Phenyl urea antagonists of the IL-8 receptor

• US 6,211,373 B1
• Filed: 07/08/1998
• Issued: 04/03/2001
• Est. Priority Date: 03/20/1996
• Status: Expired due to Fees

• 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): Higel, Floyd D.
• Application Number:
  US09/111,663
• Time in Patent Office: 1,000 Days
• Field of Search: 564/55, 564/49, 564/57, 546/164, 549/65, 514/311, 514/445, 514/586, 514/597, 514/371, 514/524, 548/192, 558/413
• US Class Current: 546/146
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• 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: 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 (I), and a novel use of these compounds in treating chemokine mediated diseases, wherein the chemokine binds to an IL-8 a or b receptor. Compounds of Formula (1) are represented by the structure:

wherein interalia, X is oxygen or sulfur;

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; C₁-C₁₀ alkyl; halosubstituted C_1-10 alkyl; C_2-10 alkenyl; C_1-10 alkoxy; halosubstituted C_1-10 alkoxy; azide; (CR₈R₈)_qS(O)_tR₄; 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; heterocyclic C_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;

n 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_1-1- alkoxy; azide; (CR₈R₈)_qS(O)_tR₄, (CR₈R₈)_qOR₄; hydroxy; hydroxy substituted C_1-4 alkyl; aryl; aryl C_1-4 alkyl; aryloxy; aryC_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; heterocyclic C_2-10 alkenyl;

or a pharmaceutically acceptable salt thereof.

Claims

1. A compound of the formula:

wherein

X is oxygen or sulfur;

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

R_b is a NR₆R₇, alkyl, aryl, arylC_1-4alkyl, aryl C_2-4alkenyl, heteroaryl, heteroarylC_1-4alkyl, heteroarylC_2-4 alkenyl, heterocyclic, or heterocyclic C_1-4alkyl, or a heterocyclic C_2-4alkenyl moiety, camphor, all of which are substituted or unsubstituted;

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;

S(O)_mR_a, C(O)NR₆R₇, S(O)₃H, 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 does or does not contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur, which ring are substituted or unsubstituted;

R₉ is hydrogen or a C_1-4 alkyl, preferably hydrogen;

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_1-10alkoxy;

azide;

S(O)_tR₄;

(CR₈R₈)q S(O)_tR₄;

hydroxy;

hydroxy substituted C_1-4alkyl;

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_1-4alkyl;

heterocyclicC_1-4alkyloxy;

heterocyclicC_2-10 alkenyl;

(CR₈R₈)q NR₄R₅;

(CR₈R₈)q C(O)NR₄R₅;

C_2-10 alkenyl C(O)NR₄R₅;

(CR₈R₈)q C(O)NR₄R₁₀;

S(O)₃R₈;

(CR₈R₈)q C(O)R₁₁;

C_2-10 alkenyl C(O)R₁₁;

C_2-10 alkenyl C(O)OR₁₁;

(CR₈R₈)q C(O)OR₁₁;

(CR₈R₈)q C(O)OR₁₂, (CR₈R₈)q OC(O)R₁₁;

(CR₈R₈)qNR₄C(O)R₁₁;

(CR₈R₈)q C(NR₄)NR₄R₅;

(CR₈R₈)q NR₄C(NR₅)R₁₁, (CR₈R₈)q NHS(O)₂R₁₃;

(CR₈R₈)q S(O)₂NR₄R₅, or two R₁ moieties together form O—

(CH₂)_sO—

or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, and heterocyclic alkyl moities are substituted or unsubstituted;

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, substituted or unsubstituted C_1-4 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl C_1-4alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl C_1-4alkyl, 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 does or does not comprise an additional heteroatom selected from O, N and S;

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;

(CR₈R₈)qS(O)_tR₄, (CR₈R₈)qOR₄;

hydroxy;

hydroxy substituted C_1-4alkyl;

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_1-4alkyl;

heterocyclicC_2-10 alkenyl;

(CR₈R₈)qNR₄R₅;

