IL-8 receptor antagonists

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

• ##STR15## wherein X is oxygen or sulfur;
• R is OH;
• 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, 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, pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, tbiazole, thiadiazole, triazole, imidazole, benzimidazole;
• pyrrole C.sub.1-4 alkyl, pyrazole C.sub.1-4 alkyl, furan C.sub.1-4 alkyl, thiophene C.sub.1-4 alkyl, quinoline C.sub.1-4 alkyl, isoquinoline C.sub.1-4 alkyl, quinazolinyl C.sub.1-4 alkyl, pyridine C.sub.1-4 alkyl, pyrimidine C.sub.1-4 alkyl, oxazole C.sub.1-4 alkyl, thiazole C.sub.1-4 alkyl, thiadiazole C.sub.1-4 alkyl, triazole C.sub.1-4 alkyl, imidazole C.sub.1-4 alkyl, or benzimidazole C.sub.1-4 alkyl;
• pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, imidazolidine, pyrrolidinyl C.sub.1-4 alkyl, piperidinyl C.sub.1-4 alkyl, piperazinyl C.sub.1-4 alkyl, morpholinyl C.sub.1-4 alkyl, tetrahydropyranyl C.sub.1-4 alkyl, imidazolidinyl C.sub.1-4 alkyl, pyrrole C.sub.1-4 alkyloxy, pyrazole C.sub.1-4 alkyloxy, furlan C.sub.1-4 alkyloxy, thiophene C.sub.1-4 alkyloxy, quinoline C.sub.1-4 alkyloxy, isoquinoline C.sub.1-4 alkyloxy, quinazolinyl C.sub.1-4 alkyloxy, pyridine C.sub.1-4 alkyloxy, pyrimidine C.sub.1-4 alkyloxy, oxazole C.sub.1-4 alkyloxy, thiazole C.sub.1-4 alkyloxy, thiadiazole C.sub.1-4 alkyloxy, triazole C.sub.1-4 alkyloxy, imidazole C.sub.1-4 alkyloxy, benzimidazole C.sub.1-4 alkyloxy, aryl C.sub.2-10 alkenyl, pyrrole C.sub.2-10 alkenyl, pyrazole C.sub.2-10 alkenyl, furan C.sub.2-10 alkenyl, thiophene C.sub.2-10 alkenyl, quinoline C.sub.2-10 alkenyl, isoquinoline C.sub.2-10 alkenyl, quinazolinyl C.sub.2-10 alkenyl, pyridine C.sub.2-10 alkenyl, pyrimidine C.sub.2-10 alkenyl, oxazole C.sub.2-10 alkenyl, thiazole C.sub.2-10 alkenyl, thiadiazole C.sub.2-10 alkenyl, triazole C.sub.2-10 alkenyl, imdazole C.sub.2-10 alkenyl, benzimidazole C.sub.2-10 alkenyl;
• pyrrolidinyl C.sub.2-10 alkenyl, piperidinyl C.sub.2-10 alkenyl, piperazinyl C.sub.2-10 alkenyl, morpholinyl C.sub.2-10 alkenyl, tetrahydropyranyl C.sub.2-10 alkenyl, imidazolidinyl C.sub.2-10 alkenyl, NR.sub.4 R.sub.5, C.sub.2-10 alkenyl C(O)NR.sub.4 R.sub.5, C(O)NR.sub.4 R.sub.5, C(O)NR.sub.4 R.sub.10, S(O).sub.3 R.sub.8, C.sub.1-10 alkyl 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, C(O)OR.sub.12, OC(O)R.sub.11, NR.sub.4 C(O)R.sub.11, or two R.sub.1 moieties together may form O--(CH.sub.2).sub.s O-- or a 5 to 6 membered unsaturated ring;
• 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 akyl, optionally substituted aryl C.sub.1-4 alkyl, optionally substituted heteroaryl selected from pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrnldine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole, optionally substituted heteroaryl C.sub.1-4 alkyl selected from pyrrole C.sub.1-4 alkyl, pyrazole C.sub.1-4 alkyl, furan C.sub.1-4 alkyl, thiophene C.sub.1-4 alkyl, quinoline C.sub.1-4 alkyl, isoquinoline C.sub.1-4 alkyl, quinazolinyl C.sub.1-4 alkyl, pyridine C.sub.1-4 alkyl, pyrimidine C.sub.1-4 alkyl, oxazole C.sub.1-4 alkyl, thiazole C.sub.1-4 alkyl, thiadiazole C.sub.1-4 alkyl, triazole C.sub.1-4 alkyl, imidazole C.sub.1-4 alkyl, or benzimidazole C.sub.1-4 alkyl, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, imidazolidine, pyrrolidine C.sub.1-4 alkyl, piperidinyl C.sub.1-4 alkyl, piperazinyl C.sub.1-4 alkyl, morpholineyl C.sub.1-4 alkyl, tetrahydropyranyl C.sub.1-4 alkyl, imidazolidinyl 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, S(O).sub.t R.sub.4, hydroxy, hydroxy C.sub.1-4 alkyl, aryl, aryl C.sub.1-4 alkyl, aryloxy, arylC.sub.1-4 alkyloxy, pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imtidazole, benzimidazole;
