Imidazo(1,2-a)pyridines, processes for their preparation and pharmaceutical compositions containing them

Claim 2

Imidazo[1,2-a]pyridines of the general formula wherein R 2 represents hydrogen, C, to C 6 -loweralkyl, trifluoromethyl, B―CF 3 ; B―Ar, Ar, B-halogen, BOR 8 , B―SO (n) -(C 1 to C 6 -lower-alkyl), B―O―CO―R 1 , R 3 represents C 1 to C 6 -loweralkyl, BCN, BOR 8 , B―O―CO―R 1 , B―NO 2 , B-halogen or provided R 2 is not hydrogen, hydrogen; X is hydrogen, C, to C 6 -loweralkyl, halogen, hydroxy, trifluoromethyl or C 1 to C 6 -loweralkoxy; Z represents O, S, SO, SO 2 , NR 6 or a single bond between the group T―Ar and position 8 of the imidazo[1,2-a]pyridine nucleus; T represents a single bond between Z and Ar or a branched or straight alkylene group having 1 to 12 carbon atoms with no more than 5 binding carbon atoms between Z and Ar; and Ar represents phenyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 2- or 3-furanyl, 2- or 4-imidazolyl, whereby the pyridyl-; thienyl-; furanyl- and imidazolyl- groups may be substituted by halogen or C 1 to C 6 -loweralkyl, or X'-, Y'- and/or Z'-substituted phenyl wherein each of X', Y' and Z' independently is hydrogen, halogen, C, to C 6 -loweralkyl, C 1 to C 6 -loweralkoxy, OH, NO 2 , CN, CF 3 , with m being zero, one or two whereby m represents two when R, represents whereby in the above definitions B is a straight or branched chain C 1 to C 6 -lower alkylene group; n represents zero, one or two; R 4 and R 5 each independently represent hydrogen, C 1 to C 6 -loweralkyl C 1 to C 6 -loweralkoxy-(C 1 to C 6 loweralkyl, trifluoromethyl-(C 1 to C 6 -loweralkyl), Ar-(C 1 to C 6 -loweralkyl), Ar or, when taken together with the nitrogen to which they are attached, form a 4- to 6-membered cyclic amino- group; R 1 represents Ar-, C 1 to C 6 -loweralkyl, or Ar-(C 1 to C 6 -loweralkyl) R 6 represents hydrogen, C 1 - to C 12 -alkyl, aryl or an aralkyl group having up to 12 carbon atoms; R 7 represents hydrogen or C 1 to C 6 -loweralkyl; and R 8 represents hydrogen, C 1 to C 6 -loweralkyl, C 1 to C 6 -loweralkoxy-(C 1 to C 6 -loweralkyl), trifluoromethyl-(C 1 to C 6 -loweralkyl), Ar-(G 1 to C 6 -loweralkyl) or Ar; the 2,3-dihydro-5,6,7,8-tetrahydro- and 2,3,5,6,7,8-hexahydro-analogues thereof and the pharmaceutically acceptable salts of such compounds.

Claim 3

Compounds according to claim 1 wherein, in Formula I R 2 represents hydrogen, loweralkyl with 1 to 3 carbon atoms, CH 2 OH, CH 2 CN, CH 2 O―O―H 2 N(CH 3 ) 2 or with n being zero, one or two; R 3 is selected from CH 3 , (with Rg representing methyl, ethyl, propyl, isopropyl or t-butyl) and, provided R 2 is not hydrogen, hydrogen; X represents hydrogen; Z represents 0, NH, SO or a single bond; T represents a branched or straight lower alkylene group having up to 5 carbon atoms, and Ar is selected from phenyl, thienyl, pyridyl or a X'-, Y'-, Z'-substituted phenyl group wherein each of X', Y' and Z' independently is selected from H, CI, F, CH 3 , t-butyl, CF 3 , OCH 3 and CN.

Claim 4

Compounds according to claim 2 wherein in Formula I R 2 represents H, CH 3 , C 2 H 5 , i-C 3 H 7 or CH 2 OH; R 3 represents CH 3 , CH 2 CN, CH 2 OH, CH 2 OCOCH 3 or Z represents -0, NH or a single bond; T represents ―CH 2 ―, ana Ar represents phenyl, o- or p-fluorophenyl, p-chlorophenyl, or 2,4,6-trimethylphenyl.

