IL-8 receptor antagonists
First Claim
Patent Images
1. A compound of the formula:
-
whereinX is oxygen;
X1 is oxygen or sulfur;
R1 is independently selected from hydrogen;
halogen;
nitro;
cyano;
C1-10 alkyl;
halosubstituted C1-10 alkyl;
C2-10 alkenyl;
C1-10 alkoxy;
halosubstituted C1-10alkoxy;
azide;
S(O)tR4;
(CR8R8)q S(O)tR4;
hydroxy;
hydroxy substituted C1-4alkyl;
aryl;
aryl C1-4 alkyl;
aryl C2-10 alkenyl;
aryloxy;
aryl C1-4 alkyloxy;
heteroaryl;
heteroarylalkyl;
heteroaryl C2-10 alkenyl;
heteroaryl C1-4 alkyloxy;
heterocyclic, heterocyclic C1-4alkyl;
heterocyclicC1-4alkyloxy;
heterocyclicC2-10 alkenyl;
(CR8R8)q NR4R5;
(CR8R8)q C(O)NR4R5;
C2-10 alkenyl C(O)NR4R5;
(CR8R8)q C(O)NR4R10;
S(O)3R8;
(CR8R8)q C(O)R11;
C2-10 alkenyl C(O)R11;
C2-10 alkenyl C(O)OR11;
(CR8R8)q C(O)OR11;
(CR8R8)q OC(O)R11;
(CR8R8)qNR4C(O)R11;
(CR8R8)q C(NR4)NR4R5;
(CR8R8)q NR4C(NR5)R11;
(CR8R8)q NHS(O)2R13;
(CR8R8)q S(O)2NR4R5;
or two R1 moieties together may form O—
(CH2)sO—
or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, and heterocyclic moieties are substituted;
or unsubstituted t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
R4 and R5 are independently hydrogen, substituted or unsubstituted C1-4 alkyl, substituted aryl, substituted aryl C1-4alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl C1-4 alkyl, heterocyclic, heterocyclic C1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which does or does not contain an additional heteroatom selected from O, N or S;
Y is hydrogen;
halogen;
nitro;
cyano;
halosubstituted C1-10 alkyl;
C1-10 alkyl;
C2-10 alkenyl;
C1-10 alkoxy;
halosubstituted C1-10 alkoxy;
azide;
(CR8R8)qS(O)tR4;
(CR8R8)qOR4;
hydroxy;
hydroxy substituted C1-4alkyl;
aryl, aryl C1-4 alkyl;
aryloxy;
arylC1-4 alkyloxy;
aryl C2-10 alkenyl;
heteroaryl;
heteroarylalkyl;
heteroaryl C1-4 alkyloxy;
heteroaryl C2-10 alkenyl;
heterocyclic, heterocyclic C1-4alkyl;
heterocyclicC2-10 alkenyl;
(CR8R8)qNR4R5;
C2-10 alkenyl C(O)NR4R5;
(CR8R8)qC(O)NR4R5;
(CR8R8)q C(O)NR4R10;
S(O)3R8;
(CR8R8)qC(O)R11;
C2-10 alkenylC(O)R11;
(CR8R8)qC(O)OR11;
C2-10alkenylC(O)OR11;
(CR8R8)qOC(O) R11;
(CR8R8)qNR4C(O)R11;
(CR8R8)q NHS(O)2Rb;
(CR8R8)q S(O)2NR4R5, (CR8R8)qC(NR4)NR4R5;
(CR8R8)q NR4C(NR5)R11;
or two Y moieties together may form O—
(CH2)sO—
or a 5 to 6 membered unsaturated ring; and
wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups are substituted;
or unsubstituted 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;
R6 and R7 are independently hydrogen or a C1-4 alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring does or does not contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;
R8 is hydrogen or C1-4 alkyl;
R10 is C1-10 alkyl C(O)2R8;
R11 is hydrogen, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl C1-4alkyl, substituted or substituted heteroaryl, substituted heteroaryl C1-4alkyl, substituted or substituted heterocyclic, or substituted or unsubstituted heterocyclicC1-4alkyl;
R12 is hydrogen, C1-1alkyl, substituted or substituted aryl or substituted or substituted arylalkyl;
