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United States Patent [19] [11] 15 Re. 30,811 Dykstra et a1. [45] Reissued Dec. 1, 1981
[54] SUBSTITUTED PIPERIDINES 2,780,577 2/1957 Phillips et a]...... 424/267 THERAPEUTIC PROCESS AND 3,192,213 1/1965 Krapcho ...... 260/253 COMPOSITIONS 3,789,072 1/1974 Bernstein ...... 260/557 D 3,931,195 1/1976 Dykstra et a1...... 260/293.58 [75] Inventors: Stanley J. Dykstra; Joseph L. OTHER PUBLICATIONS Minielli, both of Evansville, Ind. 73 A. - ._ Mead J hnson 81 C a Lawson, J. Pharm. Ex p . Thera p ., 160, pp . 21-31 (1968). [ 1 ‘Slgnee Evansv?le in mm’ ‘W’ Krapcho et al., J. Med. Chem, 6, p. 219 (1963). ' Krapcho et al., J. Med. Chem, 7, pp. 376-377 (1964). [2!] Appl- NW 98.008 Krapcho et 31., .1. Med. Chem, 9, pp. 809-812 (1966). [22] Filed. No“ 28, 1979 Krapcho et al., J. Med. Chem, 12, pp. 164-166 (1969). Phillips, J. Am. Chem. Soc., 72, pp. 1850-1852 (1950). Related US. Patent Documents Primary Examiner—Stanley J. Friedman Reissue of. Attorney, Agent, or Firm-Robert H. Uloth; Robert E. [64] Patent NO.I 4,064,254 Camha" Issued: Dec. 20, 1977 [57] ABSTRACT AF531: 1. N 0 .: 734,5830cL 21 1976 The compounds are of the heterocycltc, class of 2 v _ ’ phenethylpiperidines having an amido substituent in the U-5- APPl1cat1°I151 ortho position of the phenethyl moiety. Substituents in 160] Dlvisio" 0151?’ NO- 620-207’ Ocl- 3» 19751 Pa" N°~ the ortho position include formamido, benzamido, cin 4‘00Oé143' wh‘ch '5 agd‘wls‘gn 025:", No- 384'34l' Jul" namamido, 2-thiophenecarboxamido, alkanesul 31' 1. 73' .pal'. NO‘ 3' 3 l’ 9 ’ w ‘c ‘S a fonamido and alkanoylamido. They are useful as antiar contmuation-ln-parlabandonm of Ser. No. 120,754, Mar. 3, 1971, rhythmic. and/or antlserotomn. . agents. The novel com pounds are prepared by reaction of appropriately substi [51] “1- CL] ------~- A61K 31/445; A6|K 31/455 tuted o-aminophenethylpiperidines and the carbonyl or [52] U_-5- 0------~ 424/266; 424/267 sulfonyl halides or anhydrides. Typical embodiments of Fleld 01' Search ...... invention are 4.methoxy-2'-[2-(l-methyLZ [56] References Cited piperidyl)ethyl]benzanilide and 2'-{2-(1-rnethyl-2 U S PATENT DOCUMENTS p1per1dyl)ethyl]c1nnaman1l1de.
2,686,784 8/ 1954 Finkestein et a1...... 260/293 22 Claims, N0 Drawings Re. 30,811 1
SUBSTITUTED PIPERIDINES THERAPEUTIC Formula I PROCESS AND COMPOSITIONS
Matter enclosed in heavy brackets [ ] appears in the 5 original patent but forms no part of this reissue speci?ca tion; matter printed in italics indicates the additions made by reissue.
CROSS-REFERENCE TO RELATED Formula X11 APPLICATIONS This application is a division of co-pending U.S. ap plication Ser. No. 620,907 filed Oct. 8, 1975 and now US. Pat. No. 4,000,143 granted Dec. 28, 1976, which is a division of then co-pending US. application Ser. No. 384,341 ?led July 31, 1973 and now US. Pat. No. ,, Nit-R9 3,931,195 granted Jan. 6, 1976, which is a continuation in-part of then co-pending US. application Ser. No. The substances of Formula I and Formula XII are new 20 120,754 ?led Mar. 3, 1971, now abandoned. compositions of matter possessing valuable pharmaco BACKGROUND OF THE INVENTION logical properties which render them useful as synthetic medicinals. In particular, the substituted piperidines of The present invention is concerned with certain het Formula I and Formula XII exhibit utility as antiseroto erocyclic organic compounds which can be referred to nin and/or antiarrhythmic agents in standard pharma as substituted piperidines and acid addition salts thereof. cological tests in mammals. This invention also is con In particular, this invention relates to physiologically active novel piperidine compounds which are particu cerned with the production of the compounds of For larly effective as antiarrhythmic and antiserotonin mulas I and XII from novel chemical intermediates, agents. It is also concerned with chemical intermediates 30 pharmaceutical compositions containing them and a useful in the preparation of the piperidine compounds. therapeutic process for producing an antiserotonin ef Other features of the invention are pharmaceutical com fect in mammals comprising the administration of such positions containing the piperidines as active ingredi compounds thereto. Another feature of this invention is ents and a therapeutic process for producing antiseroto a therapeutic process for producing an antiarrhythmic nin and antiarrhythmic effects in mammals by adminis 35 effect in mammals by administration of compounds of tration of them. Formula I wherein R5 is R6 substituted cinnamoyl as Agents which antagonize serotonin are of interest in depicted by Formula Ia or R7 substituted benzoyl as experimental biology and in treatment of various physi depicted by Formula Ib. , ological disorders such as migraine headache, serotonin Still another feature of this invention provides novel producing tumors, toxemia in pregnancy, habitual abor o-aminophenethylpiperidines of Formula II which are tion and management of various in?ammatory and aller gic reactions. Methysergide and lysergide are well useful as chemical intermediates in the production of known antiserotonin agents. Other serotonin antago compounds of Formula I. nists which have been reported in the prior art literature 45 on the subject are 2'-(3-dimethylaminopropylthio)cin Formula II namanilide and related compounds disclosed by Krap R‘ cho, et al., J. Med. Chem, 6, 219 (1963); 7, 376 (1964); 9,809, (1966); and 12, 164 (1969); and U8. Patent 3,192,213. 50 A number of structurally unrelated chemical sub stances have been employed in the treatment of cardiac NH arrhythmia; refer to A. Burger, Medicinal Chemistry, RI 3rd Edition, pages 1082-1085 (Wiley). One of the most important drugs in clinical treatment of disorders of 55 In the compounds characterized by the above general cardiac rhythm is quinidine. Another chemical agent Formulas I and II, the R1 substituent stands for hydro which has been used as an antiarrhythmic is the local gen or lower alkyl. The substituent R2 represents hydro anesthetic procaine amide. Still other antiarrhythmic gen, lower alkoxy or methylenedioxy attached in the agents are lidocaine, and diphenylhydantoin. None of benzenoid 4,5-position. R3 stands for hydrogen or a these compounds are structurally related to the piperi lower alkyl substituent. Substituent R4 represents hy dines of the present invention. drogen, lower alkyl, or a dialkylcarboxarnido substitu SUMMARY OF THE INVENTION ent wherein the dialkyl groups are lower alkyl. Substituent R5 represents radicals selected from the This invention relates to a series of substituted piperi 65 dines characterized by Formula I and Formula XII and group comprised of lower alkanoyl of from 1 to 4 car non-toxic pharmaceutically acceptable acid addition bon atoms inclusive, lower alkanesulfonyl of from 1 to salts thereof. 4 carbon atoms inclusive, Re. 30,811 3 4
0 0 Formula la n \ N R‘ H—N c—, C-. / 5 N R2 N "isonipecotoyl" “pyridylcarbonyl“ ,L; 0 ii: 5 if R‘ ii R6 U ' I] I] c“ w 0 wherein R‘, R2, R3, R4 and R6 have the meanings here inabove given for Formula 1. Representative of these “3-furylcarbonyl“ "l-lhioph??ecarbo?yl” compounds is the individually preferred compound 0 15 2'-[2-(l-methyl-2-piperidyl)ethyl]cinnamanilide. ll Compounds of the present invention which are par ticularly preferred for their strong antiarrhythmic ac tivity are those of Formula Ib. "phenylpropioloyl" ll 20 Formula lb 4 u c- R CH=C—c-, R7 R6 R2 if "cinnamoyl" “benzoyl” 25 R 3
The symbol R6 represents hydrogen or lower alkyl R1‘T7? 0 R 1 and R7 is selected from the group consisting of hydro gen, halogen, tri?uorornethyl, amino, dimethylamino, 0 _ ‘ hydroxy, acetoxy, carboxy, alkylthio of from 1 to 4 Lu) Where!“ R_1r R2, R3- R4, and R7113“ the meamngs hel'e' carbon atoms inclusive, alkyl of from 1 to 4 carbon mabove Ewen for Formula 1- Representative of these atoms inclusive, lower alkoxy of from 1 to 4 carbon compounds f‘re the mdlvldually Preferred compo‘fnds atoms inclusive, and wherein when R7 is hydrogen or ll'methoxy'? '[2‘(l'methyl‘z'P'p‘indynethyllbcnzam‘ alkoxy the phenyl ring can have up to 2 additional alk- 35 Me’ and 2 'l2,'(1'methyl'2'p1pendyl)ethyl]'3’4’s'mme' oxy substituents of from I to 4 carbon atoms inclusive. thoxybenzamhde' . A still further group of preferred compounds are In the ctgmpounds characterized by Formula XII, the those characterized by Formula Ib whmein R1, R2’ and symbol R represents hydrogen or lower alkyl. The symbol R9 represents a radical selected from the group R 4 are hydrogen’ R 3 ‘S' methyl and R 7 is‘ hydrogen or . . . alkoxy. . conslstmg of cmnamuyl or 40 A particularly preferred antiarrhythmic compound of Formula XII is 2'-[3-(1-methyl~2-piperidyl)propyl]-p O anisanilide. II The o-aminophenethylpiperidines of Formula II are Rm C- 45 considered to be another aspect of the present inven tion. They are particularly useful as chemical intermedi ates in the preparation of compounds of Formula I. wherein R10 is lower alkoxy. The symbol “A” repre- Apart from being particularly suitable as key intermedi sents a divalent radical selected from the group consist- ates in the preparation of compounds of Formula 1, ing of 50 some of the members such as 2-(o-aminophenethyl)-l methylpiperidine have antiarrhythmic properties. A compound of Formula XII particularly preferred as an antiarrhytmic agent is 2-[2~[(p-methoxybenzyl CH3 OH CH3 CH3 )amino]phenethy1]-l-methylpiperidine and non-toxic _CHCHZCH2_, and _(CHZ)3__ 55 pharmaceutically acceptable salts thereof. OHI It will be apparent to those skilled in the art that the compounds of Formula I, Formula II and formula XII It is to be understood that the term “lower alkyl” and exists in at least one racemic stereoisomeric form since they contain one asymmetric carbon atom (the 2 posi “lower alkoxy” as used herein refers to carbon chains . . . . . 4 . which include both straight and branched chain carbon 60 itéorilo?isgrggfgrgiggl?gé[mhglirrgé?clia?zil?gz radicals of from to 4 carbon atoms inclusive. Illustra- (the 5 position of the piperidine ring) is present and two ""6 of these radlcals are carbon Chams whlch can be racemic modi?cations exist. Such mixture of racemates methyl, ethyl, PTOPYL i“OPTOPYL l'butylt l'methylpro' can be separated into the individual racemic compounds Pyl, z'melhylpl'opyl and tert‘butyl 65 on the basis of physico-chemieal differences such as Compounds which are particularly preferred for solubility; for example, by fractional crystallization of their strong antiserotonin activity are compounds of the basis or as acid addition salts thereof or by chroma Formula Ia. tography. Optically active stereoisomers are obtained Re. 30,811 5 6 by resolution mcthods well known to the art such as the placed in Chenoweth‘s solution warmed to 30° C. and use of optically active acids. irrigated with 95% oxygen: 5% carbon dioxide. The It is to be understood that as used herein, the term lower end of the atrium is attached to a small hook fixed “non-toxic pharmaceutically acceptable acid addition in the bath and the upper end is connected to a trans salts“ refers to a combination of compounds of the pres ducer to record contractile activity. The atrium is elec ent invention with relatively non-toxic inorganic or trically stimulated at a basic rate of 30 per minute em organic acids. Illustrative of suitable acids which may ploying square wave pulses of 10 millisecond duraction be used are sulfuric, phosphoric, hydrochloric, hydro at 1.2-1.5 >< threshold voltage. A test compound is intro bromic. hydroiodic, sulfamic, methanesulfonic, ben duced into the bath and the test repeated after a 5 min zenesulfonic, para-toluenesulfonic, acetic, lactic, suc ute interval. A dose-response relationship is obtained by cinic. maleic, mucic, tartaric, citric, gluconic, benzoic, additional doses of the test compound. The potency of cinnamic, isethionic and related acids. a test agent can be expressed as the effective concentra The compounds characterized by Formula I and tion which produces 50% of the maximal increase in the Formula XII exhibit valuable antiarrhythmic activity in measured refractory period of the steady state atrium. mammals. These antiarrhytmic effects are illustratively 5 This value is designated the EC50. demonstrated in standard in vitro and in vivo pharma In the in vitro rabbit atrium test, the EC50 of 4 cological tests. rnethoxy-2'-[2-( l -methyl-Z-piperidyl)ethyl]benzanilide In the dog, for example, electrically or aconitine is 2.4 microgram per milliliter while the value for quini induced arrhythmia is prevented by oral or parenteral dine is 18.0 microgram per milliliter. administration of the piperidines of Formula I accord 20 Examplary of compounds of the present invention ing to the following in vivo test. which have particularly good antiarrhythmic properties The chest of an anesthetized dog is opened in the are: midline and the right and left atrial appendages exposed 2'-[2-(l-methyl-2-piperidyl)ethyl]benzanilide, through small slits in the pericardium. Bypolar record 4-hydroxy-2'-[2-(l-methyl-2-piperidyl)ethyl]benzani ing electrodes are affixed to the atrial surfaces and a 25 lide, 4><4 mm. piece of clean cloth is fixed to the surface of 4-chloro-2'-[2-(l-methyl-2-piperidyl)ethyl]benzani the right auricular appendage. Control recordings are lide, made of various heart functions including femoral arte 4-amino-2’-[2-( 1-methyl-2-piperidyl)ethy1]benzani rial blood pressure and right and left atrial electro lide, grams. Atrial arrhythmia is then induced by placing 3-5 30 4-acetoxy-2'-[2-[2-(l-methyl-2-piperidyl)ethyl]ben drops of a solution of aconitine on the cloth which is zanilide, fixed to the right atrium. An irregular, rapid atrial rate 2'-[2-(l-methyl-2-piperidyl)ethyl]-3,4,S-trimethox is produced within one minute. Throughout the experi ybenzanilide, ment, fresh aconitine is (2—3 drops) placed on the cloth 2'-[2-( l-methyl-2-piperidyl)ethyl]-2-thiophenecar at 10 minute intervals. The test compound is adminis boxanilide, tered intravenously ?ve minutes after the initial estab 2’-[2-(l-methyl-2-piperidyl)ethyl]methanesulfonani lishment of the arrhythmia and infusion continued at a lide, slow rate until an effective does which re‘establishes 2'-[2-(l-methyl-2-piperidyl)ethyl]acetanilide, normal rhythm of the heart is obtained. 