JP2000513359A - IL-8 receptor antagonist - Google Patents

Abstract

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 symbols 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 and ENA-78 As well as pharmaceutical compositions for use in such treatments.   Background of the Invention   Interleukin-8 (IL-8) includes neutrophil attractant / activating protein-1 (NAP-1), monocyte-derived neutrophil chemotactic factor (MDNCF), neutrophil activator Many different names apply, such as (NAF) and T-cell lymphocyte chemotactic factor Have been. Interleukin-8 is a subset of neutrophils, basophils, and T-cells. It is a chemoattractant for the plant. It is TNF, IL-1α, IL-1β Macrophages, fibroblasts, endothelial cells and epithelial cells exposed to LPS or LPS By chemotactic factors such as LPS or FMLP When exposed to neutrophils, it is produced by neutrophils themselves. M. Baggiolini et al.J . Clin. Invest. 84, 1045 (1989); Schroder et al.J . Immunol.139, 3474 (1987) AndJ . Immunol. 144, 2223 (1990); Strieter et al.,Science 243, 1467 (1989) andJ . Biol. Chem. 264, 10621 (1989); Cassatella et al.,J . Immunol. 148, 3 216 (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 129 375 (1986) and Chang et al.J . Immunol.148, 451 (1992). CXC model All of the α-family chemokines with ELR motif immediately before the chief Binds to the IL-8B receptor.   IL-8, Groα, GROβ, GROγ, NAP-2 and ENA-78 Stimulates many functions in vitro. They are all chemoattractants for neutrophils IL-8 and GROα have been shown to have T-lymphocyte and It showed basophil chemotaxis activity. In addition, IL-8 is found in normal individuals and atopic Histamine release from basophils from both individuals can be induced. GR O-α and IL-8 are also responsible for lysosomal enzyme release and Pilate bursts can be triggered. IL-8 is also a de novo protein Surface expression of Mac-1 (CD11b / CD18) on neutrophils without synthesis It was shown to increase. This is due to the increased attachment of neutrophils to vascular endothelial cells. Contribute. Many known diseases are characterized by massive neutrophil infiltration. IL- 8, Groα, GROβ, GROγ and NAP-2 are responsible for neutrophil accumulation and activity. Because they promote sexual development, these chemokines can help reduce dry habits and rheumatoid arthritis. It has been implicated in a wide range of acute and chronic inflammatory diseases, including: Baggiolini et al.FEBS Lett . 307 , 97 (1992); Miller et al.,Crit . Rev. Immunol. 12, 17 (1992); Oppe nheim et al.Annu . Rev. Immunol. 9, 617 (1991); Seitz et al.,J . Clin. Invest. 87 , 463 (1991); Miller et al.,Am . Rev. Respir.Dis. 146, 427 (1992); Donnely et al. ,Lancet 341, 643 (1993). In addition, ELR chemokines (just before the CXC motif) (Containing the amino acid ELR motif) have also been implicated in hemostasis. Stri eter et al., Science 258, 1798 (1992).   In vitro, IL-8, Groα, GROβ, GROγ and NAP-2 Seven-transmembrane, which binds to and receives receptors from the G-protein coupled family By activating the receptors, the IL-8 receptor, most notably the B-receptor, Neutrophil shape change, chemotaxis, granule release and respiratory -Trigger a burst. Thomas et al.J . Biol. Chem. 266, 14839 (1991); And Holmes et al.Science 253, 1278 (1991). For members of this receptor family There are precedents for the development of non-peptide small molecule antagonists. For reconsideration, R. Freid inger in:Progress in Drug Research, Volume 40, Pages 33-98, Birkhauser Verlag See Basel 1993. Thus, the IL-8 receptor is a key to the development of new anti-inflammatory drugs. Promising Represents a goal.   Two high-affinity human IL-8 receptors (77% homology) are characterized as follows: Marked: IL-8Rα, which binds only IL-8 with high affinity, if And GRO-α, GROβ, GROγ and NAP-2. IL-8Rβ with high affinity for. Holmes et al., Supra; Murphy et al.Scienc e 253 , 1280 (1991); Lee et al.,J . Biol. Chem.267, 16283 (1992); LaRosa et al.J . Biol. Chem. 267 , 25402 (1992); and Gayle et al.J . Biol. Chem. 268, 7283 (1993).   Capable of binding to IL-8α or β receptor in the art for therapy There is still a need for compounds. Therefore, IL-8 production (neutrophils and And T-cell subsets are responsible for chemotaxis to inflammatory sites) Possible conditions are what can be achieved with compounds that are inhibitors of IL-8 receptor binding. There will be.   Summary of the Invention   The present invention is a method for treating a chemokine-mediated disease, wherein the chemokine is IL-8. which binds to an α or β receptor, wherein the method is a compound of formula (I) or Provides a therapeutic method comprising administering an effective amount of a pharmaceutically acceptable salt thereof. Things. In particular, the chemokine is IL-8.   The invention also relates to a mammal in need of inhibiting the binding of IL-8 to its receptor. Wherein the effective amount of the compound of formula (I) is To an inhibitory method comprising administering to a subject.   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_Four R_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_2-10 Alkenyl C (O) R₁₁C_2-10Alkenyl C (O) OR₁₁(CR₈R₈)_qC (O) OR_{1 Two} ; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁, (CR₈R₈)_qNH S (O)_TwoR₁₇, (CR₈R₈)_qS (O)_TwoNR_FourR_FiveOr two R₁ The groups together form O- (CH_Two)_sO- or a 5- or 6-membered unsaturated ring may be formed. ;   q is 0 or an integer having a value from 1 to 10;   m is an integer having a value of 1 to 3;   t is 0 or an integer having a value of 1 or 2;   s is an integer having a value from 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;   HET is an optionally substituted heteroaryl group;   R₈Is hydrogen or C_1-4Alkyl;   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, an optionally substituted heterocycle, or an optional 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 May be used);   E is optionally Or May be selected from^*Indicates the bonding position of the ring)] or Is a pharmaceutically acceptable salt of   Detailed description of the invention   Compounds of formula (I) bind to IL-8 or IL-8 α and β receptors Veterinary treatment of non-human mammals that require inhibition of another chemokine You may use it. Chemokine-mediated diseases related to therapeutic or prophylactic treatment of animals Include conditions as described in the methods of treatment section herein. You.   In the compounds of formula (I), R is less than or equal to 10, preferably about 3 to 9, More preferably, the functional group provides an ionizable hydrogen having a pKa of about 3-7. It is preferred that Such functional groups include, but are not limited to, hydroxy, Bonic acid, thiol, -SR_Two, -OR_Two, -NH-C (O) R_a, -C (O) NR₆R₇ , Formula -NHS (O)_TwoR_bA substituted sulfonamide represented by -S (O)_TwoNHR_c, NH C (X_Two) NHR_bOr tetrazolyl; wherein X_TwoIs oxygen or Is sulfur, preferably oxygen. Preferably, the functional group is intact or Or SR_TwoOr OR_TwoAryl, heteroaryl or as in The substituent on the heterocyclic group is other than sulfonic acid. More preferably, R is OH, SH or NHS (O)_TwoR_bIt is. Preferably, R_TwoIs a substituted aryl, A teloaryl or heterocyclic group, wherein the ring is an ion having a pKa of 10 or less. And has a functional group that provides a labile hydrogen.   Preferably, R₆And R₇Is independently hydrogen or C_1-4Is it an alkyl group Or R₆And R₇Together with the nitrogen to which they are attached May contain additional heteroatoms selected from more oxygen, nitrogen or sulfur To form a 5- to 7-membered ring. The heterocycle may be optionally selected as defined herein. It may be more substituted.   