United States Patent (19. 11) Patent Number: 4,996,215 Oinuma et al. 45) Date of Patent: Feb. 26, 1991
54) PIPERIDINEDERIVATIVE AND 57 ABSTRACT PHARMACEUTICAL COMPOSITION A new piperidine compound is pharmacologically ef CONTAINING THE SAME fective for treatment of the arrythmia and is defined by 75) Inventors: Hitoshi Oinuma, Ibaraki; Motosuke the formula: Yamanaka, Abiko; Kazutoshi Miyake, Ushiku; Tomonori Hoshiko, Tsuchiura; Norio Minami, Sakura; R (CH), R-S-N X-( N-Y Tadao Shoji, Kukizakimachi; I / Yoshiharu Daiku, Sakuramura; Kohei O (CH2)h Sawada, Toride; Kenichi Nomoto, Tsuchiura, all of Japan R2 73) Assignee: Eisai Co., Ltd., Tokyo, Japan in which R1 is a lower alkyl or a tolyl, R2 is hydrogen, hydroxyl, a lower alkoxy or a lower alkyl, R is hydro 21 Appl. No.: 408,106 gen, a lower alkyl, a lower alkenyl, a cycloalkyl or a 22 Filed: Sep. 15, 1989 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 Related U.S. Application Data hydrogen, a lower alkyl, a lower alkenyl, cyano, -CH 62) Division of Ser. No. 16,035, Feb. 18, 1987, Pat. No. 2COOR, R being hydrogen or a lower alkyl, a cycloal 4,876,262. kyl, a cycloalkylalkyl,
(30) Foreign Application Priority Data Feb. 26, 1986 JP Japan ...... 61-392.70 51) Int. Cl...... A61K 31/40; A61K 31/435; CO7D 207/09; CO7D 211/28 52 U.S. Cl...... 514/316; 514/319; 514/323; 514/325; 514/326; 514/330; 514/331; 514/.414: 514/422; 514/423; 546/189: 546/190; 546/191; 546/203; 546/204; 546/205; 546/206; being 1 or 2, -A-B, A being -(CH2)-, n being an 546/208; 546/214; 546/225; 546/232; 548/467; integer of 1 to 5, a straight-chain alkylene group having 548/468; 548/518; 548/523; 548/524; 548/528; 1 to 5 carbon atoms which is a divalent group derived 548/570; 548/571; 548/575; 548/576; 548/578 from a straight-chain alkane having lower alkyl, phenyl 58 Field of Search ...... 546/203, 205, 225, 232, or hydroxyl group(s) bonded directly to one or more 546/189, 190, 191, 206, 208; 514/325, 330, 331, carbon atoms constituting said alkane by removing a 316, 319, 323, 422,423, 326,414; 548/467, 468, hydrogen atom bonded to each of the carbon atoms 518, 523, 528,570 placed at both ends thereof, a straight-chain alkylene group having 1 to 5 carbon atoms which is a divalent 56 References Cited group derived from a straight-chain alkene having a U.S. PATENT DOCUMENTS double bond formed between carbon atoms adjacent to each other by removing a hydrogen atom bonded to 4,876,262 10/1989 Oinuma et al...... 54.6/194X each of the carbon atoms placed at both ends thereof, FOREIGN PATENT DOCUMENTS -(CH2)k-S-, k being an integer of 2 to 5, -(CH2 )p-CO-, p being an integer of 1 to 4, B being cyano, 0158775 10/1985 European Pat. Off. . -NR4R5, a heterocyclic ring or a condensed aromatic 2067562 7/1981 United Kingdom . ring. Primary Examiner-Joseph Paul Brust Attorney, Agent, or Firm-Flynn, Thiel, Boutell & Tanis 9 Claims, No Drawings 4,996,215 1. 2
PPERIDINE DERVATIVE AND O R3 (CH2)g PHARMACEUTICAL COMPOSITION R-S-N x-( N N-Y CONTAINING THE SAME / O (CH2) This is a division of Ser. No. 07/016,035, filed Feb. 18, 1987 now U.S. Pat. No. 4,876,262. The present invention relates to piperidine deriva in which R1 is a lower alkyl or a tolyl, R2 is hydrogen, tives and pharmacologically acceptable salts thereof 10 hydroxyl, a lower alkoxy or a lower alkyl, R3 is hydro having excellent medicinal effects, processes for pro gen, a lower alkyl, a lower alkenyl, a cycloalkyl or a ducing them and medicines containing them. 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 PRIOR ART hydrogen, a lower alkyl, a lower alkenyl, cyano, -CH Arrhythmias often occur as complications to cardiac 5 2COOR-, R being hydrogen or a lower alkyl, a cyclo diseases such as myocardial infarction and heart failure. alkyl, a cycloalkylalkyl, In a serious case, arrhythmias give rise to a ventricular fibrillation to cause sudden death. Although various antiarrythmic agents are now avail- 20 able on the market, those having both satisfactory ef fects 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 25 1 being 1 or 2, -A-B, A being -(CH2)n-, n being an upstroke of the action potential (Vmax) have only insuf integer of 1 to 5, ficient effects for preventing the ventricular fibrillation. a straight-chain alkylene group having 1 to 5 carbon In addition, they have problems regarding safety, atoms which is a divalent group derived from a namely, they cause a depression of the myocardial con- 30 straight-chain alkane having lower alkyl, phenyl or tractility and have a tendency to induce arrythmias due hydroxyl group(s) bonded directly to one or more to an inhibition of the impulse conduction. Beta carbon atoms constituting said alkane by removing adrenoceptor blockers and calcium antagonists which a hydrogen atom bonded to each of the carbon belong to Class II and IV respectively, have a defect atoms located at both ends thereof, that their effects are either limited to a certain type of 35 a straight-chain alkenylene group having 2 to 5 car arrhythmia or are unreliable, though their safety is bon atoms which is a divalent group derived from higher than that of the antiarrhythmic agents of Class I. a straight-chain alkene having a double bond Antiarrhythmic agents of Class III are drugs which formed between carbon atoms adjacent to each cause a selective prolongation of the duration of the other by removing a hydrogen atom bonded to action potential without a significant depression of the each of the carbon atoms located at both ends thereof, Vmax. Although there has been no available drug -(CH2)k-S-, k being an integer of 2 to 5, -(CH2 which possess pure and potent properties of Class III )p-, p being an integer of 1 to 4, B being cyano, antiarrhythmics, drugs of this class are expected to be -NR4R5, effective in preventing ventricular fibrillations. More- 45 over, they are, by definition, not considered to cause a myocardial depression or an induction of arrhythmias 21 R8 due to the inhibition of the action potential conduction as seen with Class I antiarrhythmic agents. -3-Sas N Under these circumstances, the development of pure 50 and potent antiarrhythmic agents of Class III has been R7 awaited. SUMMARY OF THE INVENTION 55 An object of the present invention is to provide new S R N N piperidine derivatives and pharmacologically accept able salts thereof, processes for producing the piperi dine derivatives and pharmacologically acceptable salts thereof and medicines containing said piperidine deriva 60 tive or pharmacologically acceptable salts thereof as the active ingredient. -C-O il. The invention provides a new piperidine derivative, an analogous compound thereto, however having a 65 heterocyclic ring other than the piperidine ring and a -EO pharmacologically acceptable salt thereof. These com pounds have the formula shown below. 4,996,215 3 4. located at both ends thereof" in the definition of A -continued means a divalent group derived from a straight-chain 1n 1Sa alkane having lower alkyl such as methyl, phenyl or hydroxyl group(s) bonded to terminal carbon atoms or L= N L= 5 other carbon atoms by removing a hydrogen atom from each of the terminal carbon atoms. Preferred examples R of these groups include a group of the formula:
