JP2000515495A - IL-8 receptor antagonist - Google Patents

Abstract

SUMMARY The present invention relates to the use of phenylureas of formula (I) in the treatment of conditions mediated by the chemokine interleukin-8 (IL-8). The variables of formula (I) are defined herein.

Description

DETAILED DESCRIPTION OF THE INVENTION                      IL-8 receptor antagonist Field of the invention   The present invention provides a novel phenylurea compound group, a method for producing the same, IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78. As well as pharmaceutical compositions for use in such treatments. Background of the Invention   Interleukin-8 (IL-8) contains neutrophil attractant / activating protein- 1 (NAP-1), monocyte-derived neutrophil chemotactic factor (MDNCF), neutrophil activator ( Many different names have been applied, such as NAF) and T-cell lymphocyte chemotactic factor. Was. Interleukin-8 is a subset of neutrophils, basophils, and T-cells Is a chemoattractant. It can be TNF, IL-1α, IL-1β or Including macrophages, fibroblasts, endothelial cells and epithelial cells exposed to LPS Exposed to the majority of nucleated cells and to chemotactic factors such as LPS or FMLP If produced, it is produced by neutrophils themselves. M. Baggiolini et al,J . Clin. In vest. 84, 1045 (1989); Schroder et al,J . Immunol.139, 3474 (1987) AndJTImmunol . 144, 2223 (1990); Strieter, et al,Science243, 1467 (198 9) andJ . T. Biol. Chem. 264,10621 (1989); Cassatella et al,J.Immunol .148 , 3216 (1992).   GROα, GROβ, GROγ and NAP-2 are also chemokines α Belongs to Millie. Like IL-8, these chemokines also have various names. Has been called in. For example, GROα, β, γ are MGSAα, β, and γ, respectively. (Melanoma growth promoting activity). Richmond et al. Cell Physiology 1 29, 375 (1986) and Chang et al,J . Immunol 148, 451 (1992). CX Of α-family chemokines having an ELR motif immediately preceding the C motif Everything Binds to the IL-8B receptor.   IL-8, GROα, GROβ, GROγ, NAP-2 and ENA-78 Stimulates many functions in vitro. They all respond to neutrophils IL-8 and GROα have been shown to have chemoattractant properties. It showed chemotactic and basophil chemotactic activity. In addition, IL-8 is found in normal individuals and Can induce histamine release from basophils from both normal and atopic individuals it can. GRO-α and IL-8 also release lysosomal enzymes from neutrophils. Egress and respiratory bursts can be triggered. IL-8 also Mac-1 (CD11b / CD1 on neutrophils without de novo protein synthesis 8) was shown to increase the surface expression. This is a neutrophil Contributes to increased adhesion. Many known diseases are characterized by massive neutrophil infiltration Be killed. IL-8, GROα, GROβ, GROγ and NAP-2 are neutrophils These chemokines are useful for psoriasis and psoriasis because they promote sphere accumulation and activation. It has been implicated in a wide range of acute and chronic inflammatory diseases, including rheumatoid arthritis. Ba ggiolini et al,FEBS Lett . 307, 97 (1992); Miller et al,Crit . Rev. Immun ol. 12 Oppenheim et al., 17 (1992);Annu . Rev. Immunol. 9, 617 (1991); Sei tz et al.,J . Clin. Invest. 87, 463 (1991); Miller et al.,Am . Rev. Resir . Dis. 146 , 427 (1992); Donnely et al.,Lancet 341, 643 (1993). Furthermore, E LR chemokines (containing an amino acid ELR motif immediately before the CXC motif) ) Was also involved in hemostasis. Strieter et al, Science 258, 1798 (1992) .   In vitro, IL-8, GROα, GROβ, GROγ and NA P-2 is a seven-transmembrane, receptor for the G-protein binding family. Activating the receptor by binding to a receptor, particularly an IL-8 receptor -, Most notably, neutrophil shape change and chemotaxis by binding to B-receptor Induces sex, granule release and respiratory burst. Thomas et al.,J.Bio l . Chem. 266 , 14839 (1991); and Holmes et al.,Science 253, 1278 (1991). Non-peptide small molecule antagonists to members of this receptor family There is a precedent in the development of. For reference, R.E. Freidinger in:Progress in Drug Research , Vol. 40, pp. 33-98, Birkhauser Verlag, Basel 1993. did Thus, the IL-8 receptor represents a promising target for the development of new anti-inflammatory drugs .   The two high affinity human IL-8 receptors (77% homology) are as follows: Characterized: IL-8Rα, which binds only IL-8 with high affinity. And GRO-α, GROβ, GROγ and NAP- IL-8Rβ with high affinity for 2. Holmes et al., Supra; Murphy et al.,Science253, 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).   For treatment, the art has the ability to bind to IL-8α or β receptors. There is still a need for such compounds. Therefore, IL-8 production (neutrophils And T-cell subsets are responsible for chemotaxis to inflammatory sites) In particular, the conditions conceivable for compounds that are inhibitors of IL-8 receptor binding are obtained. There will be places.Summary of the Invention   The present invention relates to a chemokine wherein the chemokine binds to the IL-8α or β receptor. A method of treating a protein-mediated disease, comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof. And administering an effective amount of the desired salt. In particular, Mokine is IL-8.   The present invention also provides a mammal in need of inhibiting the binding of IL-8 to its receptor. A method of said inhibition in an animal, comprising administering an effective amount of a compound of formula (I) to said mammal. The present invention also relates to a method of inhibition comprising administering to an animal.   Compounds of formula (I) useful in the present invention have the structural formula: [Where,   X is oxygen or sulfur;   R is an ionizable hydrogen and a functional group having a pKa of 10 or less;   R₁Is independently hydrogen; halogen; nitro; cyano; halo-substituted C_1-10Archi Le; C_1-10Alkyl; C_2-10Alkenyl; C_1-10Alkoxy; halo-substituted C_1-10A Lucoxy; azide; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4Al Kill; aryl; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Al Heteroaryl; Heteroarylalkyl; Heterocycle, Heterocycle C_1-4 Alkyl; heteroaryl C_1-4Alkyloxy; aryl C_2-10Alkenyl; Heteroaryl C_2-10Alkenyl; heterocyclic C_2-10Alkenyl; (CR₈R₈)_qNR_FourR_FiveC_2-10Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_TenS (O)_ThreeH; S (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁C_2-10 Alkenyl C (O) OR₁₁(CR₈R₈)_qC (O) OR₁₂; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁, (CR₈R₈)_qNHS (O)_TwoR₁₇, (CR₈R₈)_qS (O)_TwoNR_FourR_FiveSelected from; Or two R₁The groups together form O- (CH_Two)_sO- or a 5- to 6-membered unsaturated ring May be formed;   q is 0 or an integer having a value from 1 to 10;   t is 0 or an integer having a value of 1 or 2;   s is an integer having a value from 1 to 3;   m is an integer having a value of 1 to 3;   n is an integer having a value of 1 to 3;   v is 0 or an integer having a value from 1 to 4;   R_FourAnd R_FiveIs independently hydrogen, optionally substituted C_1-4A Alkyl, optionally substituted aryl, optionally substituted Good aryl C_1-4Alkyl, optionally substituted heteroaryl Optionally substituted heteroaryl C_1-4Alkyl, heterocycle, Heterocycle C_1-4Alkyl or R_FourAnd R_FiveAre they combined Together with additional nitrogen, optionally an additional selected from oxygen, nitrogen or sulfur. Forming a 5- to 7-membered ring optionally containing a heteroatom;   Y is independently hydrogen; halogen; nitro; cyano; halo-substituted C_1-10Alkyl C_1-10Alkyl; C_2-10Alkenyl; C_1-10Alkoxy; halo-substituted C_1-10Al Coxy; azide; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4Archi Aryl; aryl; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Archi Heterooxy; heteroarylalkyl; heteroaryl C_1-4A Alkyloxy; heterocycle, heterocycle C_1-4Alkyl; aryl C_2-10Alkenyl; f Teloaryl C_2-10Alkenyl; heterocyclic C_2-10Alkenyl; (CR₈R₈)_qNR_FourR_FiveC_2-10Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_TenS (O)_ThreeH; S (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁; C_2-10Alkenyl C (O) OR₁₁C (O) R₁₁; (CR₈R₈)_qC (O) OR₁₂; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁, (CR₈R₈)_qNHS (O)_TwoR_d, (CR₈R₈)_qS (O)_TwoNR_FourR_FiveSelected from; Or two Y groups are joined together to form O- (CH_Two)_sO- or form a 5- to 6-membered unsaturated ring May be made;   R₆And R₇Is independently hydrogen or C_1-4An alkyl group, or R₆And R₇Together with the nitrogen to which they are attached, optionally oxygen, 5 to 7 members optionally containing additional heteroatoms selected from nitrogen or sulfur Forming a ring;   R₈Is independently hydrogen or C_1-4Selected from alkyl;   R_TenIs C_1-10Alkyl C (O)_TwoR₈Is;   R₁₁Is hydrogen, C_1-4Alkyl, optionally substituted aryl, Optionally substituted aryl C_1-4Alkyl, optionally substituted Optionally substituted heteroaryl, optionally substituted heteroaryl C_1-4Alkyl, optionally substituted heterocycle, or optionally Optionally substituted heterocycle C_1-4Alkyl;   R₁₂Is hydrogen, C_1-10Alkyl, optionally substituted aryl or Or an optionally substituted arylalkyl;   R₁₃And R₁₄Is independently hydrogen or C_1-4Alkyl;   R₁₇Is C_1-4Alkyl, aryl, arylalkyl, heteroaryl, f Teloaryl C_1-4Alkyl, heterocycle, or heterocycle C_1-4Alkyl here Wherein the aryl, heteroaryl and heterocycle are all optionally substituted Often;   R_dIs NR₆R₇, Alkyl, aryl C_1-4Alkyl, aryl C_2-4Arche Nil, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_2-4A Lucenyl, heterocycle, heterocycle C_1-4Alkyl, where aryl, heteroa All of the reels and heterocycles are optionally substituted;   Z is (Where the asterisk * indicates the bonding position of the ring); E is optionally (Asterisk * indicates the bonding position of the ring)] Or a pharmaceutically acceptable salt thereof.Detailed description of the invention   Compounds of formula (I) are directed to IL-8 or IL-8 α and β receptors. Veterinary treatment of non-human mammals requiring inhibition of another binding chemokine May be used. Chemokine-mediated for therapeutic or prophylactic treatment of animals Diseases include conditions as described in the methods of treatment section herein. Can be   In the compounds of formula (I), R is less than or equal to 10, preferably about 3 to 9, More preferably with a functional group providing an ionizable hydrogen having a pKa of about 3-7. It is appropriate that there is. Such functional groups include, but are not limited to, hydroxy, Rubonic acid, thiol, -SR_Two, -OR_Two, -NH-C (O) R_a, -C (O) NR₆R₇, Formula -NHS (O) R_bA substituted sulfonamide represented by -S (O)_TwoNHR_c, NHC (X_Two) NHR_bOr tetrazolyl; Where X_TwoIs oxygen or sulfur, preferably oxygen. Preferably, the The functional group can be used as is or_TwoOr OR_TwoAryl, as in The substituent on the heteroaryl or heterocyclic group is other than sulfonic acid. Sa More preferably, R is OH, SH or NHS (O)_TwoR_bIt is. Suitably, R_Two Is a substituted aryl, heteroaryl, or heterocycle, wherein the ring is 10 or less A functional group that provides an ionizable hydrogen with a pKa of   Suitably, R₆And R₇Is independently hydrogen or C_1-4Is it an alkyl group Or R₆And R₇Together with the nitrogen to which they are attached form 5-7 To form a membered ring, wherein said ring optionally has an additional member selected from oxygen, nitrogen or sulfur. It may contain a hetero atom. This heterocycle is defined as defined herein. It may be substituted as desired.   Suitably, R_aIs an alkyl, aryl, aryl C_1-4Alkyl, hetero ant , Heteroaryl C_1-4Alkyl, heterocycle, or heterocycle C_1-4With an alkyl group All of which may be optionally substituted as defined below .   Suitably, R_bIs NR₆R₇, Alkyl, aryl, aryl C_1-4Alkyl, Aryl C_2-4Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, f Teloaryl C_2-4Alkenyl, heterocycle, or heterocycle C_1-4Alkyl or multiple Prime ring C_2-4An alkenyl group, camphor; all of which are optionally halo Gen; Nitro; CF_ThreeHalo-substituted C such as_1-4Alkyl; C such as methyl_1-4A Lucyl; C like methoxy_1-4Alkoxy; NR₉C (O) R_aC (O) NR₆R₇ , S (O)_ThreeH or C (O) OC_1-4Independently substituted 1-3 times by alkyl May be. R_bIs preferably an optionally substituted phenyl, Benzyl or styryl. R_bWhen is a heteroaryl ring, optionally Optionally substituted thiazole, optionally substituted thienyl Or an optionally substituted quinolinyl ring.   Suitably, R₉Is hydrogen or C_1-4Alkyl. Preferably, R₉Is the water Is prime. Suitably, R_bWhen the substituent is NR₉C (O) R_aIf R_aIs preferably Is an alkyl group such as methyl.   Suitably, R_cIs hydrogen, alkyl, aryl, aryl C_1-4Alkyl, ant C_1-4Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, hetero Aryl C_1-4Alkenyl, heterocycle, or heterocycle C_1-4Alkyl or heterocyclic C_1-4Alkenyl groups, all of which are optionally halogen, nitro, ha B substitution C_1-4Alkyl, C_1-4Alkyl, C_1-4Alkoxy, NR₉C (O) R_a, C ( O) NR₆R₇, S (O)_ThreeH or C (O) OC_1-41 to 3 independently by alkyl It may be substituted twice. Preferably, R_cMay be optionally substituted Phenyl.   R is OR_TwoOr SR_TwoIf the group is an ionizable, an aryl ring is required Those of skill in the art will recognize that they must contain significant hydrogen. The aryl ring is And may be further independently substituted with 1 to 3 groups, May contain additional ionizable groups, including but not limited to But halogen, nitro, halo substituted C_1-4Alkyl, C_1-4Alkyl, C_1-4Al Coxy, hydroxy, SH, -C (O) NR₆R₇, -NH-C (O) R_a, -NHS ( O)_TwoR_b, S (O)_TwoNR₆R₇, C (O) OR₈Or a tetrazolyl ring.   In the compounds of formula (I), suitably R₁Is independently hydrogen; halo Gen; Nitro; Cyano; CF_ThreeHalo-substituted C such as_1-10Alkyl; methyl, ethi C, such as toluene, isopropyl, or n-propyl_1-10Alkyl; C_2-10Arche Nil; C such as methoxy or ethoxy_1-10Alkoxy; trifluoromethoxy Halo-substituted C_1-10Alkoxy; azide; (CR₈R₈)_dS (O)_tR_Four(here , T is 0, 1 or 2); hydroxy; methanol or ethanol Hydroxy C_1-4Alkyl; aryl such as phenyl or naphthyl; Aryl C such as benzyl_1-4Alkyl; aryloxy such as phenoxy Aryl C such as benzyloxy_1-4Alkyloxy; heteroaryl; f Teloarylalkyl; heteroarylC_1-4Alkyloxy; aryl C_2-10 Alkenyl; heteroaryl C_2-10Alkenyl; heterocyclic C_2-10Alkenyl; (C R₈R₈)_qNR_FourR_FiveC_2-10Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_TenS (O)_ThreeH; S (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁; C_2-10Alkenyl C (O) OR₁₁C (O) R₁₁; (CR₈R₈)_qC (O) OR₁₂; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈) qNR_FourC (O) R₁₁, (CR₈R₈)_qNHS (O)_TwoR₁₇, (CR₈R₈)_qS (O)_TwoNR_FourR_FiveSelected from; Or two R₁Together form O- (CH_Two)_sO- or 5- or 6-membered unsaturated ring May be formed; s is an integer having a value of 1 to 3. The aryl, ally Alkyl, arylalkenyl, heteroaryl, heteroarylalkyl, Heteroarylalkenyl, heterocycle, heterocyclealkyl, and heterocyclealkenyl All groups may be optionally substituted as defined below.   Suitably, q is 0 or an integer having a value from 1 to 10.   Suitably, R_FourAnd R_FiveIs independently hydrogen, optionally substituted C_1-4Alkyl, optionally substituted aryl, optionally substituted Aryl C which may be_1-4Alkyl, optionally substituted Teloaryl, optionally substituted heteroaryl C_1-4Alkyl , Heterocycle, heterocycle C_1-4Alkyl or R_FourAnd R_FiveIs that they Conclusion Together with the combined nitrogen, an optional additional O / N / S A 5- to 7-membered ring which may contain a terror atom is formed.   The Z ring is indicated by its point of attachment by an asterisk. Z ring is R₁Substituted by group Or both the phenyl and Z rings are independently R₁Has been replaced by You may. Suitably, R₁Is substituted, the nitrogen-containing Z ring is C (O) NR_FourR_Fiveetc Substituted on the nitrogen group by an amide function of R;_FourOr R_Fiveof One is an optionally substituted aryl, such as phenyl. Preferably The larger saturated nitrogen-containing ring may also be substituted by an aryl ring.   R₈Is suitably, independently, hydrogen or C_1-4Selected from alkyl.   R_TenIs suitably CH_TwoC (O)_TwoH or CH_TwoC (O)_TwoCH_ThreeEtc. C_1-10Al Kill C (O)_TwoR₈It is.   R₁₁Is suitably hydrogen, C_1-4Alkyl, aryl, aryl C_1-4Alkyl , Heteroaryl, heteroaryl C_1-4Alkyl, heterocycle, or heterocycle C_1-4 Alkyl.   R₁₂Is suitably hydrogen, C_1-10Alkyl, optionally substituted Aryl or optionally substituted arylalkyl.   R₁₇Is, appropriately, C_1-4Alkyl, aryl, arylalkyl, heteroa Reel, heteroaryl C_1-4Alkyl, heterocycle, or heterocycle C_1-4With alkyl Wherein the aryl, heteroaryl and heterocycle are all optionally It may be substituted.   Preferably, R₁Is halogen, cyano, nitro, CF_Three, C (O) NR_FourR_Five, Lucenyl C (O) NR_FourR_Five, C (O) R_FourR_Ten, Alkenyl C (O) OR₁₂, Heteroa Reel, heteroarylalkyl, heteroarylalkenyl, or S (O) N R_FourR_FiveAnd preferably R_FourAnd R_FiveAre both hydrogen or one Is phenyl. R₁A preferred ring substitution for is at position 4 of the phenyl ring. It is.   R is OH, SH or NHS (O)_TwoR_bIf R₁Is preferably third It is substituted at the 4- and 4-positions or disubstituted at the 3- and 4-positions. The substituent is , Suitably, it is an electron withdrawing group. Preferably, R is OH, SH or NHS (O)_Two R_bIf R₁Is a nitro, halogen, cyano, trifluoromethyl group, C (O) NR_FourR_FiveIt is.   When R is a carboxylic acid, R₁Is preferably hydrogen or R₁ Is preferably substituted at the 4-position, more preferably trifluoromethyl Or substituted by chloro.   Ring E, indicated by its point of attachment by an asterisk (*), is optionally present Is also good. If not present, the ring is a phenyl group substituted by a Y group as described above. . Ring E is independently substituted with a Y group in either a saturated or unsaturated ring. May be substituted only in the unsaturated ring (s) herein. Show things.   In the compounds of formula (I), suitably R₁₃And R₁₄Is independently hydrogen or Is a straight-chain or branched C as defined herein._1-4Archi V is 0, or an integer having a value of 1-4, preferably when v = 0 is there.   Suitably, Y is independently hydrogen; halogen; nitro; cyano; halo-substituted C_{1- Ten} Alkyl; C_1-10Alkyl; C_2-10Alkenyl; C_1-10Alkoxy; halo substituted C_1-10Alkoxy; azide; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4Alkyl; aryl; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C_1-4Alkyloxy; heterocycle, heterocycle C_1-4Alkyl; aryl C_2-10Al Kenyl; heteroaryl C_2-10Alkenyl; heterocyclic Cq_2-10Alkenyl; (CR₈ R₈)_qNR_FourR_FiveC_2-10Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_TenS (O)_ThreeH; S (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁; C_2-10Alkenyl C (O) OR₁₁; (CR₈R₈)_qC (O) OR₁₂; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁, (CR₈R₈)_qNHS (O)_TwoR_d, (CR₈R₈)_qS (O)_TwoNR_FourR_FiveSelected from or Or two Y groups are joined together to form O- (CH_Two)_sO- or a 5- or 6-membered unsaturated ring It may be formed. When Y forms a dioxy bond, S is preferably 1. . When Y forms an additional unsaturated ring, it preferably forms a naphthylene ring system. The resulting six-membered ring. This naphthylene ring may be formed one to three times by another Y group as defined above. It may be substituted. Aryl, arylalkyl, arylalkenyl , Heteroaryl, heteroarylalkyl, heteroarylalkenyl, Elementary rings, heterocyclic alkyl, and heterocyclic alkenyl groups are all defined herein. May be substituted.   