BE553401A - - Google Patents

Description

       

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   The present invention relates to the production of piperidin derivatives and, in particular, to N- (ss -arylalkyl) -4,4-disubstituted piperidine compounds and to processes for the preparation of these compounds.



   These compounds have been found to possess analgesic activity.



   N- (ss -aryalkyl) -4,4-disubstituted piperidines are compounds having the following structural formula:
 EMI1.1
 where x is equal to 1 or 2, y is equal to 1,2 or 3,
R1 is an aryl group, denotes hydrogen or an alkyl group, R33 denotes hydrogen or a lower alkyl group, R4 denotes an aryl group and R denotes an O "" 5 groupa -O-C- alkyl or -C-alkyl, R possibly, when x = 2, also denote a -C -alkyl group;

   and the salts of these compounds Although these compounds are designated, in the present specification, under the name of II piperidines "when x = 2 the structure of the nucleus is an azacycloheptano nucleus.
The chemical relationship between these N- (ss-a- rylalkyl) -4,4-disubstituted piperidines and the well-known synthetic pain relievers, such as meperidine, ketobermidone and

 <Desc / Clms Page number 2>

 prisilidene, emerges clearly from a comparative examination of the preceding formula with the following structural formulas.
 EMI2.1
   ;

   Although these compounds and in particular mepidine have been widely used as analgesics, their toxicity has been a drawback in many cases. They have another drawback, in that their activity is greatly reduced if not zero, when administered orally, so that it is necessary to administer them subcutaneously to obtain the analgesic effect. maximum. A large number of N-substituted analogs have heretofore been prepared in the hope of obtaining a compound having comparable analgesic activity and reduced toxicity, but none of the compounds thus prepared have been a satisfactory substitute.

   He had no reason to expect, in view of previous work, that this route of investigation would lead to an improved analgesic of the meperidine type, since it was found that the increase in the molecular dimensions of the N-substituent actually increases toxicity (for example, N-benzyl-4-phenyl-4-carbethoxy -piperidine has been reported to be about 3-4 times more toxic and has less than half of that analgesic activity. meperidine).



   The various N- (ss-arylalkyl) -4,4-dk- substituted piperdines of the present invention are superior in various respects to most known synthetic pain relievers. Some of these derivatives are less toxic, others

 <Desc / Clms Page number 3>

 are more active as analgesics, when administered orally or subcutaneously *
N- (ss -arylalkyl) -4,4-disubstituted piperidines (Compound III) are prepared by reacting a 4,4-disubstituted piperidines (Compound I) with an ss-arylalkyl halide (Compound II) .

   This reaction can be chemically represented as follows:
 EMI3.1
 
Compound III
In these formulas, X is halogen and x, y, R2, R3, R4 and R5 have the meanings given above.



   The reaction between the 4,4-di-substituted piperidine compounds and the ss-arylalkyl halide is advantageously carried out by heating the reactants in a liquid medium, which is substantially inert under the reaction conditions and which constitutes a solvent for the reagents. The liquid medium is preferably a lower alcohol, such as methanol, ethanol, propanol and the like.

   The reaction is preferably carried out by heating the reagents in the preferred liquid medium at reflux temperature, in the presence of a

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 alkali metal bicarbonate, such as sodium bicarbonate. dium or potassium bicarbonate, or an alkali metal hydroxide, such as sodium hydroxide, potassium hydroxide and the like. When using the preferred reagents and reaction conditions, the reaction is ordinarily substantially complete in about 24-48 hours The N- (ss -aryalkyl) -4,4-disutstituted piperidine thus formed is advantageously recovered from the reaction mixture, separating the inorganic salts by filtration and evaporating the resulting alcoholic solution in vacuo. to dryness.



  The residual gummy mass is triturated with water or alcohol, the water is decanted and the residual material is dried in vacuo, which gives the piperidine N- (ss -aryalkyl) -4,4 -disbustituted base.



   The starting ss-arylalkyl halide can be the chloride, bromide or iodide, but it is preferred to employ the bromide or the chloride. The β-arylalkyl halide is preferably a compound of the formulation:
 EMI4.1
 in which R "is a monovalent radical attached in the ortho, meta or para position and denotes hydrogen or a hydroxy, alkyl-0-alkyl, nitro, amino, -HN-alkyl, bromo, chloro or iodo group ; denotes hydrogen or an alkyl group, y has the meaning given above and X is halogen.Alkyl groups preferably contain 1 to 4 carbon atoms.

