IL-8 receptor antagonists

• US 5,780,483 A
• Filed: 08/21/1996
• Issued: 07/14/1998
• Est. Priority Date: 02/17/1995
• Status: Expired due to Term

• Current Assignee: GlaxoSmithKline LLC (GSK plc)
• Original Assignee: Smithkline Beecham Corporation (GSK plc)
• Inventors: Widdowson, Katherine Louisa, Veber, Daniel Frank, Rutledge, Melvin Clarence Jr., Hertzberg, Robert Philip, Jurewicz, Anthony Joseph
• Primary Examiner(s): Jarvis, William R. A.
• Application Number:
  US08/701,299
• Time in Patent Office: 692 Days
• Field of Search: 514/311, 514/369, 514/445, 514/586, 514/597
• US Class Current: 514/311
• CPC Class Codes: A61K 31/17 having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 31/223 of alpha-aminoacids
• CPC Class Codes: A61K 31/275 Nitriles; Isonitriles
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/36 Compounds containing methylenedioxyphenyl groups, e.g. sesamin
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: C07C 2602/08 the other ring being five-membered, e.g. indane
• 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 275/38 being further substituted by doubly-bound oxygen atoms
• 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 307/10 having nitrogen atoms of the sulfamide groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 309/15 the nitrogen atom of at least one of the amino groups being part of any of the groups , X being a hetero atom, Y being any atom
• CPC Class Codes: C07C 311/10 of a saturated carbon skeleton containing rings
• CPC Class Codes: C07C 311/13 the carbon skeleton containing 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 311/46 : 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
• CPC Class Codes: C07D 213/30 : Oxygen atoms
• CPC Class Codes: C07D 213/71 : to which a second hetero atom is attached
• CPC Class Codes: C07D 215/36 : Sulfur atoms C07D215/24 takes precedence
• CPC Class Codes: C07D 217/02 : with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
• CPC Class Codes: C07D 277/36 : Sulfur atoms
• CPC Class Codes: C07D 277/46 : by carboxylic acids, or sulfur or nitrogen analogues thereof
• CPC Class Codes: C07D 317/66 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 333/28 : Halogen atoms
• CPC Class Codes: C07D 333/34 : Sulfur atoms
• CPC Class Codes: C07D 333/36 : Nitrogen atoms
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• 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 and a novel use of phenyl ureas in the treatment of disease scates mediated by the chemokine, Interleukin-8 (IL-8). In particular, this invention relates to the novel compounds of Formula (Ia) and their use in treating chemokine mediated diseases wherein the chemokine binds to an IL-8 a or b receptor. Compounds of Formula (Ia) are represented by the structure: ##STR1## wherein interalia, X is oxygen or sulfur;

Rb is NR₆ R₇, alkcyl, aryl, arylC_1-4 alkyl, aryl C_2-4 alkenyl, heteroaryl, heteroarylC_1-4 alkyl, heteroarylC_2-4 alkenyl, heterocyclic or heterocyclic C_1-4 alkyl, or a heterocyclic C_2-4 alkenyl moiety, camphor, all of which may be optionally substituted;

R₁ is independently selected from hydrogen; halogen; nitro; cyano; C_1-10 alkyl; halosubstituted C_1-10 alkyl; C_2-10 alkoxy; halosubstituted C_1-10 alkoxy; azide; (CR₈ R₈)q S(O)_t R₄ ; hydroxy; hydroxy substituted C_1-4 alkyl; aryl; aryl C_1-4 alkyl; aryl C_2-10 alkenyl; aryloxy; aryl C_1-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C_2-10 alkenyl; heteroaryl C_1-4 alkyloxy; heterocyclic; heterocyclic C_1-4 alkyl; heterocyclicC_1-4 alkyloxy; heterocyclic C_2-10 alkenyl;

q is 0 or an integer having a value of 1 to 10; n is an integer having a value of 1 to 3;

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

Y is hydrogen; 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; (CR₈ R₈)qS(O)_t R₄, (CR₈ R₈)qOR₄ ; hydorxy; hydroxy substituted C_1-4 alkyl; aryl; aryl C_1-4 alkyl; aryloxy; arylC_1-4 alkyloxy; aryl C_2-10 alkenyl; heteroaryl; heteroarylalkyl; heteroaryl C_1-4 alkyloxy; heteroaryl C_2-10 alkenyl; heterocyclic, heterocyclic C_1-4 alkyl; heterocyclicC_2-10 alkenyl;

or a pharmaceutically acceptable salt thereof.

