JP2001501172A - IL-8 receptor antagonist - Google Patents

Abstract

  (57) [Summary] The present invention relates to novel compounds of formula (I), pharmaceutical compositions and uses thereof in the treatment of diseases mediated by chemokines, interleukin-8 (IL-8).

Description

DETAILED DESCRIPTION OF THE INVENTION                     IL-8 receptor antagonist   Field of the invention   The present invention relates to a novel guanidine-substituted compound, a pharmaceutical composition, a method for producing the same and a method for preparing the same. L-8, GROα, GROβ, GROγ, ENA-78 and NAP-2 mediated diseases It relates to use in the treatment of a disease.   Background of the Invention   Neutrophil attracting / activating protein-1 (interleukin-8 (IL-8)) NAP-1), monocyte-derived neutrophil chemotactic factor (MDNCF), neutrophil activator ( Many different names are used, such as NAF) and T-cell lymphocyte chemotactic factor ing. Interleukin-8 is a subset of neutrophils, basophils, and T-cells. It is a chemoattractant for the plant. This includes TNF, IL-1α, IL-1β Or macrophages, fibroblasts, endothelial cells and epithelial cells exposed to LPS Exposure to most nucleated cells, including and chemotactic factors such as LPS or FMLP Is produced by neutrophils when they occur. M. Baggiolini et al.J . Clin. Invest .  84, 1045 (1989); Schroder et al.J . Immunol.139, 3474 (1987) andJ . Im munol. 144 Strieter et al., 2223 (1990);Science 243, 1467 (1989) andJ . Biol. Chem. 264 , 10621 (1989); Cassatella et al.J . Immunol. 148, 3216 (1992).   Groα, GROβ, GROγ and NAP-2 also belong to the chemokine α family Belong. Like IL-8, these chemokines have been called by different names . For example, GROα, β, γ are referred to as MGSAα, β, and γ, respectively (black Melanoma growth stimulating activity). Richmond et al. Cell Physiology 129, 375 (1986) and And Chang et al.J . Immunol 148, 451 (1992). Immediately after the CXC motif All of the α-family chemokines that have an ELR motif are IL-8 Binds to beta receptor.   IL-8, Groα, GROβ, GROγ and NAP-2 are abundant in vitro. Stimulates many functions. All of these can be chemoattractant to neutrophils As demonstrated, IL-8 and GROα are T-lymphocyte and basophil chemotaxis. Showed sex. In addition, IL-8 is a good candidate from both normal and atopic individuals. It can induce histamine release from base spheres. GROα and IL-8 are more favorable. Lysosomal enzyme release from neutrophils and respiratory burst can be triggered. IL-8 is Furthermore, Mac-1 (CDI) on neutrophils without newly synthesizing proteins 1b / CD18). This means It may contribute to the increased attachment of neutrophils to vascular endothelial cells. Many known diseases The disease is characterized by massive neutrophil infiltration. IL-8, GROα, GROβ , GROγ and NAP-2 promote neutrophil accumulation and activation, These chemokines are widely used in acute and chronic diseases, including psoriasis and rheumatoid arthritis. Baggiolini et al. Have been implicated in inflammatory disorders.FEBS Lett . 307, 97 (1992); Miller et al.Crit . Rev. Immunol. 12, 17 (1992); Oppenheim et al.Annu . Rev. Immun ol. 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)]. Addition The ELR chemokine (containing the amino acid ELR motif immediately before the CXC motif) Has also been associated with hemostasis. Strieter et al., Science 25 8, 1798 (1992).   In vitro, IL-8, GROα, GROβ, GROγ and NAP-2 , 7-transmembrane, binds to receptors of the G-protein binding family Activates, in particular, the IL-8 receptor, most notably the β-receptor Neutrophil shape change, chemotaxis, granule release and respiratory berth Trigger. Thomas et al.J . Biol. Chem. 266, 14839 (1991); and Holmes et al. ,Science 253, 1278 (1991). Non-peptides for members of this receptor family The development of small molecule antagonists has been pursued. For a review, see F reidinger in:Progress in Drug Research, Vol. 40, pp. 33-98, Birkhauser V See erlag, Basel 1993. Thus, the IL-8 receptor is a novel anti-inflammatory It represents a promising target for developing symptomatic agents.   Two high affinity human IL-8 receptors (77% homology): as high as IL-8 alone For IL-8Ra, which binds with affinity, and IL-8, and GROα, IL-8Rb with high affinity for GROβ, GROγ and NAP-2 Was characterized. Holmes et al., Supra; Murphy et al.,Science 253, 1280 (1991); Lee et al.J . Biol. Chem . 267, 16283 (1992); LaRosa et al.J . Biol. Chem. 267, 25402 (1992 ); And Gayle et al.J . Biol. Chem. 268, 7283 (1993).   In the art, compounds capable of binding to IL-8α or β receptor There still exists a need for processing. Thus, increased IL-8 production (Involved in chemotaxis of neutrophils and T-cell subsets into sites of inflammation) Symptoms benefit from compounds that are inhibitors of IL-8 receptor binding Will.Summary of the Invention   The present invention relates to the binding of chemokines to IL-8α or β receptors. A method of treating a chemokine-mediated disease, comprising administering to a subject an effective amount of a compound of formula (I) or a physician thereof. A method comprising administering a pharmaceutically acceptable salt is provided. In particular, chemokines IL-8.   The present invention further relates to its receptor for IL-8 in primates that require it. A method of inhibiting binding to a mammal, comprising administering to said mammal an effective amount of a compound of formula (I). To a method consisting of:   Compounds of formula (I) useful in the present invention have the structural formula:   [Where,   Z is cyano, OR₁₁, C (O) NR_FifteenR₁₆, R₁₈, C (O) R₁₁, C (O) OR₁₁, Or S (O)_TwoR₁₇Is;   R is a functional group having an ionizable hydrogen having a pKa of 10 or less. Yes;   R₁Is 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_1-4Al Kill; aryl; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Al A heteroaryl; a heteroarylalkyl; a heterocyclic, Heterocyclic C_1-4Alkyl; heteroaryl C_1-4Alkyloxy; ant 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)_TwoR₁₉; (CR₈R₈ )_qS (O)_TwoNR_FourR_FiveOr two R₁The groups together form O- ( CH_Two)_sForming an O- or 5- or 6-membered saturated or unsaturated ring (here, aryl , Heteroaryl and heterocyclic containing groups are optionally substituted. May be used);   q is 0, or an integer from 1 to 10;   t is 0, or an integer of 1 or 2;   s is an integer from 1 to 3;   m is an integer from 1 to 3;   n is an integer from 1 to 3;   v is 0, or an integer 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, heterosa Iclic or heterocyclic C_1-4Alkyl or R_FourAnd And R_FiveTogether with the nitrogen to which they are attached, optionally oxygen, nitrogen or Forms a 5- to 7-membered ring which may contain another heteroatom selected from sulfur Make;   R₆And R₇Is independently hydrogen or C_1-4An alkyl group; or R₆ And R₇Is, together with the nitrogen to which they are attached, optionally oxygen, 5 to 7 which may contain another heteroatom selected from nitrogen or sulfur Form a member ring;   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_1-4Al Kill; aryl; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Al Heteroaryl; Heteroarylalkyl; Heteroaryl C_1-4 Alkyloxy; heterocyclic, heterocyclic C_1-4Alkyl; Reel C_2-10Alkenyl; heteroaryl C_2-10Alkenyl; heterocyclyl 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)_Three H; S (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁ C_2-10Alkenyl C (O) OR₁₁C (O) R₁₁; (CR₈R₈)_qC (O) O R₁₂; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁, (C R₈R₈)_qNHS (O)_TwoRd, (CR₈R₈)_qS (O)_TwoNR_FourR_FiveTo be selected from Or two Y groups together form O- (CH_Two)_sO- or 5- or 6-membered saturated Or may form an unsaturated ring (wherein aryl, heteroaryl and The telocyclic-containing group may be optionally substituted);   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 heterocyclic, or Heterocyclic C optionally substituted_1-4Alkyl;   R₁₂Is hydrogen, C_1-10Alkyl, optionally substituted aryl or Is an optionally substituted arylalkyl;   R₁₃And R₁₄Is independently hydrogen or C_1-4Alkyl;   R_FifteenAnd R₁₆Is 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, if desired Optionally substituted heterocyclic, optionally substituted Heterocyclic C_1-4Alkyl or R_FifteenAnd R₁₆Are they Another selected from oxygen, nitrogen or sulfur together with the nitrogen being bound Form a 5- to 7-membered ring optionally containing two heteroatoms;   R₁₇Is C_1-4Alkyl, NR_FifteenR₁₆, OR₁₁, Even if optionally substituted Good aryl, optionally substituted aryl C_1-4Alkyl, desired Optionally substituted by heteroaryl, optionally substituted Heteroaryl C_1-4Alkyl, optionally substituted heterocycle Or optionally substituted heterocyclic C_1-4Al A kill;   R₁₈Is an optionally substituted C_1-4Alkyl, optionally substituted Optionally substituted aryl, optionally substituted aryl C_1-4Al Killed, optionally substituted heteroaryl, optionally substituted Optionally heteroaryl C_1-4Alkyl, optionally substituted Telocyclic or optionally substituted heterocyclic C_1-4Alkyl;   R₁₉Is C_1-4Alkyl, aryl, arylalkyl, heteroaryl, f Teloaryl C_1-4Alkyl, heterocyclic, or heterocyclic C_1-4Alkyl, wherein all of these groups are optionally substituted Also good);   Rd is NR₆R₇, Alkyl, aryl C_1-4Alkyl, aryl C_2-4Arche Nil, heteroaryl, heteroaryl-C_1-4Alkyl, heteroaryl C_2-4 Alkenyl, heterocyclic, heterocyclic C_1-4Is alkyl ( Where alkyl, aryl, arylalkyl, heteroaryl, heteroali Alkyl, heterocyclic, and heterocyclic alkyl rings Optionally substituted);   The X-containing ring is (Where the asterisk * indicates the point of attachment of the ring);   R₂₀Is W₁An optionally substituted heteroaryl, optionally Optionally substituted C_5-8Cycloalkyl, optionally substituted C_1-10Alkyl, optionally substituted C_2-10Alkenyl or place Optionally substituted C_2-10Alkynyl;   W₁Is   The E'-containing ring optionally has And an asterisk * indicates the point of attachment of the ring.] Or a pharmaceutically acceptable salt thereof.Detailed description of the invention   The compounds of formula (I) may further be combined with IL-8 or IL-8 α and β receptors. Veterinary treatment of non-human mammals requiring inhibition of other binding chemokines Used in connection with Chemokines for therapeutic or prophylactic treatment in animals Intervening diseases include those conditions listed herein in the Therapies section.   