JP2003501470A - IL-8 receptor antagonist - Google Patents

Abstract

  (57) [Summary] The present invention relates to novel phenylureas useful in the treatment of disease states mediated by the chemokine interleukin-8 (IL-8).

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention relates to a new group of phenylurea compounds, a process for their preparation, IL-
8, their use in treating diseases mediated by GROα, GROβ, GROγ, NAP-2 and ENA-78, as well as pharmaceutical compositions used for such treatment.

BACKGROUND OF THE INVENTION Many different names have been given to interleukin-8, such as neutrophil attracting / activating protein-1 (NAP-1), monocyte-derived neutrophil chemotactic factor. (MDN
CF), neutrophil activator (NAF), and T-cell lymphocyte chemotactic factor. Interleukin-8 is a chemoattractant for neutrophils, basophils and some T cells. It is used by macrophages and fibroblasts to induce TNF, I
By most nucleated cells including endothelial and epidermal cells when exposed to L-1α, IL-1β or LPS, and when exposed to chemotactic factors such as LPS or FMLP neutrophils themselves Produced by. M. Baggiolini et a
l, J. Clin. Invest. 84, 1045 (1989); J. Schroder et al, J. Immunol. 13
9, 3474 (1987) and J. Immunol 144, 2223 (1990);.. Strieter, et al, Sci ence 243, 1467 (1989) and J. Biol Chem 264, 10621 (1989);. Cassatella e
t al, J. Immunol. 148 , 3216 (1992). GROα, GROβ, GROγ and NAP-2 also belong to the chemokine α family. Like IL-8, these chemokines are also called by other names. For example, GRO α, β and γ are called MGSA (melanoma growth stimulating activity) α, β and γ, respectively. Richmond et al, J. Cell Physiology 129, 375 (1986) a
See nd Chang et al, J. Immunol 148, 451 (1992). All chemokines of the α-family that have an ELR motif immediately preceding the CXC motif are IL-8β.
It binds to the receptor.

IL-8, GROα, GROβ, GROγ, NAP-2 and ENA-78 stimulate many functions in vitro. Although they have all been shown to have chemoattractant properties for neutrophils, IL-8 and GROα show T lymphocyte and basophil chemotactic activity. Furthermore, IL-8 can induce histamine release from basophils from normal and atopic individuals, while GROα and IL-8 induce release of lysosomal enzymes and respiratory burst from neutrophils. can do. IL-8 has also been shown to increase Mac-1 (CD11b / CD18) expression on the surface of neutrophils without de novo protein synthesis. This may contribute to increased neutrophil adherence to vascular endothelial cells. Since IL-8, GROα, GROβ, GROγ and NAP-2 promote neutrophil accumulation and activation, these chemokines are involved in a wide range of acute and chronic inflammatory diseases including psoriasis and rheumatoid arthritis. is doing. Ba
ggiolini et al, FEBS Lett. 307 , 97 (1992); Miller et al, Crit. Rev. Immu nol. 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)
. Furthermore, ELR chemokines, which contain the amino acid ELR motif immediately before the CXC mochigue, are also involved in angiostatic. Strieter et al., Science 258, 1798
(1992).

In vitro, IL-8, GROα, GROβ, GROγ and NAP
-2 binds to and activates receptors of the 7-transmembrane G protein-coupled family, specifically the IL-8 receptor, and most specifically β-.
Binding to the receptor induces neutrophil shape change, chemotaxis, granule release, and respiratory burst. Thomas et al., J. Biol. Chem. 266 , 14839 (1991);
and Holmes et al., Science 253 , 1278 (1991). There is precedent for the development of non-peptide small molecule antagonists for members of this receptor family. For review, see R. Freidinger in: Progress in Drug Research , Vol. 40, pp. 33.
-98, Birkhauser Verlag, Basel 1993. Therefore, the IL-8 receptor is a promising target for the development of new anti-inflammatory agents. Two high affinity human IL-8 receptors (77% homology) have been characterized: IL-8Rα binds only IL-8 with high affinity and IL
-8Rβ has high affinity with IL-8 and GROα, GROβ, G
Binds ROγ and NAP-2. Holmes et al., Supra ; Murphy et al., S cience 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. Bi ol Chem 268, 7283 (1993) reference.

There is a need in the art for compounds that can bind to IL-8 α or β receptors. Therefore, conditions associated with increased IL-8 production (due to chemotaxis of neutrophils and some T cells into the site of inflammation) would be benefited by compounds that are inhibitors of IL-8 receptor binding. Will receive.

SUMMARY OF THE INVENTION The present invention provides a method of treating a chemokine-mediated disease, wherein the chemokine binds to an IL-8 α or β receptor, the method comprising:
) Is administered, or a pharmaceutically acceptable salt thereof is administered. Specifically, the chemokine is IL-8. The present invention also relates to a method of inhibiting the binding of IL-8 to its receptor in a mammal in need of inhibiting the binding of IL-8 to its receptor, the method comprising: It is characterized in that the compound of I) is administered to said mammal.

[0007]   Compounds of formula (I) useful in the present invention have the following structural formula:

[Chemical 6] [Wherein, X is oxygen or sulfur; R is (CR ₈ R ₈ ) _r C (O) ₂ H, (CR ₈ R ₈ ) _r NH-C (O) R _a , (CR ₈ R ₈ ). _{r C (O) NR 6 '} R 7', (CR 8 R 8) r NH
S (O) ₂ R _b , (CR ₈ R ₈ ) _r S (O) ₂ NHR _c , (CR ₈ R ₈ ) _r NHC (X ₂ ) NHR _b , or a tetrazolyl ring; X ₂ is oxygen or sulfur. R ₁ is hydrogen; halogen; nitro; cyano; halo-substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; halo-substituted C _1-10 alkoxy; azide
; (CR ₈ R ₈ ) _q S (O) _t R ₄ ; hydroxy; hydroxy C _1-4 alkyl; aryl; aryl C _1-4 alkyl; aryloxy; aryl C _1-4 alkyloxy; heteroaryl; heteroaryl Alkyl; heterocyclic; heterocyclic C _1-4 alkyl; heteroaryl C _1-4 alkyloxy; aryl C _2-10 alkenyl; heteroaryl C _2-10 alkenyl; heterocyclic C _2-10 alkenyl; (CR ₈ R ₈ ) _q NR ₄ R ₅ ; C _2-10 alkenyl C (O) NR ₄ R ₅ ; (CR ₈ R ₈ ) _q C (O) NR ₄ R ₅ ; (CR ₈ R ₈ ) _q C (O ) NR ₄ R ₁₀ ;
S (O) ₃ R ₈ ; (CR ₈ R ₈ ) _q C (O) R ₁₁ ; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR _{1 1} (CR ₈ R ₈ ) _q C (O) OR ₁₂ ; (CR ₈ R ₈ ) _q OC (O) R ₁₁ ; (CR ₈ R ₈ ) _q NR ₄ C (O) R ₁₁ ; (CR ₈ R ₈ ) _q NHS (O ) ₂ R ₁₇ ; (CR ₈ R ₈ ) _q S (O) ₂ NR ₄ R ₅ independently selected; or two R ₁ moieties taken together are O- (CH ₂ ) _s O -Or a 5- to 6-membered saturated or unsaturated ring may be formed; where the aryl, heteroaryl, and heterocyclic containing moieties may be substituted; provided that the 3- to 2-position on the phenyl ring is 10 pKa
And n is an integer having a value of 1 to 3; m is an integer having a value of 1 to 3; q is 0 or 1 R is an integer having a value of 1 to 4; r is 0 or an integer having a value of 1 to 4; s is an integer having a value of 1 to 3; t is 0 or Is an integer having a value of 1 or 2; v is an integer having a value of 1 to 4; R ₄ and R ₅ are independently hydrogen, optionally substituted C _1-4 alkyl, substituted Optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl, heterocyclic, heterocyclic C _{1 −} Or alkyl, or R ₄ and R ₅ may form a ring of 5 to together with the nitrogen to which they are attached 7-membered, one ring is selected from the more O / N / S R ₆ and R ₇ are independently hydrogen or a C _1-4 alkyl group, or R ₆ and R ₇ together with the nitrogen to which they are attached are 5 or It may form a 7-membered ring, which may further contain one heteroatom selected from O / N / S; R _{6 ′} and R _{7 ′} are independently hydrogen, C _1-4 alkyl, aryl, aryl C _-4
Alkyl _, aryl C _2-4 alkenyl, heteroaryl, heteroaryl C _1-4 alkyl, heteroaryl C _2-4 alkenyl, heterocyclic, heterocyclic C _1-4 alkyl, heterocyclic C _2-4 alkenyl moiety Where one of R _{6 ′} and R _{7 ′} is hydrogen but both are not hydrogen; Y is hydrogen; halogen; nitro; cyano; halo-substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; halo-substituted C _1-10 alkoxy; azide; (
_{CR 8 R 8) q S (} O) t R 4; hydroxy; hydroxyalkyl C _1-4 alkyl; aryl; aryl C _{1 -4} alkyl; aryloxy; aryl C _1-4 alkyloxy; heteroaryl;
Heteroarylalkyl; Heteroaryl C _1-4 alkyloxy; Heterocyclic, heterocyclic C _1-4 alkyl; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; Heterocyclic C _2-10 alkenyl; (CR ₈ R ₈ ) _q NR ₄ R ₅ ; C _2-10 alkenyl C (O) NR ₄ R ₅ ; (CR ₈ R ₈ ) _q C (O) NR ₄ R ₅ ; (CR ₈ R ₈ ) _q C (O) NR ₄ R ₁₀ ; S (O) ₃ R _8; (CR ₈ R ₈ ) _q C (O) R ₁₁ ; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O ) OR ₁₁ ; C (
O) R _11; (CR ₈ R ₈ ) _q C (O) OR ₁₂ ; (CR ₈ R ₈ ) _q OC (O) R ₁₁ ; (CR ₈ R ₈ ) _q NR ₄ C (O) R ₁₁ ; ( CR ₈ R ₈ ) _q N
HS (O) ₂ R _d ; (CR ₈ R ₈ ) _q S (O) ₂ NR ₄ R ₅ independently selected; or two Y moieties taken together are O- (CH ₂ ). _s O-or a 5- or 6-membered saturated or unsaturated ring may be formed; where aryl, heteroaryl, and heterocyclic containing moieties may be substituted; R ₈ is hydrogen or C _1-. Independently selected from ₄ alkyl; R ₁₀ is C _1-10 alkyl C (O) ₂ R ₈ ; R ₁₁ is hydrogen, C _1-4 alkyl, optionally substituted aryl, substituted _Optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl, optionally substituted heterocyclic, or optionally substituted hetero. It is a cyclic _{C 1-4} alkyl; _{R 12} is hydrogen , C _1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl; R ₁₃ and R ₁₄ are independently hydrogen, optionally substituted C _1-4 alkyl. Alternatively, one of R ₁₃ and R ₁₄ may be optionally substituted aryl; R ₁₇ is C _1-4 alkyl, aryl, arylalkyl, heteroaryl, heteroaryl C _1-4 alkyl, hetero Cyclic or heterocyclic C _1-4 alkyl, wherein aryl, heteroaryl, and heterocyclic ring may all be optionally substituted; R _a is alkyl, aryl, aryl C _1-4 alkyl, heteroaryl, heteroaryl C _1-4 alkyl, heterocyclic or heterocyclic C _{1 -4} alkyl, A portion, here may be all of these moieties substituted; R _b is NR ₆ R _7, alkyl, aryl, aryl C _1-4 alkyl, aryl C _2-4 alkenyl, heteroaryl, heteroaryl C _1-4 alkyl, heteroaryl C _2-4 alkenyl, heterocyclic, heterocyclic C _1-4 alkyl, heterocyclic C _2-4 alkenyl moiety, or camphor, where all of these moieties are substituted. R _c may be alkyl, aryl, aryl C _1-4 alkyl, aryl C _2-4 alkenyl, heteroaryl, heteroaryl C _1-4 alkyl, heteroaryl C _2-4 alkenyl, heterocyclic, hetero. a cyclic C _1-4 alkyl or heterocyclic C _2-4 alkenyl moiety, here it may be all of these moieties substituted R _d is NR ₆ R _7, alkyl, aryl C _1-4 alkyl, aryl C _2-4 alkenyl,
Heteroaryl, heteroaryl-C _1-4 alkyl, heteroaryl C _2-4 alkenyl, heterocyclic, heterocyclic C _1-4 alkyl, wherein aryl, heteroaryl and heterocyclic containing rings are substituted. W may be