2'-[2-( l -methyl-2-piperidyl)ethyl]formanilide, Intravenous administration of as little as 0.8 mg./kg. Z-(o-aminophenethyD-l-methylpiperidine, of 4-methoxy-2'-[2-( l -methyl-2-piperidyl)ethyl]benzani 2'-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide, lide, a preferred compound of the present invention, 2'-[3-(l-methyl-2-piperidyl)propyl]-p-anisanilide. effectively restores normal cardiac rhythm to aconitine The compounds of Formula Ia and Formula Ib are induced arrhythmia in the dog. A well known antiarr characterized as particularly useful antiserotonin agents hythmia agent such as quinidine administered in the 45 as can be demonstrated in the rat uterus. According to same manner has an effective dose of 6.0 mg./kg. When this test one of the uterine horns of a rat uterus is sus arrhythmia is induced electrically, the effective dose of pended in oxygenated salt solution at 30° C. The con 4'methoxy-2’-[2-(lmethyl-2-piperidyl)-ethyl]benzani tractions of this tissue are then recorded and varying lide is 1.9 mg./kg. Under like conditions, the effective concentrations of the test compound introduced into dose for quinidine is 14 mg./kg. the bath in order to determine the concentration that Intraduodenal administration, which is a measure of would decrease the spasmogenic effect of 0.4 micro oral effectiveness, of 4-methoxy-2'-[2-(l-methyl-2 gram per milliliter of serotonin by 50%. This value is piperidyl)ethyl]benzanalide prevents aconitine induced designated the IC50. arrhythmia in the dog at a dose of less than 10 mg./kg. A preferred antiserotonin compound of the present while the effective dose in the prevention of aconitine invention is 2'-[2-(l-methyl-2-piperidyl)ethyl]cin induced arrhythmia of quinidine is greater than 14 namanilide, which has an IC5Q of 0.00185 microgram mg./ kg. per milliliter. Another preferred substance, 4-methoxy Another in vivo test involves the inhibition of chloro 2’-[2-(1-methyl-2-piperidyl)ethyl]benzanilide, has an form induced arrhythmia in the mouse according to the IC5Q of 0.0046 microgram per milliliter. The antiseroto method of J. W. Lawson, J. Pharmacol. Exp. Therap., 60 nin agents lysergide (LSD) and methysergide have an 160, 22 (1968). Intraperitoneal administration of 4 IC50 of 0.012 and 0.0025 microgram per milliliter re methoxy-2'-[2-(l-methyI-Z-piperidyl)ethyl]benzanilide spectively. to the mouse prevents chloroform induced arrhythmia The antiarrhythrnic and antiserotonin therapeutic at an ED5Q of 7.1 mg./kg. compared to an Edso of 83 for process of the present invention is carried out in mam quinidine. 65 mals by systemic administration of a non-toxic effective An in vitro test which demonstrates the antiarrhyth dose of the piperidines of Formulas I and XII ranging mic effects of the compounds of the present invention from about 0.01 to 20 milligram per kilogram of body employs the rabbit atrium. In this test, the left atrium is weight of the mammal or more preferably from 0.1 to Re. 30,811 7 l0 mg./kg. Acceptable forms of systemic administration are oral and parenteral. Examples of parenteral adminis Equation 1. tration are intramuscular, intravenous, intraperitoneal, R4 and subcutaneous administration. The dosage of the + nix % present therapeutic agents of Formulas I and XII will a1 N vary with the form of administration and particular compound chosen. Generally, the compound is admin ,L; istered at a dosage substantially less than the optimum NH dose of the compound Thereafter, the dosage is in in creased by small increments until the optimum effect Formula ll Formula I + IIX under the circumstances is reached. It will generally be found that when the composition is administered orally, wherein R1, R2, R4, and R5 have the meaning stated larger quantities of the active agent will be required to above and R3 is limited to lower alkyl provided that produce the same effect as a smaller quantity given when R5 is “R7-benzoyl", R7 additionally represents parenterally. In general, the compounds of this inven “NO2" but cannot stand for NH; or OH. Compounds tion are most desirably administered at a concentration wherein R7 is “N02” are converted to compounds of level that will generally afford effective results without Formula I wherein R7 is “NHz” by hydrogenation. causing any harmful or deleterious side effects. Compounds wherein R7 is “acetoxy" are converted to The antiserotonin activity of 2’-[2-(l-methyl-2 20 compounds of Formula I wherein R7is “()H" by hydro piperidyl)ethyl]-cinnamanilide can also be demon lysis. The symbol "X” represents a halogenide of a R5 strated in mice according to the method of S. J. Corne, carbonyl or sulfonyl radical or R5X taken together et al., Brit. J. Pharmacol, 20, 106 (1963). This test is represents an anhydride. dependent on the metabolism of S-hydroxytryptophan Illustrative of RSX reactants which can be reacted to serotonin in the brain in mice which are pretreated 25 with o-aminophenethylpiperidines of Formula II are: with a monamine oxidase inhibitor. Depending on the acetic-formic anhydride, route of administration and the pretreatment time, the acetic anhydride, following ED5Q values are obtained; subcutaneous, 4.3 n-propionic anhydride, mg./kg. (30 minute pretreatment), l0 mg./kg. (60 min n-butyric anhydride, ute pretreatment); intraperitoneal, 21 mg./kg. (60 min isobutyric anhydride, benzoic anhydride, ute pretreatment). These values compare favorably acetyl chloride, with that obtained with methyldopa, a known serotonin propionyl chloride, inhibitor, which has an intraperitoneal ED50 of 37 butyryl chloride, mg./kg. (60 minute pretreatment). 35 methanesulfonyl chloride, When the compounds of this invention characterized methanesulfonic anhydride, by Formulas I and XII are employed as antiserotonin or ethanesulfonic anhydride, antiarrhythmic agents they may be administered to isopropylsulfonyl chloride, mammals alone or in combination with a pharmaceuti n-butanesulfonyl chloride, cally acceptable carrier. The proportion of the pharma 40 4-methoxybenzoyl chloride, ceutical carrier is determined by the solubility and 3,4,5-trimethoxybenzoyl chloride, 3,5-dimethoxybenz chemical nature of the compound and chosen route of oyl chloride, administration in standard pharmaceutical practice. For Z-methoxybenzoyl chloride, example, they may be administered orally in form of 2-chlorobenzoyl chloride, tablets, coated tablets or capsules containing such excip 45 B-acetoxybenzoyl chloride. ients as starch, milk, sugar, certain types of clay, gelatin, In addition R5X taken together can represent a reac stearic acid or salts thereof, magnesium or calcium stea tive ester such as, for example, methyl 4-(t-butoxy)ben rate, talc, vegetable fats or oils, gums, glycols, and other zoate, ethyl picolinate, ethyl propiolate, ethyl 4-dime known excipients. They may be administered orally in thylaminobenzoate, ethyl furan-3-carboxylate and the the form of solutions which may contain coloring and like. flavoring agents or they may be injected parenterally, The reaction proceeds when the reactants are con that is intramuscularly, intravenously, or subcutane tacted and mixed in an inert organic solvent as a reac ously. For parenteral administration they may be used tion medium. Representative inert organic solvents in the form of sterile solution. Said pharmaceutical com which can be employed as reaction media include ether, positions are prepared by conventional methods. benzene, toluene, acetonitrile halogenated hydrocar A recommended dosage unit form comprises a phar bons such as chloroform, and the like. Whenever halo~ genide reactants such as acetyl chloride, etc., are em maceutical carrier and the therapeutically active com ployed, it is desirable to add a hydrogen halide acceptor pound in an amount sufficient to provide a nontoxic such as triethylamine to the reaction mixture. Pyridine effective antiserotonin or antiarrhythmic dose ranging is preferred particularly as a reaction medium because from about 0.0l to 20 milligram per kilogram of body of its suitability both as a solvent and as an acid accep weight of the mammal treated. tor. The temperature at which the reaction is carried Advantageously, the compositions can be adapted to out is not critical, although from a convenience and ease supply a fixed dose containing from 1 to 500 mg. and of operability viewpoint, room temperature is pre preferably 5 to I00 mg. of the active ingredient. ferred. The exact proportions of the reactants to be Preparation of compounds of Formula I according to employed is not critical. However, since the o-amino the process of the present invention is carried out ac phenethylpiperidines of Formula II and the R5X reac cording to Equation 1. tants are consumed in equimolar proportions, the reac Re. 30,811 9 10 tants are preferably employed in such proportions. The reaction is generally complete in about I to 24 hr. de Equation 3 pending upon the reaction temperature employed. The \ R4 product can be conveniently separated from the reac» | - tion mixture by concentrating the reaction mixture R2 N under reduced pressure, dissolving the resulting residue in water and adding thereto a base such as aqueous Formylation sodium hydroxide, aqueous sodium carbonate. or aque NH; ous potassium carbonate to make the mixture strongly Formula lV basic. The product can then be separated by extraction with a halogenated hydrocarbon solvent, ether, ben \ R4 zene. ethyl acetate. etc. Generally, the product can be / puri?ed by recrystallization from organic solvents such R2 N as isopropyl ether. heptane, methanol, ethanol, isopro pyl alcohol, ethyl acetate, water, acetone, and the like, or it can be converted to an acid addition salt. Other NHCHO means of puri?cation include chromatography, e.g. Formula V thin-layer or column. Conversion of the substances characterized by For Equation 4 illustrates the alkylation of a Formula V mula l and Formula Xll to pharmaceutically acceptable pyridine with an alkyl iodide to provide a pyridinium acid addition salts is accomplished by admixture of the salt of Formula Vl. Depending on the R3 substituent Formula I and Formula Xll bases with substantially one desired, alkyl halides such as ethyl iodide, ethyl bro chemical equivalent of any of the various acids herein mide, n-propyl iodide, 2-iodopropane, l-iodobutane, before de?ned. Generally the reactions are carried out 25 l-iodo-Z-methylpropane, l-chloro-2-methylpropane, in an inert solvent. Suitable solvents by way ofexample, 2-iodo-2-methylpropane and the like are employed. The are ethanol. benzene, ethyl acetate, ether, and haloge alkylation is carried out in an inert solvent such as ace— nated hydrocarbons. tone, acetonitrile, etc. Synthesis of the novel o-aminophenethylpiperidine intermediates of Formula I] begins with preparation of Equation 4 Z-styrylpyridines of Formula II] which are obtained \ R4 according to the method of L. Horwitz, J. Org. Chem.