R suitably has a pKa of 10 or less, preferably about 3 to 9, and More preferably, about 3 to 7 functional groups that provide ionizable hydrogen. It is. Such functional groups include, but are not limited to, hydroxy, carboxylic acid , Thiol, SR_Two, OR_Two, NH-C (O) Ra, C (O) NR₆'R₇', Formula: NHS (O)_TwoRb, S (O)_TwoA substituted sulfonamide of NHRc, NHC (X_Two) NHRb also Includes tetrazolyl; where X_TwoIs oxygen or sulfur, preferably oxygen is there. Preferably, the functional group is a group other than sulfonic acid, either directly or SR_TwoOr OR_TwoAryl, heteroaryl, or as in On a heterocyclic ring. More preferably, R is OH, SH, or NH S (O)_TwoRb.   Suitably, R_TwoIs substituted aryl, heteroaryl, or heterocyclic A ring wherein the ring is an ionizable hydrogen having a pKa of 10 or less. It has a functional group to be provided.   Suitably, R₆'And R₇'Is hydrogen, C_1-4Alkyl, aryl, aryl C_{1 -Four} Alkyl, aryl C_2-4Alkenyl, heteroaryl, heteroaryl C_1-4 Alkyl, heteroaryl C_2-4Alkenyl, heterocyclic, heterocyclic Click C_1-4Alkyl, heterocyclic C_2-4Alkenyl groups; Are optionally one to three times independently halogen; nitro; halo-substituted C_1-4 Alkyl, for example CF_ThreeC_1-4Alkyl, for example methyl; C_1-4Alkoxy, example For example, methoxy; NR₉C (O) Ra; C (O) NR₆R₇S (O)_ThreeH; or C (O) OC_1-4May be substituted with alkyl (provided that R₆'And R₇Only one of Are hydrogen and must not be both hydrogen).   Suitably, R₆And R₇Is independently hydrogen or C_1-4Is it an alkyl group Or R₆And R₇Together with the nitrogen to which they are bound, oxygen, nitrogen Or still another heteroatom which is a heteroatom selected from sulfur Forms a 5- to 7-membered ring which may be contained. This heterocycle is referred to herein as May be substituted as desired.   Suitably, Ra is aryl, aryl C_1-4Alkyl, heteroaryl, f Teloaryl C_1-4Alkyl, heterocyclic, or heterocyclic C_1-4Alkyl groups, all of which are defined hereinbelow. It may be optionally substituted as described above.   Suitably, Rb is NR₆R₇, Alkyl, aryl, aryl C_1-4Alkyl , Aryl C_2-4Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, Heteroaryl C_2-4Alkenyl, heterocyclic, heterocyclic C_{1 -Four} Alkyl, heterocyclic C_2-4An alkenyl group or camphor; These are all halogen; nitro; halo substituted C_1-4Alkyl, for example CF_ThreeC_1-4 Alkyl, for example methyl; C_1-4Alkoxy, such as methoxy; NR₉C (O) Ra; C (O) NR₆R₇S (O)_ThreeH; or C (O) OC_1-4Optionally with alkyl It may be substituted one to three times independently. Rb is preferably optionally substituted Phenyl, benzyl, or styryl, which may be substituted. Rb is heteroa If reel, this is preferably an optionally substituted chia Sol, optionally substituted thienyl, or optionally substituted Is a quinolinyl ring which may be substituted.   Suitably, R₉Hydrogen or C_1-4Alkyl, preferably hydrogen. Preferably And the substituent is NR₉When C (O) Ra, Ra is preferably an alkyl group, for example, Methyl.   Suitably, Rc is hydrogen, alkyl, aryl, arylC_1-4Alkyl, a Reel C_2-4Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, Hete Lower aryl C_2-4Alkenyl, heterocyclic, or heterocyclic C_1-4Alkyl or heterocyclic C_2-4Alkenyl groups; Are optionally one to three times independently halogen, nitro, halo substituted C_1-4 Alkyl, C_1-4Alkyl, C_1-4Alkoxy, NR₉C (O) Ra) C (O) NR₆ R₇, S (O)_ThreeH; or C (O) OC_1-4Alkyl (where R₉Is hydrogen or C_1-4 Alkyl). Preferably, Rc is optionally Phenyl which may be substituted.   R is OR_TwoOr SR_TwoGroup, and therefore those skilled in the art will appreciate the aryl ring Must contain certain ionizable hydrogen. Aryl The ring may be further independently substituted with one to three groups, which further comprises It may contain groups that can be turned on, such as, but not limited to, halogen, nitro B, halo substituted C_1-4Alkyl, C_1-4Alkyl, C_1-4Alkoxy, hydroxy, SH, C (O) NR₆R₇, NH-C (O) Ra, NHS (O)_TwoRb, S (O)_TwoNR₆R₇ , C (O) OR₈Or a tetrazolyl ring.   In the compounds of formula (I), suitably₁Is independently hydrogen; halogen; d. Toro; Cyano; Halo-substituted C_1-10Alkyl, for example CF_ThreeC_1-10Alkyl, for example Methyl, ethyl, isopropyl or n-propyl; C_2-10Alkenyl; C_1-10 Alkoxy, such as methoxy, or ethoxy; halo-substituted C_1-10Alkoxy For example, trifluoromethoxy; azide; (CR₈R₈)_qS (O)_tR_Four(Where t Is 0, 1 or 2); hydroxy; hydroxy C_1-4Alkyl, e.g. Aryl, such as phenyl or naphthyl; aryl Le C_1-4Alkyl, such as benzyl; aryloxy, such as phenoxy; C_1-4Alkyloxy, such as benzyloxy; heteroaryl; heteroa Reel alkyl; heteroaryl C_1-4Alkyloxy; aryl C_2-10Arche Nil; 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)_q C (O) R₁₁C_2-10Alkenyl C (O) R₁₁C_2-10Alkenyl C (O) OR₁₁C (O) R₁₁; (CR₈R₈)_qC (O) OR₁₂; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_q NR_FourC (O) R₁₁, (CR₈R₈)_qNHS (O)_TwoR₁₉, (CR₈R₈)_qS (O)_TwoNR_FourR_Five Or two R₁The groups together form O- (CH_Two)_sO-Also Forms a 5- or 6-membered saturated or unsaturated ring; s is an integer from 1 to 3. A Reel, heteroaryl, and heterocyclic-containing groups are referred to herein. May be optionally substituted as defined below.   Suitably, q is 0 or an integer from 1 to 10.   Suitably, R_FourAnd R_FiveIs independently hydrogen, optionally substituted C_1-4Alkyl, optionally substituted aryl, optionally substituted Optionally substituted aryl C_1-4Alkyl, optionally substituted hete Loaryl, optionally substituted heteroaryl C_1-4Alkyl, Heterocyclic, heterocyclic C_1-4Alkyl or R_FourYou And R_FiveIs selected from O / N / S together with the nitrogen to which they are attached. Form a 5- to 7-membered ring optionally containing yet another heteroatom. To achieve.   X-containing rings are indicated by their asterisks indicating their point of attachment. X ring is R₁Substituted by group Or both the phenyl ring and the X ring are independently R₁By May be substituted. Suitably, if the X ring is substituted, the nitrogen-containing X The ring is C (O) NR_FourR_FiveSubstituted with a nitrogen moiety by an amide functionality such as More preferably, R_FourOr R_FiveIs an optionally substituted aryl, e.g. For example, phenyl. Preferably, larger saturated nitrogen-containing rings are also aryl In the ring Therefore, it may be replaced.   R₈Is suitably independently hydrogen or C_1-4Selected from alkyl.   R_TenIs suitably C_1-10Alkyl C (O)_TwoR₈, For example, CH_TwoC (O)_TwoH or CH_TwoC (O)_TwoCH_ThreeIt is.   R₁₁Is suitably hydrogen, C_1-4Alkyl, aryl, aryl C_1-4Alkyl, Heteroaryl, heteroaryl C_1-4Alkyl, heterocyclic, or Heterocyclic C_1-4Alkyl.   R₁₂Is suitably hydrogen, C_1-10Alkyl, optionally substituted Reel or optionally substituted arylalkyl.   R₁₉Is C_1-4Alkyl, aryl, arylalkyl, heteroaryl, f Teloaryl C_1-4Alkyl, heterocyclic, or heterocyclic C_1-4Alkyl, wherein all of these groups are optionally substituted I).   Preferably, R₁Is halogen, cyano, nitro, CF_Three, C (O) NR_FourR_Five, Al Kenyl C (O) NR_FourR_Five, C (O) R_FourR_Ten, Alkenyl C (O) OR₁₂, Hetero ant , Heteroarylalkyl, heteroarylalkenyl, or S (O) NR_Four R_FiveAnd preferably R_FourAnd R_FiveAre both hydrogen or one is hydrogen Enyl. R₁A preferred ring substitution for is at the 4-position of the phenyl ring. is there.   R is OH, SH or NSO_TwoIf Rb, then R₁Is preferably in the 3-position, Monosubstituted in the 4-position or disubstituted in the 3,4-position You. The substituent is suitably an electron withdrawing group. Preferably, R is OH, SH or Or NSO_TwoIf Rb, then R₁Is nitro, halogen, cyano, trifluoromethyl Chill group, C (O) NR_FourR_FiveIt is.   When R is a carboxylic acid, R₁Is preferably hydrogen or R₁Is preferred Or at the 4-position, more preferably trifluoromethyl or Substituted with chloro.   In the compounds of formula (I), suitably₁₃And R₁₄Is independently hydrogen, An optionally substituted straight or branched chain as defined herein Good C_1-4Alkyl or R₁₃And R₁₄One of which is optionally substituted V is 0, or an integer from 1 to 4.   R₁₃Or R₁₄When is an optionally substituted alkyl, The alkyl moiety is one to three times independently halogen; halo-substituted C_1-4Alkyl, For example, trifluoromethyl; hydroxy; hydroxy C_1-4Alkyl, C_1-4Al Coxy; eg methoxy, or ethoxy, halo-substituted C_1-10Alkoxy, S (O)_t R_FourAryl; NR_FourR_Five; NHC (O) R_FourC (O) NR_FourR_FiveOr C (O) O R₈May be substituted.   In the compound of formula (I), the X-containing ring is (Where the asterisk * indicates the point of attachment of the ring). Asterisk(*) Is an X-containing ring whose bonding point is represented by (R₁)_mBased on In the present specification, when only the phenyl ring is substituted Is shown.   In compounds of formula (I), R₂₀Is suitably W₁Optionally substituted An optionally substituted heteroaryl, an optionally substituted C_5-8Cycloalkyl , An optionally substituted C_1-10Alkyl, optionally substituted May be C_2-10Alkenyl, or optionally substituted C_2-10Al Kinyl.   Suitably, W₁Is It is.   Suitably, the E'-containing ring optionally comprisesMay be selected.   An E'-containing ring whose point of attachment is indicated by an asterisk (*) Good. If not present, the ring is substituted by a Y group as shown. Phenyl group. The ring E is represented by (Y) in either a saturated or unsaturated ring._n May be substituted by a group, wherein only unsaturated rings are substituted herein. Show the case.   R₂₀Is optionally substituted C_5-8When it is a cycloalkyl ring, The ring is (Y) as defined above._nMay be substituted.   R₂₀Is optionally substituted C_1-10Alkyl, optionally substituted May be C_2-10Alkenyl, or optionally substituted C_2-10 When alkynyl groups, these groups may be independent of one or more if desired. And halogen; nitro; cyano; halo-substituted C_1-10Alkyl, for example trifluoro Lomethyl; C_1-10Alkoxy; halo-substituted C_1-10Alkoxy; S (O)_tR_Four; Hydro Xy; hydroxy C_1-4Alkyl; aryloxy; aryl C_1-4Alkyloxy C; heteroaryloxy; heteroaryl C_1-4Alkyloxy; heterocyclyl Click; Heterocyclic C_1-4Alkyl; heterocyclicoxy; f Terror cyclic C_1-4Alkyloxy; NR_FourR_FiveC (O) NR_FourR_Five; C (O) N R_FourR_TenS (O)_ThreeH; S (O)_ThreeR₈C (O) R₁₁; C (O) OR₁₂; OC (O) R₁₁ ; NR_FourC (O) R₁₁May be optionally substituted. R₂₀If desired Optionally substituted C_2-10Alkenyl or optionally substituted C_2-10When alkynyl, in addition to the above groups, these groups are also aryl , Aryl C_1-4Alkyl, heteroaryl and heteroarylalkyl It may be substituted as desired.   