United States Patent 1 Aberg et al. [54] METHOD AND COMPOSITION FOR THE ‘TREATMENT OF CARDIAC ARRHYTHMIAS Gunnar A. K, Aberg, 519 Bergen St, Lawrenceville, NJ. 08648; Peter R. Maroko, Cherry Hill, NJ: Bo T. af Bkenstam, Hialteby, Sweden [75] Inventors: [73] Assignee: Gunnar A, K, Aberg, Lawrenceville, Nd. [21] Appl No: $88,955 [22] Filed: = Mar, 13, 1988 [si] Int, + ABIK 31/445 [2] US.ci, “514/330, 3147821, [Sa] Field of Search 424/267; 46/225, 514/330, 821 (86) References Cited US. PATENT DOCUMENTS 22792,399 5/1987 Ekenstam etal. 250/399 2798.69 8/1978 Ebenstam et 260/298 S)80986 5/1974 kentem et 2 eager Sea321 1/1975 Adams eta aaa 8/1976 Kaplan 224316 S/19T8. Peterson nn 467228 TASHO Cooke nnn 44/328 1) Patent Number: 4,556,664 145] Date of Patent: Dee. 3, 1985 49465 11/1981 Ehsan ta sors FOREIGN PATENT DOCUMENTS 161236 11/1957 Swedes 16063 "7/1988. Sweden OTHER PUBLICATIONS (Chem. Abst. 76: 81348p (1972)-Tullar. (Chem, Abst. 62: 132713n (1975)-Goehl et al ‘Chem. Abst 98: 62003y (1981)-Fkenstam, (Chem. Abst 96: 115484a (1982)-Dennhardt Primary Examiner-—Douglas W. Robinson Attorney, Agent, or Firm—Lerner, David, Littenberg, ‘Kromhotz & Ment (1 ABSTRACT ‘A method and pharmaceutical composition are dis: ‘closed for treating cardiac arrhythmias employing as an ‘active ingredient atleast one compound selected from piperidine-2-carborylic acid-2,6dimethyl —anilde Piperidine-2-carborylic _acid-24-dimethyl _anilide; piperidine-2-carborvlc acd-2,4.6-timethylanilide; and methylS-chloro anil.4,556,664 1 METHOD AND COMPOSITION FOR THE ‘TREATMENT OF CARDIAC ARRHYTHMIAS BACKGROUND OF THE INVENTION ‘The present invention relates to a method and com- position for treating cardiac archythmias, More particu- farly, the invention relates to the treatment of cardiac arrhythmias with at least one compound selected from piperidine-2-carboxylic acid-26-dimethyl —anilide; piperidine carboxylic acid-24-dimethyl —anilide: piperidine. 2-carboxylic acd-2,4.6-rimethyl anid; and Piperidine.2-carboxylicacid-2-methyl-.chloro anilide. "The compound piperidine-2-cerboxylic acid-2.6- dimethyl anilide s known in the prior art. For example, Ekenstam etal. US. Pat. No. 4,302.46 discloses piperi- dine-2-carboxylic acid-2,6-dimethylanilde as an inter- mediate for use in making of, eg, N-2-hydroxyethyl)- Pipecolinyl2,6-dimethyl anilide. The latter compound fdislosed in Ekenstam etal. Swedish Pat. No. 161,236 as having antiarrhythmic activity, but piperidine-2-car- Doxylic acid-2,6dimethyl anilide is not disclosed 3s possessing such activity. Other patents disclosing piperidine 2-carboxylic.acid-2,6dimethyl anlide in lade Pettersson U:S, Pat. No. 4110331 and Swedish Pat. Nos. 161236 and 164,063. However, none ofthese patents disclose or suggest the use of piperidine-2-car- boxylic acid-2-6-dimethylanlide; piperdine-2-carboxy- lie. acid-2,4-dimethyl anilide, piperidine-2-carboxylic scid-2,4trimethyl anil; piperidine 2-carboxylic acid-2-methyl--chloro anilide in the treatment of car- diac arrhythmias. ‘The compounds N-methyl-piperiine-2-carborylic scid-2,6 rial being dependent upon the dosage form desired. The Pharmaceutical composition of the invention can also Include other conventional adjuvants for such comp tions, including lubricants, buffers, or the like. “The method and pharmaceutical composition of the invention preferably employs oral dosage forms: how- fever, parenteral or transcutaneous administrations can also be employed. Multiple, single or divided doses of fone or more of these four compounds in amounts of from about to about 1,000 mailigrams, preferably from 2» 6 ” « 4 about 50 to about 800 miligrams, one-to four times per ‘day, may be administered in dosage forms as described above The following examples are intended to illustrate, but not to limit, the method and composition of the inven EXAMPLE | Piperidine-2-carboxylic acid-2,6-dimethy! anilide was administered in an oral dose of 50 mg/kg body weight 10 conscious dogs with ischemia-induced archythmias produced according to