IL-8 receptor antagonists

• US 6,005,008 A
• Filed: 08/15/1997
• Issued: 12/21/1999
• Est. Priority Date: 02/16/1996
• Status: Expired due to Term

• Current Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC)
• Original Assignee: Smithkline Beecham Corporation (Smithkline Beecham PLC)
• Inventors: Widdowson, Katherine Louisa, Veber, Daniel Frank, Rutledge, Melvin Clarence Jr., Hertzberg, Robert Philip, Jurewicz, Anthony Joseph
• Primary Examiner(s): Lambkin, Deborah C.
• Application Number:
  US08/894,291
• Time in Patent Office: 858 Days
• Field of Search: 514/596, 514/597, 514/598, 564/48, 564/49, 564/50, 564/52
• US Class Current: 514/596
• CPC Class Codes: C07C 2602/42 the bicyclo ring system containing seven carbon atoms
• CPC Class Codes: C07C 2603/18 Fluorenes; Hydrogenated fluorenes
• CPC Class Codes: C07C 275/34 having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 275/40 being further substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 275/42 being further substituted by carboxyl groups
• CPC Class Codes: C07C 311/13 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 311/14 Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of rings other than six-membered aromatic rings
• CPC Class Codes: C07C 311/21 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/29 having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/44 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/46 Y being a hydrogen or a carbon atom
• CPC Class Codes: C07C 317/42 Y being a hetero atom
• CPC Class Codes: C07C 323/44 X or Y being nitrogen atoms
• CPC Class Codes: C07C 335/18 being further substituted by singly-bound oxygen atoms

Abstract

This invention relates to the novel use of phenyl ureas in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8).

Claims

1. A compound of the formula:

##STR15## wherein X is oxygen;

X₁ is oxygen;

R₁ is independently selected from hydrogen;

halogen;

cyano;

halosubstituted C_1-10 alkyl;

C_1-10 alkyl;

C_2-10 alkenyl;

C_1-10 alkoxy;

halosubstituted C_1-10 alkoxy;

azide;

S(O)_t R₄ ;

hydroxy;

hydroxyC_1-4 alkyl;

aryl;

aryl C_1-4 alkyl;

aryloxy;

aryl C_1-4 alkyloxy;

heteroaryl;

heteroarylalkyl;

heterocyclic;

heterocyclicC_1-4 alkyl;

heteroarylC_1-4 alkyloxy;

aryl C_2-10 alkenyl;

heteroaryl C_2-10 alkenyl;

heterocyclic C_2-10 alkenyl;

NR₄ R₅ ;

C_2-10 alkenyl C(O)NR₄ R₅ ;

C(O)NR₄ R₅ ;

C(O)NR₄ R₁₀ ;

S(O)₃ H;

S(O)₃ R₈ ;

C_1-10 alkyl C(O)R₁₁ ;

C_2-10 alkenyl C(O)R₁₁ ;

C_2-10 alkenyl C(O)OR₁₁ ;

C(O)R₁₁ ;

C(O)OR₁₂ ;

OC(O)R₁₁ ;

NR₄ C(O)R₁₁ ;

or two R₁ moieties together may form O--(CH₂)_S O-- or a 5 to 6 membered unsaturated ring;

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 C_1-4 alkyl, optionally substituted aryl, optionally substituted aryl C_1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C_1-4 alkyl, heterocyclic, heterocyclic C_1-4 alkyl, or R₄ and R₅ together with the nitrogen to which they are attached from a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;

Y is independently selected from halogen;

nitro;

cyano;

halosubstituted C_1-10 alkyl;

C_1-10 alkyl;

C_2-10 alkenyl;

C_1-10 alkoxy;

halosubstituted C_1-10 alkoxy;

azide;