Claims

1. A method of treating a chemokine mediated disease in a mammal in need thereof, wherein the chemokine binds to an IL-8 a or b receptor, which method comprises administering to said mammal an effective amount of a compound of the formula:

##STR19## wherein X is oxygen or sulfur;

R_a is an alkyl, aryl, arylC_1-4 alkyl, heteroaryl, heteroaryl C_1-4 alkyl, heterocyclic, or a heterocyclic C_1-4 alkyl moiety, all of which may be optionally substituted;

R_b is a NR₆ R₇, alkyl, aryl, arylC_1-4 alkyl, aryl C_2-4 alkenyl, heteroaryl, heteroarylC_1-4 alkyl, heteroarylC_2-4 alkenyl, heterocyclic, or heterocyclic C_1-4 alkyl, or a heterocyclic C_2-4 alkenyl 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;

NR₉ C(O)R_a, S(O)_m R_a, C(O)NR₆ R₇, S(O)₃ H, or C(O)OC_1-4 alkyl;

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 which heteroatom is selected from oxygen, nitrogen or sulfur, which ring may be optionally substituted;

R₉ is hydrogen or a C_1-4 alkyl;

R₁ is independently selected from hydrogen;

halogen;

nitro, cyano;

C_1-10 alkyl;

halosubstituted C_1-10 alkyl;

C_2-10 alkenyl;

C_1-10 alkoxy;

halosubstituted C_1-10 alkoxy;

azide;

(CR₈ R₈)q S(O)_t R₄ ;

hydroxy;

hydroxy substituted C_1-4 alkyl;

aryl;

aryl C_1-4 alkyl;

aryl C_2-10 alkenyl;

aryloxy;

aryl C_1-4 alkyloxy;

heteroaryl;

heteroarylalkyl;

heteroaryl C_2-10 alkenyl;

heteroaryl C_1-4 alkyloxy;

heterocyclic, heterocyclic C_1-4 alkyl;

heterocyclicC_1-4 alkyloxy;

heterocyclicC_2-10 alkenyl;

(CR₈ R₈)q NR₄ R₅ ;

(CR₈ R₈)q C(O)NR₄ R₅ ;

C_2-10 alkenyl C(O)NR₄ R₅ ;

(CR₈ R₈)q C(O)NR₄ R₁₀ ;

S(O)₃ R₈ ;

(CR₈ R₈)q C(O)R₁₁ ;

C_2-10 alkenyl C(O)R₁₁ ;

C_2-10 alkenyl C(O)OR₁₁ ;

(CR₈ R₈)q C(O)OR₁₁ ;

(CR₈ R₈)q C(O)OR₁₂ ;

(CR₈ R₈)qOC(O)R₁₁ ;

(CR₈ R₈)qNR₄ C(O)R₁₁ ;

(CR₈ R₈)q C(NR₄)NR₄ R₅ ;

(CR₈ R₈)q NR₄ C(NR₅)R₁₁, (CR₈ R₈)q NHS(O)₂ R₁₃ ;

(CR₈ R₈)q S(O)₂ NR₄ R₅, or two R₁ moieties together may form O--(CH₂)_s O-- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl heterocyclic, and heterocyclic alkyl moieties 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 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, heterocyclicC_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 O/N/S;

Y is hydrocgen;

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;

(CR₈ R₈)qS(O)_t R₄, (CR₈ R₈)qOR₄ ;

hydroxy;

hydroxy substituted C_1-4 alkyl;

aryl, aryl C_1-4 alkyl;

aryloxy;

arylC_1-4 alkyloxy;

aryl C_2-10 alkenyl;

heteroaryl;

heteroarylalkyl;

heteroaryl C_1-4 alkyloxy;

heteroaryl C_2-10 alkenyl;

heterocyclic, heterocyclic C_1-4 alkyl;

heterocyclicC_2-10 alkenyl;

(CR₈ R₈)qNR₄ R₅ ;

C_2-10 alkenyl C(O)NR₄ R₅ ;

(CR₈ R₈)qC(O)NR₄ R₅ ;

(CR₈ R₈)q C(O)NR₄ R₁₀ ;

S(O)₃ R₈ ;

(CR₈ R₈)qC(O)R₁₁ ;

C_2-10 alkenylC(O)R₁₁ ;

(CR₈ R₈)qC(O)OR₁₁ ;

C_2-10 alkenylC(O)OR₁₁ ;

(CR₈ R₈)qOC(O)R₁₁ ;

(CR₈ R₈)qNR₄ C(O)R₁₁ ;

(CR₈ R₈)q NHS(O)₂ R_b ;

(CR₈ R₈)q S(O)₂ NR₄ R₅ ;

(CR₈ R₈)qC(NR₄)NR₄ R₅ ;

(CR₈ R₈)q NR₄ C(NR₅)R₁₁ ;

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

wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups nay be optionally substituted;

q is 0 or an integer having a value of 1 to 10;

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

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

m'"'"' is 0 or an integer having a value of 1 or 2;

R₈ is hydrogen or C_1-4 alkyl

R₁₀ is C_1-10 alkyl C(O)₂ R₈ ;

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

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

R₁₃ is C_1-4 alkyl, aryl, aryl C_1-4 alkyl, heteroaryl, heteroarylC_1-4 alkyl, heterocyclic, or heterocyclicC_1-4 alkyl;

or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 wherein R₁ is substituted in the 3-position, the 4- position or di-substituted in the 3,4- position by an electron withdrawing moiety.

3. The method according to claim 1 or 2 wherein Y is mono-substituted in the 2'"'"'-position or 3'"'"'- position, or is disubstituted in the 2'"'"'- or 3'"'"'- position of a monocyclic ring.

