5-Substituted 1,2,4-oxadiazole derivatives, their preparation and pharmaceutical compositions containing them

Claim 1

A process for preparing a compound of the formula, wherein R is a group selected from the group consisting of the following formulas (A), (B), (C), (D) and (E) : wherein R 1 is lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkenyl, phenyl, substituted phenyl or heterocyclic group; R 2 and R 3 are independently hydrogen, halogen, amino, hydroxy, lower alkoxy or lower alkyl; and X 1 is the radical -CH 2 -, -CH 2 0-, C=O, -0-, -S- or -NH-, or a single bond, wherein R 4 and R 5 are independently hydrogen, lower alkyl, phenyl or substituted phenyl; R 6 is phenyl, substituted phenyl, benzoyl or substituted benzoyl; A is nitrogen, oxygen or sulfur; and B and D may be the same or different and are carbon or nitrogen, wherein R 7 is lower alkyl, lower alkoxy, phenyl or substituted phenyl; E is nitrogen or carbon; F is oxygen, sulfur or carbon, or a double bond of the formula and the dotted line means a single bond or a double bond, wherein R 8 is hydrogen or lower alkyl; R 9 is hydrogen, halogen or lower alkoxy; R 10 is hydrogen, cyclohexyl or substituted benzoyl; and G is methylene, substituted benzoylimino, cinnamoylimino or substituted styrylidene, provided that when R 10 is cyclohexyl or substituted benzoyl G is methylene; and the dotted line means a single bond or a double bond, wherein R 11 is hydrogen, halogen, lower alkyl or lower alkoxy; X 2 and X 3 are different and selected from -CH 2 -, -O-, -S-, -NH-, and a single bond; J is an aromatic ring which is selected from the group consisting of benzene, pyridine, thiophene, furan and pyrrole; and n is 0 or 1; T is lower alkylene or lower alkenylene, both of which may bear an oxo, a hydroxy or a lower alkoxy radical on their carbon chains, or is a single bond; U is hydrogen, lower alkyl, lower alkenyl, polyhalo-lower alkyl, lower cycloalkyl, lower cycloalkenyl, phenyl, substituted phenyl, pyridyl, a group of the formula R 12 -T 1 - [wherein R 12 is halogen, hydroxy, mercapto, lower alkylsulfinyl, di-lower alkoxymethyl, lower alkoxycarbonyl, carboxy, sulfo, cyano, the group (wherein R' and R" may be the same or different, and are hydrogen, lower alkyl or hydroxy-lower alkyl and when taken together with the adjacent nitrogen atom they may form a 5- or 6-membered saturated or unsaturated heterocyclic ring, which may contain another nitrogen or oxygen atom, or may form a quaternary ammonium salt or the group (wherein R 1 ' and R 1 " may be the same or different and are lower alkyl or lower alkenyl; and X is a negative monovalent ion such as halide ion and sulfonate ion); and T 1 is lower alkylene or lower alkenylene, both of which may bear an oxo or a hydroxy group on their carbon chains], or a group of the formula R 13 -X 4 -T 1 - [wherein R 13 is lower alkyl, lower alkenyl, hydroxy-lower alkyl, acyloxy-lower alkyl, amino-lower alkyl, acylamino-lower alkyl, lower cycloalkyl, lower cycloalkenyl, phenyl, substituted phenyl, phenyl-lower alkyl, heterocyclic group, heterocyclic-lower alkyl, acyl, acylthio-lower alkanoyl, mercapto-lower alkanoyl, lower alkoxycarbonyl, lower alkylsulfonyl or the group (wherein R 2 ' and R 2 " are independently hydrogen, lower alkyl or hydroxy-lower alkyl); X 4 is the radical -0-, -S-, -NH-, (wherein R 14 and R 15 are independently hydrogen or lower alkyl) or a single bond; and T 1 is as defined above], which comprises (a) reacting a carboxylic acid of the formula, wherein R and T are as defined above, or its reactive ester, with an amidoxime of the formula, wherein U is as defined above, to yield an O-acylamidoxime of the formula, wherein R, T and U are as defined above, and further effecting intramolecular condensation to produce a compound of the formula, wherein R, T, and U are as defined above, (b) reacting a nitrile of the formula, wherein R and T are as defined above, with a nitrile oxide-of the formula, wherein U 1 is lower alkyl, lower alkenyl, polyhalo-lower alkyl, lower cycloalkyl, lower cycloalkenyl, phenyl, substituted phenyl, pyridyl or a group of the formula R 16 -T 2 - (wherein R 16 is halogen, lower alkoxy, lower alkenyloxy, di-lower alkoxymethyl, carboxy, lower cycloalkyl, phenyl, substituted phenyl, pyridyl, (wherein R', R", R 2 ' and R 2 " are as defined above); and T 2 is lower alkylene or lower alkenylene, to yield a compound of the formula, wherein R, T and U 1 are as defined above, (c) reacting a thioamide derivative of the formula, wherein R, T and U 1 are as defined above, with hydroxylamine to yield a compound of the aforesaid formula (Ia), (d) reacting an aldehyde of the formula, wherein R 0 is the same as R provided that X 1 , X 2 and X 3 in the definition R are not the radical -S-; and T 1 is as defined above, with an amidoxime of the formula, wherein U 1 is as defined above, to yield a compound of the formula, wherein R 0 , T 1 and U 1 are as defined above, and further oxidizing it to produce a compound of the formula, wherein R 0 , T 1 and U 1 are as defined above, (e) reacting a compound of the formula, wherein R, T 1 and T 2 are as defined above, and V is a radical that affords -O-, -S-, -NH- or (wherein R 14 and R 15 are as defined above) on the reaction with the radical W of a compound of the formula, wherein R 13 is as defined above, and W is a radical that affords -O-, -S-, -NH- or (wherein R 14 and R 15 are as defined above) on the reaction with the aforesaid radical V, with said compound (IX), to yield a compound of the formula, wherein R, R 13 , T 1 and T 2 are as defined above; and X 5 is -O-, -S-, -NH- or (wherein R 14 and R 15 are as defined above), (f) reacting an alcohol compound of the formula, wherein R, T 1 and T 2 are as defined above, or its reactive ester with a compound of the formula, wherein R 17 is sulfo, cyano, or the group (wherein R' and R" are as defined above provided that this amine is not a quaternary ammonium salt or N-oxide), or a salt of said compound (X) to yield a compound of the formula, wherein R, R 17 , T 1 and T 2 are as defined above, (g) hydrolyzing a compound of the formula, wherein R, T 1 and T 2. are as defined above, and R 18 is cyano, lower alkoxycarbonyl, di-lower alkoxy- methyl, acylamino, acyloxy, acylthio, or tetra- hydropyranyloxy, to yield a compound of the formula, wherein R, T 1 and T 2 are as defined above, and R 19 is carboxy, formyl, amino, hydroxy or mercapto, or (h) reacting a compound of the formula, wherein R, T and T 1 are as defined above, and R20 is a group of the formula (wherein R', R" and R 1 ' are as defined above), with a compound of the formula, wherein R 1 " and X are as defined above, to yield a compound of the formula, wherein R, T and T 1 are as defined above,and R 21 is a group of the formula (wherein R', R", R 1 '. R 1 " and X are as defined above).