Preferably, R_aIs an alkyl, aryl, aryl C_1-4Alkyl, hetero ant , Heteroaryl C_1-4Alkyl, heterocycle, or heterocycle C_1-4With an alkyl group Yes, all of which may be optionally substituted as defined below.   Preferably, 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 halogenated N; nitro; CF_ThreeHalo-substituted C such as_1-4Alkyl; C such as methyl_1-4Al Kill; 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 You may.   Preferably, R_bIs an optionally substituted phenyl, benzyl, Or styryl. R_bIf is a heteroaryl ring, optionally substituted An optionally substituted thiazole, an optionally substituted thienyl, or It is preferably an optionally substituted quinolinyl ring.   Preferably, R₉Is hydrogen or C_1-4Alkyl. Preferably, R₉Is the water Is prime. R_bIs a substituent NR₉C (O) R_aIf R_aIs preferably methyl And an alkyl group such as   Preferably, 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, halo Exchange 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 times independently by alkyl Where R₉Is hydrogen or C_1-4Alkyl. Preferred Or R_cIs phenyl which is optionally substituted.   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 the formula (I), preferably R₁Is independently hydrogen; halo Get Nitro; cyano; CF_ThreeHalo-substituted C such as_1-10Alkyl; methyl, ethyl C, such as, isopropyl, or n-propyl_1-10Alkyl; C_2-10Alkene C; such as methoxy or ethoxy_1-10Alkoxy; trifluoromethoxy Halo-substituted C such as_1-10Alkoxy; azide; (CR₈R₈)_qS (O)_tR_Four(here , T is 0, 1 or 2); hydroxy; of 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_Four R_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_FiveChoose from Or two R₁Together form O- (CH_Two)_sO- or 5-6 members May form an unsaturated ring; s is an integer having a value of 1 to 3. The ally , Arylalkyl, arylalkenyl, heteroaryl, heteroaryl Alkyl, heteroarylalkenyl, heterocycle, heterocyclealkyl, and heterocycle All alkenyl groups can be optionally substituted as defined below. No.   Suitably, q is 0 or an integer having a value between 1 and 10.   R₁Forms a dioxy bond, s is preferably 1. R₁Added When it forms an unsaturated ring, it is a 6-membered ring that gives rise to a naphthylene ring preferable. This naphthylene ring has another R as defined above.₁1-3 times independently depending on the group It may be substituted.   Preferably, R_FourAnd R_FiveIs independently hydrogen, optionally substituted C_1-4Alkyl, optionally substituted aryl, optionally substituted To 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 Together with the nitrogen to which it is attached, an optional additional selected from O / N / S It forms a 5- to 7-membered ring which may contain a hetero atom.   R₈Is preferably independently hydrogen or C_1-4Selected from alkyl.   R_TenIs preferably CH_TwoC (O)_TwoH or CH_TwoC (O)_TwoCH_ThreeSuch as C_1-10A Lucil C (O)_TwoR₈It is.   R₁₁Is preferably hydrogen, C_1-4Alkyl, aryl, aryl C_1-4Alkyl , Heteroaryl, heteroaryl C_1-4Alkyl, heterocycle, or heterocycle C_1-4 Alkyl.   R₁₂Is preferably hydrogen, C_1-10Alkyl, optionally substituted Aryl or optionally substituted arylalkyl.   R₁₇Is preferably C_1-4Alkyl, aryl, arylalkyl, heteroa Reel, heteroaryl C_1-4Alkyl, heterocycle, or heterocycle C_1-4With alkyl Where the aryl, heteroaryl and heterocycle are all optionally substituted It may be replaced.   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-position or di-substituted at the 3- and 4-positions. The substituent is And preferably an electron withdrawing group. Preferably, R is OH, SH or NSO_TwoR_b If R₁Represents 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.   In the compounds of formula (I), preferably R₁₃And R₁₄The water independently A linear or branched C as defined herein._1-4Alkyl V is 0, or an integer having a value of 1-4, preferably when v = 0 is there.   Asterisk(^*The ring E, which is indicated by its bonding position via Good. If not present, the ring is a given R and R₁Is replaced by Nyl group. R₁The group is a saturated or unsaturated ring, including any E ring. An unsaturated substituent containing an R group, which may be substituted for the purposes herein, Indicates that it is substituted only on the nyl ring.   In compounds of formula (I), HET is a heteroaryl ring or ring system. Preferably, there is. When the HET group is polycyclic, the ring containing a heteroatom is Need not be directly attached to the urea moiety. All rings in this ring system are described herein. May be optionally substituted as defined in Preferably, The HET group is pyridyl, 2-, 3- or 4-pyridyl, more preferably Preferable is 3- or 4-pyridyl. When the ring is polycyclic, preferably , Benzimidazole, dibenzothiophene are also or indole rings. Honcho Other heterocycles of interest for use in the textbook include, but are not limited to, thiophene Ring, furan ring or pyridine ring.   In the compound represented by the formula (I), the HET ring is optionally 1 to 3 times depending on Y. [That is, (Y_(n)) (Where n is an integer having a value of 1 to 3)] It may be independently substituted. Y is independently hydrogen; halogen; nitro; Ano; halo-substituted C_1-10Alkyl; C_1-10Alkyl; C_2-10Alkenyl; C_1-10A Lucoxy; halo-substituted C_1-10Alkoxy; azide; (CR₈R₈)_qS (O)_tR_Four; Hydro Xy; hydroxy C_1-4Alkyl; aryl; aryl C_1-4Alkyl; aryl Oxy; aryl C_1-4Alkyloxy; heteroaryl; heteroaryl Alkyl; heteroaryl C_1-4Alkyloxy; heterocycle, heterocycle C_1-4Alkyl; Aryl C_2-10Alkenyl; heteroaryl C_2-10Alkenyl; heterocyclic C_2-10A Lucenyl; (CR₈R₈)_qNR_FourR_FiveC_2-10Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_q C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_TenS (O)_ThreeH; S (O)_ThreeR₈; (C R₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁C_2-10Alkenyl C (O) O R₁₁; (CR₈R₈)_qC (O) OR₁₂; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_Four C (O) R₁₁, (CR₈R₈)_qNHS (O)_TwoR_d, (CR₈R₈)_qS (O)_TwoNR_FourR_FiveChoose from Or two Y groups are taken together to form O- (CH_Two)_sO- or 5-6 members May form an unsaturated ring. When Y forms a dioxy bond, s is preferably Is 1. If Y forms an additional unsaturated ring, it is preferably 5- It is a six-membered ring. Aryl, arylalkyl, arylalkenyl, hete Roaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclic, multiple The prime ring alkyl and the heterocyclic alkenyl groups are all as defined herein. It may be substituted.   Preferably, R_dIs NR₆R₇, Alkyl, aryl C_1-4Alkyl, aryl C_2-4 Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl Le C_1-4Alkenyl, heterocycle, heterocycle C_1-4Alkyl or heterocyclic C_2-4Arche An aryl, arylalkyl, arylalkenyl , Heteroaryl, heteroarylalkyl, heteroarylalkenyl, All of the prime rings and the heterocyclic alkyl and alkenyl groups are defined herein. It may be substituted as defined.   In the compounds of formula (I), X is preferably oxygen or sulfur; Preferably, it is oxygen.   Exemplary compounds of formula (I) include the following:   N- (2-hydroxy-4-nitrophenyl) -N ′-(2-pyridyl) urea,   N- (2-hydroxy-4-nitrophenyl) -N ′-(3-pyridyl) urea,   N- (2-hydroxy-4-nitrophenyl) -N ′-(4-pyridyl) urea,   N- [2-hydroxy-3-cyanophenyl) -N '-[2-chloro-3-pyridi Le] urea ,.   Further compounds within the scope of formula (I) include the following compounds:   N- (2-hydroxy-4-nitrophenyl) -N '-(4-dibenzothiophene )urea,   N- (2-hydroxy-4-nitrophenyl) -N ′-(2-benzimidazole )urea,   N- (2-hydroxy-4-nitrophenyl) -N '-(4-indole) urea.   