Suitably, R_dIs NR₆R₇, Alkyl, aryl C_1-4Alkyl, aryl C_2-4 Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl Le C_2-4Alkenyl, heterocycle, heterocycle C_1-4Alkyl or heterocyclic C_2-4Arche An aryl, arylalkyl, arylalkenyl , Heteroaryl, heteroarylalkyl, heteroarylalkenyl, Elementary rings, and heterocyclic alkyl and heterocyclic alkenyl groups are all defined herein. It may be substituted as defined.   Y may be substituted at any of the five ring positions, but Y is preferably It is monosubstituted at the 2 'or 3' position, and the 4 'position is preferably unsubstituted. If the ring is disubstituted, the substituent is preferably at the 2'-position of the monocyclic ring or It is in the 3 'position. R₁And Y can both be hydrogen, but at least one of the rings Is preferably substituted, and more preferably both rings are substituted.   In the compounds of formula (I), X is suitably oxygen or sulfur; Preferably, it is oxygen.   Exemplary compounds of formula (I) include the following:   N- [1-[[(2-bromophenyl) amino] carbonyl] -4-hydroxybe Nzimidazol-5-yl] -N '-[2-bromophenyl] urea;   N-7- (8-hydroxy 1-phenyl 2,3,4,5-tetrahydro 1H3-benzazepine) -N ', N "-(2-bromophenyl) diurea;   N- (6-hydroxy-4-sulfonylbenzothien-7-yl) -N '-(2 − Bromophenyl) urea Is included.   As used herein, “optionally substituted” is specifically defined. Unless otherwise defined, halogen such as fluorine, chlorine, bromine or iodine; hydroxy; Droxy substituted C_1-10Alkyl; C such as methoxy or ethoxy_1-10Alkoxy; S (O) such as methylthio, methylsulfinyl or methylsulfonyl_{m '}C_1-10A Alkyl (where m 'is 0, 1 or 2); amino, NR_FourR_FiveIn the base Mono- and disubstituted amino; NHC (O) R^FourC (O) NR_FourR_FiveC (O) O H; S (O)_TwoNR_FourR_Five; NHS (O)_TwoR₁₅; Methyl, ethyl, propyl, isopro Pill or C such as t-butyl_1-10Alkyl; CF_ThreeHalo substituted C such as_1-10Archi An optionally substituted aryl such as phenyl or benzyl; Or an optionally substituted arylalkyl such as phenethyl, A heterocyclic ring optionally substituted by Alkyl, optionally substituted heteroaryl, optionally substituted A heteroarylalkyl (wherein these aryl, heteroaryl Or a heterocyclic group is halogen; hydroxy; hydroxy-substituted alkyl;_1-10 Alkoxy; S (O)_{m '}C_1-10Alkyl; amino, NR_FourR_FiveAs in the base Monosubstituted and disubstituted amino; C_1-10Alkyl or CF_ThreeHalo substituted C such as_1-10 (Which may be substituted once or twice with alkyl).   R₁₅Is, appropriately, C_1-4Alkyl, aryl, aryl C_1-4Alkyl, Hete Low aryl, heteroaryl C_1-4Alkyl, heterocycle, or heterocycle C_1-4Archi It is.   Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include hydrochloric, hydrobromic, sulfuric acids , Phosphoric acid, methanesulfonic acid, ethanesulfonic acid, acetic acid, malic acid, tartaric acid, Enic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salici And basic salts of inorganic and organic acids such as acetic acid, phenylacetic acid and mandelic acid. Can be In addition, pharmaceutically acceptable salts of the compounds of formula (I) also include, for example, When the substituent contains a carboxy group, it is formed with a pharmaceutically acceptable cation. Re You may. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include Cations, alkaline earth cations, ammonium cations and quaternary ammonium Cations.   The following terms, as used herein, mean the following.   "Halo" is all halogens, i.e., chloro, fluoro, bromo and And iodine.   "C_1-10Neither “alkyl” nor “alkyl” are specifically limited in chain length Represents a linear or branched group having 1 to 10 carbon atoms, and is not limited to , Methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl Butyl, iso-butyl, tert-butyl, n-pentyl and the like.   The term "cycloalkyl" as used herein is preferably a ring of 3 to 8 carbons Used to represent a group in the form of, but not limited to, cyclopropyl, cyclopentene And cyclohexyl.   The term "alkenyl" is used herein to refer to a carbon atom unless the chain length is limited. Used to represent 2 to 10 straight-chain or branched groups, without limitation Is ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl , 1-butenyl, 2-butenyl and the like.   "Aryl" refers to phenyl and naphthyl.   "Heteroaryl" (alone or "heteroaryloxy" or "heteroaryl") In combinations such as `` arylalkyl ''), but is not limited to , Pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolini Pyridine, pyrimidine, oxazole, thiazole, thiadiazole, tri One or more rings such as azole, imidazole, or benzimidazole are N, 5 to 10 containing one or more heteroatoms selected from the group consisting of O or S Represents a membered aromatic ring system.   "Heterocycle" (alone or in combination like "heterocyclealkyl") Is, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tet Whether one or more rings, such as lahydropyran or imidazolidine, is N, O or S Saturated or partially unsaturated containing one or more heteroatoms selected from the group consisting of: Represents a 4- to 10-membered ring system.   “Arylalkyl” or “heteroarylalkyl” or “heterocyclic al The term "kill" is used herein unless otherwise defined. Or a heteroaryl or heterocyclic group as defined above._1-10Alkyl Used to represent   “Sulfinyl” denotes the oxide S (O) of the corresponding sulfide, “thio” Represents the sulfide, and "sulfonyl" represents fully oxidized S (O)_TwoTable You.   "Two Rs₁The groups (or two Y groups) together form a 5- or 6-membered unsaturated The term "forms a ring" is used herein to refer to C₆Cycloalkenyl, ie 6-membered partially unsaturated ring such as xane or C_FiveCycloalkenyl group, cyclopentene, etc. To form a naphthylene ring system or a phenyl group.   Compounds of formula (I) have been prepared by synthetic methods, some of which are described in the schemes below. It is obtained by using. The syntheses shown in these schemes are described herein. Any suitable protection that achieves compatibility with the reactions outlined in the Various R, R₁And an aryl group-containing formula (I) The present invention is applicable to the production of a compound to be prepared. Then, in these cases, Thus, compounds having the properties generally described are obtained. Once the urea nucleus is established In turn, another compound of these formulas can be substituted with functional groups well known in the art. Manufactured by applying standard techniques for conversion. The scheme has the formula It is shown using the compound shown only in (I), but this is for illustrative purposes only. is there.   UreaScheme 1Can be synthesized from nitrophenol as shown in Nitrofe Nol or hydroxyanilineScheme 2Can be synthesized as shown in No. 4,327,023 or Feiser, L.F. Kennelly, R.C . J. Am. Chem. Soc. It can be synthesized by the method outlined in 1937, 37, 1611. this The nitrophenol was then treated with hydrogen gas and SnCl 2 in Pd / C or EtOH._Two Can be converted to the corresponding aminophenol by standard reduction methods such as Hydroxy Shi The aniline is then condensed with a commercially available isocyanate to form urea (2-Scheme 1) Can be converted to                                Scheme 1   If nitroaniline cannot be obtained from an external source, it can be Rule3Can be synthesized from Diaminophenol is refluxed in formic acid to give imidazole. Form. The hydroxyimidazole is then replaced with nitric acid or nitrosonium tetra Nitrification using standard conditions in the art such as fluoroborate,6To form . This nitrophenolScheme 1The desired urea is determined by the reaction sequence shown in3 Convert to                                Scheme 2   Alternatively,Scheme 3As shown in FIG. Tert (butyl) dimethylsilyl chloride in an aprotic solvent such as MF and It can be protected with a known reagent such as imidazole (Scheme 3). Then aniline heavy coal Phosgene or an equivalent of triphosgene in the presence of a base such as sodium acid React with bonnylimidazole to produce isocyanate8(Or thiopho The thioisocyanate is formed using sugen). Then add this isocyanate Can be condensed with any commercially available desired amine. Then the protected phenol Is deprotected by standard conditions such as triethylamine hydrofluoride and urea9To Can be formed.                                Scheme 3   Where RNH_TwoR in the formula is represented as phenyl here, but in formula (I) (CR₁₃R₁₄) A phenyl or phenyl (E) ring derivative, Is also good.Scheme 4   Desired 2-substituted aniline11-Scheme 4Is not commercially available, The corresponding nitro compound10-Scheme 4From standard nitrification conditions at 23 ° C ( HNO_ThreeOr BF_FourNO_Three). Isomer nitro compounds Can be separated by chromatography. Then, the nitro compound was replaced with EtOH Medium SnCl_Two(Or alternatively, H_Two/ Pd or LiAlH_Four) Aniline11-Scheme 4To be reduced to                                Scheme 5   Desired 2-aminobenzenethiol13-Scheme 5But not on the market Phenylaniline in the presence of an oxidizing agent (such as bromine) To produce 2-aminobenzthiol. Chromatog After separation of the isomeric thiazoles by Raffy, the desired thiazoles are converted to a protic solvent. Hydrolysis with a strong base such as NaOH in a solvent (ie, EtOH) Nzenthiol12-Scheme 5Can be obtained.Scheme 6   Where R'NH_TwoR ′ in the formula (I) is shown as phenyl here, (CR₁₃R₁₄) A phenyl or phenyl (E) ring derivative You may.   Alternatively, the isocyanate is converted to the Curtius rearrangement (dppa and triethyl Using an amine, oxalyl chloride followed by sodium azide, Scheme 6) Can be synthesized from the corresponding carboxylic acid. The commercially available hydroxy isocyanate Condensed with cyaniline, ureaFifteen(Scheme 6) can be prepared.   