21, i039 (1956) from the reaction of a Rz-o-nitroben 2 I zaldehyde and a R4-2-methylpyridine. As shown in R N R3- halide ; Equation 2, the nitro-Z-styrylpyridines of Formula II] 35 "alkylation" are reduced to an o-aminophenethylpyridine of For NHCHO mula lV. It is preferred that reduction be carried out Formula V catalytically in a solvent employing palladium on car bon catalyst. Suitable solvents by way of example are R4 the lower alkanoyls such as methanol, ethanol, isopro panol, etc. R1 N l e Equation 2. 113$ halide R4 NHCHO Formula Vl 2 R H Compounds of Formula VI are converted to the “reduetion" phenethylpiperidines of Formula VII by reduction ac N01 50 cording to Equation 5. The reduction is carried out Formula Ill catalytically employing platinum as the catalyst in a \ R4 suitable solvent such as the lower alkanols. The phene thylpiperidines of Formula VII can also be obtained by
/ reduction ?rst with metal borohydrides such as sodium R1 N 55 borohydride, or potassium borohydride to provide a tetrahydropyridine which is then further reduced by NH; well known catalytic methods to the piperidines of Formula Vll. For example, reduction of 5-diethylcarba— Formula [V myl-2-(0-formamidophenethyD-l-methylpyridinium The o-aminophenethylpyridines of Formula IV are iodide with sodium borohydride in methanol solution then formylated in order to block alkylation of the mo provides N,N-diethyl-é-(o-formamidophenethyl)-1 matic amine when the R3 substituent is introduced by methyltetrahydropyridin-3-carboxamide which is then quaternization of the pyridine nitrogen with an R3 hydrogenated in ethanol with a 10% palladium on car halide. This conversion of the o-aminophenethylpyri 65 bon catalyst. It will be recognized that compounds of dines of Formula IV to the Formula V formyl deriva formula VII represent the products of Formula I of the tive is illustrated by Equation 3 and is preferably carried present invention wherein RI is a hydrogen and R5 is out with acetic-formic anhydride. formyl. Re. 30,811 11 12 2-(o-aminophenethyl)-1,5-dimethylpiperidine, Equation 5. Z-(o-aminophenethyl)-5-ethyl-l-methylpiperidine, 2-(o-amin0phenethyl)-S-n-butyl-l-methylpiperidine, “reduction" 5 2-(o-aminophenethyl)- l -isopropylpiperidine, R2 2-(o-aminophenethyl)-n-butylpiperidine, l e Z-(Z-amino-S-methoxyphenethyl)- 1 -methylpiperidine, R3 69 halide 2-(2-amino-5-n-butoxyphenethyl)- l-methylpiperidine, NHCHO 2-(2-amino~5-isopropoxyphenethyl)-l-methylpiperi Formula VI dine, 6-(o-aminophenethyl)-N,N-dimethyl- l-methylpiperi R4 dine-3-carboxamide, 6-(o-aminophenethyl)-N,N-diethyl- 1 -methyl R2 N piperidine)-3-carboxamide, 6-(o-aminophenethyl)-N,N-di-n-butyl-l-methy1piperi 1'‘, dine-3-carboxamide, NI-ICHO 6-(2-amino-5-methoxyphenethyl)~N,N-diethyl- l - Formula VII methylpiperidine-3-carboxamide. Reduction of some of the compounds of Formula VII Representative of the formanilides of Formula VII with lithium aluminum hydride provide o-aminophene are: thylpiperidine intermediates of Formula II wherein Rl 2'-[2-(1-methyl-2-piperidyl)ethyl]formanilide, is alkyl. Representative of o-(N-alkylaminophenethyl)— 2'-[2-(5-methyl- l -methyl-2-piperid yl)ethyl]formanilide, piperidines which can be obtained in this manner are: 2'-[2-(5-n-butyl- l -methyl-2-piperid yl)ethyl]-formani 2-(o-methylaminophenethyl)- l-methylpiperidine, lide, 25 Z-(o-methylaminophenethyD-1,5-dimethylpiperidine, 2'-[2-(1-isopropyl-2-piperidyl)ethyl]formanilide, Z-(o-methylaminophenethyl)-S-ethyl-l-methylpiperi 2’-[2-(1-n-butyl-2-piperidyl)ethyl]formanilide, dine, 4'-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]-formani Z-(o-methylaminophenethyl)-S-n-butyl-1-methylpiperi lide, dine, 4'-n-butoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]-formani 2-(o-methylaminophenethyl)- l-isopropylpiperidine, lide, 2-(o-methylaminophenethyl)- l-n-butylpiperidine, 4’-isopropoxy-2'-[Z-(S-isopropyl-l-methyl-2-piperidyl~ )ethyl]formanilide, 2-(Z-methylamino-S-methoxyphenethyD-l-methyl N,N-dimethyl-?-(o-formamidophenethyD- l-methyl piperidine, piperidine-3-carboxamide, 2-(2-methylamino-5-n-butoxyphenethyl)- [-methyl N,N-diethyl-6-(o-formamidophenethyl)- l-methyl 35 piperidine, piperidine-B-carboxamide, 2-(2-methylamino-5-isopropoxyphenethyD-l-methyl N,N-di-n-butyl-6-(o-formamidophenethyl)- l-methyl piperidine, ~ piperidine-B-carboxamide, 2-(o-ethylaminophenethyD-l-methylpiperidine, N,N-diethyl-6-[(2-f0rmamido-5-methoxyphenethyl)-l 2-(2-ethylamino-5-methoxyphenethyl)- l-methylpiperi dine, methylpiperidine-3-carboxamide. 2-(2-ethylaminophenethyl)- l-n-butylpiperidine, If the o-aminophenethylpyridines of Formula IV are 2-(2-ethylaminophenethyl)- S-ethyl- l-methylpiperidine, acylated with alkanoyl halides such as acetyl chloride, 2-(2-n-butylaminophenethyl)-l-methylpiperidine, propionyl chloride, isobutyryl chloride, butyryl chlo 2-(2-isobutylaminophenethyl)- l-methylpiperidine, ride and the like, and the sequence of reactions illus 45 trated by Equations 3-5 repeated, products of Formula 2-(2-n-propylamino-S-n-butoxyphenethyD-I-methyl I are obtained wherein R1 is hydrogen and R5 is alkan piperidine. 0y]. Representative of the alkanoylanilides of Formula I An alternate method for the preparation of com thus formed are: pounds of Formula II wherein R1 is hydrogen is de picted in Equation 6. 2'-[2-(l-methyl-2-piperidyl)ethyl]acetanilide, 50 4'-methoxy-2’-[2-( l -methyl-2-piperidyl)ethyl]-acetani lide, Equation 6. 2’-[2-(l-n-butyl-2-piperidyl)ethyl]acetanilide, R4 2’-[2-(5~ethyl-l-methyl-2-piperidyl)ethyl]acetanilide, N,N-diethyl-6-(o-acetamidophenethyl)-l-methylpiperi 55 R2 dine-3-carboxamide, 1 m1 2'-[2-(l-methyl-2-piperidyl)ethyl]butyranilide, R 3 691 9 Q“reduction" 2'-[2-(I-methyl-2-piperidyl)ethyl]-2-methylpropionani N01 lide, Formula VII 4'-n-butoxy-2'-[2-(l-methyl-2-piperidyl)ethyl]-prop rionanilide, R4 Acid hydrolysis of the formanilides of Formula VII or the analogous alkanoylanilides provide o-amino R1’- N phenethylpiperidine intermediates of Formula II wherein R1 is hydrogen. Representative of o-amino 65 1L1 phenethylpiperidines which can be obtained in this NH] manner are: Formula IX 2-(o-aminophenethyl)- l -methylpiperidine, Re. 30,811 13 14 Pyridinium iodides of Formula VIII prepared from -continued the corresponding aromatic aldehyde and the 2-alkyl pyridinium salt according to the method of L. Horwitz, J. Org. Chem. 2], 1039 (1956) are reduced according to the method of A. P. Phillips, J. Am. Chem. Soc. 72, CHCHZCHZ 1850(1950). Preferably the catalytic reduction is carried ‘i’ R8 out employing a platinum catalyst in methanol solution. NHR" An alternate method for the preparation of com pounds of Formula II wherein Rl is alkyl is depicted in Equation 7. 10 Formula XV The following examples illustrate the best mode con Equation 7. templated for carrying out the present invention. They R4 are merely illustrative and are not to be construed as Reduction limiting the scope of the claims in any manner whatso , Alkylation R~ N ever. 1,; EXAMPLES OF SPECIFIC EMBODIMENTS NH; EXAMPLE 1 Formula X 20 Z-(O-AminophenethyD-l-methylpiperidine R4 A suspension of 2-(o-nitrostyryl)-l-methylpyridinium iodide (40.5 mg., 0.11 mole) prepared according to the R1 N method of L. Horwitz, J. Org. Chem., 21, 1039 (1956) in 25 200 ml. of ethanol is hydrogenated in a Parr hydrogena ,L; tion apparatus employing 0.3 g. of platinum oxide cata NH lyst while maintaining a reaction temperature of from l RI about 50° to 74° C. When the hydrogen uptake ceases Formula XI (about 3 hours), the reduction mixture is ?ltered, the 30 ?ltrate evaporated and the resulting residue taken up in Reductive alkylation of o-aminophenethylpiperidines of 500 ml. of water. The aqueous solution is basi?ed with Formula X with an aldehyde such as acetaldehyde, 40% sodium hydroxide and extracted with several 200 propionaldehyde, n-butyraldehyde, isobutyraldehyde, ml. portions of ether. Ethereal extracts are combined, or a ketone such as acetone or butanone provide RI washed with water, dried over magnesium sulfate, and aminophenethylpiperidines of Formula XI. This the ether evaporated. Distillation of the residue thus method is well known to those skilled in the art, refer to obtained provides 20.8 g. (87% yield) of 2-o‘amino Synthetic Organic Chemistry, Wagner and look, Wi phenethyl)-l-methylpiperidine base having a boiling point of l2l°—l25° C. at 0.04 mm. ley, 1953, page 662. Analysis Calcd. for C14H12N2: C, 77.01; H, 10.16; N, Compounds of Formula I and Formula XII wherein 40 12.83. Found: C, 76.68; H, 9.83; N, 12.76. R3 and R3 are hydrogen, lower alkyl, or R5 or R9 are Treating the base with ethanolic hydrogen chloride isonipecotoyl are obtained by catalytic reduction of the in ethanol provides 2-(o~aminophenethyl)-l-methyl corresponding pyridyl compounds. For example, re piperidine dihydrochloride (crystallized from me duction of 2'-[2-(2-pyridyl)ethyl]-p-anisanilide employ thanol-isopropyl ether), m.p. 268.5°-271.5° C. (corr.). ing a palladium on carbon catalyst provides 2'-[~2-(2 45 Analysis. Calcd. for C14H24Cl2N2: C, 57.73; H, 8.31; piperidyl)ethyl]-p-anisanilide. Similarly, reduction of N, 9.62. Found: C, 57.67; H, 8.22; N, 9.60. 