[Chemical 7] And the E-containing ring is:

[Chemical 8] Asterisk * indicates the point of attachment of the ring; R ₂₀ is W ₁ , optionally substituted heteroaryl, optionally substituted C _5-8 cycloalkyl, _optionally substituted A good C _1-10 alkyl, an optionally substituted C _2-10 alkenyl, or an optionally substituted C _2-10 alkynyl; W ₁ is

[Chemical 9] And the E′-containing ring is:

[Chemical 10] Asterisk * represents the point of attachment of the ring] or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION The compounds of formula (I) are also used for veterinary treatment of non-human mammals in need of inhibition of IL-8 or other chemokines that bind to IL-8 α and β receptors. Can be done. Chemokine-mediated animal diseases that are therapeutically or prophylactically treated include disease states such as those described in the Methods of Treatment section herein.

[0009]   In the compound of formula (I), R is (CR₈R₈)_rC (O)₂H, (CR₈R₈)_rNH-C (O) R_a, (CR₈R ₈ )_rC (O) NR_{6 '}R_{7 '}, (CR₈R₈)_rNHS (O)₂R_b, (CR₈R₈)_rS (O)₂NHR_c, (CR₈R₈)_rNHC (X₂) NHR _b Or a tetrazolyl ring. Each of these moieties is attached directly to the 3-position of the ring
Or linker (CR₈R₈)_rMay be attached to the ring via
Yes.   Suitably r is 0 or an integer from 1 to 4, preferably 0.   Suitably X_TwoIs oxygen or sulfur, preferably oxygen, where r
Is 0 or an integer having a value of 1 to 4.   Suitably R₆And R₇Are independently hydrogen, or C_1-4Is an alkyl group
Or R₆And R₇5 to 7 together with the nitrogen to which they bind
A member of a ring, wherein the ring is a further ring selected from oxygen, nitrogen or sulfur.
It may contain a seed atom.   Suitably R_{6 '}And R_{7 '}Is hydrogen, C_1-4Alkyl, aryl, aryl C_{1 -Four} Alkyl, aryl C_2-4Alkenyl, heteroaryl, heteroaryl C_1-4A
Ruquil, heteroaryl C_2-4 Alkenyl, heterocyclic, heterocyclic
Rick C_1-4Alkyl or heterocyclic C_2-4Alkenyl part,
Dashi R_{6 '}And R_{7 '}One is hydrogen, but R_{6 '}And R_{7 '}Both of
Is not hydrogen. All of these moieties are halogen; nitro; CF_ThreeLike
Halo substitution C_1-4Alkyl; C such as methyl_1-4Alkyl; C such as methoxy_1-4A
Rukoxy; NR₉C (O) R_a; C (O) NR₆R₇; S (O)₃H; or C (O) OC_1-4Germany by alkyl
It may be upright and may be substituted once to three times.

[0010]   Suitably R_aIs alkyl, aryl, aryl C_1-4Alkyl, heteroary
Le, heteroaryl C_1-4Alkyl, heterocyclic, or heterocyclic
CK C_1-4An alkyl moiety, where all of these moieties are defined herein.
May be replaced as described above.   Suitably R_bIs NR₆R₇, Alkyl, aryl, aryl C_1-4Alkyl, ant
C_2-4Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, heteroa
reel_2-4Alkenyl, heterocyclic, heterocyclic C_1-4Alkyl
, Or heterocyclic C_2-4Alkenyl moiety, or camphor
Where the alkyl, aryl, heteroaryl and heterocyclic containing moieties are
All, halogen; nitro; CF_ThreeHalo Substitution C_1-4Alkyl; methyl
When C_1-4Alkyl; C such as methoxy_1-4Alkoxy; NR₉C (O) R_a; C (O) NR₆R₇;
S (O)₃H; or C (O) OC_1-4Independently substituted 1 to 3 times with alkyl
May be. Preferably R_bIs an optionally substituted phenyl, benzyl or
It is styryl. R_bWhen is a heteroaryl ring, it is preferably
Optionally substituted thiazole, optionally substituted thienyl, or substituted
It is an optionally substituted quinolinyl ring.   Suitably R₉Is hydrogen or C_1-4An alkyl group, preferably hydrogen
It R₉Is the substituent NR₉C (O) R_aWhen present, preferably R_aHame
It is an alkyl group such as chill.   Suitably R_cIs hydrogen, alkyl, aryl, aryl C_1-4Alkyl, ally
Le C_1-4Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, hetero ant
C_1-4Alkenyl, heterocyclic, or heterocyclic C_1-4Al
Kill or heterocyclic C_1-4Alkenyl moieties, all of which are
Halogen, nitro, halo substituted C_1-4Alkyl, C_1-4Alkyl, C_1-4Alkoxy, NR ₉ C (O) R_a, C (O) NR₆R₇, S (O)₃H or C (O) OC_1-41 to 3 times depending on alkyl
It may be independently substituted. Preferably R_cMay be replaced
Nil.

[0011]   Suitably, W is

[Chemical 11] Is. Suitably, the E-containing ring is

[Chemical 12] An asterisk *, which is a substituent that may be present, selected from

[0012]   In the compounds of formula (I), suitably R₁Is hydrogen; halogen; nitro; sia
No; CF_ThreeHalo Substitution C_1-10Alkyl; methyl, ethyl, isopropyl or
Or C such as n-propyl_1-10Alkyl; C_2-10Alkenyl; methoxy or d
Toxy's C_1-10Alkoxy; halo-substituted C such as trifluoromethoxy_1-10 Alkoxy; Azide; (CR₈R₈)_qS (O)_tR_FourHydroxy; methanol or ethano
Hydroxy C_1-4Alkyl; aryl such as phenyl or naphthyl
Lu; Aryl C such as benzyl_1-4Alkyl; aryloxy such as phenoxy
Si; Aryl C such as benzyloxy_1-4Alkyloxy; heteroaryl; f
Teloarylalkyl; Heteroaryl C_1-4Alkyloxy; Aryl C_2-10A
Lucenyl; heteroaryl C_2-10Alkenyl; heterocyclic C_2-10Archeni
Le; (CR₈R₈)_qNR_FourR_Five; C_2-10Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R₈)_q C (O) NR_FourR_Ten; S (O)₃S (O) like H₃R₈; (CR₈R₈)_qC (O) R₁₁; C_2-10Alkenyl C (O) R ₁₁ ; C_2-10Alkenyl C (O) OR₁₁; C (O) R₁₁; (CR₈R₈)_qC (O) OR₁₂; (CR₈R₈)_qOC (O) R₁₁ ; (CR₈R₈)_qNR_FourC (O) R₁₁; (CR₈R₈)_qNHS (O)₂R₁₇; (CR₈R₈)_qS (O)₂NR_FourR_FiveIndependent from
Selected; or two Rs₁The parts together become O- (CH_Two)_sO-
Alternatively, it may form a 5- or 6-membered saturated or unsaturated ring. Aryl, hetero
Aryl and heterocyclic containing moieties are all described later in this specification.
It may be replaced as defined.   Suitably, t is 0 or an integer having a value of 1 or 2.   Suitably, s is an integer having a value of 1 to 3.   Suitably q is 0 or an integer having a value from 1 to 10.   R₁When forms a dioxy bridge, s is preferably 1. R ₁ Preferably forms a further saturated or unsaturated ring, it preferably
It is a 6-membered ring that results in a thylene ring system. These saturated or unsaturated ring systems
Is any other R defined above₁May be independently substituted 1 to 3 times by a moiety
Yes.