10 CH3 -CH-, a group of the formula:
CH3 -CH2-CH-, a group of the formula: 20
W
-N 25 W O -CH2-CH-, a group of the formula:
30 O ur'sCH N 1so 35 th and a group of the formula:
-CH2-CH. al-N -N O or -N 40 OH \-/ The term "a straight chain alkenylene group having 2 to R“ and Reach being hydrogen or a lower alkyl, R 5 carbon atoms which is a divalent group derived from being hydrogen, a lower alkyl, a lower alkoxy, 45 a straight-chain alkene having a double bond formed cyano, imidazolyl, hydroxyl or a halogen, between carbon atoms adjacent to each other by remov R7 and R8 each being hydrogen, a halogen, a lower ing a hydrogen atom bonded to each of the carbon alkyl, a lower alkoxy or methanesulfonamido, R', atoms located at both ends thereof" means, for example, R10 and R11 each being hydrogen or a lower alkyl. a group of the formula: -CH2-CH=CH-and a Then are preferably proposed embodiments where g 50 group of the formula: -CH2-CH2-CH=CH-. and h each are 2; g is 3 and h is l; g is 2 and h is 3; g is The pharmacologically acceptable salts include inor 1 and his 2; and g is 1 or 2 and h is 2 or 3. ganic acid salts such as hydrochlorides, sulfates, hydro The lower alkyl group for R, R2, R3, R*, R5, R6, R7, bromides, perchlorates and hydriodides and organic R8, R9, R10, R1 and A is preferred to have 1 to 6 carbon acid salts such as oxalates, maleates, fumarates, succi atoms, being either straight or branched, such as 55 nates and methanesulfonates. methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, The intended compounds (I) or pharmacologically 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, acceptable salts thereof of the present invention having isoamyl and n-hexyl. The lower alkoxy for R2, R6, R7 an excellent antiarrhythmic activity and a high safety and R8 is preferred to be one derived from the above 60 can be used as antiarrhythmic agents. In addition, the defined alkyl. The halogen for R6, R7 and R8 is pre effects of these compounds on intractable arrythmia or ferred to be chlorine, bromine, iodine or fluorine. arrythmia on which other medicines are ineffective are The term "a straight-chain alkylene group having 1 expectable. to 5 carbon atoms which is a divalent group derived from a straight-chain alkane having lower alkyl, phenyl PRODUCTION PROCESSES 65 or hydroxyl group(s) bonded directly to one or more The compounds (I) of the present invention can be carbon atoms constituting said alkane by removing a produced by various processes. Typical examples of the hydrogen atom bonded to each of the carbon atoms processes are as follows: 4,996,215 5 6 PRODUCTION PROCESS B Production process A The intended compounds of the above general for mula in which R3 is a lower alkyl, a lower alkenyl, or a cycloalkyl can be produced as shown below. RI-S-N( (II) (wherein R, R2 and R3 E. are as defined above) R2 Step
O R3 O (CH2)g Ri-S-N 3-( N N-COR' (III) I / O (CH2)h R2 Step o R G (CH.) R-5-N 2-( NH.HCl (IV) O (CH2) R2 Z-Y (wherein Z represents a halogen atom such as a chlorine, bromine or iodine atom or a free group such as a methanesuifonyloxy or p-toluene-sulfonyloxy group and n is as Step 3 defined above) Y is defined above except for hydrogen excluded. o 21 R6 CHECH2 (VI) Sa N R ( (CH) R-5-N 3-( N-Y (VII) O (CH2) R2 step 4 of step 5 of reduction reduction
G F / \ pH (CH), R-5-N &H-{ N-Y' (VIII) O (CH2) h R2 step 6 of reduction
O R3 (CH2) R-5-N CH,-( O
65 4,996,215 7 8
Process 1 H (CH2)g R1-S-N C N-Y (VII) I / O (CH2)h R2 step 7 of R.Hal (X) alkylation (Hal is a halogen)
O R3 Q (CH2) Rl-S-N 3-( N N-Y (XI) I / O (CH2)h R2
reduction reduction
O R3 OH (CH2)g R-S-N &H-{ N N-Y (VIII) l / O (CH2)h R2 reduction
O R3 (CH2)g N Rl-S-N CH;-( N-Y (IX) / O (CH2).h R2
Process 2 H (CH2)g Ri-S-N C N-COR' (XII) / O (CH2)h step 8 of 3 alkylation R.Hal (X)
O R3 9 (CH2)g N R-i-N C N-COR" (III) 5 (CH2)h
55 PRODUCTION PROCESS C The compounds of the above general formula (I) in O R3 OH (CH2) (XIII) which Y is H and X is a group of the formula: 2's 60 R-5-N &H-{ N-H ph O (CH2), -CH- R2 can be produced by directly reducing the abovemen- 65 PROCESS D tioned compound (IV), omitting the step 3, to obtain the compound (XIII). The reduction is conducted in the The compound in which X is -CH2-in the formula same way as shown in the step 4. (I) is produced below. 4,996,215 9 10
O R3 Q (CH2) O (III) R (CH2)g Rl-S-N 2-( N N-C Z I / N 5 R-5-N X-( NH (XVII) O (CH2)h R O (CH2) R2 R2 t 9 of reduction HCHO and 10 (XVIII) R-S-NS R CH,-( ch), N-C o " O R10 I / N O (CH2)h R step 12 (XIV) R2 5 N s 10 of hydrolysis Rll O R (CH), (XV) W R-S-N CH;-( N-H.HC - 20 - N (XX) / N =/ O (CH2) R2 (CH2)g ll of alkylation 25 R-5-N X-( N-Y2 (XXI) O R3 (CH2) (IX) O (CH2) N Rl-S-N CH,-( N-Y" R2 / O (CH2), 3O METHOD E-2 R2 A compound in which A is -(CH2)2-and B is PROCESS E The process A provides the invention compound in 35 the step 3. The invention compound is also produced by each below shown method when Y is one of the follow IOCDO ings. METHOD E- 40 is produced below. This -A-B is called Y. A compound in which A is -CH2-and B is O R3 (CH2)g N R-S-N x-( NH (XVII) I / 45 O w (CH2) N R2 kn HCHO and N e 50 1.S. O (XXII) CH3 N N a O R10 e is produced. A compound in which A is 55 step l3 ? (XXIII) Sa CH N -CH CH 21 s (XXIV) 60 Sa N and B is CH3 N1 /- N. (CH2) 65 R-5-N X-( N-Y3 (XXV) O (CH2)h is produced. This B is called Y2. 4,996,215 11 12 Each above shown step is conducted as described and potassium iodide (used when Z is not iodine) in a below in detail. solvent such as N,N-dimethylformamide, dimethylsulf oxide, acetonitrile, acetone, butanol, propanol, ethanol STEP 1 or methanol at a temperature of about 50 to 120° C. to A sulfonanilide derivative (II) is reacted, according 5 obtain the compound (VII). to the Friedel-Crafts reaction, with a reactive acid de (2) A compound in which A is -(CH2)2- and B is rivative such as a halogenate or anhydride of a carbox ylic acid having the following formula: O O -3- R6 Ho-2-( N is produced below. The reaction in detail is illustrated below.
