Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/79—Acids; Esters
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
  • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4

Definitions

• the present invention relates to novel piperidine derivatives with valuable pharmacological properties, to pharmaceutical compositions, and to methods of alleviating pain and producing an antitussive effect comprising administering these compounds.
• the present invention relates to compounds of the formula wherein R is alkyl having at most 10 carbon atoms, cinnamyl or phenyl-loweralkyl wherein the phenyl moiety is unsubstituted or substituted by halogen up to the atomic number 35, loweralkyl or loweralkoxy, whereby the substituted or unsubstituted phenyl-loweralkyl contains at most 12 carbon atoms, and wherein the phenyl moiety is bound directly to the loweralkyl group or by way of oxygen, a carbonyl, a hydroxymethylene, an imino, a
• R is allyl or propinyl or alkyl containing from 2 to 4 carbon atoms
• R is alkyl containing from 2 to 4 carbon atoms, and the pharmaceutically acceptable acid addition salts thereof, which compounds have been found to have in particular analgesic and antitussive activity. Some of them also possess a tranquilizing action on the central nervous system. These activities are combined with a favorable therapeutic index.
• lower alkyl and derivations thereof utilizing the root alk is intended a group comprising a branched or straight hydrocarbon chain containing from one to four carbon atoms.
• Halogen up to the atomic number 35 can be fluoro, chloro or bromo.
• R denotes, e.g. alkyl groups, such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.
• a preferred subclass of compounds are, on account of their pharmacological activity, the compounds of Formula I, wherein R is lower alkyl, cinnamyl or phenyl-loweralkyl, wherein the phenyl moiety is bound directly to the loweralkyl group or by way of a hydroxymethylene, a loweralkanoyloxymethylene, and imino, a loweralkenylimino or a lower alkanoylimino group, and wherein the phenyl moiety is unsubstituted or substituted by halogen up to the atomic number 35,
• R is allyl, propinyl or propyl
• R is propyl
• Preferred members of this subclass are, on account of their strong analgesic activity, the following compounds:
• a compound of the Formula II R co-u wherein R and R5 have the meaning given under Formula I is reacted with a reactive ester of a compound of the Formula III (R OH (III) wherein R has the meaning given under Formula I, and optionally the obtained compound of Formula I is converted into an additional salt with an inorganic or organic acid.
• the reaction is carried out at room temperature or at a moderately increased temperature in a suitable organic solvent, such as, e.g. ethanol, acetone, diethyl ketone or dimethyl formamide.
• a suitable organic solvent such as, e.g. ethanol, acetone, diethyl ketone or dimethyl formamide.
• acid binding agents such as, e.g.
• Suitable reactive esters of compounds of the Formula III are, in particular, hydrohalic acid esters, such as bromides, chlorides and iodides, also arene sulphonic acid esters, e.g. p-toluene sulphonic acid esters.
• the starting materials of the Formula II are, for their part, new compounds, the production of which is explained below.
• compounds of the Formula l with the exception of compounds, which contain an alkanoyloxy group as R and the corresponding acid addition salts are produced by reacting a compound of Formula IV wherein R is a group corresponding to the definition for R given under Formula I, whereby groups containing a carbonyl or alkanoyloxy moiety are excepted, and if X represents the -COCl group also the irnino or hydroxyl containing groups R, are excepted, and
• X represents -CN, -COCl or a lower alkoxy carbonyl group and R has the meaning given under Formula I,
• Suitable as reac tion media are the normal appropriate orgaru'c solvents containing ether oxygen, which can be used for producing magnesium organic compounds, such as diethyl ether, dibutyl ether or tetrahydroturan, on their own or in admixture with inert organic solvents, such as benzene or toluene.
• the reaction temperature is raised towards the end of the reaction by distilling oif the ether from its mixture with an inert organic solvent having a higher boiling point.
• the decomposition of the direct reaction products is carried out in the normal manner, e.g. using water and dilute hydrochloric acid.
