United States Patent (19) 11, 3,931, 195 Dykstra et al. (45) Jan. 6, 1976 (54) SUBSTITUTED PIPERIDINES Krapcho et al., J. Med. Chem. Vol. 7, pp. 376 to 377, 75 Inventors: Stanley J. Dykstra; Joseph L. (1964). Minielli, both of Evansville, Ind. Krapcho et al., J. Med. Chem. Vol. 9, pp. 809 to 812, (1966). 73) Assignee: Mead Johnson & Company, Krapcho et al., J. Med. Chem. Vol. 12, pp. 164 to Evansville, Ind. 166, (1969). (22 Filed: July 31, 1973 Phillips, J. Am. Chem. Soc. Vol. 72, pp. 1850 to 1852, (21) Appl. No. 384,341 (1950). Related U.S. Application Data Primary Examiner-John D. Randolph 63 Continuation-in-part of Ser. No. 20,754, March 3, Attorney, Agent, or Firm-R. H. Uloth; R. E. 1971, abandoned. Carnahan 52 U.S. Cl.......... 260/293.58; 424/267; 260/240 J; 260/293.73; 260/293.57; 260/293.58; 57 ABSTRACT 260/293.59; 260/293.77 The compounds are of the heterocyclic class of 2 (5ll Int. Cl’........................................ C07D 211/08 phenethylpiperidines having an amido substituent in (58) Field of Search..... 260/293.77, 293.57, 293.58, the ortho position of the phenethyl moiety. Substitu 260/293.59, 240 J, 293.73 ents in the ortho position include formamido, ben Zamido, cinnamamido, 2-thiophenecarboxamido, al (56) References Cited kanesulfonamido and alkanoylamido. They are useful as antiarrhythmic and/or antiserotonin agents. The UNITED STATES PATENTS novel compounds are prepared by reaction of appro 2,686,784 81954 Finkelstein et al.............. 260.1293.7 priately substituted o-aminophenethylpiperidines and 2,780,577 2/1957 Phillips et al.................... 260/293.7 the carbonyl or sulfonyl halides or anhydrides. Typical 3, 192.23 6/1965 Krapcho............................. 260/253 embodiments of this invention are 4-methoxy-2'-2- OTHER PUBLICATIONS (1-methyl-2-piperidyl)ethylbenzanilide and 2'-2-(l- Lawson, J. Pharm. Exp. Therap. 160, pp. 22 to 31, methyl-2-piperidyl)ethyl)cinnamanilide. (1968). Krapcho et al., J. Med. Chem. Vol. 6, p. 219, (1963). 28 Claims, No Drawings 3,931, 195 1 sUBSTITUTED PIPERIDINEs. CROSS-REFERENCE TO RELATED APPLICATIONS 5 This application is a continuation-in-part of co-pend ing U.S. application Ser. No. 120,754 filed. Mar. 3, 1971, now abandoned. BACKGROUND OF THE INVENTION 10 The present invention is concerned with certain het erocyclic organic compounds which can be referred to as substituted piperidines and acid addition salts thereof. In particular, this invention relates to physio logically active novel piperidine compounds which are 15 particularly effective as antiarrhythmic and antiseroto Formula XII nin agents. It is also concerned with chemical interme diates useful in the preparation of the piperidine com pounds. Other features of the invention are pharma ceutical compositions containing the piperidines as 20 active ingredients and a therapeutic process for pro ducing antiserotonin and antiarrhythmic effects in mammals by administration of them. Agents which antagonize serotonin are of interest in experimental biology and in treatment of various physi 25 ological disorders such as migraine headache, seroto nin producing tumors, toxemia in pregnancy, habitual The substances of Formula I and Formula XI are new abortion and management of various inflammatory and compositions of matter possessing valuable pharmaco allergic reactions. Methysergide and lysergide are well logical properties which render them useful as syn known antiserotonin agents. Other serotonin antago 30 thetic medicinals. In particular, the substituted piperi nists which have been reported in the prior art litera dines of Formula I and Formula XII exhibit utility as ture on the subject are 2'-(3-dimethylaminopropylthi antiserotonin and/or antiarrhythmic agents in standard o)cinnamanilide and related compounds disclosed by pharmacological tests in mammals. This invention also Krapcho, et al., J. Med. Chem., 6, 219 (1963); 7, 376 is concerned with the production of the compounds of (1964); 9,809 (1966); and 12, 164 (1969); and U.S. 35 Formulas I and XII from novel chemical intermediates, Pat. No. 3, 192,213. pharmaceutical compositions containing them and a A number of structurally unrelated chemical sub therapeutic process for producing an antiserotonin stances have been employed in the treatment of cardiac effect in mammals comprising the administration of arrhythmia; refer to A. Burger, Medicinal Chemistry, such compounds thereto. Another feature of this inven 3rd Edition, pages 1082-1085 (Wiley). One of the 40 tion is a therapeutic process for producing an antiar most important drugs in clinical treatment of disorders rhythmic effect in mammals by administration of com of cardiac rhythm is quinidine. Another chemical agent pounds of Formula I wherein R is R substituted cin which has been used as an antiarrhythmic is the local namoyl as depicted by Formula Ia or R." substituted anesthetic procaine amide. Still other antiarrhythmic benzoyl as depicted by Formula Ib. agents are lidocaine, and diphenylhydantoin. None of 45 Still another feature of this invention provides novel these compounds are structurally related to the piperi o-aminophenethylpiperidines of Formula II which are dines of the present invention. useful as chemical intermediates in the production of compounds of Formula I. SUMMARY OF THE INVENTION This invention relates to a series of substituted piperi 50 dines characterized by Formula I and Formula XII and non-toxic pharmaceutically acceptable acid addition salts thereof. 