Patent EA-001436-B1 (EA)
Title: Il-8 receptor antagonists
Inventor: WIDDOWSON KATHERINE LOUISA
IPC: A61K31/18
Filed: 1996-08-21
Abstract: 1. A method of treating a chemokine mediated disease state, wherein the chemokine binds to an IL-8 a- or b-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 any functional moiety having an ionizable hydrogen and a pKa of 10 or less; R1 is independently selected from hydrogen; halogen; nitro; cyano; C1-10-alkyl; halosubstituted C1-10-alkyl; C2-10alkenyl; C1-10alkoxy; halosubstituted C1-10alkoxy; azide; S(O)tR4; (CR8R8)qS(O)tR4; hydroxy; hydroxysubstituted C1-4-alkyl; aryl; aryl-C1-4-alkyl; aryl-C2-10-alkenyl; aryloxy; aryl-C1-4-alkyloxy; heteroaryl; heteroaryl-alkyl; heteroaryl-C2-10-alkenyl; heteroaryl-C1-4-alkyloxy; heterocyclic group, heterocyclic C1-4-alkyl; heterocyclic C1-4-alkyloxy; heterocyclic C2-10-alkenyl; (CR8R8)qNR4R5; (CR8R8)qC(O)NR4R5; C2-10-alkenyl C(O)NR4R5; (CR8R8)q-C(O)NR4R10; S(O)3H; S(O)3R8; (CR8R8)qC(O)R11; C2-10-alkenyl C(O)R11; C2-10-alkenyl C(O)OR11; (CR8R8)qC(O)OR11; (CR8R8)qOC(O)R11; (CR8R8)q-NR4C(O)R11; (CR8R8)qC(NR4)NR4R5; (CR8R8)qNR4C(NR5)R11, (CR8R8)qNHS-(O)2R13; (CR8R8)qS(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, aryl-alkyl, heteroaryl, heterocyclic moities may be optionally substituted; 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, optionally substituted C1-4-alkyl, optionally substituted aryl, optionally substituted aryl-C1-4-alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4-alkyl, heterocyclic group, 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 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 C1-4-alkyl; aryl; aryl-C1-4-alkyl; aryloxy; aryl-C1-4-alkyloxy; aryl-C2-10-alkenyl; heteroaryl; heteroaryl-alkyl; heteroaryl-C1-4-alkyloxy; heteroaryl-C2-10-alkenyl; heterocyclic group, heterocyclic C1-4-alkyl; heterocyclic C2-10-alkenyl; (CR8R8)qNR4R5; C2-10-alkenyl-C(O)NR4R5; (CR8R8)qC(O)NR4R5; (CR8R8)qC(O)NR4R10; S(O)3R8;  (CR8R8)q-C(O)R11; C2-10-alkenyl-C(O)R11; (CR8R8)qC(O)OR11; (CR8R8)qC(O)OR12; C2-10-alkenyl-C(O)OR11; (CR8R8)qOC(O)R11; (CR8R8)qNR4C(O)R11; (CR8R8)qNHS(O)2Rb; (CR8R8)qS(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, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclic, heterocyclic-alkyl groups may be optionally substituted; q is 0 or an integer having a value of 1 to 10; m is an integer having a value of 1 to 3;  n 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 may 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, optionally substituted C1-4-alkyl, optionally substituted aryl, optionally substituted aryl-C1-4-alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-C1-4-alkyl, optionally substituted heterocyclic group, or optionally substituted heterocyclic C1-4-alkyl; R12  is hydrogen, C1-10-alkyl, optionally substituted aryl or optionally substituted aryl-alkyl; R13  is suitably C1-4-alkyl, aryl, aryl-C1-4-alkyl, heteroaryl, heteroaryl-C1-4-alkyl,  heterocyclic group, or heterocyclic C1-4-alkyl; Rb is NR6R7, -alkyl, aryl, aryl-C1-4-alkyl, aryl-C2-4-alkenyl, heteroaryl, heteroaryl-C1-4-alkyl, heteroaryl-C2-4-alkenyl, heterocyclic group, heterocyclic C1-4-alkyl, heterocyclic C2-4-alkenyl, or camphor, all of which groups may be optionally substituted; or a pharmaceutically acceptably salt thereof.  