The pharmaceutically acceptable salt of the compound of formula (I) can be prepared by known methods, for example, It may be obtained by treating with an appropriate amount of an acid or base in the presence of a suitable solvent. .   Many of aryl halides to aryl cyano derivatives using copper (I) cyanide The conversion has been announced. However, on the aryl ring where the hydroxy group is present No examples were described. Obtain cyanophenol groups with published results Some attempts to do so have failed. 170 as 180-210 ° Using known conditions at elevated temperatures above ℃, substitution of halogen for cyano groups does not occur. won. In addition, standard bases such as DMF and pyridine do not give the desired products. Was not. 2-amino-5-fluorophenol, 2-nitro-5-fluoro Intermediates such as phenol and 2-nitro-5-methyl-6-bromophenol are With the change of halogen from nitrogen to chlorine or bromine, and copper (I) cyanide Attempted with the use of 2-Nitro-5-methine together with dimethylformamide Using a bromine derivative such as tyl-6-bromophenol, at low temperatures, i.e. <1. At 00 ° C, preferably 60 to about 80 ° C, in a shorter time than standard methods, That is, in <18 hours, preferably in about 4-6 hours, a catalytic amount of dimethylaminopyri Using triethylamine with gin and copper (I) cyanide to give the desired product Obtained.   In the examples, all temperatures are in degrees Celsius (° C). Mass spectra are noted Unless otherwise noted, runs were performed on a VG Zab mass spectrometer using fast atom bombardment.¹H-N MR (hereinafter referred to as “NMR”) spectra were obtained from Bruker AM 250 or A Recording was performed at 250 MHz or 400 MHz using m400, respectively. Predetermined many The singlets are s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. , Br indicate a wide range of signals. Sat. indicates a saturated solution, and the equivalent The ratio of the molar equivalent of the reagent to the ratio is shown.   Flash chromatography is performed on Merck Silica gel 6 0 (230-400 mesh). Synthesis example   It is merely illustrative of the invention and is not intended to limit the scope of the invention. The invention is not described by the following examples. All temperatures are indicated in Celsius And all solvents used herein are of the highest available purity. All reactions are performed under anhydrous conditions in an argon atmosphere unless otherwise noted. General Method A: Synthesis of N-phenyl, N'-phenylurea   Solution of phenyl isocyanate (1.0 equivalent) in dimethylformamide (1 mL) The corresponding aniline (1.0 eq. 8) was added. Complete the reaction mixture at 80 ° C. And the solvent was removed in vacuo. For individual compounds The purification, yield and spectral properties of the product are shown below.                                Example 1 N- (6-hydroxy-4-sulfonylbenzothien-7-yl) -N '-(2- Production of (bromophenyl) urea   N- (6-hydroxy-4-sulfonylbenzothien-7-yl) -N '-(2- Bromophenyl) urea is converted to 1-amino-6-hydroxy-4-sulfonylbenzothi En-7-yl (Feiser, LF Kennelly, RC J. Am. Chem. Soc. 1937, 37) , 1611, 48.5 mg), triethylamine (1 equivalent, 27 μL) and 2-bromo From mophenyl isocyanate (1 equivalent, 24 μL), according to the method of General Method A Prepared. The product was partitioned between methylene chloride and water. Separate the organic layer, Dried over sodium acid. The solid was filtered and the filtrate was concentrated under vacuum. Reverse the residue Purified by layer chromatography (10 mg, 11%). EI-MS m / z 443 (M + H)⁺.                                Example 2 N-7- (8-hydroxy 1-phenyl 2,3,4,5-tetrahydro 1H3-benzazepine) -N ', N "-(2-bromophenyl) diurea a) 7-amino 8-hydroxy 1-phenyl 2,3,4,5-tetrahydride (B) Production of 1H3-benzazepine   7-nitro 8-hydroxy 1-phenyl 2,3,4,5-tetrahydro 1H3-Benzazepine (Example 9, US 4,327,023, 7.0 g) was converted to Me Treated with HCl in OH. This was then combined with 10% Pd / C (2.0 g) and Parr The reaction was carried out under hydrogen for 2 hours. The reaction mixture was filtered through celite. Filtrate Was adjusted to pH 3 and concentrated under vacuum to a volume of 50 mL. Add ether, The title compound crystallized out on cooling (3.83 g, 63%). Melting point (227-229 ° C). b) N-7- (8-hydroxy 1-phenyl 2,3,4,5-tetrahydro Production of 1H3-benzazepine) -N ', N "-(2-bromophenyl) diurea   N-7- (8-hydroxy 1-phenyl 2,3,4,5-tetrahydro 1H3-benzazepine) -N ′, N ″-(2-bromophenyl) diurea was converted to 7- Amino 8-hydroxy 1-phenyl 2,3,4,5-tetrahydro 1H 3-benzazepine hydrochloride (51 mg), triethylamine (2 equivalents, 39 μL) and And the method of General Method A from 2-bromophenyl isocyanate (2 equivalents, 34 μL) To Therefore manufactured. The product was diluted with methylene chloride and precipitated with hexane (1 5 mg, 52%). EI-MSm / z649 (M + H)⁺.                                Example 3 N- [1-[[(2-bromophenyl) amino] carbonyl] -4-hydroxybe Preparation of Nzimidazol-5-yl] -N '-[2-bromophenyl] urea a) Preparation of 2-hydroxybenzimidazole   2,3-Diaminophenol (2.00 g, 16.13 mmol) in formic acid (25 (0 ml) was refluxed under argon until completion. The solvent was evaporated and the resulting solid The product was chromatographed on silica gel (5% MeOH / CH_TwoCl_Two) (2.00 g, 93%).¹HNMR (CD_ThreeOD): δ 8.38 (s , 1H), 7.15 (m, 2H), 6.71 (d, 1H). b) Preparation of 2-hydroxy-3-nitrobenzimidazole   2-hydroxybenzimidazole (1.00 g, 7.50 mmol) was added to Dissolve in styrene (40 ml) and then sodium nitrate (0.7 g, 8.30 mm ol) was added. Then, sulfuric acid (7.5 ml / 3 M) was added, followed by a catalytic amount. Sodium nitrate was added. The mixture was stirred. After 24 hours, the reaction mixture was Dilute with methylene and extract with water. Organic layer_FourDried on and filtered . The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% Me OH / CH_TwoCl_Two) To give the desired product (700 mg, 52%).¹HNM R (CD3COCD_Three): Δ 8.29 (s, 1H), 8.12 dd, 1H), 6.8 2 (d, 1H). c) Preparation of 2-hydroxy-3-aminobenzimidazole   2-hydroxy-3-nitrobenzimidazole (700 mg, 3.90 mm ol) in methanol (50 ml) was added 10% Pd / C (1 g). Mixed The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 minutes. The hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite, Celite was washed with methanol. Evaporate the solvent and filter the resulting solid on silica gel. Upper Chromatography (10% MeOH / CH_TwoCl_Two) To give the desired product ( 500 mg, 86%). d) N- [1-[[(2-bromophenyl) amino] carbonyl] -4-hydroxy Production of Benzimidazol-5-yl] -N '-[2-bromophenyl] urea   N- [1-[[(2-bromophenyl) amino] carbonyl] -4-hydroxybe Nsimidazol-5-yl] -N '-[2-bromophenyl] urea was converted to 2- From droxy-3-aminobenzimidazole (60 mg, 0.40 mmol) Prepared according to the method of General Method A. The product was obtained on solid silica gel. Purify by chromatography (30% EtOAc / hexane) to give the desired product. (300 mg, 84.5%).¹HNMR (CD_ThreeCl): δ 7.95 (d, 1H) , 7.91 (d, 1H), 7.57 (dd, 2H), 7.47 (d, 1H), 7.39 ( dd, 1H), 7.05 (s, 1H), 6.95 (dd, 2H), 6.78 (d, 1H) ). Method of treatment   Monocytes and / or macros, without limitation, in humans or other mammals Excessive or unregulated IL-8 cytokine production by the mammalian cells, such as phage IL-8α or β receptors, also referred to as raw or type I or type II receptors Prophylaxis for conditions aggravated or caused by other chemokines that bind to Or in the manufacture of a medicament for therapeutic treatment, a compound of formula (I) or Its pharmaceutically acceptable salts can be used.   Thus, the present invention provides that chemokines bind to IL-8α or β receptors. A method for treating a chemokine-mediated disease, comprising the compound represented by formula (I) or (II): A therapeutic method comprising administering an effective amount of a substance or a pharmaceutically acceptable salt thereof. To offer. In particular, chemokines include IL-8, GROα, GROβ, GR Oγ, NAP-2 or ENA-78.   Compounds of formula (I) have cytokine function, especially IL-8, GROα, G Injected in amounts sufficient to inhibit ROβ, GROγ, NAP-2 or ENA-78. Consequently, their cytokine function is reduced to normal levels of physiological function. In some cases, it is biologically down-regulated to subnormal levels, Improve medical condition. For example, in the context of the present invention, IL-8, GROα, GRO Abnormal levels of β, GROγ or NAP-2 are: (i) 1 picogram per ml Free IL-8 levels above; (ii) cell-bound I higher than normal physiological levels L-8, GROα, GROβ, GROγ or NAP-2; or (iii) IL- 8. Cells or tissues producing GROα, GROβ, GROγ or NAP-2 In each, IL-8, GROα, GROβ, GROγ, or Constitutes the existence of NAP-2.   Excessive or unregulated IL-8 production is associated with worsening and / or onset of the disease There are many medical conditions that may be considered. Chemokine-mediated diseases include psoriasis, Eczema, arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory Bowel disease, Crohn's disease, ulcerative colitis, seizures, septic shock, endotoxin Shock, gram-negative sepsis, toxic shock syndrome, heart and kidney reperfusion Flow injury, glomerulonephritis, thrombosis, graft-versus-host reaction, Alzheimer's disease, allogeneic Graft rejection, malaria, restenosis, angiogenesis or unwanted hematopoietic stem cell release Out.   