55 60 65 Formula I Formula I 3,931, 195 3 - 4. In the compounds characterized by the above general The symbol R represents hydrogen or lower alkyl Formulas I and II, the R substituent stands for hydro and R' is seleeted from the group consisting of hydro gen or lower alkyl. The substituent R represents hy gen, halogen, trifluoromethyl, amino, dimethylamino, drogen, lower alkoxy or methylenedioxy attached in hydroxy, acetoxy, carboxy, alkylthio of from 1 to 4 the benzenoid 4,5-position. R' stands for hydrogen or a 5 carbon atoms inclusive, alkyl of from 1 to 4 carbon lower alkyl substituent. Substituent R represents hy atoms inclusive, lower alkoxy of from 1 to 4 carbon drogen, lower alkyl, or a dialkylcarboxamido substitu atoms inclusive, and wherein when R is hydrogen or ent wherein the dialkyl groups are lower alkyl. alkoxy the phenyl ring can have up to 2 additional Substituent R represents radicals selected from the alkoxy substituents of, from 1 to 4 carbon atoms inclu group comprised of lower alkanoyl of from 1 to 4 car O SWC. bon atoms inclusive, lower alkanesulfonyl of from 1 to In the compounds characterized by Formula XII, the 4 carbon atoms inclusive, symbol R represents' hydrogen or lower alkyl. The symbol. R9 represents a radical selected from the group consisting of cinnamoyl or . 15 p O 20 wherein R is lower alkoxy. The symbol A represents a "isonipecotoyl" "pyridylcarbonyl" divalent radical selected from the group consisting of -CH,-, --GH-, --GH-, 25 . .CH, bH . -HCH- -CHCH-, -CHCHCH--, bh, &H, ÖH - - - - 30 and -(CH2)3-. It is to be understood that the term “lower alkyl" and “lower alkoxy” as used herein refers to carbon chains --C- - which include both straight and branched chain carbon . ) radicals of from 1 to 4 carbon atoms inclusive. Illustra tive of these radicals are carbon chains which can be methyl, ethyl, propyl, isopropyl, 1-butyl, 1-methylpro "3-furylcarbonyl". pyl, 2-methylpropyl and tert-butyl. Compounds which are particularly preferred for their strong antiserotonin activity are compounds of For - 40. mula Ia. - . 45 9 50. CuC-C- , CHC-C- "phenylpropioloyl" "cinnamoyl" 55 Formula Ia 60 O wherein R', R°, R, R and R have the meanings here inabove given for Formula I. Representative of these C compounds is the individually preferred compound R” 2'-(2-(1-methyl-2-piperidyl)ethyl)cinnamanilide. 65. Compounds of the present invention which are par ticularly preferred for their strong antiarrhythmic ac "benzoyl" tivity are those of Formula Ib. 3,931,195 S 6 Zenesulfonic, para-toluenesulfonic, acetic, lactic, suc - R' cinic, maleic, mucic, tartaric, citric, gluconic, benzoic, cinnamic, isethionic and related acids. R N The compounds characterized by Formula I and For mula XII exhibit valuable antiarrhythmic activity in mammals. These antiarrhytmic effects are illustratively Ne-C demonstrated in standard in vitro and in vivo pharma 1. R7 cological tests. R In the dog, for example, electrically or aconitine 10 induced arrhythmia is prevented by oral or parenteral administration of the piperidines of Formula I accord ing to the following in vivo test. The chest of an anesthetized dog is opened in the midline and the right and left atrial appendages ex Formula. Ib 15 posed through small slits in the pericardium. Bypolar recording electrodes are affixed to the atrial surfaces and 4 x 4 mm. piece of clean cloth is fixed to the sur face of the right auricular appendage. Control record ings are made of various heart functions including fem 20 oral arterial blood pressure and right and left atrial electrograms. Atrial arrhythmia is then induced by wherein R, R, R, R, and R7 have the meanings here placing 3-5 drops of a solution of aconitine on the cloth inabove given for Formula I. Representative of these which is fixed to the right atrium. An irregular, rapid compounds are the individually preferred compounds atrial rate is produced within one minute. Throughout 4-methoxy-2'-(2-(1-methyl-2-piperidyl)ethyl)benzani 25 the experiment, fresh aconitine is (2-3 drops) placed lide, and 2'-(2-(1-methyl-2-piperidyl)ethyl-3,4,5- on the cloth at 10 minute intervals. The test compound trimethoxybenzanilide. is administered intravenously five minutes after the A still further group of preferred compounds are initial establishment of the arrhythmia and infusion those characterized by Formula Ib wherein R, R, and continued at a slow rate until an effective dose which Rare hydrogen, R is methyl and R is hydrogen or 30 re-establishes normal rhythm of the heart is obtained.