2. The method according to claim 1 wherein the ionizable hydrogen has a pKa of 3 to 10.  3. The method according to claim 2 wherein R is hydroxy, carboxylic acid, thiol, SR2OR2, NH-C(O)Ra, C(O)NR6R7, NHS(O)2Rb, S(O)2NHRc, NHC(X)NHRb, or tetrazolyl; wherein R2 is a substituted aryl, heteroaryl, or heterocyclic moiety which ring has the functional moiety providing the ionizable hydrogen having a pKa of 10 or less; Ra is an -alkyl, aryl, aryl-C1-4-alkyl, heteroaryl, heteroaryl-C1-4-alkyl, heterocyclic or C1-4-alkyl heterocyclic moiety, all of which may be optionally substituted; R9  is hydrogen or a C1-4-alkyl; Rc is -alkyl, aryl, aryl-C1-4-alkyl, aryl-C2-4-alkenyl, heteroaryl, heteroaryl-C1-4-alkyl, heteroaryl-C2-4-alkenyl, heterocyclic group, heterocyclic C1-4-alkyl , or a heterocyclic C2-4-alkenyl, all of which may be optionally substituted one to three times independently by halogen, nitro, cyano, halosubstituted C1-4-alkyl, C1-4-alkyl, C1-4-alkoxy, C1-4-amino, NR9C(O)Ra, C(O)NR6R7, S(O)3H, or C(O)OC1-4-alkyl.  4. The method according to claim 3 wherein the R2 is optionally substituted one to three times by halogen, nitro, halosubstituted C1-10-alkyl, C1-10-alkyl, C1-10-alkoxy, hydroxy, SH, C(O)NR6R7, NH-C(O)Ra, NHS(O)Rb, S(O)NR6R7, C(O)OR8, or a tetrazolyl ring.  5. The method according to claim 3 wherein R is OH, NHS(O)2Rb or C(O)OH.  6. The method according to claim 1 wherein R1 is halogen, cyano, nitro, CF3, C(O)NR4R5, alkenyl C(O)NR4R5, C(O) R4R10, heteroaryl, heteroaryl-alkyl, heteroarylalkenyl, or S(O)NR4R5.  7. The method according to claim 1 wherein Y is halogen, C1-4-alkoxy, optionally substituted aryl, optionally substituted arylalkoxy, methylenedioxy, NR4R5, thio-C1-4-alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C1-4-alkyl, hydroxy-alkyl.  8. The method according to claim 1 wherein R is OH, SH, or NHS(O)sRb and R1 is substituted in the 3-position, the 4-position or disubstituted in the 3,4-position by an electron withdrawing moiety.  9. The compound according to claims 1 or 8 wherein Y is mono-substituted in the 2'-position or 3'- position, or is disubstituted in the 2'- or 3'-position of a phenyl ring.  10. The compound according to claims 1, 8 or 9 wherein n and m are each equal to 1 or more.  11. The method according to claim 1 wherein R is a carboxylic acid, and R1 is hydrogen, or R1 is substituted in the 4-position.  12. The method according to claim 1 wherein the mammal is afflicted with a chemokine mediated disease selected from psoriasis, atopic dermatitis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, restenosis, angiogenesis, cardiac and renal reperfusion injury, glomerulo-nephritis, thrombosis, Alzheimer's disease, graft vs. host reaction, or allograft rejections.  