EP0948330A1 - Antagonistes du recepteur d'il-8 - Google Patents

Antagonistes du recepteur d'il-8

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Publication number
EP0948330A1
EP0948330A1 EP97937142A EP97937142A EP0948330A1 EP 0948330 A1 EP0948330 A1 EP 0948330A1 EP 97937142 A EP97937142 A EP 97937142A EP 97937142 A EP97937142 A EP 97937142A EP 0948330 A1 EP0948330 A1 EP 0948330A1
Authority
EP
European Patent Office
Prior art keywords
optionally substituted
alkyl
4alkyl
heterocyclic
heteroaryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97937142A
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German (de)
English (en)
Other versions
EP0948330A4 (fr
Inventor
Katherine L. Widdowson
John Gerald Gleason
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Publication date
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Publication of EP0948330A1 publication Critical patent/EP0948330A1/fr
Publication of EP0948330A4 publication Critical patent/EP0948330A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring

Definitions

  • This invention relates to novel alkene diamino substituted compounds, pharmaceutical compositions, processes for their preparation, and use thereof in treating L -8, GRO ⁇ , GRO ⁇ , GRO ⁇ , ENA-78, and NAP-2 mediated diseases.
  • Interleukin-8 such as neutrophil attractant/activation protein- 1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor.
  • Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells. It is produced by a majority of nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL-l ⁇ , LL-l ⁇ or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP. M.
  • GRO ⁇ , GRO ⁇ , GRO ⁇ and NAP-2 also belong to the chemokine ⁇ family. Like LL-8 these chemokines have also been referred to by different names. For instance GRO ⁇ , ⁇ , ⁇ have been referred to as MGS A ⁇ , ⁇ and ⁇ respectively
  • LL-8 can induce histamine release from basophils from both normal and atopic individuals GRO- ⁇ and LL-8 can in addition, induce lysozomal enzyme release and respiratory burst from neutrophils.
  • LL-8 has also been shown to increase the surface expression of Mac- 1 (CD1 lb/CD 18) on neutrophils without de novo protein synthesis. This may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many known diseases are characterized by massive neutrophil infiltration.
  • GRO ⁇ , GRO ⁇ , GRO ⁇ and NAP-2 promote the accumulation and activation of neutrophils
  • these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis, Baggiolini et al, FEBS Lett. 307. 97 ( 1992.: Miller et al. Crit. Rev. Immunol. 12. 17 (1992); Oppenheim et al, Annu. Rev. Immunol. 9. 617 (1991): Seitz et al., J. Clin. Invest. 87. 463 ( 19 I V Milter M al.. Am. Rev. Respir. Pis. 146.
  • ELR chemokines (those containing the amino acids ELR motif just prior to the CXC motif) have also been implicated in angiostasis. Strieter et al, Science 258, 1798 ( 1992).
  • LL-8, Gro ⁇ , GRO ⁇ , GRO ⁇ and NAP-2 induce neutrophil shape change, chemotaxis, granule release, and respiratory burst, by binding to and activating receptors of the seven-transmembrane, G-protein-linked family, in particular by binding to LL-8 receptors, most notably the B-receptor. Thomas et al., J. Biol. Chem. 266. 14839 (1991); and Holmes et al., Science 253. 1278 ( 1991 ).
  • the development of non-peptide small molecule antagonists for members of this receptor family has precedent. For a review see R. Freidinger in: Progress in Drug Research. Vol. 40, pp. 33-98, Birkhauser Verlag, Basel 1993.
  • the IL-8 receptor represents a promising target for the development of novel anti-inflammatory agents.
  • IL-8R ⁇ which binds only LL-8 with high affinity
  • LL-8R ⁇ which has high affinity for LL-8 as well as for GRO- ⁇ , GRO ⁇ , GRO ⁇ and NAP-2.
  • IL-8R ⁇ which binds only LL-8 with high affinity
  • LL-8R ⁇ which has high affinity for LL-8 as well as for GRO- ⁇ , GRO ⁇ , GRO ⁇ and NAP-2.
  • This invention provides for a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 ⁇ or ⁇ receptor and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the chemokine is IL-8.
  • This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I).