2'-[2-(1-methyl-2-piperidyl)ethyl]isonicotanilide affords 2-(o-Aminophenethyl)-l-methylpiperidine has antiar 2'-[2-(1-methyl-Z-piperidyl)ethyl]isonipecotoicanilide. rhythmic properties having an EC50 of 44 microgram Compounds of Formula XII (illustrated by Formula per milliliter in the hereinabove described rabbit atrium 50 XV) wherein the divalent radical “A” is test. EXAMPLE 2 2-(0-Methylaminophenethyl)- l-methylpiperidine 55 a. 2-(o-Aminophenethyl)pyridine. and R3 is lower alkyl can also be obtained by reaction of A solution of 2-(o-nitrostyryl)pyridine (94.3 g., 0.42 an o-formylanilide of Formula XIII with a 2-(N-R8-2 mole) in 400 ml. of ethanol is reduced on a Parr hydro piperidyl)ethyl magnesium chloride of Formula XIV as genation apparatus employing 2 g. of 10% palladium on depicted by Equation 8. carbon catalyst to provide 2-(o-aminophenethyl)pyri 60 dine, m.p. 59°—6l° C. The isolation of the pyridine prod uct is carried out in the usual manner by collecting the 0 Equation 8. catalyst and evaporating the ethanolic solvent. '6'“ b. 2-(o-Formamidophenethyl)pyridine An aceticformic anhydride mixture is prepared by + CIMgCHZCI-IZ-O 65 mixing acetic anhydride (140 ml.) and formic acid (70 NHR‘) N ml.). To this mixture, 2-(o-aminophenethyl)pyridine (59 It g., 0.3 mole) is added in one portion with vigorous Formula XIII Formula XIV stirring at 25° C. After 15 minutes the solution is diluted Re. 30,811 15 16 with 450 ml. of water and concentrated in vacuo. The c. Z-(Z-Formamido-5-methoxyphenethy1)-l-rnethyl resulting residue is taken up in 1 liter of water and made pyridinium iodide. basic with 50% sodium hydroxide. The basi?ed solution The pyridinium iodide is obtained by treating 2-(2 is extracted with chloroform, the chloroform extract formamido-5methoxyphenethy1)pyridine with methyl washed with water, dried over magnesium sulfate and iodide according to the procedure described in Exam the chloroform solvent evaporated. Crystallization of ple 2 (c) for 2-(o-formamidophenethyl)pyridine. Ana the residue from isopropyl acetate provides 57 g. (83% lytically pure 2-(2-formamido-S-methoxyphenethyl)-l yield) of 2-(0-formamidophenethyl)pyridine melting at methylpyridium iodide is obtained in a yield of 95% and 78°—81° C. (uncorrected). An analytical sample (from isopropyl acetate) has a melting point of 83°-83.5° C. has a melting point of 184°—186.5° C. (corr.). (corr.). Analysis. Calcd. for C16H191N2Oz: C, 48.25; H, 4.81; N, 7.04. Found: C, 48.18; H, 4.84; N, 7.16. Analysis. Calcd. for C14H14N2O: C, 74.31; H, 6.24; N, d. 2~(2-Amino-5-methoxyphenethyl)-l-methylpiperi 12.38. Found: C, 74.56; H, 6.25; N, 12.45. dine. c. 2-(o-Formamidophenethyl)-l-methylpyridinium iodide. Catalytic reduction of 2-(2-formamido-5-methoxy~ A solution of 2-(0-formamidophenethyl)pyridine (55 phenethy1)-l-methylpyridinium iodide as described in g., 0.243 mole) and methyl iodide (38 g., 0.268 mole) in Example 1 for 2-(o-nitrostyryl)-l-methylpyridinium 500 m1. of acetone is re?uxed for 20 hours. The mixture iodide provides Z-(Z-formamido-5-methoxyphenethyl) is cooled at 5° C. and ?ltered to provide 82 g. (92%) of lmethylpiperidine. This material is deformylated in 1 N the pyridinium iodide having melting point of methanolic hydrogen chloride providing 2-(2-amino-5 199.5°—201.5° C. methoxyphenethyl)- l -methylpiperidine. Analysis. Calcd. for C15HnIN1O: C, 48.92; H, 4.65; Another method of preparing 2-(2-formamido-5 N, 7.61. Found: C, 48.74; H, 4.83; N, 7.65. methoxyphenethy1)-l-methylpiperidine is to reduce d. 2'-[2-(1-Methy1-2-piperidyl)ethyl]formanilide. 2-(2-formamido-5-methoxyphenethyl)- 1 -methyl Reduction of 2-(o-formamidophenethyl)-1~methyl 25 pyridinium iodide ?rst with sodium borohydride to pyridinium iodide as described in Example 1 for 2-(0 provide 2-(2-t'ormamido-5-methoxyphenethyl)-1 nitrostyryl)-l-methylpyridinium iodide provides 2'~[2 methyltetrahydropyridine which is then reduced cata (1-methyl-2-piperidy1)-ethy1]formanilide which is puri lytically with palladium on carbon. This procedure is ?ed by crystallization from isopropyl ether, (79% yield) described in Example 4 ((1). mp. 81°-84.5° C. (corr.). 30 Analysis. Calcd. for C|5H22N2O: C, 73.13; H, 9.00; N, EXAMPLE 4 11.37. Found: C, 73.12; H, 8.75; N, 11.31. 6-(o-Aminophenethyl)-N,N-diethyl-l-methylpiperi e. 2-(0-Methylaminophenethy1)-l-methylpiperidine dine-3-carboxamide (Racemate A and Racemate B) A solution of 2'-[2-(1-methy1-2-piperidyl)ethyl]for a. N,N-Diethyl-?-(o-nitrostyryl)nicotinamide. manilide (20 g., 0.0815 mole) in 100 ml. of tetrahydrofu Reaction of o-nitrobenzaldehyde (41.7 g., 0.276 mole) ran is added dropwise to a stirred mixture of lithium with N,N-diethy1-6-methy1nicotinamide (53.1 g., 0.276 aluminum hydride (4.4 g., 0.11 mole) in 100 ml. of tetra‘ mole) in the presence of acetic anhydride (56.3 g., 0.552 hydrofuran. The mixture is re?uxed for 75 minutes, mole) according to the method of L. Horwitz, J. Org. cooled, and hydrolyzed by the sequential addition of 4.4 Chem, 21,.1039 (1956) provides 67.4 g. (75%) of N,N ml. or water, 4.4 m1. of 15% sodium hydroxide and then diethyl-(i-(o-nitrostyryl)-nicotinamide. Crystallization 13.2 ml. of water. The hydrolyzed mixture is ?ltered, from acetonitrile affords the analytically pure nicotina the ?lter cake washed with a 50 ml. portion of tetrahy mide having a melting point of 145°-l47° C. (corr.). drofuran and the ?ltrate concentrated in vacuo. The Analysis. Calcd. for C;gH19N3O3: C, 66.44; H, 5.89; residue thus obtained is distilled to provide 16.6 g. of 45 N, 12.92 Found: C, 66.62; H, 6.01; N, 12.68. 2-(o-methylaminophenethyl)-1-methy1piperidine hav b. 6-(o-Aminophenethyl)-N,N-diethylnicotinamide. ing a boiling point of 150°~l55° C. at 0.05 mm. Hg. N,N-diethy1-6-(o-nitrostyryl)nicotinamide (16.3 g., EXAMPLE 3 0.05 mole) reduced in 150 ml. of ethanol employing 0.1 2-(2-Amino-S-methoxyphenethyl)-l-methylpiperidine g. of 10% palladium on carbon catalyst according to the 50 procedure described in Example 2 (a) for 2(o-amino a. 2’-(2-Amino-S-methoxyphenethyl)pyridine. phenethyliipyridine provides 6-(o-aminophenethyl) Reduction of 2-(2-nitro-5-methoxystyry1)pyridine as N,N~diethylnicotinamide base. Addition of ethanolic described in Example 2 (a) for 2-(o-nitrostyryl)pyridine hydrogen chloride to the nicotinamide base in ethanol provides 2-(2-amirio-5-methoxyphenethy1)pyridine hav provides 6-(o-aminophenethy1)-N,N-diethylnicotina ing a melting point of 77.5°-78.5° C. (corr.) as the mono mide dihydrochloride, m.p. 224°~226° C. (corr.). hydrate obtained by crystallization from isopropyl ace Analysis. Calcd. for C;3H25C12N3O: C, 58.38; H, tate-ethanol-water. 6.80; N, 11.35. Found: C, 58.21; H, 6.86; N, 11.31. Analysis. Calcd. for C|4H16N2O.H2O: C, 68.27; H, c. S-Diethylcarbamyl-2-(o-formamidophenethyl)- l - 7.37; N, 11.37. Found: C, 68.04; H, 7.30; N, 11.30. methylpyridinium iodide. b. 2-(2-Formamido-5-methoxyphenethyl)pyridine. Formylation of 6-(o-aminophenethyl)-N,N-diethyl Formylation of 2-(2-amino-5-methoxyphenethyl) nicotinamide as described in Example 2 (b) for 2-(o-for pyridine as described in Example 2 (b) for Z-(o-amino mamidophenethyl)pyridine provides 6-(o-formamido phenethyl)pyridine provides a 71% yield of 2-(2-for» phenethyl)-N,N-diethylnicotinamide which is then mamido-S-methoxyphenethyl)pyridine. An analytical methylated as described in Example 2 (c) for 2-(o-for sample obtained by crystallization from isopropyl ace mamidophenethyl)-l-methylpyridinium iodide to pro tate has a melting point of 93.5°—94° C. (corr.). vide S-diethylcarbamyl-2-(o-formamidophenethyD-1 Analysis. Calcd. for C|5H16N1O2: C, 70.29; H, 6.29; methylpyridinium iodide. This product is employed in N, 10.93. Found: C, 70.28; H, 6.51; N, 10.98. the following step without further puri?cation. Re. 30,811 . 