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 F531:A 1. N 0 .: 0cL734,583 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 .