  • Z is cyano, nitro, CF 3 , C(O)NR 15 R 16 , S(O) 2 NR ⁇ 5 R 16> or S(O) 2 Ri7;
  • Rl8 is hydrogen, halogen, cyano, optionally substituted Ci-4 alkyl, halo substituted
  • R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;
  • Rl is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C i . i o alkyl ; C i . i o alkyl ; C 2 - 10 alkeny 1 ; C i . i o alkoxy ; halosubstituted C i .
  • R4 and R5 are independently hydrogen, optionally substituted Ci -4 alkyl, optionally substituted aryl, optionally substituted aryl C ⁇ _4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C 1 -4alkyl, heterocyclic, or heterocyclic C j-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from oxygen, nitrogen or sulfur; m is an integer having a value of 1 to 3; n is an integer having a value of 1 to 3;
  • Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C 2 - io alkenyl; C i-io alkoxy; halosubstituted C JMO alkoxy; azide; (CR 8 R 8 )q S(O)tR4; hydroxy; hydroxyC i-4alkyl; aryl; aryl Ci-4 alkyl; aryloxy; arylC i-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl Ci-4 alkyloxy; heterocyclic, heterocyclic C i-4alkyl; aryl C -io alkenyl; heteroaryl
  • R6 and R7 are independently hydrogen or a Ci-4 alkyl group; or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom selected from oxygen, nitrogen or sulfur; Rg is independently selected from hydrogen or C i-4 alkyl;
  • RlO is C1- 10 alkyl C(O)2R8;
  • Rl 1 is hydrogen, Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substi tuted heterocyclicC 1 -4alky 1 ;
  • Rl2 is hydrogen, C j-io alkyl, optionally substituted aryl or optionally substituted arylalkyl;
  • Rl3 and R 14 are independently hydrogen or C 1.4 alkyl; v is 0, or an integer having a value of 1 to 4;
  • Rj5 and Rj6 are independently hydrogen, optionally substituted C j-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, optionally substituted heterocyclicCi-4alkyl, or R15 and Rig may together with the nitrogen to which they are attached form a 5 to 7 member ring optionally containing an additional heteroatom selected from oxygen, nitrogen, or sulfur;
  • R 17 is C 1-4 alkyl, ORj ⁇ , optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC _4alkyl;
  • Rl9 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or heterocyclicCi-4alkyl, wherein the all of these moieties may be optionally substituted;
  • Rj is NR6R7, alkyl, arylCl-4alkyl, arylC 2 _4 alkenyl, heteroaryl, hetroaryl-C ⁇ _4alkyl, heteroarylC 2 _4 alkenyl, heterocyclic, heterocyclicCj.4 alkyl, wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, and heterocyclic alkyl rings may be optionally substituted;
  • R 2 o is Wj, optionally substituted heteroaryl, optionally substituted C5_ 8 cycloalkyl, optionally substituted alkyl, optionally substituted C .jo alkenyl, or optionally substituted C 2 . JQ alkynyl;
  • the X containing ring is selected from the group consisting of
  • the compounds of Formula (I) may also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of LL-8 or other chemokines which bind to the LL-8 ⁇ and ⁇ receptors.
  • Chemokine mediated diseases for treatment, therapeutical ly or prophylactically, in animals include disease states such as those noted herein in the Methods of Treatment section.
  • R is suitably any functional moiety which provides an ionizable hydrogen having a pKa of 10 or less, preferably from about 3 to 9, more preferably from about 3 to 7.
  • Such functional groups include, but are not limited to, hydroxy, carboxylic acid, thiol, SR , OR 2 , NH-C(O)R a , C(O)NR6'R7', a substituted sulfonamides of the formula NHS(O) 2 R D , S(O) 2 NHR c , NHC(X 2 )NHRb, or a tetrazolyl.
  • X 2 is oxygen or sulfur, preferably oxygen.
  • the functional group is other than a sulfonic acid, either directly or as a substituent group on the aryl, heteroaryl, or heterocyclic moiety ring, such as in SR 2 or OR . More preferably R is OH, SH, or NHS(O) 2 Rb-
  • R2 is a substituted aryl, heteroaryl, or heterocyclic ring which ring contains the functional moiety providing the ionizable hydrogen having a pKa of 10 or less.