As used herein, “optionally substituted” is specifically defined. Unless otherwise defined, halogen such as fluorine, chlorine, bromine or iodine; hydroxy; Hydroxy-substituted C_1-10Alkyl; C such as methoxy or ethoxy_1-10Alkoki S; S (O) such as methylthio, methylsulfinyl or methylsulfonyl_{m '}C_1-10 Alkyl, wherein m ′ is 0, 1 or 2; amino, NR_FourR_FiveBase Mono- and disubstituted amino as in NHC (O) R_FourC (O) NR_FourR_Five; C (O) OH; S (O)_TwoNR_FourR_Five; NHS (O)_TwoR₁₅Methyl, ethyl, propyl, C such as isopropyl or t-butyl_1-10Alkyl; CF_ThreeHalo substitutions such as C_1-10Alkyl; optionally substituted aryl such as phenyl, or Or an optionally substituted ant such as benzyl or phenethyl. Arylalkyl, an optionally substituted heterocycle, optionally substituted An optionally substituted heterocyclic alkyl, an optionally substituted heteroaryl, An optionally substituted heteroarylalkyl (wherein A reel, heteroaryl, or heterocyclic group is halogen; hydroxy; hydroxy; Disubstituted alkyl; C_1-10Alkoxy; S (O)_{m '}C_1-10Alkyl; amino, NR_Four R_FiveMono- and disubstituted amino as in a group; C_1-10Alkyl or CF_Three Halo substituted C such as_1-10Which may be substituted once or twice with alkyl) means.   R₁₅Is preferably C_1-4Alkyl, aryl, aryl C_1-4Alkyl, Hete Low aryl, heteroaryl C_1-4Alkyl, heterocycle, or heterocycle C_1-4Al Kill.   Suitable pharmaceutically acceptable salts are well known to those skilled in the art, and include hydrochloric acid, hydrobromic acid , Sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, acetic acid, malic acid, tartar Acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, Basicity of inorganic and organic acids such as salicylic acid, phenylacetic acid and mandelic acid Salts. In addition, pharmaceutically acceptable salts of the compounds of formula (I) A pharmaceutically acceptable cation, for example when the substituent comprises a carboxy group It may be formed by using. Suitable pharmaceutically acceptable cations will be familiar to those skilled in the art. Known, alkaline cation, alkaline earth cation, ammonium cation And quaternary ammonium cations.   The following terms, as used herein, mean the following.   "Halo" is all halogen, 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, i Examples include so-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 a linear or branched group of 2-10 children, 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 " In combinations such as "teroarylalkyl"), but is not limited to Roll, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazoli Nil, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, One or more rings, such as liazole, imidazole, or benzimidazole, 5- containing one or more heteroatoms selected from the group consisting of N, O or S Represents a 10-membered aromatic ring system.   "Heterocycle" (alone or in combination like "heterocyclealkyl" ) Is one or more rings wherein one or more rings are selected from the group consisting of N, O or S Represents a saturated or partially unsaturated 4-10 membered ring system containing a terrorist atom, without limitation But pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran Or imidazolidine.   “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 phrase “forming a ring” is used herein to refer to a naphthylene ring system or a C₆Cycloa Lucenyl, ie hexane or C_FiveCycloalkenyl group, cyclopentene It is meant to form a phenyl group connecting any six membered partially unsaturated rings.   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, a compound having the properties outlined is obtained. Once the urea nucleus is established And other compounds of these formulas have functional groups well known in the art. Manufactured and applied by applying standard techniques for interconversion. scheme Is shown using a compound of formula (I) alone or a particular moiety, simply, For illustrative purposes only.                               Scheme 1   2- The ortho-substituted phenylurea shown in Scheme 1 is prepared using an aprotic solvent (D Commercially available ortho-substituted anilines (Milwa, Wis.) In MF, toluene Aldrich Chemical Co. and the city Optionally substituted heteroaryl isocyanates (WISCO With Aldrich Chemical Company of Milwaukee, N.C. It is manufactured under standard conditions. 1- (RSO_TwoNH)_Two− (NH_Two) Ph is commercial Aprotic solvent (such as methylene chloride or DMF) if not available Commercially available RSO in the presence of a base such as triethylamine or NaH_TwoCorresponds to Cl By treating with 2-phenylenediamine.                                 Scheme 2   a) TBSCl, imide b) Triphosgene, NaHCO_Three  c) RNH_Two  d) Et_ThreeN ・ HF   When used in Scheme 2, R-NH_TwoIs defined as R in formula (I) HET group. Alternatively, as described above in Scheme 2, 2- Hydroxyaniline is dissolved in an aprotic solvent such as DMF in tert (butyl) dimethyl Reagents known in the art, such as lucylyl chloride and imidazole It can be more protected (Scheme 2). The aniline is then converted to sodium bicarbonate. Triphosgene or carbonyldiimidazole in the presence of a base such as lium To form isocyanate 4. Next The isocyanate is then converted to the desired heterocyclic amine which can be purchased commercially. Can be condensed with The protected phenol is then removed from triethylamine fluoride. Deprotection with standard conditions such as borohydride to form urea 5 Wear.                               Scheme 3   When the desired 2-substituted aniline (7-Scheme 3) is not commercially available At 23 ° C. under standard nitration conditions (HNO_ThreeOr BF_FourNO_TwoUnder) , 6-Scheme 3, the corresponding nitro compound can be prepared. Then SnCl in EtOH_Two(Or alternatively, H_Two/ Pd or LiAlH_FourUsing ) To reduce the nitro compound to the corresponding aniline.                                 Scheme 4   The desired 2-aminobenzenethiol (8-Scheme 4) is commercially available Phenylaniline and thiocyanate in the presence of an oxidant (such as bromine) A 2-aminobenzothiazole by reacting with a cation anion. Can be synthesized. The thiazole is then converted to a protic solvent (eg, , EtOH) with a strong base such as NaOH to give the desired 2-aminobenzenethiol (9- 4) can be hydrolyzed.                               Scheme 5 (Where R is HET)   Alternatively, the heterocyclic isocyanate can be prepared using the Curtius rearrangement (dppa And triethylamine, oxalyl chloride, then sodium azide, ski 5) can be synthesized from the corresponding carboxylic acid. This isocyanate is It can be condensed with commercially available hydroxyaniline to form urea 11 (ski 5).   The pharmaceutically acceptable salts of the compounds of formula (I) can be prepared by known methods, for example, by adding Can be obtained by treating with an appropriate amount of an acid or base in the presence of a suitable solvent. Good.   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. The desired product may be obtained with standard bases such as DMF and pyridine. I couldn't. 2-amino-5-fluorophenol, 2-nitro-5-fluoro Intermediates such as rophenol and 2-nitro-5-methyl-6-bromophenol With the change of halogen from fluorine to chlorine or bromine, and copper cyanide Attempted with the use of (I). 2-Nitro-5 together with dimethylformamide Using a bromine derivative such as -methyl-6-bromophenol at low temperature, i.e. At <100 ° C., preferably 60 to about 80 ° C., in a shorter time than standard methods I.e., in <18 hours, preferably in about 4-6 hours, a catalytic amount of dimethylamide Using triethylamine with pyridine and copper (I) cyanide to give the desired product A product was obtained.   In the examples, all temperatures are in degrees Celsius (° C). Mass spectra are noted Unless otherwise noted, measurements were performed on a VGZab mass spectrometer using the fast atom bombardment method.¹H-NMR The spectra (hereinafter referred to as "NMR" s) are Bruker AM 250 or Am 4 00 were recorded at 250 MHz or 400 MHz, respectively. The given multiplet is , S = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br is Shows a wide range of signals. Sat. indicates a saturated solution, and the equivalent weight is based on the main reactant. The ratio of the molar equivalent of the reagent is shown.   