These diseases are primarily massive neutrophil infiltration, T-cell infiltration, or angiogenesis Characterized by proliferation, chemotaxis or endothelial cell orientation of neutrophils to sites of inflammation Increased IL-8, GROα, GROβ, GROγ or NA responsible for proliferation It is associated with P-2 production. Other inflammatory cytokines (IL-1, TNF, and And IL-6), in contrast to IL-8, GROα, GROβ, GROγ or N AP-2 is neutrophil chemotaxis, enzyme release including but not limited to elastase release, And has the unique property of promoting peroxide production and activation. Α-chemokines acting through IL-8 type I or type II receptors, in particular GROα, GROβ, GROγ or NAP-2 promote directional proliferation of endothelial cells By proceeding, tumor angiogenesis can be promoted. Therefore, IL- Inhibition of 8-induced chemotaxis or activation leads to a direct decrease in neutrophil infiltration.   Recent evidence also implicates the role of chemokines in the treatment of HIV infection. It indicates that Littleman et al., Nature 381, pp. 661 (1996) and K oupet al., Nature 381, pp. 667 (1996).   The present invention also provides a chemokine receptor antagonist compound represented by the formula (I) Means for treating CNS injury in acute sclerosis and susceptibility to CNS injury It also provides a means of preventing said CNS damage in a given individual.   CNS injury as defined herein refers to an open or penetrating head Includes both injuries or non-open head injuries, such as due to head injuries. Especially to the brain Also, ischemic stroke is included within the scope of this definition.   Ischemic stroke is usually the result of a local atheromatous closure of an embolus, thrombus or blood vessel Defined as focal neuropathy caused by inadequate blood supply to a specific brain . The role of inflammatory cytokines in this field is becoming evident and Ming provides an effective method of treating these injuries. Steep like these For sexual injuries, relatively few treatments are available.   TNF-α is a cytokine that has pro-inflammatory effects, including endothelial leukocyte adhesion molecule expression. It is. Leukocytes infiltrate into ischemic brain lesions and thus inhibit TNF Compounds that reduce or reduce the levels thereof are useful for treating ischemic brain injury. Liuet al., Stoke, Vol. 25, No. 7, pp 1481-88 (1994) (cited See).   A model of non-open head injury and treatment with a mixed 5-LO / CO agent is described in Shoham i et al., J. Amer. of Vaisc & Clinical Physiology and Pharmacology, Vol. 3, No . 2, pp. 99-107 (1992), which is incorporated herein by reference. You. Treatments that reduce edema formation improve functional outcome in these treated animals It turned out to be.   Compounds of formula (I) have been demonstrated by reduced neutrophil chemotaxis and activation. Thus, IL-8 that binds to IL-8 alpha or beta receptor It is administered in an amount sufficient to inhibit binding to these receptors. Formula (I) The finding that the compound represented by is an inhibitor of IL-8 is described in the present specification. Of the compound of formula (I) in an in vitro receptor binding assay It is based on The compounds of the formula (I) have one receptor, type II only. Is an inhibitor.   As used herein, “IL-8 mediated disease or condition” refers to IL-8, GR By the production of Oα, GROβ, GROγ, NAP-2 or ENA-78 itself, Alternatively, another monokine such as, but not limited to, IL-1, IL-6 or TNF. IL-8, GROα, GROβ, GROγ, NAP-2 or ENA to be released By -78, IL-8, GROα, GROβ, GROγ, NAP-2 or E Represents all conditions in which NA-78 plays a role. Thus, for example, IL-1 Is a major factor, whose production or action is exacerbated in response to IL-8 or The pathology secreted may be a pathology mediated by IL-8.   As used herein, the term "chemokine-mediated disease or condition" is defined as limiting. Not IL-8, GROα, GROβ, GROγ, NAP-2 or ENA Chemokines that bind to IL-8α or β receptors such as -78 play a role Represents all medical conditions. This may be due to the production of IL-8 itself, or I but not releasing another monokine such as IL-1, IL-6 or TNF L-8 includes conditions in which IL-8 plays a role. So, for example, , IL-1 is a major factor whose production or action is exacerbated in response to IL-8. The pathology that is caused or secreted can be a pathology mediated by IL-8.   As used herein, the term “cytokine” affects the function of a cell. Regulates cell-cell interactions in immune, inflammatory or hematopoietic responses Represents a secreted polypeptide that is a molecule. Examples of the cytokine include, but are not limited to, Monokine and lymphokine are listed, regardless of which cells produce them Can be For example, monokines are commonly used for macrophages and / or monocytes. It is said to be produced and secreted by mononuclear cells. However, Nach Ralkiller cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow Many other cells, such as stromal cells, epidermal keratinocytes and B-lymphocytes, are also Produces monokine. Lymphokines are generally produced by lymphocytes It is said that. Examples of cytokines include, but are not limited to, interleukin In -1 (IL-1), interleukin-6 (IL-6), interleukin-8 (I L-8), tumor necrosis factor-alpha (TNF-α) and tumor necrosis factor beta (T NF-β).   As used herein, the term “chemokine” refers to any of the above “cytokines”. Affects the functioning of cells, as well as immune, inflammatory or hematopoietic responses. In the following, the term refers to secreted polypeptides that are molecules that regulate interactions between cells. Ke Mokines are mainly secreted via cell transmembrane and specific leukocytes And leukocytes, neutrophils, monocytes, macrophages, T-cells, B-cells, endothelial cells And results in chemotaxis and activation of smooth muscle cells. Examples of chemokines include Although not specified, IL-8, GRO-α, GRO-β, GRO-γ, NAP-2, ENA-78, IP-10, MIP-1α, MIP-β, PF4 and MCP 1, 2 and 3.   Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in therapy. Is usually formulated into a pharmaceutical composition according to standard pharmaceutical practices. Will be. Accordingly, the present invention provides an effective non-toxic amount of a compound of formula (I) And a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent. .   A compound represented by the formula (I), a pharmaceutically acceptable salt thereof and a composition comprising the compound Pharmaceutical compositions may be conveniently administered, for example, by the routes conventionally used for dosing. For example, they are administered orally, topically, parenterally or by inhalation. Compounds of formula (I) Combines the compound of formula (I) with a standard pharmaceutical carrier according to conventional methods. It is administered in a conventional dosage form prepared by mixing. Formula (I) The compound can also be administered in conventional dosages in combination with a second known therapeutically active compound. May be administered. These methods involve mixing the active ingredients depending on the desired preparation, Includes granulation and tableting or dissolution. Pharmaceutically acceptable carrier or diluent form And characteristics will depend on the amount of active ingredient to be incorporated, the route of administration and other well-known variables. It will be appreciated that it is determined by the prime. The carrier (or carriers) Must be "acceptable" in the sense that it is compatible with another ingredient and not harmful to its recipients. I have to.   The pharmaceutical carrier employed can be, for example, solid or liquid. Examples of solid carriers include lactose, clay, sucrose, talc, gelatin, cold Heaven, pectin, gum arabic, magnesium stearate, stearic acid, etc. I can do it. Examples of liquid carriers include syrup, peanut oil, olive oil, water and the like. I can do it. Similarly, the carrier or diluent may be used alone or with the wax. Well known in the art, such as glyceryl nostearate or glyceryl distearate May be included.   Various pharmaceutical forms can be used. Therefore, when using a solid carrier, The preparation can be tableted or hard gelatin capsules in powder or pellet form Or it can be in the form of a troche or lozenge. solid The amount of carrier will vary widely but, preferably, will be from about 25 mg to about 1 g. Would. If a liquid carrier is used, the preparation may be a syrup, emulsion, soft gelatin capsule, It may be in the form of a sterile injectable solution such as a liquid, ampoule or non-aqueous liquid suspension.   The compounds of formula (I) can be administered topically, that is, by non-systemic administration. Wear. This includes external application of the compound of formula (I) to the epidermis or oral cavity And inhalation of the compound into the ear, eye and nose, such that the compound is Does not enter the bloodstream significantly. In contrast, systemic administration is oral, intravenous , Represents intraperitoneal and intramuscular administration.   Formulations suitable for topical administration include liniments, lotions, creams Suitable for penetrating skin through inflammation sites such as skin preparations, ointments or pastes Liquid or semi-liquid preparation and drops suitable for administration to the eye, ear or nose Is mentioned. The active ingredient may range from 0.001% to 1% by weight of the formulation for topical administration. 0% w / w, for example 1% to 2%. However, 10% w / w, but preferably less than 5% w / w, more preferably 0.1% w / w. 1% to 1% w / w is contained.   Lotions according to the present invention are suitable for application to the skin or eyes Is mentioned. Eye lotions are sterile and may optionally contain a bactericide It is composed of an aqueous solution and is prepared by a method similar to the method of preparing drops. Apply to skin Lotion or liniment for alcohol or acetone Agent to dry and cool skin and / or moisturizer or castor such as glycerol Oils such as oil or peanut oil may be included.   