In compounds of formula (I), R₂₀Is a heteroaryl (HET) ring; Suitably, it is a heteroaryl ring or ring system. If the HET group is polycyclic, The ring containing the b atom does not need to be directly attached to the urea group. All in the ring system All rings may be optionally substituted as defined herein. Preferably, the HET group is pyridyl, which may be 2-, 3- or 4-pyridyl. It is. If the ring is a polycyclic ring, preferably benzimidazole, diben It is a zothiophene or indole ring. Other related heterocyclic rings are But not limited to, thiophene, furan, pyrimidine, pyrrole, pyra Sol, quinoline, isoquinoline, quinazolinyl, pyridine, oxazole, Azole, thiadiazole, triazole, imidazole or benzimidazo Incl.   In the compounds of formula (I), the HET ring may be independently, optionally 1-3 times , Y, that is, (Y_(n)) (Where n is an integer from 1 to 3) It may be substituted. Y is suitably independently hydrogen; halogen; nitro; Cyano; halo-substituted C_1-10Alkyl; C_1-10Alkyl; C_2-10Alkenyl; C_1-10 Alkoxy; halo-substituted C_1-10Alkoxy; azide; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4Alkyl; aryl; aryl C_1-4Alkyl; Reeloxy; aryl C_1-4Alkyloxy; heteroaryl; heteroaryl Alkyl; heteroaryl C_1-4Alkyloxy; heterocyclic, hete Cyclic C_1-4Alkyl; aryl C_2-10Alkenyl; heteroaryl C_{Two -Ten} Alkenyl; heterocyclic C_2-10Alkenyl; (CR₈R₈)_qNR_FourR_Five; C_2-10Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_Five; (CR₈ R₈)_qC (O) NR_FourR_TenS (O)_ThreeH; S (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁C_2-10Alkenyl C (O) O R₁₁C (O) R₁₁; (CR₈R₈)_qC (O) OR₁₂; (CR₈R₈)_qOC (O) R₁₁ ; (CR₈R₈)_qNR_FourC (O) R₁₁; (CR₈R₈)_qNHS (O)_TwoR_dOr (CR₈R₈)_qS (O)_TwoNR_FourR_FiveOr two Y groups are taken together And O- (CH_Two)_sForming an O- or 5- or 6-membered saturated or unsaturated ring May be. These aryl, heteroaryl and heterocyclic containing The groups may also be optionally substituted as defined herein.   Suitably, R. Is NR₆R₇, Alkyl, aryl C_1-4Alkyl, aryl C_2-4Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, hetero ant C_2-4Alkenyl, heterocyclic, heterocyclic C_1-4Alkyl (Including alkyl, aryl, heteroaryl, and heterocyclic The radical may be optionally substituted as defined herein) You.   R₂₀Is preferably an optionally substituted phenyl, allyl, C_1-10 Alkyl, ethoxycarbonylethyl, dimethylacetal, 2-methoxy Isopropyl or 2-methoxyethyl.   In the compounds of formula (I), Z is suitably cyano, OR₁₁, C (O) NR_Fifteen R₁₆, R₁₈, C (O) R₁₁, C (O) OR₁₁Or S (O)_TwoR₁₇It is.   Suitably, R_FifteenAnd R₁₆Is independently hydrogen, optionally substituted Good C_1-4Alkyl, optionally substituted aryl, optionally substituted Optionally substituted aryl C_1-4Alkyl, optionally substituted Heteroaryl, optionally substituted heteroaryl C_1-4Archi Optionally substituted heterocyclic, optionally substituted heterocyclic May be heterocyclic C_1-4Alkyl or R_FifteenAnd R_{1 6} Selected from oxygen, nitrogen or sulfur, together with the nitrogen to which they are attached A 5- to 7-membered ring optionally containing another heteroatom It may be formed.   Suitably, R₁₇Is hydrogen, C_1-4Alkyl, NR_FifteenR₁₆Optionally substituted Optionally substituted aryl, optionally substituted aryl C_1-4Archi , Optionally substituted heteroaryl, optionally substituted Optionally heteroaryl C_1-4Alkyl, optionally substituted hete Heterocyclic C optionally substituted_{1- Four} Alkyl.   R₁₈Is suitably an optionally substituted C_1-4Alkyl, as desired More optionally substituted aryl, optionally substituted aryl C_1-4Alkyl, optionally substituted heteroaryl, optionally Optionally substituted heteroaryl C_1-4Alkyl, optionally substituted Heterocyclic or optionally substituted heterocyclic Click C_1-4Alkyl.   As used herein, “optionally substituted” refers to Unless otherwise noted, halogen such as fluorine, chlorine, bromine or iodine; hydroxy A hydroxy-substituted C_1-10Alkyl; C such as methoxy or ethoxy_1-10Arco Kishi; S (O) m'C_1-10Alkyl (where m 'is 0, 1 or 2), e.g. Methylthio, methylsulfinyl or methylsulfonyl; amino, one and Disubstituted amino, such as NR_FourR_FiveGroup; NHC (O) R_FourC (O) NR_FourR_FiveC (O) O H; S (O)_TwoNR_FourR_Five; NHS (O)_TwoR_{twenty one}, C_1-10Alkyl, such as methyl, d Tyl, propyl, isopropyl, or t-butyl; halo-substituted C_1-10Alkyl, For example, CF_ThreeAn optionally substituted aryl, such as phenyl, or Or an optionally substituted arylalkyl such as benzyl or Phenethyl, optionally substituted heterocyclic, optionally Optionally substituted heterocyclic alkyl, optionally substituted Heteroaryl, optionally substituted heteroarylalkyl (Wherein these aryl, heteroaryl or heterocyclic moieties Is halogen once or twice; hydroxy; hydroxy-substituted alkyl; C_1-10Al Coxy; S (O) m'C_1-10Alkyl; amino, mono- and disubstituted amino, such as N R_FourR_FiveGroup; C_1-10Alkyl or halo substituted C_1-10Alkyl, for example CF_ThreeTo Which may be more substituted).   R_{twenty one}Is, appropriately, C_1-4Alkyl, aryl, aryl C_1-4Alkyl, Hete Low aryl, heteroaryl C_1-4Alkyl, heterocyclic or hetero Cyclic C_1-4Alkyl.   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, tartaric acid , Citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, Basic salts of inorganic and organic acids such as lylic acid, phenylacetic acid and mandelic acid Include. In addition, pharmaceutically acceptable salts of the compounds of formula (I) may further be prepared, e.g. When the substituent comprises a carboxy group, it is formed together with a pharmaceutically acceptable cation. May be. Suitable pharmaceutically acceptable cations are well known to those skilled in the art, and Includes metals, alkaline earth metals, ammonium and quaternary ammonium cations I do.   The following terms, as used herein, mean the following:   "Halo"-any halogen, i.e. chlorine, fluorine, bromine and iodine U.   ・ "C_1-10`` Alkyl '' or `` alkyl ''-if the chain length is not limited, A straight-chain or branched group having a prime number of 1 to 10, methyl, ethyl, n-propyl , Iso-propyl, n-butyl, sec-butyl, iso-butyl, tert -Butyl, n-pentyl and the like, but are not limited thereto.   The term "cycloalkyl", as used herein, preferably Cyclic radical having from 3 to 8 carbon atoms, cyclopropyl, cyclopropyl Including but not limited to lopentyl, cyclohexyl and the like.   The term “alkenyl”, as used herein, in all cases Unless the chain length is limited, a straight chain having 2 to 10 carbon atoms or Means a branched group, ethenyl, 1-propenyl, 2-propenyl, 2-methyl- Including, but not limited to, 1-propenyl, 1-butenyl, 2-butenyl and the like. Not.   -"Aryl"-refers to phenyl and naphthyl.   "Heteroaryl" (itself or "heteroaryloxy" or " Tyrarylalkyl ")-pyrrole, pyrazole, fura Thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidi , Oxazole, thiazole, thiadiazole, triazole, imidazole Or one or more such as, but not limited to, benzimidazole One or more heterocycles wherein the upper ring is selected from the group consisting of N, O or S A 5- to 10-membered aromatic ring system containing atoms.   ・ "Heterocyclic" (itself or "heterocyclylalkyl") In any combination) -pyrrolidine, piperidine, piperazine, morpholine, te One such as, but not limited to, trahydropyran, or imidazolidine Or one or more of which rings are selected from the group consisting of N, O or S A saturated or partially unsaturated 4- to 10-membered ring system containing the above heteroatoms. U.   “Arylalkyl” or “heteroarylalkyl” or “heterocyclyl” The term "click alkyl" is used herein unless otherwise specified. Linked to an aryl, heteroaryl or heterocyclic group C_1-10Means alkyl   "Sulfinyl"-refers to the oxide S (O) of the corresponding sulfide, "thio" The term “sulfonyl” refers to sulfide and the term “sulfonyl” (O)_TwoMeans a group.   ・ "Two Rs₁Groups (or two Y groups) together form a 5 or 6 membered saturated or Form an unsaturated ring.₆Cycloalkenyl, That is, a 6-membered partially unsaturated ring such as hexene, or C_FiveCycloalkenyl moiety, That is, it is intended to form a naphthylene ring system or a phenyl group to which cyclopentene is bonded. To taste.   The compounds of the present invention may be stereoisomers, regioisomers, or diastereomers. It is considered to exist. These compounds have one or more asymmetric carbon sources. And can exist in racemic and optically active forms. All of these compounds Included within the scope of the present invention.   Compounds of formula (I) were obtained using synthetic methods, some of which are shown in the scheme below. It is. The synthetic methods used in these schemes are based on a variety of different R, R₁And ants Is applicable to the preparation of compounds of formula (I) having Reaction utilizing any of the substituents provided, and is compatible with the reactions outlined herein. Let it. In these cases, then deprotected and its properties are generally disclosed Obtain the compound. Once the urea nucleus is established, yet another compound of these formulas Can be prepared using standard techniques for functional group transformation well known in the art. The scheme is Shown only with reference to compounds of formula (I), this is for illustrative purposes only.   Preparation method   The title compound is a thiouronium salt (2, Scheme 1). R 'is ,-(R) as defined in compounds of formula (I)₁₃R₁₄)_v-R₂₀Represents a bond. For the purposes of the present description, the scheme represented by W comprises an R group and an X It is a substituted phenyl containing a ring.                                