Flash chromatography was performed on Merck Silicagel 6 0 (230-4,00 mesh).   Synthesis example   The present invention is merely illustrative of the present invention and is not intended to limit the scope of the present invention. This will be illustrated by the following non-limiting example. All temperatures are in degrees Celsius All solvents shown and used herein are of the highest available purity All reactions were performed under anhydrous conditions in an argon atmosphere unless otherwise noted. You.                                 Example 1 Preparation of N- (2-hydroxy-4-nitrophenyl) -N ′-(2-pyridyl) urea Construction   At 80 ° C., 2-pyridylcarboxylic acid (2 mmol) is added to diphenylphosphoric acid in DMF. Treat with sphoryl azide (0.475 mL) and triethylamine (0.14 mL) Thus, the urea was synthesized. After 24 hours, 5-nitro-2-aminophen No (1 equivalent) was added. The reaction was heated at 80 C for 24 hours. The reaction product is Dissolved in hexane. The residue is dissolved in methanol and the solid is Precipitated (180 mg, 32%). EI-MS m / z 273 (MH)^-.                                 Example 2 Preparation of N- (2-hydroxy-4-nitrophenyl) -N ′-(3-pyridyl) urea Construction   a) Preparation of 2- (tert-butyldimethylsiloxy) -4-nitroaniline   2-amino-5-nitropheninol (17 g, 0.11 moles) at 23 ° C. for 64 hours. ) In DMF with tert-butyldimethylsilyl chloride and imidazole To give 2- (tert-butyldimethylsiloxy) -4-nitroani Phosphorus was produced. The reaction mixture was then added to 0.1N HCl and 1: 1 EtOAc / Ether. Separate the aqueous phase and wash the organic phase once with 0.1N HCl. , NaHCO_ThreeWashed twice with a saturated aqueous solution and twice more with distilled water. Organic phase with sulfuric acid Dried over magnesium and concentrated in vacuo to 30 mL. The obtained solid is collected by filtration. Collected and washed with ether. Grind with 3: 1 methanol: water and filter. And the remaining starting material was removed. Recover the title compound as a pale orange solid (15.3 g, 50%).¹H NMR (CDCl_Three): Δ 7.82 (d, 1H), 7.67 (s, 1H), 6.67 (d, 1H), 4.52 (s, 2H), 1.16 (s, 9H), 0.38 (s, 6H).   b) 2-tert-butyldimethylsilyloxy-4-nitrophenyl isocyanate Manufacturing   A solution of phosgene (2 equivalents) and triethylamine (2 equivalents) in toluene -(Tert-butyldimethylsilyloxy) -4-nitroaniline (2.0 g, 7.5 mg Lmol) was added. The reaction mixture was stirred at 23 ° C. for 12 hours. Filter off the solid Was. The filtrate was concentrated in vacuo to give the desired compound, which was immediately purified without further purification Using.¹H NMR (CDCl_Three): Δ 7.83 (d, 1H), 7.75 (s, 1H), 7.11 (d, 1H), 1.03 (s, 9H), 0.43 (s, 6H).   c) N-[(2-tert-butyldimethylsiloxy) -4-nitrophenyl] -N'- Production of [(3-pyridyl) urea   3-aminopyridine (180 mg, 1.9 mmol) in DMF at 80 ° C. overnight. The solution was treated with 2-tert-butyldimethylsilyloxy-4-nitrophenyl isocyanate Treated with catenate. The reaction mixture was partitioned between methylene chloride and water. Yes The phases were separated, washed twice with water and then dried over magnesium sulfate, filtered. , Concentrated in vacuo. Flash chromatography of the residue (30% EtOAc / hex) Purification by subjecting to the desired compound as a pale yellow solid (52) mg, 7%).¹1 H NMR (DMSO): δ 9.9 (s, 1H), 8.65 (s, 1H), 8.28 (m, 3H), 7.95 (m, 2H), 7.19 (s, 1H), 7.35 (m, 1H), 1.03 (s, 9H), 0.43 (s, 6H).   d) of N- (2-hydroxy-4-nitrophenyl) -N ′-(3-pyridyl) urea Manufacture   N-[(2-tert-butyldimethylsiloxy) -4-nitrophenyl] -N '-[( A solution of [3-pyridyl] urea (45 mg, 0.112 mmol) in methanol with acetic acid By treatment, N- (2-hydroxy-4-nitrophenyl) -N ′-(3-pi (Risyl) urea was produced. After 30 minutes, the reaction mixture is poured between water and methylene chloride. Was distributed. The organic layer was separated, dried over sodium sulfate, concentrated in vacuo and The desired product was obtained (23 mg, 74%).¹1 H NMR (DMSO): δ 8.6 (s, 1 H, br), 8.34 (d, 1H), 8.20 (s, 1H, br), 8.05 (d, 1H), 7. 75 (d, 1H), 7.67 (s, 1H), 7.38 (m, br).                                 Example 3 Preparation of N- (2-hydroxy-4-nitrophenyl) -N ′-(4-pyridyl) urea Construction   a) N-[(2-tert-butyldimethylsiloxy) -4-nitrophenyl] -N ' Production of-[(4-pyridyl) urea   A solution of 4-aminopyridine in DMF at 80 ° C. overnight was treated with 2-tert-butyl dimethyl Treated with Lucylyloxy-4-nitrophenylisocyanate (Example 2b) . The reaction mixture was partitioned between methylene chloride and water. Separate the organic layer and water And washed twice. It is then dried over magnesium sulfate, filtered, and then evacuated. Concentrated. Flash chromatography of the residue (30% EtOAc / hexane) To afford the desired compound as a pale yellow solid.   b) of N- (2-hydroxy-4-nitrophenyl) -N '-(4-pyridyl) urea Manufacture   N-[(2-tert-butyldimethylsiloxy) -4-nitrophenyl] -N '-[( A solution of [3-pyridyl] urea (25 mg, 0.065 mmol) in methanol with acetic acid By the treatment, N- (2-hydroxy-4-nitrophenyl) -N ′-(4- Pyridyl) urea was produced. After 30 minutes, the reaction mixture was washed with water and methylene chloride. Was distributed in between. The organic layer was separated, dried over sodium sulfate, concentrated in vacuo, The desired compound was obtained (16 mg, 90%).¹1 H NMR (DMSO): δ 10.38 (s, 1H, br), 9.14 (s, 1H), 8.08 (s, 1H), 8.05 (d, 1H), 7 .59 (d, 2H), 7.55 (d, 1H), 6.95 (d, 1H), 6.86 (s, 1H), 6 .64 (d, 2H).                                 Example 4   N- [2-hydroxy-3-cyanophenyl] -N '-[2-chloro-3-pyridi Production of urea   2-chloronicotinic acid (310 mg, 2 mmol) in 50 ml of toluene for 2 hours , Diphenylphosphoryl azide (550 mg, 2 mmol) and triethylamido (200 mg, 2 mmol) was heated to 80 ° C. Then, 2-amino -6-Cyanophenol was added and the reaction was stirred overnight. 12 hours later, Torue The solid was chromatographed on silica gel (4%). MeOH / CH_TwoCl_Two) To give the desired product (260 mg, 4 mg). 5%).₁H NMR (CD_ThreeSO_TwoCD_Three): Δ 10.89 (s, 1H), 9.37 (s, 1H) 1H), 9.11 (s, 1H), 8.49 (d, 1H), 8.19 (d, 1H), 8.05 (d d, 1H), 7.40 (d, 1H), 7.29 (d, 11H), 6.99 (t, 1H).   Treatment method   Monocytes and / or macros, without limitation, in humans or other mammals Excess or unregulated IL-8 cytokines by the mammalian cells, such as phage Production or binding to the IL-8a or b receptor, also referred to as type I or type II receptor Prophylactic treatment of conditions that relapse or develop with other associated chemokines or A compound of formula (I) or a medicament thereof in the manufacture of a medicament for therapeutic treatment The above acceptable salts can be used.   Therefore, the present invention provides a method for treating a chemokine-mediated disease, Binds to the IL-8a or b receptor, and the method is represented by formula (I): Comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof. It provides the law. In particular, chemokines are IL-8, GROα, GROβ , GROγ, 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, (i) a level of free IL-8 of 1 picomole / mL or more (Ii) cell-associated IL-8, GROα, GROβ, above normal physiological levels; GROγ, NAP-2 or ENA-78; or (iii) IL-8, GROα Or tissue in GROβ, GROγ, NAP-2 or ENA-78 IL-8, GROα, GROβ, GROγ, NAP- IL-8, GROα, related to the present invention, which constitutes the presence of ENA-2 or ENA-78, Abnormal levels of GROβ, GROγ, NAP-2 or ENA-78 are obtained .   