   As typical examples of such compounds, the following may be mentioned: ss- (o-hydroxyphenyl) -ethyl, ss- (o-methoxyphenyl) -ethyl bromide,

 <Desc / Clms Page number 5>

 
 EMI5.1
 / 3 - (o-chlorophenyl) -ethyl bromide, t - (0- ¯, r () 1il (\ phenyl) ethyl bromide, / 3 - (o-nitrophenyl) ethyl chloride, 3 - bromide (O-7tt11210To "iC'-Tly.) -Ét'hy le, 3 - (p-arrtinophenyl) ethyl bromide,; / 3 - (p-aminoPhenyl) -! - (ethyl) -ethyl, bromide t - (p-aminophenyl) -6 - (methyl) -ethyl bromide, j3- (o-aminophenyl)! 3 -methyl-ethyl bromide, (m-cilloroplié-tlyl) -3 - (tethyl) - bromide ethyl,!, - (p-hydroXYPhenyl) 1- (methyl) -ethyl chloride, 1 - (p-aminophenyl} -propyl bromide, - (p.-aminophenyl) -buty7.e bromide and f - bromide (p-nitrophenyl) -propyl.



   The 4,4-disubstituted piperidine compound is preferably a compound of the formula;
 EMI5.2
 in which x = 1 or 2, R3 denotes hydrogen or a
 EMI5.3
 alkyl group, R is an -O-C-alkyl or -C¯alkyl group and, when x = 2, R can also be a -GO-alkyl group and R6 denotes hudrogen or an alkyl group, 0- alkyl, hydroxy or amino, the alkyl groups containing 1 to 4 carbon atoms. The starting materials are prepared by processing
 EMI5.4
 the corresponding H-methylniperidine with cyanogen bromide, so as to form the corresponding H-cyano pipcridine, which is then treated with an acid, so as to form the corresponding piperidine.

   Typical examples of these compounds include the following:
 EMI5.5
 4.-Phenyl-H-propionoxy-pipE: riditle, 4-ph (llyl-4-acetoxy-piperi. Dine, 4- (m-hydroxyphériyl) -4-acé, tyl-I) ip ('. Ridiiie 4- (m-hydrox pMnyl) -4-pror> ionyl-piperidino, 4-phenyl-4-propionyl-pipprī

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 EMI6.1
 dihe, 4- (m-methylphenyl) -4-acetoxy-piperidine, 4- (p-amino- 3-methyl-4-phenyl-4-propionoxy-piperidine phenyl) ¯4-propionoxy-piperidine,% 3-methyl- .- (m-hydroxyphenyl) -4-acetyl-piperidine, 4-phenyl-4-carbethoxy-azacycloheptane, 4- (in-hydroxyphéiiyl) -4-propioiioxy-azacycloheptatie, 4-phenyl-- 4-acetyl-azacycloheptane and 4 - (m-ethoxyphenyl) -4-acetoxy-piperidine.



   The N- (ss -aminophenylalkyl) - 4,4-disubstituted pipridine compounds prepared by the process described above can be reacted with an acylating agent, so as to monoacylate the primary amino substituent on the group. phenyl, so as to form the corresponding N- (ss -acylamino-phenyl) -ethyl-4,4-disubstituted piperidine.

   Suitable acylating agents are acid halides, such as acid chlorides, acid anhydrides and the like, with acid anhydrides being preferred and the acylating agent containing the acyl residue of a. organic carbocyclic acid, especially those containing 1 to 8 carbon atoms inclusive. Among these acids, we can avoid the acids formic, acetic, propionic, butyric, valeric, hexanoic,
 EMI6.2
 ocuanoic, cyclopentane carboxylic, cyclopentylpropionic, benzoic, toluic, oxalic and the like. The acids can also contain substituents, such as halogen, alkyl, alkoxy and the like which do not react under the applied reaction conditions.