Scheme 1   a) Na, EtOH, cyanamide b) EDC · HCl   Thiouronium salt (2Scheme 1) shows that sodium cyanamide is commercially available Thiocyanate1(If isothiocyanate is not commercially available, desirable The amine is reacted with thiophosgene in the presence of a base such as sodium bicarbonate. Can be synthesized by reacting Thiouronium salt(2) Is then coupled with an appropriately substituted aniline, such as EDC.HCl Condensed or acidified in the presence of an agent to form a cyanothiourea, and then Can react.   Alternatively,4Is a commercially available diphenylcyanocarbodii (Aldrich Chem. Co.) Middate (5, Scheme 2) is reacted with an amine to form an intermediate O-phenylisourine Elementary6Which is then combined with the appropriately substituted aniline and trimethylaluminum. In the presence, the method of Atwal (Atwal, K.S., Tetrahedron Lett, 35, 8085 (1994)) It can be synthesized by further reacting. Compounds wherein R 'is alkyl are Prepared by heating with the substituted alkylamine, but in the absence of a catalyst. Made.                                Scheme 2   a) acetonitrile, heating b) AlMe_Three   Alternatively, the title compound is a protected ortho-substituted aniline (8Using scheme 3) And can be synthesized. US Provisional Application USSN 60/020655 June 27, 1996 Application No., Agent Reference Number: P50467P; USSN60 / 020657 19 Filed on June 27, 1996, Agent Reference Number P50470P; WO96 / 25157 Widowson et al. (Attorney Docket No .: P503) filed on August 22, 1996 24-1); and USSN 08/701299, filed on August 21, 1996 ( Attorney Reference Number: P50324-2) (All disclosures of the present invention are made by reference.) ). Ortho-substituted aniline (7, Ski 3) is combined with a suitable alkyl or silyl halide with a suitable base (ie, carbonate Aprotic solvent in the presence of cesium, potassium carbonate or imidazole) The protection (ie, tert-butyldimethylsilyl, allyl) Benzyl or other suitable protecting group). Protected ortho substituted anili Is further substituted with ortho-substituted nitrobenzene (9), Which can be combined with protecting groups in the field It is also synthesized by reacting under known conditions (Greene, T,Protecting G rouos in Organic Synthesis , Wiley & Sons, New York, 1981). This Of the protected ortho-substituted nitro compound is then converted to SnCl_TwoOr alternatively a non- H in rotonic solvents_Two/ Pd or LiAlH_FourTo reduce the corresponding anili Turn on                                Scheme 3   a) alkyl or silyl halide, base b) reducing agent   This protected ortho-substituted aniline (8) Is then treated with thiophosgene to give Can be converted to anate, and then the anion ZNH^-(ZNH_TwoAnd bases such as NaH From the reaction). Z is as defined in the compound of formula (I) . The resulting thioanion is then alkylated with an alkylating agent such as methyl iodide. And thioimidate, for example10(Scheme 4) can be formed.                                Scheme 4      a) ClCSCl, NaHCO_Three    b) ZNH^-    c) MeI   Thioimidate (10, Scheme 5) uses the amine R'NH_TwoReaction with The compound4Can be converted to This reaction is a metal salt with a high affinity for sulfur For example, adding mercury oxide or silver acetate or removing sulfur with dimethyloxirane It can be facilitated by oxidizing to form better leaving groups. Eventually, Feno The protection of the title compound by standard methods4To form                                Scheme 5   a) R'NH_Two  b) Deprotection   Alternatively, the title compound is a protected carbodiimide (11, Scheme 6) On NH-Z (NH_TwoZ formed from the reaction of Z with a base such as NaH) or neutral compound Thing NH_TwoZ (Z = CN) and tertiary amine bases such as Hunig's base (diisopropane Propyl ethylamine), triethylamine, triisopropylethylamine, N , N-dimethylbenzylamine or N, N-dimethylisopropylamine; A large excess of nucleophiles is present and can be monitored by careful monitoring of the completion of the reaction. Reaction under conditions that keep the reaction time as short as possible, followed by deprotection. Can be synthesized. Other suitable bases for use in the present invention are secondary amines such as, for example, Pyridine and amino-substituted pyridine derivatives. When Z is cyano Suitable solvents for use in the present invention include various aprotic solvents, such as Nitriles; halogenated solvents such as chloroform and methylene chloride; Recol-dimethyl ether (monoglyme), dioxane, DMF and DM SO; or mixtures thereof. Preferably it is acetonitrile. The present invention What limits the use of the solvent in is that the solubility of the cyano derivative is It will be understood by those skilled in the art. When Z is a compound other than cyano, an aprotic solvent is preferred. Preferably, other suitable solvents, such as protic solvents, i.e. alcohols It can be understood by those skilled in the art.   Preferably, the temperature of the reaction (when Z is cyano) is from about -10C to about 100C. ℃, preferably about 10 ℃ to about 50 ℃, more preferably around room temperature Ie, 20-30 ° C.   The protected R ″ group may be suitably deprotected using art recognized techniques. Preferably, deprotection is with palladium (O) when the protecting group is an allyl derivative. By catalyzed deallylation.                                Scheme 6   a) Z = OR, COOEt, CHO, RNHSO_Two, ArNHSO_TwoThen, ZN H^-(ZNH_Two+ NaH); b) for Z = OH, ZNH_Two・ HCl c) Z = CN Then, ZNH_TwoAnd NR_Three  d) Deprotection   Carbodiimide11Is treated with phosgene and a tertiary amine base to give thiourine Element (12aFrom scheme 7) or from triphenylphosphine, carbon tetrachloride and And thiourea (by reaction with triethylamine)12a) Or urea (12b) Prepared from Carbodiimides further include thioureas (12b), Excess, analogy 2 or more equivalents of methanesulfonyl chloride and a tertiary amine base, eg For example, Hunig's base (diisopropylethylamine), triethylamine, triethylamine Sopropylethylamine, N, N-dimethylbenzylamine, or N, N-di Prepared by reaction with methyl isopropylamine, preferably triethylamine It is. The reaction may be, for example, methylene chloride, chloroform, or tetrachloroethylene. Use any halogenated solvent such as butane; a suitable reaction temperature is about -30 ° C About 80 ° C., preferably -10 ° C. to about 50 ° C., more preferably about 0 ° C. Or around room temperature. Fell and Coppola (Fell, J.B., Coppola, J.B., SynCom munications 25, 43, (1995)).                                Scheme 7   a) Phosgene, Et_ThreeN, b) Ph_ThreeP, CCl_Four, Et_ThreeN; c) MsCl, NEt_ThreeN   Thiourea or urea derivatives are described in US provisional application USSN 60/020655, US SN 60/020657, WO 96/25157 and USSN 08/7012 99 (supra). Thiourea (12a, Scheme 8) further comprises converting the protected ortho-substituted aniline to 2 equivalents of a suitable base such as NaH, KH, calcium hydride and the anion Aneto (W₁−NCS, where W₁Is as defined for compounds of formula (I) Is prepared by reacting The reaction is performed using any suitable non-pro The reaction is carried out in a solvent or a halogenated solvent, preferably dimethylformamide. You. Suitable reaction temperatures for this reaction are from about -10C to about 50C.   If the desired isothiocyanate is not commercially available, then the corresponding Reaction of aniline with thiophosgene and a suitable base such as sodium bicarbonate May be prepared.                                Scheme 8  a) base, b) R'NCS   Another embodiment of the present invention provides a compound of formula (II)             R₂₀-N = C = N-W (II)   [Wherein, R₂₀Is as defined for formula (I), and W is a compound of formula (I) X-containing ring systems containing protected or unprotected R groups (R ") as defined for Is] Is a novel compound represented by   Another embodiment of the present invention provides a compound of formula (III)             R₂₀—NH—C (S) —NH—W (III)   [Wherein, R₂₀Is as defined for formula (I), and W is a compound of formula (I) X-containing ring systems containing protected or unprotected R groups (R ") as defined for Is] Is a novel compound represented by   In addition, the protected (R ″) compound of formulas (I), (II) and (III) The forms are considered to be within the scope of the present invention.   The guanidine function can be any of a variety of different tautomers, such as R₂₀-NC (= NZ) −NW; ZN = C (NR₂₀) -NW; R₂₀-NC (= NW) -NZ All within the scope of the present invention, wherein W is as defined for compounds of formula (I) X-containing ring systems containing such protected or unprotected R groups (R ").   Pharmaceutically acceptable salts of the compounds of formula (I) can be prepared by known methods, It is obtained by treating with an appropriate amount of acid or base in the presence of a suitable solvent. Treatment   The compound of formula (I), or a pharmaceutically acceptable salt thereof, may be a human or other mammal. In an animal, such mammalian cells, eg, monocytes and / or macro Phage, or IL-8α or β receptor (type I or type II receptor ) Or other chemokines that bind (but are not limited to) Is a predictor of conditions exacerbated or caused by unregulated IL-8 cytokine production. It can be used in the manufacture of a medicament for preventive or therapeutic treatment.   Thus, the present invention provides that the chemokines bind to IL-8α or β receptors. For the treatment of a chemokine-mediated disease, comprising an effective amount of a compound of formula (I) Or a pharmaceutically acceptable salt thereof. In particular , Chemokines are IL-8, GROα, GROβ, GROγ, ENA-78 or Is NAP-2.   Compounds of formula (I) have cytokine function, especially IL-8, GROα, GROβ Inhibits GROγ, ENA-78 or NAP-2 and restores physiological function to normal Biologically down-regulate or possibly normal It is administered in an amount effective below the level to improve the condition. For example, the present invention IL-8, GROα, GROβ, GROν, ENA-78 or NAP for Abnormal level of -2 means (i) the level of free IL-8 of 1 picogram / mL or more. (Ii) any cellular IL-8, GRO above normal physiological levels α, GROβ, GROγ, ENA-78 and NAP-2; or (iii) I Each of L-8, GROα, GROβ, GROγ, ENA-78 or NAP-2 Above the basal level of IL-8, GROα, GR in cells or tissues producing The presence of Oβ, GROγ, ENA-78 or NAP-2.   