4. The method according to claim 1 or 2 wherein n and m are each equal to 1 or more.

5. The method according to claim 1 wherein the compound is:

N-(4-Nitro 2-(phenylsulfonylamino)phenyl-N'"'"'-phenyl urea,

N- (2-Phenylsulfamido) 4-cyanophenyl!- N'"'"'-(2-bromo phenyl)urea,

N-(2-(Amino sulfonamido phenyl)phenyl)N'"'"'-(2-bromo phenyl)urea,

N-(2-(Amino sulfonyl styryl)phenyl)N'"'"'-(2-bromo phenyl)urea,

2- (3,4 Di-methoxyphenylsulfonyl)amino!phenyl)N'"'"'-(2-bromo phenyl)urea,

N-(2- (4-Acetamidophenylsulfonyl)amino!phenyl)N'"'"'-(2-bromo phenyl)urea,

N-(2-(Amino sulfonyl(2-thiophene)phenyl)N'"'"'-(2-bromo phenyl)urea,

N-(2-(Amino sulfonyl(3-tolyl)phenyl)N'"'"'-(2-bromo phenyl)urea,

N-(2-(Amino sulfonyl(8-quinolinyl))phenyl)N'"'"'-(2-bromo phenyl)urea,

N-(2-(Amino sulfonyl benzyl)phenyl)N'"'"'-(2-bromo phenyl)urea,

N- 2- 2-(Trifluoromethyl)phenyl!sulfonyl!amino!phenyl!-N'"'"'(2-bromophenyl)urea,

N-(2-Bromophenyl)-N'"'"'- 2-dimethylaminosulfonylamino!phenyl!urea,

N- 2-(Phenethylsulfonylamino)phenyl!-N'"'"'-(2-bromophenyl)urea,

N- 2- (2-Acetamido-4-methylthiazol-5-ylsulfonylamino!phenyl!-N'"'"'-(2-bromophenyl)urea,

N-(2- (2,3-Dichlorothieth-5-yl)!sulfonylamino!phenyl!-N'"'"'-(2-bromophenyl)urea,

N- 2- (3,5-Bistrifluoromethylphenyl)sulfonylamino!phenyl!-N'"'"'-(2-bromophenyl)urea,

N- 2- (2-Benzylsul)sulfonylamino!-(5-trifluoromethyl)phenyl)-N'"'"'-(2-bromophenyl)urea,

N- 2- 2-(3-Nitrophenyl)sulfonylamino!-phenyl!-N'"'"'-(2-bromophenyl)urea,

N- 2-(1S)-10-Camphorsulfonylamino!phenyl!-N'"'"'-(2-bromophenyl)urea,

N- 2-(1R)-10-Camphorsulfonylamino!phenyl!-N'"'"'-(2-bromophenyl)urea,

N- 2- 2-(2-Nitro-(4-trifluoromethyl)phenyl)sulfonylamino!phenyl-N'"'"'-(2-bromophenyl)urea,

N- 2-(Aminosulfonyl phenyl)-3-amino phenyl!N'"'"'-(2-bromo phenyl)urea,

or a pharmnaceutically acceptable salt thereof.

6. The method according to claim 1 wherein R_b is NR₆ R₇, optionally substituted aryl, optionally substituted arylC_1-4 alkyl, optionally substituted aryl C_2-4 alkenyl, optionally substituted heteroaryl, or optionally substituted camphor.

7. The method according to claim 6 wherein R_b is phenyl, di-alkoxy substituted phenyl, acetamido substituted phenyl, optionally substituted thienyl, benzyl, quinolyl trifluoromethyl substituted phenyl, dimethyl amino, phenethyl, optionally substituted thiazole, nitro substituted phenyl, nitro, or trifluoromethyl disubstituted phenyl.

8. The method according to claim 1 wherein R₁ is halogen, cyano, nitro, CF₃, C(O)NR₄ R₅, alkenyl C(O)NR₄ R₅, C(O) R₄ R₁₀, alkenyl C(O)OR₁₂, heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or S(O)NR₄ R₅.

9. The method according to claim 1 wherein Y is halogen, C_1-4 alkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted arylalkyloxy, optionally substituted heteroarylalkyloxy, methylenedioxy, NR₄ R₅, thioC_1-4 alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C_1-4 alkyl, or hydroxy alkyl.

10. 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, glomerulonephritis, thrombosis, Alzheimer'"'"'s disease, graft vs. host reaction, and allograft rejections.

11. The method according to claim 1 wherein the mammal is a human.

12. A method of treating a chemokine mediated disease in a mammal in need thereof, wherein the chemokine binds to an IL-8 a or b receptor, which method comprises administering to said mammal an effective amount of a compound which is:

N- 2- 2-(4-Phenoxyphenyl)sulfonylamino!phenyl!-N'"'"'-(2-bromophenyl)urea, N- 2-(2-Amino-(4-trifluoromethyl)phenyl)sulfonylamino!phenyl!-N'"'"'-(2-bromophenyl)urea , or

a pharmaceutically acceptable salt thereof.