• a ketal grouping contained in R can be split and the corresponding carbonyl group liberated.
• R contains an imino or hydroxyl group, i.e. a reactive hydrogen atom
• the, at least, double molecular amount of metal-organic compound is used in place of the, at least, molecular amount for the compound of the Formula II.
• the compounds of the Formula I and their acid addition salts are produced by reacting a compound of the Formula VI wherein R is a group according to the definition of R with exception of the groups containing an imino, hydroxyl, alkanoyloxymethylene or alkanoylimino group,
• R is methyl, ethyl or propyl
• Y is lower alkyl
• Z is the COOY group or the cyano group with an acid and if desired, liberating from the obtained acid addition salt of a compound of the Formula I this compound and converting the latter, or the initially obtained salt into another addition salt with an inorganic or organic acid.
• a compound of Formula VI is reacted with a concentrated mineral acid, e.g. concentrated hydrochloric acid, hydrobromic acid or sulphuric acid at a temperature range of 60l50, whereby the necessary reaction temperature and duration can be easily determined by means of the evolution of carbon dioxide.
• a concentrated mineral acid e.g. concentrated hydrochloric acid, hydrobromic acid or sulphuric acid
• R has the meaning given under Formula I, is reacted with an alkali metal compound or an alkoxymagnesium compound of a malonic acid diester or cyanoacetic acid ester of the Formula VIII Z (VIII) wherein R X and Y have the meanings given under Formula VI.
• solvents for example, ether, methanol, ethanol or benzene.
• the starting materials for the Formula II and IV, for the first and second process and the acid halides of the Formula VII used as starting materials in the third process can, for example, be produced as follows: By reacting isonipecotamide with a reactive ester of a compound of the Formula III, selected according to the definition for R analogously to the first mentioned process for the production of compounds of the Formula I, and then by splitting off of water, e.g., by boiling with thionyl chloride in benzene or in chloroform, or by heating with phosphorus pentoxide, isonipecotonitriles, substituted in l-position by the group R are obtained.
• correspondingly substituted lower isonipecotic acid alkyl esters can be obtained by the reaction of lower isonipecotic acid alkyl esters with reactive esters of compounds of the Formula III, which are selected according to the definition of R
• a further production process is the quaternisation of lower isonicotinic acid alkyl esters with reactive esters of compounds of the Formula III, selected according to the definition for R and subsequent catalytic hydrogenation, e.g. in the presence of rhodium/ aluminium oxide/ catalysts.
• nitriles and esters of isonipecotic acid are coverted into their alkali metal derivatives and the latter reacted with allyl halides or (2-propinyl)-halides, e.g. with the bromides or iodides, to give nitriles or esters of the Formula IV.
• Suitable as reaction medium for these condensations is, for example, a mixture of absolute diethyl ether or tetrahydrofuran with 1,2 dimethoxyethane (ethylene glycol dimethylether).
• the required alkali metal compounds of l-substituted isonipecotonitriles and isonipecotic acid alkyl esters are produced in situ from other suitable alkali metal compounds.
• Triphenylmethyl lithium which as such a compound is particularly suitable, is preferably formed likewise in situ from another organic lithium compound, such as phenyl lithium, by adding, for example, a solution of triphenyl methane in 1,2-dimethoxyethane to the phenyl lithium produced in the known manner, which is present in diethyl ether. Since the triphenylmethyl lithium produces intensively coloured solutions, its formation and also its consumption by the subsequently added l-substituted isonipecotinic acid ester can be easily followed.
• triphenylmethyl lithium In place of triphenylmethyl lithium, t is also possible to use, for example, triphenylmethyl sodium or -potassium.
• the aforementioned stages of the process are for the most part slightly exothermic and can be carried out at room temperature or at slightly elevated temperature. It must also be possible, depending on the starting materials and amounts thereof used, for the reaction mixture, if necessary, to be cooled.
