Claims
- 1. A compound according to Formula (I) below: wherein Rb is independently selected from the group consisting of hydrogen, NR6R7, OH, ORa, C1-5alkyl, aryl, arylC1-4alkyl, aryl C2-4alkenyl; cycloalkyl, cycloalkyl C1-5 alkyl, heteroaryl, heteroarylC1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C1-4alkyl, and a heterocyclic C2-4alkenyl moiety, all of which moieties may be optionally substituted one to three times, independently, by a substituent selected from the group consisting of halogen, nitro, halosubstituted C1-4 alkyl, C1-4 alkyl, amino, mono or di-C1-4 alkyl substituted amine, ORa, C(O)Ra, NRaC(O)ORa, OC(O)NR6R7, hydroxy, NR9C(O)Ra, S(O)m′Ra, C(O)NR6R7, C(O)OH, C(O)ORa, S(O)tNR6R7, and NHS(O)tRa; or the two Rb substituents can join to form a 3-10 membered ring, optionally substituted and containing, in addition to optionally substituted C1-4 alkyl, independently, 1 to 3 NRa, O, S, SO, or SO2 moieties which can be optionally unsaturated; Ra is selected from the group consisting of alkyl, aryl, arylC1-4alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic, COORa′, and a heterocyclic C1-4alkyl moiety, all of which moieties may be optionally substituted; Ra′ is selected from the group consisting of alkyl, aryl, arylC1-4alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic and a heterocyclic C1-4alkyl moiety, all of which moieties may be optionally substituted; m is an integer having a value of 1 to 3; X, D, and E are optionally C, N, or NO provided at least one of X, D and E is not C m′ is 0, or an integer having a value of 1 or 2; n 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; R1 is independently selected from the group consisting of 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)qS(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)qNR4R5, (CR8R8)qC(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)qC(O)OR11, (CR8R8)qOC(O)R11, (CR8R8)qNR4C(O)R11, (CR8R8)qC(NR4)NR4R5, (CR8R8)qNR4C(NR5)R11, (CR8R8)qNHS(O)tR13, and (CR8R8)qS(O)tNR4R5, or two R1 moieties together may form O—(CH2)sO or a 5 to 6 membered saturated or unsaturated ring, wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moieties may be optionally substituted; R4 and R5 are independently selected from the group consisting of hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, heterocyclic, and 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 O, N and S; R6 and R7 are independently selected from the group consisting of hydrogen, C1-4 alkyl, heteroaryl, aryl, alkyl aryl, and alkyl C1-4 heteroalkyl, which may all be optionally substituted; 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, selected from oxygen, nitrogen or sulfur, such that the ring may be optionally substituted; Y is selected from the group consisting of 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)tRa, (CR8R8)qORa, 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)qNHS(O)tR13, (CR8R8)qS(O)tNR4R5, (CR8R8)qC(NR4)NR4R5, and (CR8R8)qNR4C(NR5)R11; or two Y moieties together may form O—(CH2)s—O or a 5 to 6 membered saturated or unsaturated ring, such that the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, or heterocyclicalkyl groups may be optionally substituted; R8 is hydrogen or C1-4 alkyl; R9 is hydrogen or a C1-4 alkyl; R10 is C1-10 alkyl C(O)2R8; R11 is selected from the group consisting of hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, and optionally substituted heterocyclicC1-4alkyl; and R13 is selected from the group consisting if C1-4 alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, and heterocyclicC1-4alkyl; or a pharmaceutically acceptable salt thereof.
- 2. The compound according to claim 1 wherein R1 is substituted in the 4-position by an electron withdrawing moiety.
- 3. The compound according to claim 2 wherein R1 is halogen, cyano or nitro.
- 4. The compound according to claim 3 wherein R1 is halogen.
- 5. The compound according to claim 4 wherein R1 is independently, fluorine, chlorine, cyano, or bromine.
- 6. The compound according to claim 1 wherein Y is mono-substituted in the 2′-position or 3′-position, or is disubstituted in the 2′- or 3′-position of a monocyclic ring.
- 7. The compound according to claim 6 wherein Y is halogen.
- 8. The compound according to claim 4 wherein Y is independently fluorine, chlorine, or bromine.
- 9. The compound according to claim 1 wherein Rb is hydrogen, C1-4 alkyl, or C1-4 alkyl substituted with C(O)OH, or C(O)ORa.
- 10. The compound according to claim 1 wherein Y is halogen, n is 1 or 2, R1 is halogen, m is 1 or 2, and Rb is, independently, hydrogen, C1-4 alkyl, C1-4 alkyl substituted with C(O)OH, or C(O)ORa.