Suitably R ₄ and R ₅ 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, or heterocyclic C _1-4 alkyl, or R ₄ and R ₅ are 5 together with the bonding nitrogen
To 7-membered ring, which may contain one further heteroatom selected from O / N / S. Suitably R ₈ is independently selected from hydrogen or C _1-4 alkyl. Suitably R ₁₀ is C _1-10 alkyl C (O such as CH ₂ C (O) ₂ H or CH ₂ C (O) ₂ CH _3.
) ₂ R ₈ . Suitably, R ₁₁ is independently hydrogen, C _1-4 alkyl, aryl, aryl C _1-4 alkyl, heteroaryl, heteroaryl C _1-4 alkyl, heterocyclic,
Or heterocyclic C _1-4 alkyl. Suitably R ₁₂ is hydrogen, C _1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl. Suitably R ₁₇ is C _1-4 alkyl, aryl, arylalkyl, heteroaryl, heteroaryl C _1-4 alkyl, heterocyclic or heterocyclic C _1-4 alkyl, wherein aryl, hetero All aryl and heterocyclic rings may be substituted.

Preferably, R ₁ is halogen, cyano, nitro, CF ₃ , C (O) NR ₄ R ₅ , alkenyl C (O) NR ₄ R ₅ , C (O) R ₄ R ₁₀ , alkenyl C (O ) OR ₁₂ , heteroaryl, heteroarylalkyl, heteroarylalkenyl, or S (O) NR ₄ R ₅ , preferably R ₄ and R ₅ are both hydrogen, or R ₄ and R ₅ One is phenyl. Preferred ring substitutions for the R ₁ group are at the 4-position of the phenyl ring. R is _{(CR 8 R 8) r OH} , in the case of (CR _{8 R 8) r} SH or _{(CR 8 R 8) r NHS} (O) 2 R b is preferably, R ₁ is in the 4-position Substituted or disubstituted at the 2,4-position. Preferably, the R ₁ substituent is an electron withdrawing moiety such as nitro, halogen, cyano, trifluoromethyl, or C (O) NR ₄ R ₅ . When R is a carboxylic acid, preferably R ₁ is hydrogen or, preferably, R ₁ is substituted at the 4-position, more preferably substituted by trifluoromethyl or chloro. There is.

[0015]   In the compounds of formula (I), suitably R_ThirteenAnd R₁₄Independently hydrogen,
Or C, which may be substituted or may be linear or branched_1-4Archi
Or R_ThirteenAnd R₁₄One of which is optionally substituted
It is Le.   R_ThirteenAnd R₁₄Is an optionally substituted alkyl,
Kill moiety is halogen; halo-substituted C such as trifluoromethyl₁₄Alkyl; hydr
Roxy; hydroxy C_1-4C such as alkyl, methoxy or ethoxy_1-4Arco
Xy; halo-substituted C₁₁₀Alkoxy; S (O)_tR_FourAryl; NR_FourR_Five; NHC (O) R_Four; C (O) NR _Four R_Five; Or C (O) OR₈May be independently substituted once to thrice.   Suitably v is 0 or an integer having a value from 1 to 4.

[0016]   Suitably Y is hydrogen; halogen; nitro; cyano; halo substituted C_1-10Alkyl; C _1-10 Alkyl; C_2-10Alkenyl; C_1-10Alkoxy; halo-substituted C_1-10Alkoxy;
 Azide; (CR₈R₈)_qS (O)_tR_FourHydroxy; hydroxy C_1-4Alkyl; aryl;
Aryl C_1-4Alkyl; Aryloxy; Aryl C_1-4Alkyloxy; hetero
Aryl; Heteroarylalkyl; Heteroaryl C_1-4Alkyloxy; het
Rocyclic, Heterocyclic C_1-4Alkyl; aryl C_2-10Akkenyl;
 Heteroaryl C_2-10Alkenyl; heterocyclic C_2-10Alkenyl; (CR₈R ₈ )_qNR_FourR_Five; C_2-10Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_{1 0} ; S (O)₃H; S (O)₃S (O) like H₃R₈; (CR₈R₈)_qC (O) R₁₁; C_2-10Alkenyl C (O) R ₁₁ ; C_2-10Alkenyl C (O) OR₁₁; (CR₈R₈)_qC (O) OR₁₂; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈) _q NR_FourC (O) R₁₁; (CR₈R₈)_qNHS (O)₂R_d; (CR₈R₈)_qS (O)₂NR_FourR_FiveIndependently selected from
Or; the two Y moieties together form O- (CH_Two)_sO- or 5 or
A 6-membered saturated or unsaturated ring may be formed. Aryl, heteroaryl, oh
And all heterocyclic containing moieties may be substituted.   When Y forms a dioxy bridge, s is preferably 1. Y is
When forming an additional unsaturated ring, it is preferably a naphthylene ring.
It is a 6-membered ring that gives rise to the system. These saturated and unsaturated rings are the same as the other Y moieties described above.
May be substituted 1 to 3 times.   Suitably R_dIs NR₆R₇, Alkyl, aryl C_1-4Alkyl, aryl C_2-4A
Lucenyl, heteroaryl, heteroaryl-C_1-4Alkyl, heteroaryl C_{2- Four} Alkenyl, heterocyclic, heterocyclic C_1-4Alkyl, or
Heterocyclic C_2-4An alkenyl moiety, where aryl, heteroaryl
, And heterocyclic containing moieties are all replaced as defined above.
May be.

Preferably Y is halogen, C _1-4 alkoxy, optionally substituted aryl, optionally substituted aryloxy or arylalkoxy, methylenedioxy, NR ₄ R ₅ , thio C _1-4 Alkyl, thioaryl, halo-substituted alkoxy, optionally substituted C _1-4 alkyl, or hydroxyalkyl. More preferably, Y is monosubstituted halogen, disubstituted halogen, monosubstituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl. More preferably, these groups are mono- or di-substituted at the 2'-position or 2 ', 3'-position of the phenyl ring. Y can be substituted at any of the five positions on the ring, but preferably R is (
If a _{CR 8 R 8) r C (} O) 2 H is preferably, Y is monosubstituted in the 2'-position or 3'-position, is preferably the 4'-position is unsubstituted . When the ring is disubstituted and R is (CR ₈ R ₈ ) _rC (O) ₂ H, preferably the substituent is 2 ′ or 3 ′ of the monocyclic ring. In rank. When R ₁ and Y can both be hydrogen, it is preferred that at least one ring is substituted, more preferably both rings are substituted. Suitably in the compounds of formula (I) X is oxygen or sulfur, preferably oxygen. The E and E'rings may be present and their point of attachment is indicated by the asterisk *. If it is not present, the ring is a phenyl moiety substituted with R ₁ and Y as shown here. The E and E ′ rings may be substituted with R ₁ and Y in either an unsaturated ring or a saturated ring, respectively, and in the present specification, only the unsaturated ring is substituted.

In the compound of formula (I), R ₂₀ is W ₁ , optionally substituted heteroaryl, _optionally substituted C _5-8 cycloalkyl, _optionally substituted C _1-10
Alkyl, optionally substituted C _2-10 alkenyl, or optionally substituted C _2-10 alkynyl. When R ₂₀ is an optionally substituted C _5-8 cycloalkyl ring, the ring may be optionally substituted by (Y) _{n as} defined above. When R ₂₀ is an optionally substituted C _1-10 alkyl, an optionally substituted C _2-10 alkenyl, or an optionally substituted C _2-10 alkynyl, these moieties are Halogen; nitro; cyano; halo-substituted C _1-10 alkyl such as trifluoromethyl; C _1-10 alkoxy; halo-substituted C _1-10 alkoxy; S (O) _t R ₄ ; hydroxy; hydroxy C _1-4 alkyl; Aryloxy; Aryl C _1-4 alkyloxy; Heteroaryloxy; Heteroaryl C _1-4 alkyloxy; Heterocyclic, heterocyclic C _1-4 alkyl; Heterocyclic oxy; Heterocyclic C _1-4 alkyl Oxy; NR ₄ R ₅ ; C (O) NR ₄ R ₅ ; C (O) NR ₄ R ₁₀ ; S (O) ₃ H; S (
O) ₃ R ₈ ; C (O) R ₁₁ ; C (O) OR ₁₂ ; OC (O) R ₁₁ ; or NR ₄ C (O) R ₁₁ even if it is independently substituted one or more times Good. When R ₂₀ is an optionally substituted C _2-10 alkenyl or an optionally substituted C _2-10 alkynyl, these moieties are in addition to the above moieties, aryl, arylC _1-4. It may be substituted with alkyl, heteroaryl or heteroaryl C _1-4 alkyl (and these aryl and heteroaryl containing rings may be substituted).

Suitably, W ₁ is

[Chemical 13] Is. Suitably, the E'containing ring is

[Chemical 14] May be selected from

In the compounds of formula (I), when R ₂₀ is a heteroaryl (HET) ring, it is suitably a heteroaryl ring or ring system. If the HET moiety is a polycyclic system, the heteroatom-containing ring need not be directly attached to the urea moiety or (CR ₁₃ R ₁₄ ) _v . All rings in this ring system are
It may be substituted by (Y _(n) ) as defined above. Preferably the HET moiety is 2-, 3- or 4-pyridyl. If the ring is a polycyclic system,
Preferably it is a benzimidazole, dibenzothiophene, or indole ring. Other heterocycles of interest include, but are not limited to, thiophene, furan, pyrimidine, pyrrole, pyrazole, quinoline, isoquinoline, quinazolinyl, pyridine, oxazole, thiazole, thiadiazole, triazole, or imidazole. Preferably, R ₂₀ is an optionally substituted phenyl, allyl, C _1-10 alkyl, ethoxycarbonylethyl, dimethylacetal, 2-methoxyisopropyl or 2-methoxyethyl group.

A typical compound of formula (I) is: N- (3-carboxyphenyl) -N ′-(2-bromophenyl) urea N- (3-carboxymethylphenyl) -N ′-(2-bromo Phenyl) urea N- (3-carboxymethylphenyl) -N '-(2,3-dichlorophenyl) urea N- (3-carboxyphenyl) -N'-(2,3-dichlorophenyl) urea N- [3- ( 2-Carboxyethyl) phenyl] -N '-(2,3-dichlorophenyl) urea N- (2,4-dichloro-3-carboxy) -N'-(2-bromophenyl) urea N- (4-chloro- 3-carboxyphenyl) -N '-(2-bromophenyl) urea N- (4-chloro-3-carboxyphenyl) N'-(2,3-dichlorophenyl) urea; and N- (4-chloro-3-) Carboxyphenyl) -N- (3-chlorophenyl) urea; or pharmaceutically acceptable salts thereof.