• the l-substituted 4-allyland 4-(2-propinyl)-isonipecotinoyl chlorides respectively, which are likewise embraced by the general Formula V, are obtained from the corresponding esters in the normal manner, e.g. by hydrolysis and treatment of the formed acids or their hydrochlorides with oxalyl chloride.
• the other acid halides, which are comprised by the Formula VII, are obtained in an analogous manner.
• lower isonipecotic acid alkyl esters or isonipecotamide are, for example, firstly reacted with chloroformic acid benzyl ester instead of with reactive esters of compounds of the Formula III.
• the thus obtained l-benzyloxycarbonyl isonipecotinic acid ester or the l-carbobenzyloxy isonipecotonitrile obtained from the amide after subsequent splitting oil? of water, are converted, analogously to the above stated reaction sequence, into their alkali metal derivatives and the latter condensed with allyl or (2 propinyl)-halides.
• the starting materials of the Formula H are also obtained by reacting a compound of the Formula I, obtained according to the second or third mentioned process, wherein R denotes the methyl or benzyl group, with chloroformic acid benzyl ester and splitting the obtained l-benzyloxycarbonyl compound, e.g. again in the aforestated manner by means of hydrogen bromide in glacial acetic acid.
• compounds are produced, according to a fourth process, of the Formula I, wherein R represents the allyl group, and their addition salts with inorganic and organic acids by reacting a compound of the more restricted Formula IX R1 (IX) which is already comprised by the Formula I and wherein R and R have the meaning given under Formula I, in the presence of a catalyst suitable for the partial hydrogenation of triple bonds, with hydrogen until the equimolecular amount has been taken up.
• a catalyst use is made, for example, of palladium on CaCO partially deactivated with lead acetate, in ethanol as the solvent, and further deactivated in situ by the addition of quinoline, (Lindlar catayst, see, Helv. Chim. Acta 35,450 (1952)).
• the obtained compound of the Formula I is converted into an addition salt with an inorganic or organic acid.
• piperidine derivatives of the general Formula I obtained using the process according to the invention are subsequently converted in the normal manner into their addition salts with inorganic and organic acids.
• a solution of a piperidine derivative of the Formula I in an organic solvent such as diethyl ether, methanol or ethanol
• an organic solvent such as diethyl ether, methanol or ethanol
• the acid desired as the salt component or a solution thereof
• the salt which precipitates direct, or after the addition of a second organic liquid, such as, e.g. diethyl ether to methanol, is isolated.
• a second organic liquid such as, e.g. diethyl ether to methanol
• salts for use as active substances for medicaments, pharmaceutically acceptable acid addition salts can be used instead of free bases, i.e. salts with those acids the anions of which, in the case of the dosages in question, have either no pharmacological action or which, in themselves, have a desired pharmacological action. Furthermore, it is of advantage if the salts to be used as active substances, crystallise well and are not, or only slightly, hygroscopic.
• Hydrochloric acid hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, fi-hydroxyethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic, aid, succinic acid, fumaric, acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, embonic acid, cyclohexylamine sulphonic acid or 1,5-naphthalene disulphonic acid, for example, can be used.
• mice The analgesic activity of the compounds of the invention is illustratively demonstrated in mice according to the method of Gross, Helv. Physiol. Acta. 5, C. 31 (1947) whereby the apparatus of H. Friebel and C. Reichle, Arch. exp. Path. and Pharmakol. 226, 551 (1955), is used.
• the apparatus comprises an electrically heated lamp which is placed in the focus of a semi-elliptical metal concave mirror.
• a semi-elliptical metal concave mirror Under the mirror, on a turn-table, there are located small plexiglass cages, each holding a white mouse in such a position that the mouse-tail rests stretched out in a small groove on a plexiglass plate.
• the turn-table can be turned so that the mouse-tails, one after the other, come to be placed into the second focus of the elliptical mirror. Pain is induced by the convergent heat radiation from the mirror and the time is measured from the moment when the heat reaches the mouse-tail till the moment at which the mouse twitches its tail.
