ZA200207325B - IL-8 receptor antagonists. - Google Patents

IL-8 receptor antagonists. Download PDF

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Publication number
ZA200207325B
ZA200207325B ZA200207325A ZA200207325A ZA200207325B ZA 200207325 B ZA200207325 B ZA 200207325B ZA 200207325 A ZA200207325 A ZA 200207325A ZA 200207325 A ZA200207325 A ZA 200207325A ZA 200207325 B ZA200207325 B ZA 200207325B
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South Africa
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alkyl
chloro
aryl
hydroxy
optionally substituted
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ZA200207325A
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Katherine Louisa Widdowson
Qi Jin
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Smithkline Beecham Corp
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Description

IL-8 RECEPTOR ANTAGONISTS
FIELD OF THE INVENTION
This invention relates to novel sulfonamide substituted diphenyl urea compounds, pharmaceutical compositions, processes for their preparation, and use thereof in treating IL-8, GROq, GRO, GROy, NAP-2, and ENA-78 mediated diseases.
BACKGROUND OF THE INVENTION
Many different names have been applied to Interleukin-8 (IL-8), such as neutrophil attractant/activation protein-1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCEF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor. Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells. It.is produced by a majority of nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to
TNF, IL-10, IL-1B or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP. M. Baggiolini et al., J. Clin. Invest. 84, 1045 (1989); I. Schroder et al, J. Immunol. 739, 3474 (1987) and J. Immunol. /44, 2223 (1990) ; Strieter, et al., Science 243, 1467 (1989) and J. Biol. Chem. 264, 10621 (1989); Cassatella et al., J. Immunol. 748, 3216 (1992).
GROaq, GROB, GROy and NAP-2 also belong to the chemokine family.
Like IL-8 these chemokines have also been referred to by different names. For instance GROq, B, y have been referred to as MGSAa., JB and 7 respectively (Melanoma Growth Stimulating Activity), see Richmond et al., J. Cell Physiology 129, 375 (1986) and Chang et al., J. Immunol 148, 451 (1992). All of the chemokines of the o-family which possess the ELR motif directly preceding the
CXC motif bind to the IL-8 B receptor (CXCR2).
IL-8, GROa, GROB, GROY, NAP-2, and ENA-78 stimulate a number of functions in vitro. They have all been shown to have chemoattractant properties for neutrophils, while IL-8 and GRO have demonstrated T-lymphocytes, and basophilic chemotactic activity. In addition IL-8 can induce histamine release from basophils from both normal and atopic individuals. GRO-o. and IL-8 can in addition, induce lysozomal enzyme release and respiratory burst from neutrophils.
IL-8 has also been shown to increase the surface expression of Mac-1 (CD11b/CD18) on neutrophils without de novo protein synthesis. This may contribute to increased adhesion of the neutrophils to vascular endothelial cells. . Many known diseases are characterized by massive neutrophil infiltration. As IL- 5 8, GROaq, GRO, GROy and NAP-2 promote the accumulation and activation of ’ neutrophils, these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis,
Baggiolini et al., FEBS Lett. 307, 97 (1992); Miller et al., Crit. Rev. Immunol. 12, 17 (1992); Oppenheim et al., Annu. Rev. Immunol. 9, 617 (1991); Seitz et al., J.
Clin. Invest. 87, 463 (1991); Miller et al., Am. Rev. Respir. Dis. 146, 427 (1992);
Donnely et al., Lancet 341, 643 (1993). In addition the ELR chemokines (those containing the amino acids ELR motif just prior to the CXC motif) have also been : implicated in angiostasis, Strieter et al., Science 258, 1798 (1992).
In vitro, IL-8, GRO, GROB, GROy and NAP-2 induce neutrophil shape change, chemotaxis, granule release, and respiratory burst, by binding to and ’ activating receptors of the seven-transmembrane, G-protein-linked family, in particular by binding to IL-8 receptors, most notably the IL-8 receptor (CXCR?2).
Thomas et al., J. Biol. Chem. 266, 14839 (1991); and Holmes et al., Science 253, 1278 (1991). The development of non-peptide small molecule antagonists for members of this receptor family has precedent. For a review see R. Freidinger in
Progress in Drug Research, Vol. 40, pp. 33-98, Birkhauser Verlag, Basel 1993.
Hence, the IL-8 receptor represents a promising target for the development of novel anti-inflammatory agents.
Two high affinity human IL-8 receptors (77% homology) have been characterized: IL-8Ra, which binds only IL-8 with high affinity, and IL-8R}3, which has high affinity for IL-8 as well as for GROo, GROB, GROy and NAP-2.
See Holmes et al., supra; Murphy et al., Science 253, 1280 (1991); Lee et al., J.
