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US 6,271,261 B1Granted
IL-8 receptor antagonists
AssigneeSmithKline Beecham Corporation
InventorKatherine L Widdowson
Life of this patent
Estimating the term…
Abstract
Novel IL-8 receptor antagonists and methods of using them are provided.
Claims23
A method of treating a chemokine mediated disease state, wherein the chemokine binds to an IL-8 α or β receptor in a mammal, which comprises administering to said mammal an effective amount of a compound of the formula:
- wherein
- X is oxygen or sulfur;
- R is hydroxy, carboxylic acid, thiol, SR2, OR2, —NH—C(O)Ra, —C(O)NR6R7, —NHS(O)2Rb, —S(O)2NHRc, NHC(X2)NHRb, or tetrazolyl;
- wherein R2 is a substituted aryl, heteroaryl, or heterocyclic ring which ring contains the functional moiety providing the ionizable hydrogen having a pKa of 10 or less;
- Ra is an alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic, or a heterocyclic C1-4alkyl moiety, all of which may be optionally substituted;
- Rb is a NR6R7, alkyl, aryl, arylC1-4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylC1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C1-4alkyl, heterocyclic C2-4alkenyl moiety, camphor, all of which may be optionally substituted one to three times independently by halogen;
- nitro;
- halosubstituted C1-4 alkyl;
- C1-4 alkyl;
- C1-4 alkoxy;
- NR9C(O)Ra;
- C(O)NR6R7, S(O)3H, or C(O)OC1-4 alkyl;
- R9 is hydrogen or a C1-4 alkyl;
- Rc is alkyl, aryl, arylC1-4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylC1-4alkyl, heteroarylC2-4alkenyl, heterocyclic, heterocyclic C1-4alkyl, or a heterocyclic C2-4alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen, nitro, halosubstituted C1-4 alkyl, C1-4 alkyl, C1-4 alkoxy, NR9C(O)Ra, C(O)NR6R7, S(O)3H, or C(O)OC1-4 alkyl;
- and
- X2 is oxygen or sulfur;
- R1 is independently selected from hydrogen;
- halogen;
- nitro;
- cyano;
- halosubstituted C1-10 alkyl;
- C1-10 alkyl;
- C2-10 alkenyl;
- C1-10 alkoxy;
- halosubstituted C1-10 alkoxy;
- azide;
- (CR8R8)q S(O)tR4;
- hydroxy;
- hydroxy C1-4alkyl;
- aryl;
- aryl C1-4 alkyl;
- aryloxy;
- aryl C1-4 alkyloxy;
- heteroaryl;
- heteroarylalkyl;
- heterocyclic, heterocyclic C1-4alkyl;
- heteroaryl C1-4 alkyloxy;
- aryl C2-10 alkenyl;
- heteroaryl C2-10 alkenyl;
- heterocyclic C2-10 alkenyl;
- (CR8R8)qNR4R5;
- C2-10 alkenyl C(O)NR4R5;
- (CR8R8)q C(O)NR4R5;
- (CR8R8)q C(O)NR4R10;
- S(O)3H;
- S(O)3R8;
- (CR8R8)q C(O)R11;
- C2-10 alkenyl C(O)R11;
- C2-10 alkenyl C(O)OR11(CR8R8)q C(O)OR12;
- (CR8R8)q OC(O) R11;
- (CR8R8)qNR4C(O)R11, (CR8R8)q NHS(O)2R17, (CR8R8)q S(O)2NR4R5;
- or two R1 moieties together may form O—(CH2)sO— or a 5 to 6 membered unsaturated ring;
- n is an integer having a value of 1 to 3;
- m is an integer having a value of 1 to 3;
- q is 0, or an integer having a value of 1 to 10;
- t is 0, or an integer having a value of 1 or 2;
- s is an integer having a value of 1 to 3;
- v is an integer having a value of 1 to 4;
- R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, heterocyclic, heterocyclicC1-4 alkyl, or R4 and R5 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 oxygen, nitrogen or sulfur;
