Europaisches Patentamt ® J European Patent Office @ Publication number: 0 235 752 A2 Office europeen des brevets EUROPEAN PATENT APPLICATION n) Application number: 87102743.9 a) mt. ci- C 07 D 211/28, C 07 D 207/09, C07D 401/06, C 07 D 401/12, of 26.02.87 §) Date filing: C07D 409/06, C 07 D 409/12, C07D 405/06, C 07 D 405/12, C07D 417/06, C 07 D 417/12, C07D 471/04// C 07 D 21 1/36, C 07 D 207/10 , (C07D 471/04,235:00,221:00) <§) Priority: 26.02.86 JP 39270/86 |) Inventor: Oinuma, Hitoshi, 204, 1860-112, Namiki 2-chome Sakuramura, Niihari-gun Ibaraki (JP) Inventor: Yamanaka, Motosuke, 22-5, Tsukushino 6-chome, Abiko-shi Chiba (JP) Inventor: Miyake, Kazutoshi, 56-51, Sakaechol-chome, Ushiku-shi Ibaraki (JP) ® Date of publication of application: 09.09.87 Inventor: Hoshiko, Tomonori, 10-13, Bulletin 87/37 Arakawaokinishi 1 -chome, Tsuchiura-shi Ibaraki (JP) . Inventor: Minami, Norio, 702-59, Ohaza Shimohirooka Sakuramura, Niihari-gun Ibaraki (JP) Inventor: Shoji, Tadao, 57-7, Houyoudai Kukizakimachi, Inashiki-gun Ibaraki (JP) Inventor: Daiku, Yoshiharu, 15-3, Umezono 2-chome @ Designated Contracting States: AT BE CH DE ES FR GB Sakuramura, Niihari-gun Ibaraki (JP) GRIT LI LU NL.SE Inventor: Sawada, Kohei, E-601, 1, Nishi 2-chome, Toride-shi Ibaraki (JP) Inventor: Nomoto, Kenichi, 110-8, Ohaza Arakawaoki, Tsuchiura-shi Ibaraki (JP) §) Representative : Hansen, Bernd, Dr.rer.nat. et al, n) Applicant: Eisai Co., Ltd., 6-10, Koishikawa 4-chome Hoffmann, Eitle & Partner Patentanwalte Bunkyo-ku, Tokyo 112 (JP) Arabellastrasse 4, D-8000 Munchen 81 (DE) 54) Piperidine derivative, pharmaceutical composition containing the same and use. © A new piperidine compound is pharmacologically effec- 1 being 1 or 2, -A-B, A being -(CH2)n- n being an integer of tive for treatment of the arrythmia and is defined by the for- 1to 5, mula: a straight-chain alkylene group having 1 to 5 carbon atoms which is a divalent group derived from a straight- chain alkane having lower alkyl, phenyl or hydroxyl , •(Cllj)g ■ carbon atoms IN-Y group(s) bonded directly to one or more con- stituting said alkane by removing a hydrogen atom bonded O R2 to each of the carbon atoms placed at both ends thereof, a straight-chain alkylene group having 1 to 5 carbon CM in which R1 is a lower alkyl or a tolyl, R2 is hydrogen, hydro- atoms which is a divalent group derived from a straight- R3 lower chain alkene double bond formed between carbon < xyl, a lower alkoxy or a lower alkyl, is hydrogen, a having a alkyl, a lower alkenyl, a cycloalkyl or a cycloalkylalkyl, X is atoms adjacent to each other by removing a hydrogen atom -CO-, -CH2- or -CHOH-, g is an integer of 1 to 3, h is an in- bonded to each of the carbon atoms placed at both ends M teger of 1 to 3, Y is hydrogen, a lower alkyl, a lower alkenyl, thereof, -CH2-C-, -(CH2)k-S-, k being an integer of 2 to 5, - 1ft cyano, -CH2COOR, R being hydrogen or a lower alkyl, a cy- cloalkyl, a cycloalkylalkyl, CH2 (CH2)p-CO-, p being an integer of 1 to 4, B being cyano, - in NR4RS, a heterocyclic ring or a condensed aromatic ring. A CO pharmaceutical composition containing said compounds as CM active ingredient, and the use of said compound in the pre- paration of a medicament for the treatment of arrhythmia (CH»)i are also disclosed. Q. Ul ACTORUM AG 0 235 752 Piperidine derivative, pharmaceutical composition containing the same and use The present invention relates to piperidine derivatives and pharmacologically allowable salts' thereof having excellent medicinal effects, pro- cesses for producing them and medicines containing them. Prior Art Arrhythmias often occur as complications to cardiac diseases such as myocardial infarction and heart failure. In a serious case, arrhythmias give rise to a ventricular fibrillation to cause sudden death. Though various- antisrrythmic agents are now available on the market, those having both satisfactory effects and high safety have not been obtained yet. For example, antiarrythmic agents of Class I according to the classification of . Vaughan-Williams which' cause a selective inhibition of the maximum velocity of the upstroke of the action potential (Vmax) have only insufficient effects for preventing the ventricular fibrillation. In addition, they have problems regarding safety, namely, they cause a depression of the myocardial contractility and have a tendency to induce arrythmias due to an inhibition of the impulse conduction. Beta-adrenoceptor blockers and calcium antagonists which belong to Class II and IV respectively, have a defect that their effects are either