Biol. Chem. 267, 16283 (1992); LaRosa et al., J. Biol. Chem. 267, 25402 (1992), and Gayle et al., J. Biol. Chem. 268, 7283 (1993). » 30 There remains a need for treatment, in this field, for compounds, which are capable of binding to the IL-8 ot or 3 receptor. Therefore, conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T-cells subsets into the inflammatory site) would benefit by compounds, which are inhibitors of IL-8 receptor binding.
SUMMARY OF THE INVENTION ~~
This invention provides for a method of treating a chemokine mediated . 5 disease, wherein the chemokine is one which binds to an IL-8 a or b receptor and which method comprises administering an effective amount of a compound of
Formula (I) or a pharmaceutically acceptable salt thereof. In particular the chemokine is IL-8.
This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I).
The present invention also provides for the novel compounds of Formula (I), and pharmaceutical compositions comprising a compound of Formula'(I), and a pharmaceutical carrier or diluent.
Compounds of Formula (I) useful in the present invention are represented by the structure:
R14 R15
R14
OH
CY Mp
THON
0 R14 R15 gm ® wherein
Rp is independently selected rom the group consisting of hydrogen, NRgR7, OH, OR,,
C1-salkyl, aryl, arylC1_4alkyl, aryl C2_4alkenyl; cycloalkyl, cycloalkyl C1.5 . alkyl, heteroaryl, heteroarylC1-4alkyl, heteroarylC9_4 alkenyl, heterocyclic, heterocyclic C1-4alkyl, and a heterocyclic C2-4alkenyl, all of which moieties may be optionally substituted one to three times independently by a substituent selected from the group consisting of halogen, nitro, halosubstituted C1-4 alkyl, C1-4 alkyl, _3-
amino, mono or di-Cj_4 alkyl substituted amine, OR,, C(O)R,, NR;C(O)OR,,
OC(O)NRgR7, hydroxy, NR9C(O)Ra, S(O)mRa, C(O)NRgR?7, C(O)OH,
C(O)ORg, S(O)2NRgR7, NHS(O)9R,, or, the two Ry, substituents join to form a 3- membered ring, optionally substituted and containing, in addition to carbon, } 5 independently, 1 to 3 moieties selected from the group consisting of NR, O, S,
SO, or SO»; and wherein the substituent can be optionally unsaturated;
Rj is selected from the group consisting of alkyl, aryl, arylC1-4alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic, COOR13, and a heterocyclic C1-4alkyl moiety, all of which moieties may be optionally substituted; 10 mis an integer having a value of 1 to 3; mis 0, or an integer having a value of 1 or 2; n is an integer having a value of 1 to 3; qis 0, or an integer having a value of 1to 10; tis 0, or an integer having a value of 1 or 2; sis an integer having a value of 1 to 3;
R1 is independently selected from the froup consisting of hydrogen, halogen, nitro, cyano, C1-10 alkyl, halosubstituted C1-10 alkyl, C2-10 alkenyl, C1-10 alkoxy, halosubstituted C]-10alkoxy, azide, S(O)tR4, (CRgRg)q S(O)tR4, hydroxy, hydroxy substituted C1-galkyl, aryl, aryl C1-4 alkyl, aryl C2-10 alkenyl, aryloxy, aryl C1.4 alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl C2-10 alkenyl, heteroaryl C1-4 alkyloxy, heterocyclic, heterocyclic C1-4alkyl, heterocyclicCj-4alkyloxy, heterocyclicC2-10 alkenyl, (CRgRg)q NR4R 5, (CRgRg)qC(O)NR4R5, C2-10 alkenyl C(O)NR4R35, (CRgRg)q C(O)NR4R 10, S(O)3R8, (CRgRg)q C(O)R11,
C2-10 alkenyl C(O)R11, C2-10 alkenyl C(O)OR]1, (CRgRg)q C(O)OR11, (CRgRg)q OC(O)R11, (CRgRg)qNR4C(O)R11], (CRgRg)q C(NRg)NR4Rs, (CRgRg)g NR4C(NR5)R]1, (CRgRg)q NHS(O)2R 3, and (CRgRg)q S(O)2NR4Rs5; or two R1 moieties together may form O-(CH2)sO or a 5 to 6 membered saturated or . unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moieties may be optionally substituted;

Claims (13)

What is Claimed Is:
1. A compound of the formula (I): ’ R14 R15 R14 OH mee or Y TW 0 R14 Ri5 : (Rm M0 wherein CL Rp is independently selected rom the group consisting of hydrogen, NRe6R7, OH, OR,, Ci-salkyl, aryl, arylC1-4alkyl, aryl C2-4alkenyl; cycloalkyl, cycloalkyl C1.5 alkyl, heteroaryl, heteroarylCj-4alkyl, heteroarylC2_4 alkenyl, heterocyclic, heterocyclic C1-galkyl, and a heterocyclic C2-4alkenyl, all of which moieties may be optionally substituted one to three times independently by a substituent selected from the group consisting of halogen, nitro, halosubstituted C}-4 alkyl, C1-4 alkyl, amino, mono or di-C1_4 alkyl substituted amine, OR,, C(O)R,, NR;C(O)OR,, OC(O)NRgR7, hydroxy, NRgC(O)R4, S(O) Ra, C(O)NRgR7, C(O)OH, C(O)ORy,, S(O)2NRgR7, NHS(O)2R,, or, the two Ry, substituents join to form a 3- 10 membered ring, optionally substituted and containing, in addition to carbon, independently, 1 to 3 moieties selected from the group consisting of NR, O, S, SO, or SO; and wherein the substituent can be optionally unsaturated; R, is selected from the group consisting of alkyl, aryl, arylCj].4alkyl, heteroaryl, heteroaryl C1.-4alkyl, heterocyclic, COOR 3, and a heterocyclic C1-4alkyl moiety, all of which moieties may be optionally substituted; m is an integer having a value of 1 to 3; m’is 0, or an integer having a value of 1 or 2; n is an integer having a value of 1 to 3;
q is 0, or an integer having a value of 1 to 10; tis 0, or an integer having a value of 1 or 2; s 1s an integer having a value of 1 to 3; . Rj is independently selected from the froup consisting of hydrogen, halogen, nitro, cyano, C1-10 alkyl, halosubstituted C1-1¢ alkyl, C2-10 alkenyl, C1-10 alkoxy, halosubstituted C1-10alkoxy, azide, S(O)tR4, (CRgRg)q S(O){R4, hydroxy, hydroxy substituted C1-4alkyl, aryl, aryl C1-4 alkyl, aryl C2-10 alkenyl, aryloxy, aryl C14 alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl C2-1( alkenyl, heteroaryl C1-4 alkyloxy, heterocyclic, heterocyclic C1-4alkyl, heterocyclicCj-4alkyloxy, heterocyclicC2.10 alkenyl, (CRgRg)q NR4Rj5, (CRgRg)qC(O)NR4R5, C2-10 alkenyl C(O)NR4R3, (CRgRg)q C(O)NR4R10, S(O)3R8, (CRgRg)q C(O)R11, C2-10 alkenyl C(O)R11, C2-10 alkenyl C(O)OR11, (CRgRg)q C(O)OR11, (CRgRg)q OC(O)R11, (CRgRg)qNR4C(O)R 1, (CRgRg)q C(NR4)NR4Rs, (CRgRg)q NR4C(NR5)R11, (CRgRg)q NHS(0)2R 13, and (CRgRg)q S(O);NR4Rs5; or two R1 moieties together may form O-(CH2)sO ora 5 to 6 membered saturated or unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moieties may be optionally substituted; R4 and Rj are independently selected from the group consisting of hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl Cj-g4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1i-4alkyl, heterocyclic, and heterocyclicC1-4 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 and S; Rg and R7 are independently selected from the group consisting of hydrogen, C14 alkyl, heteroaryl, aryl, aklyl aryl, and alkyl C_4 heteroalkyl; or Rg 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 is selected from oxygen, nitrogen and sulfur; wherein the ring may be optionally substituted; Y is selected from the group conisting of CR14Cj5, NR14, O, CO, and S(O); Rg is hydrogen or C14 alkyl;
Rg is C1-4 alkyl; R10is C1-10 alkyl C(O)2Rg; R11 is selected from the group consisting of hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-galkyl, optionally , 5 substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, and optionally substituted heterocyclicC1-4alkyl; and R12 is selected from the group consisting of hydrogen C1-4 alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, and heterocyclicC1-4alkyl; R13 is selected from the group consisting of C1-4 alkyl, aryl, aryl C}-4alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, and heterocyclicC1-4alkyl; - R14 and R15 are, independently, selected from the group consisting of hydrogen, optionally substituted C1-4 alkyl group, OR,, and NR4R35; or R14 and R15 together with the atom (s) to which they are attached may form a 4 to 7 member ring which may optionally contain an additional heteroatom which heteroatom is selected from the group consisting of oxygen, nitrogen and sulfur; wherein the ring maybe optionally substituted; or a pharmaceutically acceptable salt thereof.