- 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 may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;
- Y is independently selected from hydrogen;
- halogen;
- nitro;
- cyano;
- halosubstituted C1-10 alkyl;
- C1-10 alkyl;
- C2-10 alkenyl;
- C1-10 alkoxy;
- halosubstituted C1-10 alkoxy;
- azide;
- S(O)tR4;
- hydroxy;
- hydroxyC1-4alkyl;
- aryl;
- aryl C1-4 alkyl;
- aryloxy;
- arylC1-4 alkyloxy;
- heteroaryl;
- heteroarylalkyl;
- heteroaryl C1-4 alkyloxy;
- heterocyclic, heterocyclic C1-4alkyl;
- aryl C2-10 alkenyl;
- heteroaryl C2-10 alkenyl;
- heterocyclic C2-10 alkenyl;
- NR4R5;
- C2-10 alkenyl C(O)NR4R5;
- C(O)NR4R5;
- C(O)NR4R10;
- S(O)3H;
- S(O)3R8;
- C1-10 alkyl C(O)R11;
- C2-10 alkenyl C(O)R11;
- C2-10 alkenyl C(O)OR11;
- C(O)R11;
- C(O)OR12;
- OC(O) R11;
- NR4C(O)R11;
- or two Y moieties together may form O—(CH2)sO— or a 5 to 6 membered unsaturated ring;
- R8 is hydrogen or C1-4 alkyl;
- R10 is C1-10 alkyl C(O)2R8;
- R11 is hydrogen, C1-4 alkyl, optionally 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 and R14 are independently hydrogen, optionally substituted C1-4 alkyl or one of R13 and R14 may be optionally substituted aryl;
- R17 is C1-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclicC1-4alkyl, wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted;
- Rd is NR6R7, alkyl, arylC1-4alklyl, arylC2-4 alkenyl, heteroaryl, hetroaryl-C1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclicC1-4 alkyl, wherein the aryl, heteoaryl and heterocyclic rings may all be optionally substituted;
- provided that
- R1 is not 3-phenyl, or 4-isopropyl, or 5-phenyl or 5-ethylsulfonyl, when R is OH, v is 1,
- R13 and R14 are hydrogen, and Y is hydrogen;
- or a pharmaceutically acceptable salt thereof.
106 more elements
A compound of the formula:
- wherein
- X is oxygen or sulfur;
- R is hydroxy, carboxylic acid, thiol, SR2, OR2, NH—C(O)Ra, C(O)NR6R7, NHS(O)2Rb, S(O)2NHRc, NHC(X2)NHRb, or tetrazolyl;
- wherein R2 is a substituted aryl, heteroaryl, or heterocyclic ring which ring contains the functional moiety providing the ionizable hydrogen having a pKa of 10 or less;
- Ra is an alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic, or a heterocyclic C1-4alkyl moiety, all of which may be optionally substituted;
- Rb is a NR6R7, alkyl, aryl, arylC1-4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylC1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C1-4alkyl, heterocyclic C2-4alkenyl moiety, camphor, all of which may be optionally substituted one to three times independently by halogen;
- nitro;
- halosubstituted C1-4 alkyl;
- C1-4 alkyl;
- C1-4 alkoxy;
- NR9C(O)Ra;
- C(O)NR6R7, S(O)3H, or C(O)OC1-4 alkyl;
- R9 is hydrogen or a C1-4 alkyl;
- Rc is alkyl, aryl, arylC1-4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylC1-4alkyl, heteroarylC2-4alkenyl, heterocyclic, heterocyclic C1-4alkyl, or a heterocyclic C2-4alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen, nitro, halosubstituted C1-4 alkyl, C1-4 alkyl, C1-4 alkoxy, NR9C(O)Ra, C(O)NR6R7, S(O)3H, or C(O)OC1-4 alkyl;
- and
- X2 is oxygen or sulfur;
- R1 is independently selected from hydrogen;
