Patent CA-1158649-A (CA)
Inventor: CLITHEROW JOHN W
IPC: A61K31/41
Filed: 1981-02-27
Granted: 1983-12-13
Abstract: ABSTRACT        The invention provides compounds of the general formula (I)                    (I) and physiologically acceptable salts, hydrates and bioprecursors thereof, in which R1 represents hydrogen, C1-14 alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, trifluoroalkyl, or alkyl substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino or cycloalkyl; and R2 represents hydrogen or C1-4  alkyl; or R1 and R2 may together with the nitrogen atom to which they are attached form a 5 to 10 membered ring which may be saturated or may contain at least one double bond, may be unsubstituted or may be substituted by one or more C1-3 alkyl groups or a hydroxy group and/ or may contain another heteroatom selected from oxygen or sulphur;        Alk represents a straight or branched alkylene chain of 1 to 6 carbon atoms, Q represents a furan or thiophon ring in which incorporation into the rest of the molecule is through bonds at the 2- and 5- positions, the furan or thiophen ring optionally bearing a further substituent R5 adjacent to the group R1R2N-Alk-; or Q represents a thiophen ring in which incorporation into the rest of the molecule is through bonds at the 2- and 4- positions, the thiophen ring optionally bearing a further substituent R5 adjacent to the group R1R2NAlk with the proviso that where the group R1R2NAlk is in the 4- position then the group R5 is in the 5- position; or Q represents a benzene ring in which incorporation into the rest of the molecule is through bonds at the 1- and 3- or 1- and 4- positions;          R5 represents halogen or C1-4 alkyl which may be substituted by hydroxy or C1-4 alkoxy;        X represents oxygen, sulphur, -NH-, methylene or a bond;        Y represents oxygen, sulphur, methylene or a bond n represents zero, 1, 2 or 3, and m is an integer from 2 to 5, with the provisos that (a) the total number of atoms in the chain X(CH2)nY(CH2)m is an integer from 3 to 8, (b) when X and Y represent oxygen or sulphur then n is 2 or 3, and (c) when X represents -NH- then Q is a benzene ring and Y represents methylene or a bond;        R3 represents hydrogen, alkyl, alkenyl, aralkyl, or C2-6 alkyl substituted by hydroxy or alkoxy;        R4 represents the group (CH2)pCH=CHR6 or (CH2)qR7 where p is zero, 1, or 2 and q is zero, 1,2, 3, 4, 5 or 6 and the alkylene chain (CH2)q may be straight or branched, and R6 is hydroxymethyl, 1H-tetrazol-5-yl, cyano, or the group CH2NHCOR17 or CH2NHSO2R17 where R17 is alkyl; or the group COR19 where R19 is hydrogen, hydroxyl, alkyl, alkoxy, amino, alkylamino or dialkylamino; or the group CRa19 = NR20 where Ra19 is hydrogen or alkyl and R20 is hydroxy, alkoxy, aralkyloxy or -NHC(=A)NH2 where A is oxygen or sulphur;         R7 is nitro, cyano, halomethyl, heteroaryl, arylaminomethyl, aralkylaminomethyl, alkylthioalkyl, arylthioalkyl, 1H-tetrazol-5-yl, aryl CH = NCH2- or CH2NHC(=B)NHR17 where B is NCN, NSO2methyl,NSO2Phenyl or CHNO2;      or R7 is the group SO2R8 in which R8 is hydroxy, alkyl, aryl or the group NR9R10 wherc R9 and R10 are the same or different and represent hydrogen, alkyl, aryl or aralkyl;         or R7 is the group COR11 where R11 is hydrogen, hydroxy, alkoxy, aryloxy, aralkyloxy, alkyl, aryl, aralkyl or the group NR12R13 where R12 is hydrogen or alkyl optionally substituted by a hydroxy or alkoxy group, and R13 is hydrogen. alkyl (optionally substituted by a hydroxy or alkoxy group), alkenyl, aryl, aralkyl or cycloalkyl, or NR12R13 forms a 5 to 8 membered ring which may contain another heteroatom e.g. oxygen, or a double bond and/or may be substituted by hydroxy or one or two C1-3 alkyl (e.g. methyl) groups; or R7 is the group CRa11 = NR20 where Ra11 is hydrogen, alkyl, aryl or arlkyl and R20 is as defined above;      or R7 is the group CH2NR18SO2R14 where R14 is alkyl or aryl and R18 is hydrogen or alkyl;      or R7 is the group CH2NR18COR15 where R15 is hydrogen, alkyl, aryl, aralkyl, alkoxy, halomethyl, or the group NHR16 where R16 is hydrogen, alkyl, cycloalkyl, aryl or aralkyl;      with the proviso that when the group R7 contains a carbon atom through which it is linked to the alkylene group (CH2)q then the total number of carbon atoms in the resulting chain is not greater than 6 (i.e. q is not greater than 5).           The compounds show pharmaceutical activity as selective histamine H2-antagonists.