S(O)_t R₄ ;

hydroxy;

hydroxyC_1-4 alkyl;

aryl;

aryl C_1-4 alkyl;

aryloxy;

arylC_1-4 alkyloxy;

heteroaryl;

heteroarylalkyl;

heteroarylC_1-4 alkyloxy;

heterocyclic;

heterocyclic C_1-4 alkyl;

aryl C_2-10 alkenyl;

heteroarylC_2-10 alkenyl;

heterocyclic C_2-10 alkenyl;

NR₄ R₅ ;

C_2-10 alkenyl C(O)NR₄ R₅ ;

C(O)NR₄ R₅ ;

C(O)NR₄ R₁₀ ;

S(O)₃ H;

S(O)₃ R₈ ;

C_1-10 alkyl C(O)R₁₁ ;

C_2-10 alkenyl C(O)R₁₁ ;

C_2-10 alkenyl C(O)OR₁₁ ;

C(O)R₁₁ ;

C(O)OR₁₂ ;

OC(O)R₁₁ ;

NR₄ C(O)R₁₁ ;

or two Y moieties together may form O--(CH₂)_S O-- or a 5 to 6 membered unsaturated ring;

n is an integer having a value of 1 to 2;

m is an integer having a value of 1 to 3;

R₈ is hydrogen or C_1-4 alkyl;

R₁₀ is C_1-10 alkyl C(O)₂ R₈ ;

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

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

provided that;

when n=1 then Y is substituted in the 2- or 3-position;

when n=2 then Y is di-substituted in the 2'"'"'- or 3'"'"'-position, the 2'"'"'-5'"'"'-position, the 2'"'"'-6'"'"' position, the 3'"'"'-5'"'"' or the 3'"'"'-6'"'"' position;

when n=3 then Y is trisubstituted in the 2'"'"'-3'"'"'-5'"'"' or the 2'"'"'-3'"'"'-6'"'"'-positions;

further provided that

when m=1, R₁ is hydrogen, and n=1 than Y is not 2'"'"'--OH, 2'"'"'-nitro, 2'"'"'--Cl, or 2'"'"'--Br;

when m=1, R₁ is COOH, and n=2 than Y is not 2'"'"'--OH, 3'"'"'--COOH;

when m=2, R₁ is 2-t-butyl, 4-methyl, and n=3 than Y is not 2'"'"'--OH, 3'"'"'-t-butyl, 5'"'"'-methyl;

when m=1, R₁ is 4-methyl, and n=2 then Y is not 2'"'"'--OH, 5'"'"'-methyl;

when m=1, R₁ is hydrogen, and n=2 then Y is not 2'"'"'-6'"'"'-diethyl;

when m=1, R₁ is 6--OH, and n=2 then Y is not 2'"'"'-5'"'"'-methyl;

when m=1, R₁ is 5-nitro, and n=2 then Y is not 2-fluoro-5-nitro;

or 2-methyl-5-nitro, or 2,3,-dichloro, or 2-methyl-6-chloro, or 2,5-dimethoxy, or 2-methyl-3-chloro;

when m=1, R₁ is 3-nitro, and n=1, then Y is not hydrogen;

when m=1, R₁ is 3-nitro, and n=2, then Y is not 2,5-dichloro;

when m=1, R₁ is hydrogen, and n=2, then Y is not 2-methyl-5-chloro;

when m=1, R₁ is 5-chloro, and n=1, then Y is not hydrogen;

when m=1, R₁ is 5-chloro, and n=2, then Y is not 2-fluoro-5-nitro, or 3,4,-dichloro, or 2-methyl-5-nitro;

when m=1, R₁ is 4-amino, and n=1, then Y is not hydrogen;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein n amd m are each equal to 1 or more.

3. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

4. The compound according to claim 1 wherein the R₁ moiety is cyano, or halogen.

5. The compound according to claim 1 wherein the R₁ is moiety is cyano, or bromine.

6. The compound according to claim 1 wherein the monosubstituted Y moiety is halogen, alkoxy, or alkyl.

7. The compound according to claim 1 wherein Y is a mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl.

8. The compound according to claim 7 wherein Y is substituted in the 2'"'"'-position or 2,3-position.

9. The compound according to claim 1 wherein both Y and R₁ are other than hydrogen.

10. The compound acording to claim 2 wherein n+m=2.

11. The compound according to claim 1 which is N--(2-Hydroxy-4-cyanophenyl)--N'"'"'-(2-bromophenyl)urea, or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 which is:

[N--([-Hydroxy-4-(methoxycarbonyl)phenyl]--N'"'"'--phenylurea;

]

[N--(2-Hydroxy-5-nitro-phenyl)--N'"'"'--phenyl urea;

]

[N--(2-Hydroxy-4-fluorophenyl)--N'"'"'--phenyl urea;

]

[N--[2-Hydroxy-4-(trifluoromethyl)phenyl]--N'"'"'--phenyl urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(2-hydroxy-4-nitrophenyl) urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--phenyl-thiourea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(3-methoxyphenyl)urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(2-methoxyphenyl)urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(3-trifluoromethylphenyl)urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(2-trifluoromethylphenyl)urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(4-trifluoromethylphenyl)urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(2-bromophenyl)urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(3-bromophenyl)urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(4-bromophenyl)urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(2-phenylphenyl)urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(2-nitrophenyl)urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(2-fluorophenyl)urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(2,6-difluorophenyl)urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(2-ethoxyphenyl)urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(2-ethylphenyl)urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(2-trifluoromethoxyphenyl)urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(2-methylthiophenyl)urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(2-chloro 6-methyl phenyl)urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(2-sulfoxymethyl phenyl) urea;

]

N--(2-Hydroxy-4-trifluoromethyl phenyl)--N'"'"'--(2-bromo phenyl) urea;

N--(2-Hydroxy-4-trifluoromethyl phenyl)--N'"'"'--(2-phenyl phenyl) urea;

N--(2-Hydroxy-4-carbomethoxy phenyl)--N'"'"'--(2-phenyl phenyl) urea;

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(2,3-dichloro phenyl) urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(2,4-dichloro phenyl) urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(2-chloro phenyl) urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(2,4-dibromo phenyl) urea;

]

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(2,3-methylenedioxyphenyl)urea;

]

[N--(2-Hydroxy-4-nitrophenyl) N'"'"'--(3-chloro 2-methoxy phenyl) urea;

]

N--[2-Hydroxy-4-(Benzylamino)carbonyl phenyl]--N'"'"'--(2-bromophenyl)urea;

N--(2-Hydroxy-4-fluorophenyl)--N'"'"'--(2-bromo phenyl) urea;

N--(2-Hydroxy-3,4-difluorophenyl)--N'"'"'--(2-bromo phenyl) urea;

N--(2-Hydroxy 4-phenylphenyl) N'"'"'--(2-bromo phenyl) urea;

N--(2-Hydroxy 4-methylphenyl)--N'"'"'--(2-bromo phenyl) urea;

[N--(2-Hydroxy-4-nitrophenyl)--N'"'"'--(2-phenylamino phenyl) urea;

]

N--(2-Hydroxy 3-carboxyphenyl)--N'"'"'--(2-bromo phenyl) urea;

[N--(2-Sulfhydryl-4-bromophenyl)--N'"'"'--(2-bromo phenyl) urea;

]

[N--(2-Hydroxy 4-nitrophenyl)--N'"'"'--(2-iodo phenyl) urea;

]

[N--(2-Hydroxy 4-nitrophenyl)--N'"'"'--(2-bromo phenyl) thiourea;

]

N--(2-Hydroxy-4-azidophenyl)--N'"'"'--(2-methoxyphenyl)urea;

N--[2-Hydroxy-5-cyanophenyl]--N'"'"'--[2-bromophenyl] urea;

N--[2-Hydroxy-3-fluorophenyl]--N'"'"'--[2-bromophenyl] urea;

N--[2-Hydroxy-3-fluoro-5-bromophenyl]--N'"'"'--[2-bromophenyl] urea;