C_2-10 alkenyl C(O)NR₄R₅;

(CR₈R₈)qC(O)NR₄R₅;

(CR₈R₈)q C(O)NR₄R₁₀;

S(O)₃R₈;

(CR₈R₈)qC(O)R₁₁;

C_2-10 alkenylC(O)R₁₁;

(CR₈R₈)qC(O)OR₁₁;

C_2-10 alkenylC(O)OR₁₁;

(CR₈R₈)qOC(O)R₁₁;

(CR₈R₈)qNR₄C(O)R₁₁;

(CR₈R₈)q NHS(O)₂R_b;

(CR₈R₈)q S(O)₂NR₄R₅;

(CR₈R₈)qC(NR₄)NR₄R₅;

(CR₈R₈)q NR₄C(NR₅)R₁₁;

or two Y moieties together form O—

(CH₂)_sO—

or a 5 to 6 membered unsaturated ring; and

wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups are substituted or unsubstituted;

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_1-10alkyl C(O)₂R₈;

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

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

R₁₃ is C_1-4 alkyl, aryl, aryl C_1-4alkyl, heteroaryl, heteroarylC_1-14 alkyl, heterocyclic, or heterocyclicC_1-4alkyl;

or a pharmaceutically acceptable salt thereof.

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

10. The compound 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-(Amono sulfonamido phenyl) phenyl)N′

-(2-bromo phenyl) urea

N-(2-(Amono sulfonyl styryl) phenyl)N′

-(2-bromo phenyl) urea

2-[(3,4 Di-methoxyphenylsulfonyl)amino]phenyl)N′

-(2-bromo phenyl) urea

N-(2-[(4Acetamidophenylsulfonyl)amino]phenyl)N′

-(2bromo phenyl) urea

N-(2-(Amino sulfony (2-thiophene) phenyl)N∝

-(2-bromo phenyl) urea

N-(2-(Amino sulfonyl (3tolyl) 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-yl)sulfonylamino]phenyl]-N′

-(2-bromophenyl)urea

N-[2-[(2,3-Dichlorothien-5-yl)]sulfonylamino]phenyl]-N′

-(2-bromophenyl)urea

N-[2-[(3,5-Bistrifluoromethylphenyl)sulfonylamino]phenyl]-N′

-(2-bromophenyl)urea

N-[2-[(2-Benzyl)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′

-(2bromophenyl)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-bomo phenyl) urea;

or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound according to claim 10, and a pharmaceutically acceptable carrier or diluent.

12. The compound according to claim 1 wherein R_b is NR₆R₇, substituted or unsubstituted aryl, substituted or unsubstituted arylC_1-4alkyl, substituted or unsubstituted aryl C_2-4alkenyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted camphor.

13. The compound according to claim 12 wherein R_b is phenyl, dialkoxy substituted phenyl, acetamido substituted phenyl, substituted or unsubstituted thienyl, benzyl, quinolyl, trifluoromethyl substituted phenyl, dimethyl amino, phenthyl, substituted or unsubstituted thiazole, nitro substituted phenyl, nitro and trifluoromethyl disubstituted phenyl.

14. The compound 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.

15. The compound according to claim 1 wherein Y is halogen, C_1-4 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkoxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted heteroarylalkyloxy, methylenedioxy, NR₄R₅, thioC_1-4alkyl, thioaryl, halosubstituted alkoxy, substituted or unsubstituted C_1-4alkyl, or hydroxy alkyl.