17 18 d. N,N-Diethyl-6-(o-formamidophenethyl)-l-methyl a melting point of 52.5°—53.5° C. (corr.) when crystal piperidine-3-carboxamide. lized from isopropyl ether~l1eptane. A 50% sodium hydroxide solution (9.6 g., 0.12 mole) c. 5~Ethyl-2-(o-formamidophenethyl)pyridine. in 45 ml. of water is added to a solution of 5~diethylcar~ Reaction of 2-(o-aminophenethyl)-5-ethylpyridine bamyl <2-(o-formamidophenethyl)-l-methylpyridinium with acetic anhydride and formic acid according to the iodide (46.7 g., 0.1 mole) in 300 ml. of methanol. Sodium procedure described in Example 2 (b) for 2-(o-amino borohydride (4.56 g., 0.12 mole) is added in portions phenethyl)pyridine provides the formylated product with stirring to the reaction mixture. After 2 hr. the 5-ethyl-Z-(o-formamidophenethyl)pyridine which can mixture is evaporated and water (500 ml.) is added to be crystallized from isopropyl ether, m.p. 62°-63.5° C. the resulting residue. This mixture is extracted with (corr.). ether. the ethereal extracts washed with water, dried Analysis. Calcd. for C16H13N20: C, 75.56; H, 7.13; N, over magnesium sulfate and the other evaporated. The 11.02. Found: C, 75.53; H, 7.07; N, 10.96. resulting residue consisting of N,N-dicthyl-6-(o-for (1. S-Ethyl-Z-(o-formamidophenethyl)-l-methyl mamidophenethyl)- l -methyltetrahydropyridine-S-car pyridinium iodide. boxamide hydrogenated in a Parr apparatus in 200 ml. Reaction of 5-ethyl-2~(o-formamidophenethy1)pyri of ethanol employing 4 g. of 10% palladium on carbon dine with methyl iodide in acetone according to the as the catalyst at a temperature of 50°-70° C. provides procedure of Example 2 (c) for 2-(o-formamidophene N.N-diethyl-6-(o-formamidophenethyl)-1-methyl thyl)pyridine provides a 74% yield of analytically pure piperidine-J-carboxamide. S-ethyl-2-(o-formamidophenethyl)-l-methylpyridinium e. b-(o-Aminophenethyl)-N,N-diethyl-l-methyl~ 20 iodide having a melting point of 134.5°—136.5° C. piperidine-J-carboxamide. Analysis. Calcd. for C17H21IN2O: C, 51.53; H, 5.34; N,N-Diethyl-6-(o-formamidophenethyl)- l-methyl N, 7.07. Found: C, 51.79; H, 5.35; N, 6.84. piperidine-3-carboxamide is hydrolyzed to 6-(o R2 N 1L3 NH ,t. Procedure Example R1 R2 R3 R4 Starting Materials (Example No.) 7 H H CH3 CH3 2,5-dimethylpyridine and o-nitro~ 5 benzaldellyde 8 H H CH3 n-C4H9 S-n-bulyl-2-methylpyridine and 5 o-nitrobenzaldehyde 9 H H CH3 (CH3)1CH S-isopropyI-Z-methylpyridine and 5 o-nitrobenzaldehyde 10 H (CH3)2CHO CH3 CH(CH3)1 S-isopropyl-Z-methylpyridine and S 2-nitro-S-isopropoxybenzaldehyde 11 H H CH3 CON(CH3)Z o-nitrobenzaldehyde and N,N-dimethyl- 4 6-methylnicotinamide l2 H H CH3 CON(n-C4H9)1 o-nitrobenzaldehyde and N,N-di(n- 4 butyl)-6-methylnicotinamide 13 H CH3O CH3 CH3 2,5-dimethylpyridine and 2~nitro- S imethoxybenzaldehyde 14 H n-C4HgO CH3 Z-methylpyridine, 2-nitro-5-n-butoxy- 3 benzaldehyde and methyl iodide l5 H H n-C4H9 Z-rnethylpyridine, o—nitrobenzaldehyde 3 and l-iodobutane H H (CH 3)3C Z-methylpyridine, o-nitrobenzaldehyde 3 and l-iodo-Z-methylpropane H CH30 (CH3)2CH H 2-methylpyrirline, 2-nitro-S-rnethoxy- 3 benzaldehyde and Z-iodopropane CH3 H CH3 CH3 2,5-dimethylpyridine, o-nitrobenz- 2 aldehyde n-CaHq H CH3 H Z-methylpyridine, o-nitrobenzaldehyde 2 and butyryl chloride 20 CH3 CH3O CH3 H Z-methylpyridine and Z-nitro-S- 2 methoxybenzaldehyde 2! H H (CH3)2CH H l-is¢opropyI-Z-methylpyridinium l iodide and o-nitrobenzaldehyde 22 CZHS H CH3 H 2-(o-aminophenethyl)~l-methylpiperidine 6 and acetaldehyde 23 (CH3);CH CH3O CH3 H 2‘(2-arnino-5-methoxyphenethyl)-l~ 6 methylpiperidine and acetone 24 CH3 CH3O CH3 C2H5 S-ethyI-Z-methylpyridine and 2‘nitro- 2 S-methoxybenzaldehyde Re. 30,811 21 22 Analysis. Calcd. for C24H30N2022 C, 76,15; H, 7.99; EXAMPLE 25 N, 7.40. Found: C, 76.37; H, 7.93; N, 7.36. 2'~[2-( l-Methyl-2-piperidyl)ethyll-cinnamanilide EXAMPLE 29 Cinnamoyl chloride (6.0 g., 0.036 mole) is added to a solution of 2-(o-aminophenethyl)-l-methylpiperidine 6-(o-Cinnamidophenethyl)-N,N-diethyl-l-methyl (7.8 g., 0.036 mole) in lOO ml. of pyridine in one portion piperidine-3-carboxamide mucate (Racemate A) with vigorous stirring. Stirring is continued for 3 hours Reaction of the Racemate A of 6-(o-aminophene and the pyridine solution is then concentrated in vacuo. thyl)-N,N-diethyl-1-methylpiperidine-3-carboxamide The resulting residue is taken up to 150 ml. of water and (5.1 g., 0.16 mole) obtained in Example 4 (t) with cin made basic with 40% sodium hydroxide. The basil'ied namoyl chloride (3.2 g., 0.19 mole) in 70 ml. of pyridine solution is extracted with several 200 ml. portions of according to the method of Example 25 provides 7.3 g. ether, which are combined, washed with water, dried of the free piperidine carboxamide base. The free base over magnesium sulfate and the ether solvent evapo reacted with mucic acid in boiling methanol provides rated. The residue thus obtained crystallizes and is fur the mucate salt. This methanol soluble mucate salt is ther puri?ed by crystallizing from isopropyl ether pro dissolved in methanol and precipitated therefrom by the viding 8.7 g. (70% yield) of analytically pure 2'-[2-(l addition of isopropyl ether. Crystallization from methyl-Z-piperidyl)ethyl]cinnamanilide melting at ethanol-isopropyl ether provides 3.4 g. of 6-(o-cin l0l.5°—l03.5° C. (corr.). namidophenethyD-N,N-diethyl-1-methylpiperidine-3 Analysis. Calcd. for Cz3H28N1O: C, 79.27; H, 8.10; N, 20 carboxamide mucate hydrated with water, m.p. 8.04. Found: C, 79.24; H, 8.35; N, 8.09. 79°—1l0° C. EXAMPLE 26 Analysis. Calcd. for C23H37N3O2.§C6H|0Og.%H2O: C, 64.45; H, 7.50; N, 7.27. Found: C, 64.38; H, 7.69; N, 2'-[2-( l -Methyl-2-piperidyl)ethyl]-a-methylcinnamani 6.89. lide mucate 25 Crystallization of this material from methanol pro By substituting a molar equivalent of a-methylcin vides a methanol solvated mucate salt. The methanol namoyl chloride in lieu of cinnamoyl chloride in Exam solvate is removed by drying at 82° C. in vacuo for 24 ple 25, the substituted phenethylpiperidine free base is hr. to provide a methanol free product having a melting obtained. The mucate salt is prepared by dissolving the point of l17°—l20° C. (corr.). free base in methanol and adding mucic acid to the methanolic solution until the solid mucic acid no longer EXAMPLE 30 dissolves. Undissolved mucic acid is removed by ?lter 6-(O-Cinnamidophenethyl)-N,N-diethyl-l-methyl ing and the ?ltrate concentrated. The residue which piperidine-3-carboxamide cinnamate (Racemate B) remains in crystallized from ethanol-ethyl acetate to provide analytically pure 2'-[2-(l-methyl-2-piperidyl)e Reaction of the Racemate B of 6-(o-aminophenethyl) thyl]-a.-methylcinnamanilide mucate having a melting N,N-diethyl-l-methylpiperidine-3-carboxamide (4.1 g., point of l54.5°-l56.5° C. (dec.) (corr.). 0.13 mole) obtained in Example 4 (") with cinnamoyl Analysis. Calcd. for C24H3QN20.§C6H|0O3: C, 69.35; chloride (2.6 g., 0.015 mole) in 40 ml. of pyridine ac H, 7.54; N, 5.99. Found: C, 69.25; H, 7.59; N, 5.89. cording to the method of Example 25 provides 6.0 g., of the free base. The free base is taken up in 100 ml. of EXAMPLE 27 ethanol and treated with cinnamic acid (1.98 g., 0.013 N-Methyl-2'-[2-(l-methyl-2-piperidyl)-ethyl]cinnamani mole). The cinnamic acid salt of 6-(o-cinnamidophene lide mucate thyl)-N,N-diethyl-1-methy1piperidine-3-carboxamide is 45 precipitated from the ethanolic solution by the addition By substituting a molar equivalent of 2-(0 of isopropyl ether to provide 5.3 g. of solid with a melt methylaminophenethyl)-l-methylpiperidine in lieu of ing point of 156°—160° C. 2-(o-aminophenethyl)-l-methylpiperidine in Example Crystallization from methanol-isopropyl ether pro 25, N-methyl-Z'-[2-(methyl-2-piperidyl)ethyl]cin vides analytically pure Racemate B product which has namanilide is obtained. The mucate salt is prepared according to Example 26, and is crystallized from meth a melting point of 158°-164° C. (corr.). anol to provide analytically pure N-methyl-2’-[2-(l Analysis. Calcd. for C23H37N3O2.C9HgO2:C, 74.59; methyl-2-piperidyl)ethyl]cinnamanilide mucate in 38% H, 7.61; N, 7.05. Found: C, 74.33; H, 7.89; N, 7.07. yield having a melting point of 174°—l76° C. (corr.). EXAMPLE 31 Analysis. Calcd. for C24H3QN2O.