Excessive or unregulated IL-8 production is associated with relapse and / or onset of the disease There are many medical conditions. Chemokine-mediated diseases include psoriasis, atopic dermatitis , Arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease, Disease, ulcerative colitis, seizures, septic shock, endotoxin shock, Ram-negative sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, glomeruli Systemic nephritis, thrombosis, graft-versus-host reaction, Alzheimer's disease, allograft rejection Response, malaria, restenosis, angiogenesis or unwanted hematopoietic stem cell release You.   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 that act through IL-8 type I or type II receptors, in particular GR Oα, GROβ, GROγ or NAP-2 promote directional proliferation of endothelial cells This can promote tumor angiogenesis. Therefore, IL-8 induction Inhibition of chemotaxis or activation leads to a direct decrease in neutrophil infiltration.   Recent evidence also implicates the role of chemokines in treating HIV infection. It indicates that Littleman et al., Nature 381, 661 (1996) and Koup et al. Nature 381, p. 667 (1996).   The present invention also provides a chemokine receptor antagonist compound of the formula (I) Means to treat S injury in acute sclerosis and likely to be susceptible to CNS injury It also provides a means for preventing the CNS damage in certain individuals.   CNS injury as defined herein refers to an open or penetrating head, such as by surgery. Includes both non-open head injuries, such as head and neck injuries. Especially the brain Partial ischemic stroke is also included within 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 were 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. Liu et al., Stoke, Vol. 25, No. 7, pp. 1481-88 (1994) (cited herein. See).   A model of non-open head injury and treatment with a mixed 5-LO / CO agent is described in Shoham i et al. of Vaisc & Clinical Physiology and Pharmacology, Volume 3, Issue 2 , Pp. 99-107 (1992), which are incorporated herein by reference. . Treatments that reduce edema formation improve functional outcome in these treated animals Turned out to be.   Compounds of formula (I) have been demonstrated by reduced neutrophil chemotaxis and activation. As such, IL-8 binding to IL-8 alpha or beta receptor is It is administered in an amount sufficient to inhibit binding to the receptor. Represented by formula (I) The discovery that certain compounds are inhibitors of IL-8 is described in in vit described herein. ro based on the effect of the compound of formula (I) in the receptor binding assay. You. Compounds of formula (I) may, in some cases, be recombinant type I and type II IL-8 It was shown to be a dual inhibitor of the receptor. Preferably, the compound comprises one Receptors only, more preferably inhibitors of type II.   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, Or, another monokine such as, but not limited to, IL-1, IL-6 or TNF , GROα, GROβ, GROγ, NAP-2 or EN According to A-78, IL-8, GROα, GROβ, GROγ, NAP-2 or Represents all medical conditions for which ENA-78 plays a role. Thus, for example, IL-1 Is a major factor whose production or action is rekindled 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-8a or b receptors, such as -78, play a whole role Represents all medical conditions. This may be due to or limited to the production of IL-8 itself. IL that does not release another monokine such as IL-1, IL-6 or TNF By -8, pathologies in which IL-8 plays a role. So, for example, IL-1 is a major component whose production or action is rekindled in response to IL-8 A condition that is secreted or secreted may be a condition 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, Nazi Neural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone Many other cells such as medullary stromal cells, epidermal keratinocytes and B-lymphocytes are also present. In addition, it produces monokine. Lymphokines are generally produced by lymphocytes. It is said to be. Examples of cytokines include, but are not limited to, interface Kin-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 any of the above “cytokines”. Affects the functioning of cells, as well as immune, inflammatory or hematopoietic responses. The answer is a molecule that regulates interactions between cells. Chemokines are mainly cells Secreted through the transmembrane, specific leukocytes and leukocytes, neutrophils, Chemotaxis of monocytes, macrophages, T-cells, B-cells, endothelial cells and smooth muscle cells Gender and activation. Examples of chemokines include, but are not limited to, IL-8 , GRO-α, GRO-β, GRO-γ, NAP-2, ENA-78, IP-1 0, MIP-1α, MIP-β, PF4 and MCPs 1, 2, and 3 Can be   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, administration may be topical, parenteral or by inhalation. The compound of the formula (I) Combining the compound of formula (I) with a standard pharmaceutical carrier according to conventional methods. Administration in a conventional dosage form. Compounds of the formula (I) The substance may also be administered at conventional dosages in combination with a second known therapeutically effective compound. May be given. These methods involve mixing active ingredients, granules depending on the desired preparation. And tableting or dissolution. In the form of a pharmaceutically acceptable carrier or diluent The properties and characteristics of the active ingredient to be incorporated, the route of administration and other well known It will be appreciated that this is determined by the variables The carrier is another component of the formulation. Must be "acceptable" in the sense that it is compatible with the minutes and is not harmful to its recipients. No.   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. No. Examples of liquid carriers are syrup, peanut oil, olive oil, water, etc. Is mentioned. Similarly, the carrier or diluent may be used alone or with the wax. Technology such as glyceryl monostearate or glyceryl distearate It may include time delay materials well known in the art.   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. U. 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 an ampoule or a non-aqueous liquid suspension.   The compound of formula (I) may be administered topically, that is, by non-systemic administration. It is. 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 ointments, ointments or pastes Liquid or semi-liquid preparation and drops suitable for administration to the eye, ear or nose Agents. The active ingredient is from 0.001% by weight of the formulation for topical administration. Consists of 10% w / w, for example, 1% to 2%. However, 10% w of the formulation / W, preferably less than 5% w / w, more preferably 0.1% Will consist of 1% w / w.   Lotions according to the present invention are suitable for application to the skin or eyes Is mentioned. Eye lotion is sterile, which 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 Agents that dry quickly and cool the skin, and / or moisturizers such as glycerol Oils such as isers or castor 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. Liquid, soft or liquid paraffin, glycerol, beeswax, metal soap, etc. Hydrocarbons; Demulsifiers; Tonsil oil, corn oil, peanut oil, castor oil or olly Oils of natural materials such as butane oil; wool fat or its derivatives or propylene glycol Stearic acid or oley with alcohol such as Consists of fatty acids such as acid. The preparation comprises sorbitan ester or its polyoxoate. Such as anionic, cationic or nonionic surfactants, such as ethylene derivatives A suitable surfactant may be included. Suspending agents such as natural gums, cellulose derivatives Or other inorganic substances such as silica containing silica, and other components such as lanolin. Minutes.   