid, tartaric acid and the like.



   The process for the preparation of these new substances can be carried out by using a compound of the formula
EMI1.3
 optionally in the presence of a solvent, heated with a compound of the formula BYZ, where one of the symbols A and B represents a halogen atom and the other O-metal, or the symbol A represents a halogen atom and the symbol B represents an OH group, or the symbols A and B both represent OH groups.



   A very suitable embodiment of the process consists in allowing the two alcohols to react in the presence of a dehydrating agent and, if appropriate, a solvent.



  Preferably used as the dehydrating agent is an organic sulfonic acid, e.g. B. p-toluenesulfonic acid, but you can also use other dehydrating agents such. B. sulfuric acid, apply.



   However, you can also achieve very satisfactory results in other ways by z. B. reacts a trifluoromethylbenzhydryl halide with the free amino alcohol. In this case, the reaction can be carried out in such a way that the amino alcohol is used in excess or another acid-binding substance is added.



   The chloride of the substituted benzhydrol is preferably allowed to react with an excess of the amino alcohol at a temperature of 140 = 160 ° C., the hydrochloride of the amino alcohol being formed in addition to the free base of the desired compound.



   The benzhydrols substituted by a trifluoromethyl group and used as the starting material are easily accessible insofar as they are compounds substituted by a CF3 group in the 2- or 3-position.



   The preparation of 2-trifluoromethylbenzhydrol is described in Swiss patent specification no. 400 110.



   3-Trifluoromethylbenzhydrol can be produced by converting commercially available 3-trifluoromethylaniline into 3-trifluoromethylbromobenzene and reacting the Grignard compound produced therefrom with benzaldehyde.



   The benzhydrol with a p-CF3 group can be produced by reducing the corresponding ketone. The preparation of this ketone is described in the literature. For example, 4-methylbenzophenone can be converted into 4-trichloromethylbenzophenone by the process described by Thömer (Ann. 189, 83 [1877]), from which 4-trifluoromethylbenzhydrol according to that of Rooney and Boums in Canad, using SbF3 as fluorinating agent. J. of Chem. 33, 1633 (1955).



   Other manufacturing methods can also be used, e.g. B. Markarian, J. Am. Chem.



  Soc. 74, 1858 (1952), starting with 4-bromobenzotribromide, or according to Jones c. s., J.



     At the. Chem. Soc. 74, 6119 (1952), 4-nitrobenzotribromide serving as the starting product.



   Finally, 4-amino-3-nitrobenzotrifluoride, which is a commercial product, can be converted into 4-trifluoromethylbenzhydrol via 4-bromobenzotrifluoride.



   Compounds of the type r Ar2-CH-O-alkylene-N (alkyl) 2, in which one of the aryl groups is substituted, were already known from several patents. The Swiss patent specification No. 338 846 can be cited as an example. These known compounds are particularly benzhydryl ethers in which one or both phenyl nuclei can contain substituents at different positions. However, the trifluoromethyl group has not yet been proposed as a substituent.



   It has been found that the compounds obtained by the process according to the invention have interesting pharmacological properties. Many of these have fairly strong anti-acetylcholine effects, close to atropine in some cases.



   Furthermore, especially the compounds which contain a p-substituent have a stimulating effect, which z. B. results in an increase in the motility of mice.



   The motility measurements are carried out in such a way that statistically responsible selected groups of mice are placed in cages in which, when they move from the left to the right side and vice versa, they interrupt a light beam, thereby activating a counter. If a control group is also included in the perceptions, a stimulating or sedative effect for an administered compound can be determined from a sufficiently large number of perceptions.



   It was also found that the compounds obtainable according to the invention have a psychotropic effect, as can be seen from their influence on the metabolism of brain tissue. Tissue ventilation is inhibited, as evidenced by a decrease in oxygen consumption in the metabolism of rat brain under aerobic conditions, while the metabolism of γ-aminobutyric acid and glutamic acid is stimulated. Because these two amino acids play an extremely important role in the central nervous system, increasing their concentration in the brain tissue is essential.



   Also other drugs that have proven to be important for therapy because of their psychotropic effects, such as Orphenad! rjn and Cblorpromazin, have a similar influence on the amino-oxygen metabolism as of Nauta c. s. (The Lancet 1958, pp. 591-592).