the method of Harris (Cirewla- tion, 1950, Volume 1, page 13-18). This compound decreased the frequency of arrythmic heart beats from 950% 10 0%, without causing cardiovascular or CNS side effects, The duration of the antarrythmic effect of piperidine-2-carboxylic acid-2¢-dimethyl anilide was in excess of six hours. N-methylpiperidine-2-carboxylic fcid-2,6-dimethyl anilide, -N-butyl-piperidine-2-car- boxylic acid-2,¢-dimethyl anilde; and. N-ethyl-piperi- dine2-carboxylic acid-2,6-dimethyl anilide when ad- ministered intraveneously provided antiarrhythmic ac- tivity of very short duration and were accompanied by both cardiovascular side effects such as impaired car- diac contractility (cardiac arrest) and CNS side effects such as convulsions and/or respiratory effects. ‘The acute toxicity of these same compounds was studied in conscious mice. The LDso values after intra ‘venous administration were 45 mg/kg for piperiine-2- carboxylic aci-2,6-dimethylanilide, 28 mg/kg for lido~ caine, 25 mg/kg. for N-ethylpiperidine-2-carboxylic acid-2,6-dimethyl anilide, 34 mg/kg for N-methyl. piperidine-2-carboxylic acid-2,6-dimethyl anilide, and 9 mg/kg for N-butyLpiperidine-2-carboxylic acid-2,6- dimethyl anilide, Tn summary, —piperidine-2-carboxylic acid-2,6- dimethyl anilide provided unexpectedly advantageous antiarrhythmic effects with relatively low tonicity and ‘without causing cardiovascular or CNS side effects. EXAMPLE 2 ‘The compounds piperidine-2-carboxylic acid-24- dimethyl anilde; piperidine-2-carboxylic acid-24,6- trimethyl anilide; and_piperidine-2-carboxylic acid-2- ‘methyl-3-chloro anilide were administered to conscious ‘coronary-ligated dogs with ischemia-induced arrhyth- ‘mias by the Harris procedure cited above. In a dose of 50 mg/kg body weight given orally, all three com- pounds totally abolished the ischemia-induced arshyth= Imias and provided an antiarchythmic effect for several hours. EXAMPLE 3 Tablets were prepared by mixing 1000 grams of piperidine-2-carboxylic acid-2,6-dimethyl anilide hy- ‘rochloride (m.p. 264°-265" C.) with lactose, potato Starch and colloidal slic acid. The mixture was moist- ened with a 10% solution of gelatin and was granulated through a 12-mesh sieve. After drying, potato starch, fale and magnesium stearate were admixed and the resulting mixture was pressed into tablets (10,000) which contained 100 mg of piperidine-2-carboxylic acid-2,6-dimethyl anilde each, Tablets were provided ‘with a breaking score to give another dose than 100 mg OF to give multiple doses thereof when broken. Similar tablets can be prepared by substituting pipesi dine2-carboxylic acid-24dimethyl anilide; piperidine- 2-carboxylie acid-2,4,6-trimethyl anilide; or piperidine>4,556,664 5 carboxylic acid-2-methyl-S-chloro anilde for piperi= dine 2-carboxylic acid-2,6-dimethyl anid. EXAMPLE 4 Coated tablets were prepared by the following prove- * duce. Granules were prepared from piperidine-2-car boxylicacid-2,6dimethy1 anilide hydrochloride (1,000 2) lactose, and an alcoholic solution of polyvinylpyr- rolidone. After the drying step, the granules were mixed with tale potato starch and magnesium stearate The resulting mixture was pressed into 10,000 tablets being biconvex. The tablets were primarily coated with 110% alcoholic solution of shellac and thereupon with ‘an aqueous solution containing saccharose ($5%), gua arabicum (5%), gelatin (49%) and dye stu (02%). Tale and powdered sugar were used for powdering after the first five coatings. The resulting coating was then coated with a 10% carnauba wax solution in carbon tetrachloride. 