[0022] As used herein, the term "optionally substituted", unless otherwise stated, a fluorine, chlorine, such bromine or iodine halogen; hydroxy; hydroxy substituted C _{1-1 0} alkyl; such as methoxy or ethoxy C _1-10 alkoxy; methylthio, methylsulfinyl or _{S (O) m 'C 1-1} 0 alkyl (m' is 0, 1 or 2) such as methylsulfonyl; _NR 4 _{R 5,} such as in the group amino, mono- and Disubstituted amino; NHC (O) R ₄ ; C (O) NR ₄ R ₅ ; C (O) OH;
S (O) ₂ NR ₄ R ₅ ; NHS (O) ₂ R ₂ ; C _1-10 alkyl such as methyl, ethyl, propyl, isopropyl, or t-butyl; halo-substituted C _1-10 alkyl such as CF ₃ . Optionally substituted aryl such as phenyl, or optionally substituted arylalkyl such as benzyl or phenethyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, substituted Heteroaryl, optionally substituted heteroarylalkyl, and the like, wherein these aryl, heteroaryl or heterocyclic moieties are halogen; hydroxy; hydroxy-substituted alkyl; C _{1- 10 alkoxy; S (O) m 'C} 1-10 alkyl; each of _NR 4 _{R 5} group Amino, mono- and di-C _1-4 alkyl-substituted amino; C _1-10 alkyl, or may be substituted once or twice with halo-substituted C _1-10 alkyl such as CF ₃ .

Suitably R ₂ is C _1-4 alkyl, aryl, aryl C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, heterocyclic or heterocyclic C _1-4 alkyl. Is.

Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include hydrochloric acid, hydrobromic acid,
Inorganic such as sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid Includes basic salts of acids and organic acids. Furthermore, pharmaceutically acceptable salts of the compounds of formula (I) can be prepared, for example, by
If the substituent comprises a carboxy moiety, it may be formed with a pharmaceutically acceptable cation. Suitable pharmaceutically acceptable cations are well known to those skilled in the art,
Includes alkali metal, alkaline earth metal, ammonium and quaternary ammonium cations.

The following terms as used herein are as follows: “halo” -all halogens, ie chloro, fluoro, bromo and iodo. “C _1-10 alkyl” or “alkyl” -unless otherwise specified for chain length, straight-chain and branched-chain groups of 1 to 10 carbon atoms, such as methyl, ethyl,
It includes, but is not limited to, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like. -The term "cycloalkyl" as used herein refers to a cyclic group preferably of 3 to 8 carbons and includes, but is not limited to, cyclopropyl, cyclopentyl, cyclohexyl and the like. The term “alkenyl” as used herein, in all cases, unless otherwise indicated for the chain length, means a straight-chain or branched-chain group of 2 to 10 carbon atoms, ethenyl, 1-propenyl, 2- Propenyl, 2-methyl-1-propenyl, 1-
Includes, but is not limited to, butenyl, 2-butenyl and the like. "Aryl" -phenyl and naphthyl. "Heteroaryl" (with respect to itself, or "heteroaryloxy")
Or in any combination such as "heteroarylalkyl")-5 to 10 membered aromatic ring system in which one or more rings are selected from the group consisting of N, O or S Containing one or more heteroatoms, such as pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole. , But not limited to these. "Heterocyclic" (per se or in any combination such as "heterocyclic alkyl")-a saturated or partially unsaturated 4- to 10-membered ring system, one of which Or more of the rings contain one or more heteroatoms selected from the group consisting of N, O or S, for example pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine. However, it is not limited to these. -The terms "arylalkyl" or "heteroarylalkyl" or "heterocyclicalkyl" herein are unless otherwise indicated attached to an aryl, heteroaryl or heterocyclic moiety as defined above. Meaning defined C _1-10 alkyl. “Sulfinyl” -the oxide S (O) of the corresponding sulfide, the term “thio” refers to the sulfide, and the term “sulfonyl” refers to the fully oxidized S (O) ₂ moiety. The term “two R ₁ moieties (or two Y moieties) taken together is 5
Or may form a 6-membered saturated or unsaturated ring "means a C ₆ cycloalkenyl, ie a 6-membered partially unsaturated ring such as hexene, or a C ₅ cycloalkenyl moiety such as a cyclopentene ring. Naphthylene ring system or formation of a phenyl moiety.

Preparative Methods By applying the synthetic methods shown in the scheme below, some of the formula (
A compound of I) may be obtained. The syntheses shown in these schemes are based on a variety of different R,
It is applicable to the preparation of compounds of formula (I) having R ₁ and an aryl group, and is reacted with the appropriate substituents appropriately protected to be compatible with the reactions described herein. In those cases, subsequent deprotection provides compounds with generally disclosed properties. Once the urea nucleus is established, additional compounds having these formulas can be prepared by applying standard methods for functional group interconversions well known in the art. Although W and R ₂₀ are shown in the scheme as phenyl, this is for illustration purposes only.

When not commercially available, the desired aniline 2-Scheme-1 can be synthesized by reduction of the corresponding nitro. This reduction can be accomplished with hydrogen and many reducing agents such as catalytic palladium on carbon or tin chloride in polar solvents such as DMF or ethyl acetate. This aniline (2-Scheme-1) can then be condensed with a commercially available isocyanate in an aprotic solvent such as DMF, DMSO or toluene.

Scheme 1 R = CH ₂ CH ₂ COOH, COOH, CH ₂ COOH a) H ₂ , Pd / C b) PhCNO

Alternatively, the desired compound may be synthesized by protecting the carboxylic acid to form the methyl ester under conditions well known in the art such as diazomethane. This compound can then be reduced with hydrogen and many reducing agents such as catalytic palladium on carbon or tin chloride in polar solvents such as DMF or ethyl acetate. Condensation with a phosgene equivalent such as di- or triphosgene in the presence of a base such as trimethylamine or bicarbonate gives isocyanate 4-Scheme-2 . This compound can then be reacted with the desired commercial aniline. The carboxylic acid is then deprotected by standard conditions in the art such as the use of metal hydroxides in polar solvents such as THF / water, followed by acidification with acids such as HCl to give Scheme 2, 3. Obtainable.

[Chemical 16] R = CH ₂ CH ₂ COOH, COOH, or CH ₂ COOH; Protected R where R = CH ₂ CH ₂ COOMe, C
OOMe, or CH ₂ COOMe a) CH ₂ N ₂ , ether b) H ₂ , 5% Pd / C c) triphosgene, Et ₃ N d) PhNH ₂ , DMF e) Li
OH, THF / H ₂ O f) HCl / H ₂ O

A pharmaceutically acceptable salt of a compound of formula (I) is obtained by known methods, eg by treating a compound of formula (I) with a suitable amount of an acid or base in the presence of a suitable solvent. May be.

Another aspect of the invention is a similar process for preparing a compound of formula (I), which process comprises:

[Chemical 17] [Wherein R, R ₁ and m are the same as defined in formula (I)], and a compound represented by the following formula: -N (X)-(CR ₁₃ R ₁₄ ) _v -R ₂₀ , R ₁₃ , R ₁₄ , v and R ₂₀ are the same as defined in formula (I)] to obtain a compound of formula (I).

[0031]   Alternatively, formula (A1):

[Chemical 18] [Wherein E, R, R ₁ and m are the same as those defined for formula (I)], or a compound of formula (A2):

[Chemical 19] [Wherein E, R, R ₁ and m are the same as those defined for the formula (I)], and a compound represented by the following formula: -N (X)-(CR ₁₃ R ₁₄ ) _v -R ₂₀ ; A compound of formula (I) may be obtained by reacting with a compound of the formula: wherein X, R ₁₃ , R ₁₄ , v and R ₂₀ are the same as defined in formula (I).

Another aspect of the invention is an alternative process for preparing compounds of formula (I)
The method has the following formula:

[Chemical 20] [Wherein R ₁ , m and R are the same as those defined for the formula (I)], and a compound represented by the following formula: NH _2- (CR ₁₃ R ₁₄ ) _v -R ₂₀ [wherein R ₁₃ , R ₁₄ , v and R ₂₀ are the same as defined in formula (I)] to give a compound of formula (I); then deprotection of the R group if necessary. Characterize.

[0033]   Alternatively, as described above, formula (B1):

[Chemical 21] [Wherein E, R, R ₁ and m are the same as defined for formula (I)], or a compound of formula (B2):

[Chemical formula 22] [Wherein E, R, R ₁ and m are the same as defined for formula (I)], and a compound represented by the following formula: NH _2- (CR ₁₃ R ₁₄ ) _v -R ₂₀ [wherein R ₁₃ , R ₁₄ , v and R ₂₀ are the same as defined in formula (I)] to give a compound of formula (I) and then deprotection of the R group if necessary. You may.

In the examples, all temperatures are in degrees Celsius (° C.). Mass spectra were taken on a VG Zab mass spectrometer using fast atom bombardment unless otherwise noted. ¹ H-NMR (hereinafter "NMR") spectra were recorded at 250 MHz and 400 MHz, respectively, using a Bruker AM 250 or Am 400 spectrometer. The multiplicity is indicated as follows: s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, br showing a broad signal. Sat. Is a saturated solution, equiv. Indicates the ratio of the molar equivalents of the reagents to the main reactants. Flash chromatography was performed using a Merck Silica gel 60 (230-400 mesh).