- halogen;
- nitro;
- cyano;
- halosubstituted C1-10 alkyl;
- C1-10 alkyl;
- C2-10 alkenyl;
- C1-10 alkoxy;
- halosubstituted C1-10 alkoxy;
- azide;
- (CR8R8)q S(O)tR4;
- hydroxy;
- hydroxy C1-4alkyl;
- aryl;
- aryl C1-4 alkyl;
- aryloxy;
- aryl C1-4 alkyloxy;
- heteroaryl;
- heteroarylalkyl;
- heterocyclic, heterocyclic C1-4alkyl;
- heteroaryl C1-4 alkyloxy;
- aryl C2-10 alkenyl;
- heteroaryl C2-10 alkenyl;
- heterocyclic C2-10 alkenyl;
- (CR8R8)qNR4R5;
- C2-10 alkenyl C(O)NR4R5;
- (CR8R8)q C(O)NR4R5;
- (CR8R8)q C(O)NR4R10;
- S(O)3H;
- S(O)3R8;
- (CR8R8)q C(O)R11;
- C2-10 alkenyl C(O)R11;
- C2-10 alkenyl C(O)OR11(CR8R8)q C(O)OR12;
- (CR8R8)q OC(O) R11;
- (CR8R8)qNR4C(O)R11, (CR8R8)q NHS(O)2R17, (CR8R8)q S(O)2NR4R5;
- or two R1 moieties together may form O—(CH2)sO— or a 5 to 6 membered unsaturated ring;
- n is an integer having a value of 1 to 3;
- m is an integer having a value of 1 to 3;
- q is 0, or an integer having a value of 1 to 10;
- t is 0, or an integer having a value of 1 or 2;
- s is an integer having a value of 1 to 3;
- v is an integer having a value of 1 to 4;
- R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, heterocyclic, heterocyclicC1-4 alkyl, or R4 and R5 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 oxygen, nitrogen or sulfur;
- 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 may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;
- Y is independently selected from hydrogen;
- halogen;
- nitro;
- cyano;
- halosubstituted C1-10 alkyl;
- C1-10 alkyl;
- C2-10 alkenyl;
- C1-10 alkoxy;
- halosubstituted C1-10 alkoxy;
- azide;
- (CR8R8)q S(O)tR4;
- hydroxy;
- hydroxyC1-4alkyl;
- aryl;
- aryl C1-4 alkyl;
- aryloxy;
- arylC1-4 alkyloxy;
- heteroaryl;
- heteroarylalkyl;
- heteroaryl C1-4 alkyloxy;
- heterocyclic, heterocyclic C1-4alkyl;
- aryl C2-10 alkenyl;
- heteroaryl C2-10 alkenyl;
- heterocyclic C2-10 alkenyl;
- (CR8R8)q NR4R5;
- C2-10 alkenyl C(O)NR4R5;
- (CR8R8)q C(O)NR4R5;
- (CR8R8)q C(O)NR4R10;
- S(O)3H;
- S(O)3R8;
- (CR8R8)q C(O)R11;
- C2-10 alkenyl C(O)R11;
- C2-10 alkenyl C(O)OR11;
- C(O)R11;
- (CR8R8)q C(O)OR12;
- (CR8R8)q OC(O) R11;
- (CR8R8)q NR4C(O)R11, (CR8R8)q NHS(O)2Rd, (CR8R8)q S(O)2NR4R5;
- or two Y moieties together may form O—(CH2)sO— or a 5 to 6 membered unsaturated ring;
- R8 is hydrogen or C1-4 alkyl;
- R1-10 is C1-10 alkyl C(O)2R8;
- R11 is hydrogen, C1-4 alkyl, optionally 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 and R14 are independently hydrogen, optionally substituted C1-4 alkyl or one of R13 and R14 may be optionally substituted aryl;
- R17 is C1-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclicC1-4alkyl, wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted;
- Rd is NR6R7, alkyl, arylC1-4alklyl, arylC2-4 alkenyl, heteroaryl, hetroaryl-C1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclicC1-4 alkyl, wherein the aryl, heteoaryl and heterocyclic rings may all be optionally substituted;
- provided that
- R1 is not 3-phenyl, or 4-isopropyl, or 5-phenyl or 5-ethylsulfonyl, when R is OH, v is 1,
- R13 and R14 are hydrogen, and Y is hydrogen;
- or a pharmaceutically acceptable salt thereof.