The cream, ointment or paste according to the present invention is a semi-solid active ingredient for external use. It is a body preparation. They are based on oily or non-oily bases and with the aid of suitable machinery Finely divided or powdered, alone or in solution or suspension in aqueous or non-aqueous liquids It is prepared by mixing the active ingredient in the active form. The base is a solid paraffin. Charcoal such as wax, soft or liquid paraffin, glycerol, beeswax, metal soap, etc. Hydrogen hydride; Demulcent; Tonsil oil, corn oil, peanut oil, castor oil or olive Oils of natural materials such as oil; wool fat or its derivatives or propylene glycol Or stearic acid or oleic acid with alcohol such as macro gel Consisting of fatty acids. The preparation comprises sorbitan ester or its polyoxyethylene. Suitable interfaces such as anionic, cationic or nonionic surfactants An active agent may be included. Suspending agents such as natural gums, cellulose derivatives, or Including inorganic substances such as silica-containing silica, and other components such as lanolin Is also good.   Drops according to the present invention may comprise a sterile aqueous or oily solution or suspension. Often, fungicides and / or fungicides and / or other suitable preservatives are preferred. Preferably, the active ingredient is dissolved in a suitable aqueous solution containing a surfactant. Can be prepared. The resulting solution was then clarified by filtration and transferred to a suitable container. Then sealed and autoclaved or maintained at 98-100 ° C for 1.5 hours Sterilize by doing. Alternatively, the solution is sterilized by filtration and sterile techniques are used. It may be transferred to a container. Fungicides and fungicides suitable for inclusion in the drops Examples of such agents include phenylmercuric nitrate or phenylmercuric acetate (0.002%), Benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%) were listed. I can do it. Suitable solvents for the preparation of an oily solution include glycerol, diluted And propylene glycol.   The compounds of formula (I) can be administered parenterally, ie, intravenously, intramuscularly. , Administered by subcutaneous, intranasal, rectal, vaginal or intraperitoneal administration You may. Subcutaneous and intramuscular forms of parenteral administration are generally preferred. Take Suitable dosage forms for administration can be prepared by conventional techniques. Represented by formula (I) Compounds also can be administered by inhalation, i.e., intranasal inhalation administration and oral inhalation administration. May be administered. Such injections as aerosol preparations or metered inhalers Suitable dosage forms for administration can be prepared by conventional techniques.   All uses described herein for the compounds of formula (I) are described. The daily oral administration policy is preferably about 0.01 to about 8 / kg of total body weight. 0 mg. The daily parenteral administration policy is from about 0.001 to about 80 mg. The daily topical administration policy is preferably 0.1 mg to 150 mg. Yes, administered 1 to 4 times, preferably 2 or 3 times a day. The daily inhalation administration policy is Preferably about 0.01 mg / kg to about 1 mg / kg per day. formula( Optimum amounts and individual doses for individual administration of a compound of formula I) or a pharmaceutically acceptable salt thereof. And the interval will depend on the nature and extent of the condition being treated, the mode of administration, route and site, As well as determined by the particular patient being treated, and such optimal values It will also be appreciated by those skilled in the art that such determinations can be made by conventional techniques. The optimal treatment method, i.e. the formula (I) administered per day for a predetermined number of days, The number of doses of the compound to be administered or a pharmaceutically acceptable salt thereof depends on routine treatment methods. It can be confirmed by those skilled in the art using a fixed test.   The present invention is described with reference to the following biological examples, which are merely illustrative. It is not intended to limit the scope of the invention.Biological examples   The IL-8 and GRO-α chemo of the compound of the present invention were determined by the following in vitro assay. The inhibitory effect of Caine was determined. Receptor binding assay:   Amersham Corp. Specific activity 2000 Ci / mmol from (Arlington Heights, IL) With [¹²⁵[I] IL-8 (human recombinant) was obtained. GRO-α is NEN-N ew Obtained from England Nuclear. All other chemicals are for analysis. Was. High levels of recombinant human IL-8α and β-type receptors have been disclosed previously (Holme s, et al., Science, 1991, 253, 1278). Expressed in the vesicle. Homogenization buffer was added to 10 mM Tris-HCl, 1 mM MgSO_Four0.5 mM EDTA (ethylene-diaminetetraacetic acid), 1 mM P MSF (α-toluenesulfonyl fluoride), 0.5 mg / L leupeptin, pH The Chinese hamster ovary membrane was previously disclosed except that it was replaced by 7.5. Protocol (Haour et al., J Biol Chem., 249 pp. 2195-2205 (1974)). Was homogenized. Using Pierce Co.'s micro-assay kit, Membrane protein concentration was determined using bovine serum albumin as a feed. All Assays were performed in a 96-well microplate format. Each reaction mixture Is 1.2 mM MgSO_Four0.1 mM EDTA, 25 mM NaCl and 0 mM 20 mM Bis-Tris propane containing 0.03% CHAPS and 0.4 mM T in risHCl buffer¹²⁵IIL-8 (0.25 nM) or¹²⁵I GRO-α and And 0.5 μg / mL IL-8Rα or 1.0 μg / mL IL-8Rβ membrane. I had. Further, the drug or compound of interest has a final concentration of 0.01 nM to 1 nM. It was dissolved in DMSO in advance so as to have a concentration of 00 μM and added. The assay is¹²⁵ Started by the addition of I-IL-8. After 1 hour at room temperature, 1% polyethyleneimine / Tomtec 96-well on glass fiber filter mat blocked with 0.5% BSA The plate is harvested using a luharvester and 25 mM NaCl, 10 mM Tris HCl, 1 mM MgSO_Four, 0.5 mM EDTA, 0.03% CHAPS, Washed three times at pH 7.4. The filter was then dried and the beta plate ( (Betaplate) liquid scintillation counter. Recombinant IL-8Rα Or type I receptor, also referred to as non-permissive receptor, is a recombinant IL-8R Beta or type II receptors are also referred to as permissive receptors.   In the present specification, the synthetic chemistry section is represented by the formula (I) exemplified in Examples 1 to 3. The compounds used are about 30 to about <1 in a permissive model of IL-8 receptor inhibition. μg / mL IC₅₀showed that. Chemotaxis assay   The in vitro inhibitory properties of these compounds are described in Current Protocols in Immunology, v. ol I, Suppl 1, Unit 6.12.3. (cited in this description) Neutrophil chemotaxis assay. Current Protocols in Immunolog y Vol I, Suppl 1 Unit 7.23.1 (cited and described in this specification) Neutrophils were isolated from human blood as described. Chemoattractant IL-8, GRO-α , GRO-β, GRO-γ and NAP-2 at a concentration of 0.1-100 nM for 48 hours. Place in the lower chamber of multi-well chamber (Neuro Probe, Cabin John, MD) Good. The two chambers are separated by a 5 μm polycarbonate filter . When testing the compounds of the present invention, they are compared to cells (0.001-1000 nM). Mix immediately before adding the cells to the upper chamber. 5% CO_TwoHumidification with Incubation at about 37 ° C for about 45 to 90 minutes in a sealed incubator. Perform After the incubation period, remove the polycarbonate membrane and Wash, Diff Quick staining protocol (Baxter Products, McGaw Park, IL, USA) The membrane was stained using. Cells that showed chemotaxis to chemokines were examined using a microscope. Visibly counted. In general, four areas were counted for each sample and these Average the numbers to get the average number of cells that migrated. Each sample is tested in triplicate and The compound is repeated at least four times. For certain cells (positive control cells) Without any addition, these cells show the maximal chemotactic response of the cells. Negative control (stimulus Is not added, no chemokine is added to the lower chamber. Differences between positive and negative controls indicate chemotactic activity of the cells. Elastase release assay:   The compounds of the present invention were tested for their ability to prevent elastase release from human neutrophils. Test. Neutrophils, Current Protocols in Ilnmunology Vol I, Suppl 1 Unit 7 Isolated from human blood as disclosed in .23.1. Ringer's solution (NaCl 118, KCl 4.56, NaHCO_Three  25, KH_TwoPO_Four1.03, glucose 11.1, PMN 0.88 x 10 suspended in HEPES 5 mM, pH 7.4)⁶Fine 50 cells μl was placed in each well of a 96-well plate. The test compound ( 0.001-1000 nM) in a volume of 50 μl and cytochalasin B in a volume of 50 μl. (20 μg / ml) and Ringer's buffer in a volume of 50 μl. these After warming the cells for 5 minutes (37 ° C, 5% CO_Two, 95% RH), IL-8, GRO α, GROβ, GROγ or NAP-2 at a final concentration of 0.01-1000 nM Was added. After performing the reaction for 45 minutes, the 96-well plate was centrifuged (80 0 × g, 5 minutes) and remove 100 μl of supernatant. This supernatant was used for the second 96 wells. Rate and then dissolved in phosphate buffered saline to a final concentration of 6 μg / Ml until an artificial elastase substrate (MeOSuc-Ala-Ala-Pro -Val-AMC, Nova Biochem, La Jolla, C) is added. Immediately the plate Fluorescent 96-well plate reader (Cytofluor 2350, Millipore, Bedford, MA) Nakajima et al J. Biol Chem2543 minutes according to the method of 4027 (1979) Collect data every time. The amount of elastase released from PMN was determined by MeOS By measuring the rate of uc-Ala-Ala-Pro-Val-AMC decomposition Is calculated. TNF-α in traumatic brain injury assay   This assay allows for lateral fluid-percussion in rats Tumor necrosis factor mR in specific brain regions that experimentally induced traumatic brain injury (TBI) Experiments on the expression of NA are performed. Adult Sprague-Dawley rats (n = 42) Anesthetized with sodium barbital (60 mg / kg, i.p.), collected in left temporal parietal cortex Medium (2.4 atm) side liquid impact (n = 18) or "sham" treatment (Anesthesia and surgery without injury, n = 18). 