• test compound Two series of 10 mice each are tested prior to the administration of the test compound and the normal reaction time for each mouse is recorded. Then the test compound is administered intraperitioneally or orally and the reaction times after the injection are recorded, thus enabling determination of the intensity and the duration of the analgesic effect of the test compound administered.
• the fumarate of l-[1-(3- phenylpropyl)-4-allyl-4-piperidyl]-l butanone exhibits an analgesic effect if administered intrapeitoneally in amounts of about 1.7 mg./ kg. and orally of about 19 mg./ kg. Similar results are obtained with other preferred members of the strong analgesic group.
• I-[I-(Z-phenylethyl)-4-(2-propinyl)-4 piperidyl] 1- butanone exhibits in form of its fumarate and analgesic effect in amounts of about 12 mg./kg. on intraperitoneal and of about 26 rug/kg. on oral administration. Similar results are obtained with the other preferred members of the mild to moderate analgesic group.
• the favorable relation between the intraperitioneal and the peroral activities is of particular advantage, as it shows that the compounds of the invention are very well absorbed and that they are, therefore, suitable for oral application.
• the antitussive activity of the compound of the present invention is demonstrated according to the method of R. Domenjoz, Arch. exp. Path. and Pharmakol. 215, 19-24 Healthy cats of normal weight are narcotized by intraperitoneal injection of 30-65 mg./kg. of aprobarbital so that a relatively superficial narcosis is obtained. About 45 minutes after the injection of the narcotic, the preparation of the Nervus laryngeus superior is started by fitting on an irritation-electrode. An apparatus manufactured by Grass 8 Medical Instruments, Type SD 5, allowing irritation of th aforesaid nerve with rectangular current-impulses of any desired frequency and intensity is connected to the electrode. The irritation-frequency applied is 5 cycles at an irritation-intensity between 0.5 and 3 volts.
• the irritation-duration is about 8 seconds and the interval between two irritations is about 120 seconds.
• a Marey capsule is used for the registrations of the cough reflexes.
• a respiration-cannula is introduced through the oral cavity down to the glottic chink.
• the test compound is injected intravenously in form of an 0.5% aqueous solution just before the irritation starts.
• Cough reflexes are inhibited with about 1-3 mg./kg. of l-(l-methy1-4-allyl-4- piperidyl)-l-butanone furnarate.
• a further method of showing the antitussive activity is to determine the manner in which tussive irritation in guinea pigs caused by sulphur dioxide is stopped as a result of subcutaneous or oral administration of the test substances:
• male guinea pigs are exposed in a plexiglass chamber to a SO -CO -air mixture, flowing through at atmospheric pressure, and with a constant mixture ratio of 20 ml.:1.5 liters:10.5 liters per minutes, until commencement of coughing or for a maximum of 120 secs.
• the assessment of the commencement of coughing is made by inspection.
• the guinea pigs reacting by coughing (ca.
• the toxicity of the compounds of the invention as demonstrated in rats intravenously and perorally is of favorable low order.
• the new piperidine derivatives of the Formula I and their pharmaceutically acceptable acid addition salts are suitable as active substances for pharmaceutical preparations for the amelioration and the elimination of pains of varying origin and of tussive irritation. They can be administered orally, rectally or parenterally.
• the daily dosages of free bases or of pharmaceutically acceptable salts thereof vary between 0.1 to 10 mg./kg. for mammals.
• Suitable dosage units such as drages, capsules, tablets, suppositories or ampoules, preferably contain 1-100 mg. of a piperidine derivative of the Formula I, or of a pharmaceutically acceptable salt thereof.
• Dosage units for oral administration preferably contain as active substance between 1% and 90% of a piperidine derivative of the Formula I, or of a pharmaceutically ac ceptable salt thereof. They are produced by combining the active substance with, e.g. solid, pulverulent carriers, such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols, to form tablets or drage cores. The latter are coated, e.g. with concentrated sugar solutions which can also contain, e.g.
