US 5,780,483 A · IL-8 receptor antagonists

Abstract

This invention relates to novel compounds and a novel use of phenyl ureas in the treatment of disease scates mediated by the chemokine, Interleukin-8 (IL-8). In particular, this invention relates to the novel compounds of Formula (Ia) and their use in treating chemokine mediated diseases wherein the chemokine binds to an IL-8 a or b receptor. Compounds of Formula (Ia) are represented by the structure: ##STR1## wherein interalia, X is oxygen or sulfur; Rb is NR.sub.6 R.sub.7, alkcyl, aryl, arylC.sub.1-4 alkyl, aryl C.sub.2-4 alkenyl, heteroaryl, heteroarylC.sub.1-4 alkyl, heteroarylC.sub.2-4 alkenyl, heterocyclic or heterocyclic C.sub.1-4 alkyl, or a heterocyclic C.sub.2-4 alkenyl moiety, camphor, all of which may be optionally substituted; R.sub.1 is independently selected from hydrogen; halogen; nitro; cyano; C.sub.1-10 alkyl; halosubstituted C.sub.1-10 alkyl; C.sub.2-10 alkoxy; halosubstituted C.sub.1-10 alkoxy; azide; (CR.sub.8 R.sub.8)q S(O).sub.t R.sub.4 ; hydroxy; hydroxy substituted C.sub.1-4 alkyl; aryl; aryl C.sub.1-4 alkyl; aryl C.sub.2-10 alkenyl; aryloxy; aryl C.sub.1-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C.sub.2-10 alkenyl; heteroaryl C.sub.1-4 alkyloxy; heterocyclic; heterocyclic C.sub.1-4 alkyl; heterocyclicC.sub.1-4 alkyloxy; heterocyclic C.sub.2-10 alkenyl; q is 0 or an integer having a value of 1 to 10; n is an integer having a value of 1 to 3; m is an integer having a value of 1 to 3; Y is hydrogen; halogen; nitro; cyano; halosubstituted C.sub.1-10 alkyl; C.sub.1-10 alkyl; C.sub.2-10 alkenyl C.sub.1-10 alkoxy; halosubstituted C.sub.1-10 alkoxy; azide; (CR.sub.8 R.sub.8)qS(O).sub.t R.sub.4, (CR.sub.8 R.sub.8)qOR.sub.4 ; hydorxy; hydroxy substituted C.sub.1-4 alkyl; aryl; aryl C.sub.1-4 alkyl; aryloxy; arylC.sub.1-4 alkyloxy; aryl C.sub.2-10 alkenyl; heteroaryl; heteroarylalkyl; heteroaryl C.sub.1-4 alkyloxy; heteroaryl C.sub.2-10 alkenyl; heterocyclic, heterocyclic C.sub.1-4 alkyl; heterocyclicC.sub.2-10 alkenyl; or a pharmaceutically acceptable salt thereof.

A method of treating a chemokine mediated disease in a mammal in need thereof, wherein the chemokine binds to an IL-8 a or b receptor, which method comprises administering to said mammal an effective amount of a compound of the formula:

##STR19## wherein X is oxygen or sulfur;
R.sub.a is an alkyl, aryl, arylC.sub.1-4 alkyl, heteroaryl, heteroaryl C.sub.1-4 alkyl, heterocyclic, or a heterocyclic C.sub.1-4 alkyl moiety, all of which may be optionally substituted;
R.sub.b is a NR.sub.6 R.sub.7, alkyl, aryl, arylC.sub.1-4 alkyl, aryl C.sub.2-4 alkenyl, heteroaryl, heteroarylC.sub.1-4 alkyl, heteroarylC.sub.2-4 alkenyl, heterocyclic, or heterocyclic C.sub.1-4 alkyl, or a heterocyclic C.sub.2-4 alkenyl moiety, camphor, all of which may be optionally substituted one to three times independently by halogen;
nitro;
halosubstituted C.sub.1-4 alkyl;
C.sub.1-4 alkyl;
C.sub.1-4 alkoxy;
NR.sub.9 C(O)R.sub.a, S(O).sub.m R.sub.a, C(O)NR.sub.6 R.sub.7, S(O).sub.3 H, or C(O)OC.sub.1-4 alkyl;
R.sub.6 and R.sub.7 are independently hydrogen, or a C.sub.1-4 alkyl group, or R.sub.6 and R.sub.7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur, which ring may be optionally substituted;
R.sub.9 is hydrogen or a C.sub.1-4 alkyl;
R.sub.1 is independently selected from hydrogen;
halogen;
nitro, cyano;
C.sub.1-10 alkyl;
halosubstituted C.sub.1-10 alkyl;
C.sub.2-10 alkenyl;
C.sub.1-10 alkoxy;
halosubstituted C.sub.1-10 alkoxy;
azide;
(CR.sub.8 R.sub.8)q S(O).sub.t R.sub.4 ;
hydroxy;
hydroxy substituted C.sub.1-4 alkyl;
aryl;
aryl C.sub.1-4 alkyl;
aryl C.sub.2-10 alkenyl;
aryloxy;
aryl C.sub.1-4 alkyloxy;
heteroaryl;
heteroarylalkyl;
heteroaryl C.sub.2-10 alkenyl;
heteroaryl C.sub.1-4 alkyloxy;
heterocyclic, heterocyclic C.sub.1-4 alkyl;
heterocyclicC.sub.1-4 alkyloxy;
heterocyclicC.sub.2-10 alkenyl;
(CR.sub.8 R.sub.8)q NR.sub.4 R.sub.5 ;
(CR.sub.8 R.sub.8)q C(O)NR.sub.4 R.sub.5 ;
C.sub.2-10 alkenyl C(O)NR.sub.4 R.sub.5 ;
(CR.sub.8 R.sub.8)q C(O)NR.sub.4 R.sub.10 ;
S(O).sub.3 R.sub.8 ;
(CR.sub.8 R.sub.8)q C(O)R.sub.11 ;
C.sub.2-10 alkenyl C(O)R.sub.11 ;
C.sub.2-10 alkenyl C(O)OR.sub.11 ;
(CR.sub.8 R.sub.8)q C(O)OR.sub.11 ;
(CR.sub.8 R.sub.8)q C(O)OR.sub.12 ;
(CR.sub.8 R.sub.8)qOC(O)R.sub.11 ;
(CR.sub.8 R.sub.8)qNR.sub.4 C(O)R.sub.11 ;
(CR.sub.8 R.sub.8)q C(NR.sub.4)NR.sub.4 R.sub.5 ;
(CR.sub.8 R.sub.8)q NR.sub.4 C(NR.sub.5)R.sub.11, (CR.sub.8 R.sub.8)q NHS(O).sub.2 R.sub.13 ;
(CR.sub.8 R.sub.8)q S(O).sub.2 NR.sub.4 R.sub.5, or two R.sub.1 moieties together may form O--(CH.sub.2).sub.s O-- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl heterocyclic, and heterocyclic alkyl moieties may be optionally substituted;
t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
R.sub.4 and R.sub.5 are independently hydrogen, optionally substituted C.sub.1-4 alkyl, optionally substituted aryl, optionally substituted aryl C.sub.1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C.sub.1-4 alkyl, heterocyclic, heterocyclicC.sub.1-4 alkyl, or R.sub.4 and R.sub.5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;
Y is hydrocgen;
halogen;
nitro;
cyano;
halosubstituted C.sub.1-10 alkyl;
C.sub.1-10 alkyl;
C.sub.2-10 alkenyl, C.sub.1-10 alkoxy;
halosubstituted C.sub.1-10 alkoxy;
azide;
(CR.sub.8 R.sub.8)qS(O).sub.t R.sub.4, (CR.sub.8 R.sub.8)qOR.sub.4 ;
hydroxy;
hydroxy substituted C.sub.1-4 alkyl;
aryl, aryl C.sub.1-4 alkyl;
aryloxy;
arylC.sub.1-4 alkyloxy;
aryl C.sub.2-10 alkenyl;
heteroaryl;
heteroarylalkyl;
heteroaryl C.sub.1-4 alkyloxy;
heteroaryl C.sub.2-10 alkenyl;
heterocyclic, heterocyclic C.sub.1-4 alkyl;
heterocyclicC.sub.2-10 alkenyl;
(CR.sub.8 R.sub.8)qNR.sub.4 R.sub.5 ;
C.sub.2-10 alkenyl C(O)NR.sub.4 R.sub.5 ;
(CR.sub.8 R.sub.8)qC(O)NR.sub.4 R.sub.5 ;
(CR.sub.8 R.sub.8)q C(O)NR.sub.4 R.sub.10 ;
S(O).sub.3 R.sub.8 ;
(CR.sub.8 R.sub.8)qC(O)R.sub.11 ;
C.sub.2-10 alkenylC(O)R.sub.11 ;
(CR.sub.8 R.sub.8)qC(O)OR.sub.11 ;
C.sub.2-10 alkenylC(O)OR.sub.11 ;
(CR.sub.8 R.sub.8)qOC(O)R.sub.11 ;
(CR.sub.8 R.sub.8)qNR.sub.4 C(O)R.sub.11 ;
(CR.sub.8 R.sub.8)q NHS(O).sub.2 R.sub.b ;
(CR.sub.8 R.sub.8)q S(O).sub.2 NR.sub.4 R.sub.5 ;
(CR.sub.8 R.sub.8)qC(NR.sub.4)NR.sub.4 R.sub.5 ;
(CR.sub.8 R.sub.8)q NR.sub.4 C(NR.sub.5)R.sub.11 ;
or two Y moieties together may form O--(CH.sub.2).sub.s O-- or a 5 to 6 membered unsaturated ring;
and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups nay be optionally substituted;
q is 0 or an integer having a value of 1 to 10;
n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3;
m' is 0 or an integer having a value of 1 or 2;
R.sub.8 is hydrogen or C.sub.1-4 alkyl
R.sub.10 is C.sub.1-10 alkyl C(O).sub.2 R.sub.8 ;
R.sub.11 is hydrogen, optionally substituted C.sub.1-4 alkyl, optionally suLbstituted aryl, optionally substituted aryl C.sub.1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC.sub.1-4 alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC.sub.1-4 alkyl;
R.sub.12 is hydrogen, C.sub.1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;
R.sub.13 is C.sub.1-4 alkyl, aryl, aryl C.sub.1-4 alkyl, heteroaryl, heteroarylC.sub.1-4 alkyl, heterocyclic, or heterocyclicC.sub.1-4 alkyl;
or a pharmaceutically acceptable salt thereof.

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IL-8 receptor antagonists

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IL-8 receptor antagonists

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Abstract

Claims12