The drops according to the invention consist of a sterile aqueous or oily solution or suspension. The use of fungicides and / or fungicides and / or other suitable preservatives. Preferably, the active ingredient is dissolved in a suitable aqueous solution containing a surfactant. 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. Transferred to container. Fungicides and fungicides suitable for inclusion in the drops; Examples include phenylmercuric nitrate or acetate (0.002%), Zarkonium chloride (0.01%) and chlorohexidine acetate (0.01%) Is mentioned. Suitable solvents for the preparation of an oily solution include glycerol, Dilute alcohols and propylene glycol.   The compounds of formula (I) can be administered parenterally, ie, intravenously, intramuscularly. , Subcutaneous, intranasal, rectal, vaginal or intraperitoneal May be. Subcutaneous and intramuscular forms of parenteral administration are generally preferred. Heel Suitable dosage forms for administration can be prepared by conventional techniques. Formula (I) The compounds that are also administered by inhalation, i.e., intranasal inhalation administration and oral inhalation It may be administered by administration. Whether it is an aerosol formulation or a metered inhaler Suitable dosage forms for administration can be prepared by conventional techniques.   For all uses described herein for the compounds of formula (I) The daily oral administration policy is preferably about 0.01 to about 80 mg / kg of total body weight. There will be. The daily parenteral administration policy is about 0.001 to about 80 mg / kg / kg of total body weight. It is. The daily topical administration regimen will preferably be from 0.1 mg to 150 mg, It is administered 1 to 4 times, preferably 2 or 3 times a day. Daily inhalation administration policy is preferred Alternatively, it may be from about 0.01 mg / kg to about 1 mg / kg per day. Represented by formula (I) Optimal amounts and intervals for individual administration of the compound or pharmaceutically acceptable salt thereof will be determined by The nature and extent of the condition to be placed, the mode of administration, the route and site, and the The optimal value will depend on the particular patient It will also be appreciated by those skilled in the art that more can be determined. Optimal treatment A compound of formula (I) administered per day for a predetermined number of days. object Or the frequency of administration of a pharmaceutically acceptable salt thereof is determined using a conventional treatment method determination test. Can be confirmed by those skilled in the art.   The invention is merely illustrative and is not intended to limit the scope of the invention , Will be described with reference to the following biological examples.   Biological examples   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 Corporation, Arlington Heights, Illinois (Amersham Corp.) with a specific activity of 2000 Ci / mmol [¹²⁵I] IL-8 (Human recombination) was obtained. Gro-α is NEN (New England Nu -New England Nuclear). All other chemicals are It was for analysis. High levels of recombinant human IL-8α and β-type receptors Chinese Hamsters in accordance with the disclosure of (Holmes et al., Science, 1991, 253, 1278). -Expressed in ovarian cells. Chinese hamster ovary membrane previously disclosed According to the protocol (Haour et al., J Biol Chem., 249, pp. 2195-2205 (1974)). Modified. 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, p Except replacing H7.5. Pierce Co. Micro-A Membrane protein using bovine serum albumin as a standard sample. The concentration was determined. All assays are in 96-well microplate format I went in. Each reaction mixture contains 1.2 mM MgSO_Four, 0.1 mM EDTA, 25 mM 20 mM Bis-Tris propane containing NaCl and 0.03% CHAPS And in 0.4 mM TrisHCl buffer¹²⁵IIL-8 (0.25 nM) or¹²⁵ I Gro-α and 0.5 μg / mL IL-8Rα or 1.0 μg / mL I L-8Rβ membrane was included. Further, the drug or compound of the present invention has a final concentration of 0%. It was dissolved in DMSO in advance so that the concentration became 0.01 nM to 100 μM, and added. Said a Issay¹²⁵ Started by the addition of I-IL-8. After 1 hour at room temperature, the plate is Harvest on fiber filaments using a Tomtec 96-well harvester and add 1% po Block with ethyleneimine / 0.5% BSA, 25 mM NaCl, 10 mM Tris  HCl, 1 mM MgSO_Four, 0.5 mM EDTA, 0.03% CHAPS, pH 7.4 Washed three times. The filter was then dried and the Betaplate ) Counted on liquid scintillation counter. Recombinant IL-8Rα or type I Receptors, also referred to as non-permissive receptors, are known to be recombinant IL-8Rβ or type II receptors. The body is also called an acceptable receptor.   Examples of Formula (I) exemplified in Examples 1-4 in the Synthetic Chemistry section Compounds are present in the permissive model for IL-8 receptor inhibition from about 30 to about <1 μg. / ML IC₅₀showed that. Compound N- (6-methyl-2-pyridine) -N ′-(2- (Hydroxy-4-nitrophenyl) urea is inactive in this assay. Turned out to be.   Chemotaxis assay   The in vitro inhibitory properties of these compounds are described in Current Protocols in Immunology, Volume I, Suppl 1, Unit 6.12.3. (Cited and described herein) Neutrophil chemotaxis assay as described. Neutrophils use the Current Protocol s in Immunology, Volume I, Suppl 1 Unit 7.23.1 (cited as the description in this specification) ) Was isolated from human blood. Chemoattractant IL-8, GRO-α , GRO-β, GRO-γ and NAP-2 at a concentration of 0.1-100 nM for 48 hours. Multi-well chamber (NeuroProbe, Cabin Jo (Cabin John, MD) in the lower chamber. Two chambers Are separated by a 5 μm polycarbonate filter. Try the compound of the present invention. When performing the experiments, they were combined with cells (0.001-1000 nM) and Mix just before adding to the plate. 5% CO_TwoWith an air humidifier Incubate for about 45-90 minutes at about 37 ° C in a thermometer. Inn After the incubation period, remove the polycarbonate membrane, wash the top, and ・ Diff Quick staining protocol (McGa, Illinois, USA) U The membrane was stained using Park's Baxter Products. Was. Chemokine chemotactic cells are counted visually using a microscope . Generally, four regions are counted for each sample, these numbers are averaged, and the Obtain the average number of cells that have moved. Each sample was tested in triplicate and each compound was Repeat it. For some cells (positive control cells) no compound was added These cells show the maximal chemotactic response of the cells. Negative controls (unstimulated) are desirable If not, do not add any chemokines to the lower chamber. Positive and negative controls The difference between and indicates the chemotactic activity of the cell.   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 Immunology Volume I, Suppl 1 Unit 7.2 Isolated from human blood as disclosed in 3.1. Ringer's solution (NaCl11 8, KCl 4.56, NaHCO_Three 25, KH_TwoPO_Four1.03, glucose 11.1, HE 0.88 × 10 PMN suspended in 5 mM PES, pH 7.4)⁶Cell volume 50 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 buffer in a volume of 50 μl. this After heating these cells for 5 minutes (37 ° C., 5% CO 2)_Two, 95% RH), IL-8, GROα, GROβ, GROγ or NAP-2 at a final concentration of 0.01-1000. Added at nM. After performing the reaction for 45 minutes, the 96-well plate was centrifuged. (800 × g, 5 minutes), remove 100 μl of supernatant. This supernatant was used for a second 96 The final concentration, added to the L-plate and then dissolved in phosphate buffered saline, was An artificial elastase substrate (MeOSuc-Ala-Ala-Pro-Val-A) was added to reach 6 μg / ml. MC with Nova Biochem from La Jolla, California) Add. Immediately load the plate with a fluorescent 96-well plate reader (Cytofluor) 2350, Millipore, Bedford, Mass. pore)), Nakajima et al. Biol Chem 254 4027 (1979) And collect data every 3 minutes. Elastase released from PMN Is determined by measuring the rate of MeOSuc-Ala-Ala-Pro-Val-AMC degradation. Is calculated.   