O R3 O (CH2)g Rl-S-N 2-( N NH (IV) I O (CH2)h R2 21 R6 CH=CH2. (VI) Sa
O R3 O (CH2)
R S aa- -{ N a- (CH2)22 21 R6 / Sa (CH2) N R2 (XXVI) in which R" is a lower alkyl or phenyl and g and h are defined above, in the presence of a Lewis acid such as More particularly, an unsubstituted or substituted aluminum chloride, tin chloride and zinc chloride in an 35 vinylpyridine (VI) is reacted with the compound (free inert solvent such as carbon disulfide, dichloromethane, base) (IV) obtained in the above-mentioned step 2 or chloroform and nitrobenzene to form a corresponding pharmacologically acceptable acid-addition salt thereof anilide derivative (III). in a lower alkyl alcohol such as methanol, ethanol or propanol or a mixture thereof with water at a tempera STEP 2 40 ture ranging from room temperature to about 100° C. to The acetyl group of the compound (III) obtained in obtain the intended compound (XXVI). When a free the step 1 is hydrolyzed in this step. The hydrolysis is base is used as the starting material in this process, pre effected in, for example, a dilute aqueous alkali solution ferred results are obtained by using an acidic catalyst or dilute aqueous mineral acid solution. In a preferred such as acetic or hydrochloric acid or an alkali metal embodiment, the hydrolysis is effected in 2 to 6N hy 45 catalyst such as sodium. - drochloric acid under reflux or in a 0.5 to 3N aqueous In the steps 4 to 6, the compound (VII) obtained in solution of sodium hydroxide under reflux. the step 3 is reduced to fproduce the compounds (VIII) or (IX). STEP 3 STEP 4 (1) in case Y is other than hydrogen, that is, Y is Y' SO The compound (IV) of the step 2 is normally con The compound (VII) prepared in the step 3 is re densed with a compound having the formula: Z-Y' (V), duced in this step. The reduction is effected by an ordi such as Z-A-B and nary method wherein, for example, the compound (VII) is treated with sodium borohydride or lithium borohy 55 dride in a solvent such as methanol, ethanol, 2-propanol, dimethylformamide or dimethylsulfoxide at a tempera ture ranging from about -10° C. to room temperature to obtain the intended alcohol (VIII) of the present Z-CH2 invention. (CH2)| STEP 5 An arylketone compound (VII) is reacted with two in which Z is a group to eliminate and is a halogen such or more equivalents of a trialkylsilane, preferably trie as chlorine, bromine and iodine, methansulfonyloxy and thylsilane, in an excess of trifluoroacetic acid, at a tem p-toluenesulfonyloxy. 65 perature ranging from room temperature to 100° C. for In a preferred embodiment of this process, the reac several days to produce the compound (IX). Dichloro tion is carried out in the presence of a deacidifying ethane, carbon tetrachloride, chloroform, dichloro agent such as potassium carbonate or sodium carbonate methane and acetonitrile are also used as a solvent. 4,996,215 13 14 5. 4-(4-methylsulfonylaminobenzoyl)-1-2-(4-pyridyl)e- STEP 6 thylpiperidine, An alcohol compound (VIII) obtained in the same 6. 1-2-(3,4-dimethoxyphenyl)ethyl)-4-(4-methylsul way as shown in the step 4 is treated with an acid, pref fonylaminobenzoyl)piperidine, erably with 20% sulfuric acid-acetic acid for a short 5 7. 4-(4-methylsulfonylaminobenzoyl)-1-4-(3-pyridyl)- time to obtain a dehydrate and the dehydrate is catalyti butylpiperidine, cally hydrogenated to produce the compound (IX). 8. 4-(4-methylsulfonylaminobenzoyl)-1-(2-(4-pyridylthi o)ethylpiperidine, STEP 7 9. 4-(4-methylsulfonylaminobenzoyl)piperidine, The compound (VII)' of the above general formula 10 10. 4-(4-methylsulfonylaminobenzoyl)-1-3-(3-pyridyl)- (I) wherein R3 is His N-alkylated in this step. The com propylpiperidine, pound (VII)''' is reacted with an alkyl halide of the 11. 4-(4-methylsulfonylaminobenzoyl)-1-(5-(3-pyridyl)- formula (X) in the presence of a base in a solvent such pentylpiperidine, as dimethylformamide, dimethyl sulfoxide, a lower 12. 1-(6-chloro-3-pyridyl)methyl-4-(4-methylsul alkyl alcohol, e.g. methanol, ethanol or propanol, or 15 fonylaminobenzoyl)piperidine, acetone at a reaction temperature of about 50 to 120° 13. 4-(4-methylsulfonylaminobenzoyl)-1-(2-(2-pyridyl C. to obtain the intended compound (XI). The bases )ethylpiperidine, used in this step include, for example, potassium carbon 14. 4-(4-methylsulfonylaminobenzoyl)-1-(2-phenyle ate, sodium carbonate, sodium hydrogencarbonate, so thyl)piperidine, dium ethoxide, sodium methoxide and sodium hydride. 20 15. 4-(2-hydroxy-4-methylsulfonylaminobenzoyl)-1-(4- When 2 mole equivalents or more of R3Hal (X) is pyridyl)methylpiperidine, used, dialkylation, alkenylation for di-lower alkenyl and 16. 4-(2-hydroxy-4-methylsulfonylaminobenzoyl)-1-(2- alkylation for dicycloalkyl may be carried out as far as phenylethyl)piperidine, Y is hydrogen. Similarly the step 8 of the process B can 17. 4-(4-methylsulfonylaminobenzoyl)-1-(3-pyridyl)me be conducted for N-alkylation. 25 thylpiperidine, The compound (XI) obtained is reduced in the same 18. 4-(4-methylsulfonylaminobenzoyl)-1-(2-pyrindyl)- way as shown in the steps 4 to 6 to further obtain the methylpiperidine, compound (VIII)" or (IX)'. 19. 4-(4-methylsulfonylaminobenzoyl)-1-nicotinoylme thylpiperidine, STEPS 9 to 11 30 20. 4-(4-methylsulfonylaminobenzoyl)-1-(2-(2-thienyl)e- Each step is conducted in the same way as shown the thylpiperidine step 5 (reduction), the step 2 (hydrolysis) and the steps 21. 4-(4-methylsulfonylaminophenyl) -hydroxymethyl 7 and 8 (alkylation). 1-(2-(2-pyridyl)ethyl)piperidine 22. 4-(2-methoxy-4-methylsulfonylaminobenzoyl)-1-(4- STEP 12 35 pyridyl)methylpiperidine, A secondary amine (XVII) is converted to a tertiary 23. 1-2-(4-chlorophenyl)ethyl)-4-4-methylsul amine (XXI) by the Mannich reaction. An active hydro fonylaminobenzoyl)piperidine, gen-having compound, such as a furan compound, a 24. 1-2-(4-methoxyphenyl)ethyl)-4-(4-methylsul pyrrole compound and a nitrogen-including heterocy fonylaminobenzoyl)piperidine, clic compound having a methyl group, is condensed 40 25. 4-(4-methylsulfonylaminobenzoyl)-1-3-(3-pyridyl)- with an amine and formaldehyde or para-formaldehyde, 2-propenylpiperidine, preferably in a solvent such as water and an alcohol, 26. 4-(4-ethylsulfonylaminobenzoyl)-1-(4-pyridyl)- under the acidic condition with acetic acid or hydro methylpiperidine, chloric acid, at a temperature ranging from room tem 27. 4-(4-ethylsulfonylaminobenzoyl)-1-(2-phenylethyl)- perature to 100° C. 45 piperidine, 28. 1-benzyl-4-(4-methylsulfonylaminobenzoyl)piperi STEP 3 dine, A secondary amine is alkylated by the Mannich reac 29. 1-2-(4-fluorophenyl)ethyl)-4-(4-methylsul tion. The reaction proceeds in the same way as shown in fonylaminobenzoyl)piperidine, the step 12. It is also possible that the secondary amine 50 30. 4-(4-methylsulfonylaminobenzoyl)-1-(3-phenyl is used in the form of hydrochloric acid salt, not a free propyl)piperidine, acid, to produce the compound (XXV). 31. 4-(4-methylsulfonylaminobenzoyl)-1-(2thienylme The piperidine derivative obtained above can be con thyl)methylpiperidine, verted to a pharmacologically acceptable salt thereof 32. 1-2-(4-hydroxyphenyl)ethyl)-4-(4-methylsul by a conventional method. 55 fonylaminobenzoyl)piperidine, To facilitate the understanding of the present inven 33. 1,4-di (4-methylsulfonylaminobenzoyl)piperidine, tion, typical examples of the compounds of the present 34. 1-6,7-dihydro-5H-7-cyclopentab)pyridinyl-meth invention will be shown below, which by no means yl-4-(4-methylsulfonylaminobenzoyl)-piperidine, limit the invention. The compounds are shown in their 35. N-methyl-4-(4-methylsulfonylaminobenzoyl)-1-(2- free form. 60 (3-pyridyl)ethyl)piperidine, 1. 4-(4-methylsulfonylaminobenzoyl)-1-(2-(3-pyridyl)e- 36. N-butyl-4-(4-methylsulfonylaminobenzoyl)-1-2-(3- thyl)piperidine, pyridyl)ethyl)piperidine, 2. 4-(4-methylsulfonylaminobenzoyl)-1-(4-pyridyl)me 37. 4-(4-methylsulfonylaminobenzoyl)-1-1-(4-pyridyl thylpiperidine, )ethylpiperidine, 3. 4-(4-methylsulfonylaminobenzoyl)-1-3-(4-pyridyl)- 65 38. 4-(4-methylsulfonylaminobenzoyl)-1-1-phenyl-1-(4- propylpiperidine, pyridyl)methylpiperidine, 4. 1-(6-methyl-3-pyridyl)methyl-4-(4-methylsul 39. 1-2-(4-methylphenyl)ethyl)-4-(4-methylsul fonylaminobenzoyl)piperidine fonylaminobenzoyl)piperidine,
