Substituted benzene-fused hetero- and carbocyclics as nuerokinin antagonists

A compound represented by the structural formula ##STR81## or a pharmaceutically acceptable salt thereof, wherein:

• A.sup.1, A.sup.2, A.sup.3 and A.sup.4 are independently selected from the group consisting of --(C(R.sup.2)(R.sup.10))--, --(C(R.sup.2c)(R.sup.10))--, --(C(R.sup.2)).dbd., --(C(R.sup.2c)).dbd., --NR.sup.16 --, --N.dbd., --O--, --S(O).sub.e --, --C(O)-- and a bond, wherein A.sup.1, A.sup.2, A.sup.3 and A.sup.4, together with the carbon atoms to which they are attached, form a 5- or 6-membered ring, and wherein two adjacent A groups are selected from the group consisting of the following combinations:
• --(C(R.sup.2)(R.sup.10))--(C(R.sup.2)(R.sup.10))--;
• --(C(R.sup.2)(R.sup.10))--(C(R.sup.2c)).dbd.;
• --(C(R.sup.2c)(R.sup.10))--NR.sup.16 --;
• --(C(R.sup.2c)(R.sup.10))--N.dbd.;
• --(C(R.sup.2c)(R.sup.10))--O--;
• --(C(R.sup.2c)(R.sup.10))--S(O).sub.e --;
• --(C(R.sup.2)(R.sup.10)--C(O)--;
• --(C(R.sup.2)).dbd.(C(R.sup.2))--;
• --(C(R.sup.2)).dbd.N--;
• .dbd.(C(R.sup.2))--(C(R.sup.2)).dbd.;
• .dbd.(C(R.sup.2))--NR.sup.16 --;
• .dbd.(C(R.sup.2))--N.dbd.;
• .dbd.(C(R.sup.2))--O--;
• .dbd.(C(R.sup.2))--S(O).sub.e --;
• .dbd.(C(R.sup.2))--C(O)--;
• --NR.sup.16 --N.dbd.;
• --NR.sup.16 --S(O).sub.e --;
• --NR.sup.16 --C(O)--;
• --N.dbd.N--;
• .dbd.N--N.dbd.;
• .dbd.N--O--;
• .dbd.N--S(O).sub.e --;
• .dbd.N--C(O)--;
• --O--S(O).sub.e --;
• and
• --O--C(O)--;
• provided that three adjacent A groups do not represent --C(O)--O--C(O)--, --S(O)--O--C(O)-- or --S(O)--O--S(O)--, and provided that when an aromatic nitrogen is present in the ring formed by A.sup.1, A.sup.2, A.sup.3 and A.sup.4, the N-oxide can be formed;
• E is R.sup.3 -aryl or R.sup.3 -heteroaryl;
• W is R.sup.4 -cycloalkyl, R.sup.4 -aryl, R.sup.4 -heterocycloalkyl or R.sup.4 -heteroaryl;
• R.sup.1, R.sup.3 and R.sup.4 are independently 1-3 substituents independently selected from the group consisting of H, halogeno, C.sub.1 -C.sub.6 alkyl, --CF.sub.3, --C.sub.2 F.sub.5, --OR.sup.11, --COR.sup.11, --CO.sub.2 R.sup.11, --CON(R.sup.11)(R.sup.12), --N(R.sup.11)(R.sup.12), --N(R.sup.11)COR.sup.12, --SH, --S(O).sub.e R.sup.13, --OC(O)R.sup.11, --OC(O)N(R.sup.11)(R.sup.12), --NR.sup.11 CO.sub.2 R.sup.13, --NR.sup.11 C(O)N(R.sup.12)(R.sup.14), R.sup.15 -phenyl, R.sup.15 -benzyl, --NO.sub.2, --NR.sup.11 S(O).sub.2 R.sup.13 and --S(O).sub.2 NR.sup.11 R.sup.12 ;
• or adjacent R.sup.1, R.sup.3 or R.sup.4 substituents can form a --O--CH.sub.2 --O-- group;
• R.sup.2 is independently selected from the group consisting of R.sup.2a, R.sup.2b or R.sup.10 ;
• and R.sup.2c is independently selected from the group consisting of R.sup.2a and R.sup.10 ;
• wherein R.sup.2a is selected from the group consisting of --CF.sub.3, --C.sub.2 F.sub.5, --COR.sup.11, --CO.sub.2 R.sup.11, --CON(R.sup.11)(R.sup.12), R.sup.15 -phenyl and R.sup.15 -benzyl;
• and R.sup.2b is selected from the group consisting of halogeno, --OR.sup.11, --NO.sub.2, --N(R.sup.11)(R.sup.12), --N(R.sup.11)COR.sup.12, --SH, --S(O).sub.e R.sup.13, --OC(O)R.sup.11, --OC(O)N(R.sup.11)(R.sup.12), --NR.sup.11 CO.sub.2 R.sup.13, --NR.sup.11 C(O)N(R.sup.12)(R.sup.14), --NR.sup.11 S(O).sub.2 R.sup.13 and --S(O).sub.2 NR.sup.11 R.sup.12 ;
• provided that from any combination of ring members A.sup.1, A.sup.2, A.sup.3 and A.sup.4 comprising R.sup.2 and R.sup.2c, no more than one substituent can be selected from R.sup.2a and no more than one substituent can be selected from R.sup.2b ;
• R.sup.5, R.sup.7, R.sup.9, R.sup.11, R.sup.12 and R.sup.14 are independently selected from the group consisting of H, C.sub.1 -C.sub.6 alkyl, R.sup.15 -phenyl, R.sup.15 -benzyl, --CF.sub.3 and --C.sub.2 F.sub.5 ;