Claim 5

Compounds according to claim 3, namely 8-benzyloxy-3-cyanomethyl-2-methyl-imidazo[1,2-]pyridine; 8-benzyloxy-3-hydroxymethyl-2-methyl-imidazo[1,2-a]pyridine; 3-cyanomethyl-8-(2-fluorobenzyloxy)-2-methyl-imidazo[1,2-a]pyridine; 3-cyanomethyl-8-(4-fluorobenzyloxy)-2-methyl-imidazo[1,2-a]pyridine; 3-cyanomethyl-2-methyl-8-(2,4,6-trimethylbenzyloxy-imidazo[1,2-a]pyridine and 8-benzylamino-3-cyanomethyl-2-methyl-imidazo[1,2-a]pyridine. 5. Compounds according to claim 3, namely 3-cyanomethyl-2-methyl-8-(2-phenylethyl)-imidazo[1,2-a]pyridine; 8-benzyloxy-2-methyl-imidazo[1,2-a]pyridine-3-thioacetamide; 3-cyanomethyl-2-methyl-8-(3-phenylpropoxy)-imidazo[1,2-a]pyridine 8-benzylamino-2,3-dimethyl-imidazo[1,2-a]pyridine. 8-benzyloxy-2-methyl-imidazo[1,2-a]pyridine-3-methylacetate; 8-benzyloxy-2,3-dimethyl-imidazo[1,2-a]pyridine; 3-cyanomethyl-2-methyl-8-(2-phenylethoxy)-imidazo[1,2-a]pyridine and 3-cyanomethyl-2-methyl-8-( 1-phenylethoxy)-imidazo[1,2-a]pyridine. 6. Compounds according to claim 3, namely 8-benzyloxy-3-cyanomethyl-imidazo[1,2-a]pyridine; 8-benzyloxy-3-eyanomethyl-2-isopropyl-imidazo[1,2-a]pyridine; 8-benzyloxy-3-cyanomethyl-2-ethyl-imidazo[1,2-a]pyridine and 8-benzyloxy-3-cyanomethyl-2-hydroxymethyl-imidazo[1,2-a]pyridine.

Claim 6

A compound according to claim 4 namely 8-benzyloxy-3-cyanomethyl-2-methyl-imidazo[1,2-a]pyridine.

Claim 7

Pharmaceutical compositions comprising as an active ingredient a compound as defined in any one of claims 1 to 7.

Claim 8

Process for preparing pharmaceutical compositions as defined in claim 8, characterized in that a compound as defined in any one of claims 1 to 7 is admixed with a suitable pharmaceutical carrier.

Claim 9

Process for preparing compounds of Formula I as defined in claim 1, characterized in that, either A: a compound of the general formula is reacted with a compound of the general Formula whereby in the formulae R 2 , R 3 , X, Z, T and Ar are as defined in claim 1, except that any free amino or hydroxy groups present in R 2 , R 3 , X orAr may be protected by a protecting group which is subsequently removed, and Z" represents a good leaving group; or, for preparation of compounds wherein Z is S, 0, NR 6 or a single bond B: a compound of the general Formula is reacted with a compound of the general Formula whereby in the above formulae R 2 , R 3 , X, T and Ar are as defined in claim 1, Hal, represents Br, CI or I and Z'" represents hydrogen, halogen, OH, SH or NHR 6 , with R 6 being as defined in claim 1; or that, for the preparation of compounds wherein R 3 represents BCN, C: a compound of general Formula I wherein R 2 , X, Z, T and Ar are as defined in claim 1 but wherein R 3 is replaced by a group BX" wherein B is as defined in claim 1 and X" represents a good leaving group, is reacted with a metal cyanide; or D: a compound of Formula I wherein R 2 , X, T, Z and Ar as defined in claim 1, but wherein R 3 is replaced by a group BCONH 2 or is subjected to a dehydration; or E: a compound of Formula I wherein R 2 , X, T, Z and Ar as defined in claim 1, but R 3 is substituted by a group B-CHO, is treated with a suitable cyanide whereby the formyl function is replaced by CN; or F: a compound of Formula I wherein R 2 , X, T, Z and Ar are as defined in claim 1 but wherein R 3 is replaced by the group BCOOR, is treated with a suitable amine; or G: a compound of Formula I wherein R 2 , S, T, Z and Ar are as defined claim 1 but wherein R 3 is replaced by the group is reacted with NaOCI; or H: a compound of Formula I wherein R 2 , X, Z, T and Ar are as defined in claim 1 but wherein R 3 is replaced by the group BCH 2 NO 2 is subjected to a reductive dehydration; or I: a compound of Formula I wherein R 2 , X, T, Z and Ar are as defined in claim 1, and R 3 is hydrogen, is reacted with a compound hal-BCN, with hal representing chlorine or bromine in the presence of a Lewis acid; or J: a compound of Formula I, wherein R,, X, T, Z and Ar are as defined in claim 1 but wherein R, is replaced by the group is subjected to a reduction replacing the SCH 3- group by hydrogen, and that a compound obtained according to either of process A to J above is, if desired, transformed into a pharmaceutically accetable salt.

Claim 10

Process according to claim 10, characterized in that in process A: Z" represents halogen, tosyl or mesyl and the reaction is carried out by heating the reactants together in an inert solvent; C: X" represents Si(CH 3 ) 2 , halogen, alkoxy, aryloxy, mesyl, tosyl, a quaternary group, preferably N⊕(CH 3 ) 3 ·I⊖, or a quaternary group wherein the quaternary ion is a non-nucleophilic counter ion selected from BF 4 ⊖, PF 6 ⊖, CF 3 SO 3 ⊖ and FSO 3 ⊖ and the metal cyanide is an alkali metal cyanide; D: the hydration is carried out by using (CF 3 CO) 2 O, SeO 2 or POCl 3 as dehydrating agent; E: Tosyl-CH 2 CN is used as cyanocompound and the reaction is carried out in the presence of potassium-t-butoxyde; F: dimethylaluminium-amine is used as a suitable amine; H: the reductive dehydration is carried out by means of PCI 3 ; I: the reaction is carried out in the presence of a Lewis acid, preferably aluminium chloride, Zinc chloride or boron chloride; J: the reduction is carried out by means of Raney-nickel.