4,996,215 17 18 107. 3-(4-methylsulfonylaminobenzoyl)-1-2(3-pyridyl Compound H: 4-(4-methylsulfonylaminobenzoyl)-1-(2- )ethylpyrrolidine (2-pyridyl)ethylpiperidine dihydrochloride O8. 1-2-(6-methyl-2-pyridyl)ethyl-3-(4-methylsul Compound I: 4-(4-methylsulfonylaminobenzoyl)-1-(2- fonylaminobenzoyl)pyrrollidine (3-pyridyl)ethylpiperidine dihydrochloride 109. 1-2-(3,4-dimethoxyphenyl)ethyl)-3-(4-methylsul Compound J: 4-(4-methylsulfonylaminobenzoyl)-1-2- fonylaminobenzoyl)piperidine (4-pyridyl)ethylpiperidine dihydrochloride, and 110. 1-ethyl-4-(N-ethyl-4 -methylsulfonylaminoben Compound K: 4-(4-methylsulfonylaminobenzoyl)-1- zoyl)piperidine nicotinoylpiperidine. 11 l. l-n-butyl-4-(N-n-butyl-4-methylsulfonylaminoben Compound L(28): 4-(4-methylsulfonylaminobenzoyl)-1- zoyl)piperidine O (2-quinolylmethyl)piperidine dihydrochloride 112. 1-cyclohexylmethyl-4-(N-cyclohexylmethyl-4- Compound M(29): 4-(4-methylsulfonylaminobenzoyl)- methylsulfonylaminobenzoyl)piperidine 1-(3-quinolylmethyl)piperidine dihydrochloride 113. 1-(2-methyl-2-propenyl)-4-N-(2-methyl-2- Compound N(7): 1-2-(3-imidazo(1,2-apyridyl)-2-oxoe propenyl)-4-methylsulfonylaminobenzoyl)-piperidine thyl)-4-(4-methylsulfonylaminobenzoyl)piperidine 114. 4-(4-methylsulfonylaminobenzoyl)-1-(2-(4-methyl 15 dihydrochloride sulfonylaminophenyl)-2-oxoethyl)piperidine Compound O(30): 1-(1-imidazol,2-apyridylmethyl)-4- The piperidine derivatives obtained according to the (4-methylsulfonylaminobenzoyl)piperidine dihydro present invention prolong the refractory period by spe chloride cifically prolonging the action potential duration to Compound P(12): 1-ethyl-4-(4-methylsul prevent arrhythmia without exerting any influence on fonylaminobenzoyl)piperidine hydrochloride the myocardiac conduction velocity. These derivatives Compound Q(31): 1-(6-imidazol,2-alpyridylmethyl)-4- are antiarrhythmic agents of Class III of the above-men (4-methylsulfonylaminobenzoyl)piperidine dihydro tioned Vaughan-Williams classification. chloride The following experimental examples will further Compound R: 4-(4-methylsulfonylaminobenzoyl)-1-(3- illustrate the effects of the compounds of the present 25 (4-pyridyl)propyl)piperidine dihydrochloride invention. Compound S: 1-(2-(6-methyl-2-pyridyl)ethyl)-4-(4- methylsulfonylaminobenzoyl)piperidine dihydro EXPERIMENTAL EXAMPLE 1 chloride; Effects on the action potential duration in the isolated myocardium of guinea-pigs 30 TABLE 10-6 M 10-5 M Right ventricular papillary muscles were isolated APD90 Vmax APD90 Vmax from male guinea-pigs of Hartley strain weighing 300 to Test prolongation inhibition prolongation inhibition 400 g and fixed at the botton of an acrylic bath with Compound (%) (26) (%) (%) pins. They were perfused with Tyrode solution kept at 35 A. 0 O 7 O 37 C. and saturated with a mixture of 95% O2 and 5% B 26 O 34 9 C 7 O 15 O CO2. The muscles were stimulated at 1 Hz with rectan D 3 O 10 O gular pulses of 1 msec duration and supramaximal volt E 2 O 4. O age. Action potentials were recorded using conven F 8 O l O tional glass microelectrodes filled with 3M KCI. The 40 G 18 O 33 O H 2 O 5 O duration of the action potential and the maximum veloc O O 7 O ity of the upstroke of the action potential (Vmax) were J 4. O O O determined. Each of the test compounds was included K 9 O 24 14 in Tyrode solution at 10-6 or 10-5M and perfused. The R 8 O 27 O effects of the 10-6M solution was observed for the first S 20 O 30 O 45 Sotaol O O 7 O 10 min, then those of the 105M solution were observed L 18 O 26 2 for another 10 min. M 3 O 5 O The results are shown in Table 1. The test com N 8 O 8 O O 6 O 2 5 pounds shown in Example were as follows. Sotalol, a P 7 O 23 2 beta-adrenoceptor antagonist was employed as the ref. SO Q 4. O 23 O erence drug because this compound is known to pro long the duration of the myocardial action potential. Test compound Compound A: 1-benzyl-4-(4-methylsulfonylaminoben EXPERIMENTAL EXAMPLE 2 zoyl)piperidine hydrochloride 55 Effects on QTc-interval of ECG in anesthetized dogs Compound B: 4-(4-methylsulfonylaminobenzoyl)-1-(2- Mongrel dogs were anesthetized with enflurane. The phenylethyl)piperidine hydrochloride chest was opened at the fifth intercosta and the pericar Compound C: 1-2-(4-chlorophenyl)ethyl)-4-(4-methyl dium was incised to expose the left ventricle. A mono sulfonylaminobenzoyl)piperidine hydrochloride polar electrode fixed on an acrylic plate was sutured to Compound D: 1,4-di(4-methylsulfonylaminobenzoyl)- 60 a ventricular surface of the region where the left ante piperidine hydrochloride rior descending branch of the coronary artery was dom Compound E: 1-2-(3,4-dimethoxyphenyl)ethyl)-4-(4- inant. The electrocardiogram was recorded from the methylsulfonylaminobenzoyl)piperidine hydrochlo surface of the left ventricle through the electrode. Test ride compounds were injected through a catheter inserted Compound F: 4-(4-methylsulfonylaminobenzoyl)-1-(2- 65 into a forearm vein. (2-thienyl)ethylpiperidine methylsulfonate Compound B caused a 51% prolongation of QTc Compound G: 4-(4-methylsulfonylaminobenzoyl)-1-(4- interval (i.e. from 435 to 665 msec) at 0.1 mg/kg. Com pyridyl)methylpiperidine dihydrochloride pound G produced 17, 27 and 35% prolongation of 4,996,215 19 20 QTc-interval at 0.1, 0.3 and 1 mg/kg, respectively. of arrhythmias including ventricular and atrial (su When the test compound J was injected at 0.1 and 0.3 praventricular) arrhythmias. The compounds of the mg/kg, QTc-interval was prolonged by 21 and 42%, present invention are especially expected to control respectively. 