0 EXAMPLE 5 Ampoules containing. piperidine 2-carboxylic acid- 26-dimethyl anilide hydrochloride were prepared by ™ dissolving one gram of the compound, 0.8 grams of sodium chloride, and 0.1 grams of ascorbic acid in a sulficent amount of water 10 give 100 ml of solution. The solution, which contains 10 mg of active substance in each ml, was used in filling ampoules, which were sterilized by heating at 120" C. for twenty minutes. ‘Similar ampoules can be prepared by substituting piperidine 2-carboxylic aci-2,4-dimethyl —_anilide: piperidine-2-carboxylic acid-2,46-rimethyl anilide; or piperidine-2-carboxylic acid-2-methyl-S-chloro anilide for piperidine-2-carboxylicacid-2,6-dimethyl anilide. It willbe understood thatthe embodiments described herein are merely exemplary and that a person skilled in the art may make many variations and modifications ‘without departing from the spirit and scope of the in- vention. All such modifications and variations are in- tended to be included within the scope ofthe invention as defined in the appended claims. What is claimed i: A method for treating cardiac archythmias in mam- ‘mals comprising administering to a mammal susceptible to cardiac arrhythmias an effective amount t0 inhibit gy cardiae arrhythmias of at least one compound selected from On = as 4s 6s 6 continued On ‘an optically active isomer of such compounds, a phar- maceutically acceptable acid addition salt of such com- pounds, or mixtures thereof 2. A method according to claim 1, wherein said com: pout i I an optically active isomer thereof and/or pharmaceuti= cally acceptable acid addition sat thereof. '3.A method according to claim 2, wherein said com- pound is administered in its racemic form. 4A method according to claim 2, wherein sid com- pound is administered in its optically active éform. 8. A method according to claim 2, wherein sid com- ‘pound is administered in its optically active Lform. 6. A method according to claim 1, wherein sid com- ae Cem (B)-n h os os ‘an optically active isomer thereof and/or pharmaceuti- cally acceptable acid addition salt thereot 7. A method according to claim 4, wherein said com- an optically active isomer thereof and/or @ pharmaceu- tically acceptable acid addition salt thereof. '8. A method according to claim 1, wherein said com- pound is4,556,664 1 an optically active isomer thereof and/or a pharmaceu- tically acceptable addition sal thereof. '9. A method according to claim 1, wherein said at least one compound is administered orally. 10. A method according to claim 1, wherein said at least one compound is administered parenterally. 11. A method according to claim 1, wherein said at least one compound is administered at a dosage of from bout $0 t0 about 800 milligrams, one to four times per day. 12, A pharmaceutical composition for treating car- diac arrhythmias in mammals, suid composition com- prising an effective amount to inhibit cardiac archyth- ‘mias of at least one compound selected from On ‘an optically active isomer of such compounds, a phar- maceutically acceptable acid addition salt of such com- pounds or mixtures thereof, and pharmaceutically acceptable carrier, 13. A pharmaceutical composition according to claim 12, wherein said compound is. Fy ss 45 0 “s 8 An . ‘an optically active isomer thereof and/or a pharmaceu- tically acceptable acid addition salt thereof. 14. A pharmaceutical composition according to claim 13, wherein said compound isin its racemic form, 15. A pharmaceutical composition according to claim 13, wherein said compound is in its optically active form, 16. A pharmaceutical composition according to claim 13, wherein said compound is in its optically active form. 17. A pharmaceutical composition according to claim 12, wherein said compound is ‘an optically active isomer thereof and/or a pharmaceu- tically acceptable acid addition salt thereot. 18. A pharmaceutical composition according to claim 12, wherein said compound is. I cs an optically active isomer thereof and/or a pharmaceu> tically acceptable acid addition salt thereof. 19, A pharmaceutical composition according to claim 12, wherein said compound Ca an optically active isomer thereof and/or a pharmaceu- tically acceptable acid addition salt thereof. 20, A pharmaceutical composition according to claim 12, wherein said at least one compound is contained in said pharmaceutical composition in a dosage unit of rom about $0 to about 800 milligrams.