Patent ID: 6218539
Filing Date: 2001-04-17
Classification: A61K,C07D,Y02A

Abstract:
A method of treating a chemokine mediated disease state, wherein the chemokine binds to an IL-8 .alpha. or .beta. receptor in a mammal, which comprises administering to said mammal an effective amount of a compound of the formula: ##STR11##whereinX is oxygen or sulfur;A is nitrogen, provided that only one of the A moieties is a nitrogen and the remainder are carbon substituted by hydrogen or R.sub.1 ;R is hydroxy, carboxylic acid, thiol, --SR.sub.2, --OR.sub.2, --NH--C(O)R.sub.a, --C(O)NR.sub.6 R.sub.7, --NHS(O).sub.2 R.sub.b, --S(O).sub.2 NHR.sub.c, NHC(X.sub.2)NHR.sub.b, or tetrazolyl;wherein R.sub.2 is a substituted aryl, heteroaryl, or heterocyclic ring which ring contains a functional moiety providing an ionizable hydrogen having a pKa of 10 or less;R.sub.a is an alkyl, aryl, aryl C.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 NR.sub.6 R.sub.7, alkyl, aryl, arylC.sub.1-4 alkyl, arylC.sub.2-4 alkenyl, heteroaryl, heteroarylC.sub.1-4 alkyl, heteroarylC.sub.2-4 alkenyl, heterocyclic, heterocyclic C.sub.1-4 alkyl, 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 ; C(O)NR.sub.6 R.sub.7, S(O).sub.3 H, or C(O)OC.sub.1-4 alkyl;R.sub.9 is hydrogen or a C.sub.1-4 alkyl;R.sub.c is alkyl, aryl, arylC.sub.1-4 alkyl, arylC.sub.2-4 alkenyl, heteroaryl, heteroarylC.sub.1-4 alkyl, heteroarylC.sub.2-4 alkenyl, heterocyclic, heterocyclic C.sub.1-4 alkyl, or a heterocyclic C.sub.2-4 alkenyl moiety, all of which moieties 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, C(O)NR.sub.6 R.sub.7, S(O).sub.3 H, or C(O)OC.sub.1-4 alkyl; andX.sub.2 is oxygen or sulfur;R.sub.1 is independently selected from 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)q S(O).sub.t R.sub.4 ; hydroxy; hydroxy C.sub.1-4 alkyl; aryl; aryl C.sub.1-4 alkyl; aryloxy; aryl C.sub.1-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic C.sub.1-4 alkyl; heteroaryl C.sub.1-4 alkyloxy; aryl C.sub.2-10 alkenyl; heteroaryl C.sub.2-10 alkenyl; heterocyclic C.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)q 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 H; 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.12 ; (CR.sub.8 R.sub.8)q OC(O)R.sub.11 ; (CR.sub.8 R.sub.8)q NR.sub.4 C(O)R.sub.11, (CR.sub.8 R.sub.8)q NHS(O).sub.2 R.sub.17, (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;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 0, or an integer having a value of 1 to 4;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, heterocyclic C.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 independently selected from 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)q S(O).sub.t R.sub.4 ; hydroxy; hydroxyC.sub.1-4 alkyl; aryl; aryl C.sub.1-4 alkyl; aryloxy; arylC.sub.1-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C.sub.1-4 alkyloxy; heterocyclic, heterocyclic C.sub.1-4 alkyl; aryl C.sub.2-10 alkenyl; heteroaryl C.sub.2-10 alkenyl; heterocyclic C.sub.2-10 alkenyl; (CR.sub.8 R.sub.8)q 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.5 ; (CR.sub.8 R.sub.8)q C(O)NR.sub.4 R.sub.10 ; S(O).sub.3 H; 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 ; C(O)R.sub.11 ; (CR.sub.8 R.sub.8)q C(O)OR.sub.12 ; (CR.sub.8 R.sub.8)q OC(O)R.sub.11 ; (CR.sub.8 R.sub.8)q NR.sub.4 C(O)R.sub.11, (CR.sub.8 R.sub.8)q NHS(O).sub.2 R.sub.d, (CR.sub.8 R.sub.8)q S(O).sub.2 NR.sub.4 R.sub.5 ; or two Y moieties together may form O--(CH.sub.2).sub.s O-- or a 5 to 6 membered unsaturated ring;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;n is an integer having a value of 1 to 3;m is an integer having a value of 1 to 3;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, C.sub.1-4 alkyl, optionally substituted 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 and R.sub.14 are independently hydrogen, optionally substituted C.sub.1-4 alkyl, or one of R.sub.13 and R.sub.14 may be optionally substituted aryl;R.sub.17 is C.sub.1-4 alkyl, aryl, arylalkyl, heteroaryl, heteroarylC.sub.1-4 alkyl, heterocyclic, or heterocyclicC.sub.1-4 alkyl, wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted;R.sub.d is NR.sub.6 R.sub.7, alkyl, arylC.sub.1-4 alklyl, arylC.sub.2-4 alkenyl, heteroaryl, hetroaryl-C.sub.1-4 alkyl, heteroarylC.sub.2-4 alkenyl, heterocyclic, heterocyclicC.sub.1-4 alkyl, wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted;E is optionally selected from ##STR12##the asterix * denoting point of attachment of the ring, with at least one E being present;or a pharmaceutically acceptably salt thereof.