5 recurrent arrhythmias and prevent sudden death due to When the test compound L was used, the QTc pro the ventricular fibrillation. longation of 31% with 0.1 mg/kg and 56% with 0.3 The compounds of the present invention can be used mg/kg thereof were recognized. When the test com either orally or parenterally (intramuscular, subcutane pound M was used, the QTc prolongation of 7% with ous or intravenous injection). The dose is not particu 0.1 mg/kg, 13% with 0.3 mg/kg and 21% with 1.0 10 larly limited, since it varies depending on the type of the mg/kg thereof were recognized. When the test com arrhythmia, symptoms, age, condition and body weight pound P was used, the QTc prolongation of 7% with of the patient. In case when used in combination with 0.1 mg/kg and 14% with 0.3 mg/kg thereof were rec other drugs or treatments, it also depends on the kind, ognized. The administrations of 0.03 mg/kg and 0.1 15 frequency and intended effects of the drug or the treat mg/kg of the compound R were found to provide 13% ment. The usual oral dose for the adults dose is esti prolongation and 21% prolongation of QTc-interval, mated to be 1 to 100 mg/day, preferably 5 to 50 mg/day respectively. As to the compound S, the administrations and particularly 5 to 15 mg/day. The administration of 0.01 mg/kg and 0.03 mg/kg were found to provide will be made once a day or more. In the case of injec 30% prolongation and 42%. With 1.0 mg/kg of Sotanol 20 tion, the dose is estimated to be 0.0l to 1 mg/kg, prefer used as a control, 12% prolongation was observed. ably 0.03 to 0.1 mg/kg. EXPERIMENTAL EXAMPLE 3 The compound of the present invention can be given Acute toxicity in mice in the form of, for example, powders, finely divided 25 particles, granules, tablets, capsules suppositories and Male ddy mice weighing 20 to 30 g were used for the injections. The preparations are produced by an ordi acute toxicity test. LD50 values were calculated by the nary process by using an ordinary carrier. up-and-down method. The compounds G, J, M, N, O, R More particularly, for example, an oral solid prepara and sotalol were dissolved in saline to obtain 16 mg/ml 30 tion is produced by adding an excipient and, if neces stock solution. Administration of 0.1 ml of the solution sary, a binder, disintegrator, lubricant, colorant, corri to 10 g body weight of the animal corresponds to 160 gent, etc. to the active ingredient and the mixture is mg/kg of the sample. The compounds B, F, L and S shaped into tablets, coated tablets, granules, powder, (the free body) were each dissolved in 20% polye capsules, etc. thyleneglycol to obtain stock Solutions having a con 35 centration of 8 mg/ml. The dose to be administered was Examples of the excipients include lactose, corn determined on the basis of the volume of the stock starch, white sugar, glucose, sorbitol, crystalline cellu lose and silicon dioxide. Examples of the binders in solution. The solutions were injected into a tail vein by clude polyvinyl alcohol, polyvinyl ethers, ethylcellu means of a 1-ml tuberculin syringe. The judgement of lose, methylcellulose, acacia gum, tragacanth, gelatin, survival or death was made 30 min after each injection. 0 shellac, hydroxypropylcellulose, hydroxypropylstarch The results are shown in Table 2. and polyvinylpyrrollidone. Examples of the disintegra TABLE 2 tors include starch, agar, gelatin powder, crystalline Compound LD50 (iv) mg/kg cellulose, calcium carbonate, sodium hydrogencarbon B 00 45 ate, calcium citrate, dextrin and pectin. Examples of the F 112 lubricants include magnesium stearate, talc, polyethyl G 108 195 ene glycol, silica and hardened vegetable oils. The col L 112 orants are those acceptable as additives for medicines. M 112 50 Examples of the corrigents include cocoa powder, men N 224 thol, aromatic acids, peppermint oil, borneol and cinna O 302 R 138 mon powder. As a matter of course, these tablets and S 12 granules may be coated suitably with sugar, gelatin or Sotalo 113 55 the like. In the production of the injection, a pH adjustor, It is apparent from the above Experimental Examples buffer, stabilizer, solubilizer, etc. are added, if neces 1 and 2 that the compounds of the present invention sary, to the active ingredient and an intravenous injec have the pharmacological properties required for the tion is produced by an ordinary method. antiarrhythmic agents of Class III, namely the prolon 60 The following examples will further illustrate the gation of the myocardial action potential in vitro with present invention, which by no means limit the present out a significant depression of the Vmax and the prolon invention. gation of QTc-interval in anesthetized dogs. Moreover, The final step in the production of the intended con their effects were much more potent than the reference 6s pound of the present invention will be shown in the drug, Sotalol. following examples and the production of the starting It is expected that the compounds of the present in materials used in the examples will be shown in the vention are effective in treating and preventing all types following referential examples. 4,996,215 21 22
Process for the preparation (CH2)n n = 1 - 3 n = 1 - 2 HOC- NH O I (CH2) R-S-NH O R = Me, CH3
Step I
N1NR, R2 = -CH3
Step II
O
N l R2
Step III
O O (CH2) O O O N/- Step IV % R-S-NHI / N-( --GeR-S-NHreduction I CH2 N O (CH2) R2 O R2
Step V
O (CH2) O N R-S-NH X-( NH.HCl x = -C-, -CH2 / O (CH2)
Step VI
O (CH2) "n R-S-NH| x-( / N-Y O (CH2)
3N Elementary analysis for C13H8N2O4S.HCl: O O hydrochloric C H N CH3SONH N ( acid-e 55 calculated (%) 46.64 5.72 8.37 found (%) 46.7 5.97 8.30 CH 3
O 60 EXAMPLE 4 CH3SONH NHHC 4-(2-Methoxy-4-methylsulfonylaminobenzoyl)piperi dine hydrochloride Melting point (C.): >220 (decomp.) 4-(4-Methylsulfonylaminobenzoyl)piperdine 65 NMR (90 MHz, DMSO-d6) 8: 1.5-2.1 (4H, m), 3.12 hydrochloride (3H, s), 3.88 (3H, s), 6.86 (1H, dd, J = 8, 2 Hz), 6.96 (1H, 43.4 g (0.142 mol) of l-acetyl-4-(4-methylsul d, J = 2 Hz), 7.58 (1H, d, J =8 Hz), 9.0 (2H, br, D2O fonylaminobenzoyl)piperidine was suspended in 1 l of exchange), 10.32 (1H, s, D2O exchange). 4,996,215 27 28
O 3N hydrochloric O CH3SONH I - acid-e CH3SO;NH N NH.HCl I O
C H N 15 (+)-3-(4-Methylsulfonylaminobenzoyl)piperidine calculated (%) 48.20 5.78 8.03 hydrochloride found (%) 48.32 5.93 7.81 5.70 g (14.8 mmol) of (+)-1-benzoyl-3-(4-methylsul The same procedure as above was repeated except fonylaminobenzoyl)piperidine obtained in Referential that 1-acetyl-4-(4-methylsulfonylaminobenzoyl)piperi- 20 Example 3 was dissolved in a mixture of 120 ml of 5N dine was replaced with 1-acetyl-4-(4-p-toluenesul hydrochloric acid and 80 ml of methanol and the ob fonylaminobenzoyl)piperidine or 1-acetyl-4-(4-methyl tained solution was refluxed for 8 h. The reaction solu sulfonylaminobenzyl)piperidine to obtain the following tion was concentrated and the obtained solid residue was recrystallized from ethanol to obtain 2.61 g (yield: compounds: 55%) of the intended compound in the form of white EXAMPLE 5 crystals. Melting point: 235 to 237 C. NMR (90 MHz, DMSO-de) 8 1.4-2.2 (4H, m) 2.6–4.1 (5H, m) 3.11 (3H, s) 7.35 (2H, d, J = 8 Hz) 7.98 (2H, d, CH3 SO-NH C NH J=8 Hz) 8.0-8.5 (2H, br) 10.48 (1H, brs).
Elementary analysis for C3H18N2O3S.HCl: 4-(4-p-toluenesulfonylaminobenzoyl)piperidine C H N hydrochloride calculated (%) 48.98 6.0 8.79 Melting point: 240 to 242 C. 35 found (%) 48.86 5.87 8.77 NMR (90 MHz, DMSO-d6) 8 1.6-2.1 (4H, m) 2.5-3.8 (5H, m) 2.36 (3H, s) 7.24 (2H, d, J = 8 Hz) 7.36 (2H, d, EXAMPLE 8 ar t; 6. a- Hz) 7.90 (2H, d, J = 8 Hz) 9.0 The same procedure as in Example 7 was followed except that (h)-1-benzoyl-3-(4-methylsul fonylaminobenzoyl)piperidine was replaced with Elementary analysis for C19H22N2O2S.HCl, H2O: (h)-1-benzoyl-3-(4-methylsulfonylaminobenzoyl)pyr C H N rolidine to obtain the following compound: also (%) : 3. 3. 45 (+)-3-(4-Methylsulfonylaminobenzoyl)pyrrolidine hydrochloride Melting point: 198' to 200 C. EXAMPLE 6 NMR (90 MHz, DMSO-d6) 8 1.7-2.5 (2H, m) 3.0-3.8 (4H, m) 3.14 (3H, s)4.20(1H, q-like, J.7 Hz)7.36 (2H, d, J =8 Hz) 8.01 (2H, d, J = 8 Hz) 9.5 (2H, br) 10.26 (1H, s).
