US 6,140,351 A · Ortho-anthranilamide derivatives as anti-coagulants

Abstract

This invention is directed to compounds of formula (III): ##STR1## wherein B, C, D, E, R.sup.1, R.sup.2 and R.sup.3 are disclosed herein. These compounds are disclosed as being useful as anti-coagulants.

A compound of formula (I):

##STR55## wherein:
A is =N--;
m is 1 to 3;
n is 1 to 4;
D is --N(R.sup.5)--C(Z)-- or --N(R.sup.5)--S(O).sub.p -- (where p is 0 to 2;
Z is oxygen, sulfur or H.sub.2 ;
and the nitrogen atom is directly bonded to the phenyl ring having the R.sup.1 and R.sup.2 substituents);
E is --C(Z)--N(R.sup.5)-- or --S(O).sub.p --N(R.sup.5)-- (where p is 0 to 2;
Z is oxygen, sulfur or H.sub.2 ;
and the nitrogen atom can be bonded to the phenyl ring having the R.sup.1 and the R.sup.2 substituents or to the aromatic ring having the R.sup.4 substituent);
each R.sup.1 is independently hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, --OR.sup.5, --S(O).sub.p --R.sup.9 (where p is 0 to 2), --C(O)OR.sup.5, --C(O)N(R.sup.5)R.sup.6, --N(R.sup.5)R.sup.6, --O--C(O)R.sup.5, or --N(R.sup.5)--CH(R.sup.12)--C(O)OR.sup.5 ;
or two adjacent R.sup.1, s together with the carbons to which they are attached form a heterocyclic ring fused to the phenyl ring wherein the heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl and aralkyl;
R.sup.2 is hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, --OR.sup.5, --S(O).sub.p --R.sup.9 (where p is 0 to 2), --C(O)OR.sup.5, --OC(O)--R.sup.5, --C(O)N(R.sup.5)R.sup.6, --N(R.sup.10)R.sup.11, --C(R.sup.7)H--N(R.sup.10)R.sup.11, --C(R.sup.7)H--R.sup.8 --N(R.sup.10)R.sup.11, --C(R.sup.7)H--OR.sup.5, --C(R.sup.7)H--R.sup.8 --OR.sup.5, --C(R.sup.7)H--S(O).sub.p --R.sup.9 (where p is 0 to 2), --C(R.sup.7)H--R.sup.8 --S(O).sub.p --R.sup.9 (where p is 0 to 2), --O--R.sup.8 --S(O).sub.p --R.sup.9 (where p is 0 to 2), --C(R.sup.7)H--N(R.sup.5)R.sup.6, --C(R.sup.7)H--R.sup.8 --N(R.sup.5)R.sup.6, --O--R.sup.8 --CH(OH)--CH.sub.2 --N(R.sup.10)R.sup.11, --O--R.sup.8 --N(R.sup.10)R.sup.11, --O--R.sup.8 --O--C(O)R.sup.5, --O--R.sup.8 --CH(OH)--CH.sub.2 --OR.sup.5, --O--(R.sup.8 --O).sub.t --R.sup.5 (where t is 1 to 6), --O--(R.sup.8 --O).sub.t --R.sup.19 (where t is 1 to 6), --O--R.sup.8 --C(O)R5, --O--R.sup.8 --C(O)R.sup.19, --O--R.sup.8 --C(O)OR.sup.5, --N(R.sup.5)--R.sup.8 --N(R.sup.10)R.sup.11, --S(O).sub.p --R.sup.8 --N(R.sup.5)R.sup.6 (where p is 0 to 2), --S(O).sub.p --R.sup.8 --C(O)OR.sup.5 (where p is 0 to 2), or --N(R.sup.5)--CH(R.sup.12)--C(O)OR.sup.5 ;
R.sup.3 is a radical of formula (i):
##STR56## where:
r is 1 or2;
R.sup.13 is hydrogen, alkyl, halo, haloalkyl, --N(R.sup.5)R.sup.6, --C(R.sup.7)H--N(R.sup.5)R.sup.6, O--R.sup.5, --R.sup.8 --OR.sup.5, --S(O).sub.p --R.sup.8 --N(R.sup.5)R.sup.6 (where p is 0 to 2) or heterocyclylalkyl (where the heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, aralkyl, nitro and cyano);
and