• pyrrole C.sub.1-4 alkyl, pyrazole C.sub.1-4 alkyl, furan C.sub.1-4 alkyl, thiophene C.sub.1-4 alkyl, quinoline C.sub.1-4 alkyl, isoquinoline C.sub.1-4 alkyl, quinazolinyl C.sub.1-4 alkyl, pyridine C.sub.1-4 alkyl, pyrimidine C.sub.1-4 alkyl, oxazole C.sub.1-4 alkyl, thiazole C.sub.1-4 alkyl, thiadiazole C.sub.1-4 alkyl, triazole C.sub.1-4 alkyl, imidazole C.sub.1-4 alkyl, benzimidazole C.sub.1-4 alkyl;
• pyrrole C.sub.1-4 alkyloxy, pyrazole C.sub.1-4 alkyloxy, furan C.sub.1-4 alkyloxy, thiophene C.sub.1-4 alkyloxy, quinoline C.sub.1-4 alkyloxy, isoquinoline C.sub.1-4 alkyloxy, quinazolinyl C.sub.1-4 alkyloxy, pyridine C.sub.1-4 alkyloxy, pyrimidine C.sub.1-4 alkyloxy, oxazole C.sub.1-4 alkyloxy, thiazole C.sub.1-4 alkyloxy, thiadiazole C.sub.1-4 alkyloxy, triazole C.sub.1-4 alyloxy, imidazole C.sub.1-4 alkyloxy, benzimidazole C.sub.1-4 alkyloxy;
• pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, imidazolidine, pyrrolidine C.sub.1-4 alkyl, piperidinyl C.sub.1-4 alkyl, piperazinyl C.sub.1-4 alkyl, morpholinyl C.sub.1-4 alkyl, tetrahydropyranyl C.sub.1-4 alkyl, imidazolidinyl C.sub.1-4 alkyl;
• aryl C.sub.2-10 alkenyl, pyrrole C.sub.2-10 alkenyl, pyrazole C.sub.2-10 alkenyl, furan C.sub.2-10 alkenyl, thiophene C.sub.2-10 alkenyl, quinoline C.sub.2-10 alkenyl, isoquinoline C.sub.2-10 alkenyl, quinazolinyl C.sub.2-10 alkenyl, pyridine C.sub.2-10 alkenyl, pyrimidine C.sub.2-10 alkenyl, oxazole C.sub.2-10 alkenyl, thiazole C.sub.2-10 alkenyl, thiadiazole C.sub.2-10 alkenyl, triazole C.sub.2-10 alkenyl, imidazole C.sub.2-10 alkenyl, benzimidazole C.sub.2-10 alkenyl;
• pyrrolidinyl C.sub.2-10 alkenyl, piperidinyl C.sub.2-10 alkenyl, piperazinyl C.sub.2-10 aIkenyl, morpholinyl C.sub.2-10 alkenyl, tetrahydropyranyl C.sub.2-10 alkenyl, imidazolidinyl C.sub.2-10 alkenyl, NR.sub.4 R.sub.5, C.sub.2-10 alkenyl C(O)NR.sub.4 R.sub.5, C(O)NR.sub.4 R.sub.5, C(O)NR.sub.4 R.sub.10, S(O).sub.3 R.sub.8, C.sub.1-10 alkyl C(O)R.sub.11, C.sub.1-10 alkenyl C(O)R.sub.11, C.sub.2-10 alkenyl C(O)OR.sub.11, C(O)R.sub.11, C(O)OR.sub.12, OC(O) R.sub.11, NR.sub.4 C(O)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;
• 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 selected from pyrrole, pyrazole, furan, thiophene, quinoilne, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole, optionally substituted heteroaryl C.sub.1-4 alkyl selected from pyrrole C.sub.1-4 alkyl, pyrazole C.sub.1-4 alkyl, furan C.sub.1-4 alkyl, thiophene C.sub.1-4 alkyl, quinoline C.sub.1-4 alkyl, isoquinoline C.sub.1-4 alkyl, quinazolinyl C.sub.1-4 alkyl, pyridine C.sub.1-4 alkyyl, pyrimidine C.sub.1-4 alkyl, oxazole C.sub.1-4 alkyl, thiazole C.sub.1-4 alkyl, thiadiazole C.sub.1-4 alkyl, triazole C.sub.1-4 alkyl, imidazole C.sub.1-4 alkyl, or benzimidazole C.sub.1-4 alkyl, optionally substituted heterocyclic selected from pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine, or optionally substituted heterocyclic C.sub.1-4 alkyl selected from pyrrolidine C.sub.1-4 alkyl, piperidinyl C.sub.1-4 alkyl, piperazinyl C.sub.1-4 alkyl, niorpholinyl C.sub.1-4 alkyl, tetrahydropyranyl C.sub.1-4 alkyl, or imnidazolidinyl C.sub.1-4 alkyl;
• R.sub.12 is hydrogen, C.sub.1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;
• or a pharmaceutically acceptable salt thereof.