Excessive or unregulated IL-8 production is involved in its exacerbation and / or development. I have many diseases. Chemokine-mediated diseases include dry habits, atopic dermatitis, arthritis, asthma Breathing, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, ulcerative Colitis, stroke, septic shock, endotoxin shock, gram-negative sepsis, toxic Shock syndrome, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, graft-versus-host Reaction, Alzheimer's disease, allograft rejection, malaria, restenosis, angiogenesis Or unwanted hematopoietic stem cell release.   These conditions may be due to massive neutrophil infiltration, T-cell infiltration, or neovascular growth. Source of neutrophil chemotaxis or endothelial cell directional growth to sites of inflammation Increased IL-8, GROα, GROβ, GROν or NAP-2 production Is associated with Other inflammatory cytokines (IL-1, TNF and IL-6 In contrast, IL-8, GROα, GROβ, GROν or NAP-2 Enzyme release, including but not limited to neutrophil chemotaxis, elastase release And have unique properties that promote superoxide production and activation. Special In addition, GROα, GROβ, which are acted on by IL-8 type I or II receptors, GROν or NAP-2, but α-chemokines are dependent on endothelial cell orientation Promotion of growth may promote tumor neovascularization. Therefore, IL-8 induction Inhibition of chemotaxis or activation results in a direct decrease in neutrophil infiltration.   Recently, the role of chemokines in the treatment of HIV infection has been demonstrated. man et al., Nature 381, pp 661 (1996) and Koup et al., Nature 381, pp 667 (1996).   The present invention further provides a chemokine receptor antagonist compound of formula (I) Acute treatment in individuals deemed susceptible to CNS injury and Provide preventive measures.   CNS injuries as defined herein may be open or due to surgery, for example. Includes both penetrating head trauma and closed head trauma due to damage to the head area Include. In particular, ischemic strokes to brain parts are also included in this definition.   Ischemic stroke is usually the result of a local atheromatous occlusion of an embolus, thrombus or blood vessel Defined as localized neuropathy resulting from insufficient blood supply to specific brain regions Is done. The role of inflammatory cytokines in this region has been elucidated and Provides a potential cure for these injuries. For acute injuries like these There are relatively few treatments available.   TNF-α is a proinflammatory drug that includes endothelial leukocyte adhesion molecule expression. Itokine. Leukocytes infiltrate into ischemic brain lesions and block TNF levels. Harmful or reducing compounds are useful for treating ischemic brain injury. Li u et al., Stoke, Vol. 25., No. 7, pp 1481-88 (1994) (the disclosure of ).   A model of closed head injury and treatment with a 5-LO / CO mixture has been described by Shohami et al. , J. of Vaisc & Clinical Physiology and Pharmacology, Vol. 3, No. 2, pp. 99-107 ( 1992), the disclosure of which is hereby incorporated by reference. Floating Treatments that reduce tumor formation improve functional outcome in these treated animals It turned out to be.   Compounds of formula (I) are used to bind IL-8 alpha or beta receptors These L-8s are demonstrated, for example, by reduced neutrophil chemotaxis and activation. It is administered in an amount sufficient to inhibit binding to the receptor. Compounds of formula (I) The finding that it is an inhibitor of L-8 binding has been identified in the in vivo described herein. Based on the effect of the compound of formula (I) in the receptor binding assay. Formula (I) The combination may optionally be a recombinant form of both recombinant type I and type II IL-8 receptors. It has been found to be a principal inhibitor. Preferably, the compound has one receptor And more preferably a type II inhibitor.   As used herein, the term "IL-8 mediated disease or condition" IL-8, GROα, GROβ, GROν, ENA-78 or NAP-2, IL-8, GROα, GROβ, GROγ, ENA-78 or NAP-2 that Or IL-8, GROα, GROβ, GROγ, ENA-78 or Means that NAP-2 is a different monokine, such as IL-1, IL-6 or TNF (which And any disease involved in inducing the release of Means state. Thus, for example, IL-1 is the main component and its production or Conditions whose effects are exacerbated or secreted in response to IL-8 are mediated by IL-8 It is considered to be a pathological condition.   As used herein, the term "chemokine-mediated disease or condition" is Chemokines that bind to IL-8a or b receptors, such as IL-8, GR Oα, GROβ, GROν, ENA-78 or NAP-2 (but not limited to B) means any and all conditions involved. This is IL-8 Production, or IL-8 is another monokine, such as IL-1, IL-6 or Disease states involving IL-8 by triggering the release of (but not limited to) TNF Is included. Thus, for example, IL-1 is the main component and its production or production Conditions that are exacerbated or secreted in response to IL-8 are mediated by IL-8 Is considered to be a pathological condition.   As used herein, the term “cytokine” affects the function of a cell. Molecules that affect and modulate cell-cell interactions in the immune, inflammatory or hematopoietic response Means a polypeptide that is secreted. Which cells are cytokines Including monokines and lymphokines, regardless of whether they produce It is not limited to. For example, monokines are commonly found in mononuclear cells, such as macrophages. And / or secreted by monocytes. However And many other cells are also natural killer cells, fibroblasts, basophils, neutrophils Spheres, endothelial cells, brain astrocytes, bone marrow stromal cells, epidermal keratinocytes and B-li Produces monokines, such as tampa balls. Lymphokines are generally released by lymphocytes What is produced. Examples of cytokines include interleukin-1 (I L-1), interleukin-6 (IL-6), interleukin-8 (IL- 8), tumor necrosis factor-alpha (TNF-α) and tumor necrosis factor beta (TN F-β).   As used herein, the term “chemokine” refers to the aforementioned “site Like Cain, it affects the functioning of cells and can be used in immune, inflammatory or hematopoietic responses. By any secreted polypeptide that is a molecule that regulates the interaction between vesicles. Chemokines are mainly secreted from cellular transmembrane and are used for certain leukocytes, neutrophils. , Chemotaxis of monocytes, macrophages, T-cells, B-cells, endothelial cells and smooth muscle cells Causes gender and activation. Examples of chemokines are IL-8, GROα, GRO β, GROν, ENA-78, NAP-2, IP-10, MIP-1α, MIP -Β, PF4, and MCPs 1, 2, and 3, including but not limited to No.   Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in therapy This is usually formulated into pharmaceutical compositions according to standard pharmaceutical practice. Therefore, The present invention further provides an effective and non-toxic amount of a compound of formula (I) and a pharmaceutically acceptable carrier. Or a pharmaceutical composition comprising a diluent.   Compound of formula (I), pharmaceutically acceptable salt thereof and pharmaceutical composition containing the same Can be administered by any suitable route commonly used for drug administration, eg, oral, topical, parenteral Alternatively, it is conveniently administered by inhalation. The compound of formula (I) is a compound of formula (I) The compound prepared by combining the compound with a standard pharmaceutical carrier in a conventional manner. It is administered in the usual dosage form. The compounds of formula (I) may further comprise a second known therapeutically active agent. The compound can be administered in a usual administration form in combination with a sexual compound. These methods use the components Mix, granulate and compress, or dissolve, as appropriate, to obtain the desired preparation. Consisting of The form and characteristics of the pharmaceutically acceptable carrier or diluent are It will depend on the amount of active ingredient combined, the route of administration and other known factors. Carriers are "acceptable" in the sense that they are compatible with the other ingredients of the formulation and are not harmful to the consumer. "There must be.   The pharmaceutical carrier employed can be, for example, either a solid or liquid. Solid carrier Examples are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, Acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers Is syrup, peanut oil, olive oil, water and the like. Similarly, carrier or dilute Excipients include glyceryl monostearate or glyceryl distearate. Retarders well known in the art may be included alone or with a wax.   A wide variety of pharmaceutical forms can be used. Therefore, use a solid carrier If appropriate, the formulation may be in the form of tablets or hard gelatin capsules in powder or pellet form. Or in the form of a troche or lozenge. Wide range of solid carriers It ranges from about 25 mg to about 1 g. When using a liquid carrier Preparations can be sterile injectable, such as syrups, emulsions, soft gelatin capsules, and ampoules Liquid or non-aqueous suspensions.   The compounds of the formula (I) are administered locally, ie by non-systemic administration. this is, External and epidermal or oral administration of compounds of formula (I) and such Includes compound instillation into ears, eyes and nose, preventing compound from significantly entering the bloodstream To do. In contrast, systemic administration is oral, intravenous, intraperitoneal and intramuscular. Means internal administration.   Formulations suitable for topical administration are liquids suitable for penetration through the skin at the site of inflammation. Or semi-liquid preparations, such as liniments, lotions, creams, ointments or paces And drops suitable for administration to the eye, ear or nose. Active ingredients For local administration, 0.001% to 10% w / w of the formulation, eg 1% to 2% % By volume. However, it may contain 10% w / w of the formulation, but is preferred. Or less than 5% w / w, more preferably between 0.1% and 1% w / w.   