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; R is OH; R1 is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C1-10 alkyl; C1-10 alkyl; C2-10 alkenyl; C1-10 alkoxy; halosubstituled C1-10 alkoxy; azide; (CR8R8)q S(O)tR4; hydroxy; hydroxy C1-4alkyl; aryl; aryl C1-4 alkyl; aryloxy; aryl C1-4 alkyloxy; aryl C2-10 alkenyl; (CR8R8)qNR4R5; C2-10 alkenyl C(O)NR4R5; (CR8R8)q C(O)NR4R5; (CR8R8)q C(O)NR4R10; S(O)3H; S(O)3R8; (CR8R8)q C(O)R11; C2-10 alkenyl C(O)R11; C2-10 alkenyl C(O)OR11; (CR8R8)q C(O)OR12; (CR8R8)q OC(O)R11; (CR8R8)qNR4C(O)R11; (CR8R8)q NHS(O)2R19; (CR8R8)q S(O)2NR4R5; or a 5 to 6 membered saturated or unsaturated ring, and wherein the aryl moiety may be optionally substituted; m is an integer having a value of 1 to 3; q is 0, or an integer having a value of 1 to 10; s is an integer having a value of 1 to 3; t is 0, or an integer having a value of 1 or 2; 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, or optionally substituted aryl C1-4alkyl; HET is a six-membered ring with one nitrogen atom; R6 and R7 are independently hydrogen or a C1-4 alkyl group; 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, or optionally substituted aryl C1-4alkyl; R12 is hydrogen, C1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl; R13 and R14 are independently hydrogen or C1-4 alkyl; R15 and R16 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, or optionally substituted aryl C1-4alkyl; R17 is C1-4 alkyl, NR15R16, OR11, optionally substituted aryl, or optionally substituted aryl C1-4alkyl; R18 is optionally substituted C1-4 alkyl, optionally substituted aryl, or optionally substituted aryl C1-4alkyl; R19 is C1-4alkyl, aryl, or aiylalkyl, wherein the all of these moieties may be optionally substituted; Rd is NR6R7, alkyl, arylC1-4 alkyl, arylC2-4 alkenyl, wherein the alkyl, or aryl containing moieities may be optionally substituted; the E′ containing ring is optionally selected from
- 2. The method according to claim 1 wherein the R2 is optionally substituted one to three times by halogen, nitro, halosubstituted C1-10 alkyl, C1-10 alkyl, C1-10 alkoxy, OH, SH, C(O)NR6′R7′, NH—C(O)Ra, NHS(O)Rb, S(O)NR6R7, or C(O)OR8.
- 3. 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, or S(O)NR4R5.
- 4. The method according to claim 1 wherein HET is substituted by (Y)n;n is an integer having a value of 1 to 3; Y is independently selected from hydrogen; halogen; nitro, cyano; halosubstituted C1-10 alkyl; C1-10 alkyl; C2-10 alkenyl; C1-10 alkoxy; halosubstituted C1-10 alkoxy; azide; (CR8R8)q S(O)tR4; hydroxy; hydroxyC1-4alkyl; aryl; aryl C1-4 alkyl; aryloxy; arylC1-4 alkyloxy; aryl C2-10 alkenyl; (CR8R8)q NR4R5; C2-10 alkenyl C(O)NR4R5; (CR8R8)q C(O)NR4R5; (CR8R8)q C(O)NR4R10; S(O)3H; S(O)3R8; (CR8R8)q C(O)R11; C2-10 alkenyl C(O)R11; C2-10 alkenyl C(O)OR11; (CR8R8)q C(O)OR12; (CR8R8)q OC(O)R11; (CR8R8)q NR4C(O)R11; (CR8R8)q NHS(O)2Rd; or (CR8R8)q S(O)2NR4R5 or a 5 to 6 membered saturated or unsaturated ring; wherein the aryl containing moieties may be optionally substituted as defined herein; and Rd is NR6R7, alkyl, arylC1-4 alkyl, arylC2-4 alkenyl, wherein the alkyl, or the aryl containing moieties may be optionally substituted.
- 5. The method according to claim 4 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.
- 6. 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, alzheimers disease, graft vs. host reaction, or allograft rejections.
RELATED APPLICATIONS
This application is the §371 national stage entry of PCT/US97/14583, filed Aug. 15, 1997 which claims the benefit of provisional application Ser. No. 60/023,988, filed Aug. 15, 1996.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
PCT/US97/14583 |
|
WO |
00 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO98/06399 |
2/19/1998 |
WO |
A |
US Referenced Citations (3)
Number |
Name |
Date |
Kind |
4057636 |
Petersen |
Nov 1977 |
A |
5262415 |
Takemoto et al. |
Nov 1993 |
A |
5371086 |
Takemoto et al. |
Dec 1994 |
A |
Provisional Applications (1)
|
Number |
Date |
Country |
|
60/023988 |
Aug 1996 |
US |