US 5,328,908 A · Antimicrobial quinolone thioureas

Abstract

Antimicrobial quinolone thiourea compounds of the general formula: ##STR1## wherein (1) A.sup.1, A.sup.2, A.sup.3, R.sup.1, R.sup.3, R.sup.4, and R.sup.6 form any of a variety of quinolone and related heterocyclic structures similar to those known in the art to have antimicrobial activity; and (2) (1) R.sup.1 is X, R.sup.3 is X, or both R.sup.1 and R.sup.3 are X; and (2) X is --R.sup.15 --N(R.sup.16)(R.sup.17) or --R.sup.15 --R.sup.18 --N(R.sup.19)(R.sup.17), where (a) (1) R.sup.15 is nil, alkyl, a carbocyclic ring, or a heterocyclic ring; and (2) R.sup.16 is hydrogen; alkyl; alkenyl; a carbocyclic ring; a heterocyclic ring; or (3) when X is R.sup.15 --N(R.sup.16)(R.sup.17), R.sup.16 and R.sup.15 may together comprise a heterocyclic ring including the nitrogen atom to which R.sup.15 and R.sup.16 are bonded; (b) R.sup.17 is C(.dbd.S)--NR.sup.20 R.sup.21 ; where R.sup.20 is, hydrogen, alkyl, alkenyl, a carbocyclic ring or a heterocyclic ring; and R.sup.21 is R.sup.20 or N(R.sup.20)(R.sup.20); or R.sup.20 and R.sup.21, together with the nitrogen to which they are bonded, form a heterocyclic ring; and (c) (1) R.sup.18 is alkyl, a carbocyclic ring, or a heterocyclic ring; and (2) R.sup.19 is hydrogen; alkyl; alkenyl; a carbocyclic ring; a heterocyclic ring; or (3) R.sup.18 and R.sup.19 may together comprise a heterocyclic ring including the nitrogen atom to which R.sup.18 and R.sup.19 are bonded; and pharmaceutically-acceptable salts and biohydrolyzable esters thereof, and hydrates thereof.

Thiourea-containing compounds having one of the following structures:

##STR12## wherein (A)
(1) X is the thiourea-containing moiety --R.sup.15 --N(R.sup.16)(R.sup.17) or --R.sup.15 --R.sup.18 --N(R.sup.19)(R.sup.17), where
(a)
(i) R.sup.15 is nil;
C.sub.1 -C.sub.8 alkyl;
a 3-9 atom monocyclic or 7-17 atom polycyclic carbocycle;
or a 4-9 atom monocyclic or 7-17 atom polycyclic heterocycle;
wherein said heterocycles have one or more heteroatoms chosen from O, S, or N;
and
(ii) R.sup.16 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;
a 4-9 atom monocyclic or 7-17 atom polycyclic heterocycle;
wherein said heterocycles have one or more heteroatoms chosen from O, S, or N;
or
(iii) when X is R.sup.15 --N(R.sup.16)(R.sup.17), R.sup.16 and R.sup.15 may together comprise a 4-9 atom monocyclic or 7-17 atom polycyclic heterocycle including the nitrogen atom to which R.sup.15 and R.sup.16 are bonded;
wherein said heterocycles have one or more heteroatoms chosen from O, S, or N;
(b) R.sup.17 is --C(.dbd.S)--NR.sup.20 R.sup.21, where R.sup.20 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 4-9 atom monocyclic or 7-17 atom polycyclic heterocycle;
wherein said heterocycles have one or more heteroatoms chosen from O, S, or N;
and R.sup.21 is R.sup.20 or N(R.sup.20)(R.sup.20);
or R.sup.20 and R.sup.21, together with the nitrogen to which they are bonded, form a 4-9 atom monocyclic or 7-17 atom polycyclic heterocycle;
wherein said heterocycles have one or more heteroatoms chosen from O, S, or N;
and
(c)
(i) R.sup.18 is C.sub.1 -C.sub.8 alkyl;
a 3-9 atom monocyclic or 7-17 atom polycyclic carbocycle;
or a 4-9 atom monocyclic or 7-17 atom polycyclic heterocycle;
wherein said heterocycles have one or more heteroatoms chosen from O, S, or N;
and
(ii) R.sup.19 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;
a 4-9 atom monocyclic or 7-17 atom polycyclic heterocycle;
wherein said heterocycles have one or more heteroatoms chosen from O, S, or N;
or
(iii) R.sup.18 and R.sup.19 may together comprise a 4-9 atom monocyclic or 7-17 atom polycyclic heterocycle including the nitrogen atom to which R.sup.18 and R.sup.19 are bonded;
wherein said heterocycles have one or more heteroatoms chosen from O, S, or N;
(2) A.sup.1 is C(R.sup.7);
where
(a) 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
(b) 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;
3-9 atom monocyclic or 7-17 atom polycyclic carbocycle;
or 4-9 atom monocyclic or 7-17 atom polycyclic heterocycle;
or R.sup.8 and R.sup.9 together comprise a 4-9 atom monocyclic or 7-17 atom polycyclic heterocycle that includes the nitrogen atom to which they are bonded;
wherein said heterocycles have one or more heteroatoms chosen from O, S, or N;
(3) A.sup.2 is C(R.sup.2);
where R.sup.2 is hydrogen or halogen;
(4) A.sup.3 is C(R.sup.5);
where R.sup.5 is hydrogen;
(5) R.sup.1 is hydrogen;
C.sub.1 -C.sub.8 alkyl;
a 3-9 atom monocyclic or 7-17 atom polycyclic carbocycle;
a 4-9 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);
wherein said heterocycles have one or more heteroatoms chosen from O, S, or N;
(6) R.sup.3 is hydrogen;
halogen;
C.sub.1 -C.sub.8 alkyl;
a 3-9 atom monocyclic or 7-17 atom polycyclic carbocycle;
or a 4-9 atom monocyclic or 7-17 atom polycyclic heterocycle;
wherein said heterocycles have one or more heteroatoms chosen from O, S, or N;
(7) R.sup.4 is hydroxy;
and
(8) R.sup.6 is hydrogen, C.sub.1 -C.sub.8 alkyl, halogen, nitro, N(R.sup.8)(R.sup.9), or S(R.sup.8a);
(B) and where
(1) R.sup.1 and R.sup.7 may together comprise a 4-9 atom monocyclic or 7-17 atom polycyclic heterocycle including N' and A.sup.1, wherein said heterocycles have one or more heteroatoms chosen from O, S, or N;
(2) R.sup.2 and R.sup.3 may together comprise --O--(CH.sub.2).sub.n --O--, where n is from 1 to 4;
(3) R.sup.4 and R.sup.5 may together comprise a 4-9 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;
wherein said heterocycles have one or more heteroatoms chosen from O, S, or N;
and
(4) R.sup.1 and R.sup.5 may together comprise a 4-9 atom monocyclic or 7-17 atom polycyclic heterocycle including N') and the adjacent carbon to which R.sup.5 is bonded;
wherein said heterocycles have one or more heteroatoms chosen from O, S, or N;
and pharmaceutically-acceptable salts and biohydrolyzable esters thereof, and hydrates thereof.

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Antimicrobial quinolone thioureas

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Antimicrobial quinolone thioureas

Life of this patent

Abstract

Claims26