   As typical examples of
 EMI6.3
 such compounds, the following may be mentioned: N - j3- (p-acetylaminophenyl) -ethyl7'-4-pheny 1-4- propionoxy-piperidine, N- / E - (p¯propionyl-aminophenyl) - ethyl7-4- (m-hydroxyphenyl) -4- propionyyl-piperid ine, Ii- / / 3 - (o-acetylaminophenyl .ethylT l- ph nyl-4-butyroxy-piporidine, N- / T3 - (p-benzoylamino- phenyl) - ethy 4-phenyl-4-carbcthoxy-azaciyeloheptane, N- <j3 -cyclopentan6barboxylaminophenylethyl) -4-phenyl-4-propionoxy piperidine

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 and the like. The acylation is ordinarily carried out in solution in an inert solvent under substantially anhydrous conditions. For example,. when a lower alkanoic anhydride, such as acetic anhydride, is used, the reaction is preferably carried out in glacial acetic acid.

   The acylation can be carried out at room temperature or at elevated temperature up to about 100 ° C., the reaction usually being complete in about 1 hour under these conditions. The product is advantageously recovered from the reaction mixture by diluting the latter with water and neutralizing the acidic components with sodium carbonate, sodium bicarbonate and the like. so that the acylated product precipitates as a gum, or crystals, which are easily separated from the aqueous layer by decantation. This material is further purified by washing with water and drying in vacuo.
 EMI7.1
 



  1d - (/ 3 -aryla7.coyl) -4,4-disubstituted piperidine can be converted to an addition salt with a corresponding acid by reaction with an acid, in particular mineral acids, such as hydrochloric acids, hydrobromic and sulfuric acids, but organic acids can also be used, such as citric, tartaric and the like under substantially anhydrous conditions. This salt forming reaction is preferably carried out in a medium comprising a lower alkanol, such as methanol, ethanol, propanol and the like. On dilution of the alkanolic reaction medium with ether, the corresponding acid salt precipitates. The salt thus formed can be recovered from the alcoholic slurry by filtration or centrifugation.



   The compounds according to the present invention can be formulated in the usual manner to form compounds.
 EMI7.2
 sitions to be administered by mouth or parent. ra1 "Thus, if these compounds can be administered to us form '

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 tablets, capsules, pills or tablets and may contain, in addition to the active compound, various binders, fillers, or diluents. Suitable materials for this purpose are, for example
 EMI8.1
 eg, starch, for example corn starch and sugars, such as lactose and sucrose.

   If the compounds are placed in capsules, they may also contain material
 EMI8.2
 additional, such as a liquid vehicle, such as, for example, a fatty oil. These compositions can also contain various fillers, such as oil of wintergreen, and excipients such as dicalcium phosphate. Various other materials may be present as coatings or to otherwise modify the physical form of the positions. Thus, the pills or capsules may be coated with shellac and / or sugar. A suitable liquid composition can be prepared. by adaition of the active compound to a soft diluent such as water, or to an oil, such as sesame oil or olive oil.

   For administration by mouth, unit dosages of 10 to 100 mg can be used. A typical daily adult dose is 4 to 8 tablets of 15 mg.
 EMI8.3
 



  Y. (lJy.7. 11L1 1.- 1- / 3 - (n-aminophenyl) f thyl7 -.- (m-hydrox3r-phenyl) -4-piperldyl ethyl ketone.- dihydrochloride.
3.1 g of 4- (m-hydroxyphenyl) -4-piperidyl ethyl ketone hydrochloride and 0.8 g of sodium hydroxide are added to 40 cc of absolute ethanol. After 15 minutes, 3.2 gr
 EMI8.4
 of 3 - (p-aminophenyl) thy chloride: Le and 1.0 mr of sodium bicarbonate are added and the mixture is heated under reflux for 35 hours with stirring.

   The solution is then filtered, the solid material is washed with two fractions of alcohol and the combined filtrates are concentrated in vacuo until.

 <Desc / Clms Page number 9>

 than to obtain a thick porridge. 35 cc of water are added and the resulting crystals of free base are filtered off.



   The solid material is dissolved in this hot alcohol, after which hydrochloric acid in alcoholic solution is added until the medium is strongly acidic and the resulting dihydrochloride is crystallized by addition of ether and cooling in a bath. of ice. The product is recrystallized from a minimum quantity of hot ethanol.



