IL-8 receptor antagonists

• US 6,204,294 B1
• Filed: 02/04/1999
• Issued: 03/20/2001
• Est. Priority Date: 08/15/1996
• Status: Expired due to Fees

• Current Assignee: Smithkline Beecham Corporation (GSK plc)
• Original Assignee: Smithkline Beecham Corporation (GSK plc)
• Inventors: Widdowson, Katherine L., Gleason, John Gerald, Bryan, Deborah Lynn
• Primary Examiner(s): Jarvis, William R. A.
• Assistant Examiner(s): KIM, VICKIE Y
• Application Number:
  US09/230,977
• Time in Patent Office: 775 Days
• Field of Search: 514/634, 514/609
• US Class Current: 514/609
• CPC Class Codes: A61K 31/275 Nitriles; Isonitriles
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C07C 279/28 having nitrogen atoms of guanidine groups bound to cyano groups, e.g. cyanoguanidines, dicyandiamides
• CPC Class Codes: C07D 317/66 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

This invention relates to novel compounds of Formula (1), pharmaceutical compositions and their use in the treatment of disease states mediated by the chemokine, Interleukins-8 (IL-8).

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;

wherein

Z 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 C_1-10 alkyl;

C_1-10 alkyl;

C_2-10 alkenyl;

C_1-10 alkoxy;

halosubstitutedC_1-10alkoxy;

azide;

(CR₈R₈)q S(O)_tR₄;

hydroxy;

hydroxyC_1-4alkyl;

aryl;

arylC_1-4alkyl;

aryloxy;

aryl C_1-4 alkyloxy;

heteroaryl;

heteroarylalkyl;

heterocyclic, heterocyclic C_1-4alkyl;

heteroaryl C_1-4 alkyloxy;

aryl C_2-10 alkenyl;

heteroaryl C_2-10 alkenyl;

heterocyclic C_2-10 alkenyl;

(CR₈R₈)qNR₄R₅;

C_2-10alkenylC(O)NR₄R₅;

(CR₈R₈)q C(O)NR₄R₅;

(CR₈R₈)qC(O)NR₄R₁₀;

S(O)₃R₈;

(CR₈R₈)q C(O)R₁₁;

C_2-10alkenyl C(O)R₁₁;

C_2-10alkenylC(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 C_1-4 alkyl, optionally substituted aryl, optionally substituted aryl C_1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C_1-4alkyl, heterocyclic, heterocyclic C_1-4 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 C_1-10 alkyl;

C_1-10 alkyl;

C_2-10 alkenyl;

C_1-10 alkoxy;

halosubstitutedC_1-10alkoxy;

azide;

(CR₈R₈)q S(O)_tR₄;

hydroxy;

hydroxyC_1-4alkyl;

aryl;

arylC_1-4alkyl;

aryloxy;

arylC_1-4 alkyloxy;

heteroaryl;

heteroarylalkyl;

heteroarylC_1-4alkyloxy;

heterocyclic, heterocyclic C_1-4alkyl;

arylC_2-10 alkenyl;

heteroarylC_2-10 alkenyl;

heterocyclic C_2-10 alkenyl;

(CR₈R₈)qNR₄R₅;

C_2-10 alkenyl C(O)NR₄R₅;

(CR₈R₈)q C(O)NR₄R₅;

(CR₈R₈)qC(O)NR₄R₁₀;

S(O)₃R₈;

(CR₈R₈)q C(O)R₁₁;

C_2-10alkenylC(O)R₁₁;

C_2-10 alkenyl C(O)OR₁₁;

C(O)R₁₁;

(CR₈R₈)qC(O)OR₁₂;

(CR₈R₈)qOC(O) R₁₁;

(CR₈R₈)q NR₄C(O)R₁₁;

(CR₈R₈)qNHS(O)₂R_d;

(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 C_1-4 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 C_1-4 alkyl;

R₁₀ is C_1-10 alkyl C(O)₂R₈;

R₁₁ is hydrogen, C_1-4 alkyl, optionally substituted aryl, optionally substituted aryl C_1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC_1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC_1-4alkyl;

R₁₂ is hydrogen, C_1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;