5. A compound of the formula:

wherein

X is oxygen or sulfur;

X₁ is oxygen or sulfur;

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_1-10alkoxy;

azide;

S(O)_tR₄;

(CR₈R₈)q S(O)_tR₄;

hydroxy;

hydroxy substituted C_1-4alkyl;

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_1-4alkyl;

heterocyclicC_1-4alkyloxy;

heterocyclicC_2-10 alkenyl;

(CR₈R₈)q NR₄R₅;

(CR₈R₈)q C(O)NR₄R₅;

C_2-10 alkenyl C(O)NR₄R₅;

(CR₈R₈)q C(O)NR₄R₁₀;

S(O)₃R₈;

(CR₈R₈)q C(O)R₁₁;

C_2-10 alkenyl C(O)R₁₁;

C_2-10 alkenyl C(O)OR₁₁;

(CR₈R₈)q C(O)OR₁₁;

(CR₈R₈)q OC(O)R₁₁;

(CR₈R₈)qNR₄C(O)R₁₁;

(CR₈R₈)q C(NR₄)NR₄R₅;

(CR₈R₈)q NR₄C(NR₅)R₁₁, (CR₈R₈)q NHS(O)₂R₁₃;

(CR₈R₈)q S(O)₂NR₄R₅, or two R₁ moieties together form O—

(CH₂)_sO—

or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moieties are substituted or unsubstituted;

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, substituted or unsubstituted C_1-4 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl C_1-4alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl C_1-4 alkyl, 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 does or does not contain an additional heteroatom selected from O, N and S;

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;

(CR₈R₈)qS(O)_tR₄, (CR₈R₈)qOR₄;

hydroxy;

hydroxy substituted C_1-4alkyl;

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_1-4alkyl;

heterocyclicC_2-10 alkenyl;

(CR₈R₈)qNR₄R₅;

C_2-10 alkenyl C(O)NR₄R₅;

(CR₈R₈)qC(O)NR₄R₅;

(CR₈R₈)q C(O)NR₄R₁₀;

S(O)₃R₈;

(CR₈R₈)qC(O)R₁₁;

C_2-10 alkenylC(O)R₁₁;

(CR₈R₈)qC(O)OR₁₁;

C_2-10alkenylC(O)OR₁₁;

(CR₈R₈)qOC(O)R₁₁;

(CR₈R₈)qNR₄C(O)R₁₁;

(CR₈R₈)q NHS(O)₂R_b;

(CR₈R₈)q S(O)₂NR₄R₅, (CR₈R₈)qC(NR₄)NR₄R₅;

(CR₈R₈)q NR₄C(NR₅)R₁₁;

or two Y moieties together form O—

(CH₂)_sO—

or a 5 to 6 membered unsaturated ring; and

wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups are substituted or unsubstituted;

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;

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 does or does not contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;

R₈ is hydrogen or C_1-4 alkyl;

R₁₀ is C_1-10 alkyl C(O)₂R₈;

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

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

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

R_b is NR₆R₇, alkyl, aryl, aryl C_1-4 alkyl, aryl C_2-4 alkenyl, heteroaryl, heteroaryl C_1-4 alkyl, heteroarylC_2-4 alkenyl, heterocyclic, heterocyclic C_1-4alkyl, heterocyclic, C_2-4 alkenyl, or camphor, all of which groups are substituted or unsubstituted;

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′

-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 X₁ is O, m=2, R₁ is 2-t-butyl, 4-methyl, and n=3 then Y is not 2′

—

OH,3′

-t-butyl, 5′

-methyl;

when X₁ is O, m=1, R₁ is 4-methyl, and n=2 then Y is not 2′

—

OH, 5′

-methyl;

when X₁ is O, m=1, R₁ is hydrogen, and n=2 than Y is not 2′

-6′

-diethyl;

when X₁ is O, m=1, R₁ is 6—

OH, and n=2 than Y is not 2′

-5′

-methyl;

when X₁ is S, m=1, R₁ is 4-ethyl, and n=1 than Y is not 2-methoxy;

or a pharmaceutically acceptably salt thereof.

6. The compound according to claim 5 wherein R₁ is substituted in the 3-position, the 4-position or di-substituted in the 3,4-position by an electron withdrawing moiety.

7. The compound according to claim 5 or 6 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.

8. The compound according to claim 5 or 6 wherein n and m are each equal to 1 or more.

9. A pharmaceutical composition comprising a compound according to any of claims 5 to 8 and a pharmaceutically acceptable carrier or diluent.