   The starting piperidine is prepared as follows:
 EMI9.1
 z7 gr of. 4- (m-hydroxyphenyl) -1-methyl-4-piperidyl ethyl ketone are dissolved in 25 cc of anhydrous ether and treated
 EMI9.2
 tees with 2, U gr of bromocyanogen. After the initial development of heat, the mixture is heated in a steam bath until all ether has been removed and heating is continued for 2 hours. By adding 50 cc of anhydrous ether, the Quaternary salt separates. After filtration of the reaction mixture, 4- (m-hydroxyphenyl) -1-cyano-4-piperidyl ethyl ketone is recovered by evaporation of the ethereal filtrate.



  The residue is heated to reflux with 25 cc of a 1: 1 mixture of water and concentrated hydrochloric acid, then concentrated to dryness. The solid residue thus obtained is chlor-
 EMI9.3
 4-C rtt-hydroxynlz :: uylj .¯piperidyZ ethyl ketone hydrate.



  E, {;:, "'1iJ.L.:; Id- / ¯methocyplnuyl hydrochloride) = ethyl /.- 3-Tnethyl-4-phcnyl-r.- propionoxy prn-ridine - 2.6 gr of hydrochloride 3-mebhyl-4-phenyl-4-pro of pionoxy piperidine and 0.8 g of hydroxide / sodium are added to 40 cc of absolute ethanol.

   After 15 minutes, 3.4 gr of bromide
 EMI9.4
 of 13 - (P-rnftlloxyphé; tiyl), tliyl and 1, U g of sodium carbonate: are added and the mulane is heated under reflux for 35 hours with stirring. The solution is then filtered, the material

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 The solid is washed with two portions of alcohol and the filtrates concentrated in vacuo until a thick slurry is obtained, 35 cc of water are combined again are added and the resulting crystals of free base are filtered off.



   The solid is dissolved in 25 cc of hot alcohol, after which hydrochloric acid in alcoholic solution is added until the medium is strongly acidic and the hydrochloride is crystallized by addition of ether and cooling. in an ice bath. It is recrystallized from a minimum quantity of hot ethanol.



   The starting piperidine is prepared as follows:
 EMI10.1
 29.7 g of, 3-dimethyl-4-phenyl-4-propionoxypiperidine hydrochloride are treated with 300 cc of chloroform and 100 cc of sodium hydroxide at 0 C The chloroform layer of the free base is then dried over sodium sulfate and added at 0-10 C 10.6 g of bromocyanogen '.



  When the initial reaction has subsided, the mixture is heated under reflux for 4 hours. The reaction mixture is then concentrated to dryness and the 1-cyano-3-methyl-
 EMI10.2
 The desired 4-phenyl-4-propionoxy-pippridine is extracted from the quaternary salt by digestion of the residue with 500 cc of anhydrous ether. It is not necessary to further purify the N-cyano derivative. The ethereal extract is evaporated to dryness and the residue is stirred with ON hydrochloric acid for 24 hours. The solution of 3-methyl-4-phenyl-4-propionoxypiperidine hydrochloride thus obtained is concentrated to a small volume and crystallized by adding methanol or acetone.
 EMI10.3
 



  E .. #, s1P LB 3. - Hydrochloride of 1- / / 3 - (o-hydroxyph.nyl) ethyl T.-phenyl-4- piperidyl-ethyl # tone.- A sample of 2.6 gr of hydrochloride of 4 - (4-

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   phenyDpiperidyl ethyl ketone and Q, 8 g of sodium hydroxide are charged with 40 cc of absolute ethanol. After 15 minutes,
 EMI11.1
 4.02 g of p - (o-hydroxy-phenyl) ethyl bromide and 1.0 g of sodium carbonate are added and the mixture is heated under reflux for 35 hours with stirring.

   The solution is then filtered, the solid is washed with two portions of alcohol, and the combined filtrates are concentrated in vacuo until a thick slurry is obtained. 35 cc of water are added and the resulting crystals of 1- @ ss - (o-hydroxyphé
 EMI11.2
 nyl) ethyl 1,.-phenyl-4-piperidyl ethyl ketone are filtered.



   The solid material is dissolved in 25 cc of hot alcohol, after which alcoholic hydrochloric acid is added until the medium is strongly acidic and the resulting monohydrochloride is crystallized by adding ether and cooling in an ice bath. It is recrystallized from a minimum quantity of hot ethanol.