- 11. The compound according to claim 1 selected from the group consisting of:N-(6-(4-(aminosulfonyl) 3-chloro 5-hydroxy pyridine) N′-(2-bromo phenyl) urea; N-(6-(4-(aminosulfonyl) 3-chloro 5-hydroxy pyridine) N′-(2,3-dichloro phenyl) urea; N-(5-(3-(aminosulfonyl) 2-chloro 4-hydroxy pyridine) N′-(2-bromo phenyl) urea; N-(5-(3-(aminosulfonyl) 2-chloro 4-hydroxy pyridine) N′-(2,3-dichloro phenyl) urea; N-(6-(4-(aminosulfonyl) 3-chloro 5-hydroxy pyridazine) N′-(2-bromo phenyl) urea; N-(6-(4-(aminosulfonyl) 3-chloro 5-hydroxy pyridazine) N′-(2,3-dichloro phenyl) urea; N-(6-(4-(aminosulfonyl) 3-cyano 5-hydroxy pyridine) N′-(2-bromo phenyl) urea; N-(6-(4-(aminosulfonyl) 3-cyano 5-hydroxy pyridine) N′-(2,3-dichloro phenyl) urea; N-(5-(3-(aminosulfonyl) 2-cyano 4-hydroxy pyridine) N′-(2-bromo phenyl) urea; N-(5-(3-(aminosulfonyl) 2-cyano 4-hydroxy pyridine) N′-(2,3-dichloro phenyl) urea; N-(6-(4-(aminosulfonyl) 3-cyano 5-hydroxy pyridazine) N′-(2-bromo phenyl) urea; and N-(6-(4-(aminosulfonyl) 3-cyano 5-hydroxy pyridazine) N′-(2,3-dichloro phenyl) urea; or a pharmaceutically acceptable salt thereof.
- 12. A compound according to claim 11 wherein the compound is in its sodium salt form.
- 13. A compound according to claim 11 wherein the compound is in its potassium salt form.
- 14. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
- 15. A method of treating a chemokine mediated disease, wherein the chemokine binds to an IL-8 a or b receptor in a mammal, which method comprises administering to said mammal an effective amount of a compound of the formula according to claim 1.
- 16. The method according to claim 15 wherein the mammal is afflicted with a chemokine mediated disease selected from the group consisting of psoriasis, atopic dermatitis, osteo arthritis, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, stroke, septic shock, multiple sclerosis, endotoxic shock, gram negative sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, graft vs. host reaction, alzheimers disease, allograft rejections, malaria, restenosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis and undesired hematopoietic stem cells release and diseases caused by respiratory viruses, herpesviruses, and hepatitis viruses, meningitis, cystic fibrosis, pre-term labor, cough, pruritus, multi-organ dysfucntions, trauma, strains, sprains, contusions, psoriatic arthritis, herpes, encephalitis, CNS vasculitis, traumatic brain injury, CNS tumors, subarachnoid hemorrhage, post surgical trauma, interstitial pneumonitis, hypersensitivity, crystal induced arthritis, acute and chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, uveitis, polymyositis, vasculitis, acne, gastric and duodenal ulcers, celiac disease, esophagitis, glossitis, airflow obstruction, airway hyperresponsiveness, bronchiolitis obliterans organizing pneumonia, bronchiectasis, bronchiolitis, bronchiolitis obliterans, chronic bronchitis, cor pulmonae, dyspnea, emphysema, hypercapnea, hyperinflation, hypoxemia, hyperoxia-induced inflammations, hypoxia, surgerical lung volume reduction, pulmonary fibrosis, pulmonary hypertension, right ventricular hypertropy, sarcoidosis, small airway disease, ventilation-perfusion mismatching, wheeze, colds and lupus.
Parent Case Info
This application is a 371 of PCT/US 01/11102 filed Apr. 5, 2001, which claims the benefit of U.S. Provisional Application 60/196,022, filed Apr. 7, 2000.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
PCT/US01/11102 |
|
WO |
00 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO01/76530 |
10/18/2001 |
WO |
A |
US Referenced Citations (1)
Number |
Name |
Date |
Kind |
5696138 |
Olesen et al. |
Dec 1997 |
A |
Foreign Referenced Citations (2)
Number |
Date |
Country |
WO 97 49400 |
Dec 1997 |
WO |
WO 00 35442 |
Jun 2000 |
WO |
Provisional Applications (1)
|
Number |
Date |
Country |
|
60/196022 |
Apr 2000 |
US |