1 hour and 6 hours after injury And 24 hours later the animals are sacrificed by decapitation, the brain is removed and the left (damaged) parietal skin Quality (LC), corresponding region in contralateral right cortex (RC), adjacent to damaged parietal cortex Cortex (LA), corresponding adjacent area in right cortex (RA), left hippocampus (LH) and A right hippocampus (RH) tissue sample is prepared. Isolate total RNA and use Northern blot After hybridization, TNF-α positive control RNA (macrophage = 10 0%). One hour after injury, a significant increase in TNF-α mRNA Were injured hemispheric LH (104 ± 17% of positive control, p compared to sham) <0.05), LC (105 ± 21%, p <0.05) and LA (69 ± 8%, p < 0.01). Six hours after injury, increased TNF-α mRNA expression also Also, LH (46 ± 8%, p <0.05), LC (30 ± 3%, p <0.01) and LA (32 ± 3%, p <0.01), which was observed by 24 hours after injury. Dissipate. In the contralateral hemisphere, the expression of TNF-α mRNA is reduced 1 hour after injury With RH (46 ± 2%, p <0.01), RC (4 ± 3%) and RA (22 ± 8%), Six hours after injury, RH (28 ± 11%), RC (7 ± 5%) and RA (26 ± 6%). %, P <0.05) and does not increase 24 hours after injury. Siam (no damage 6 surgeries in any hemisphere at any time in naive animals) No consistent change in TNF-α mRNA expression was observed in any of the parts. No. These results indicate that TNF-α mRNA transients after lateral sagittal fluid impact brain injury. Indicates that expression is altered in certain brain areas, including those in the intact hemisphere You. TNF-α can induce nerve growth factor (NGF) and activate it Since it can stimulate the release of other cytokines from astrocytes, TNF- This post-traumatic change in α gene expression is associated with an acute response to CNS trauma and Plays an important role in both the regenerative response. CNS damage model for IL-β mRNA   This assay allows for experimental lateral liquid shock traumatic brain injury (TB) in rats. Part of the interleukin-1β (IL-1β) mRNA in specific brain parts of the value of I) Expression is characterized. Adult Sprague-Dawley rats (n = 42) Anesthetized with rubital sodium (60 mg / kg, i.p.) and concentrated in left temporal parietal cortex Medium (2.4 atm) side liquid impact (n = 18) or "sham" treatment (damage Without anesthesia and surgery, n = 18). 1 hour, 6 hours after injury and Twenty-four hours later, animals are sacrificed, brains removed, left (injured) parietal cortex (LC), contralateral Corresponding region (RC) in cortical right cortex, cortex adjacent to damaged parietal cortex (LA) ,right Corresponding adjacent regions (RA), left hippocampus (LH) and right hippocampus (RH) tissues in the cortex Prepare sample. Isolate total RNA and Northern blot hybridization And the amount of brain tissue IL-1β mRNA was loaded on the same gel. Expressed as a percentage of radioactivity of positive macrophage RNA. Brain damage 1 After time, a significant and significant increase in IL-1β mRNA was observed in the injured hemisphere. LC (20.0 ± 0.7% of positive control, n = 6, p <0.05 compared to sham animals ), LH (24.5 ± 0.9%, p <0.05) and LA (21.5 ± 3.1%, p < 0.05) and LC (4.0 ± 0.4%, n = 6, p <6 hours) up to 6 hours after injury. 0.05) and LH (5.0 ± 1.3%, p <0.05). Siamese Or in na ナ イ ve animals, IL-1β mRN No expression of A is observed. These results indicate that after TBI, IL-1β mRNA Shows that transient expression is locally stimulated in specific brain parts. Like IL-1β These local changes in various cytokines play a role after trauma.   All publications, including but not limited to patents and patent applications, cited herein are Citations should be made as if each and every publication was individually and completely described. Will be described in this specification. The above description fully describes the invention including preferred embodiments thereof. Honcho Modifications and improvements of the specific examples described in detail in the specification are within the scope of the following claims. It is. Without further elaboration, those skilled in the art will, using the preceding description, use the It seems to be able to make the most of it. Thus, the examples herein are: It is merely an explanation and does not limit the scope of the present invention in any case. Exclusive The specifics of the invention in which exclusive ownership and privileges are claimed are defined below. .

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Claims (1)

[Claims] 1. Chemokines bind to IL-8α or β receptors in mammals A method of treating a chemokine-mediated condition, comprising: [Where,   X is oxygen or sulfur;   R is an ionizable hydrogen and a functional group having a pKa of 10 or less;   R₁Is independently hydrogen; halogen; nitro; cyano; halo-substituted C_1-10Archi Le; C_1-10Alkyl; C_2-10Alkenyl; C_1-10Alkoxy; halo-substituted C_1-10A Lucoxy; azide; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4Al Kill; aryl; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Al Heteroaryl; Heteroarylalkyl; Heterocycle, Heterocycle C_1-4 Alkyl; heteroaryl C_1-4Alkyloxy; aryl C_2-10Alkenyl; Heteroaryl C_2-10Alkenyl; heterocyclic C_2-10Alkenyl; (CR₈R₈)_qNR_FourR_FiveC_2-10Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_TenS (O)_ThreeH; S (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁; C_2-10Alkenyl C (O) OR₁₁(CR₈R₈)_qC (O) OR₁₂; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁, (CR₈R₈)_qNHS (O)_TwoR₁₇, (CR₈R₈)_qS (O)_TwoNR_FourR_FiveSelected from; Or two R₁The groups together form O- (CH_Two)_sO- or a 5- to 6-membered unsaturated ring May be formed;   q is 0 or an integer having a value from 1 to 10;   t is 0 or an integer having a value of 1 or 2;   s is an integer having a value from 1 to 3;   R_FourAnd R_FiveIs independently hydrogen, optionally substituted C_1-4Alkyl, place Optionally substituted aryl, optionally substituted aryl C_1-4Alkyl, Optionally substituted heteroaryl, optionally substituted heteroaryl C_1-4 Alkyl, heterocycle, heterocycle C_1-4Alkyl or R_FourAnd R_FiveIs Selected from oxygen, nitrogen or sulfur, together with the nitrogen to which they are bound Form a 5- to 7-membered ring which may contain additional heteroatoms;   m is an integer having a value of 1 to 3;   n is an integer having a value of 1 to 3;   Y is independently hydrogen; halogen; nitro; cyano; halo-substituted C_1-10Alkyl C_1-10Alkyl; C_2-10Alkenyl; C_1-10Alkoxy; halo-substituted C_1-10Al Coxy; azide; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4Archi Aryl; aryl; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Archi Heterooxy; heteroarylalkyl; heteroaryl C_1-4A Alkyloxy; heterocycle, heterocycle C_1-4Alkyl; aryl C_2-10Alkenyl; f Teloaryl C_2-10Alkenyl; heterocyclic C_2-10Alkenyl; (CR₈R₈)_qNR_FourR_FiveC_2-10Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_TenS (O)_ThreeH; S (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁; C_2-10Alkenyl C (O) OR₁₁C (O) R₁₁; (CR₈R₈)_qC (O) OR₁₂; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁, (CR₈R₈)_qNHS (O)_TwoR_d, (CR₈R₈)_qS (O)_TwoNR_FourR_FiveSelected from; Or two Y groups are joined together to form O- (CH_Two)_sO- or form a 5- to 6-membered unsaturated ring May be made;   R₆And R₇Is independently hydrogen or C_1-4An alkyl group, or R₆And R₇Is, together with the nitrogen to which they are attached, oxygen, nitrogen or Forming a 5- to 7-membered ring which may contain additional heteroatoms selected from sulfur And;   R₈Is independently hydrogen or C_1-4Selected from alkyl;   R_TenIs C_1-10Alkyl C (O)_TwoR₈Is;   R₁₁Is hydrogen, C_1-4Alkyl, optionally substituted aryl, substituted Optional aryl C_1-4Alkyl, optionally substituted heteroaryl, Optionally substituted heteroaryl C_1-4Alkyl, optionally substituted complex A ring or an optionally substituted heterocyclic C_1-4Alkyl;   R₁₂Is hydrogen, C_1-10Alkyl, optionally substituted aryl or substituted Arylalkyl which may be substituted;   R₁₃And R₁₄Is independently hydrogen or C_1-4Alkyl;   R₁₇Is C_1-4Alkyl, aryl, arylalkyl, heteroaryl, f Teloaryl C_1-4Alkyl, heterocycle, or heterocycle C_1-4Alkyl here Wherein the aryl, heteroaryl and heterocycle are all optionally substituted;   v is 0 or an integer having a value from 1 to 4;   R_dIs NR₆R₇, Alkyl, aryl C_1-4Alkyl, aryl C_2-4Arche Nil, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_2-4A Lucenyl, heterocycle, heterocycle C_1-4Alkyl, where aryl, heteroa All of the reels and heterocycles may be substituted;   Z is (Where the asterisk * indicates the bonding position of the ring); E is optionally (Asterisk * indicates the bonding position of the ring)] Is administered to the mammal an effective amount of the compound represented by or a pharmaceutically acceptable salt thereof. A method that includes: 2. The method of claim 1 wherein the ionizable hydrogen has a pKa of 3-10. 