   EXAMPLE 4.-
 EMI11.3
 Lü- / 3 - (o-nitrophenyl) ethy l-phenyl-4-carbethoxy azacycloheptane hydrochloride.
A sample of 2.5 g of 4-phenyl-4-carbethoxy azacycloheptane and 0.8 g of sodium hydroxide are added
 EMI11.4
 at 40 cc of absolute e1-11-nol. After 15 minutes, t -,} 7 g of p - (o-nh ", phenyl) ethyl bromide and 1.0 g of sodium bicarbonate are added and the mixture is refluxed for 35 hours with stirring. is then filtered, the solid is washed with two portions of alcohol and the combined filtrates are concentrated in vacuo until a thick slurry is obtained. 35 cc of so: it water is added and the crystals are obtained.
 EMI11.5
 resulting 1V - (o-nitrophenyl) ethyl = 1 + -phenyl - + - carbethoxy azacycloheptane are filtered.



   The solid matter is dissolved in 25 cc of alcohol

 <Desc / Clms Page number 12>

 
 EMI12.1
 hot, after which hydrochloric, alcoholic acid is added until the medium is strongly acidic and the resulting monohydrochloride is crystallized by addition of ether; and cooling in an ice bath. Is it recrystall? dried in a minimum quantity of hot ethanol.
 EMI12.2
 



  2 g of 1-methyl-4-phenyl-4-carbethoxy azacyclohep-tane are dissolved in 40 cc of anhydrous chloroform. 1.5 g of bromocyanogen are then added and the mixture is heated in a steam bath for 3 1/2 hours. The mixture is then concentrated to dryness in vacuo and the residue is digested with 400 cc of anhydrous ether. The mixture is filtered and the filtrate is concentrated in vacuo to dryness.



   The crude N-cyano intermediate is stirred with 20 cc of 6N hydrochloric acid for 20 hours. The solution is concentrated in vacuo to dryness, so that crude 4-phenyl-4-carbethoxy azacycloheptane hydrochloride is obtained.



  The material obtained in this way is recrystallized by adding acetone to an aqueous solution of this material.
 EMI12.3
 



  L..PI 5. - N-Lj- (p-chlorophenyl) ethYY-4-phenyl-4-piperidyl ethyl ketone hydrochloride.
A sample of 2.0 g of 4- (4-phenyl) -piperidyl ethyl ketone and 0.8 g of sodium hydroxide are added with 40 cc of absolute ethanol. After 15 minutes, 3.5 gr of dichlor-
 EMI12.4
 e // 3 - (p-chlor.ophéuyl) ethyl hydrate and 1.0 g of sodium bicarbonate are added and the mixture is refluxed for 35 hours with stirring.

   The solution is then filtered, the solid material is washed with two portions of alcohol, and the combined filtrates are concentrated in vacuo to a thick slurry. 35 cc of water are added and
 EMI12.5
 the resulting crystals of N- [/ 3 - (p-chlorophenyl) ethyl / -4-piperidyl ethyl ketone are filtered off.

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   The solid is dissolved in 25 cc of hot alcohol, after which alcoholic hydrochloric acid is added until the medium is strongly acidic and the resulting monohydrochloride is crystallized by addition of ether and cooling in an ice bath. It is recrystallized from a minimum quantity of hot ethanol.



   EXAMPLE 6. -
 EMI13.1
 N- / 3 - (m-aminophenyl) ethylT 3-methyl-.phenyl-4-propionoxy piperidine.- dihydrochloride
A sample of 3.1 g of 3-methyl-4-phenyl-4-propionoxy piperidine hydrochloride and 0.8 g of sodium hydroxide are added to 40 cc of absolute ethanol. After 15 minutes, 3.2 g of / 3 - (m-aminophenyl) -ethyl chloride and 1.0 g of sodium bicarbonate are added and the mixture is heated under reflux for 35 hours with stirring.

   The solution is then filtered, the solid material is washed with two portions of alcohol and the combined filtrates are concentrated in vacuo until a thick slurry is obtained. 35 cc of water are added and the resulting crystals of N- [ss- (m-aminophenyl) -ethy -3-methyl-4-phenyl-4-propionoxy piperidine are filtered off.