TNF-α in traumatic brain injury assay   This assay allows lateral fluid-percussion in rats Tumor necrosis factor in specific brain regions that experimentally induced traumatic brain injury (TBI) Experiments on mRNA expression are performed. Adult Spray Good-Lead Rat (n = 42) Was anesthetized with sodium pentobarbital (60 mg / kg, i.p.) and left parietal cortex Medium (2.4 atm) side liquid impact (n = 18) or "sham" concentrated on Treatment (anesthesia and surgery without injury, n = 18) was imposed. 1 hour after injury, 6 o'clock After and 24 hours later, the animals are sacrificed by decapitation, the brain is removed and the left (injured) ) Parietal cortex (LC), corresponding region in contralateral right cortex (RC), damaged head Cortex adjacent to the apical cortex (LA), corresponding adjacent area in right cortex (RA), left Prepare hippocampal (LH) and right hippocampal (RH) tissue samples. Isolating total RNA, Northern blot hybridization was performed and TNF-α positive control RNA ( (Macrophage = 100%). One hour after injury, TNF-α  Significant increase in mRNA was due to injured hemisphere LH (104 ± 17% of positive control). , P <0.05 compared to sham, LC (105 ± 21%, p <0.05) and And LA (69 ± 8%, p <0.01). 6 hours after injury, TNF-α mRNA expression was also determined by LH (46 ± 8%, p <0.05), LC (3 0 ± 3%, p <0.01) and LA (32 ± 3%, p <0.01), It dissipates by 24 hours after injury. In the contralateral hemisphere, TNF-α mR At 1 hour after injury, the expression of NA was RH (46 ± 2%, p <0.01), RC ( 4 ± 3%) and RA (22 ± 8%), RH (28 ± 11) after 6 hours of injury. %), RC (7 ± 5%) and RA (26 ± 6%, p <0.05) It does not increase 24 hours after the wound. Siam (surgery without damage) or naive animals Then, at any time, in any hemisphere, in any of the six brains, TNF- No consistent change in α mRNA expression is observed. These results are After body impact brain injury, transient expression of TNF-α mRNA is Certain brains, including those of the sphere Indicates that it will be changed by the department. TNF-α induces nerve growth factor (NGF) And stimulate the release of other cytokines from activated astrocytes. This post-traumatic alteration in TNF-α gene expression is Plays an important role in both the acute and regenerative responses to wounds.   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 the specific brain part of the value of I) Minute expression is characterized. Adult Spray Good-Leer Rat (n = 42) with pen Anesthetized with sodium tobarbital (60 mg / kg, i.p.) and collected in left parietal cortex Intermediate (2.4 atm) side liquid impact (n = 18) or "sham" Treatment (anesthesia and surgery without injury, n = 18) was imposed. 1 hour after injury, 6 o'clock After and 24 hours later the animals are sacrificed, the brain is removed and the left (damaged) parietal cortex (LC), corresponding region in contralateral right cortex (RC), next to damaged parietal cortex Bordered cortex (LA), corresponding adjacent area in right cortex (RA), left hippocampus (LH ) And right hippocampus (RH) tissue samples. Isolate total RNA and Lot hybridization was performed to determine the amount of IL-1β mRNA in the brain tissue. Percentage of radioactivity of IL-1β positive macrophage RNA loaded on one gel Expressed as cents. One hour after brain injury, significant and significant IL-1β mRNA Significant increase was due to injured hemispheric LC (20.0 ± 0.7% of positive control, n = 6, P <0.05 compared to Siamese animals, LH (24.5 ± 0.9%, p <0.05) and And LA (21.5 ± 3.1%, p <0.05) and up to 6 hours after injury LC (4.0 ± 0.4%, n = 6, p <0.05) and LH (5.0 ± 1.3%, (p <0.05). In siamese or naive animals, each brain No expression of IL-1β mRNA is observed in any of the parts. These conclusions The result is that after TBI, the transient expression of IL-1β mRNA is localized in specific brain areas. Indicates that it is stimulated. These localities in cytokines like IL-1β Objective change plays a role after trauma.   All publications, including but not limited to patents and patent applications, cited herein are , Quote as if each of the publications were individually and completely described It will be described in this specification.   The above description fully describes the invention including preferred embodiments thereof. Book Modifications and improvements of the specific example which are set forth in detail in the specification are set forth in the following claims. Is within. Without further elaboration, those skilled in the art will, using the preceding description, adopt the present invention. It seems that you can 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. Exhaustion The specifics of the invention for which other ownership and privileges are claimed are defined below. You.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/00 617 A61K 31/00 617E 609 619A 626 626N 637 637E 637D 643 643D 31/44 31/44 C07D 521 / 00 C07D 521/00

Claims (1)

[Claims]   1. A method for treating a chemokine-mediated condition, wherein said chemokine is present in a mammal. Binds to IL-8α or β receptors by the 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_Four R_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_2-10 Alkenyl C (O) R₁₁C_2-10Alkenyl C (O) OR₁₁(CR₈R₈)_qC (O) OR_{1 Two} ; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁, (CR₈R₈)_qNH S (O)_TwoR₁₇, (CR₈R₈)_qS (O)_TwoNR_FourR_FiveOr two R₁ The groups together form O- (CH_Two)_sO- or a 5- or 6-membered unsaturated ring may be formed. ;   q is 0 or an integer having a value from 1 to 10;   m is an integer having a value of 1 to 3;   t is 0 or an integer having a value of 1 or 2;   s is an integer having a value from 1 to 3;   v is 0 or an integer having a value from 1 to 4;   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;   HET is an optionally substituted heteroaryl group;   R₈Is hydrogen or C_1-4Alkyl;   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, an optionally substituted heterocycle, or an optional 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 May be used);   E is optionallyOr May be selected from^*Represents a bonding position of a ring)] Administering to the mammal an effective amount of a pharmaceutically acceptable salt thereof. Treatment method.   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; wherein:   R_TwoIs a substituted aryl, heteroaryl, or heterocyclic ring, and the ring is 10 or less. Containing a functional group that provides an ionizable hydrogen with a pKa of   R_aIs alkyl, aryl, aryl C_1-4Alkyl, heteroaryl, hetero Aryl C_1-4Alkyl, heterocycle, or heterocycle C_1-4Alkyl group May be optionally substituted;   R_bIs NR₆R₇, Alkyl, aryl, aryl C_1-4Alkyl, aryl C_{2- Four} Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_2-4Alkenyl, heterocycle, heterocycle C_1-4Alkyl, heterocyclic C_2-4Alkenyl group, Camphor, all of which are optionally halogen; nitro; halo substituted C_{1- Four} Alkyl; C_1-4Alkyl; C_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   R₆And R₇Is independently hydrogen or C_1-4An alkyl group, or R₆And R₇Together with the nitrogen to which they are attached, optionally oxygen, 5-membered ring which may contain additional heteroatoms selected from nitrogen or sulfur Forming a 7-membered ring;   R₉Is hydrogen or C_1-4Alkyl;   R_cIs alkyl, aryl, aryl C_1-4Alkyl, aryl C_2-4Alkene , Heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_2-4Al Kenyl, heterocycle, heterocycle C_1-4Alkyl or heterocyclic C_2-4Alkenyl group All of which are optionally halogen, nitro, halo substituted C_1-4Alkyl, C_1-4 Alkyl, C_1-4Alkoxy, NR₉C (O) R_a, C (O) NR₆R₇, S (O)_ThreeH, ma Or C (O) OC_1-4May be independently substituted 1-3 times with alkyl;   X_TwoThe method according to claim 2, wherein is oxygen or sulfur.   