co-o-o-O)-al-O Elementary analysis for C12H16N2O3S.HCl: 55 C H N 4-(4-Methylsulfonylaminobenzyl)piperidine calculated (%) 47.29 5.62 9.9 hydrochloride found (%) 47.7 5.49 9.1 Melting point: 255 to 257 C. NMR (90 MHz, DMSO-d6) 8 1.2-2.0 (5H, m) 2.94 60 EXAMPLE 9 (3H,3H, s) 7.14 (4H, s) 9.0 ((2H, br)r) 9.67 (1H, s)s). N-Methyl-4-(4-methylsulfonylaminobenzoyl)piperidine- - - - hydrochloride Elementary analysis Cutlans HCl 1.43 g (yield: 90%) of the intended compound was H N 65 obtained from 1.90 g of 1-acetyl-N-methyl-4-(4-methyl calculated (%) 5.22 6.94 9.9 sulfonylaminobenzoyl)piperidine prepared in Referen found (%) 51.26 6.86 9. 16 tial Example 4. Melting point (C): 254 to 255. 4,996,215 29 30 NMR (90 MHz, DMSO-d6) 8: 1.5-2.1 (4H, m), 3.04 (3H, s), 3.32 (3H, s), 7.57 (2H, d, J=8 H2), 8.06 (2 H, d, J=8H2), 8.8-9.6 (2H, br, D2O exchange). Elementary analysis for C20H2S.N.O.S.2HC C H N calculated (%) 52.7 5.91 9.13 Elementary analysis for C14H2ON2SO3.HCl: found (%) 52.00 5.86 8.83 C H N calculated (%) 50.50 6.37 8.42 found (%) 50.43 6.42 8.39 EXAMPLE 12 4-(4-Methylsulfonylaminobenzoyl)-1-3-(4-pyridyl)- EXAMPLE 10 propylpiperidine dihydrochloride 0.295 g (0.926 mmol) of 4-(4-methylsul 4-(4-Methylsulfonylaminobenzoyl)-1-(4-pyridylme fonylaminobenzoyl)piperidine hydrochloride and 0.380 thyl)piperidine dihydrochloride g (4.52 mmol) of sodium hydrogencarbonate were sus 1.13 g (18.8 mmol) of sodium methoxide was added to 15 pended in 4 ml of dimethylformamide and the suspen a suspension of 3.0 g (9.4 mmol) of 4-(4-methylsul sion was stirred at 85 C. for 40 min. 0.20 g (1.04 mmol) fonylaminobenzoyl)piperidine hydrochloride and 1.55g of 4-(3-chloropropyl)pyridine hydrochloride and 0.31 g (9.4 mmol) of 4-chloromethylpyridine hydrochloride in (1.87 mmol) of potassium iodide were added to the 90 ml of acetonitrile. The mixture was stirred at room suspension and the mixture was stirred at 85°C. for 1.5 temperature for 10 min. 2.88 g of potassium carbonate 20 h. The liquid reaction mixture was filtered and the fil was added to the mixture and the obtained mixture was trate was concentrated. The obtained residue was puri refluxed for 3 h. After cooling, the liquid reaction mix fied according to silica gel column chromatography ture was filtered and the filtrate was concentrated, (chloroform:methanol:aqueous ammonia = 96:4:0.4). while the residue was purified according to silica gel The purified product was converted into its hydrochlo chromatography (chloroform:methanol =95:5). The 25 ride with ethanolic hydrogen chloride and recrystal product was converted into its hydrochloride with lized from ethanol to obtain 0.288 g (66%) of the in ethanolic hydrogen chloride and recrystallized from tended compound. methanol/isopropanol to obtain 1.4 g of the intended Melting point: 230 C, (decomp.). compound: 30 NMR (100 MHz, DMSO-d6) 8 1.8-2.4 (6H, m) 3.10 Melting point: ~ 207 C. (decomp.). (3H, s) 7.30 (2H, d, J = 8 Hz) 7.95 (2H, d, J =8 Hz) 7.97 NMR (400 MHz, DMSO-ds) 8: 1.85-2.30 (4H, m), (2H, d, J = 6 Hz) 8.83 (2H, d, J = 6 Hz) 10.44 (1H, brs, 3.11 (3H, s), 4.53 (2H, s), 7.31 (2H, d, J = 8.8 Hz), 7.98 D2O exchange) 10.9-11.4 (1H, br, D2O exchange); (2H, d, J = 8.8 Hz), 8.17 (2H, d, J = 4.9 Hz), 8.92 (2H, d, J=5.9 Hz), 10.41 (1H, s, D2O exchange), 11.6- 12.0 (1H, brs, D2O exchange). 35 Elementary analysis for C2H27NO2S.2HC C H N calculated (%) 53.16 6, 16 8.86 Elementary analysis for C19H23NO S.2HCl: found (%) 52.95 6.10 8.73
calculated (%) 51.2 5.64 9.4 40 found (%) 5.04 5.4 9.28 EXAMPLE 13 1-2-(6-Methyl-2-pyridyl)ethyl)-4-(4-methylsul EXAMPLE 11 fonylaminobenzoyl)piperidine dihydrochloride 4-(4-Methylsulfonylaminobenzoyl)-1-(2-(3-pyridyl)e- 45 0.254 g (0.797 mmol) of 4-(4-methylsulfor thyl)piperidine dihydrochloride nylaminobenzoyl)piperidine hydrochloride, 0.22 g (1.88 mmol) of 6-methyl-2-vinylpyridine and 0.15g of sodium 35 g (0.10 mol) of 4-(4-methylsulfonylaminoben acetate were suspended in 3 ml of a mixture of methanol zoyl)piperidine hydrochloride and 55 g of potassium and water (1:1) and the suspension was refluxed for 2 h. carbonate were suspended in 700 ml of dimethylform SO The liquid reaction mixture was filtered and the filtrate amide and the suspension was stirred at 40 C. for 20 was concentrated. The obtained residue was purified min. 19.6 g (0.101 mol) of 3-(2-chloroethyl)pyridine according to silica gel column chromatography (chlo hydrochloride and 6.0 g (0.036 mol) of potassium iodide roform:methanol:aqueous ammonia = 96:4:0.4). The pu were added to the suspension and the mixture was rified product was converted into its hydrochloride stirred at 90° C. for 3.5 h. The liquid reaction mixture 55 with ethanolic hydrogen chloride and recrystallized was filtered and the filtrate was concentrated, while the from ethanol to obtain 0.285 g (yield: 81%) of the in residue was purified according to silica gel chromatog tended compound. raphy (chloroform:methanol =93:7). The purified prod Melting point: 219 C. (decomp.). uct was converted into its hydrochloride with ethanolic NMR (90 MHz, DMSO-d6) 8 1.6-2.4 (4H, m) 2.74 hydrogen chloride and recrystallized from methanol 60 (3H, s) 3.12 (3H, s) 7.33 (2H, d, J = 8 Hz) 7.70 (1H, d, /isopropanol to obtain 13.4 g of the intended com J=7 Hz) 7.78 (1H, d, J = 7 Hz) 8.02 (2H, d, J = 8 Hz) pound. 8.33 (1H, t, J-7 Hz) 10.47 (1H, s, D2O exchange) 11.2 Melting point (C.): 200 to 203. (1H, br, D2O exchange). NMR (100 MHz, DMSO-de) 8: 1.8-2.3 (4H, m), 3.11 (3H, s), 7.32 (2H, d, J =8 Hz), 7.90-8.10 (3H, m), 8.50 65 (1H, dt, J = 6, 2 Hz), 8.8 (1H, d, J = 6 Hz), 8.93 (1H, d, Elementary analysis for C2H27.N.O.S.2HCl J= 2 Hz), 10.43 (1H, s, D2O exchange), 10.90 - 11.40 C H (1H, br, D2O exchange). calculated (%) 53.6 6.16 8.86 4,996,215 31 32 -continued NMR (90 MHz, DMSO-d6) 8 1.4-1.9 (4H, m) 2.18 (2H, m) 2.4-3.6 (7H, m) 3.10 (3H, s) 6.80 (1H, dt, J = 5.2 Elementary analysis for C21H27N3O3S.2HCl Hz) 7.04-7.34 (4H, m) 7.72 (1H, s) 7.95 (2H, d, J = 8 Hz) C H N 8.45 (1H, d, J = 7 Hz). found (%) 52.94 6.16 8.73 5 Elementary analysis for C22H26N4OS EXAMPLE 1.4 C H N 4-(4-Methylsulfonylaminobenzoyl)-1-2-(4-pyridyl)e- calculated (%) 6.95 6.14 3.14 thyl)piperidine- dihydrochloride O foundound (%)(% 61.92 6.10 12.92 (another process for synthesizing the compound of Example 29) EXAMPLE 6 10.0 g (31.4 mmol) of 4-(4-methylsulfonylaminoben zoyl)piperidine hydrochloride was suspended in 20 ml 15 Bt of an aqueous solution of 1.32 g of sodium hydroxide 2O and the suspension was stirred at room temperature for 1 h. The formed solid was filtered, washed with water / 1N and dried to obtain 8.28 g of crystals, which were sus pended in a solution comprising 15 ml of water, 15 ml of 20 O 1. 21 methanol and 0.2 ml of acetic acid. 3.39 g of 4-vinylpyri- CHSONH NH-N-S-> dine was added to the suspension and the mixture was refluxed for 10 h. After cooling, the formed crystals were filtered and converted into its hydrochloride with HCl ethanolic hydrogen chloride to obtain 7.54 g of the 25 intended compound. The melting point and NMR signals of this com- / \ pound coincided with those of the compound produced from 4-(4-methylsulfonylaminobenzoyl)piperidine hy- N drochloride and 4-(2-chloroethyl)pyridine in Example 30 O ~-s- N 29 in the same manner as in Example 13. CH3SONH N N