   The solid is dissolved in 25 cc of hot alcohol, after which alcoholic hydrochloric acid is added until the medium is strongly acidic and the resulting monohydrochloride is crystallized by addition of ether and cooling. in an ice bath. It is recrystallized from a minimum amount of hot ethanol.
 EMI13.2
 



  LC; .iP 7. - N- (ss -phenylpropyl) -3-methyl-4-phenyl-4-propionoxy piperidine hydrochloride.
A mixture of 25.5 gr of 3-methyl-4- carbonate

 <Desc / Clms Page number 14>

 phenyl-4-propionoxy-piperidine, 19.9 g of 1-bromo-2-phenylpropane and 16.8 g of sodium bicarbonate in 250 cc of absolute ethanol is stirred at reflux temperature for 40 hours . The mixture is then cooled to 25 ° C. and filtered to separate the inorganic salts. The filtrate is concentrated under reduced pressure until a semi-solid mass is obtained. This residue is dissolved in 100 cc of water and 100 cc of ether.

   The ethereal layer is separated and dried over anhydrous magnesium sulphate and evaporated to dryness, leaving
 EMI14.1
 so that N- (2-phenylpropyl) -3-nibthyl-4-phenyl-4-propionoxypiperidine is obtained. Excess hydrogen chloride is passed through the dry ethereal solution, which produces a suspension of crystals. These are collected, washed with ether and dried. We thus obtain chic
 EMI14.2
 Id- (2-phenylpropyl) -3-mcahy7.-I + -phenyl-4-propion? drate. substantially pure piperidine.



   EXE PLE 8. -
A tablet of the following composition is prepared:
 EMI14.3
 1-day 3 - (p-aminophenyl) ethyl17 -.- (m-hydroxyphenyl, (4-piperidyl ethyl ketone) dihydrochloride 0.015 gr Lactose USP 0.142 gr Starch USP 0.028 gr (Sucrose '0 005 gr Paste 10% ((Starch 0.005 gr Magnesium stearate 0.001 gr 0.196 gr
 EMI14.4
 The l-L / 3 (p-aj) iiiiopli6iiyl) ethyl7 -4- (m-hydroxyphenyl) -4-pip''ridyl ethyl ketone dihydrochloride and lactose were mixed, then granulated with the sucrose paste and; starch. The wet mass was then passed through an n-sieve and dried at 40 ° C for 16 hours.

   We have

 <Desc / Clms Page number 15>

 then pass the dry granules through a No. 12 sieve. The starch and magnesium stearate were then. added to the mixture and the mixture was kneaded for 15 minutes. The material was then tableted to a thickness of 10/32 of an inch.



   CLAIMS.-
1.- Compounds of formula:
 EMI15.1
 in which y is an integer varying from 1 to 3, R1 is an aryl group, R2 and R3 denote hydrogen or a '@ lower alkyl group, R4 is an aryl group, X is an integer varying from 1 to 2 and R5 denotes a group
 EMI15.2
 rr 0-C-alkyl or C-alkyl, when x = or a group 0 il 0 Il 0 il
 EMI15.3
 O-C-alkyl, C-alkyl or C-O-alkyl, when x = 2, as well as the additions with acids of these compounds.



  2.- 1- / 3 - (p-aminophéayl) -éthy .- (m-hydroxy-phenyl) -4-piperidyl ethyl ketone. @
 EMI15.4
 3.- 1-Lf - (p-aminophény1) -éthy '-4- (m-hydroxy-phenyl) -4-piperidyl ethyl ketone dihydrochloride.



  4. - N-IJ - (p-methoxyphenoxy) -ethyrY-3-llTethyl-4- Phenyl-4-propionoxy pipcridine.



  5.- hS- /, f3 ¯ (p¯methoxyphetzyl) -ethy -3-methyl-4-phenyl-4-propionoxy piperidine hydrochloride.



  6.- H-1'3 - (0-hydroxyphenyl) ethy-4-phenyl-4-piperidyl ethyl ketone.



  7.- N - // 3- (o-hydroxyphenyl) -ethyl] 7 -4-phenyl-4-pipcridyl ethyl ketone hydrochloride. a- / 7 ¯ (o-uitrophGuyl) -ethyl ./- l..pheclyl -.- car-

 <Desc / Clms Page number 16>

 bethoxy azacycloheptane.
 EMI16.1
 



  9.- I 4- / J3 sulfate. (o-nitrophéuyl) -ethyl .4-pheuyl-4-carbethoxy azacycloheptane.