each R.sup.14 is independently hydrogen, alkyl, halo, formyl, acetyl, cyano, --R.sup.8 --CN, --N(R.sup.10)R.sup.11, --C(R.sup.7)H--N(R.sup.10)R.sup.11, --C(R.sup.7)H--R.sup.8 --N(R.sup.10)R.sup.11, --C(R.sup.7)H--N.sup..sym. (R.sup.9)(R.sup.16).sub.2, --C(R.sup.7)H--R.sup.8 --N.sup..sym. (R.sup.9)(R.sup.16).sub.2, --C(O)OR.sup.5, --C(R.sup.7)H--C(O)OR.sup.5, --C(R.sup.7)H--R.sup.8 --C(O)OR.sup.5, --OR.sup.5, --C(R.sup.7)H--OR.sup.5, --C(R.sup.7)H--R.sup.8 --OR.sup.5, --C(R.sup.7)H--O--R.sup.15, --S(O).sub.p --R.sup.15 (where p is 0 to 2), --C(R.sup.7)H--S(O).sub.p --R.sup.15 (where p is 0 to 2), --C(R.sup.7)H--R.sup.8 --S(O).sub.p --R.sup.15 (where p is 0 to 2), --S(O).sub.p --N(R.sup.5)R.sup.6 (where p is 0 to 2), --C(O)N(R.sup.5)R.sup.6, --C(R.sup.7)H--C(O)N(R.sup.5)R.sup.6, --C(R.sup.7)H--R.sup.8 --C(O)N(R.sup.5)R.sup.6, --C(R.sup.7)H--N(R.sup.5)--(R.sup.8 --O).sub.t --R.sup.5 (where t is 1 to 6), --C(R.sup.7)H--R.sup.8 --N(R.sup.5)--(R.sup.8 --O).sub.t --R.sup.5 (where t is 1 to 6), --C(R.sup.7)H--O--(R.sup.8 --O).sub.t --R.sup.5 (where t is 1 to 6), --C(R.sup.7)H--R.sup.8 --O--(R.sup.8 --O).sub.t --R.sup.5 (where t is I to 6), --O--R.sup.8 --CH(OH)--CH.sub.2 --OR.sup.5, --C(R.sup.7)H--O--R.sup.8 --CH(OH)--CH.sub.2 --OR.sup.5, --C(R.sup.7)H--N(R.sup.5)--R.sup.8 --[CH(OH)].sub.t --CH.sub.2 --OR.sup.5 (where t is 1 to 6), --C(R.sup.7)H--N(R.sup.5)--S(O).sub.2 --N(R.sup.10)R.sup.11, --C(R.sup.7)H--N(R.sup.10)--C(NR.sup.17)--N(R.sup.10)R.sup.11, --C(R.sup.7)H--N(R.sup.10)--C(N R.sup.17)--R.sup.10, --C(NR.sup.17)--N(R.sup.5)R.sup.6, --C(R.sup.7)H--C(NR.sup.17)--N(R.sup.5)R.sup.6, --C(R.sup.7)H--O--N(R.sup.5)R.sup.6, heterocyclyl (wherein the heterocyclyl radical is not attached to the radical of formula (i) through a nitrogen atom and is optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, --OR.sup.5, --C(O)OR.sup.5, --N(R.sup.5)R.sup.6 or --C(O)N(R.sup.5)R.sup.6), or heterocyclylalkyl (wherein the heterocyclyl radical is not attached to the alkyl radical through a nitrogen atom and is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, --OR.sup.5, --C(O)OR.sup.5, --N(R.sup.5)R.sup.6 and --C(O)N(R.sup.5)R.sup.6);
each R.sup.4 is independently hydrogen, alkyl, halo, haloalkyl, cyano, nitro, --OR.sup.5, --C(O)OR.sup.5, --N(R.sup.5)R.sup.6, --C(O)N(R.sup.5)R.sup.6, or --R.sup.8 --N(R.sup.5)R.sup.6 ;
R.sup.5 and R.sup.6 are each independently hydrogen, alkyl, aryl or aralkyl;
each R.sup.7 is independently hydrogen or alkyl;
each R.sup.8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R.sup.9 is independently alkyl, aryl or aralkyl;
R.sup.10 and R.sup.11 are each independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl, cyano, --R.sup.8 --CN, --OR.sup.5, --R.sup.8 --OR.sup.5, --S(O).sub.p --R.sup.15 (where p is 0 to 2), --R.sup.8 --S(O)p--R.sup.15 (where p is 0 to 2), --N(R.sup.5)R.sup.6, --R.sup.8 --N(R.sup.5)R.sup.6, --R.sup.8 --C(O)OR.sup.5, --C(O)--R.sup.15, --C(O)NH.sub.2, --R.sup.8 --C(O)NH.sub.2, --C(S)NH.sub.2, --C(O)--S--R.sup.5, --C(O)--N(R.sup.5)R.sup.15, --R.sup.8 --C(O)--N(R.sup.5)R.sup.15, --C(S)--N(R.sup.5)R.sup.15, --R.sup.8 --N(R.sup.5)--C(O)H, --R.sup.8 --N(R.sup.5)--C(O)R.sup.15, --C(O)O--R.sup.8 --N(R.sup.5)R.sup.6, --C(N(R.sup.5)R.sup.6)=C(R.sup.18)R.sup.10, --R.sup.8 --N(R.sup.5)-P(O)(OR.sup.5).sub.2, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and --OR.sup.5), heterocyclyl (optionally substituted by one or more substituents selected from alkyl, aryl, aralkyl, halo, haloalkyl, oxo, --OR.sup.5, --R.sup.8 --OR.sup.5, --C(O)OR.sup.5, --S(O).sub.p --R.sup.9 (where p is 0 to 2), --R.sup.8 --S(O).sub.p --R.sup.9 (where p is 0 to 2), --N(R.sup.5)R.sup.6 and --C(O)N(R.sup.5)R.sup.6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, --OR.sup.5, --R.sup.8 --OR.sup.5, --C(O)OR.sup.5, --S(O).sub.p --R.sup.9 (where p is 0 to 2), --R.sup.8 --S(O).sub.p --R.sup.9 (where p is 0 to 2), --N(R.sup.5)R.sup.6 and --C(O)N(R.sup.5)R.sup.6);