4. R_TwoIs optionally halogen, nitro, halo substituted C_1-10Alkyl, C_{1-1 0} Alkyl, C_1-10Alkoxy, hydroxy, SH, -C (O) NR₆R₇, -NH -C (O) R_a, -NHS (O)_TwoR_b, S (O) NR₆R₇, C (O) OR₈Or tetra The method according to claim 3, which may be substituted one to three times by a zolyl ring.   5. R is OH, -NHS (O)_TwoR_bOr C (O) OH. .   6. R₁Is halogen, cyano, nitro, CF_Three, C (O) NR_FourR_FiveAlkenyl C (O) NR_FourR_Five, C (O) R_FourR_Ten, Alkenyl C (O) OR₁₂, Heteroaryl, f Teroarylalkyl, heteroarylalkenyl, or S (O) NR_FourR_FiveIn The method according to claim 1.   7. HET ring is (Y)_nHas been replaced by:   n is an integer having a value of 1 to 3;   Y is hydrogen; halogen; nitro; cyano; halo-substituted C_1-10Alkyl; C_1-10Al Kill; C_2-10Alkenyl; C_1-10Alkoxy; halo-substituted C_1-10Alkoxy; horse mackerel C; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4Alkyl; aryl An aryl C_1-4Alkyl; aryloxy; aryl C_1-4Alkyloxy; f Teloaryl; heteroarylalkyl; heteroarylC_1-4Alkyloxy A heterocycle, a heterocycle C_1-4Alkyl; aryl C_2-10Alkenyl; heteroa Reel C_2-10Alkenyl; heterocyclic C_2-10Alkenyl; (CR₈R₈)_qNR_FourR_Five, C_{Two -Ten} Alkenyl 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_2-10Alkene Le C (O) R₁₁C_2-10Alkenyl C (O) OR₁₁C (O) R₁₁; (CR₈R₈)_qC (O ) OR₁₂; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁, (CR₈R₈)_q NHS (O)_TwoR_b, (CR₈R₈)_qS (O)_TwoNR_FourR_FourSelected from or 2 Two Y groups together form O- (CH_Two)_sO- or to form a 5- to 6-membered unsaturated ring And   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, wherein the aryl, hetero 2. The method of claim 1, wherein all of the aryl and heterocycle are optionally substituted. Law.   8. Y is halogen, C_1-4Alkoxy, optionally substituted ants , Optionally substituted arylalkoxy, methylenedioxy , NR_FourR_Five, Thio C_1-4Alkyl, thioaryl, halo-substituted alkoxy, optionally A more optionally substituted C_1-4Alkyl or hydroxyalkyl The method of claim 7.   9. R is OH, SH, or NHS (O)_TwoR_bAnd R₁Is due to the electron withdrawing group Claimed to be substituted at the 3 or 4 position or disubstituted at the 3 and 4 position Item 7. The method according to Item 1.   10. 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, defeat Blood shock, endotoxin shock, gram-negative sepsis, toxic shock Syndrome, seizures, heart and kidney reperfusion injury, glomerulonephritis, or thrombosis, Selected from Ruzheimer's disease, graft-versus-host reaction, or allograft rejection 10. The method according to any one of claims 1 to 9, wherein the patient is suffering from a chemokine-mediated disease. .   11. 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_Four R_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_2-10 Alkenyl C (O) R₁₁C_2-10Alkenyl C (O) OR₁₁(CR₈R₈)_qC (O) OR_{1 Two} ; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁, (CR₈R₈)_qNH S (O)_TwoR₁₇, (CR₈R₈)_qS (O)_TwoNR_FourR_FiveOr two R₁ The groups together form O- (CH_Two)_sO- or a 5- or 6-membered unsaturated ring may be formed. ;   q is 0 or an integer having a value from 1 to 10;   m is an integer having a value of 1 to 3;   t is 0 or an integer having a value of 1 or 2;   s is an integer having a value from 1 to 3;   v is 0 or an integer having a value from 1 to 4;   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;   HET is an optionally substituted heteroaryl group;   R₈Is hydrogen or C_1-4Alkyl;   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, an optionally substituted heterocycle, or an optional 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 May be used);   E is optionallyOr May be selected from^*Represents a bonding position of a ring)] Is a pharmaceutically acceptable salt thereof.   12. The compound according to claim 11, wherein the ionizable hydrogen has a pKa of 3 to 10. .   13. 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; wherein:   R_TwoIs a substituted aryl, heteroaryl, or heterocyclic ring, and the ring is 10 or less. Containing a functional group that provides an ionizable hydrogen with a pKa of   R_aIs alkyl, aryl, aryl C_1-4Alkyl, heteroaryl, hetero Aryl C_1-4Alkyl, heterocycle, or heterocycle C_1-4Alkyl group May be optionally substituted;   R_bIs NR₆R₇, Alkyl, aryl, aryl C_1-4Alkyl, aryl C_{2- Four} Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_1-4Alkenyl, heterocycle, heterocycle C_1-4Alkyl, heterocyclic C_2-4Alkenyl group, Camphor, all of which are optionally halogen; nitro; halo substituted C_{1- Four} Alkyl; C_1-4Alkyl; C_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   R₆And R₇Is independently hydrogen or C_1-4An alkyl group, or R₆And R₇Together with the nitrogen to which they are attached, optionally oxygen, 5-membered ring which may contain additional heteroatoms selected from nitrogen or sulfur Forming a 7-membered ring;   R₉Is hydrogen or C_1-4Alkyl;   R_cIs alkyl, aryl, aryl C_1-4Alkyl, aryl C_2-4Alkene , Heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_2-4Al Kenyl, heterocycle, heterocycle C_1-4Alkyl or heterocyclic C_2-4Alkenyl group All of which are optionally halogen, nitro, halo substituted C_1-4Alkyl, C_1-4 Alkyl, C_1-4Alkoxy, NR₉C (O) R_a, C (O) NR₆R₇, S (O)_ThreeH, ma Or C (O) OC_1-4May be independently substituted 1-3 times with alkyl;   X_Two12. The compound according to claim 11, wherein is oxygen or sulfur.   14． R_TwoIs optionally halogen, nitro, halo substituted C_1-10Alkyl, C_{1 -Ten} Alkyl, C_1-10Alkoxy, hydroxy, SH, -C (O) NR₆R₇, -N HC (O) R_a, -NHS (O)_TwoR_b, S (O) NR₆R₇, C (O) OR₈Or Tet 14. The compound according to claim 13, which may be substituted one to three times by a lazolyl ring.   15. R is OH, -NHS (O)_TwoR_bOr C (O) OH. Compound.   16. 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_Fiveso The compound according to claim 11,   17． HET ring is (Y)_nHas been replaced by:   n is an integer having a value of 1 to 3;   Y is hydrogen; halogen; nitro; cyano; halo-substituted C_1-10Alkyl; C_1-10Al Kill; C_2-10Alkenyl; C_1-10Alkoxy; halo-substituted C_1-10Alkoxy; horse mackerel C; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4Alkyl; aryl An aryl C_1-4Alkyl; aryloxy; aryl C_1-4Alkyloxy; f Teloaryl; heteroarylalkyl; heteroarylC_1-4Alkyloxy A heterocycle, a heterocycle C_1-4Alkyl; aryl C_2-10Alkenyl; heteroaryl C_2-10Alkenyl; heterocyclic C_2-10Alkenyl; (CR₈R₈)_qNR_FourR_Five, C_2-10A Lucenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_Four R_TenS (O)_ThreeH; S (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C ( O) R₁₁C_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_FiveOr two Y groups are taken together to form O- (C H_Two)_sForming an O- or 5- to 6-membered unsaturated ring,   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, wherein the aryl, hetero 12. The method of claim 11, wherein all of the aryl and heterocycle are optionally substituted. Compound.   18. Y is halogen, C_1-4Alkoxy, optionally substituted a Reel, optionally substituted arylalkoxy, methylenedioxy Si, NR_FourR_Five, Thio C_1-4Alkyl, thioaryl, halo-substituted alkoxy, desired C optionally substituted by_1-4Alkyl or hydroxyalkyl A compound according to claim 17.   19. R is OH, SH, or NHS (O)_TwoR_bAnd R₁Is due to the electron withdrawing group A substituent that is substituted at the 3- or 4-position or di-substituted at the 3- or 4-position The compound according to claim 11.   20. An effective amount and a pharmaceutically acceptable amount of the compound according to any one of claims 11 to 19. A pharmaceutical composition comprising a carrier or a diluent.