§C6H10O3: C, 69.35; H, 7.54; N, 5.99. Found: C, 69.38; H, 7.56; N, 5.97. 2'-[2-(5-Ethyl-1-methyl-2-piperidyl)-ethyllcinnamani lide hydrochloride (Racemate A) EXAMPLE 28 Reaction of 2'-(o-aminophenethyl)-5-ethyl-l-methyl 4'-Methoxy-2’-[2-(l-methyl-2-piperidyl)-ethyl]cin piperidine (3.3 g., 0.0134 mole) obtained in Example 5 namanilide (f) with cinnamoyl chloride (2.7 g., 0.016 mole) in 50 ml. By substituting a molar equivalent of 2-(2-amino-5 of pyridine according to the method of Example 25 methoxyphenethyD-l-methylpiperidine in lieu of 2-(0 provides 4.2 g. of the hydrochloric salt, m.p. l84°-l86° aminophenethyl)-l-methylpiperidine in Example 25, the C. Crystallization of the salt from isopropanol affords phenethylpiperidine free base is obtained. Analytically 3.6 g., (65%) of 2‘-[2-(5-ethyl-l-methyl-2-piperidyl)e pure 4'-methoxy-2'-[2-(l-methyl‘2-piperidyl)ethyl]cin 65 thyl]cinnamaldehyde hydrochloride (Racemate A), namandilide is obtained by crystallizing the crude free m.p. l84°-l87° C. (corr.). base from isopropyl acetate and has a melting point of Analysis. Calcd. for C25H33ClN2O: C, 72.70; H. 8.05; l26.5°-l27.5° C. (corr.). N, 6.78. Found: C, 72.82; H, 8.37; N, 6.45. Re. 30,811 23 24 2'-[2-(5-ethyl- l-rnethyl-2-piperidyl)ethyl]cinnamanilide EXAMPLE 32 hydrate, m.p. 9l°-98° C. (corn). 2'-[2-(5-Ethyl-l-methyl-Z-piperidyl)-ethyl]cinnamani Analysis. CalCd. for C25H32N20.H20: C, 76.10; H, lide hydrate (Racemate B) 8.69; N, 7.10; H20, 4.57. Found: C, 76.24; H, 8.47; N, Racemate B of 5-ethyl-2'-(o-formamidophenethyl)-l 5 7.19; H2O, 4.29. methylpiperidine free base (55 g., 0.0224 mole) ob EXAMPLES 33-54 tained in Example 5 (f) reacted with cinnamoyl chloride (4.1 g., 0.0246 mole) in 75 m1. of pyridine according to Additional Cinnamanilides and formanilides the method of Example 25 provides 2'~[2-(5-ethyl-l The cinnamanilides and formanilides listed in Table II methyl-2-piperidyl)ethyl]cinnamanilide (Racemate B). 10 are prepared from the speci?ed reactants according to This substance is puri?ed by crystallization from ace the procedures described in Examples 25-32 as will be tone containing a trace of water and yields 3.4 g of clear to those skilled in the art. TABLE II ADDITIONAL CINNAMANILIDES AND FORMANILIDES R2 Example Rl R2 R3 Reactants —CH=CH—¢ 2‘(2-ethylamino-S-n-butoxyphenethyl)-l~ melhylpiperidine and cinnamoyl chloride H 2‘(2-ethylamino-S-n-butoxyphenelhyl}1~ melhylpiperidine and formic acid-acetic anhydride 35 CH3 n-Cdh H 2~(o Re. 30,811 27 28 EXAMPLE 65 2-(o-acetamidophenethyl)-5-diethylcarbamyl-l-methyl pyridinium chloride which is isolated by concentration 2'-[2-(l-Methyl-2-piperidyl)ethyl]-acetanilide mucate. of the aqueous solution. By substituting a molar equivalent of acetyl chloride Reduction of 2-(o-acetamidophenethyl)-5-diethylcar in lieu of cinnamoyl chloride in Example 25, 2’-[2-(1 bamyl-l-methylpyridinium chloride in ethanol accord methyl-2-piperidyl)ethyl]acetanilide free base is ob ing to the method of Example 1 provides a mixture of tained. The crude free base is converted to the crystal the two racemates (Racemate A and Racemate B) of line mucate according to the procedure of Example 26 6-(0-acetamidophenethyl)-N,N-diethyl- l~methylpiperi and crystallized from ethanol to provide analytically dine-3-carboxamide which are chromatographically pure 2'-[(2-(l-methyl-2-piperidyl)ethyl]acetanilide mu separated as follows. A chromatographic column (4 cm. cate, m.p. l73.5°—l74.5° C. (corn). diameter) is packed to a height of 45 cm. with silica gel Analysis. Calcd. for C]6H24N20.%C6H1Q081 C, 62.44; (300 g., 100-200 mesh, Davison Chemical Company, H, 8.00; N, 7.66. Found: C, 62.47; H, 8.29; N, 7.79. Grade 923) as a slurry in benzene. A mixture of Race An alternative preparation of 2'-[2-(l-methyl-2 mate A and B of ?-(o-acetamidophenethyl)-N,N-dieth piperidyl)ethyl]acetanilide mucate is as follows. 2-(o yl-l-methylpiperidine-3-carboxamide (10.8 g.) is loaded Acetamidophenethyl)pyridine (12.6 g., 0.05 mole) ob on the column in 50 ml. of benzene. The following 100 tained according to D. H. Hey and J. M. Osbond, J. ml. fractions were collected. Fractions 1 to 3, benzene; Chem. Soc., 3170 (1949), is reacted with methyl iodide fractions 4-43, ethanol-ethyl acetate 3:7+O.2% 58% (7.9 g., 0.055 mole) in 100 ml. of acetone according to NH4OH; fractions 44-70, ethanolethyl acetate the method of Example 2 (c) to provide 11.5 g. (60%) of 20 l:1+0.5% 58 % NH4OH; fractions 71 o: 84, ethanol 2-(o-acetamidophenetyl)pyridinium iodide, m.p. +05% 58% NH4OH. Fractions 5-36 are combined and 229.5°—23l.5° C. (corn), (crystallized from ethanol). evaporated to provide 2.4 g. of chromatographhically Analysis. Calcd. for C16H1gIN2O: C, 50.37; H, 5.01; pure (thin-layer) Racemate A. Fractions 55-84 are com N, 7.33. Found: C, 49.97; H, 4.84; N, 7.22. bined and evaporated to provide 5.9 g. of Racemate B. Reduction of 2_(o_acetamidophenethynpyridinium 25 Racemates A and B are further puri?ed by distillation in iodide in ethanol employing platinum oxide catalyst a sxbhinalorlat 0l‘02 mini. Hga according to the procedure of Example 1 provides the Ila yuc? ‘I’: “68' m ire aigd n‘m‘r' Bspectra are piperidyl free base which is then converted to 2'-[2-(1- ‘201153128225 oéalsge'tgiti: lindN gce%atgo 1'6 H 9 26 geg‘xlgrspll’épéig'dynethy 1 lacelamh--d e mucate mo’d- mg 30 N, 11.69. Found:- -(Racemate 213332=,-;,-; A) c, 70.51; H, 9.40; N, ' 11.82; (Racemate B) C, 70.03; H, 9.44; N, 11.75. EXAMPLE 66 An alternate method of preparing Racemate A and o-(o-Acetamidophenethyl)-N,N-diethyl-1-methyl- Raccmate .13 (if '(o'acetamidoPhenethyniN’N'diethyl' piperidine-S-carboxamide (Racemate A and Racemate lfmethylplpepdme'3'cérboxalmlde compflscs the reac B) 35 non of acetic anhydride with 6-(o-ammophenethyl) _ _ _ N,N-diethyl-1-methylpiperidine-3-carboxamide Race Acylallon _ of 6'(o-ammqphenethyl)'N’N-dlethyl- mate A and Racemate 13 obtained in Example 4 (f). nicotinamide in chloroform with acetic anhydride pro vides 6-(o-acetarnidophenethyl)-N,N-diethylnicotina- EXAMPLES 67-75 mide which methylated with methyl iodide in acetone 40 ' Additional alkanoxy] anilides according to the procedure of Example 2 (c) yields .. . . 2-(o-acetamidophenethyl)-S-diethylcarbamyl-l-methyl- The alkanoy.‘ amhdes listed m Table Iv are prepared pyridinium iodide. Passing an aqueous solution of 2-(o- from the specl?cd reactants. according to the "oce acetamidophenethy‘)5_diethylcarbamyl_1_methy]_ dures of examples 25-32 as Wlll be clear to those skilled pyridinium idodide through a Dowex Zl-K 50-100 m the art‘ mesh ion exchange column in the Cl— form provides TABLE IV ADDITIONAL ALKANOYL ANILIDES R4 R2 N l R3 N-Rs ,1. Example R1 R2 R3 R4 R5 Reactants 67 CH 3 H CH3 H CH 3C0 2-(o-methylaminophenethyl)- l-methylpiperidine and acetic anhydride 68 n-C4H9 H CH3 H C H 3C0 2-(2-n-butylaminophenethyl)- l -methylpiperidine and acetic anhydride 69 CH3O CH 3 H CH 3C0 2-(Z-amino-S-methoxyphenethyl)- 1 -methyl piperidine and acetic anhydride 70 H H n-C4H9 H CH3CO 2-(o-aminophenethyl)-l-n-butylpiperidine and acetic anhydride 7] H H CH3 C2H5 CH3CO 2-(0-aminophenethyD-S-ethyl-l-methyl piperidine and acetic anhydride 72 H H C H 3 CON(C1H5)2 CH 3C0 6-(o-aminophenethyl)-N,N-diethyl— 1 -methyl piperidine-Ii-carboxamide and acetic anhydride 73 H H CH3 H CH3(CH2)2CO Z-(o-aminophenethyD-l-methylpiperidine and Re. 30,81 1 29 30 TABLE IV-continued ADDITIONAL ALKANGYL ANILIDES R6 R2 N ,L; N-R5 l R] Example R1 R2 R3 R4 R5 Reactants n-butyric anhydride 74 H H CH3 H [CH3)2CHCO 2~(o~aminophenethyl)-l~methylpiperidine and iso-butyric anhydride 75 H n-C4HqO CH3 H CH3CH2CO 2-(2~amino-5-n—butoxyphenethyl)-l-methyl piperidine and propionic anhydride Reduction of alkanoyl anilides with lithium alumi num hydrides provides 2-(o-alkylaminophenethyl)-l- 20 EXAMPLE 76 alkylpiperidine intermediates which can be acylated or 2'-[2-(l-Methyl-Z-piperidyl)ethyl]-methanesulfonanilide sulfonylated to provide additional products of the pres’ Reaction of methanesulfonyl chloride (5.7 g., 0.05 ent invention. For example, reduction of alkanoyl ani mole) with 2-(o-aminophenethyl)-l-methylpiperidine lides of Table IV wherein R1 is hydrogen according to (9.8 g., 0.045 mole) in 75 ml. of pyridine according to the method of Example 2 (e) with lithium aluminum 25 the procedure of Example 25 provides 5.6 g. (41%) of hydride provides analytically pure 2'-[2-(l-methyl-2-piperidyl)ethyl]me 2-(2-ethylamino-S-methoxyphenethyl)- 1 -methylpiperi thanesulfonanilide (crystallized from ethanol), m.p. dine, a c 2-(o-ethylaminophenethyl)-l-n-butylpiperidine, gllinsifs (éaézgngg'r CISHMNZOZS, C 60 78_ H 8.16 2-(o~ethylaminophenethyl)-S-ethyl-l-methylpiperidine, 30 N 9 45 Féund. 