• R.sup.6 and R.sup.8 are independently selected from the group consisting of R.sup.5, --(C(R.sup.9)(R.sup.10)).sub.n --OR.sup.11, --(C(R.sup.9)(R.sup.10)).sub.n --NR.sup.11 R.sup.12, --(C(R.sup.9)(R.sup.10)).sub.n --SH, --(C(R.sup.9)(R.sup.10)).sub.n --S(O).sub.e R.sup.13, --(C(R.sup.9)(R.sup.10)).sub.n --CO.sub.2 R.sup.11, --(C(R.sup.9)(R.sup.10)).sub.n --OC(O)R.sup.11, --(C(R.sup.9)(R.sup.10)).sub.n --CONR.sup.11 R.sup.12, --(C(R.sup.9)(R.sup.10)).sub.n --COR.sup.11 and --(C(R.sup.9)(R.sup.10)).sub.n --NR.sup.11 C(O)R.sup.12, provided that when Q is a heteroatom, R.sup.6 and R.sup.8 cannot be --OR.sup.11, --OC(O)R.sup.11, --N(R.sup.11)COR.sup.12, --NR.sup.11 R.sup.12, --SH or --S(O).sub.e R.sup.13 on adjacent carbon atoms;
• R.sup.10 is independently selected from the group consisting of hydrogen and C.sub.1 -C.sub.6 alkyl;
• R.sup.13 is independently selected form the group consisting of C.sub.1 -C.sub.6 alkyl, R.sup.15 -phenyl, R.sup.15 -benzyl, --CF.sub.3 and --C.sub.2 F.sub.5 ;
• R.sup.15 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy or halogeno;
• Q is a bond, --C(O)--, --NR.sup.17 --, --(C(R.sup.9)(R.sup.10))--, --O--, --S(O).sub.e --, --C(X)NR.sup.11 --, --N(R.sup.11)C(X)--, --N(R.sup.11)SO.sub.2 --, --SO.sub.2 N(R.sup.11)-- or --N.sup.+ (R.sup.11)(R.sup.17)--;
• R.sup.16 and R.sup.17 are independently selected from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl, --S(O).sub.e R.sup.13, --COR.sup.11, --(CH.sub.2).sub.m --CO.sub.2 R.sup.13, --CONR.sup.11 R.sup.12, C.sub.2 -C.sub.6 alkenyl, --R.sup.15 -phenyl and R.sup.15 -benzyl;
• X is .dbd.O, .dbd.S or .dbd.N(R.sup.12);
• Y.sup.1 is --(C(R.sup.9)(R.sup.10)).sub.m --, --G--(C(R.sup.9)(R.sup.10)).sub.m -- or --(C(R.sup.9)(R.sup.10)).sub.m --G--;
• G is ##STR82## provided that when m is 0, R.sup.2 is H, C.sub.1 -C.sub.6 alkyl, --CF.sub.3, --C.sub.2 F.sub.5, --COR.sup.11, --CO.sub.2 R.sup.11, --CON(R.sup.11)(R.sup.12), R.sup.15 -phenyl or R.sup.15 -benzyl;
• ##STR83## provided that when p is 0, T is not OH or --NR.sup.11 R.sup.12 ;
• ##STR84## provided that when r is 1, T is not OR.sup.11 or --NR.sup.11 R.sup.12 ;
• or ##STR85## provided T is not --OR.sup.11, --N(R.sup.11)(R.sup.12), --S(O).sub.e R.sup.13, --NR.sup.11 CO.sub.2 R.sup.13, --NR.sup.11 COR.sup.12, --NR.sup.11 CON(R.sup.12)(R.sup.14) or --OC(O)N(R.sup.11)(R.sup.12);
• T is H, R.sup.15 -aryl, R.sup.15 -heterocycloalkyl, R.sup.15 -heteroaryl, R.sup.15 -cycloalkyl, --OR.sup.11, --N(R.sup.11)(R.sup.12), --COR.sup.11, --CO.sub.2 R.sup.11, --CON(R.sup.11)(R.sup.12), --S(O).sub.e R.sup.13, --NR.sup.11 CO.sub.2 R.sup.13, --NR.sup.11 COR.sup.12, --NR.sup.11 CON(R.sup.12)(R.sup.14) or --OC(O)N(R.sup.11)(R.sup.12);
• J is a bond, --S(O).sub.e --, --O-- or --N(Z.sup.2)--, --N(Z.sup.2)C(O)-- or --N(Z.sup.2)C(S)--;
• and when G is --C(R.sup.2)H--, J can also be --N(Z.sup.2)C(O)O-- or --OC(O)N(Z.sup.2)--;
• Y.sup.2 is --(C(R.sup.9)(R.sup.10)).sub.m --;
• Z.sup.1 is H, C.sub.1 -C.sub.6 alkyl, R.sup.15 -phenyl, R.sup.15 -benzyl, --CF.sub.3, --C.sub.2 F.sub.5, --NR.sup.11 R.sup.12, --OR.sup.11 or SR.sup.11 ;
• Z.sup.2 is H, C.sub.1 -C.sub.6 alkyl, R.sup.15 -phenyl, R.sup.15 -benzyl, --CF.sub.3 or --C.sub.2 F.sub.5 ;
• provided that when Y.sup.1 is --(C(R.sup.9)(R.sup.10)).sub.m -- and m is 0, Z.sup.1 is not --NR.sup.11 R.sup.12, --OR.sup.11 or --SR.sup.11 ;
• or Z.sup.1 and Z.sup.2 together are --(C(R.sup.9)(R.sup.10)).sub.u --, wherein u is 1 to 4, and wherein with the atoms to which they are attached, form a 4 to 8 membered ring;
• e and n are independently 0, 1 or 2;
• m and p are independently 0, 1, 2 or 3;
• and
• r and s are independently 1, 2, 3 or 4.