EXAMPLES OF SYNTHESIS The present invention is illustrated with reference to the following examples, which are merely illustrative and are not to be construed as limiting the scope of the invention. All temperatures are in degrees Celsius, all solvents used are of the highest purity available, and all reactions are conducted under anhydrous conditions under an argon atmosphere unless otherwise noted. Example 1 Preparation of N- (3-carboxyphenyl) -N '-(2-bromophenyl) urea 3-aminobenzoic acid (1 equivalent (referred to as "eq") in DMF at about 80 ° C.
, 1.37 grams (referred to as "g") of the solution was treated with 2-bromophenylisocyanate (1 equivalent, 1.98 g) for about 2 hours. The solution was cooled and the product was purified by recrystallisation from methylene chloride and hexane to give 1.28g of the title compound as a white solid. MS (ES) MH = 333

Example 2 Preparation of N- (3-carboxymethylphenyl) -N '-(2-bromophenyl) urea 3-aminophenylacetic acid (1 eq, 0.151 g in DMF at about 80 ° C. )
Was treated with 2-bromophenylisocyanate (1 eq, 0.198 g) for about 2 hours. The solution was cooled and the product was purified by recrystallisation from methylene chloride and hexane to give 0.32g of the title compound as a white solid. MS (E
S) MH = 347

Example 3 Preparation of N- (3-carboxymethylphenyl) -N '-(2,3-dichlorophenyl) urea 3-aminophenylacetic acid (1 eq, 151 milligrams (referred to as "mg" ) in DMF at 80 ° C. )) Solution, 2,3-dichlorophenyl isocyanate (
1 eq, 188 mg) for 2 hours. The solution was cooled and the product was purified by recrystallisation from methylene chloride and hexane to give 0.12g of the title compound as a white solid. MS (ES) MH = 337

Example 4 Preparation of N- (3-carboxyphenyl) -N '-(2,3-dichlorophenyl) urea A solution of 3-aminobenzoic acid (1 eq, 1.37 g) in DMF at 80 ° C. was added to It was treated with 2,3-dichlorophenylisocyanate (1 eq, 1.88 g) for 2 hours. The solution was cooled and the product was purified by recrystallisation from methylene chloride and hexane to give 1.01 g of the title compound as a white solid. MS (ES) M
-H = 323

Example 5 Preparation of N- [3- (2-carboxyethyl) phenyl] -N '-(2,3-dichlorophenyl) urea a) 3-Aminodihydrocinnamic acid 3-nitrodihydro in ethyl acetate 10% solution of cinnamic acid (500 mg)
Treated with Pd / C (500 mg). Hydrogen was blown into the obtained suspension, and the mixture was stirred at room temperature overnight. The reaction mixture was bubbled with argon and then filtered through diatomaceous earth.
The filtrate was concentrated and the residue was recrystallized from toluene and ethyl acetate. 1H NMR (DM
SO) 6.95 t (1H), 6.4 m (3 H), 2.7 t (2H), 2.45 t (2H) b) N- [3- (2-carboxyethyl) phenyl] -N '-(2,3- Dichlorophenyl) urea 3-aminodihydrocinnamic acid (1 eq, 83 mg) in DMF at 80 ° C.
Solution of 2,3-dichlorophenylisocyanate (1 eq, 94 mg) in 2
Time processed. The solution was cooled and the product was purified by recrystallisation from methylene chloride and hexane to give 0.037 g of the title compound as a white solid. 1H NMR (
DMSO) 9.45 s (1H), 8.47 s (1H), 8.17 d (1H), 7.31 m (4H), 7.24 t (1H), 6
.88 d (1H), 2.73 t (2H), 2.54 t (2H)

Example 6 Preparation of N- (2,4-dichloro-3-carboxy) -N '-(2-bromophenyl) urea a) 5-Amino-2,6-dichlorobenzoic acid 5-in ethyl acetate A solution of nitro-2,6-dichlorobenzoic acid (2.0g) was treated with 10% Pd / C (1.5g). Blow hydrogen into the obtained suspension,
Stir overnight at room temperature. The reaction mixture was bubbled with argon and then filtered through diatomaceous earth. The filtrate was concentrated, and the residue was recrystallized from ethyl acetate and hexane to give the title compound (0.7 g) as a white solid. 1H NMR (DMSO) 7.15 d (1H), 6.8 d (
1H), 5.74 s (1H, br) b) N- (2,4-dichloro-3-carboxy) -N '-(2-bromophenyl) urea 5-nitro-2,6- in DMF at 80 ° C. Dichlorobenzoic acid (1 eq,
250 mg of a solution of 2-bromophenylisocyanate (1 eq, 153 μ)
I) was treated for 2 hours. The solution was cooled and the product was purified by recrystallisation from methylene chloride and hexane to give 35 mg of the title compound as a white solid. MS
(ES) M-H = 401

Example 7 Preparation of N- (4-chloro-3-carboxyphenyl) -N '-(2-bromophenyl) urea 5-amino-2-chlorobenzoic acid (1 eq, 1 in DMF at 80 ° C. .7
A solution of 1 g) was treated with 2-bromophenylisocyanate (1 eq, 1.98 g) for 2 hours. The solution was cooled and the product was purified by recrystallization from methylene chloride and hexane to give 0.880 g of the title compound as a white solid. MS (
ES) MH = 367

Example 8 Preparation of N- (4-chloro-3-carboxyphenyl) -N '-(2,3-dichlorophenyl) urea 5-amino-2-chlorobenzoic acid (1 eq, in DMF at 80 ° C. ) 1.7
1 g) of a solution of 2,3-dichlorophenyl isocyanate (1 eq, 1.88).
g) for 2 hours. The solution was cooled and the product was purified by recrystallisation from methylene chloride and hexane to give 1.57g of the title compound as a white solid. M
S (ES) M-H = 357

Example 9 Preparation of N- (4-chloro-3-carboxyphenyl) -N- (3-chlorophenyl) urea 5-amino-2-chlorobenzoic acid (1 eq, 1.7 in DMF at 80 ° C.
A solution of 1 g) was treated with 3-chlorophenylisocyanate (1 eq, 1.53 g) for 2 hours. The solution was cooled and the product was purified by recrystallisation from methylene chloride and hexane to give 0.66g of the title compound as a white solid. MS (E
S) MH = 323

Methods of Treatment Not over- or regulated by mammalian cells such as (but not limited to) monocytes and / or macrophages or other chemokines that bind to the IL-8 α or β receptor, also referred to as type I or type II Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prophylactic or therapeutic treatment of a disease state in humans or other mammals which is exacerbated or caused by IL-8 production. be able to. Accordingly, the present invention provides a method of treating diseases mediated by chemokines that bind to IL-8 α or β receptors, the method comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Is administered. In particular, chemokines include IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78.
Is. Cytokine function, specifically IL-8, GROα, GROβ, GROγ, NA
Administration of a compound of formula (I) in an amount sufficient to inhibit the function of P-2 or ENA-78 such that they reach normal, and in some cases sub-normal levels of physiological function. To be biologically regulated to improve disease state.
For example, according to the content of the present invention, IL-8, GROα, GROβ, GROγ,
Abnormal levels of NAP-2 or ENA-78 are: (i) 1 m
Free IL-8 levels higher than or equal to 1 picogram per L; (ii) Any cell-related IL-8, GROα, GROβ above normal physiological levels
, GROγ, NAP-2 or ENA-78 levels; or (iii) IL-
8, GROα, GROβ, GROγ, NAP-2 or ENA-78 produced in cells or tissues above basal levels of IL-8, GROα, GROβ, GR
Presence of Oγ, NAP-2 or ENA-78.

The link between interleukin-8 and rhinovirus has been described by Turner, et al., Clin.
Infect. Dis. (1998), 26 (4), 840-846; Sanders, et al., J. Virol. (1998)
, 72 (2), 934-942; Sethi, et al., Clin. Exp. Immunol. (1997), 110 (3), 36.
2-369; Zhu, et al., Am. J. Physiol. (1997), 273 (4, Pt. 1), L814-L824; Te
rajima, et al., Am. J. Physiol. (1997), 273 (4, Pt. 1), L749-L759; Grunbe
rg, et al., Clin. Exp. Allergy (1997), 27 (1), 36-45; and Johnston, et al.
., J. Infect. Dis. (1997), 175 (2), 323-329. The association between interleukins and osteoporosis is reviewed by Streckfus et al., J. Ger.
ontol., Ser. A (1997), 52A (6), M343-M351; Hermann, T. WO 95/31722; and C
Haudhary, et al., Endocrinology (Baltimore) (1992), 130 (5), 2528-34. These diseases are characterized primarily by massive neutrophil infiltration, T cell infiltration, or neovascular growth, and are responsible for neutrophil chemotaxis or directed growth of endothelial cells into the site of inflammation. IL-8, GROα, GROβ, GROγ or NAP-2 production. Other inflammatory cytokines (IL-1, TN
F, and IL-6), in contrast to IL-8, GROα, GROβ, GROγ.
Alternatively, NAP-2 has unique properties such as neutrophil chemotaxis, enzyme release including but not limited to elastase release and superoxide production and activation. α-chemokines, especially IL-8, GROα, GROβ
, GROγ or NAP-2 may promote tumor angiogenesis by promoting directed growth of endothelial cells via the IL-8 type I or type II receptors. Therefore, inhibiting IL-8-induced chemotaxis or activation is
It will directly reduce neutrophil infiltration. Recent evidence also suggests a role for chemokines in the treatment of HIV infection. Littleman et al., Nature 381, pp 661 (1996) and Koup et al., Natur
e 381, pp 667 (1996)

The present invention also provides therapeutic means in the acute setting as well as prophylaxis in individuals suspected of being susceptible to CNS injury by chemokine receptor antagonist compounds of formula (I). CNS Injury, as defined herein, includes both open or penetrating head trauma, eg, due to surgery, or closed head trauma, eg, due to injury to the head area. Also included in this definition are ischemic strokes, particularly ischemic strokes of the brain area. Ischemic stroke is usually defined as a localized neurological disease that results from inadequate blood supply to certain brain regions as a result of vascular embolism, thrombosis, or local atheromatous degeneration closure. It The role of inflammatory cytokines here has been elucidated and the present invention provides a potential treatment for these injuries. Few treatments are applicable to acute injuries such as these injuries. Current evidence also indicates the use of IL-8 inhibitors in the treatment of atherosclerosis. First publication, Boisvert et al., J Clin Invest, 1998, 101: 353-
363 shows that bone marrow transplantation in LDL-deficient mice suppresses the development of atherosclerotic plaques by the absence of IL-8 receptors on stem cells (and therefore monocytes / macrophages). ing. Further supporting literature is: Apos
tolopoulos et al., Arterioscler Thromb Vasc Biol. 1996, 16: 1007-1012; Li
u et al., Arterioscler Thromb Vasc Biol, 1997, 17: 317-323; Rus et al., A
therosclerosis. 1996, 127: 263-271 .; Wang et al., J Biol Chem. 1996, 271:
8837-8842; Yue et al., Eur J Pharmacol. 1993, 240: 81-84; Koch et al., A
m J Pathol, 1993, 142: 1423-1431 .; Lee et al., Immunol Lett, 1996, 53, 10
9-113 .; and Terkeltaub et al., Arterioscler Thromb, 1994, 14: 47-53.