R13 is C1-4 alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclicC1-4alkyl;
Rb is NR6R7, alkyl, aryl, aryl C1-4 alkyl, aryl C2-4 alkenyl, heteroaryl, heteroaryl C1-4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C1-4 alkyl, heterocyclic C2-4 alkenyl, or camphor, all of which groups are optionally substituted;
provided that when n=1 than Y is substituted in the 2- or 3-position;
when n=2 than Y is di-substituted in the 2′
-3′
-position, the 2′
-5′
-position, the 2′
-6′
position, the 3′
-5′
or the 3′
-6′
position;
when n=3 than Y is trisubstituted in the 2′
-3′
-5′
or the 2′
-3′
-6′
-positions;
further provided that when X1 is O, m=2, R1 is 2-t-butyl, 4-methyl, and n=3 than Y is not 2′
-OH, 3′
-t-butyl, 5′
-methyl;
when X1 is O, m=1, R1 is 4-methyl, and n=2 than Y is not 2′
-OH, 5′
-methyl;
when X1 is O, m=1, R1 is hydrogen, and n=2 than Y is not 2′
-6′
-diethyl;
when X1 is O, m=1, R1 is 6—
OH, and n=2 than Y is not 2′
-5′
-methyl;
when X1 is S, m=1, R1 is 4-ethyl, and n=1 than Y is not 2-methoxy;
when X1 is O, m=1, R1 is 5-nitro, and, n=2 than Y is not 2-fluoro-5-nitro, or 2-methyl-5-nitro, or 2,3,-dichloro, or 2-methyl-6-chloro, or 2,5-dimethoxy, or 2-methyl-3-chloro;
when X1 is O, m=1, R1 is 3-nitro, and n=1, than Y is not hydrogen;
when X1 is O, m=1, R1 is 3-nitro, and n=2, than Y is not 2,5-dichloro;
when X1 is O, m=1, R1 is hydrogen, and n=2, than Y is not 2-methyl-5-chloro;
when X1 is O, m=1, R1 is 5-chloro, and n=1, than Y is not hydrogen;
when X1 is O, m=1, R1 is 5-chloro, and n=2, than Y is not 2-fluoro-5-nitro, or 3,4,-dichloro, or 2-methyl-5-nitro;
when X1 is O, m=1, R1 is 4-amino, and n=1, than Y is not hydrogen;
or a pharmaceutically acceptable salt thereof.
2 Assignments
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Accused Products
Abstract
The present invention relates to novel compounds and a novel use of phenyl ureas in the treatment of disease states mediated by the chemokine Interleukin-8 (IL-8).
124 Citations
18 Claims
-
1. A compound of the formula:
-
wherein X is oxygen;
X1 is oxygen or sulfur;
R1 is independently selected from hydrogen;
halogen;
nitro;
cyano;
C1-10 alkyl;
halosubstituted C1-10 alkyl;
C2-10 alkenyl;
C1-10 alkoxy;
halosubstituted C1-10alkoxy;
azide;
S(O)tR4;
(CR8R8)q S(O)tR4;
hydroxy;
hydroxy substituted C1-4alkyl;
aryl;
aryl C1-4 alkyl;
aryl C2-10 alkenyl;
aryloxy;
aryl C1-4 alkyloxy;
heteroaryl;
heteroarylalkyl;
heteroaryl C2-10 alkenyl;
heteroaryl C1-4 alkyloxy;
heterocyclic, heterocyclic C1-4alkyl;
heterocyclicC1-4alkyloxy;
heterocyclicC2-10 alkenyl;
(CR8R8)q NR4R5;
(CR8R8)q C(O)NR4R5;
C2-10 alkenyl C(O)NR4R5;
(CR8R8)q C(O)NR4R10;
S(O)3R8;
(CR8R8)q C(O)R11;
C2-10 alkenyl C(O)R11;
C2-10 alkenyl C(O)OR11;
(CR8R8)q C(O)OR11;
(CR8R8)q OC(O)R11;
(CR8R8)qNR4C(O)R11;
(CR8R8)q C(NR4)NR4R5;
(CR8R8)q NR4C(NR5)R11;
(CR8R8)q NHS(O)2R13;
(CR8R8)q S(O)2NR4R5;
or two R1 moieties together may form O—
(CH2)sO—