• suitable dosage units for oral administration are hard gelatine capsules and also soft, closed capsules made of gelatine and a softener such as glycerin.
• the former preferably contain the active substance as a granulate in admixture with lubricants such as talcum or magnesium stearate, and optionally stabilisers such as sodium meta-bisulphite or ascorbic acid.
• the active substance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols to which stabilisers can also be added.
• lozengers as well as forms not made up into single dosages can be used for oral administration, e.g. cough syrups or drops prepared with the usual auxiliaries.
• Suitable dosage units for rectal administration are, e.g. suppositories which consist of a combination of a piperidine derivative of the general Formula I or a suitable salt thereof with a neutral fatty foundation, or also gelatine rectals capsules containing a combination of the active substance with polyethlene glycols.
• Ampoules for parenteral, particularly intramuscular, also intravenous, administration preferably contain a water soluble salt of a piperidine derivative of the Formula I as active substance in a concentration of, preferably, 0.5-%, optionally together with suitable stabilisers, in aqueous solution.
• a suppository mixture is prepared from 2.0 g. of
• EXAMPLE 2 1.3 g. of crude 1-(4-allyl-4-piperidyl)-1-butanone (see Example 1, first para-graph) are refluxed for 6 hours with 1.4 g. of 3-phenylpropyl bromide, 2 g. of sodium carbonate and 50 mg. of sodium iodide in 20 ml. of acetone. The reaction mixture is then filtered by suction and the filtrate washed with hot acetone. The filtrate is concentrated in vacuo, the residue dissolved in methylene chloride, the solution dried and concentrated and the residue distilled in a bulb tube.
• the 1- ⁇ 1-(3-phenylpropyD-4- allyl-4-piperidyl]-l-butanone boils in the air-bath at 160- 180/0.01 torr.
• the hydrobromide, M.P. 169-170, is produced from this in the usual manner.
• the reaction is thereby slightly exothermic.
• the reaction mixture is then refluxed for 2 hours. While cooling with ice, it is then decomposed with water and 2 N hydrochloric acid and the ether phase separated off.
• the ether solution is dried and concentrated and the residue distilled.
• the obtained 1-[1-(3-phenylpropyl) 4-allyl 4-piperidyl] l-butanone boils at 137- /0.03 torr.
• the hydrobromide is produced from this in the usual manner, M.P. 169-170", using ethereal hydrogen bromide solution.
• the mixture is stirred for 2 /2 hours at room temperature, whereby it assumes a yellowish colour and lithium bromide precipitates.
• the reaction mixture is then decomposed with 20 ml. of water and concentrated in the rotary evaporator.
• Ether is added to the residue and the obtained ether solution extracted four times with dilute hydrochloric acid.
• the acid extracts are rendered alkaline and exhaustively extracted with chloroform, the chloroform extracts then being dried and concentrated.
• the residue is taken up in ether, the ether solution dried and concentrated and the residue distilled.
• the 1-(3-phenylpropyl)-4-allyl isonipecotonitrile boils at 140- 150/().01 torr (air bath).
• the hydrochloride prepared with hydrogen chloride in ether melts after recrystallization from acetone methanol at 219-220".
• the Grignard compound is produced in the usual manner from 1.46 g. of magnesium and 6.55 g. of ethyl bromide in 30 ml. of absolute ether in a 100 ml. four-necked flask. 6 g. of 1-(3-phenylpropyl)-4-allyl isonipecotic acid ethyl ester in 18 ml. of absolute ether are then added. The reaction is only slightly exothermic. 50 ml. of absolute toluene are then added and the ether is distilled off. The starting material is then refluxed for 12 hours and decomposed, while cooling with ice, with water and 2 N hydrochloric acid.
• the organic phase is, if necessary, separated with the addition of ether, thoroughly shaken with concentrated ammonia and brine, dried, evaporated and distilled.
• the 1- (3-phenylpropyl -4-allyl-4-piperidyl] -propanone boils in the air bath at 160-180/0.02 torr.
