Patent EA-003053-B1 (EA)
Title: New substituted pyridine or piperidine compounds, a process for their preparation and pharmaceutical compositions containing them
Inventor: METH-COHN OTTO
IPC: C07D213/36
Filed: 2000-05-04
Abstract: 1. The compound of formula (I):   wherein A represents pyridine, pyridinium or piperidine group; R2 represents a hydrogen atom and R3 represents hydroxyl, or R2 and R3 together form an oxo group; R4 represents unsubstituted or substituted phenyl, unsubstituted or substituted naphtyl, or unsubstituted or substituted heteroaryl; R1 represents a hydrogen atom; or R1 and R4 together with two carbon atoms which carry them form a cycle, which comprises 6 carbon atomes; or R1 and R2 form supplementary bond and, in this case, R3 represents a heterocycle which contains 5- or 6- members, which contains a nitrogen atom via which it is attached and which can contain other heteroatom, selected from sulfur, oxygen and nitrogen; R5 represents a 5- or 6- membered heterocycle, which contains a nitrogen atom via which it is attached to cycle A and which can contain other heteroatom, selected from sulfur, oxygen and nitrogen; a group of formula (II):   wherein R'1, R'2, R'3 and R'4 can have the same values as R1, R2, R3 and R4, correspondingly; or hydrogen atom, and in such case, R4 can not represent unsubstituted phenyl, unsubstituted naphtyl or heteroaryl; R6 represents hydrogen atom or linear or branched (C1-C6)-alkyl, wherein group R6 can be present or absent depending on nature of cycle A; at that: - term "heteroaryl" is understood as any aromatic, mono- or bicyclic, 5 to 10 membered group, comprising 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur; - term "substituted" used in expressions "phenyl", "naphtyl" or "heteroaryl" is understood that the corresponding groups can be substituted with one or several groups, which can be similar or different, selected from the group, comprising linear or branched (C1-C6)-alkyl, linear or branched (C1-C6)-alkoxyl, mercapto, linear or branched alkylthio, amino, linear or branched (C1-C6) alkylamino, di[(C1-C6)-alkyl)]amino wherein each alkyl part is linear or branched, linear or branched polyhalogen-(C1-C6)-alkyl and hydroxy and halogen atoms; with proviso that: - when R2 and R3 together form oxo group and simultaneously R5 represents hydrogen atom and R6 represents hydrogen atom or is absent, then R4 is different than phenyl, substituted with one group selected from hydroxyl, alkoxyl, CF3 and halogen, with exeption of bromo in case when A represents piperidine) or several groups, selected from hydroxyl and alkoxyl, when R2 represents hydrogen atom and R3 represents hydroxyl, and simultaneously R5 represents hydrogen atom and R6 represents hydrogen atom or is absent, then R4 is different than phenyl, substituted with one group, selected from hydroxyl, linear or branched (C1-C6)-alkoxyl, linear or branched (C1-C6)-alkyl and chloro, or several groups, selected from hydroxyl and alkoxyl, the compound of formula (I) can represent neither 1-(1,3-benzodioxol-5-yl)-2-(2-pyridinyl)ethanol nor 2-(2-pyridinyl)cyclohexanone; enantiomers and diastereoisomers thereof, and addition salts of pharmaceutically acceptable acid or base. 2. The compounds of formula (I) according to Claim 1, wherein the group   is piperidinyl or N-methylpiperidinyl group, enantiomers and diastereoisomers thereof, and addition salts of pharmaceutically acceptable acid or base. 3. The compounds of formula (I) according to Claim 1, wherein the group   is pyridinyl or N-methylpyridinium group, enantiomers and diastereoisomers thereof, and addition salts of pharmaceutically acceptable acid or base. 4. The compounds of formula (I) according to Claim 1, wherein R4 represents substituted phenyl, enantiomers and diastereoisomers thereof, and addition salts of pharmaceutically acceptable acid or base. 5. The compounds of formula (I) according to Claim 1, wherein R5 represents hydrogen atom, enantiomers and diastereoisomers thereof, and addition salts of pharmaceutically acceptable acid or base. 6. The compounds of formula (I) according to Claim 1, wherein R5 represents the group of formula (II), enantiomers and diastereoisomers thereof, and addition salts of pharmaceutically acceptable acid or base. 7. The compounds of formula (I) according to Claim 1, wherein R2 and R3 together form oxo group, enantiomers and diastereoisomers thereof, and addition salts of pharmaceutically acceptable acid or base. 8. The compounds of formula (I) according to Claim 1, wherein R2 represents hydrogen atom and R3 represents hydroxyl, enantiomers and diastereoisomers thereof, and addition salts of pharmaceutically acceptable acid or base. 9. The compound of formula (I) according to Claim 1, which is 1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanone, enantiomers and diastereoisomers thereof, and addition salts of pharmaceutically acceptable acid or base. 10. The compound of formula (I) according to Claim 1, which is (R)-2-(1-methyl-2-piperidinyl)-1-(4-bromophenyl)-1-ethanone and addition salts of pharmaceutically acceptable acid or base thereof. 