or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, and heterocyclic moieties are substituted;
or unsubstitutedt is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
R4 and R5 are independently hydrogen, substituted or unsubstituted C1-4 alkyl, substituted aryl, substituted aryl C1-4alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl C1-4 alkyl, heterocyclic, heterocyclic C1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which does or does not contain an additional heteroatom selected from O, N or S;
Y is hydrogen;
halogen;
nitro;
cyano;
halosubstituted C1-10 alkyl;
C1-10 alkyl;
C2-10 alkenyl;
C1-10 alkoxy;
halosubstituted C1-10 alkoxy;
azide;
(CR8R8)qS(O)tR4;
(CR8R8)qOR4;
hydroxy;
hydroxy substituted C1-4alkyl;
aryl, aryl C1-4 alkyl;
aryloxy;
arylC1-4 alkyloxy;
aryl C2-10 alkenyl;
heteroaryl;
heteroarylalkyl;
heteroaryl C1-4 alkyloxy;
heteroaryl C2-10 alkenyl;
heterocyclic, heterocyclic C1-4alkyl;
heterocyclicC2-10 alkenyl;
(CR8R8)qNR4R5;
C2-10 alkenyl C(O)NR4R5;
(CR8R8)qC(O)NR4R5;
(CR8R8)q C(O)NR4R10;
S(O)3R8;
(CR8R8)qC(O)R11;
C2-10 alkenylC(O)R11;
(CR8R8)qC(O)OR11;
C2-10alkenylC(O)OR11;
(CR8R8)qOC(O) R11;
(CR8R8)qNR4C(O)R11;
(CR8R8)q NHS(O)2Rb;
(CR8R8)q S(O)2NR4R5, (CR8R8)qC(NR4)NR4R5;
(CR8R8)q NR4C(NR5)R11;
or two Y moieties together may form O—
(CH2)sO—
or a 5 to 6 membered unsaturated ring; and
wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups are substituted;
or unsubstitutedq 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;
R6 and R7 are independently hydrogen or a C1-4 alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring does or does not contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;
R8 is hydrogen or C1-4 alkyl;
R10 is C1-10 alkyl C(O)2R8;
R11 is hydrogen, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl C1-4alkyl, substituted or substituted heteroaryl, substituted heteroaryl C1-4alkyl, substituted or substituted heterocyclic, or substituted or unsubstituted heterocyclicC1-4alkyl;
R12 is hydrogen, C1-1alkyl, substituted or substituted aryl or substituted or substituted arylalkyl;
R13 is C1-4 alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclicC1-4alkyl;
Rb is NR6R7, alkyl, aryl, aryl C1-4 alkyl, aryl C2-4 alkenyl, heteroaryl, heteroaryl C1-4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C1-4 alkyl, heterocyclic C2-4 alkenyl, or camphor, all of which groups are optionally substituted;
provided thatwhen n=1 than Y is substituted in the 2- or 3-position;
when n=2 than Y is di-substituted in the 2′
-3′
-position, the 2′
-5′
-position, the 2′
-6′
position, the 3′
-5′
or the 3′
-6′
position;
when n=3 than Y is trisubstituted in the 2′
-3′
-5′
or the 2′
-3′
-6′
-positions;
further provided thatwhen X1 is O, m=2, R1 is 2-t-butyl, 4-methyl, and n=3 than Y is not 2′
-OH, 3′
-t-butyl, 5′
-methyl;
when X1 is O, m=1, R1 is 4-methyl, and n=2 than Y is not 2′
-OH, 5′
-methyl;
when X1 is O, m=1, R1 is hydrogen, and n=2 than Y is not 2′
-6′
-diethyl;
when X1 is O, m=1, R1 is 6—
OH, and n=2 than Y is not 2′
-5′
-methyl;