N--[2-Hydroxy-3-chlorophenyl]--N'"'"'--[2-bromophenyl] urea;

N--[2-Hydroxy-3-trifluoromethylphenyl]--N'"'"'--[2-bromophenyl] urea;

N--[2-Hydroxy-3,4-diphenylphenyl]--N'"'"'--[2-bromophenyl] urea;

N--[2-Hydroxy-3-glycinemethylestercarbonylphenyl]--N'"'"'--[2-bromophenyl] urea;

N--[2-Hydroxy-3-glycincarbonylphenyl]--N'"'"'--[2-bromophenyl] urea;

N--[2-Hydroxy-3,5-dichlorophenyl]--N'"'"'--[2-bromophenyl] urea;

[N--[2-Hydroxy-3-nitrophenyl]--N'"'"'--[2-bromophenyl] urea;

]

N--[2-Hydroxy-3,4-dichlorophenyl]--N'"'"'--[2-bromophenyl] urea;

N--[2-Hydroxy-3-cyanophenyl]--N'"'"'--[2-bromophenyl] urea;

N--[2-Hydroxy-4-cyanophenyl]--N'"'"'--[2-bromophenyl] urea;

[N--[2-Hydroxy-4-cyanophenyl]--N'"'"'--[4-methoxyphenyl] urea;

]

N--[2-Hydroxy-4-cyanophenyl]--N'"'"'--[2-phenylphenyl] urea;

N--[2-Hydroxy-4-cyanophenyl]--N'"'"'--[2-methylphenyl] urea;

N--[2-Hydroxy-4-cyanophenyl]--N'"'"'--[2-trifluoromethylphenyl] urea;

[N--[2-Hydroxy-4-cyanophenyl]--N'"'"'--[3-trifluoromethylphenyl] urea;

]

[N--[2-Hydroxy-4-cyanophenyl]--N'"'"'--[4-trifluoromethylphenyl] urea;

]

N--[2-Hydroxy-4-ethylphenyl]--N'"'"'--[2-bromophenyl] urea;

N--[2-Hydroxy-3-phenylaminocarbonyl phenyl]--N'"'"'--[2-bromophenyl] urea;

N--[2-Hydroxy-3-cyano-4-methylphenyl]--N'"'"'--[2-bromophenyl] urea;

N--[2-Hydroxy-4-carbophenyl phenyl]--N'"'"'--[2-bromophenyl] urea;

N--[2-Hydroxy-3-carbophenyl phenyl]--N'"'"'--[2-bromophenyl] urea;

N--[2-Hydroxy-3-benzyloxy phenyl]--N'"'"'--[2-bromophenyl] urea;

(E)--N--[4-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]--N'"'"'--[2-bromophenyl] urea;

(E)--N--[3-[2-(Methoxycarbonyl)ethenyl]-2-hydroxyphenyl]--N'"'"'--[2-bromophenyl]urea--N'"'"'--[2-bromophenyl] urea;

(E)--N--[3-[2-(Aminocarbonyl)ethenyl]-2-hydroxyphenyl]--N'"'"'--[2-bromophenyl]urea--N'"'"'--[2-bromophenyl] urea;

(E)--N--[4-[2-(Aminocarbonyl)ethenyl]-2-hydroxyphenyl]--N'"'"'--[2-bromophenyl]urea--N'"'"'--[2-bromophenyl] urea;

N--[2-Hydroxy-4-benzamide phenyl]--N'"'"'--[2-bromophenyl] urea;

N--[2-Hydroxy-4-aminocarbonyl phenyl]--N'"'"'--[2-bromophenyl] urea;

N--[2-Hydroxy-3,5,6-trifluorophenyl]--N'"'"'--[2-bromophenyl]urea;

N--[2-Hydroxy-3-fluoro-4-trifluoromethylphenyl]--N'"'"'--[2-bromophenyl]urea;

N--[2-Hydroxy-3-iodophenyl]--N'"'"'--[2-bromophenyl]urea;

