Claims
- 1. 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: whereinZ is cyano, OR11, C(O)NR15R16, R18, C(O)R11, C(O)OR11, or S(O)2R17; 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; halosubstitutedC1-10alkoxy; azide; (CR8R8)q S(O)tR4; hydroxy; hydroxyC1-4alkyl; aryl; arylC1-4alkyl; 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; C2-10alkenylC(O)NR4R5; (CR8R8)q C(O)NR4R5; (CR8R8)qC(O)NR4R10; S(O)3R8; (CR8R8)q C(O)R11; C2-10alkenyl C(O)R11; C2-10alkenylC(O)OR11; (CR8R8)q C(O)OR12; (CR8R8)q OC(O) R11; (CR8R8)qNR4C(O)R11; (CR8R8)qNHS(O)2R19; (CR8R8)q S(O)2NR4R5; or two R1 moieties together may form O—(CH2)sO— or a 5 to 6 membered saturated or unsaturated ring, and wherein the aryl, heteroaryl and heterocyclic moieities may be optionally substituted; 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; 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 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; halosubstitutedC1-10alkoxy; azide; (CR8R8)q S(O)tR4; hydroxy; hydroxyC1-4alkyl; aryl; arylC1-4alkyl; aryloxy; arylC1-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroarylC1-4alkyloxy; heterocyclic, heterocyclic C1-4alkyl; arylC2-10 alkenyl; heteroarylC2-10 alkenyl; heterocyclic C2-10 alkenyl; (CR8R8)qNR4R5; C2-10 alkenyl C(O)NR4R5; (CR8R8)q C(O)NR4R5; (CR8R8)qC(O)NR4R10; S(O)3R8; (CR8R8)q C(O)R11; C2-10alkenylC(O)R11; C2-10 alkenyl C(O)OR11; C(O)R11; (CR8R8)qC(O)OR12; (CR8R8)qOC(O) R11; (CR8R8)q NR4C(O)R11; (CR8R8)qNHS(O)2Rd; (CR8R8)q S(O)2NR4R5; or two Y moieties together may form O—(CH2)sO— or a 5 to 6 membered saturated or unsaturated ring, and wherein the aryl, heteroaryl and heterocyclic moieities may be optionally substituted; n is an integer having a value of 1 to 3; m 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 selected from oxygen, nitrogen or sulfur; R8 is independently selected from 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; R15 and R16 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, optionally substituted heterocyclicC1-4alkyl, or R15 and R16 may together with the nitrogen to which they are attached form a 5 to 7 member ring optionally containing an additional heteroatom selected from oxygen, nitrogen, or sulfur; R17 is C1-4 alkyl, NR15R16, OR11, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC1-4alkyl; R18 is optionally substituted 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; R19 is C1-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclicC1-4alkyl, wherein the all of these moieties may be optionally substituted; Rd is NR6R7, alkyl, arylC1-4 alkyl, arylC2-4 alkenyl, heteroaryl, hetroaryl—C1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclicC1-4 alkyl, wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, and heterocyclic alkyl rings may be optionally substituted; the E′ containing ring may be absent or present, and when present, is selected from the E containing ring may be absent or present, and when present, is selected from or a pharmaceutically acceptable 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, SR2, OR2, NH—C(O)Ra, C(O)NR6′R7′, NHS(O)2Rb, S(O)2NHRc, NHC(X2)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; R6′ and R7′ are hydrogen, C1-4 alkyl, aryl, arylC1-4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylC1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C1-4alkyl, heterocyclic C2-4alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen; nitro; halosubstituted C1-4 alkyl, such as CF3; C1-4 alkyl, such as methyl; C1-4 alkoxy, such as methoxy; NR9C(O)Ra; C(O)NR6R7, S(O)3H, or C(O)OC1-4 alkyl, provided that one of R6′ and R7′ are hydrogen, but not both; Ra is an 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.
- 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)NR6′R7′, NH—C(O)Ra, NHS(O)2Rb, 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, alkenyl C(O)OR12, heteroaryl, heteroarylalkyl , heteroaryl alkenyl, or S(O)NR4R5.
- 7. The method according to claim 1 wherein Y is halogen, C1-4 alkoxy, optionally substituted aryl, optionally substituted arylalkoxy, methylene dioxy, NR4R5 , thioC1-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C1-4alkyl, or hydroxy alkyl.
- 8. The method according to claim 1 wherein R is OH, SH, or NHS(O)2Rb, and R1 is substituted in the 3-position, the 4-position or di substituted in the 3,4-position by an electron withdrawing moiety.
- 9. 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, cardiac and renal reperfusion injury, glomerulo-nephritis, thrombosis, Alzheimer's disease, graft vs. host reaction, or allograft rejections.
- 10. The method according to claim 1 wherein the compound is:N-(2-Hydroxy-4-nitrophenyl)-N′-(2-chlorophenyl)-N″-cyanoguanidine N-(2-Hydroxy 4-nitro phenyl) N′-(2-chloro phenyl)-N″-cyano guanidine N-(4-Cyano-2-hydroxyphenyl)-N′-(phenyl(cyanoguanidine N-(2-Bromophenyl) N′-(4-cyano-2-hydroxyphenyl) N″-cyanoguanidine N-(4-Cyano-2-hydroxyphenyl)-N′-(2,3-dichlorophenyl)-N″-cyanoguanidine N-(2-Bromophenyl)-N′-(4-cyano-2-hydroxy-3-propylphenyl)-N″-cyanoguanidine N-(2-Bromophenyl)-N′-(4-cyano-2-hydroxy-3-isobutylphenyl)-N″-cyanoguanidine N-(2-Bromophenyl)-N′-(3-bromo-4-cyano-2-hydroxyphenyl)-N″-cyanoguanidine N-(4-Cyano-2-hydroxy-3-propylphenyl)-N′-(2,3-dichlorophenyl)-N″-cyanoguanidine N-(3-Bromo-4-cyano-2-hydroxyphenyl)-N′-(2,3-methylenedioxyphenyl)-N″-cyanoguanidine N-(2-Chlorophenyl)-N′-(4-cyano-2-hydroxy-3-propylphenyl)-N″-cyanoguanidine N-(2-Bromophenyl)-N′-(4-cyano-2-hydroxy-3-methoxycarbonylphenyl)-N″-cyanoguanidine; or a pharmaceutically acceptable salt thereof.
RELATED APPLICATIONS:
This application is the § 371 national stage entry of PCT/US97/14581, filed Aug. 15, 1997 which claims the benefit of provisional application 60/023,414, filed Aug. 15, 1996.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
PCT/US97/14581 |
|
WO |
00 |
2/4/1999 |
2/4/1999 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO98/06397 |
2/19/1998 |
WO |
A |
US Referenced Citations (7)
Foreign Referenced Citations (1)
Number |
Date |
Country |
387769 |
Sep 1990 |
EP |
Non-Patent Literature Citations (1)
Entry |
Manley, P.W., “Structure-Activity Studies of Potassium Channel Opening in Pinacidil-Type Cyanoguanidines etc.”, J. Med. Chem., 35(12), pp. 2327-2340 (1992). |
Provisional Applications (1)
|
Number |
Date |
Country |
|
60/023414 |
Aug 1996 |
US |