The lotions of the present invention include those suitable for application to the skin or eyes. Eye drops The lotion contains a sterile aqueous solution which may optionally contain a bactericide, Prepared by a similar method. Lotion or linimen for application to skin Is an agent that promotes drying and cooling of the skin, such as alcohol or acetone. And / or humectants such as glycerol or castor oil or peanut oil Any oil may be included.   The cream, ointment or paste according to the invention is a semi-solid active ingredient for external application. Body prescription. These concentrate the active ingredient in fine powder or powder form, alone or aqueous Or in the form of a solution or suspension in a non-aqueous fluid, using a suitable machine It is prepared by mixing with a ground or non-greasy base. Base is hydrocarbon For example, solid, soft or liquid paraffin, glycerol, beeswax, metal soap Serum, almond oil, corn oil, peanut oil, castor oil or olive oil Oils of natural sources such as wool fat or derivatives thereof or stearic acid or oley N Fatty acids such as acids are converted to alcohols such as propylene glycol or macroge May be included with the file. The formulation can be any suitable surfactant, such as an anion, Cationic or nonionic surfactants such as sorbitan esters or their Lioxyethylene derivatives may be blended. Suspending agents such as natural gum, cellulo Base derivatives or inorganic substances such as diatomaceous earth, and other components such as lanoli May be blended.   Drops of the invention may comprise a sterile aqueous or oily solution or suspension, and may contain an active ingredient. The components may be combined with fungicides and / or fungicides and / or other suitable preservatives It is prepared by dissolving in an aqueous solution and preferably incorporating a surfactant. Get The clarified solution is then clarified by filtration, transferred to a suitable container, which is sealed and pressure killed. Sterilize by maintaining the bacteria or at 98-100 ° C for half an hour. Alternatively, the solution The liquid is sterilized by filtration and transferred to the container by aseptic technique. Suitable for incorporation into drops Examples of fungicides and fungicides are phenylmercuric nitrate or acetate (0.002%), Benzalkonium chloride (0.01%) and chlorhexidine acetate (0.0%). 1%). Suitable solvents for preparing oily solutions are glycerol, diluted alcohol And propylene glycol.   The compounds of formula (I) may be administered parenterally, ie, intravenously, intramuscularly, subcutaneously, intranasally, rectally. It is administered by intra, intravaginal or intraperitoneal administration. Parenteral administration in subcutaneous and intramuscular forms Giving is generally preferred. Forms suitable for such administration are prepared by conventional techniques. You. The compounds of formula (I) may further be administered by inhalation, ie, by intranasal or oral inhalation administration. Can also be administered. Suitable for such administration, such as aerosol formulations or metered dose inhalers Dosage forms may be prepared by conventional techniques.   For any use disclosed in the specification with respect to compounds of formula (I) The daily oral dose is preferably from about 0.01 to about 80 per kg of total body weight. mg. The daily parenteral dosage is from about 0.001 to about 8 per kg of total body weight. 0 mg. The daily topical dose is preferably between 0.1 mg and 150 mg. Administration 1 to 4 times, preferably 2 or 3 times a day. Daily inhalation volume Is preferably from about 0.01 mg / kg to about 1 mg / kg per day. Of the formula (I) The optimal amount of the compound or a pharmaceutically acceptable salt thereof and the interval between each administration is treated The nature and extent of the symptoms, the mode of administration, the route and site, and the individual It is also recognized in the art that such optimum values can be determined by ordinary techniques. Will understand. Also, the optimal treatment, i.e. one day for a certain number of days The number of doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered per Can also be ascertained by those skilled in the art using routine treatment decision tests. I can do it.   The present invention will be described with reference to the following biological examples, which are merely exemplary. It is not intended to limit the scope of the invention. Biological examples   The inhibitory effects of the compounds of the present invention on IL-8 and GRO-α chemokines were as follows: Measured by the in vitro test:   Receptor binding assay Specific activity is 2000 Ci / mmol [¹²⁵I] IL-8 (human recombinant) Obtained from rsham Corp., Arlington Heights, IL. GRO-α to NEN-New Engl and from Nuclear. All other chemicals are for analysis. High level of recombination Human IL-8α and β-type receptors were isolated from Chinese hamster ovary cells, respectively. And expressed as previously described [Holmes et al., Science, 19 91, 253, 1278]. Professional Chinese hamster ovary membrane already listed [Haour et al., J Biol Chem., 249pp 2195-2205 (197 Four)]. However, the homogenization buffer was changed to 10 mM Tris-HCL, 1 mM MgSO._Four 0.5 mM EDTA (ethylenediaminetetraacetic acid), 1 mM PMSF (α- Toluenesulfonyl fluoride), 0.5 mg / L leupeptin, pH 7.5 change. The membrane protein concentration was determined by Pierce Co. Using a micro analysis kit , Using bovine serum albumin as a standard. All tests are 96- Perform in the well microplate format. Each reaction mixture contains 1.2 mM MgSO_Four, 0. Contains 1 mM EDTA, 25 mM NaCl and 0.03% CHAPS 20 mM Bis-Tris propane and 0.4 mM Tris HCl buffer In liquid (pH 8.0)¹²⁵IIL-8 (0.25 nM) or¹²⁵I GRO-α and And 0.5 μg / mL IL-8Rα or 1.0 μg / mL IL-8Rβ membrane. Have. In addition, the drug or compound in question, previously dissolved in DMSO, Add to make final concentration between 0.01 nM and 100 uM. Test ,¹²⁵Start with the addition of I-IL-8. After 1 hour at room temperature, Tomtec 96 -Blow with 1% polyethyleneimine / 0.5% BSA using a well harvester Plates are harvested on locked glass fiber filter mats and 25 mM NaC l, 10 mM Tris HCl, 1 mM MgSO_Four0.5 mM EDTA, Wash three times with 0.03% CHAPS (H7.4). The filter is then dried and B Count on an etaplate liquid scintillation counter. Recombinant IL-8 Rα (or type I) receptors are further referred to herein as non-permissive receptors. Recombinant IL-8Rβ (or type II) receptor is a permissive receptor Called.   Chemotaxis test:   The in vitro inhibitory properties of these compounds are described in Current Protocols in Immunology , Vol I, Suppl 1, Unit 6.12.3. (The disclosure of which is incorporated herein by reference in its entirety. The neutrophil chemotaxis assay is used as described in). Neutrophils Current Protocols in Immunology Vol I, Suppl 1 Unit 7.23.1 Human as disclosed herein). Isolated from blood. Chemoattractant IL-8, GRO-α, GRO-β, GRO- gamma and NAP-2 at concentrations between 0.1 and 100 nM for 48 multiwell channels Place in the bottom chamber of the bar (Neuro Probe, Cabin John, MD). Two chas The members are separated by a 5 um polycarbonate filter. Compound of the present invention When testing the cells, these are added immediately before the cells are added to the upper chamber. .001-1000 nM). Incubation is about 45 and 90 minutes Between about 37 ° C and 5% CO_TwoPerform in a humidified incubator. Incubation At the end of the installation period, the polycarbonate membrane is removed, the top is washed, and the membrane is then Diff Stain using the Quick staining method (Baxter Products, McGaw Park, IL, USA). Ke Cells showing chemotaxis to mokine are counted visually using a microscope. General Next, the four fields are counted for each sample, these numbers are averaged and Determine the average number of cells that have moved. Each sample was tested in triplicate and each compound was Repeat at least 4 times. Add compounds to certain cells (positive control cells) These cells show the maximal chemotactic response of the cells. The negative control (not stimulated) If desired, no chemokines are added to the bottom chamber. Positive and negative controls The differences between indicate the chemotactic activity of the cells. Elastase release assay:   The compounds of the present invention have been tested for their ability to prevent elastase release from human neutrophils. Test. Neutrophils, Current Protocols in Immunology Vol I, Suppl 1 Uni t Isolate from human blood as described in 7.23.1. Ringer's solution ( NaCl 118, KCl, 4.56, NaHCO_Three  25, KH_TwoPO_Four  1.0 3. PM suspended in glucose 11.1, HEPES 5 mM, pH 7.4) N 0.88 × 10⁶Individual cells at a volume of 50 ul in each well of a 96-well plate. Into the bag. The plate contains 50 ul of test compound (0.001-10 00 nM), 50 ul (20 ug / ml) of cytochalasin B and 50 u Add 1 volume Ringer's buffer. These cells are brought to a final concentration of 0.01-1. Add 000 nM IL-8, GROα, GROβ, GROγ or NAP-2 Warm for 5 minutes before doing (37 ° C, 5% CO_Two, 95% RH). Reaction is 96 wells Before centrifugation of the plate (800 × g for 5 minutes) and removal of 100 ul of supernatant 4 Proceed for 5 minutes. This supernatant was added to another 96-well plate, and then Rustase substrate (MeOSuc-Ala-Ala-Pro-Val-AMC) N ova Biochem, La Jolla, CA) in phosphate buffered saline. However, it is added to a final concentration of 6 ug / ml. Immediately, place the plate on Enter 6-well plate reader (Cytofluor 2350, Millipore, Bedford, MA) The data were obtained using the method of Nakajima et al. (J. Biol Chem254 4027 (1979)) Gather at 3 minute intervals Confuse. The amount of elastase released from PMN was determined by MeOSuc-Ala-Al Calculated by measuring the rate of a-Pro-Val-AMC degradation. TNF-α traumatic brain injury assay   This test is based on the experimentally induced lateral fluid shock traumatic brain injury (TBI) in rats. ) To examine the expression of tumor necrosis factor mRNA in specific brain regions after To do. Adult Sprague-Dawley rats (n = 42) Anesthetized with sodium barbital (60 mg / kg, ip), left parietal skin For moderate (2.4 atm) lateral fluid impact brain injury focused on quality (n = 18), Or "sham" treatment (anesthetized and operated on without injury, n = 18) . Animals were sacrificed by decapitation at 1, 6 and 24 hours after injury and the brains were removed and left (injured). Wound) parietal cortex (LC), corresponding part of contralateral right cortex (RC), damaged head Cortex adjacent to the apical cortex (LA), corresponding adjacent area in the right cortex (RA), left Prepare hippocampal (LH) and right hippocampal (RH) tissue samples. Isolate total RNA Then, Northern blot hybridization was performed and TNF-α positive control RNA was used. Quantified (macrophage = 100%). Injury in traumatic hemisphere One hour after, a significant increase in TNF-α mRNA expression was observed in LH (104 ± positive control). 