11. The compound of formula (I) according to Claim 1, which is (S)-2-(1-methyl-2-piperidinyl)-1-(4-bromophenyl)-1-ethanone and addition salts of pharmaceutically acceptable acid or base thereof. 12. The compound of formula (I) according to Claim 1, which is 1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanol, enantiomers and diastereoisomers thereof, and addition salts of pharmaceutically acceptable acid or base. 13. The compound of formula (I) according to Claim 1, which is (S,S)-1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanol and addition salts of pharmaceutically acceptable acid or base thereof. 14. The compound of formula (I) according to Claim 1, which is (R,R)-1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanol and addition salts of pharmaceutically acceptable acid or base thereof. 15 The compound of formula (I) according to Claim 1, which is 1-methyl-2-[2-oxo-2-(4-bromophenyl)ethyl]pyridinium iodide and addition salts of pharmaceutically acceptable acid or base thereof. 16. The method for producing compounds of formula (I) according to Claim 1, characterized in that the compound of formula (III):    is used as parent material, wherein X represents hydrogen atom or fluoro, which is alkylated with the help of such reactant as, for example, alkyl-p-toluene sulfonate or alkyltrifluoromethanesulfonate, obtaining the compound of formula (IV):   wherein X is determined above, R'6 represents linear or branched (C1-C6) alkyl and Y<-> represents for example, p-toluene sulfonate or trifluoromethanesulfonate group, the obtained compound is brought into reaction with one or two compounds of formula (V), which can be similar or different:   wherein Ra and Rb together with nitrogen atom which carries them form 5- or 6-memberred heterocycle, which can comprise in addition to nitrogen atom the other heteroatoms, selected from sulfur, oxygen and nitrogen, and Rc represents hydrogen atom or the group of formula (VI):   wherein R4 and R1 are determined above, at that, it is understood, that at least one of compounds of formula (V) comprises the group of formula (VI), obtaining the compound of formula (I/a), being special case of compounds of formula (I):   wherein R1, R4, Ra, Rb, R'6 and Y<-> are determined as defined above and X' represents hydrogen atom, a group -NR'aR'b (wherein R'a and R'b can have any of meanings Ra and Rb correspondingly), or the group of formula (VII):   wherein R'a, R'b, R'1 and R'4 can have any of meanings Ra, Rb, R1 and R4 correspondingly; said compound of formula (I/a) can be put into reaction with halohydrogenous acide such as HCl, HBr or HI, or reacting with ammonium salts, such as NH4<+>PF6<->, with obtaining the compound of formula (I/a')   wherein R1, R4, Ra, Rb, R'6 and X' are determined as defined above and Y'<-> represents halogen anion or the group PF6<->; said compound of formula (I/a') can be hydrolyzed using concentrated hydrochloric acid, with obtaining the compound of formula (I/b), which is special case of compounds of formula (I):   wherein R1, R4, R'6 and Y'<-> are determined as it is mentioned above and X" represents hydrogen atom, group -NR'aR'b, determined above, or the group of formula (VIII):   wherein R'1 and R'4 can have any of meanings R1 and R4 respectively; at that the compounds of formulas (I/a), (I/a') and (I/b) form the compound of formula (I/c), which is special case of compounds of formula (I):   wherein R1, R4 and R'6 have the above meaning, Y''<-> represents the group Y<-> ou Y'<-> determined as it is mentioned above, R2a and R3a together form oxo group or R2a and R1 form an additional bond, and in this case, R3a represents a group NR'aR'b determined as it is mentioned above, and X''' represents hydrogen atom, a group NR'aR'b or a group of formula (IX):   wherein R'1, R'2a, R'3a, and R'4 can have any of meanings R1, R2a, R3a, and R4 respectively, which is converted into corresponding iodinated salt by treating Nal, obtaining the compound of formula (I/d), being the special case of compounds of formula (I):   wherein R1, R2a, R3a, R4, R'6 and X''' are determined as mentioned above, which or is subjected to catalytic hydrogenation, for example, using platinum oxide, obtaining the compound of formula (I/e), being the special case of compounds of formula (I):   wherein R1, R2a, R3a, R4, X''' and R'6 are determined above; or is subjected to reaction of pyridinium salt, obtaining the compound of formula (I/f), being the special case of compounds of formula (I):     wherein R1, R2a, R3a, R4, and X''' are determined above; which can be hydrogenated by catalytic hydrogenation with obtaining the compound of formula (I/g), being the special case of compounds of formula (I):   wherein R1, R2a, R3a, R4, and X''' are determined above; the compounds of formulas (I/b) and (I/c)-(I/g) wherein R2a and R3a together form oxo group could be brought into reaction with reducing agent, such as for example NaBH4, with obtaining compound of formula (I/h), being the special case of compounds of formula (I):   wherein A, R1, R4 and R6 are determined above and X