3. R is hydroxy, carboxylic acid, thiol, -SR_Two, -OR_Two, -NH- C (O) R_a, -C (O) NR₆R₇, -NHS (O)_TwoR_b, -S (O)_TwoNHR_c, NHC ( X_Two) NHR_bOr tetrazolyl; [Where R_TwoIs a substituted aryl, heteroaryl or heterocycle, wherein the ring is Containing a functional group providing an ionizable hydrogen having a pKa of 10 or less ;   R_aIs an alkyl, aryl, aryl C_1-4Alkyl, heteroaryl, hete Lower aryl C_1-4Alkyl, heterocycle, or heterocycle C_1-4An alkyl group, May all be substituted;   R_bIs NR₆R₇, Alkyl, aryl, aryl C_1-4Alkyl, aryl C_2-4 Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl Le C_2-4Alkenyl, heterocycle, heterocycle C_1-4Alkyl, heterocyclic C_2-4Alkenyl group , Camphor, all of which are halogen; nitro; halo-substituted C_1-4Al Kill; C_1-4Alkyl; C_1-4Alkoxy; NR₉C (O) R_aC (O) NR₆R₇, S (O)_ThreeH or C (O) OC_1-4Even if independently substituted 1 to 3 times by alkyl Often;   R₉Is hydrogen or C_1-4Alkyl;   R_cIs an alkyl, aryl, aryl C_1-4Alkyl, aryl C_2-4Arche Nil, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_2-4A Lucenyl, heterocycle, heterocycle C_1-4Alkyl or heterocyclic C_2-4Alkenyl group , All of which are halogen, nitro, halo substituted C_1-4Alkyl, C_1-4Archi Le, C_1-4Alkoxy, NR₉C (O) R_a, C (O) NR₆R₇, S (O)_ThreeH or C ( O) OC_1-4May be independently substituted 1-3 times with alkyl;   X_TwoIs oxygen or sulfur The method of claim 2, wherein 4. R_TwoIs halogen, nitro, halo substituted C_1-10Alkyl, C_1-10Alkyl, C_1-10Alkoxy, hydroxy, SH, -C (O) NR₆R₇, -NH-C (O) R_a , -NHS (O)_TwoR_b, S (O) NR₆R₇, C (O) OR₈Or by a tetrazolyl ring The method according to claim 3, which may be substituted 1 to 3 times. 5. R is OH, -NHS (O)_TwoR_bOr C (O) OH. Law. 6. R₁Is halogen, cyano, nitro, CF_Three, C (O) NR_FourR_Five, Alkenyl C (O) NR_FourR_Five, C (O) R_FourR_Ten, Alkenyl C (O) OR₁₂, Heteroaryl, Heteroarylalkyl, heteroarylalkenyl or S (O) NR_FourR_FiveIn The method according to claim 1. 7. Y is halogen, C_1-4Alkoxy, optionally substituted aryl, substituted Optionally substituted arylalkoxy, methylenedioxy, NR_FourR_Five, Thio C_1-4 Alkyl, thioaryl, halo-substituted alkoxy, optionally substituted C_1-4 The method according to claim 1, which is alkyl or hydroxyalkyl. 8. R is OH, SH or NHS (O)_TwoR_bAnd R₁Is due to the electron withdrawing group. 3. The compound of claim 1, wherein the compound is substituted at the 3- and 4-positions or di-substituted at the 3- and 4-positions. The method described. 9. If the mammal has psoriasis, or atopic dermatitis, asthma, chronic obstructive pulmonary disease, Adult respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, sepsis Symptomatic shock, endotoxin shock, gram-negative sepsis, toxic shock Syndrome, seizures, heart and kidney reperfusion injury, glomerulonephritis, or thrombosis, Selected from Zuheimer's disease, graft-versus-host reaction, or allograft rejection 9. The method according to any one of claims 1 to 8, wherein the method is afflicted with a chemokine-mediated disease. . 10. formula: [Where,   X is oxygen or sulfur;   R is an ionizable hydrogen and a functional group having a pKa of 10 or less;   R₁Is independently hydrogen; halogen; nitro; cyano; halo-substituted C_1-10Archi Le; C_1-10Alkyl; C_2-10Alkenyl; C_1-10Alkoxy; halo-substituted C_1-10A Lucoxy; azide; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4Al Kill; aryl; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Al Heteroaryl; Heteroarylalkyl; Heterocycle, Heterocycle C_1-4 Alkyl; heteroaryl C_1-4Alkyloxy; aryl C_2-10Alkenyl; Heteroaryl C_2-10Alkenyl; heterocyclic C_2-10Alkenyl; (CR₈R₈)_qNR_FourR_FiveC_2-10Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_TenS (O)_ThreeH; S (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁; C_2-10Alkenyl C (O) OR₁₁(CR₈R₈)_qC (O) OR₁₂; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁, (CR₈R₈)_qNHS (O)_TwoR₁₇, (CR₈R₈)_qS (O)_TwoNR_FourR_FiveSelected from; Or two R₁The groups together form O- (CH_Two)_sO- or a 5- to 6-membered unsaturated ring May be formed;   q is 0 or an integer having a value from 1 to 10;   t is 0 or an integer having a value of 1 or 2;   s is an integer having a value from 1 to 3;   R_FourAnd R_FiveIs independently hydrogen, optionally substituted C_1-4Alkyl, place Optionally substituted aryl, optionally substituted aryl C_1-4Alkyl, Optionally substituted heteroaryl, optionally substituted heteroaryl C_1-4 Alkyl, heterocycle, heterocycle C_1-4Alkyl or R_FourAnd R_FiveIs Selected from oxygen, nitrogen or sulfur, together with the nitrogen to which they are bound Form a 5- to 7-membered ring which may contain additional heteroatoms;   m is an integer having a value of 1 to 3;   n is an integer having a value of 1 to 3;   Y is independently hydrogen; halogen; nitro; cyano; halo-substituted C_1-10Alkyl C_1-10Alkyl; C_2-10Alkenyl; C_1-10Alkoxy; halo-substituted C_1-10Al Coxy; azide; (CR₈R₈)_qS (O), R_Four; Hydroxy; hydroxy C_1-4Al Kill; aryl; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Al Kiloxy: heteroaryl; heteroarylalkyl; heteroarylC_1-4 Alkyloxy; heterocycle, heterocycle C_1-4Alkyl; aryl C_2-10Alkenyl; Heteroaryl C_2-10Alkenyl; heterocyclic C_2-10Alkenyl; (CR₈R₈)_qNR_FourR_FiveC_2-10Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_TenS (O)_ThreeH; S (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁; C_2-10Alkenyl C (O) OR₁₁C (O) R₁₁; (CR₈R₈)_qC (O) OR₁₂; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁, (CR₈R₈)_qNHS (O)_TwoR_d, (CR₈R₈)_qS (O)_TwoNR_FourR_FiveSelected from; Or two Y groups are joined together to form O- (CH_Two)_sO- or form a 5- to 6-membered unsaturated ring May be made;   R₆And R₇Is independently hydrogen or C_1-4An alkyl group, or R₆And R₇Is, together with the nitrogen to which they are attached, oxygen, nitrogen or Forming a 5- to 7-membered ring which may contain additional heteroatoms selected from sulfur ;   R₈Is independently hydrogen or C_1-4Selected from alkyl;   R_TenIs C_1-10Alkyl C (O)_TwoR₈Is;   R₁₁Is hydrogen, C_1-4Alkyl, optionally substituted aryl, substituted Optional aryl C_1-4Alkyl, optionally substituted heteroaryl, Optionally substituted heteroaryl C_1-4Alkyl, optionally substituted complex A ring or an optionally substituted heterocyclic C_1-4Alkyl;   R₁₂Is hydrogen, C_1-10Alkyl, optionally substituted aryl or substituted Arylalkyl which may be substituted;   R₁₃And R₁₄Is independently hydrogen or C_1-4Alkyl;   R₁₇Is C_1-4Alkyl, aryl, arylalkyl, heteroaryl, f Teloaryl C_1-4Alkyl, heterocycle, or heterocycle C_1-4Alkyl here Wherein the aryl, heteroaryl and heterocycle are all optionally substituted;   v is 0 or an integer having a value from 1 to 4;   R_dIs NR₆R₇, Alkyl, aryl C_1-4Alkyl, aryl C_2-4Arche Nil, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_2-4A Lucenyl, heterocycle, heterocycle C_1-4Alkyl, where aryl, heteroa All of the reels and heterocycles may be substituted;   Z is (Where the asterisk * indicates the bonding position of the ring); E is optionally (Asterisk * indicates the bonding position of the ring)] Or a pharmaceutically acceptable salt thereof. 11. 11. The compound according to claim 10, wherein the ionizable hydrogen has a pKa of 3 to 10. object. 12. R is hydroxy, carboxylic acid, thiol, -SR_Two, -OR_Two, -NH -C (O) R_a, -C (O) NR₆R₇, -NHS (O)_TwoR_b, -S (O)_TwoNHR_c, NH C (X_Two) NHR_bOr tetrazolyl; [Where R_TwoIs a substituted aryl, heteroaryl or heterocycle, wherein the ring is Containing a functional group providing an ionizable hydrogen having a pKa of 10 or less ;   R_aIs an alkyl, aryl, aryl C_1-4Alkyl, heteroaryl, hete Lower aryl C_1-4Alkyl, heterocycle, or heterocycle C_1-4An alkyl group, May all be substituted;   R_bIs NR₆R₇, Alkyl, aryl, aryl C_1-4Alkyl, aryl C_2-4 Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl Le C_2-4Alkenyl, heterocycle, heterocycle C_1-4Alkyl, heterocyclic C_2-4Alkenyl group , Camphor, all of which are halogen; nitro; halo-substituted C_1-4Al Kill; C_1-4Alkyl; C_1-4Alkoxy; NR₉C (O) R_aC (O) NR₆R₇, S (O)_ThreeH or C (O) OC_1-4Even if independently substituted 1 to 3 times by alkyl Often;   R₉Is hydrogen or C_1-4Alkyl;   R_cIs an alkyl, aryl, aryl C_1-4Alkyl, aryl C_2-4Arche Nil, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_2-4A Lucenyl, heterocycle, heterocycle C_1-4Alkyl or heterocyclic C_2-4Alkenyl group , All of which are halogen, nitro, halo substituted C_1-4Alkyl, C_1-4Archi Le, C_1-4Alkoxy, NR₉C (O) R_a, C (O) NR₆R₇, S (O)_ThreeH or C ( O) OC_1-4May be independently substituted with alkyl 1-3 times;   X_TwoIs oxygen or sulfur The compound according to claim 10, which is 13. R_TwoIs halogen, nitro, halo substituted C_1-10Alkyl, C_1-10Alkyl , C_1-10Alkoxy, hydroxy, SH, -C (O) NR₆R₇, -NH-C (O) R_a , -NHS (O)_TwoR_b, S (O) NR₆R₇, C (O) OR₈Or by a tetrazolyl ring 13. The compound according to claim 12, which may be substituted 1 to 3 times. 14． R is OH, -NHS (O)_TwoR_bOr C (O) OH. Compound. 15. R₁Is halogen, cyano, nitro, CF_Three, C (O) NR_FourR_Five, Alkene Le C (O) NR_FourR_Five, C (O) R_FourR_Ten, Alkenyl C (O) OR₁₂, Heteroaryl , Heteroarylalkyl, heteroarylalkenyl or S (O) NR_FourR_Fiveso A compound according to claim 10. 16. Y is halogen, C_1-4Alkoxy, optionally substituted aryl, Optionally substituted arylalkoxy, methylenedioxy, NR_FourR_Five, Thio C_1-4Alkyl, thioaryl, halo-substituted alkoxy, optionally substituted C_{1 -Four} The compound according to claim 10, which is alkyl or hydroxyalkyl. 17． R is OH, SH or NHS (O)_TwoR_bAnd R₁Becomes an electron withdrawing group 3. The compound of claim 1, further substituted at the 3-, 4-position or di-substituted at the 3,4-position. The compound according to 0. 18. An effective amount and a pharmaceutically effective amount of the compound according to any one of claims 10 to 17. A pharmaceutical composition comprising an acceptable carrier or diluent.