17%, p <0.05 compared to mock, LC (105 ± 21%, p <0.05) And LA (69 ± 8%, p <0.01). LH (46 ± 8 %, P <0.05), LC (30 ± 3%, p <0.01) and LA (32 ± 3%) , P <0.01), increased TNF-α mRNA expression was observed at 6 hours. Which dissipates 24 hours after injury. In the contralateral hemisphere, TNF-αmR The expression of NA was 1 hour after injury, RH (46 ± 2%, p <0.01), RC (4 ± 3%) and RA (22 ± 8%), and at 6 hours, RH (28 ± 1%). 1%), increased in RC (7 ± 5%) and RA (26 ± 6%, p <0.05). But does not increase after 24 hours. Sham (surgery without damage) or experiment In non-lighted animals, consistent changes in TNF-α mRNA expression Observed at any time in any of the six brain regions in any hemisphere Not done. These results indicate the transient expression of TNF-α mRNA following parasagittal impact brain injury. Show changes in specific brain regions, including the uninjured hemisphere. TN F-α can induce nerve growth factor (NGF), activates other cytokines Post-traumatic changes in gene expression of TNF-α may be It plays an important role in both the acute and regenerative responses to CNS trauma. CNS injury model for IL-β mRNA   This assay is specific for rats following experimental lateral fluid shock traumatic encephalopathy (TBI) in rats. Expression of interleukin-1β (IL-1β) mRNA in human brain region Characterize. Adult Sprague-Dawley rats (n = 42) with pentobarbita Sodium (60 mg / kg, ip) and left parietal cortex (n = 18). ) Or moderate (2.4 atm) lateral fluid impact brain injury or Similar treatments (injury-free anesthesia and surgery) were administered. Animals injured 1, 6 and 2 Four hours later, they are sacrificed and their brains are removed, left (injured) parietal cortex (LC), contralateral right cortex (LC) RC), Cortical area adjacent to damaged parietal cortex (LA), right cortex Of corresponding adjacent regions (RA), left hippocampus (LH) and right hippocampus (RH) in quality Prepare a tissue sample. Isolate total RNA and Northern blot hybridization And the amount of brain tissue IL-1β mRNA was loaded on the gel. Expressed as relative radioactivity of β-positive macrophage RNA. One hour after the brain injury, In traumatized hemispheres, a significant and significant increase in IL-1β mRNA expression 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), which was observed by LC (4.0 ± 0.4%) until 6 hours after injury. , N = 6, p <0.05) and LH (5.0 ± 1.3%, p <0.05) And remained high. In mock or unexperimented animals, IL-1β mRNA expression is not seen in any of the brain regions. These results show that T After BI, transient expression of IL-1β mRNA is localized in certain regions of the brain. To be stimulated. These cytokines such as IL-1β Local changes play an important role after brain injury.   The above description fully discloses the invention including preferred embodiments thereof. You. Modifications and improvements of the embodiments disclosed herein are within the scope of the following claims. is there. Without further elaboration, one skilled in the art may, using the preceding description, maximize the present invention It is considered that it can be used only for Thus, the embodiments herein are simply It is considered exemplary and not intended to limit the scope of the invention in any way. Exclusive Embodiments of the invention which claim property or priority are defined as follows.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 11/06 A61P 11/06 17/00 17/00 19/02 19/02 25/28 25/28 C07D 223/16 C07D 223/16 333/54 333/54 (81) Designated country EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL (PT) SE, JP, US (72) Inventor Widson, Catherine El United States 19406 Old Valley Valley Forge Road, King of Prussia, PA 1047

Claims (1)

[Claims]   1. Chemokines bind to IL-8α or β receptors in mammals A method of treating a chemokine-mediated disease, comprising administering to said mammal an effective amount of a formula:   [Where,   Z is cyano, OR₁₁, C (O) NR_FifteenR₁₆, R₁₈, C (O) R₁₁, C (O) OR₁₁Ma Or S (O)_TwoR₁₇Is;   R is a functional group having an ionizable hydrogen having a pKa of 10 or less. Yes;   R₁Is 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_1-4Al Kill; aryl; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Al A heteroaryl; a heteroarylalkyl; a heterocyclic, Heterocyclic C_1-4Alkyl; heteroaryl C_1-4Alkyloxy; ant 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_2-10A Lucenyl C (O) OR₁₁; (CR₈R₈)_qC (O) OR₁₂; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁; (CR₈R₈)_qNHS (O)_TwoR₁₉; (CR₈R₈)_q S (O)_TwoNR_FourR_FiveOr two R₁Groups together O- (CH_Two)_sForming an O- or 5- or 6-membered saturated or unsaturated ring (where Reel, heteroaryl and heterocyclic-containing groups may be substituted. I);   q is 0, or an integer from 1 to 10;   t is 0, or an integer of 1 or 2;   s is an integer from 1 to 3;   m is an integer from 1 to 3;   n is an integer from 1 to 3;   v is 0, or an integer from 1 to 4;   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, heterocyclic, heterocyclic C_1-4Is alkyl Or R_FourAnd R_FiveTogether with the nitrogen to which they are bound, oxygen, nitrogen Or a 5- to 7-membered ring optionally containing another heteroatom selected from sulfur Form;   R₆And R₇Is independently hydrogen or C_1-4An alkyl group; or R₆ And R₇Together with the nitrogen to which they are bound to form oxygen, nitrogen or sulfur Forming a 5- to 7-membered ring which may contain another heteroatom selected from yellow ;   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_1-4Al Kill; aryl; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Al Heteroaryl; Heteroarylalkyl; Heteroaryl C_1-4 Alkyloxy; heterocyclic, heterocyclic C_1-4Alkyl; Reel C_2-10Alkenyl; heteroaryl C_2-10Alkenyl; heterocyclyl 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_Ten; S (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)_TwoRd, (CR₈R₈)_qS (O)_TwoNR_FourR_FiveSelected from Or two Y groups are taken together to form O- (CH_Two)_sO- or 5 or 6 May form a membered saturated or unsaturated ring (where aryl, heteroaryl and And heterocyclic-containing groups may be substituted);   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 hete Cyclocyclic or optionally substituted heterocyclic C_1-4Archi Is;   R₁₂Is hydrogen, C_1-10Alkyl, optionally substituted aryl or substituted An optionally substituted arylalkyl;   R₁₃And R₁₄Is independently hydrogen or C_1-4Alkyl;   R_FifteenAnd R₁₆Is independently hydrogen, optionally substituted C_1-4Alkyl, Optionally substituted aryl, optionally substituted aryl C_1-4Alkyl , An optionally substituted heteroaryl, an optionally substituted heteroaryl C_1-4Alkyl, optionally substituted heterocyclic, optionally substituted Good heterocyclic C_1-4Alkyl or R_FifteenAnd R₁₆Is it Together with the nitrogen to which they are attached, selected from oxygen, nitrogen, or sulfur Forming a 5- to 7-membered ring which may contain another heteroatom;   R₁₇Is C_1-4Alkyl, NR_FifteenR₁₆, OR₁₁, Optionally substituted ally Aryl, optionally substituted aryl C_1-4Alkyl, optionally substituted hete Loaryl, optionally substituted heteroaryl C_1-4Alkyl, substituted Heterocyclic which may be substituted or heterocyclic which may be substituted. C_1-4Alkyl;   R₁₈Is an optionally substituted C_1-4Alkyl, optionally substituted aryl Aryl, optionally substituted aryl C_1-4Alkyl, optionally substituted hete Loaryl, optionally substituted heteroaryl C_1-4Alkyl, substituted Heterocyclic which may be substituted or heterocyclic which may be substituted. C_1-4Alkyl;   R₁₉Is C_1-4Alkyl, aryl, arylalkyl, heteroaryl, f Teloaryl C_1-4Alkyl, heterocyclic, or heterocyclic C_1-4Alkyl, wherein all of these groups are optionally substituted;   Rd is NR₆R₇, Alkyl, aryl C_1-4Alkyl, aryl C_2-4Arche Nil, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_2-4A Lucenyl, heterocyclic, heterocyclic C_1-4Alkyl (where, Alkyl, aryl, arylalkyl, heteroaryl, heteroaryl Killed, heterocyclic and heterocyclic alkyl rings may be substituted May be present);   The X-containing ring is (Where the asterisk * indicates the point of attachment of the ring);   R₂₀Is W₁, An optionally substituted heteroaryl, an optionally substituted C_5-8Cycloalkyl, optionally substituted C_1-10Alkyl, substituted Good C_2-10Alkenyl or optionally substituted C_2-10Alkynyl ;   W₁Is Is;   The E'-containing ring is And the asterisk * indicates the point of attachment of the ring.] Or a pharmaceutically acceptable salt thereof.   2. The method of claim 1 wherein the ionizable hydrogen has a pKa of 3 to 10.   3. R is hydroxy, carboxylic acid, thiol, SR_Two, OR_Two, NH-C (O) Ra, C (O) NR₆'R₇', NHS (O)_TwoRb, S (O)_TwoNHRc, NHC (X_Two) N HRb, or tetrazolyl;   Where R_TwoIs a substituted aryl, heteroaryl, or heterocyclic group Wherein the ring bears an ionizable hydrogen having a pKa of 10 or less. Having a conferring functional group;   R₆'And R₇'Is hydrogen, C_1-4Alkyl, aryl, aryl C_1-4Alkyl , Aryl C_2-4Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, Heteroaryl C_2-4Alkenyl, heterocyclic, heterocyclic C_{1 -Four} Alkyl, heterocyclic C_2-4Alkenyl groups, all of which are 1 to 3 times independently halogen, nitro; halo-substituted C_1-4Alkyl; C_1-4Al Kill; C_1-4Alkoxy; NR₉C (O) Ra; C (O) NR₆R₇S (O)_ThreeH or C (O) OC_1-4May be substituted with alkyl (provided that R₆'And R₇'One Are hydrogen and not both).   