US 5,656,623 A · Antimicrobial lactam-quinolones

Abstract

Antimicrobial lactam-quinolone compounds comprising a lactam-containing moiety linked to a quinolone moiety, of the formula: ##STR1## wherein (1) A.sup.1, A.sup.2, A.sup.3, R.sup.1, R.sup.4 and R.sup.6 generally form any of a variety of quinolone, naphthyridine or related cyclic moieties known in the art to have antimicrobial activity; and (2) R.sup.1 or R.sup.3 contain a linking moiety, linking the quinolone moiety to a lactam-containing moiety having the formula: ##STR2## wherein (3) R.sup.10, R.sup.11, R.sup.12, R.sup.13, and R.sup.14, together with bonds "a" and "b", form any of a variety of lactam-containing moieties known in the art to have antimicrobial activity; and (4) the linking moiety includes (for example) carbamate, dithiocarbamate, urea, thiourea, isouronium, isothiouronium, guanidine, carbonate, trithiocarbonate, reversed carbamate, xanthate, reversed isouronium, reversed dithiocarbamate, reversed isothiouronium, amine, imine, ammonium, heteroarylium, ether, thioether, phosphono, phosphoramide, phosphate, sulfonamide, ester, thioester, amide, and hydrazide groups.

A compound having one of the four structures:

##STR357## wherein (A)
(1) A.sup.1 is N or C(R.sup.7);
where
(i) R.sup.7 is hydrogen, hydroxy, alkoxy, nitro, cyano, halogen, C.sub.1 -C.sub.8 alkyl, or N(R.sup.8)(R.sup.9), and
(ii) R.sup.8 and R.sup.9 are, independently, R.sup.8a where R.sup.8a is hydrogen;
C.sub.1 -C.sub.8 alkyl;
C.sub.2 -C.sub.8 alkenyl;
a 3-9 atom monocyclic or 7-17 atom polycyclic carbocycle;
or a 3-9 atom monocyclic or 7-17 atom polycyclic heterocycle;
or R.sup.8 and R.sup.9 together form a 3-9 atom monocyclic or 7-17 atom polycyclic heterocycle including the nitrogen to which they are bonded;
and wherein said heterocycles have one or more heteroatoms selected from O, N, or S;
(2) A.sup.2 is N or C(R.sup.2);
where R.sup.2 is hydrogen or halogen;
(3) A.sup.3 is N or C(R.sup.5);
where R.sup.5 is hydrogen;
(4) R.sup.1 is hydrogen or R.sup.15 ;
(5) R.sup.3 is hydrogen, halogen or R.sup.16 ;
(6) R.sup.15 is a C.sub.1 -C.sub.8 alkyl;
a 3-9 atom monocyclic or 7-17 atom polycyclic carbocycle;
a 3-9 atom monocyclic or 7-17 atom polycyclic heterocycle;
alkoxy;
hydroxy;
C.sub.2 -C.sub.8 alkenyl;
arylalkyl;
or N(R.sup.8)(R.sup.9);
and wherein said arylalkyl is a C.sub.1 -C.sub.8 alkyl substituted with an aryl group;
wherein said heterocycles have one or more heteroatoms selected from O, N, or S;
(7) R.sup.16 is a C.sub.1 -C.sub.8 alkyl;
a 3-9 atom monocyclic or 7-17 atom polycyclic carbocycle;
or a 3-9 atom monocyclic or 7-17 atom polycyclic heterocycle;
wherein said heterocycles have one or more heteroatoms selected from O, N, or S;
(8) R.sup.4 is hydroxy;
and
(9) R.sup.6 is hydrogen, halogen, nitro, or N(R.sup.8)(R.sup.9);
(B) except that
(1) when A.sup.1 is C(R.sup.7), R.sup.1 and R.sup.7 may together form a 3-9 atom monocyclic or 7-17 atom polycyclic heterocycle including N' and A.sup.1 ;
wherein said heterocycles have one or more heteroatoms selected from O, N, or S;
(2) when A.sup.2 is C(R.sup.2), R.sup.2 and R.sup.3 may together form --O--(CH.sub.2).sub.n --O--, where n is an integer from 1 to 4;
(3) when A.sup.3 is C(R.sup.5), R.sup.4 and R.sup.5 may together form a 3-9 atom monocyclic or 7-17 atom polycyclic heterocycle including the carbon atoms to which R.sup.4 and R.sup.5 are bonded and the carbon atom to which said carbon atoms are bonded;
and wherein said heterocycles have one or more heteroatoms selected from O, N, or S;
and
(4) when A.sup.3 is C(R.sup.5), R.sup.1 and R.sup.5 may together form a 3-9 atom monocyclic or 7-17 atom polycyclic heterocycle including N' and the adjacent carbon to which R.sup.5 is bonded;
and wherein said heterocycles have one or more heteroatoms selected from O, N, or S;
(C) R.sup.10 is hydrogen;
halogen;
C.sub.1 -C.sub.8 alkyl;
C.sub.2 -C.sub.8 alkenyl;
a 3-8 atom heteroalkyl having 1 or 2 heteroatoms selected from O, N, or S;
a 3-9 atom monocyclic or 7-17 atom polycyclic carbocycle;
a 3-9 atom monocyclic or 7-17 atom polycyclic heterocycle R.sup.8a --O--;
R.sup.8a CH.dbd.N--;(R.sup.8)(R.sup.9) N--;
R.sup.17 --C(.dbd.CHR.sup.20)--C(.dbd.O)NH--;
R.sup.17 --C(=NO--R.sup.19)--C(.dbd.O)NH--;
or R.sup.18 --(CH.sub.2).sub.m --C(.dbd.O)NH--;
and wherein said heterocycles have one or more heteroatoms selected from O, N, or S;
and where
(1) m is an integer from 0 to 9;
(2) R.sup.17 is hydrogen;
C.sub.1 -C.sub.8 alkyl;
C.sub.2 -C.sub.8 alkenyl;
a 3-8 atom heteroalkyl having 1 or 2 heteroatoms selected from O, N, or S;
a 3-8 atom heteroalkenyl having 1 or 2 heteroatoms selected from O, N, or S;
a 3-9 atom monocyclic or 7-17 atom polycyclic carbocycle;
or a 3-9 atom monocyclic or 7-17 atom polycyclic heterocycle;
wherein said heterocycles have one or more heteroatoms selected from O, N, or S;
(3) R.sup.18 is R.sup.17, --Y.sup.1, or --CH(Y.sup.2)(R.sup.17);
(4) R.sup.19 is R.sup.17 ;
arylalkyl;
heteroarylalkyl;
--C(R.sup.22)(R.sup.23)COOH;
--C(.dbd.O)O--R.sup.17 ;
or --C(.dbd.O)NH--R.sup.17 ;
wherein said arylalkyl is a C.sub.1 -C.sub.8 alkyl substituted with an aryl group and wherein said heteroarylalkyl is a C.sub.1 -C.sub.8 alkyl substituted with an aryl group having one or more heteroatoms selected from O, N, or S;
and where R.sup.22 and R.sup.23 are, independently, R.sup.17 or together form a 3-9 atom monocyclic or 7-17 atom polycyclic carbocycle or a 3-9 atom monocyclic or 7-17 atom polycyclic heterocycle, including the carbon atom to which R.sup.22 and R.sup.23 are bonded;
and wherein said heterocycles have one or more heteroatoms selected from O, N, or S;
(5) R.sup.20 is R.sup.19, halogen, --Y.sup.1, or --CH(Y.sup.2)(R.sup.17);
(6) Y.sup.1 is --C(.dbd.O)OR.sup.21, --C(.dbd.O)R.sup.21, --N(R.sup.24)R.sup.21, --S(O).sub.p R.sup.29, or --OR.sup.29 g;
and Y.sup.2 is Y.sup.1 or --OH, --SH, or --SO.sub.3 H;
(a) p is an integer from 0 to 2;
(b) R.sup.24 is hydrogen;
C.sub.1 -C.sub.8 alkyl;
C.sub.2 -C.sub.8 alkenyl;
a 3-8 atom heteroalkyl having 1 or 2 heteroatoms selected from O, N, or S;