   The test method which was used to test the influence of the products according to the method of the invention on the metabolism of rat brain and in particular the γ-aminobutter acid and glutamic acid content is essentially that of Ernsting c. s. (J. of Neurochemistry S, 121-127 [1960]).



   The table below shows the extent to which various products according to the method of the invention inhibit the oxygen consumption in the metabolism of rat brain and the content in cg / ml of glutamic acid and γ-aminobutyric acid in the incubation liquid.



   Table 1 for salt formation inhibition
Compound Glu GABA acid used in% ss-dimethylaminoethyl-2-trifluoromethyl-fumaric acid 86 119 (10) 19 (3) benzhydryl ether ss- (N-pyrrolidyl) -ethyl-2-trifluoromethyl-fumaric acid 86 179 (16) 43 (5) benzhydryl ether tropinyl-2-trifluoromethylbenzhydryl ether methyl iodide 81 213 (17) 36 (3) (quaternized) ss- (N-pyrrolidyl) -ethyl-3-trifluoromethyl-fumaric acid 94 184 (17) 46 (3) benzhydryl ether 5-diethylamino-2- pentyl-3-trifluoro-citric acid 91 214 (38) 47 (6)

      methylbenzhydrylether ß-dimethylaminoethyl-3-trifluoromethyl-methyl iodide 75 200 (16) 44 (3) benzhydrylether ß-dimethylaminoethyl-4-trifluoromethyl-fumaric acid 94 217 (13) 48 (3) benzhydrylether ß-dimethylaminoethyl-2-methylbenz-hydrochloric acid 60 115 (18) 14 (1) hydryl ether (orphenadrine) 10- (3-unethylammopropyl) -3-chloro-hydrochloric acid 89 83 14 phenothiazine (chlorpromazine)
For the above experiments, solutions of the compounds to be tested were used in a concentration of 0.002 mol or less.

   The control values obtained without adding the relevant compound mentioned in the first column are included in brackets in the last two columns. The difference between the two values found is a measure of the effectiveness of the compound examined.



   In the table are Orphenaddn. (-Dimetbyl- aminoethyl-2-methylbenzhydrylether) and chlorpromazine (10-3'-dimethylaminopropyl-3-chlorophenothiazine) added as comparison substances. It is clearly evident that the compounds according to the invention, as far as their effect on the inhibition of oxygen consumption is concerned, with the known psychotropic agents, such as. B. chlorpromazine and orphenadrine, are comparable, while they are even clearly superior to these in terms of their influence on the amino oxygen change in rat brain.



   example 1
20.2 g (0.08 mol) 2-trifluoromethylbenz hydrol,
12.4 g (0.088 moles) tropine and
16.5 g (0.096 mol) of p-toluenesulfonic acid are heated together under reduced pressure to a temperature of 180-190 ° C. for 5 hours.



  After cooling, the reaction mixture is poured into water and extracted with ether. After the water has been made alkaline, it is drawn out twice more with ether, whereupon the combined ethereal solutions are worked up in the usual way.



  Distillation under reduced pressure gives 20.0 g (66.5%) of tropinyl 2-trifluoromethylbenzhydryl ether. Boiling point of the free base 185 C / 3 mm.



   The salts can be prepared by adding the desired acid, also dissolved in sither, to the ethereal solution of the base.



   Example 2
5 g (0.02 mol) of 4-trifluoromethylbenzhydrol are dissolved in benzene and boiled with 10 ml of thionyl chloride for 1 hour. The excess thionyl chloride is then removed by distillation.



  The residue is taken up in low-boiling petroleum ether (boiling point 28-40 ° C.), a small amount of insoluble substance remaining, which is removed by filtration.



   After the petroleum ether has been distilled off, the remaining chloride is heated to a temperature of 140-160 ° C. for 1 hour with 36 g of ss-dimethylaminoethanol (0.04 mol). After cooling, water is added, followed by extraction with ether. The ethereal solution is dried over sodium sulfate and the ether is evaporated. The free base, which can be converted into the fumarate, melting point 163.5-164.5 ° C., in the customary manner, is obtained by distilling the residue.