limited to a certain type of arrhythmias or unreliable, though their safety is higher than that of the antiarrhythmic agents of Class I. o 0 235 752 Antiarrhythmic agents of Class III are drugs which cause a selective prolongation of the duration of the action potential without a significant depression of the Vmax. Although there has been no available drug which possess pure and potent properties of Class III antiarrhythmics, drugs of this class are expected to be effective in preventing ventricular fibrillations. Moreover, they are, by definition, not considered to cause a myocardial depression or an induction of arrhythmias due to the inhibition of the action potential conduction as seen with Class I antiarrhythmic agents. Under these circumstances, the development of pure and potent antiarrhythmic agents of Class III has been awaited. j Summary of the Invention An object of the present invention is to pro- vide new piperidine derivatives and pharmacologically allowable salts thereof, processes for producing the piperidine derivatives and pharmacologically allow- able salts thereof and medicines containing said piperidine derivative or pharmacologically allowable salt thereof as the active ingredient. The invention provides a new piperidine derivative , an analogous compound thereto, however having a heterocyclic ring other than the piperidine ring and a pharmacologically acceptable salt thereof. These compounds have the formula shown below. 3 0 235 752 0 R3 II I (CHa)g\ -S -fi- N-Y ll (CH2)h^ 0 • R2 in which R1 is a lower alkyl or a tolyl , r2 is hydrogen, hydroxyl, a lower alkoxy or a lower alkyl, R3 is hydrogen, a lower alkyl, a lower alkenyl, a cycloalkyl or a cycloalkylalkyl, X is -CO-, -CH2- or -CHOH-, g is an integer of 1 to 3 , h is an integer of 1 to 3, Y is hydrogen, a lower alkyl, a lower alkenyl, cyano, -CH2C00R, R being hydrogen or a lower alkyl, a cycloalkyl, a cycloalkylalkyl, 1 being 1 or- 2, -A-B, A being -(CH2)n-, n being an integer of 1 to 5, • a straight-chain alkylene group having 1 to 5 carbon atoms which is a divalent group derived from a straight-chain alkane having lower 4 0 235 752 alkyl, phenyl or hydroxyl group (s) bonded directly to one or more carbon atoms consti- tuting said alkane by removing a hydrogen atom bonded to each of the carbon atoms placed at both ends thereof, a straight-chain alkylene group having 1 to 5 carbon atoms which is a divalent group derived from a straight-chain alkene having a double bond formed between carbon atoms adjacent to each other by removing a hydrogen atom bonded to each of the carbon atoms placed at both •ends thereof, -CH2-9- CH ' -(CH2)k-S-, k being an^ integer of 2 to 5, -(CH2)p- C0-, p being an integer of 1 to 4 , B being cyano, -NR4R5, 0 235 752 5 0 235 752 6 CH3 R4 and R5 each being hydrogen or a lower alkyl, R6 being hydrogen, a lower alkyl, a lower alkoxy, cyano, imidazolyl, hydroxyl or a halogen, R7 and R8 each being hydrogen, a halogen, a lower alkyl, a lower alkoxy or methanesulf onamido , R9 , R10 and R1 1 each being hydrogen or a lower alkyl. ) 235 752 Then are preferably proposed embodiments where j and h each are 2; g is 3 and h is 1; g is 2 and \ is 3; g is 1 and h is 2; and g is 1 or 2 and h Ls 2 or 3. The lower alkyl group for R1 , R2 , R3 , R4 , R5 , R6, R7, R8, R9, R1 0 , R1 1 and A is preferred to have 1 to 6 carbon atoms, being either straight or branched, such as methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, 1 -methylpropyl , tert-butyl, n-pentyl, 1- ethylpropyl, isoamyl and n-hexyl. The lower alkoxy for R2, R6, R7 and R8 is preferred to be one to derive from the above defined alkyl. The halogen for R6, R7 and R8 is preferred to be chlorine, bromine, iodine or fluorine. The term "a straight-chain alkylene group having 1 to 5 carbon atoms which is a divalent group derived from a straight-chain alkane having lower alkyl, phenyl or hydroxyl group (s) bonded directly to one or more carbon atoms constituting said alkane by removing a hydrogen atom bonded to each of the carbon atoms placed at both ends thereof" in the definition of A means a divalent group derived from a straight-chain alkane having lower alkyl such as methyl, phenyl or hydroxyl group (s) bonded to terminal carbon atoms or other carbon 8 0 235 752 atoms by removing a hydrogen atom from each of the terminal carbon atoms. Preferred examples of these groups include a group of the formula: -CH-, a CH_ I 3 group or the formula: -CH--CH-, a crours of the formula: -CH2~CH- , a group of the formula: -CH- and a group of the formula: -CH--CH.