a 3-8 atom heteroalkenyl comprised of 1 or 2 heteroatoms selected from O, N, or S;
a 3-9 atom monocyclic or 7-17 atom polycyclic carbocycle;
a 3-9 atom monocyclic or 7-17 atom polycyclic heterocycle;
--SO.sub.3 H;
--C(.dbd.O)R.sup.25 ;
or, when R.sup.18 is --CH(N(R.sup.24)R.sup.21)(R.sup.17), R.sup.24 and R.sup.21 may together form a 3-9 atom monocyclic or 7-17 atom polycyclic heterocycle;
wherein said heterocycles consists of one or more heteroatoms selected from O, N, or S;
and
(c) R.sup.25 is R.sup.17 ;
NH(R.sup.17);
N(R.sup.17)(R.sup.26);
O(R.sup.26);
or S(R.sup.26);
where R.sup.26 is C.sub.1 -C.sub.8 alkyl;
C.sub.2 -C.sub.8 alkenyl;
a 3-9 atom monocyclic or 7-17 atom polycyclic carbocycle;
a 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle;
or when R.sup.25 is N(R.sup.17)(R.sup.26), R.sup.26 and R.sup.17 may together form a 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle;
wherein said heterocycles have one or more heteroatoms selected from O, N, or S;
and
(7) R.sup.21 is R.sup.29 or hydrogen;
where R.sup.29 is C.sub.1 -C.sub.8 alkyl;
C.sub.2 -C.sub.8 alkenyl;
arylalkyl, consisting of a C.sub.1 -C.sub.8 alkyl substituted with an aryl group;
a 3-8 atom heteroalkyl, having 1 or 2 heteroatoms selected from O, N, or S;
a 3-8 atom heteroalkenyl, having 1 or 2 heteroatoms selected from O, N, or S;
heteroarylalkyl, consisting of a C.sub.1 -C.sub.8 alkyl substituted with an aryl group substituted with a heteroatom;
a 3-9 atom monocyclic or a 7-17 atom polycyclic carbocycle;
a 3 -9 atom monocyclic or a 7-17 atom polycyclic heterocycle;
or, when Y is N(R.sup.24)R.sup.21 and R.sup.21 is R.sup.29, R.sup.21 and R.sup.24 may together form a 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle including the nitrogen atom to which R.sup.24 is bonded;
wherein said heterocycles have one or more heteroatoms selected from O, N, or S;
(D) R.sup.11 is hydrogen, halogen, alkoxy, or R.sup.27 C(.dbd.O)NH--, where R.sup.27 is hydrogen or C.sub.1 -C.sub.8 alkyl;
(E) R.sup.33 is H or COOH;
(F) R.sup.38 is hydrogen, C.sub.1 -C.sub.8 alkyl or alkoxy;
(G) R.sup.37 is nil;
C.sub.1 -C.sub.8 alkyl;
C.sub.2 -C.sub.8 alkenyl;
a 3-9 atom monocyclic or a 7-17 atom polycyclic carbocycle;
or a 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle;
wherein said heterocycles have one or more heteroatoms selected from O, N, or S;
and
(H) L is L', --X.sup.2.sub.t --R.sup.39 --L', or --X.sup.3.sub.t --R.sup.39 --L', where L' is Q', --X.sup.2 --Q", --X.sup.3 --Q", --X.sup.4.sub.t --C(.dbd.Y.sup.3.sub.u)--Z--Q", --X.sup.5.sub.t --PO(Y.sup.4.sub.u R.sup.8a)--Z'--Q", or X.sup.5.sub.t --SO.sub.2 --Z'--Q";
where, in the case of Structure I and Structure II, L' is not a quaternary ammonium moiety, --x.sup.3 --Q" and L' is not a carbamate moiety, --O--C(.dbd.O)--Z--Q", where
(1) t and u are, independently, 0 or 1;
(2) R.sup.39 is C.sub.1 -C.sub.8 alkyl;
C.sub.2 -C.sub.8 alkenyl;
a 3-8 atom heteroalkyl having 1 or 2 heteroatoms selected from O, N, or S;
a 3-8 atom heteroalkenyl having 1 or 2 heteroatoms selected from O, N, or S;
a 3-9 atom monocyclic or a 7-17 atom polycyclic carbocycle;
or a 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle, wherein said heterocycles have one or more heteroatoms selected from O, N, or S;
(3) X.sup.2 is oxygen, or S(O).sub.v, where v is an integer from 0 to 2;
(4) X.sup.3 is nitrogen;
N(R.sup.40);
N.sup.+ (R.sup.41) (R.sup.42);
or R.sup.43 --N(R.sup.41);
and is linked to R.sup.37 by a single or double bond;
where
(a) R.sup.40 is R.sup.8a ;
--OR.sup.8 ;
or --C(.dbd.O)R.sup.8a ;
(b) R.sup.41 and R.sup.42 are, independently, hydrogen;
C.sub.1 -C.sub.8 alkyl;
C.sub.2 -C.sub.8 alkenyl;
a 3-9 atom monocyclic or a 7-17 atom polycyclic carbocycle;
a 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle;
or, together with Q", form a 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle as R.sup.15 or R.sup.16 ;
wherein said heterocycles have one or more heteroatoms selected from O, N, or S;
(c) R.sup.43 is N(R.sup.41), oxygen or sulfur;
(5) X.sup.4 is oxygen, sulfur, NR.sup.40, or R.sup.43 --NR.sup.41 ;
(6) X.sup.5 is oxygen or NR.sup.41 ;
(7) Y.sup.3 is oxygen, sulfur, NR.sup.40 or N.sup.+ (R.sup.41)(R.sup.42);
(8) Y.sup.4 is oxygen or NR.sup.41 ;
(9) Z is nil, oxygen, sulfur, nitrogen, NR.sup.40, or N(R.sup.41)--R.sup.43 ;
(10) Z' is nil, oxygen, nitrogen, or NR.sup.41 ;
(11) Q' is R.sup.15 or R.sup.16 ;
and
(12) Q" is Q';
or together with X.sup.2, X.sup.3, Z or Z', is an R.sup.15 or R.sup.16 group;
and pharmaceutically-acceptable salts and biohydrolyzable esters thereof, and hydrates thereof.

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Antimicrobial lactam-quinolones

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Antimicrobial lactam-quinolones

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Abstract

Claims101