60 55. H 8 12. ‘N ,9 5'4 1 ’ ’ 2-(2n-butylaminophenethyl)-l-methylpiperidine, ’ ' ' ' ’ ' ' ’ " ‘ ' ‘ ' Z-(o-isobutylaminophenethyl)-l-methylpiperidine, EXAMPLES 77-86 2-(Z-n-propylamino-5-n-butoxyphenethyl)-l-methyl Additional alkanesuli'onanilides piperidine. 35 The alkanesulfonanilides listed in Table V are pre pared from the speci?ed reactants according to the procedures of Examples 25-32 as will be clear to those skilled in the art. TABLE V ADDITIONAL ALKANESULFONANILIDES R4 R2 N ,L; N--R5 ,L. Example R' R1 R3 R‘ R5 Reactants 77 CH 3 H CH3 H CH3SO2 2-(o-methylaminophenethyl)‘ l -methylpiperidine and methanesulfonyl chloride 78 n-C4Hg H CH3 H CH3SO2 Z-(Z-n-butylaminophenethyl)~l-methylpiperidine and melhanesulfonyl chloride 79 H CH3O CH3 H CHJSO] 2-(2-amino—5-methoxyphenethyl)—l-methyl piperidine and methansult'onyl chloride 80 H H n-C4H9 H CHJSO] Z-(o-aminophenethyl-l-n-butylpiperidine and methanesulfonyl chloride 81 H H CH3 CH3 CH3SO2 2-(o—aminophenethyl)-5-methyl-l»methyl piperidine and methanesuli'onyl chloride 82 H H CH3 C2H5 CH3SO1 2-(o-aminophenethyD-iethyl-l-methyl piperidine and methanesulfonyl chloride 83 H H CH3 H CH3(CH2)2SO2 Z-(oaminophenethyl)l-methylpiperidine and n-butanesull'onyl chloride 84 H H CH3 H (CHJ)2CHSO2 2~(o Example R1 R2 R3 R4 Ar Reactants 90 CH3 H CH3 H C6H5 2-(o-methylaminophenethyl}lmethyl piperidine and benzoyl chloride 91 n-C4H9 H CH3 H C6H5 2~(2-n-butylaminophenethyl)-l-methyl piperidine and benzoyl chloride 92 H CH3O CH3 H C6H5 2-(2~amino-5—methoxyphenethyl)-l methylpiperidine and benzoyl chloride 93 H n-C4HqO CH3 H C6H5 2-(2-amino~5-n-butoxyphenelhyl)~l methylpiperidine and benzoyl chloride 94 H H n-C4H9 H C6H5 2-(o—aminophenethyl)-l-n~butylpipcridine and benzoyl chloride 95 H H CH3 CH3 C5H5 2-(o—aminophenethyl)-5-methyl-l-methyl— piperidine and benzoyl chloride 96 H H CH 3 n~C4H9 C?HS 2-(o-aminophenethyLS-n-butyl- l - methylpiperidine and benzoyl chloride 97 H H CH3 H p (CH3)2CHO 100 H H CH3 H n-C4H9O 2»(o Example R1 R2 R3 R4 Ar Reactants benzoyl chloride 10] H CH3O CH3 H p-NH2C6H4 2-(2~amino-S-methoxyphenethyl)-l-methyl piperidine and p~nitrobenzoyl chloride TABLE VII ADDITIONAL BENZANILIDES Analzsis Example Chemical Name Ar MP. “C. Calcd. Found 104 2‘-[2~(Lmethyl-l-piperidyl)ethyl]- 85.5-87 c 78.22 c 78.41 benzanilide @- H 8.13 H 8.13 N 8.69 N 8.68 105 4-chloro~2'-[2-(l-methyl-2-piperidyl)- [30-13] C 70.67 C 70.84 ethyl]ben1anilde C|_< >- H 7.06 H 7.05 N 7.35 N 7.84 106 4-(methyltl1io)-2'-[2-(l-methyl-Z- 145445.?! C 71.70 C 71.86 piperidylkihyllbenzanilide CH35_@_ 1-1 7.66 H 7.59 N 7.60 N 7.54 I07 4—methoxy~2‘-[2<(l-methyl-2- 1315-1315 C 74.96 C 74.9l piperidylkthy?benzanilide (31430-6- H 8.01 H 7.83 N 7.95 N 7.90 108 3-methoxy-2'-[2-(l-metliyl~2~ C1130 1245-1265 C 74.96 C 7516 piperidyl)ethy|]benzanilide U H 8.01 H 7.94 N 7.95 N 7.88 l09 3.4-dimethoxy-2'~[2~(l-methyl-2- CHJO 123-1245 C 72.22 C 72.12 piperidyl)ethyllbenzanilide n’ H 7.91 H 7.88 CHIC N 7 . 32 N 7 . 3 9 110 3.5-dimethoxy-2‘-[2-(l-methyl-Z- c1130 140.5-142 c 65.04 c 65.00 piperidyl)ethyl]benzanilide H 6.87 H 6.93 hydrogen maleate N 5.62 N 5.65 OCH; 111 2'-[2~(l-methyl-2-piperidyl)- CHJO 115-122 c 60.54 c 60.33 ethyl]3.4.5-trimethoxy- H 7.34 H 7.21 benzamhde mucate hydrate CHLO N 5.23 N 5.l8 OCH} EXAMPLE “2 Material Amount Pharmaceutical Compositions 60 4~Methoxy-2'-[2-(l-methyl-2-piperidyl) The substituted. plperldlnes. , . characterlzed. by Formula ethMazliesium l benzanilide “came 50.013 g. I are compounded with pharmacologically acceptable Corn starch 12.4 g. carriers to provide compositions useful in the present (3011‘ “arch Pregel?tlmled L305 invention. Typical of the pharmaceutical compositions Law” “35' g‘ are the following: 65 A. Tablets. The piperidines of Formula I are com The foregoing materials are blended in a twin-shell pounded into tablets according to the following exam blender and then granulated and pressed into tablets plc. weighing 250 mg. each. Each tablet contains 50 milli Re. 30,811 35 36 grams of active ingredient. The tablet may be scored in (57%) in oil (1.6 g., 0.037 mole) with intermittent cool quarters so that a dose of 12.5 mg. of active ingredient ing to moderate the resulting vigorous reaction. After 2 may be conveniently obtained. hr., the mixture is poured into 150 ml. of H20 and the B. Capsules. The piperidines of Formula I are com product isolated according to the procedure of Exam pounded into capsules according to the following exam ple 25. Crystallization from isopropyl ether affords 5.9 ple. (50%) of analytically pure 2'-[2-(1-methy1-2-piperidyl )ethyl]picolinanilide, m.p. 65.5°—67° C. (corr.). Materials Amount Analysis. Calcd. for C2QH25N30: C, 74.27; H, 7.79; N, Active Ingredient 125 mg. 12.99. Found: C, 74.33; H, 7.92; N, 12.99. Lactose 146.0 mg. Magnesium stearate 4.0 mg. EXAMPLE 116 2-[2-[2-(1-MethyI-Z-piperidyl)ethyl]phenylcarbamoyl] The foregoing materials are blended in a twin-shell benzoic acid blender and then ?lled into No. l hard gelatin capsules. To a solution of 2-(o-aminophenethy1)-l-methyl Each capsule contains 125 mg. of active ingredient. piperidine (8.73 g., 0.04 mole) in 100 ml. of EtOAc is C. Solution of Intravenous Administration rapidly added a solution of phthalic anhydride (5.93 g., The substituted piperidines characterized by Formula 0.04 mole) in 100 m1. of EtOAc. Solid product separates I are formulated for parenteral administration accord after a short time and is collected and crystallized from ing to the following example. A sterile solution suitable 20 CH3CN, yielding 7.2 g. (49%) of 2~[2-[2-(1-methy1-2 for intravenous injection is prepared by dissolving 10.0 piperidyl)ethyl]phenylcarbamoyl]benzoic acid, m.p. g. of 4-methoxy-2'-[2-(l-methy1-2-piperidyl)ethy1]ben 17l"—172° C. (corr.). zanilide in a minimal amount of 0.5 N hydrochloric Analysis. Calcd. for C22H26N2O3: C, 72.10; H, 7.15; acid. This solution is adjusted to a pH of 4.3 with 0.1 N N, 7.65. Found: C, 72.22; H, 7.10; N, 7.81. sodium hydroxide and diluted to 1000 ml. total volume 25 with saline. The solution is sterilized by passage EXAMPLE 1 17 through a bacteriological ?lter and aseptically ?lled 2'-[2-(1-Methyl-2-piperidyl)ethyl]isonipecoticanilide into 10 ml. sterile ampoules. Each milliliter of solution contains 10 mg. of the active ingredient, 4-methoxy-2' 2'-[2‘(1-Methyl-2~piperidyl)ethyl]isonicotinanilide [2-(1-methyl-2-piperidyl)ethyl]benzanilide. hydrate (9.7 g., 0.028 mole) is hydrogenated on a Parr 30 apparatus in glacial acetic acid (200 ml.) using 10% EXAMPLE 113 Pd/C (4.0 g.) as the catalyst. Evaporation of the AcOH 4-(t-Butoxy)-2'-[2-(1-methy1-2-piperidyl)methy1]ben followed by a basic workup according to the procedure zanilide of Example 25 affords the crude product which crystal lized from EtOAc yields 4.3 g. (46%) of 2'-[2-(1-methyl A mixture of 2-(o-aminophenethyl)piperidine (38.8 g., 35 Z-piperidyl)ethyl]isonipecoticanilide, m.p. 157°—159° C. 0.178 mole), methyl-4-(t-butoxy)benzoate (36.9 g., 0.178 (corr.). mole), sodium methoxide (10.6 g., 0.195 mole) and 600 Analysis. Calcd. for C2QH31N30.‘ C, 72.90; H, 9.48; N, m1. of benzene is heated to re?ux in a ?ask ?tted with a 12.76. Found: C, 73.30; H, 9.46; N, 12.76. 