O 1 C N 2 CH3SO2NH NH - Nico - >
HC
N 1 N CH3SO2NH / Y-Nu.N N 2
1-(2-(2-Imidazo[1,2-alpyridyl)ethyl)-4-(4-methylsul fonylaminobenzoyl)piperidine A mixture of 1.02 g (3.2 mmol) of 4-(4-methylsul 1-2-(3-Imidazol,2-alpyridyl)-1-oxoethyl)-4-(4-methyl fonylaminobenzoyl)piperidine hydrochloride, 1.34 g of 55 sulfonylaminobenzoyl)piperidine dihydrochloride sodium hydrogencarbonate and 10 ml of dimethylform- (i) 22.1 g of 3-acetylimidazol,2-alpyridine was dis amide was stirred at 80° C. for 1 h. 0.48g of 2-(2-chloro- solved in 220 ml of acetic acid. 35.1 ml of a 30% hydro ethyl)imidazol,2-alpyridine hydrochloride and 0.53 g gen bromide/acetic acid solution was added dropwise of potassium iodide were added thereto and the mixture to the solution at 0° C. Then 28.6 g of bromine was was stirred at 80 C. for 2 h. The mixture was filtered 60 added dropwise thereto at 40 C. The mixture was and the filtrate was concentrated to obtain a solid resi- stirred at 40 C. for 2 h and crystals thus formed were due, which was then purified according to silica gel filtered. The crystals were dissolved in 100 ml of water. column chromatography (chloroform:methanol:aque- The solution was made alkaline with an excess of an ous ammonia = 190:9:1). The fraction of the intended aqueous sodium hydrogencarbonate solution and then compound was concentrated to obtain a solid residue, 65 extracted with ethyl acetate. The organic layer was which was then recrystallized from ethyl acetate to concentrated and the obtained brown solid was purified obtain 0.25 g (yield: 18%) of the intended compound. according to silica gel column chromatography (eluted Melting point: 190° to 191° C. with ethyl acetate) to obtain 13.5 g (yield: 40%) of 4,996,215 33 34 3-bromoacetylimidazol,2-apyridine (yield: 40%) in was converted into its dioxalate with 0.32 g of oxalic the form of yellow crystals. acid in ethanol. After recrystallization from methanol (ii) A suspension comprising 1.91 g (6.0 mmol) of /ethanol, 0.40 g (yield: 10%) of the intended compound 4-(4-methylsulfonylaminobenzoyl)piperidine hydro was obtained. chloride, 3.0 g of potassium carbonate and 40 ml of 5 Melting point: 214 to 216 C. dimethylformamide was stirred at 80° C. for 1 h. After NMR (90 MHz, DMSO-de) 8 1.4-2.3 (8H, m) 2.4-3.6 cooling to room temperature, 1.99 g of 3 (13H, m) 3.08 (3H, s) 7.21 (2H, d, J = 8 Hz) 7.88 (2H, d, bromoacetylimidazo(1,2-alpyridine prepared in the J=8 Hz). above step (i) was added thereto and the mixture was stirred at room temperature for 6 h. The reaction mix- 10 ture was filtered and the filtrate was concentrated to Elementary analysis for C19H29N2O3S.2(CCOH)2 obtain a solid residue, which was then purified accord C H N ing to silica gel column chromatography (chloroform calculated (%) 49,37 5.94 7.5 :methanol = 96:4). The purified product was converted found (%) 49.40 5.85 7.37 into its dihydrochloride with ethanolic hydrogen chlo 15 ride and recrystallized from methanol/acetone to obtain 1.75 g (yield: 58%) of the intended compound. (STEP VI, PART 3> EXAMPLE 1.7 1-(5-Methyl-2-furanyl)methyl-4-(4-methylsul O CH3SONH NH (1) NaOH ad. G (2) 1N-N HCl H Cl KI (3) (COOH)2 N1N-N 20COOH) 4-(4-Methylsulfonylaminobenzoyl)-1-(2-(1-pyr fonylaminobenzoyl)piperidine rolidinyl)-ethyl)piperidine dioxalate 1.88 ml of formalin and 1.07 g of methylfuran were 10.0 g (31.4 mmol) of 4-(4-methylsulfonylaminoben added to a mixture of 4.43 g (15.7 mmol) of 4-(4-methyl zoyl)piperidine hydrochloride was suspended in 20 ml 55 sulfonylaminobenzoyl)piperidine in free form obtained of an aqueous solution of 1.32 g of sodium hydroxide in Example 17, 1.57 ml of glacial acetic acid and 10 ml and the suspension was stirred at room temperature for of water and the obtained mixture was stirred at 90° C. 1 h. The formed crystals were filtered, washed with for 2 h. After cooling, the mixture was neutralized with water and dried to obtain 8.28 g of 4-(4-methylsul a 20% aqueous sodium hydroxide solution and ex fonylaminobenzoyl)piperidine in free form. A mixture 60 tracted with dichloromethane. The organic layer was of 2.0 g (7.09 mmol) of the obtained crystals, 1.57 g of washed with water and a saturated aqueous common chloroethypyrrolidine hydrochloride, 2.35 g of potas salt solution, dried over magnesium sulfate and concen sium iodide and 40 ml of dimethylformamide was trated. The solid residue was recrystallized from stirred at 80° C. for 3 h. The reaction mixture was fil ethanol/methanol to obtain 4.16 g (yield: 70%) of the tered and the filtrate was concentrated to obtain a solid 65 intended compound. residue, which was then purified according to silica gel Melting point: 181 to 182 C. column chromatography (chloroform:methanol:aque NMR (90 MHz, DMSO-d6) 8 1.3-1.9 (4H, m) 1.9-2.3 ous ammonia=90:9:1). 0.68 g of the purified product (2H, m) 2.23 (3H, d, J = 1 Hz). 2.6-3.4 (3H, m) 3.10 (3H, 4,996,215 35 36 s) 3.43 (2H, s) 5.97 (1H, m) 6.13 (1H, d, J =3 Hz) 7.28 -continued (2H, d, J = 8 Hz) 7.94 (2H, d, J =8 Hz). CO O Elementary analysis for C19H24N2O4S 5 CH3SO2N N-Et C H N Et calculated (%) 66.62 6,43 7.44 (Fraction 1) found (%) 60.43 6.46 744 EXAMPLE 20 AND 21 N CH3SO2NH O NH.HCl (OIO)to H2O-EtOH N CH3SO2NH / N suOIO)N piperidine 30 A suspension comprising 2.54 g (7.97 mmol) of 4-(4- methylsulfonylaminobenzoyl)piperidine hydrochloride, 4-(4-Methylsulfonylaminobenzoyl)-1-(2-(2-quinox 5.0 g of potassium carbonate and 40 ml of dimethyl alinyl)ethyl)piperidine formamide was stirred at 80 C. for 1 h. 1.3 g (8.3 mmol) 5.0 g (15.7 mmol) of 4-(4-methylsulfonylaminoben 35 of ethyl iodide was added thereto and the mixture was zoyl)piperidine hydrochloride was suspended in 5 ml of stirred at 80° C. for 12 h. The mixture was filtered and ethanol. 