   Example 3
10 g of 2-trifluoromethylbenzhydrol are converted into the sodium compound by means of a sodium suspension of sodium in xylene. The base is liberated from 8.6 g of the hydrochloric acid salt of β-dimethylaminoethyl chloride and the sodium compound is added to the solution. After boiling under the reflux condenser for 4 hours, the reaction mixture is cooled and mixed with water. After the water layer has settled, the organic layer is dried over anhydrous sodium sulfate. After filtration, the solvent is distilled off and the residue is subjected to fractional distillation under reduced pressure. The oxalate can be prepared in the usual way from the free base with a boiling point of 140-148 ° C./3 mm. Melting point oxalate: 87-89 C.



   In the table below, physical constants of compounds obtained according to the invention are compiled.



   Table 11 Converted Melting Point Yield
Compound in in C in% ß-dimethylaminoethyl-3-trifluoromethylbenzhydryl ether fumarate 119-121 72 ß-dimethylaminoethyl-3-trifluoromethylbenzhydryl ether, methyl iodide 141, 5-143, 5 80 5-diethylamino-2-pentyl-3-trifluoromethylbenzhydryl ether -90 72 ss- (N-pyrrolidyl) -ethyl-3-trifluoromethylbenzhydryl ether fumarate 132, 5-133, 5 41 tropinyl-3-trifluoromethylbenzhydryl ether fumarate 156-158 70 ss- (N-morpholino) -ethyl-3-trifluoromethylbenzhydryl ether fumarate 111 -112 66 ss-dimethylaminoethyl-2-trifluoromethylbenzhydryl ether oxalate 88, 5-90,

     5 78 ß-dimethylaminoethyl-2-trifluoromethylbenzhydryl ether fumarate 103-104 65 ß-dimethylaminoethoxyethyl-2-trifluoromethylbenzhydryl ether oxalate 99-100.5 59 5-diethylamino-2-pentyl-2-trifluoromethylbenzhydryl ether, 5 40 --103 citrate ( N-pyrrolidyl) -ethyl-2-trifluoromethylbenzhydryl ether fumarate 138, 5-139, 5-60 ss- (N-morpholinyl) -ethyl-2-trifluoromethylbenzhydryl ether oxalate 138, 5-140 57 tropiny1-2-trifluoromethylbenzhydryl ether fumarate 181-183 67 Tropanyl-2-trifluoromethylbenzhydrylether methylodide 223-225 87 ss-dimethylaminoethyl-4-trifluoromethylbenzhydrylether fumarate 163-164 45 ss-dimethylaminoisopropyl-4-trifluoromethylbenzhydrylether fumarate 118-118.5 38 - (N-pyrrolidino)

  -ethyl-4-trifluoromethylbenzhydryl ether fumarate 155, 5-156, 5 54 tropinyl-4-trifluoromethylbenzhydrylate fumarate 185-186 15 ss- (N-morpholino) -ethyl-4-trifluoromethylbenzhydryl ether fumarate 148-149 38 * crystallizes with% mol of water of crystallization

 

Claims (1)

PATENT CLAIM 1 Process for the preparation of therapeutically active ethers of the formula EMI4.1 in which Y is a straight or branched hydrocarbon radical with at most 6 carbon atoms, optionally interrupted by an oxygen atom, and. Z represents a dialkylamino group in which one or both alkyl groups together with the nitrogen atom and optionally with the hydrocarbon radical Y can form one or more heterocyclic rings which, in addition to this nitrogen atom, can also contain a second heteroatom, characterized in that a trifluoromethyl - b. enzhydrol of the formula EMI4.2 or a functional derivative thereof is etherified with an alcohol of the formula H-O-Y-Z or a functional derivative thereof. SUBClaims 1. Process according to claim I, characterized in that the functional derivative is a compound of the formula EMI4.3 optionally in the presence of a solvent, and a compound of the formula BYZ is used, where one of the symbols A and B represents a halogen atom and the other O-metal, or the symbol A represents a halogen atom and the symbol B represents an OH group, or the symbols A and B both represent OH groups, and these heated together. 2. The method according to claim I, characterized in that the alcohols are heated in the presence of a dehydrating agent. 3. The method according to claim I, characterized in that one of an alcohol of the formula EMI5.1 or from a functional derivative of the same. 4. The method according to claim 1, characterized in that the radical Y-Z is a tropine radical. 5. The method according to claim I, characterized in that the reaction products are converted into their addition salts with acids. PATENT CLAIM II Use of the products obtained according to patent claim 1 for the preparation of corresponding quaternary amino compounds with the aid of alkylating agents.