13. The method according to claim 1 wherein the compound, or a pharmaceutically acceptable salt thereof is: N-(2-hydroxy-4-nitrophenyl)-N'-(2-methoxyphenyl)urea N-(2-hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea N-(2-hydroxy-4-nitrophenyl)-N'-(2-phenylphenyl)urea N-(2-hydroxy-4-nitrophenyl)-N'-(2-methylthiophenyl)urea N-(2-hydroxy-4-nitrophenyl)-N'-(2,3-dichlorophenyl)urea N-(2-hydroxy-4-nitrophenyl)-N'-(2-chlorophenyl)urea N-(2-hydroxy-4-nitrophenyl)-N'-(2,3-methylenedioxyphenyl)urea N-(2-hydroxy-4-nitrophenyl)-N'-(2-methoxy-3-chlorophenyl)urea N-(2-hydroxy-4-nitrophenyl)-N'-(2-phenyloxyphenyl)urea N-(3-chloro-2-hydroxyphenyl)-N'-(bromophenyl)urea N-(2-hydroxy-3-glycinemethylestercarbonylphenyl)-N'-(2-bromophenyl)urea N-(3-nitro-2-hydroxyphenyl)-N'-(2-bromophenyl)urea N-(2-hydroxy-4-cyanophenyl)-N'-(2-bromophenyl)urea N-(2-hydroxy-3,4-dichlorophenyl)-N'-(2-bromophenyl)urea N-(3-cyano-2-hydroxyphenyl)-N'-(2-bromophenyl)urea N-(2-hydroxy-4-cyanophenyl)-N'-(2-methoxyphenyl)urea N-(2-hydroxy-4-cyanophenyl)-N'-(2-phenylphenyl)urea N-(2-hydroxy-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea N-(2-hydroxy-4-cyanophenyl)-N'-(2-methylphenyl)urea N-(2-hydroxy-3-cyano-4-methoxyphenyl)-N'-(2-bromophenyl)urea N-(4-cyano-2-hydroxyphenyl)-N'-(2-trifluoromethylphenyl)urea N-(3-trifluoromethyl-2-hydroxyphenyl)-N'-(2-bromophenyl)urea N-(3-phenylaminocarbonyl-2-hydroxyphenyl)-N'-(2-bromophenyl)urea N-(2-hydroxy-4-nitrophenyl)-N'-(2-iodophenyl)urea N-(2-hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)thiourea N-(2-phenylsulfonamido)-4-cyanophenyl-N'(2-bromophenyl)urea (E)-N-[3-[(2-aminocarbonyl)ethenyl]-2-hydroxyphenyl]-N'-(2-bromophenyl) urea N-(2-hydroxy-3,4-dichlorophenyl)-N'-(2-methoxyphenyl)urea N-(2-hydroxy-3,4-dichlorophenyl)-N'-(2-phenylphenyl)urea N-(2-hydroxy-3,4-dichlorophenyl)-N'-(2,3-dichlorophenyl)urea N-(2-hydroxy-5-nitrophenyl)-N'-(2,3-dichlorophenyl)urea; or N-(2-hydroxy-3-cyanophenyl)-N'-(2,3-dichlorophenyl)urea.  14. The method according to claim 1 wherein the compound is N-(2-hydroxy-4-cyanophenyl)-N'-(2-bromophenyl)urea or a pharmaceutically acceptable salt thereof. 15. The method according to claim 6 wherein R1 is nitro, cyano, trifluoromethyl or C(O)NR4R5. 16. The method according to claim 15 wherein Y is halogen, alkoxy, methylendioxy, aryl or -alkyl. 17. The method according to claim 1 or 16 wherein X is oxygen. 18. A compound of the formula    X is oxygen; 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; C1-10-alkyl; halosubstituted C1-10-alkyl; C2-10-alkenyl; C1-10-alkoxy; halosubstituted C1-10-alkoxy; azide; (CR8R8)qS(O)tR4; hydroxy; hydroxy substituted C1-4-alkyl; aryl; aryl-C1-4-alkyl; aryl-C2-10-alkenyl; aryloxy; aryl-C1-4-alkyloxy; heteroaryl; heteroaryl-alkyl; heteroaryl-C2-10-alkenyl; heteroaryl-C1-4-alkyloxy; heterocyclic group, heterocyclic C1-4-