• the fumarate is produced from this in the usual manner, M.P. 150l52.
• the ester required as starting material is obtained as follows:
• EXAMPLE 5 23.7 g. of 1-(3-phenylpro yl)-4-allyl isonipecotic acid ethyl ester (produced according to Examples (4a), (b) and (c)) are refluxed with ml. of 20% potassium hydroxide solution and 160 ml. of absolute ethanol for 15 hours. The solution is then made neutral with concentrated hydrochloric acid and concentrated in the rotary evaporator. The dry residue of crude 1-(3-phenylpropyl)- 4-allyl isonipecotic acid hydrochloride is dissolved in 200 ml. of methylene chloride and a mixture of ml. of oxalyl chloride in 80 ml. of methylene chloride is added dropwise.
• reaction mixture is then evaporated to dryness in vacuo at 30 and the acid chloride dissolved in 150 ml. of absolute benzene.
• This solution is added dropwise at 30 to a cadmium Grignard solution produced in the usual manner from 7.32 g. of magnesium, 37 g. of propyl bromide and 33 g. of cadmium chloride in 240 ml. of absolute ether and 150 ml. of absolute benzene.
• the reaction mixture heats up during this process.
• the mixture is refluxed for a further 30 minutes. While cooling with ice, the mixture is decomposed with water and 2 N hydrochloric acid. The organic phase is separated, thoroughly shaken with conc.
• the 1 (3-phenylpropyl)-4-(2-propinyl) isonipecotic acid ethyl ester, B.P. 170-172/0.05 torr., fumarate M.P. 153 (from isopropanol), which is required as starting material, is produced completely analogously to Examples (4a), (b) and (c) using the same amount of propargyl bromide (3-bromopropine) in place of allyl bromide in the case of (c) Analogously to the above example, using corresponding amounts of ethyl bromide, and n-butyl bromide respectfully, the following are obtained.
• hydrochloride M.P. 148 the 1-(1- benzyl 4 allyl-44-piperidyl)-1-butanone, hydrochloride M.P. 154-155;
• EXAMPLE 9 28.2 g. of ethyl malonic acid diethyl ester with 3.45 g. of finely dispersed sodium are stirred in 900 ml. of absolute ether in a four-necked flask for 15 hours. To the thick suspension of sodinm-ethyl-malonic acid diethyl ester are added 17.1 g. of 1-(2-phenyl-ethyl)-4-allyl-isonipecotinoyl-chloride hydrochloride. The mixture is firstly stirred at room temperature and then refluxed for an hour. It is then decomposed with ice and 5 N hydrochloric acid and the ether phase separated.
• EXAMPLE 10 3.12 g. of 1 [1 (3 phenylpropyl)-4-(2-propinyl)-4- piperidyl]-1-butanone are hydrogenated at room temperature under normal pressure in the presence of 0.5 g. of Lindlar catalyst (palladium on calcium carbonate, partially deactivated with lead acetate) and 0.2 g. of guinoline in 50 ml. of ethanol. After about 107% of the theoretically necessary amount of hydrogen has been taken up, hydrogenation is discontinued, the catalyst is filtered 011 and thoroughly Washed with ethanol. The filtrate is evaporated in a rotary evaporator and the residue is distilled under high vacuum.
• the 1-[1-(3-pheny1propyl)-4 allyl-4-piperidyl]-1-butanone obtained boils at 160-180/ 0.01 torr, its hydrobrornide melts at 169-170".
• R C o-n CH2 CH2 CH2 CH2 wherein R is cinnamyl, 2-phenoxyethyl or 3-(p-fiuorobenzoyl) P py R is allyl or 2-propinly, and
• R is n-propyl
• R is 3-(p-fiuorobenzoyl)propyl and R is allyl.

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  • 1969-07-01 BG BG012567A patent/BG15396A3/bg unknown
• 1970
  • 1970-11-25 US US92906A patent/US3681501A/en not_active Expired - Lifetime

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