when X1 is S, m=1, R1 is 4-ethyl, and n=1 than Y is not 2-methoxy;
when X1 is O, m=1, R1 is 5-nitro, and, n=2 than Y is not 2-fluoro-5-nitro, or 2-methyl-5-nitro, or 2,3,-dichloro, or 2-methyl-6-chloro, or 2,5-dimethoxy, or 2-methyl-3-chloro;
when X1 is O, m=1, R1 is 3-nitro, and n=1, than Y is not hydrogen;
when X1 is O, m=1, R1 is 3-nitro, and n=2, than Y is not 2,5-dichloro;
when X1 is O, m=1, R1 is hydrogen, and n=2, than Y is not 2-methyl-5-chloro;
when X1 is O, m=1, R1 is 5-chloro, and n=1, than Y is not hydrogen;
when X1 is O, m=1, R1 is 5-chloro, and n=2, than Y is not 2-fluoro-5-nitro, or 3,4,-dichloro, or 2-methyl-5-nitro;
when X1 is O, m=1, R1 is 4-amino, and n=1, than Y is not hydrogen;
or a pharmaceutically acceptable salt thereof.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10)
N-(2-Hydroxy-4-cyanophenyl)-N′
-(2-bromophenyl)ureaN-(3-Cyano-2-hydroxyphenyl)-N′
-(2-bromophenyl)ureaN-(2-Hydroxy-4-cyanophenyl)-N′
-(2-methoxyphenyl)ureaN-(2-Hydroxy-4-cyanophenyl)-N′
-(2-phenylphenyl)ureaN-(2-Hydroxy-4-cyanophenyl-N′
-(2,3-dichlorophenyl)ureaN-(2-Hydroxy-4-cyanophenyl)-N′
-(2-methylphenyl)ureaN-(2-Hydroxy-3-cyano-4-methylphenyl)-N′
-(2-bromophenyl)urea;
orN-(2-Hydroxy-3-cyanophenyl)-N′
-(2,3 dichlorophenyl)urea;
or a pharmaceutically acceptable salt thereof.
-
-
6. The compound according to claim 2 wherein the R1 moiety is nitro, cyano, or halogen.
-
7. The compound according to claim 6 wherein the R1 moiety is cyano, or bromine.
-
8. The compound according to claim 3 wherein the monosubstituted Y moiety is halogen, alkoxy, or alkyl.
-
9. The compound according to claim 1 wherein Y and R1 are both other than hydrogen.
-
10. The compound according to claim 9 wherein n+m=2.
-
11. The compound which is N-(2-Hydroxy-4-cyanophenyl)-N′
- -(2-bromophenyl)urea, or a pharmaceutically acceptable salt thereof.
-
12. A pharmaceutical composition comprising N-(2-Hydroxy-4-cyanophenyl)
N′ - -(2-bromophenyl)urea, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
-
13. A compound of the formula:
-
wherein X is sulfur;
X1 is oxygen or sulfur;
R1 is independently selected from hydrogen;
halogen;
nitro;
cyano;
C1-10 alkyl;
halosubstituted C1-10 alkyl;
C2-10 alkenyl;
C1-10 alkoxy;
halosubstituted C1-10alkoxy;
azide;
(CR8R8)q S(O)tR4;
hydroxy;
hydroxy substituted C1-4alkyl;
aryl;
aryl C1-4 alkyl;
aryl C2-10 alkenyl;
aryloxy;
aryl C1-4 alkyloxy;
heteroaryl;
heteroarylalkyl;
heteroaryl C2-10 alkenyl;
heteroaryl C1-4 alkyloxy;
heterocyclic, heterocyclic C1-4alkyl;
heterocyclicC1-4alkyloxy;
heterocyclicC2-10 alkenyl;
(CR8R8)q NR4R5;
(CR8R8)q C(O)NR4R5;
C2-10 alkenyl C(O)NR4R5;
(CR8R8)qC(O)NR4R10;
S(O)3R8;
(CR8R8)q C(O)R11;
C2-10 alkenyl C(O)R11;
C2-10 alkenyl C(O)OR11;
(CR8R8)q C(O)OR11;
(CR8R8)q OC(O)R11;
(CR8R8)qNR4C(O)R11;
(CR8R8)q C(NR4)NR4R5;
(CR8R8)qNR4C(NR5)R11;
(CR8R8)q NHS(O)2R13;
(CR8R8)q S(O)2NR4R5;
or two R1 moieties together may form O—
(CH2)sO—
or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be substituted;