Ra is aryl, aryl C_1-4Alkyl, heteroaryl, heteroaryl Le C_1-4Alkyl, heterocyclic or heterocyclic C_1-4Alkyl Groups, all of which may be substituted;   Rb is NR₆R₇, Alkyl, aryl, aryl C_1-4Alkyl, aryl C_2-4Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, hetero ant C_2-4Alkenyl, heterocyclic, heterocyclic C_1-4Alkyl , Heterocyclic C_2-4Alkenyl groups, camphor, all of which are , Halogen; nitro; halo-substituted C_1-4Alkyl; C_1-4Alkyl; C_1-4Alkoki Si; NR₉C (O) Ra; C (O) NR₆R₇S (O)_ThreeH; or C (O) OC_1-4Al May be independently substituted 1-3 times with kills;   R₉Is hydrogen or C_1-4Alkyl;   Rc is alkyl, aryl, aryl C_1-4Alkyl, aryl C_2-4Arche Nil, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_2-4A Lucenyl, heterocyclic, heterocyclic C_1-4Alkyl or hete Cyclic C_2-4Alkenyl groups, all of which are isolated one to three times Standing, halogen, nitro, halo substituted C_1-4Alkyl, C_1-4Alkyl, C_1-4A Lucoxy, NR₉C (O) Ra, C (O) NR₆R₇, S (O)_ThreeH; or C (O) O C_1-4Optionally substituted with alkyl; and   X_Two3. The method of claim 2, wherein is oxygen or sulfur.   4. R_TwoIs substituted one to three times with halogen, nitro, halo-substituted C_1-10Alkyl, C_{1 -Ten} Alkyl, C_1-10Alkoxy, hydroxy, SH, C (O) NR₆R₇, NH- C (O) Ra, NHS (O)_TwoRb, S (O) NR₆R₇, C (O) OR₈Or tetrazori 4. The method according to claim 3, which may be substituted with a ring.   5. R is OH, NHS (O)_TwoThe method according to claim 3, which is Rb or C (O) OH. .   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, f Teloarylalkyl, heteroarylalkenyl or S (O) NR_FourR_FiveIs The method of claim 1.   7. Y is halogen, C_1-4Alkoxy, optionally substituted aryl, substituted Arylalkoxy, methylenedioxy, NR_FourR_Five, Thio C_{1- Four} Alkyl, thioaryl, halo-substituted alkoxy, optionally substituted C_1-4A The method according to claim 1, which is alkyl or hydroxyalkyl.   8. R is OH, SH or NHS (O)_TwoRb and R₁Is an electron withdrawing group, Claims substituted in the 3-, 4-position or di-substituted in the 3,4-position Item 7. The method according to Item 1.   9. Mammal has psoriasis, atopic dermatitis, asthma, chronic obstructive pulmonary disease, adult respiration Distress syndrome, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic Shock, endotoxin shock, gram-negative sepsis, toxic shock syndrome, stroke, And renal reperfusion injury, glomerulonephritis, thrombosis, Alzheimer's disease, anti-host graft Chemokine-mediated disease selected from refractory or allograft rejection 9. The method according to any one of claims 1 to 8.   10. formula:   [Where,   Z is cyano, OR₁₁, C (O) NR_FifteenR₁₆, R₁₈, C (O) R₁₁, C (O) OR₁₁Ma Or S (O)_TwoR₁₇Is;   R is any having an ionizable hydrogen having a pKa of 10 or less. Is a functional group of   R₁Is 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_1-4Al Kill; aryl; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Al Heteroaryl; Heteroarylalkyl; Heterocyclyl Click, heterocyclic C_1-4Alkyl; heteroaryl C_1-4Alkylo Xy; aryl C_2-10Alkenyl; heteroaryl C_2-10Alkenyl; heterosa Iclic 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)_Three H; 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)_TwoR₁₉: (CR₈ R₈)_qS (O)_TwoNR_FourR_FiveOr two R₁The group is together O − (CH_Two)_sForming an O- or 5- or 6-membered saturated or unsaturated ring (where , Heteroaryl and heterocyclic-containing groups may be substituted );   q is 0, or an integer from 1 to 10;   t is 0, or an integer of 1 or 2;   s is an integer from 1 to 3;   m is an integer from 1 to 3;   n is an integer from 1 to 3;   v is 0, or an integer from 1 to 4;   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, heterocyclic, or heterocyclic C_1-4With alkyl Is or R_FourAnd R_FiveIs oxygen together with the nitrogen to which they are attached 5 to 5 may contain another heteroatom selected from nitrogen or sulfur Forming a 7-membered ring;   R₆And R₇Is independently hydrogen or C_1-4An alkyl group; or R₆ And R₇Together with the nitrogen to which they are bound to form oxygen, nitrogen or sulfur Forming a 5- to 7-membered ring which may contain another heteroatom selected from yellow ;   Y is 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_1-4A Alkyl; aryl; aryl C_1-4Alkyl; aryloxy; aryl C_1-4A Alkyloxy; heteroaryl; heteroarylalkyl: heteroarylC_{1- Four} Alkyloxy; heterocyclic, heterocyclic C_1-4Alkyl; Reel C_2-10Alkenyl; heteroaryl C_2-10Alkenyl; heterocyclyl 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)_Three H; S (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁ C_2-10Alkenyl C (O) OR₁₁C (O) R₁₁; (CR₈R₈)_qC (O) O R₁₂; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁; (C R₈R₈)_qNHS (O)_TwoRd, (CR₈R₈)_qS (O)_TwoNR_FourR_FiveTo be selected from Or two Y groups together form O- (CH_Two)_sO- or 5 or 6 members May form a sum or unsaturated ring (where aryl, heteroaryl and Heterocyclic-containing groups may be substituted);   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 hete Heterocyclic C which may be cyclic or substituted_1-4Alkyl Is;   R₁₂Is hydrogen, C_1-10Alkyl, optionally substituted aryl or substituted An optionally substituted arylalkyl;   R₁₃And R₁₄Is independently hydrogen or C_1-4Alkyl;   R_FifteenAnd R₁₆Is independently hydrogen, optionally substituted C_1-4Alkyl, Optionally substituted aryl, optionally substituted aryl C_1-4Alkyl , An optionally substituted heteroaryl, an optionally substituted heteroaryl C_1-4Alkyl, optionally substituted heterocyclic, optionally substituted Good heterocyclic C_1-4Alkyl or R_FifteenAnd R₁₆Is it Together with the nitrogen to which they are attached, selected from oxygen, nitrogen, or sulfur Forming a 5- to 7-membered ring which may contain another heteroatom;   R₁₇Is C_1-4Alkyl, NR_FifteenR₁₆, OR₁₁, Optionally substituted ally Aryl, optionally substituted aryl C_1-4Alkyl, optionally substituted hete Loaryl, optionally substituted heteroaryl C_1-4Alkyl, substituted Optionally heterocyclic or optionally substituted heterocyclic C_1-4Alkyl;   R₁₈Is an optionally substituted C_1-4Alkyl, optionally substituted aryl Aryl, optionally substituted aryl C_1-4Alkyl, optionally substituted hete Loaryl, optionally substituted heteroaryl C_1-4Alkyl, substituted Optionally heterocyclic or optionally substituted heterocyclic C_1-4Alkyl;   R₁₉Is C_1-4Alkyl, aryl, arylalkyl, heteroaryl, f Teloaryl C_1-4Alkyl, heterocyclic or heterocyclic C_{1 -Four} Alkyl, wherein all of these groups are optionally substituted;   Rd is NR₆R₇, Alkyl, aryl C_1-4Alkyl, aryl C_2-4Arche Nil, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_2-4A Lucenyl, heterocyclic, heterocyclic C_1-4Alkyl (where, Alkyl, aryl, arylalkyl, heteroaryl, heteroaryl Killed, heterocyclic and heterocyclic alkyl rings may be substituted May be present);   The X-containing ring is (Where the asterisk * indicates the point of attachment of the ring);   R₂₀Is W₁, An optionally substituted heteroaryl, an optionally substituted C_5-8Cycloalkyl, optionally substituted C_1-10Alkyl, substituted Good C_2-10Alkenyl or optionally substituted C_2-10Alkynyl ;   W₁Is Is;   The E'-containing ring is And the asterisk * indicates the point of attachment of the ring.] Or a pharmaceutically acceptable salt thereof.   11. 11. The method according to claim 10, wherein the ionizable hydrogen has a pKa of 3 to 10. Compound.   12. R is hydroxy, carboxylic acid, thiol, SR_Two, OR_Two, NH-C ( O) Ra, C (O) NR₆'R₇', NHS (O)_TwoRb, S (O)_TwoNHRc, NHC (X_Two) NHRb or tetrazolyl;   Where R_TwoIs a substituted aryl, heteroaryl or heterocyclic group Wherein the ring imparts an ionizable hydrogen having a pKa of 10 or less. Having a functional group that:   R₆'And R₇'Is hydrogen, C_1-4Alkyl, aryl, aryl C_1-4Alkyl , Aryl C_2-4Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, Heteroaryl C_2-4Alkenyl, heterocyclic, heterocyclic C_{1 -Four} Alkyl, heterocyclic C_2-4Alkenyl groups, all of which are 1 to 3 times independently halogen, nitro; halo-substituted C_1-4Alkyl; C_1-4Al Kill; C_1-4Alkoxy; NR₉C (O) Ra; C (O) NR₆R₇S (O)_ThreeH; Is C (O) OC_1-4May be substituted with alkyl (provided that R₆'And R₇'of One is hydrogen and not both);   Ra is aryl, aryl C_1-4Alkyl, heteroaryl, heteroaryl Le C_1-4Alkyl, heterocyclic or heterocyclic C_1-4Alkyl Groups, all of which may be substituted;   Rb is NR₆R₇, Alkyl, aryl, aryl C_1-4Alkyl, aryl C_2-4Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, hetero ant C_2-4Alkenyl, heterocyclic, heterocyclic C_1-4Alkyl , Heterocyclic C_2-4Alkenyl groups, camphor, all of which are , Halogen; nitro; halo-substituted C_1-4Alkyl; C_1-4Alkyl; C_1-4Alkoki Si; NR₉C (O) Ra; C (O) NR₆R₇S (O)_ThreeH; or C (O) OC_1-4Al May be independently substituted 1-3 times with kills;   R₉Is hydrogen or C_1-4Alkyl;   Rc is alkyl, aryl, aryl C_1-4Alkyl, aryl C_2-4Arche Nil, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_2-4A Lucenyl, heterocyclic, heterocyclic C_1-4Alkyl or f Terror cyclic C_2-4Alkenyl groups, all of which are 1-3 times Independently halogen, nitro, halo substituted C_1-4Alkyl, C_1-4Alkyl, C_1-4 Alkoxy, NR₉C (O) Ra, C (O) NR₆R₇, S (O)_ThreeH; or C (O) O C_1-4Optionally substituted with alkyl; and   X_TwoThe compound according to claim 10, wherein is oxygen or sulfur.   13. R_TwoIs substituted one to three times with halogen, nitro, halo-substituted C_1-10Alkyl, C_1-10Alkyl, C_1-10Alkoxy, hydroxy, SH, C (O) NR₆R₇, NH -C (O) Ra, NHS (O)_TwoRb, S (O) NR₆R₇, C (O) OR₈Or tetrazo 13. The compound according to claim 12, which is substituted with a lyl ring.   14． R is OH, NHS (O)_Two13. The composition of claim 12, which is Rb or 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, substituted Optionally substituted arylalkoxy, methylenedioxy, NR_FourR_Five, Thio C_1-4 Alkyl, thioaryl, halo-substituted alkoxy, optionally substituted C_1-4 The compound according to claim 10, which is alkyl or hydroxyalkyl.   17． R is OH, SH or NHS (O)_TwoRb and R₁Is due to the electron withdrawing group Or substituted at the 3- and 4-positions or disubstituted at the 3- and 4-positions A compound according to claim 10.   18. A compound according to any one of claims 10 to 17 and a pharmaceutically acceptable A pharmaceutical composition comprising a carrier or a diluent.