Patent EP-0003663-A2 (EP)
Inventor: SHEPHERD ROBERT GORDON
IPC: C07D309/12
Filed: 1979-02-02
Abstract: The invention provides novel amino-substituted phenyl and heteroaryl compounds which show pharmaceutically useful properties, particularly as hypolipidemic and antiatherosclerotic agents, and processes for the preparation of the novel compounds. The novel compounds have the formula:
     Q is wherein Y is loweralkyl, loweralkoxy, hydroxy, nitro, acyloxy or halo, and m is an integer of from 0 to 4 inclusive, or a 5- or 6-membered heteroaryl ring containing 1 or more nitrogen, sulfur or oxygen atoms and which may be optionally substituted with one fluorine atom; R is hydrogen or a group convertible in vivo thereinto; Z is:
     wherein J is selected from the group consisting of hydroxy, loweralkoxy, loweralkoxyloweralkyloxy, diloweralkylaminoloweralkoxy, hydrogen, loweralkyl, (mono-or polyhydroxy)loweralkoxy, (mono- or polycarboxy)loweralkoxy, (mono- or polycarboxy)hydroxyloweralkoxy, allyloxy, 2,3-epoxypropoxy, substituted or unsubstituted(phen- oxy, benzyloxy and 3-pyridyloxy), pyridylmethoxy, tetra- hydropyranyloxy, (mono- or polyhydroxyl)loweralkyl- amino, (mono- or polycarboxy)loweralkylamino, (mono-or polycarboalkoxy)loweralkylamino, allylamino, propargylamino, 2-sulfoethylamino. (substituted or unsubstituted aroyl)amino, loweralkanoylamino, loweralkanesulfonylamino, (substituted or unsubstituted arene)sulfonylamino, loweralkanoylhydrazino, hydroxylamino, polymethyleneimino, (4-carboxy- or 4-carboethoxy)thiazolidino, and loweralkyl bearing one or more carboxy, carboloweralkoxy, carbamoyl, acyl, sulfinyl or sulfonyl groups, or
     wherein B is a saturated or unsaturated loweralkylene group and K is selected from the group consisting of hydrogen, loweralkyl, loweralkoxyethyl, diloweralkyl aminoethyl, (mono- or polyhydroxy)loweralkyl, (mono- or polycarboxy)loweralkyl, (mono- or polycarb- oxy)hydroxyloweralkyl, allyl, 2,3-epoxypropyl, substituted or unsubstituted (phenyl, benzyl or 3-pyridyl) or pyridylmethyl and tetrahydropyranyl; and wherein Q, Y, m and X are defined as follows:
     Formula I-A) Q is
       m is O; X is S a -T a - wherein Sa is selected from the group consisting of C 3 -C 16  cycloalkyl or C 4 -C 17  cycloalkenyl and is either unsubstituted or substituted with at least one C 1 -C 13  alkyl, C 4 -C 8  cycloalkyl, decahydronaphthyl, methylene, ethylidene, or isopropylidene group; T a  is a bond or a divalent radical selected from the group consisting of unbranched or branched C,-C, 3  alkylene or alkenylene and is either unsubstituted or substituted with at least one C 1 -C 4  alkyl group; with the proviso that the total number of carbon atoms in S a  and T a  shall not exceed twenty; and with the further proviso that when T a  is not a bond, S a  is not an unsubstituted cyclopropyl nor a cyclopropyl substituted with at least one C 1 -C 13  alkyl;   Formula I-B) Q is
     m is O; X is S b - wherein S b  is a branched or unbranched mono- or polyunsaturated or cyclopropylated C 3 -C 22  alkyl group and can be represented by the formula:
     wherein R 2  and R 3  are the same or different and are hydrogen or a saturated or unsaturated C,-Cg alkyl group: R, is a:   Formula I-B a ) C 2  to C 21  E- or Z-alkenyl group unsubstituted or substituted with at least one loweralkyl group;   Formula I-B b ) C 2  to C 20  alkynyl group unsubstituted or substituted with at least one methyl or ethyl group;   Formula I-B c ) C. to C 20  alkyl group containing at least 2 non-cumulative double bonds, said group being unsubstituted or substituted with at least one methyl or ethyl group;   Formula I-B d ) C 3  to C, 2  allenyl group unsubstituted or substituted with at least one methyl or ethyl group;   Formula I-Be) vinyl or C 3  to C 8  E- or Z-alkenyl group said vinyl or alkenyl group being unsubstituted or substituted with at least one methyl group, and in this Formula I-Be, R 2  is a vinyl or C 3  to C B  E- or Z-alkenyl group unsubstituted or substituted with at least one methyl group;   Formula I-B f ) allyl or C. to C 8  E- or Z-alkenyl group said allyl or alkenyl group being substituted with at least one exo-(methylene, ethylidene, or isopropylidene), and either further unsubstituted or substituted with at least one methyl group;   Formula I-B g ) vinyl or C 3  to C 8  E- or Z-alkenyl group substituted between the nitrogen and the double bond with at least one loweralkenyl, said vinyl or alkenyl group being unsubstituted or substituted with at least one methyl group;   Formula I-B h ) vinyl or C 3  to C s  E- or Z-alkenyl group said vinyl or alkenyl group being unsubstituted or substituted with at least one methyl and in this case, R 2  is a C 2  to C 9  alkynyl group unsubstituted or substituted with at least one methyl group;   Formula I-B,) C. to C 20  alkyl group containing at least one carbon-carbon double bond and at least one carbon-carbon triple bond said group being unsubstituted or substituted with at least one loweralkyl group; or wherein S b  is a;   Formula I-B j ) group of the formula