TNF-α is a cytokine that has pro-inflammatory effects including endothelial leukocyte adhesion molecule expression. Compounds that suppress or reduce leukocyte infiltration into the ischemic brain injury site as well as TNF levels would be useful in the treatment of ischemic brain injury. Liu et al., St
oke, Vol. 25., No. 7, pp 1481-88 (1994), the disclosure of which is incorporated herein by reference. A model for closed head injury and 5-LO / CO combination therapy is Shohami et a
l., J. of Vaisc & Clinical Physiology and Pharmacology, Vol. 3, No. 2, p
p. 99-107 (1992), the disclosure of which is incorporated herein by reference. Treatments that suppress edema formation have been found to produce improved function in those treated animals.

An amount of formula (I) sufficient to inhibit IL-8 binding to the IL-8 α or β receptor
The compound is administered, but a sufficient dose is evidenced by decreased neutrophil chemotaxis and activation. The finding that the compound of formula (I) is an inhibitor of IL-8 binding is based on the effect of the compound of formula (I) in the in vitro receptor binding assay described herein. The compound of formula (I) is, in some examples,
It has been shown to be a biphasic inhibitor of both recombinant type I and type II IL-8 receptors. Preferably the compound is an inhibitor of only one receptor,
More preferably, it is an inhibitor of the type II receptor only.

The term “IL-8-mediated disease or condition” as used herein refers to IL
-8, GROα, GROβ, GROγ, NAP-2 or ENA-78 is IL-
By producing 8, GROα, GROβ, GROγ, NAP-2 or ENA-78 itself, or IL-8, GROα, GROβ, GROγ, NAP
-2 or ENA-78 is another monokine, for example IL-1, IL-6 or T
Refers to any and all diseases that play a role by releasing NF (but not limited to). Thus, for example, a disease state in which IL-1 is the major component and whose production or action is exacerbated or secreted in response to IL-8 is
It is considered to be a disease state mediated by -8. The term "chemokine-mediated disease or condition" as used herein refers to I
Refers to any and all disease states in which chemokines that bind to IL-8α or β receptors play a role, such as but not limited to L-8, GROα, GROβ, GROγ, NAP-2 or ENA-78. . This term means that IL-8 produces IL-8 itself, or that IL-8 produces IL-1, IL-
6 or disease states that play a role by releasing another monokine such as TNF. Thus, for example, a disease state in which IL-1 is the major component and whose production or action is exacerbated or secreted in response to IL-8 is
It is considered to be a disease state mediated by 8. Such diseases include psoriasis, atopic dermatitis, arthritis, asthma, chronic obstructive pulmonary disease,
Adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, stroke, septic shock, endotoxin shock, Gram-negative sepsis, toxin shock syndrome, heart and kidney reperfusion injury, glomerulonephritis, thrombosis Disease, host-versus-graft reaction, Alzheimer's disease, allograft rejection, malaria, restenosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis, unwanted hematopoietic stem cell release, and rhinovirus and influenza virus (these Respiratory viruses including, but not limited to, herpesviruses including but not limited to herpes simplex virus types I and II, and hepatitis including but not limited to hepatitis B and hepatitis C viruses. Including but not limited to diseases caused by viruses.

As used herein, the term “cytokine” refers to a secreted polypeptide that is a molecule that affects cell function and modulates cell-cell interactions in the immune, inflammatory or hematopoietic response. Cytokines include monokines and lymphokines regardless of which cell produces them. For example, monokines generally refer to those produced and secreted by mononuclear cells such as macrophages and / or monocytes. However, many other cells, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epidermal keratinocytes and B lymphocytes also produce monokines. . Generally, lymphokines are those produced by lymphocytes. Examples of cytokines are interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8.
(IL-8), tumor necrosis factor alpha (TNF-α) and tumor necrosis factor beta (TNF-β). As used herein, the term "chemokine" refers to a secreted polypeptide, a molecule that affects the function of cells and modulates cell-cell interactions in the immune, inflammatory or hematopoietic response, and is similar to the term "cytokine" above. is there. Chemokines are secreted primarily through cell transmembranes, causing chemotaxis and activation of specific white blood cells and leukocytes, neutrophils, monocytes, macrophages, T cells, B cells, endothelial cells and smooth muscle cells. Examples of chemokines are IL-8, GROα, GRO
β, GROγ, NAP-2, ENA-78, IP-10, MIP-1α, MIP
-Β, PF4, and MCP1, 2 and 3 but not limited to.

For use in therapy, the compounds of formula (I) or pharmaceutically acceptable salts thereof will generally be formulated as pharmaceutical compositions, according to standard pharmaceutical practice. The present invention therefore also relates to pharmaceutical compositions comprising an effective and non-toxic amount of a compound of formula (I) and a pharmaceutically acceptable isolation or diluent. The compounds of formula (I), pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them can be prepared by any conventional route used for drug administration, eg, orally, topically, parenterally or by inhalation. May be administered. Compounds of formula (I) are prepared by conventional methods using the formula (
It may be administered as a conventional dosage form prepared by mixing a compound of I) with a standard pharmaceutical carrier. The compound of formula (I) may be administered as a conventional dosage form in combination with a known second therapeutically active compound. These methods may include mixing, granulating and compressing or dissolving the ingredients depending on the desired formulation. It will be appreciated that the form and characteristics of the pharmaceutically acceptable carrier or excipient will be determined by the amount of active ingredient combined, the route of administration and other well known variables. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the recipient. For example, the pharmaceutical carrier used may be solid or liquid. Examples of solid carriers are lactose, white clay, sucrose, talc, gelatin, agar, pectin,
Examples thereof include gum arabic, magnesium stearate, stearic acid and the like. Examples of liquid carriers are molasses, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may be a time delay material well known in the art, such as monostearyl glyceryl alone or in admixture with wax. Various pharmaceutical forms can be used. Thus, if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule as a powder or pellets or in the form of a troche or sweetened tablet.
The amount of solid carrier will vary but will preferably be from about 25 mg to about 1 g.
If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule or a non-aqueous suspension. The compounds of formula (I) may be administered topically, ie non-systemically. This includes applying the compound of formula (I) externally to the epidermis or oral cavity and dripping such compound into the ears, eyes and nose to prevent the compound from significantly entering the bloodstream. Say. In contrast, systemic administration means oral, intravenous, intraperitoneal and intramuscular administration. Formulations suitable for topical administration include liquid or semi-liquid formulations suitable for penetration through the skin to the site of inflammation, such as liniments, lotions, creams, ointments or pasta, as well as drops suitable for administration via the eye, ear or nose. Including agents. For topical administration, the active ingredient may comprise from 0.001% to 10% by weight of the formulation, eg 1% to 2%.
It may be up to 10% by weight, but may be up to 10% by weight of the formulation, preferably not exceeding 5% by weight, more preferably 0.1% to 1% by weight. The lotion of the present invention is suitable for application to the skin or eyes. The eye lotion may contain a sterilized aqueous solution which may optionally contain a bactericide, and can be prepared by a method similar to the method for preparing drops. Lotions or liniments for application to the skin may include agents that promote skin dryness and cool the skin, such as alcohol or acetone, and / or glycerol or oils and fats such as castor oil or peanut oil. The cream, ointment or pasta of the present invention is a semi-solid formulation of the externally applied active ingredient. They are prepared by mixing the active ingredients in finely divided or powdered form, alone or as a solution or suspension in an aqueous or non-aqueous liquid, with a greasy or non-greasy base using suitable machines. can do. Substrates include hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, metallic soaps; serous agents; naturally occurring oils and fats such as almonds, corn, peanuts, castor or olives; tree wax or its derivatives, or propylene. It may include fatty acids such as stearic acid or oleic acid mixed with alcohols such as glycols. The formulation may contain suitable surface active agents such as anionic, cationic or nonionic surface active agents such as esters or polyoxyethylene derivatives thereof. Suspending agents such as inorganic gums, cellulose derivatives or inorganic metals such as siliceous silica, as well as other ingredients such as lanolin may be included. Drops of the invention may consist of sterile aqueous or oily solutions or suspensions, prepared by dissolving a bactericide and / or fungicide and / or other suitable preservative. And is preferably prepared by dissolving the active ingredient in a suitable aqueous solution containing a surfactant. The resulting solution may then be clarified by filtration, transferred to a suitable container, then sealed and sterilized by autoclaving or by placing at 98-100 ° C for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by aseptic methods. Examples of suitable bactericides and fungicides for inclusion in drops are phenylmercuric nitrate or phenylmercuric acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01). %). Suitable solvents for the preparation of oily solutions include glycerol, dilute alcohols and propylene glycol.

The compound of formula (I) may be administered parenterally, ie intravenously, intramuscularly,
It may be administered subcutaneously, intranasally, rectally, vaginally or intraperitoneally. In general, subcutaneous and intramuscular forms of parenteral administration are preferred. Dosage forms suitable for such administration may be manufactured by conventional methods. The compounds of formula (I) may be administered by inhalation, that is by intranasal and oral inhalation. Dosage forms suitable for such administration may be manufactured in conventional manner, eg by aerosol formulation or metered dose inhaler. For all uses disclosed herein for the compound of formula (I),
The daily oral dosage regimen is preferably about 0.01 to about 80 / kg body weight.
Will be mg. The daily parenteral dosage regimen is from about 0.001 to about 80 mg / kg body weight. The daily topical dosage regimen is preferably 0.1 mg to 15 mg.
It is 0 mg and is administered 1 to 4 times a day, preferably 2 or 3 times a day. The daily inhalation dosing regimen is preferably about 0.01 mg to about 1 mg per kg body weight.
Will. The optimum amount and interval of administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof will be determined according to the nature and extent of the condition to be treated, mode of administration, route and site, and the individual patient to be treated. It will be appreciated by those skilled in the art that, and that such optimum conditions can be determined by conventional methods. The optimal course of treatment, ie, the number of doses per day of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for a given number of days may also be ascertained by one skilled in the art using a routine course of treatment decision testing. , As will be appreciated by those skilled in the art. The present invention is illustrated by reference to the following biological examples, which are merely illustrative and are not to be construed as limiting the scope of the invention.