or R.sup.10 and R.sup.11 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, aryl, aralkyl, oxo, nitro, cyano, --R.sup.8 --CN, =N(R.sup.17), --OR.sup.5, --C(O)OR.sup.5, --R.sup.8 --C(O)OR.sup.5, --N(R.sup.5)R.sup.6, --R.sup.8 --N(R.sup.5)R.sup.6, --C(O)N(R.sup.5)R.sup.6, --R.sup.8 --C(O)N(R.sup.5)R.sup.6, --N(R.sup.5)--N(R.sup.5)R.sup.6, --C(O)R.sup.5, --C(O)--(R.sup.8 --O).sub.t --R.sup.5 (where t is 1 to 6), --S(O)p--R.sup.9 (where p is 0 to 2), --R.sup.8 --S(O).sub.p --R.sup.9 (where p is 0 to 2), --(R.sup.8 --O).sub.t --R.sup.5 (where t is 1 to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, --OR.sup.5, --C(O)OR.sup.5, --N(R.sup.5)R.sup.6, and --C(O)N(R.sup.5)R.sup.6);
R.sup.12 is a side chain of an .alpha.-amino acid;
each R.sup.15 is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, --R.sup.8 --O--C(O)--R.sup.5, --R.sup.8 --OR.sup.5, --N(R.sup.5)R.sup.6, --R.sup.8 --N(R.sup.5)R.sup.6, --R.sup.8 --C(O)OR.sup.5, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, --OR.sup.5, --R.sup.8 --OR.sup.5, --C(O)OR.sup.5, --N(R.sup.5)R.sup.6, and --C(O)N(R.sup.5)R.sup.6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, --OR.sup.5, --R.sup.8 --OR.sup.5, --C(O)OR.sup.5, --N(R.sup.5)R.sup.6, and --C(O)N(R.sup.5)R.sup.6);
or R.sup.5 and R.sup.15 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, --OR.sup.5, --C(O)OR.sup.5, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl;
each R.sup.16 is independently alkyl, aryl, aralkyl, --R.sup.8 --OR.sup.5, --R.sup.8 --N(R.sup.5)R.sup.6, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and --OR.sup.5), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, --OR.sup.5, --C(O)OR.sup.5, --N(R.sup.5)R.sup.6 or --C(O)N(R.sup.5)R.sup.6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, --OR.sup.5, --C(O)OR.sup.5, --N(R.sup.5)R.sup.6 and --C(O)N(R.sup.5)R.sup.6);
or
both R.sup.16' s together with the nitrogen to which they are attached (and wherein the R.sup.9 substituent is not present) form an aromatic N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, --OR.sup.5, --C(O)OR.sup.5, --R.sup.8 --C(O)OR.sup.5, --N(R.sup.5)R.sup.6, --R.sup.8 --N(R.sup.5)R.sup.6, --C(O)R.sup.5, --C(O)--(R.sup.8 --O).sub.t --R.sup.5 (where t is 1 to 6), and --(R.sup.8 --O).sub.t --R.sup.5 (where t is 1 to 6);
each R.sup.17 is independently hydrogen, alkyl, aryl, aralkyl, cyano, --OR.sup.5, --R.sup.8 --OR.sup.5, --C(O)OR.sup.5, --R.sup.8 --C(O)OR.sup.5, --C(O)--N(R.sup.5)R.sup.6, or --R.sup.8 --C(O)--N(R.sup.5)R.sup.6 ;
R.sup.18 is hydrogen, alkyl, aryl, aralkyl, cyano, --C(O)OR.sup.5, or --NO.sub.2 ;
and
each R.sup.19 is cycloalkyl, haloalkyl, --R.sup.8 --OR.sup.5, --R.sup.8 --N(R.sup.5)R.sup.6, --R.sup.8 --C(O)OR.sup.5, --R.sup.8 --C(O)N(R.sup.5)R.sup.6, heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, --OR.sup.5, --C(O)OR.sup.5, --N(R.sup.5)R.sup.6 or --C(O)N(R.sup.5)R.sup.6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, --OR.sup.5, --C(O)OR.sup.5, --N(R.sup.5)R.sup.6 and --C(O)N(R.sup.5)R.sup.6);
as a single stereoisomer or a mixture thereof;
or a pharmaceutically acceptable salt thereof.

35 more elements

Ortho-anthranilamide derivatives as anti-coagulants

Life of this patent

Ortho-anthranilamide derivatives as anti-coagulants

Life of this patent

Abstract

Claims50