or substitutedt is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
R4 and R5are independently hydrogen, substituted or substituted C1-4 alkyl, substituted or substituted aryl, substituted or substituted aryl C1-4alkyl, substituted or substituted heteroaryl, substituted or substituted heteroaryl C1-4 alkyl, heterocyclic, heterocyclic C1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which does or does not contain an additional heteroatom selected from O, N or S;
Y is halogen;
nitro;
cyano;
halosubstituted C1-10 alkyl;
C1-10 alkyl;
C2-10 alkenyl;
C1-10 alkoxy;
halosubstituted C1-10 alkoxy;
azide;
(CR8R8)qS(O)tR4;
(CR8R8)qOR4;
hydroxy;
hydroxy substituted C1-4alkyl;
aryl;
aryl C1-4 alkyl;
aryloxy;
arylC1-4 alkyloxy;
aryl C2-10 alkenyl;
heteroaryl;
heteroarylalkyl;
heteroaryl C1-4 alkyloxy;
heteroaryl C2-10 alkenyl;
heterocyclic, heterocyclic C1-4alkyl;
heterocyclicC2-10 alkenyl;
(CR8R8)qNR4R5;
C2-10 alkenyl C(O)NR4R5;
(CR8R8)qC(O)NR4R5;
(CR8R8)q C(O)NR4R10;
S(O)3R8;
(CR8R8)qC(O)R11;
C2-10 alkenylC(O)R11;
(CR8R8)qC(O)OR11;
C2-10alkenylC(O)OR11;
(CR8R8)qOC(O) R11;
(CR8R8)qNR4C(O)R11;
(CR8R8)q NHS(O)2Rb;
(CR8R8)q S(O)2NR4R5;
(CR8R8)qC(NR4)NR4R5;
(CR8R8)qNR4C(NR5)R11;
or two Y moieties together may form O—
(CH2)sO—
or a 5 to 6 membered unsaturated ring; and
wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups are substituted;
or substitutedq 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;
R6 and R7 are independently hydrogen or a C1-4 alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring does or does not optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;
R8 is hydrogen or C1-4 alkyl;
R10 is C1-10 alkyl C(O)2R8;
R11 is hydrogen, substituted or substituted C1-4 alkyl, substituted or substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC1-4alkyl;
R12 is hydrogen, C1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;
R13 is C1-4 alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclicC1-4alkyl;
Rb is NR6R7, alkyl, aryl, aryl C1-4 alkyl, aryl C2-4 alkenyl, heteroaryl, heteroaryl C1-4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C1-4 alkyl, heterocyclic C2-4 alkenyl, or camphor, all of which groups are substituted;
unsubstituted provided thatwhen n=1 than Y is substituted in the 2- or 3-position;
when n=2 than Y is di-substituted in the 2′
-3′
-position, the 2′
-5′
-position, the 2′
-6′
position, the 3′
-5′
or the 3′
-6′
position;
when n=3 than Y is trisubstituted in the 2′
-3′
-5′
or the 2′
-3′
-6′
-positions; and
further provided thatwhen X1 is O, m=2, R1 is 2-t-butyl, 4-methyl, and n=3 than Y is not 2′
-OH, 3′
-t-butyl, 5′
-methyl;
when X1 is O, m=1, R1 is 4-methyl, and n=2 than Y is not 2′
-OH, 5′
-methyl;
when X1 is O, m=1, R1 is hydrogen, and n=2 than Y is not 2′
-6′
-diethyl;
when X1 is O, m=1, R1 is 6—
OH, and n=2 than Y is not 2′
-5′
-methyl;
when X1 is S, m=1, R1 is 4-ethyl, and n=1 than Y is not 2-methoxy;
or a pharmaceutically acceptable salt thereof. - View Dependent Claims (14, 15, 16, 17, 18)
-
Specification