[N--[2-Hydroxy-4-cyanophenyl]--N'"'"'--[4-phenylphenyl]urea;

]

N--[2-Hydroxy-4-cyanophenyl]--N'"'"'--[2,3-dichlorophenyl]urea;

N--[2-Hydroxy-4-cyanophenyl]--N'"'"'--[2-methoxyphenyl]urea;

[N--[2-Hydroxy-4-cyanophenyl]--N'"'"'--[3-methoxyphenyl]urea;

]

[N--[2-Hydroxyphenyl]--N'"'"'--[2-bromophenyl]urea

N--[Trans-3-styrl-2-hydroxyphenyl]--N'"'"'--[2-bromophenyl]urea;

N--[2-Hydroxy-3,4-dichlorophenyl]--N'"'"'--[2-methoxyphenyl]urea;

[N--[2-Hydroxy-3,4-dichlorophenyl]--N'"'"'--[4-methoxyphenyl]urea;

]

[N--[2-Hydroxy-3,4-dichlorophenyl]--N'"'"'--[3-trifluoromethylphenyl]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-4-isopropylphenyl]--N'"'"'--[3-trifluoromethylphenyl]urea;

]

N--[2-Hydroxy-4-azidophenyl]--N'"'"'--[2-iodophenyl]urea;

N--[2-Hydroxy-3-azidophenyl]--N'"'"'[2-bromohenyl]urea;

N--[2-Hydroxy-3-cyanophenyl]--N'"'"'--[2-methoxyphenyl] urea;

[N--[2-Hydroxy-3-cyanophenyl]--N'"'"'--[3-trifluoromethylphenyl] urea;

]

N--[2-Hydroxy-3-cyanophenyl]--N'"'"'--[2-phenylphenyl] urea;

N--[2-Hydroxy-3-cyanophenyl]--N'"'"'--[2,3-dichlorophenyl]urea;

N--[2-Hydroxy-4-isopropylphenyl]--N'"'"'--[2,3-dichlorophenyl]urea;

[N--[2-Hydroxy-4-isopropylphenyl]--N'"'"'--[2-chloro-5-trifluoromethylphenyl]urea;

]

N--[2-Hydroxy-3-phenylphenyl]--N'"'"'--[2,3-dichlorophenyl]urea;

[N--[2-Hydroxy-5-nitrophenyl]--N'"'"'--[2-methoxyphenyl]urea];

[N--[2-Hydroxy-5-nitrophenyl]--N'"'"'--[3-trifluoromethylphenyl]urea;

]

N--[2-Hydroxy-5-nitrophenyl]--N'"'"'--[2-phenylphenyl]urea;

N--[2-Hydroxy-5-nitrophenyl]--N'"'"'--[2,3-dichlorophenyl]urea;

N--[2-Hydroxy-5-ethylsulfonylphenyl]--N'"'"'--[2,3-dichlorophenyl] urea;

N--[2-Hydroxy-5-naphthalenesulfonic acid]--N'"'"'--[2-bromophenyl] urea;

N--[2-Hydroxy-4-naphthalenesulfonic acid]--N'"'"'--[2-bromophenyl] urea;

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound according to claim 9 and a pharmaceutically acceptable carrier or diluent.

15. The compound according to claim 1 wherein when n=1 then Y is substituted in the 2-position.

16. The compound according to claim 1 wherein when n=2 then Y is di-substituted in the 2'"'"'-3'"'"' position, the 2'"'"'-5'"'"'-position, the 2'"'"'-6'"'"' position, or the 3'"'"'-6 '"'"' position.

17. The compound according to claim 16 wherein if 2'"'"' and 3'"'"' substituents join to form a ring the attachment to the phenyl in the 2'"'"' position must be oxygen.

14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent, and N--(2-Hydroxy-4-cyanophenyl)--N'"'"'--(2-bromophenyl)urea, or a pharmaceutically acceptable salt thereof.