[0053] The IL-8, and GROα chemokines inhibitory effects of compounds of the Biological Examples The invention was determined by the following in vitro assay. Receptor binding assay: Specific activity 2000 Ci / mmo from Amersham Corp., Arlington Heights, IL.
1 [ ¹²⁵ I] IL-8 (human recombinant) was obtained. NEN- New England Nucle
GRO-α was obtained from ar. All other reagents were analytical grade. High levels of recombinant human IL-8 α and β type receptors were differentially expressed in Chinese hamster ovary cells as previously described (Holmes, et al., Science, 1991, 253, 1278). . Add homogenization buffer to 10 mM Tris-HCL,
Protocol previously described (Haour, et al., J Biol Chem., 249 pp 2195-2205 (1
974)) and homogenized the Chinese hamster ovary membrane. The membrane protein concentration was determined using a micro assay kit from Pierce, using bovine serum albumin as a standard substance. All assays were performed using the 96 well microplate format. Each reaction mixture contained 20 mM bis-Tris propane and 0.4 mM Tris H containing 1.2 mM MgSO ₄ , 0.1 mM EDTA, 25 mM NaCl and 0.03% CHAPS.
¹²⁵ I IL-8 (0.25 nM) or ¹²⁵ I Gro-α in Cl buffer, pH 8.0
And contained 0.5 μg / mL IL-8Rα or 1.0 μg / mL IL-8Rα membrane. In addition, the drug or compound of interest previously dissolved in DMSO was added so that the final concentration was between 0.01 nM and 100 μM. ¹²⁵ I-
The assay was started by adding IL-8. After 1 hour at room temperature, Tomtec
Plates were placed on glass fiber filter mats using a 96-well harvester, blocked with 1% polyethyleneimine / 0.5% BSA, 25 mM NaCl, 10 mM.
The cells were washed 3 times with mM TrisHCl, 1 mM MgSO ₄ , 0.5 mM EDTA, 0.03% CHAPS, pH 7.4. The filters were then dried and counted on a Betaplate liquid scintillation counter. Recombinant IL-8 Rα or type I receptors are also referred to herein as non-permissive receptors, and recombinant IL-8 Rβ or type II receptors are also referred to herein as permissive receptors. . All of the compounds of formula (I) shown in Examples 1-9 of the synthetic chemistry section herein showed inhibition in a permissive model for IL-8 receptor inhibition. The following compounds were found to be inactive in this assay: N- (2,4-dichloro-3-carboxy) -N '-(2,3-dichlorophenyl) urea; N- (3-carboxyphenyl ) -N '-(phenyl) urea and N- (3-methylcarboxyphenyl) -N'-(phenyl) urea.

Chemotaxis Assay: Neutrophil chemotaxis as described in Current Protocols in Immunology, vol. I, Suppl 1, Unit 6.12.3. (The disclosure of which is incorporated herein by reference). The in vitro inhibitory properties of these compounds are examined in the assay. Current Protocol
neutrophils are isolated from human blood as described in S. Immunology Vol. I, Suppl 1 Unit 7.23.1, the disclosure of which is incorporated herein by reference. IL-8, GROα, GR with a concentration of 0.1 to 100 nM which is a chemoattractant
Oβ, GROγ and NAP-2 were added to 48 multi-well chambers (Neuro Prob
e, Cabin John, MD) in the lower chamber. The two chambers are separated by a 5 micron polycarbonate filter. When testing the compounds of the invention, they are mixed with the cells (0.0) immediately before adding the cells to the upper chamber.
01-1000 nM). Approximately 3 with 5% CO ₂ during humidified incubation
Incubate at 7 ° C for about 45 to 90 minutes. At the end of the incubation period, remove the polycarbonate membrane and wash the top surface, then Diff Qui
Membranes are stained using the ck staining protocol (Baxter Products, McGaw Park, IL, USA). Cells that have chemotaxis to chemokines are counted visually using a microscope.
Generally, four fields are counted for each sample and these numbers are averaged to give the average number of migrated cells. Each sample is tested in three identical experimental systems and the test is repeated at least 4 times for each compound. No compound was added to certain cells (positive control cells) and these cells show maximal chemotactic response of the cells. Chemokines are not added to the lower chamber if a negative control is required. The difference between the positive and negative controls indicates the chemotactic activity of the cells.

Elastase release assay: Compounds of the invention are tested for their ability to interfere with elastase release from human neutrophils. Neutrophils are isolated from human blood as described in Current Protocols in Immunology Vol. I, Suppl 1 Unit 7.23.1. Ringer's solution (NaCl 118
, KCl 4.56, NaHCO ₃ 25, KH ₂ PO ₄ 1.03, glucose 11.1, HEPES 5 mM, pH 7.4
0.88 × 10 ⁶ PMNs in) are placed in each well of a 96-well plate to a volume of 50 μl. The plate was loaded with the test compound (0.
001-1000 nM), cytochalasin B (20 μg / ml) in a volume of 50 μl
) And Ringer's buffer in a volume of 50 μl. Warm these cells for 5 minutes (37 ° C., 5% CO ₂ , 95% RH), then IL-8, GROα,
GROβ, GROγ or NAP-2 was added to give a final concentration of 0.01-1000n
Let M. The reaction was run for 45 minutes, then the 96-well plate was centrifuged (80
0xg for 5 minutes), and take 100 μl of the supernatant. The supernatant was placed in a second 96-well plate and then the artificial elastase substrate (MeOSuc-Ala-Ala-Pro-Val-AMC, Nova Biochem, La Jolla, CA) dissolved in phosphate buffered saline was added. Add to a final concentration of 6 μg / ml. Immediately plate the humanized anti-B7-1 and humanized anti-B7-2 antibodies 6 well plate reader (Cytofluor 2350, Millipore,
Bedford, MA) and collect data at 3-minute intervals according to the method of Nakajima et al J. Biol. Chem. 254 4027 (1979). The amount of elastase released from PMNs is calculated by measuring the MeOSuc-Ala-Ala-Pro-Val-AMC degradation rate.

TNF-α in Traumatic Brain Injury Assay This assay is designed to detect specific brain areas after experimentally induced lateral fluid-percussion traumatic brain injury (TBI) in rats. It is for investigating the expression of tumor necrosis factor mRNA. Since TNF-α induces nerve growth factor (NGF) and stimulates the release of other cytokines from activated astrocytes, changes in TNF-α gene expression after this trauma are acute after CNS trauma. It plays an important role in both response and regenerative response. A suitable assay is
Found in WO 97/35856 or WO 97/49286, the disclosures of which are incorporated herein by reference.

CNS Injury Model for IL-β mRNA This assay is based on specific brain regions after experimentally induced lateral fluid-percussion traumatic brain injury (TBI) in rats. Characterizes the local expression of interleukin-1β (IL-1β) mRNA in E. coli. These assay results indicate that after TBI, the primary expression of IL-8 mRNA is stimulated locally in specific brain regions. Changes in these local cytokines (eg, IL-1β) play a role in posttraumatic pathological or regenerative consequences. Suitable assays are WO 97/35856 or WO 97
/ 49286, the disclosures of which are incorporated herein by reference.

In Vivo-Atherosclerosis Assay: The in vivo model for measuring atherosclerosis in mice is Pa
Based on a slight modification of the igen et al. assay. Paigen B, Morrow A, Holmes P
A, Mitchell D, Williams RA.Quantitative assessment of atherosclerotic
lesions in mice.Atherosclerosis 68: 231-240 (1987); and Groot PHE, van
Vlijmen BJM, Benson GM, Hofker MH, Schiffelers R, Vidgeon-Hart M, Havek
es LM.Quantitative assessment of aortic atherosclerosis in APOE * 3 Leid
en transgenic mice and its relationship to serum cholesterol exposure.
See Arterioscler Thromb Vasc Biol. 16: 926-933 (1996). Sectioning and staining of the aortic sinus Obtain cross-sectional sections of the aortic root as previously described (1,2). Briefly, the heart is split in two just below the horizontal plane of the atrium and the heart and the base of the aortic root taken for analysis. After overnight equilibration of the tissue in OCT compound, the aorta is directed toward the chuck and the heart is cryostat chuk (Bright In
Immerse in OCT compound on Instrument Company Ltd., UK). Freeze the tissue by covering the chuck with dry ice. The heart is then sectioned perpendicular to the axis of the aorta, starting in the heart and proceeding towards the aorta. When the aortic root is confirmed by the appearance of three valve leaflets, 10 mm sections are alternately taken and fixed on a gelatin-coated slide glass. Air-dry sections for 1 hour, then 6
Rinse briefly with 0% isopropyl alcohol. The sections are stained with oil red, counterstained with Mayer's hematoxylin, covered with glycerol gelatin and sealed with nail varnish. Quantification of atherosclerosis in aortic root Olympus equipped with 4x objective and video camera (Hitachi, HV-C10)
Visualize alternating sections of the aortic root using a BH-2 microscope. A 24-bit color image is obtained and a frame grabbing board (Snapper, Active Imaging Ltd, Ber
ks, UK) and Optimus software (version 5.1, Optimas Corp., WA, US
.A. Compatible PC (Datacell Pentium P5-133, Datacell, Berks, UK
) Was used for analysis. Images are captured under identical proof, microscope, camera and personal computer conditions. Quantification of atherosclerotic lesions is performed by manually drawing the lesion perimeter using Optimas software. Set a color threshold to quantify the red-stained area in the lesion. Absolute values for lesion cross-sectional area and red stained area are obtained by calibrating the software with the image of the grid on the hemocytometer slide.

All publications, including patents and patent applications, cited herein are hereby incorporated by reference as if fully set forth herein. The above description fully discloses the invention including preferred embodiments of the invention. Modifications and improvements of the embodiments disclosed in detail herein are included in the following claims. Without further efforts, one of ordinary skill in the art will be able to use the above description to maximize the use of the present invention. Therefore, it should be understood that the examples of the present specification are merely illustrative and do not limit the scope of the present invention in any way. Specific examples of the invention for which exclusive rights or privileges are claimed are defined below.