  • R6' and R7' are hydrogen, Ci-4 alkyl, aryl, arylCi-4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylCi-4alkyl, heteroarylC 2 -4 alkenyl, heterocyclic, heterocyclic Ci-4alkyl, or heterocyclic C 2 -4aIkenyl moiety, all of which may be optionally substituted one to three times independently by halogen; nitro; halosubstituted C1.4 alkyl, such as CF3; C1-4 alkyl, such as methyl; C1.4 alkoxy, such as ethoxy; NR9C(O)R a ; C(O)NR6R7; S(O)3H; or C(O)OCi-4 al
  • R6 and R7 are independently hydrogen or a Cj-4 alkyl group, or R ⁇ and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur. This heteroring may be optionally substituted as defined herein.
  • R a is an aryl, aryIC _4alkyl, heteroaryl, heteroaryIC i-4alkyl, heterocyclic, or a heterocyclic Ci-4alkyl moiety, all of which may be optionally substituted, independently, by one to three groups, which groups may also contain an additional ionizable group, and include but are not limited to, halogen, nitro, halosubstituted Cj-4 alkyl, C1-4 alkyl, C1.4 alkoxy, hydroxy, SH, C(O)NR6R7, NH-C(O)R a , NHS(O) 2 Rb, S(O) 2 NR6R7, C(O)OR 8 , or a tetrazolyl ring.
  • Rb is a NR6R7, alkyl, aryl, arylC ⁇ _4alkyl, arylC 2 -4alkenyl, heteroaryl, heteroarylC 1 -4alkyl, heteroarylC 2 -4 alkenyl, heterocyclic, or heterocyclic C ⁇ _4alkyl, or a heterocyclic C 2 -4alkenyl moiety, camphor, all of which may be optionally substituted one to three times independently by halogen; nitro; halosubstituted Ci-4 alkyl, such as CF3; C ⁇ _4 alkyl, such as methyl; C1-4 alkoxy, such as methoxy; NR9C(O)R a ; C(O)NR6R7; S(O)3H; or C(O)OC 1.4 alkyl.
  • R9 is hydrogen or a Cj-4 alkyl, preferably hydrogen
  • Rb is preferably an optionally substituted phenyl, benzyl,
  • Rb is a heteroaryl preferably it is an optionally substituted thiazole, an optionally substituted thienyl, or an optionally substituted quinolinyl ring.
  • Rb substituent group is NR9C(O)R a
  • R a is preferably an alkyl group, such as methyl.
  • R c is hydrogen, alkyl, aryl, arylCi-4alkyl, arylCi-4alkenyl, heteroaryl, heteroarylC i-4alkyl, heteroarylC i-4alkenyl, heterocyclic, heterocyclic
  • Ci-4alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen, nitro, halosubstituted Cj-4 alkyl, C1-4 alkyl, Ci-4 alkoxy, NR9C(O)R a , C(O)NR ⁇ R7, S(O)3H, or C(O)OCi-4 alkyl.
  • R c is an optionally substituted phenyl.
  • Rl is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl, such as CF3; Ci-io alkyl, such as methyl, ethyl, isopropyl, or n-propyl; C 2 -io alkenyl; Ci-io alkoxy, such as methoxy, or ethoxy; halosubstituted Ci-io alkoxy, such as trifluoromethoxy; azide; (CR 8 Rg)q S(O)tR4, wherein t is 0, 1 or 2; hydroxy; hydroxy C i-4alkyl, such as methanol or ethanol; aryl, such as phenyl or naphthyl; aryl -4 alkyl, such as benzyl; aryloxy, such as phenoxy; aryl Cj-4 alkyloxy, such as benzyloxy; heteroaryl;
  • NR4C(O)Ri 1 (CR 8 R 8 )q NHS(O) 2 R ⁇ 9 , (CR 8 R 8 )qS(O) 2 NR 4 R 5 ; or two R ⁇ moieties together may form O-(CH 2 ) s O- or a 5 to 6 membered saturated or unsaturated ring.
  • the aryl ⁇ heteroaryl, and heterocyclic containing moieties may all be optionally substituted as defined herein below.
  • s is an integer having a value of 1 to 3.
  • q is 0, or an integer having a value of 1 to 10.
  • Rl forms a dioxybridge
  • s is preferably 1.
  • Rj forms an additional saturated or unsaturated ring, it is preferably 6 membered resulting in a naphthylene ring system. This naphthylene ring may be substituted independently, 1 to 3 times by the other Rl moieties as defined above.
  • R4 and R5 are independently hydrogen, optionally substituted C 1-.4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, or heterocyclicCi-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S.