30 cm vacuum-jacketed fractionating column packed with Rashig rings, and a variable takeoff head. The ' EXAMPLE 1 18 methanol-benzene azeotrope is removed at intervals 4-Methoxy-2'-[2-( 1 -methy1-2-piperidyl)propyl]benzani until no more forms. After cooling to 25° C., the mix lide ture is washed (H2O, sat. brine) dried (MgSO4), and evaporated. Crystallization of the residue thus obtained a. Z-(B-Methyl-2-nitrostyryl)pyridine from heptane yields 15.2 g. (21%) of 4-(t-butoxy)-2'-[2 45 A mixture of o-nitrobenzaldehyde (127 g., 0.84 mole), (1-methyl-2-piperidyl)ethyl]benzanilide, m.p. 9l“—93.5° Z-ethylpyridine (90 g., 0.84 mole) and acetic anhydride C. (corr.). (171 g., 1.68 mole) is heated at re?ux for 24 hr. Excess Analysis. Calcd. for C25H34N2O1: C, 76.10; H, 8.69; acetic anhydride is evaporated in vacuo and the residue N, 7.10. Found: C, 76.06; H, 8.59; N, 7.10. poured into 500 ml. of water. The mixture is adjusted to 50 pH 1 l with 50% NaOH providing a precipitate which is EXAMPLE 114 collected and dried. Crystallization from isopropyl 2'-[2-(1-Methyl-2-piperidyl)ethyl]-p-toluanilide ether yields 136.7 g. (67%) of 2-B-methyl-2-nitrostyryl) pyridine, m.p. 62°-64° C. which, after a second crystal Reaction of 2-(o-aminophenethyl)-l-methylpiperi lization, is analytically pure. dine (80 g., 0.036 mole) with p-toluoyl chloride (6.2 g., 55 Analysis. Calcd. for C|4H12N2O2: C, 69.99; H, 5.03; 0.04 mole) in 50 ml. of pyridine according to the method N, 11.66. Found: C, 70.38; H, 5.07; N, 11.70. of Example 25 provides 2'-[2-(1-methyl-2-piperidyl)e b. 2-[2-(2-Aminophenyl)-1-methylethyl]pyridine thyl]p-toluani1ide. Crystallization from isopropyl ether 2-(B-Methyl»2-nitrostyryl)pyridine (24.0 g., 0.1 mole) and then from isopropyl alcohol provides 3.9 g., (32%) is hydrogenated on a Parr apparatus in 200 ml. of etha of analytically pure material, m.p. 90.5°—92° C. (corr.). nol with 3 g. of 10% Pd/C as catalyst. The catalyst is Analysis. Calcd. for CzzHggNzO: C, 78.53; H, 8.39; N, ?ltered and the ?ltrate evaporated, providing 2-[2-(2 8.33. Found: C, 78.56; H, 8.09; N, 8.05. aminopheny1)-1-methylethyl]pyridine. EXAMPLE 115 c. 2-[2-(2-Formamidophenyl)-1-methylethyl]pyridine 2'-[2-(1-Methyl-Z-piperidyl)ethyl]picolinanilide Reaction of 2-[2-(2-aminophenyl)-1-methylethyl] 65 pyridine (21 g., 0.1 mole) with 42 ml. of acetic-formic A solution of 2-(o-aminophenethyl)-l-methylpiperi anhydride, according to the procedure of Example 2(b), dine (8.0 g., 0.037 mole) and ethyl picolinate (5.5 g., affords 2-[2-(2-formamidophenyl)-l-methylethy1]-l 0.037 mole) in DMSO (20 ml.) is treated with NaH methylpyridinium iodide. Re. 30,811 37 38 d. 2-[2-(2-Formamidophenyl)-l-methylethyl]-l Analysis. Calcd. for GUI-130N202: C, 75.37; H, 8.25; methylpyridinium iodide N, 7.64. Found: (Racemate A) C, 75.26; H, 8.24; N, 7.50; Reaction of 2-[2-(2-l‘ormamidophenyl)-l-methyle (Racemate B) C, 75.06; H, 8.32; N, 7.50. thyl]pyridinc (24 g., 0.1 mole) with methyl iodide (28.4 EXAMPLE 119 g.. 0.2 mole) according to the procedure 01' Example 2(c). affords 29.5 g. (77%) of 2-[2-(2-l'ormamidophenyl) 2'-[2-(1-Ethyl-2-piperidyl)ethyl]-p-anisanilide l~methylethyl]-1-methylpyridinium iodide, m.p. a. l-Ethyl-2-(o-formamidophenethyl)pyridinium io 1841188” C. dide Analysis Calcd. for CMHwINZO: C, 50.28; H, 5.01; A solution of 2-(o-formamidophenethyl)pyridine N, 7.33. Found: C, 50.46; H, 5.01; N, 7.20. (36.1 g., 0.159 mole) and iodoethane (30.0 g., 0.191 e. 2-[2-(2-Aminophenyl)-1-methylethyl]-1-methyl mole) in Ch3CN (450 ml.) heated at re?ux for 18 hr., piperidine cooled and diluted to incipient turbidity provides 1 2<[2-(2-Formamidophenyl)-1-methy1ethy1]-l-methyl ethyl-2-(0-forrnamiclophenethyDpyridinium iodide, pyridinium iodide (25.4 g., 0.0665 mole) is hydroge 15 yield, 44.8 g. (74%), mp. 155°—157° C. nated in a Parr apparatus in 200 ml. of ethanol with b. 1-Ethyl-2-(2-formamidophenethyl)piperidine P110 (0.6 g.) as catalyst. A basic workup gave 2-[2-(2 To a solution of 1-ethyl-2-(0-formamidophenethyl) formamidophenethyh-1-methylethyl]- l‘methylpiperi pyridinium iodide (44.8 g., 0.117 mole), 50% NaOH dine which is dissolved in 200 ml. of methanol, mixed (11.2 g., 0.14 mole), and water (40 ml.) in methanol (330 with 45 ml. of concentrated hydrochloric acid, permit 20 ted to stand for 24 hr. and then heated at re?ux for 4 hr. ml.) is added portionwise NaBH4 (5.32 g., 0.14 mole). A basic workup and distillation yields 2-[2-(2-amino The solution is stirred for 2 hr. and evaporated. Water is pheny1)- 1-methylethy1]-l-methylpiperidine, n05’, added to the residue thus obtained and the mixture 1.5520, b.p. 121°—124° C./0.1 Torr. extracted with ether. The ethereal extracts are dried Analysis Calcd. for C15H24N1: C, 77.53; H, 10.41; N, 25 (MgSO4) and evaporated. The residue taken up in 200 12.06. Found: C, 77.26; H, 10.46; N, 12.07. ml. of ethanol and hydrogenated in a Parr apparatus 1'. 4-Methoxy-2'-[2-methyl-2-(l-methyl-2-piperidyl)e using 5 g. of 10% palladium on carbon as catalyst af thyl]benzanilide fords 1-ethyl-2-(2-formamidophenethyl)piperidine. Reaction of 2-[2-(2-aminophenyl)-l-methy1ethyl]-1 c. 2-(2-Aminophenethyl)- l-ethylpiperidine methylpiperidine with anisoyl chloride, according to A solution of 1-ethyl-2-(Z-fOrmamidophenethyD the procedure of Example 25, provides 4-methoxy-2'-[2 piperidine (27.6 g., 0.11 mole), methanol (450 m1.) and methyl-2-(1-methyl-2-piperidyl)ethyl]benzanilide as a concentrated HC] (100 ml.) allowed to stand for 24 hr. 72:28 mixture of diastereoisomers (according to nmr), provides 2-(2-aminophenethyl)-l-ethylpiperidine, puri ?ed by distillation, yield 17.72 g. (69%), b.p. l07°—128° m.p. l25.5°-136.5° C. (corr.). 35 Analysis. Calcd. for CZ3H3ONZOZZ C, 75.37; H, 8.25; C./0.l Torr, nD3°° 1.5510. N, 7.64. Found: C, 75.24; H, 8.42; N, 7.34. The diaste Analysis. Calcd. for C15H24N2: C, 77.53; H, 10.41; N, reoisomeric mixture of 4-methoxy-2’-[2-methyl-2-(1 12.06. Found: C, 77.29; H, 10.54; N, 11.87. methyl-2-piperidyl)ethyl]benzanilide (42 g.) is fraction (1. 2'-[2-(1-Ethyl-2-piperidyl)ethyl]-p-anisanilide ally recrystallized from ethyl acetate following a triang Reaction of 2-(2‘aminophenethyl)-l-ethylpiperidine ular scheme according to the technique of A. Weiss with anisoyl chloride according to the procudure of berger and E. S. Proshauer, “Technique of Organic Example 25 provides 2'-[2-(1-ethyl~2-piperidyl)ethyl]-p Chemistry” Vol. 111, 490, lnterscience Publishers, Inc., anisanilide, m.p. 136.5°—137.5° C. (corr.), from ethyl New York, 1955 as follows: acetate. 45 Analysis. Calcd. for C;3H30N2O1: C, 75.37; H, 8.25; N, 7.64. Found: C, 75.25; H, 8.30; N, 7.45. A:B Ratio of Racemates Crop Wt. g. M.P.(’C.) by nmr EXAMPLE 120 1 153 117-121 — 1A 11.4 123-135 72:28 4-Bromo-2'-[2-( l~Methyl-2-piperidyl)ethyl]-benzanilide 113 4.9 136-143 -— Reaction of 4-bromobenzoyl chloride with 2-(0 1C 2.9 143-146 95:5 aminophenethyD-l-methylpiperidine according to the 2 27.1 106-116 -— 2A 4.65 116~l20 52:48 procedure of Example 114 affords 4-bromo-2’-[2-(1 28 3.0 121-124 58:42 methyl-2-piperidyl)ethyl]benzanilide, m.p. 2C 2.35 139-142 80:20 55 137.5°—138.5° C. (corr.), from ethyl acetate. 3 9.35 105-111 24:76 4 6.65 100-110 20:80 Analysis. Calcd. for C21H25BrN2O: C, 62,83; H, 6.28; N, 6.98. Found: C, 62.55; H, 6.27; N, 6.92. Crops 1C and 2C are combined and recrystallized to EXAMPLE 121 give 35 g. of Racemate A, 4-methoxy-2’-[2-methyl-2-(1 4-Fluoro-2'-[2-(1-methyl-2-piperidyl)ethyl]-benzanilide methyl-Z-piperidyl)ethyl]benzanilide isomer (less than 5% Racemate B isomer), m.p. l46°-l47.5° C. (corr.), 5, Reaction of 2-(o-aminophenethyl)piperidine with 2.1 (S, N-CH3, 3H). 4-?uorobenzoyl chloride according to the procudure of Crop 4 is recrystallized from isopropyl ether to pro Example 114 affords 4-1'1uoro-2'-[2-(1-methy1-2 vide 3.45 g. of Racemate B, 4-methoxy-2'-[2-methy1-2 65 piperidyl)ethyl]benzanilide, m.p. 115.5°—116.5° C. (1-methyl-2-piperidyl)ethy1]benzanilide isomer (less (corr.), from isopropyl ether. than 5% Racemate A isomer), m.p. 96.0"-97.5° C. Analysis. Calcd. for C2;H25FN2O: C, 74.10; H, 7.41; (corr.), 8, 2.25 (S, N-—CH3, 3H). N, 8.23. Found: C, 74.18; H, 7.35; N, 8.26.