─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. ⁷ Identification Code FI Theme Coat (Reference) A61P 7/02 A61P 7/02 9/00 9/00 9/10 9/10 9/14 9/14 11 / 00 11/00 11/06 11/06 13/12 13/12 17/06 17/06 19/02 19/02 19/10 19/10 25/28 25/28 31/04 31/04 31/12 31/12 31/14 31/14 31/20 31/20 31/22 31/22 33/06 33/06 41/00 41/00 43/00 105 43/00 105 105 111 111 (81) Designated country EP ( AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA ( M, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AU, BA, BB, BG, BR, CA, CN, CZ, DZ, EE, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KP, KR, LC, LK, LR, LT, LV, MA, MG, MK, MN, MX, NO, NZ, PL, RO, SG, SI , SK, SL, TR, TT, TZ, UA, US, UZ, VN, YU, ZA (72) Inventor Gregory Martin Benson United Kingdom, CM 19.5 ADO, Essex, Harlow, New Fron Tears Science Park South F Term (Reference) 4C206 AA01 AA02 HA30 KA01 MA01 MA04 NA14 ZA02 ZA36 ZA44 ZA45 ZA51 ZA59 ZA67 ZA68 ZA75 ZA81 ZA89 ZA96 ZA97 ZB01 ZB33 ZB35 ZB38 ZC37 ZC42

Claims (7)

[Claims] 1. A group consisting of malaria, restenosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis, unwanted hematopoietic stem cell release, and diseases caused by respiratory virus, herpes virus, and hepatitis virus. A method of treating a selected chemokine-mediated disease state wherein the chemokine binds to an IL-8 α or β receptor in a mammal, wherein the mammal has a therapeutically effective amount. The following formula: [Wherein, X is oxygen or sulfur; R is (CR ₈ R ₈ ) _r C (O) ₂ H, (CR ₈ R ₈ ) _r NH-C (O) R _a , (CR ₈ R ₈ ). _{r C (O) NR 6 '} R 7', (CR 8 R 8) r NH
S (O) ₂ R _b , (CR ₈ R ₈ ) _r S (O) ₂ NHR _c , (CR ₈ R ₈ ) _r NHC (X ₂ ) NHR _b , or a tetrazolyl ring; X ₂ is oxygen or sulfur. R ₁ is hydrogen; halogen; nitro; cyano; halo-substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; halo-substituted C _1-10 alkoxy; azide
; (CR ₈ R ₈ ) _q S (O) _t R ₄ ; hydroxy; hydroxy C _1-4 alkyl; aryl; aryl C _1-4 alkyl; aryloxy; aryl C _1-4 alkyloxy; heteroaryl; heteroaryl Alkyl; heterocyclic; heterocyclic C _1-4 alkyl; heteroaryl C _1-4 alkyloxy; aryl C _2-10 alkenyl; heteroaryl C _2-10 alkenyl; heterocyclic C _2-10 alkenyl; (CR ₈ R ₈ ) _q NR ₄ R ₅ ; C _2-10 alkenyl C (O) NR ₄ R ₅ ; (CR ₈ R ₈ ) _q C (O) NR ₄ R ₅ ; (CR ₈ R ₈ ) _q C (O ) NR ₄ R ₁₀ ;
S (O) ₃ R ₈ ; (CR ₈ R ₈ ) _q C (O) R ₁₁ ; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR _{1 1} (CR ₈ R ₈ ) _q C (O) OR ₁₂ ; (CR ₈ R ₈ ) _q OC (O) R ₁₁ ; (CR ₈ R ₈ ) _q NR ₄ C (O) R ₁₁ ; (CR ₈ R ₈ ) _q NHS (O ) ₂ R ₁₇ ; (CR ₈ R ₈ ) _q S (O) ₂ NR ₄ R ₅ independently selected; or two R ₁ moieties taken together are O- (CH ₂ ) _s O -Or a 5- to 6-membered saturated or unsaturated ring may be formed; where the aryl, heteroaryl, and heterocyclic containing moieties may be substituted; provided that the 3- to 2-position on the phenyl ring is 10 pKa
And n is an integer having a value of 1 to 3; m is an integer having a value of 1 to 3; q is 0 or 1 R is an integer having a value of 1 to 4; r is 0 or an integer having a value of 1 to 4; s is an integer having a value of 1 to 3; t is 0 or Is an integer having a value of 1 or 2; v is an integer having a value of 1 to 4; R ₄ and R ₅ are independently hydrogen, optionally substituted C _1-4 alkyl, substituted Optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl, heterocyclic, heterocyclic C _{1 −} Or alkyl, or R ₄ and R ₅ may form a ring of 5 to together with the nitrogen to which they are attached 7-membered, one ring is selected from the more O / N / S R ₆ and R ₇ are independently hydrogen or a C _1-4 alkyl group, or R ₆ and R ₇ together with the nitrogen to which they are attached are 5 or It may form a 7-membered ring, which may further contain one heteroatom selected from O / N / S; R _{6 ′} and R _{7 ′} are independently hydrogen, C _1-4 alkyl, aryl, aryl C _-4
Alkyl _, aryl C _2-4 alkenyl, heteroaryl, heteroaryl C _1-4 alkyl, heteroaryl C _2-4 alkenyl, heterocyclic, heterocyclic C _1-4 alkyl, heterocyclic C _2-4 alkenyl moiety Where one of R _{6 ′} and R _{7 ′} is hydrogen but both are not hydrogen; Y is hydrogen; halogen; nitro; cyano; halo-substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; halo-substituted C _1-10 alkoxy; azide; (
_{CR 8 R 8) q S (} O) t R 4; hydroxy; hydroxyalkyl C _1-4 alkyl; aryl; aryl C _{1 -4} alkyl; aryloxy; aryl C _1-4 alkyloxy; heteroaryl;
Heteroarylalkyl; Heteroaryl C _1-4 alkyloxy; Heterocyclic, heterocyclic C _1-4 alkyl; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; Heterocyclic C _2-10 alkenyl; (CR ₈ R ₈ ) _q NR ₄ R ₅ ; C _2-10 alkenyl C (O) NR ₄ R ₅ ; (CR ₈ R ₈ ) _q C (O) NR ₄ R ₅ ; (CR ₈ R ₈ ) _q C (O) NR ₄ R ₁₀ ; S (O) ₃ R _8; (CR ₈ R ₈ ) _q C (O) R ₁₁ ; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O ) OR ₁₁ ; C (
O) R _11; (CR ₈ R ₈ ) _q C (O) OR ₁₂ ; (CR ₈ R ₈ ) _q OC (O) R ₁₁ ; (CR ₈ R ₈ ) _q NR ₄ C (O) R ₁₁ ; ( CR ₈ R ₈ ) _q N
HS (O) ₂ R _d ; (CR ₈ R ₈ ) _q S (O) ₂ NR ₄ R ₅ independently selected; or two Y moieties taken together are O- (CH ₂ ). _s O-or a 5- or 6-membered saturated or unsaturated ring may be formed; where aryl, heteroaryl, and heterocyclic containing moieties may be substituted; R ₈ is hydrogen or C _1-. Independently selected from ₄ alkyl; R ₁₀ is C _1-10 alkyl C (O) ₂ R ₈ ; R ₁₁ is hydrogen, C _1-4 alkyl, optionally substituted aryl, substituted _Optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl, optionally substituted heterocyclic, or optionally substituted hetero. It is a cyclic _{C 1-4} alkyl; _{R 12} is hydrogen , C _1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl; R ₁₃ and R ₁₄ are independently hydrogen, optionally substituted C _1-4 alkyl. Alternatively, one of R ₁₃ and R ₁₄ may be optionally substituted aryl; R ₁₇ is C _1-4 alkyl, aryl, arylalkyl, heteroaryl, heteroaryl C _1-4 alkyl, hetero Cyclic or heterocyclic C _1-4 alkyl, wherein aryl, heteroaryl, and heterocyclic ring may all be optionally substituted; R _a is alkyl, aryl, aryl C _1-4 alkyl, heteroaryl, heteroaryl C _1-4 alkyl, heterocyclic or heterocyclic C _{1 -4} alkyl, A portion, here may be all of these moieties substituted; R _b is NR ₆ R _7, alkyl, aryl, aryl C _1-4 alkyl, aryl C _2-4 alkenyl, heteroaryl, heteroaryl C _1-4 alkyl, heteroaryl C _2-4 alkenyl, heterocyclic, heterocyclic C _1-4 alkyl, heterocyclic C _2-4 alkenyl moiety, or camphor, where all of these moieties are substituted. R _c may be alkyl, aryl, aryl C _1-4 alkyl, aryl C _2-4 alkenyl, heteroaryl, heteroaryl C _1-4 alkyl, heteroaryl C _2-4 alkenyl, heterocyclic, hetero. a cyclic C _1-4 alkyl or heterocyclic C _2-4 alkenyl moiety, here it may be all of these moieties substituted R _d is NR ₆ R _7, alkyl, aryl C _1-4 alkyl, aryl C _2-4 alkenyl,
Heteroaryl, heteroaryl-C _1-4 alkyl, heteroaryl C _2-4 alkenyl, heterocyclic, heterocyclic C _1-4 alkyl, wherein aryl, heteroaryl and heterocyclic containing rings are substituted. W may be And the E-containing ring is: An asterisk * indicates the point of attachment of the ring; R ₂₀ is W ₁ , optionally substituted heteroaryl, optionally substituted C _5-8 cycloalkyl, _optionally substituted A good C _1-10 alkyl, an optionally substituted C _2-10 alkenyl, or an optionally substituted C _2-10 alkynyl; W ₁ is The E′-containing ring is as follows: Asterisk * represents a point of attachment of the ring] or a pharmaceutically acceptable salt thereof. 2. The method of claim 1, wherein R is (CR ₈ R ₈ ) _r C (O) ₂ H. 3. R ₁ is halogen, cyano, nitro, CF ₃ , C (O) NR ₄ R ₅ , alkenyl C (O) NR ₄ R ₅ , C (O) R ₄ R ₁₀ , alkenyl C (O
) OR < ₁₂ >, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or S (O) NR < ₄ > R < ₅ >. 4. The method of claim ₁ , wherein R ₂₀ is W ₁ . 5. The method of claim 1, wherein R ₂₀ is heteroaryl. 6. Y is halogen and C_1-4Alkoxy, optionally substituted
Aryl, optionally substituted arylalkoxy, methylenedioxy, NR _Four R₅, Thio C_1-4Alkyl, thioaryl, halo substituted alkoxy, substituted
May be C_1-4The method according to claim 4, which is alkyl or hydroxyalkyl.
. 7. The method of claim 1, wherein R ₁ is monosubstituted at the 2- or 4-position by an electron withdrawing moiety, or disubstituted at the 2,4-position.