106 more elements
A compound of the formula:
- wherein
- X is oxygen or sulfur;
- R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;
- R1 is independently selected from hydrogen;
- halogen;
- nitro;
- cyano;
- halosubstituted C1-10 alkyl;
- C1-10 alkyl;
- C2-10 alkenyl;
- C1-10 alkoxy;
- halosubstituted C1-10 alkoxy;
- azide;
- (CR8R8)q S(O)tR4;
- hydroxy;
- hydroxy C1-4alkyl;
- aryl;
- aryl C1-4 alkyl;
- aryloxy;
- aryl C1-4 alkyloxy;
- heteroaryl;
- heteroarylalkyl;
- heterocyclic, heterocyclic C1-4alkyl;
- heteroaryl C1-4 alkloxy;
- aryl C2-10 alkenyl;
- heteroaryl C2-10 alkenyl;
- heterocyclic C2-10 alkenyl;
- (CR8R8)qNR4R5;
- C2-10 alkenyl C(O)NR4R5;
- (CR8R8)q C(O)NR4R5;
- (CR8R8)q C(O)NR4R10;
- S(O)3H;
- S(O)3R8;
- (CR8R8)q C(O)R11;
- C2-10 alkenyl C(O)R11;
- C2-10 alkenyl C(O)OR11 (CR8R8)q C(O)OR12;
- (CR8R8)q OC(O) R11;
- (CR8R8)qNR4C(O)R11, (CR8R8)q NHS(O)2R17, (CR8R8)q S(O)2NR4R5;
- or two R1 moieties together may form O—(CH2)sO— or a 5 to 6 membered unsaturated ring;
- n is an integer having a value of 1 to 3;
- m is an integer having a value of 1 to 3;
- q is 0, or an integer having a value of 1 to 10;
- t is 0, or an integer having a value of 1 or 2;
- s is an integer having a value of 1 to 3;
- v is an integer having a value of 1 to 4;
- R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, 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 may optionally comprise an additional heteroatom selected from O/N/S;
- 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 may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;
- Y is independently selected from hydrogen;
- halogen;
- nitro;
- cyano;
- halosubstituted C1-10 alkyl;
- C1-10 alkyl;
- C2-10 alkenyl;
- C1-10 alkoxy;
- halosubstituted C1-10 alkoxy;
- azide;
- (CR8R8)q S(O)tR4;
- hydroxy;
- hydroxyC1-4alkyl;
- aryl;
- aryl C1-4 alkyl;
- aryloxy;
- arylC1-4 alkyloxy;
- heteroaryl;
- heteroarylalkyl;
- heteroaryl C1-4 alkyloxy;
- heterocyclic, heterocyclic C1-4alkyl;
- aryl C2-10 alkenyl;
- heteroaryl C2-10 alkenyl;
- heterocyclic C2-10 alkenyl;
- (CR8R8)q NR4R5;
- C2-10 alkenyl C(O)NR4R5;
- (CR8R8)q C(O)NR4R5;
- (CR8R8)q C(O)NR4R10;
- S(O)3H;
- S(O)3R8;
- (CR8R8)q C(O)R11;
- C2-10 alkenyl C(O)R11;
- C2-10 alkenyl C(O)OR11;
- C(O)R11;
- (CR8R8)q C(O)OR12;
- (CR8R8)q OC(O) R11;
- (CR8R8)q NR4C(O)R11, (CR8R8)q NHS(O)2Rd, (CR8R8)q S(O)2NR4R5;
- or two Y moieties together may form O—(CH2)sO— or a 5 to 6 membered unsaturated ring;
- R8 is hydrogen or C1-4 alkyl;
- R10 is C1-10 alkyl C(O)2R8;
- R11 is hydrogen, C1-4 alkyl, optionally 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 and R14 are independently hydrogen, optionally substituted C1-4 alkyl, or one of R13 and R14 may be optionally substituted aryl;
- R17 is C1-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclicC1-4alkyl, wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted;
- Rd is NR6R7, alkyl, arylC1-4alklyl, arylC2-4 alkenyl, heteroaryl, hetroaryl-C1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclicC1-4 alkyl, wherein the aryl, heteoaryl and heterocyclic rings may all be optionally substituted;
- E is optionally selected from
- the asterix * denoting point of attachment of the ring;
- and
- Z is optionally selected from
- the asterix * denoting point of attachment of the ring, with at least one E ring or Z ring being present;
- or a pharmaceutically acceptably salt thereof.
95 more elements
Dependencies are inferred from the claim text.