     wherein R 4  is hydrogen or a C, to C 15  alkyl group unsubstituted or substituted with at least one methyl group, R 5  is hydrogen or methyl and W is a bond or a C, to C 15  branched or unbranched alkylene group unsubstituted or substituted with at least one methyl group;   Formula I-C) Q is
     m is O; X is S c -T c - wherein Sc is selected from the group consisting of mercapto, lowerakylthio, aralkylthio, arylthio, loweralkylsulinyl, loweralkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, arylamino, acylamino, loweralkylsulfonylamino, arylsulfonylamino, azido, oxo. oximino, chloro, bromo, and iodo; wherein the substituent S c  may contain q carbon atoms with q being an integer from 0 to 8. inclusive: T e  is an unbranched or branched alkylene group, optionally saturated or (mono- or poly-)unsaturated and containing or not containing a cycloalkyl group, represented by the formula CnH 2(n-p)  with n being an integer from 7 to 18, inclusive, and p being an integer from 0 to 5, inclusive, both being selected in a manner such that the sum of n and q is greater than 6 but less than 19; provided that when S c  is halogen T c  must be a saturated alkylene group; J may not be loweralkyl bearing one or more carboxy. carboloweralkoxy, carbamoyl, acyl, sulfinyl or sulfonyl groups, and Z may not be 0 II -B-C-OK;   Formula I-D) Q is
     m is O; X is S d -T d - wherein S d  is selected from the group consisting of substituted or unsubstituted aryl and heteroaryl groups; T d  is a saturated or unsaturated alkylene group of 1-18 carbon atoms which may be branched or unbranched; such that the total number of carbon atoms in S d  and T d  shall not exceed 24; provided that J may not be hydroxyl, loweralkoxy, loweralkoxyloweralkyloxy, diloweralkylaminoloweralkoxy, or substituted or unsubstituted benzyloxy;   Formula I-E) Q is
     m is 1 to 4 inclusive; X is a saturated or unsaturated hydrocarbon radical of 7-19 carbon atoms which may be branched or unbranched and which may contain one or more radicals selected from the group consisting of saturated or unsaturated cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; Y is loweralkyl, loweralkoxy, hydroxy, nitro, acyloxy, or halo;   Formula I-F) Q is a 5- or 6-membered heteroaryl ring containing one or more nitrogen, sulfur, or oxygen atoms and optionally unsubstituted or substituted with one fluoro; X is S f -T f - wherein S f  is selected from the group consisting of hydrogen, C 3 -C 8  cycloalkyl, and substituted or unsubstituted aryl; T f  is a divalent radical selected from the group consisting of branched or unbranched C 6 -C,g alkylene, alkenylene, and alkynylene;   Formula I-G) Q is
     m is O; X is Sg-Tg- wherein Sg is selected from the group consisting of carboxy, loweralkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamyl, mono- or diloweralkyl- carbamyl, cyano, sulfo, monoalkyl- or monoarylsulfamyl; Tg is an unbranched or branched alkylene group, optionally saturated or mono- or polyunsaturated, and containing or not containing a cycloalkyl group, represented by the formula C r H 2(r-p)  with r being an integer from 1 to 18, inclusive, and p being an integer from 0 to 5, inclusive; with the proviso that when Sg is a carbamyl, cyano, or sulfo group, Sg and the nitrogen atom in Formula I may not be bonded to the same carbon atom of the group Tg;   Formula I-H) Q is
     m is O; X is a saturated or unsaturated hydrocarbon radical of 7-19 carbon atoms which may be branched or unbranched and which may contain a saturated or unsaturated cycloalkyl group, said radical containing one or more perfluorinated (-CF 2  or -CF 3 ) carbon atoms excluding the carbon adjacent to the nitrogen atom; and the pharmacologically acceptable acid-addition and cationic salts thereof.