  10. - N-Lj3- (p-chlorophenyl) ethyl1-4-phenyle4-pip (ri- dyl ethyl ketone.



  11.- 1I- / - (p-chlorophenyl) -ethyl7- 4-phenyl-4-piperidyl ethyl ketone hydrobromide.
 EMI16.2
 



  12. - N-f3- (m-aminophetlyl) -ethyl7 3-methyl -.- phenyl-4-propionoxy piperidine.



  13.- N-Lb - (m-aminoplieilyl) -etliyi7 -3-methyl-4-phenyl-4-propionoxy piperidines dihydrochloride.



  14.- N- (-phenylpropyl) -3-methyl-4-phenyl-4-propionoxy piperidine.



   15.- N- (ss -phenylpropyl) -3-methyl-4-phenyl-4-propionoxy piperidine hydrochloride. :
16.- Process in which a compound of formula is reacted:
 EMI16.3
 in which x is equal to 1 or 2, R3 is hydrogen or a
 EMI16.4
 alkyl group, R5 is an 0-C-alkyl or 8-alkyl group when x = 1 or an 0-C -alkyl, C-alkyl or CO-alkyl group when x = 2, and R 4 is an aryl group , with a compound of the formula.



   R2 t aryl-CH - (CH2) y X in which X is halogen, R2 is hydrogen or a lower alkyl group and y = 1, 2 or 3, so that

 <Desc / Clms Page number 17>

 
 EMI17.1
 produce the horn, mos' ilp- ridlninuc ï - (, f.> - ary.; '. c.) -., 1 + .- di; stlJ stitu' corresoondatit.



  17. - h'0Cd '\,, 1: ¯:', (: <:.,) ::> 1 we react with 4- (r ¯ '// droxyph% yl} -4s1 C' # ' . "## ethyl ketone with / 3 - (D-amillO-1) h <n'll} -t chloride, l1'Jrl so as to produce N- / ¯ / 3 ¯ (p-arsiinoph- 'nyl} -ethy l7-4- (m-hydroxyphenyl) -4-piperidyl
 EMI17.2
 ethyl ketone.
 EMI17.3
 



  18.- Froc- "die in which 3-methyl-4¯pli '? Tiyl-4-propinoxy piperidine is reacted with,;' r - (- mttlOJty-pllcllT2) -tllyl, so to produce N-r¯E> - (p-inethoxyphenyl) -ethyl / -: aethyl-4-pheiiyl-4-propioaoxy piperidine.



  19 - Process in which 4- (4-?) Hétlyl) -piperidy1 ethyl ketone is reacted with f - (0- hydraxy.-pheclyl) -ethy bruise, so as to produce ¯ & - / ¯ / 5- {o-hydroxyph811yl) -etllyl:! 'T .l.-pMnyl piperidyl ethyl ketone.



  <:: ü.-! 'roct: a in which or reacts 4-phenyl-4-carbeto: xy azacycloheptane with /' 3 - (o-nitrophenyl) -ethyl bromide, so as to produce id- / f'r (o-lzitrophé; lyl) - 'thJî # 17'-4-ohcnyl-4-carb6thocy azacyclohentajne.
 EMI17.4
 



  21 ..- Process in which we react to 4-
 EMI17.5
 (4-phenyl) -pipcridyl ethyl ketone with / 5- (p- cklorophenyl) - :; hyl chloride, so as to produce H- / 5 - (p-chloroohGtiy] y-phntiyiy-4-ph " 'nyl-4-pip!' 'ridyl ethyl ketone.



  M. Froccd in lcr1t101 is reacted 3-methyl-4-ph''uyl-4-propionoxy piperidine with A (m-aJl1ino-ph. ':' Nyl) -l1thy1e chloride, from so as to produce IJL-j3 - (ra-aminophenyl) -éthyVr-3-Kii'thyl-4-phûnyl-4-propionoxy pipcri-
 EMI17.6
 d inc-.
 EMI17.7
 s.j.¯ ipFri.c3iue, s tt - (/ 3 -atylalcoyl) -4,4-disubstitureo and 7i'OCF: d! ' for Ipur obtaining, in substance, such naked described, '11Iif: hnbt.