R₁₃ and R₁₄ are independently hydrogen, optionally substituted C_1-4 alkyl or one of R₁₃ and R₁₄ may be optionally substituted aryl;

R₁₅ and R₁₆ are independently hydrogen, optionally substituted C_1-4 alkyl, optionally substituted aryl, optionally substituted aryl C_1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC_1-4alkyl, optionally substituted heterocyclic, optionally substituted heterocyclicC_1-4alkyl, 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 C_1-4 alkyl, NR₁₅R₁₆, OR₁₁, optionally substituted aryl, optionally substituted aryl C_1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC_1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC_1-4alkyl;

R₁₈ is optionally substituted C_1-4 alkyl, optionally substituted aryl, optionally substituted aryl C_1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC_1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC_1-4alkyl;

R₁₉ is C_1-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC_1-4alkyl, heterocyclic, or heterocyclicC_1-4alkyl, wherein the all of these moieties may be optionally substituted;

R_d is NR₆R₇, alkyl, arylC_1-4 alkyl, arylC_2-4 alkenyl, heteroaryl, hetroaryl—

C_1-4alkyl, heteroarylC_2-4 alkenyl, heterocyclic, heterocyclicC_1-4 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)R_a, C(O)NR_6′

R_7′

, NHS(O)₂R_b, S(O)₂NHR_c, NHC(X₂)NHR_b, 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;

R_6′

and R₇′

are hydrogen, C_1-4 alkyl, aryl, arylC_1-4alkyl, arylC_2-4alkenyl, heteroaryl, heteroarylC_1-4alkyl, heteroarylC_2-4 alkenyl, heterocyclic, heterocyclic C_1-4alkyl, heterocyclic C_2-4alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen;

nitro;

halosubstituted C_1-4 alkyl, such as CF₃;

C_1-4 alkyl, such as methyl;

C_1-4 alkoxy, such as methoxy;

NR₉C(O)R_a;

C(O)NR₆R₇, S(O)₃H, or C(O)OC_1-4 alkyl, provided that one of R_6′

and R_7′

are hydrogen, but not both;

R_a is an aryl, aryl C_1-4alkyl, heteroaryl, heteroaryl C_1-4alkyl, heterocyclic, or a heterocyclic C_1-4alkyl moiety, all of which may be optionally substituted;

R_b is a NR₆R₇, alkyl, aryl, arylC_1-4alkyl, arylC_2-4alkenyl, heteroaryl, heteroarylC_1-4alkyl, heteroarylC_2-4 alkenyl, heterocyclic, heterocyclic C_1-4alkyl, heterocyclic C_2-4alkenyl moiety, camphor, all of which may be optionally substituted one to three times independently by halogen;

nitro;

halosubstituted C_1-4 alkyl;

C_1-4 alkyl;

C_1-4 alkoxy;

NR₉C(O)R_a;

C(O)NR₆R₇, S(O)₃H, or C(O)OC_1-4 alkyl;

R₉ is hydrogen or a C_1-4 alkyl;

R_c is alkyl, aryl, arylC_1-4alkyl, arylC_2-4alkenyl, heteroaryl, heteroarylC_1-4alkyl, heteroarylC_2-4alkenyl, heterocyclic, heterocyclic C_1-4alkyl, or a heterocyclic C_2-4alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen, nitro, halosubstituted C_1-4 alkyl, C_1-4 alkyl, C_1-4 alkoxy, NR₉C(O)R_a, C(O)NR₆R₇, S(O)₃H, or C(O)OC_1-4 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 C_1-10 alkyl, C_1-10 alkyl, C_1-10 alkoxy, hydroxy, SH, C(O)NR_6′

R_7′

, NH—

C(O)R_a, NHS(O)₂R_b, S(O)NR₆R₇, C(O)OR₈, or a tetrazolyl ring.

5. The method according to claim 3 wherein R is OH, —

NHS(O)₂R_b 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, C_1-4 alkoxy, optionally substituted aryl, optionally substituted arylalkoxy, methylene dioxy, NR₄R₅ , thioC_1-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C_1-4alkyl, or hydroxy alkyl.

8. The method according to claim 1 wherein R is OH, SH, or NHS(O)₂R_b, 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.