2.49 g of 2-methylduinoxaline and 7.0 ml of the filtrate was concentrated to obtain a solid residue, formalin were added to the suspension and the mixture which was then purified according to silica gel column was stirred at 90° C. for 1 h. After cooling, the mixture chromatography (chloroform:methanol:aqueous am was neutralized with a 20% aqueous sodium hydroxide 40 monia = 190:9:1). The respective fractions were concen solution and the formed crystals were recrystallized trated to obtain a solid residue, which was then con from ethyl acetate to obtain 0.32 g (yield: 5%) of the verted into its hydrochloride with ethanolic hydrochlo intended compound. ric acid and recrystallized from methanol/ethyl acetate Melting point: 156 to 157 C. to obtain the intended compound. NMR (90 MHz, DMSO-d6) 8 1.4-2.0 (4H, m) 2.0-2.4 45 EXAMPLE 20 (2H, m) 2.6-3.5 (7H, m) 3.13 (3H, s) 7.31 (2H, d, J = 8 1-Ethyl-4-(N-ethyl-4-methylsulfonylaminobenzoyl)- Hz)7.73-8.15 (6H, m) 8.91 (1H, s). piperidine hydrochloride: 0.23g Melting point: 188 to 191° C. Elementary analysis for C23H26N4O3S 50 NMR (90 MHz, DMSO-d6) 1.04 (3H, t, J = 7H2) 1.28 C H (3H, t, J=7H2) 1.65-2.30 (4 H, m) 2.60-3.95 (7H, m) calculated (%) 62.99 5.98 12.78 3.05 (3H, s) 3.78 (2H, q, J=7H2) 7.57 (2H, d, J =8H2) found (%) 62.83 5.95 2.61 8.06 (2H, d, J =8H2). 55 Elementary analysis for C17H26N2O3S.HCl Elementary analysis for CH27N3OS.2HC 35 EXAMPLE 25 N-Methyl-4-(4-methylsulfonylaminobenzoyl)-1-(2-(3- calculated 53.6 6.6 8.86 pyridyl)ethylpiperidine dihydrochloride found 53.37 6.2 8.65 (another process for synthesizing the compound of 40 Example 22) 0.8 g (2.7 mmol) of N-methyl-4-(4-methylsul EXAMPLE 23 fonylaninobenzoyl)piperidine dihydrochloride, 0.52g N-Butyl-4-(4-methylsulfonylbenzoyl)-1-(2-(3-pyridyl)e- (2.7 mmol) of 3-(2-chloroethyl)pyridine hydrochloride, thylpiperidine dihydrochloride 3.0 g of potassium carbonate and 0.2 g of potassium 45 iodide were dissolved in 15 ml of dinnethylformamide The same procedure as in Example 22 was repeated and the solution was stirred at 90° C. for 3.5 h. After except that methyl iodide was replaced with n-butyl cooling, an inorganic matter was filtered out and the iodide and the obtained product was purified according filtrate was concentrated to obtain a residue, which was to silica gel chromatography to obtain the intended purified according to silica gel chromatography (chlo compound having the following physical properties: 50 roform:methanol =97:3). The purified product was con Melting point (C): 110 to 111 verted into its hydrochloride in an ordinary manner to NMR (90 MHz, CDCl3) 8: 0.88 (3H, t), 1.2-3.3 obtain 0.6 g of the intended compound. The melting (19H, m), 2.88 (3H, s), 3.73 (2H, T, J = 8Hz), 7.2 (1H, q, point and NMR signals of this product coincided with those of the compound obtained in Example 22. J = 6. 6Hz), 7.46 (2H, d, J = 8Hz), 7.5 - 7.64 (1H, m), 55 7.98 (2H, d, J = 8Hz), 8.46 (1H, dd, J = 2, 6Hz), 8.5 (1H, EXAMPLE 26 to 115 d, J = 2Hz). Each compound listed in Tables 3 to 12 was obtained from the piperidine compound, the pyrrolidine com Elementary analysis for C24H3NiOS pound and a halide compound thereof shown in Refer 60 ential Examples 3 to 5 in the same way as shown in C H N Examples 1 to 25. calculated 76 6497 7.5 9.47 A variety of compounds of the invention was ob found (%) 64.90 7.4 9.43 tained, including a heterocyclic ring or a condensed aromatic ring. 65 4,996,215 SS 56 I.ponunuoo-9aTav H Z? S? Ll 4,996,215 67 68 TABLE 12-continued O CH3SO2NH N-Y melting structural elementary Example Y point formula analysis H NMR 113 -205 C22H28N2O3S 60.47 6.69 6.41 (90MHz, DMSO-de) 8 1.63-2.20 (4H, m) A. (decomp.) .HCl 60.33 6.636.52 2.30 (3H, s) 2.61-3.90 (9H. m) 3.12 (3H, s) -(CH2)2 HC) 6.96-7.25 (4H, m) 7.34 (2H, d, J = 8.8) 8.01 (2H, d, J = 8.8) CH3 14 178-180 C24H31N3O3S 65.287.089.52 (90MHz, DMSO-d6) 8 1.35 - 2.03 (8H, m) 64.956.879.62 2.03 - 3.40 (10H, m) 2.98 (3H, s) 6.97 -CH (1H, dd, Js 7.7, 4.6) 7.12-7.38 (3H, m) 7.81 (2H, d, J = 8.8) 8.26 (1H, dd, J = 4.6, 1.6) NO 115 O H 257-259 C23H26N4O5S 57.61 5.67 1.68 (90MHz, DMSO-d6) 8 1.38 - 1.93 (4H, m) W N .H2O 57.54 5.47 11.67 1.99 -2.37 (2H, m) 2.43-3.51 (5H, m) /- 3.11 (3H, s) 4.04 (2H, brt, J = 7) 7.08-7.32 (CH2)2-N d,(4H, J = m) 8.8) 7.66 (iH, t, J = 7.5) 7.94 (3H, M O What is claimed is: tinued 1. A compound having the formula -COe 35 R (CH2)g Rl-S-N X-( N-A-B I / or -N. O (CH2)h 40 R2 in which R1 is a lower alkyl or a tolyl; R2 is hydrogen, hydroxyl, a lower alkoxy or a lower alkyl; R is hydro gen, a lower alkyl, a lower alkenyl, a cycloalkyl or a cycloalkylalkyl; X is -CO-, -CH2- or -CHOH-; 4 s where R7 and Reach are hydrogen, a halogen, a lower g is an integer of 1, 2 or 3; h is an integer of 1, 2 or 3, alkyl, a lower alkoxy or methanesulfonamido and R1 is with the proviso that the sum of g plus h equals the hydrogen or a lower alkyl, or pharmaceutically accept integers 3 or 4: A is (1) alkylene having 1 to 5 carbon able salts thereof. atoms, (2) straight-chain alkylene having 1 to 5 carbon 2. A compound according to claim 1, wherein X is a atoms in the chain and substituted with lower alkyl, so group of the formula: -CO-. phenyl or hydroxyl, (3) straight-chain alkenylene hav- ' 3. A compound according to claim 1, wherein X is a ing 2 to 5 carbon atoms, (4) -(CH2)k-S-, wherein k group of the formula: is an integer of 2 to 5, or (5)-(CH2)CO-, wherein p is an integer of 1 to 4, and B is OH 55 -CO 4. A compound according to claim 1, wherein A is (1) alkylene having 1 to 5 carbon atoms. 5. A compound according to claim 1, wherein B is a - CO 60 group of the formula: - IJ? C. 65 4,996,215 69 70 6. A compound according to claim 1, wherein X is a 7. A compound according to claim 1, which is 1-2- group of the formula: -CO-, A is (1) alkylene having (3,4-dimethoxyphenyl)ethyl-4-(4-methylsul 1 to 5 carbon atoms and B is a group of the formula fonylaminobenzoyl)piperidine. 8. A compound according to claim 1, which is 4-(4- methylsulfonylaminobenzoyl)-1-(2-phenylethyl)piperi dine. 9. A pharmaceutical composition which comprises a pharmacologically effective amount of the compound defined in claim 1 or a pharmacologically acceptable O salt thereof and a pharmacologically acceptable carrier. k k : s: k 15 20 25 30 35 40 45 50 55 60 65