2. The compound according to Claim 1 wherein R] is substituted in the 4- position by an electron withdrawing moiety.
3. The compound according to Claim 2 wherein R is halogen, cyano or nitro.
4. The compound according to Claim 3 wherein R1 is halogen.
5. The compound according to Claim 4 wherein R] is independently, fluorine, chlorine, or bromine.
6. The compound according to Claim 1 wherein Ry, is hydrogen, C 1.4 alkyl, or C 1-4 alkyl substituted with C(O)OH, or C(O)OR;.
7. The compound according to Claim 1 which is selected from the group - consisting of: N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N’-cyclohexylurea; N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N*-(1-adamantyl)urea; N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N-(tetrahydro-2-pyranyljurea;
N-[4-chloro-2-hydroxy-3-sulfamylphenyl]-N’-(3-tetrahydrofuryl)urea; 6-Chloro-2-hydroxy-3-[3-(2-methyl-cyclopropyl)-ureido]-benzenesulfonamide; N-[4-chloro-2-hydroxy-3-sulfamylphenyl]-N-cyclohexylurea; ‘ 6-Chloro-2-hydroxy-3-[3-(2,2,3,3-tetrmethyl-cyclopropyl)-ureido]- benzenesulfonamide; ’ 6-Chloro-2-hydroxy-3-(3-piperidin-4-yl-ureido)-benzenesulfonamide; N-[4-chloro-2-hydroxy-3-sulfamylphenyl]-N’-(4-methyl-cyclohexyl) urea; 6-Chloro-2-hydroxy-3-[3-(3-methoxy-cyclohexyl)-ureido]-benzenesulfonamide; N-[4-chloro-2-hydroxy-3-sulfamylphenyl}-N-cyclopentylurea; N-[4-chloro-2-hydroxy-3-sulfamylphenyl]-N’-cyclobutylurea; N-[4-chloro-2-hydroxy-3-sulfamylphenyl]-N’-cyclopropylurea; 4-[6-Chloro-3-(3-cyclopentyl-ureido)-2-hydroxy-benzenesulfonyl]-piperazine-1- : carboxylic acid tert butyl ester; 1-[4-Chloro-2-hydroxy-3-(piperazine-1-sulfonyl)-phenyl]-3-cyclopentyl-urea; 4-[6-Chloro-3-(3-cyclobutyl-ureido)-2-hydroxy-benzenesulfonyl]-piperazine-1- carboxylic acid tert-butyl ester; . 3-[3-((1S,2S)-2-Benzyloxy-cyclohexyl)-ureido]-6-chloro-2-hydroxy- benzenesulfonamide; 6-Chloro-3-(3-cyclobutyl-ureido)-2-hydroxy-N,N’-dimethyl-benzenesulfonamide.
8. A compound according to claim 7 which is N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N’-cyclohexylurea
9. A compound according to claim 7 wherein the compound is in its sodium salt form.
10. A compound according to claim 7 wherein the compound is in its potassium salt form.
11. A pharmaceutical composition comprising a compound according to any of Claims 1 to 10 and a pharmaceutically acceptable carrier or diluent.
12. A method of treating a chemokine mediated disease, wherein the chemokine ’ binds to an IL-8 a or b receptor in a mammal, which method comprises administering } 30 to said mammal an effective amount of a compound of the formula according to any one of Claims 1 to 14.
13. The method according to Claim 12 wherein the mammal is afflicted with a chemokine mediated disease selected from the group consisting of: psoriasis, atopic dermatitis, osteo arthritis, rheumatoid arthritis, asthma, chronic
. obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, stroke, septic shock, multiple ’ sclerosis, endotoxic shock, gram negative sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, graft vs. host reaction, Alzheimer’s disease, allograft rejections, malaria, restenosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis and undesired hematopoietic stem cells release and diseases caused by respiratory viruses, herpes viruses, and hepatitis viruses, meningitis, cystic fibrosis, pre-term labor, cough, pruritus, multi- organ dysfunction, trauma, strains, sprains, contusions, psoriatic arthritis, herpes, encephalitis, CNS vasculitis, traumatic brain injury, CNS tumors, subarachnoid hemorrhage, post surgical trauma, interstitial pneumonitis, hypersensitivity, crystal induced arthritis, acute and chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, uveitis, polymyositis, vasculitis, acne, gastric and duodenal ulcers, celiac disease, esophagitis, glossitis, airflow obstruction, airway hyperresponsiveness, bronchiolitis obliterans organizing pneumonia, bronchiectasis, bronchiolitis, bronchiolitis obliterans, chronic bronchitis, cor pulmonae, dyspnea, emphysema, hypercapnea, hyperinflation, hypoxemia, hyperoxia-induced inflammations, hypoxia, surgerical lung volume reduction, pulmonary fibrosis, pulmonary hypertension, right ventricular hypertropy, sarcoidosis, small airway disease, ventilation-perfusion mismatching, - wheeze, colds and lupus.
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