  • R 8 is suitably independently selected from hydrogen or Ci -4 alkyl.
  • RlO is suitably Ci-io alkyl C(O) 2 Rg, such as CH 2 C(O) H or CH2C(O) 2 CH 3 .
  • Rl 1 is suitably hydrogen, C ⁇ _4 alkyl, aryl, aryl C ⁇ _4 alkyl, heteroaryl, heteroaryl Ci-4alkyl, heterocyclic, or heterocyclic Ci-4alkyl.
  • R12 is suitably hydrogen, Cl-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl.
  • Rl9 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC i-4alkyl, heterocyclic, or heterocycIicCl-4a!kyl, wherein the all of these moieties may be optionally substituted;
  • R l is halogen, cyano, nitro, CF3, C(O)NR4R5, alkenyl
  • R4 and R5 are both hydrogen or one is phenyl.
  • a preferred ring substitution for Rl is in the 4-position of the phenyl containg ring.
  • R is OH, SH or NSO2Rb than Rj is preferably substituted in the 3- position, or the 4- position or is di substituted in the 3,4- position.
  • the substituent group is suitably an electron withdrawing moiety.
  • R is OH, SH or NSO 2 Rb > than Rl is a nitro, halogen, cyano, trifluoromethyl, or C(O)NR4R5 group
  • Ri is preferably hydrogen, or Ri is preferably substituted in the 4-position, more preferably substituted by trifluoromethyl or chloro.
  • R13 and R14 are independently hydrogen, optionally substituted Ci-4 alkyl which may be straight or branched as defined herein, or one of R13 and R 4 are an optionally substituted aryl.
  • v is 0, or an integer having a value of 1 to 4.
  • the alkyl may be optionally substituted one to three times independently by halogen; halosubstituted Ci-4 alkyl such as trifluromethyl; hydroxy; hydroxy C ⁇ _4alkyl, Ci-4 alkoxy; such as methoxy, or ethoxy, halosubstituted -io alkoxy, S(O)tR4; aryl; NR4R5; NHC(O)R4; C(O)NR4R5; or C(O)OR 8 .
  • Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted -io alkyl; Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Cj-io alkoxy; azide; (CRgR )q S(O) f R4; hydroxy; hydroxyC ⁇ _4alkyl; aryl; aryl C1-4 alkyl; aryloxy; arylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C1-4 alkyloxy; heterocyclic, heterocyclic Ci-4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CR R 8 )q
  • (CR 8 R 8 )q NR4C(O)Ri 1, (CRgRg)q NHS(O) 2 Rd- (CR 8 R 8 )q S(O) 2 NR 4 R 5 or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered saturated or unsaturated ring.
  • the aryl, heteroaryl, and heterocyclic containing moieties noted above may all be optionally substituted as defined herein.
  • s is preferably 1.
  • Y forms an additional saturated or unsaturated ring, it is preferably 6 membered resulting in a naphthylene ring system. These rings may also be substituted 1 to 3 times by other Y moieties as defined above.
  • Rj is a NRgR7, alkyl, aryl C1.4 alklyl, arylC 9-4 alkenyl, heteroaryl, hetroaryl-Ci ⁇ alkyl, heteroarylC 2 _4 alkenyl, heterocyclic, heterocyclicC j.4 alkyl, or heterocyclic C 2 -4 alkenyl moiety, wherein the aryl, heteroaryl, and heterocyclic containing moieties noted above may all be optionally substituted as defined herein.
  • Y is preferably a halogen, C1.4 alkoxy, optionally substituted aryl, optionally substituted aryloxy or arylalkoxy, methylene dioxy, NR4R5, thio Ci-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted Ci-4 alkyl, or hydroxy alkyl.
  • Y is more preferably mono- or di-substituted halogen, mono- or di- substituted alkoxy, methylenedioxy, aryl, or alkyl; more preferably these groups are mono or di-substituted in the 2'- position or 2'-, 3'-position.
  • Y may be substituted in any of the 5 ring positions, preferably when R is OH, SH, or NSO 2 Rb* Y is preferably mono-substituted in the 2'-position or
  • R ⁇ and Y can both be hydrogen, it is prefered that at least one of the rings be substituted, preferably both rings are substituted.
  • Z is suitably cyano, nitro, CF3,
  • Rj5 and R 6 are independently hydrogen, optionally substituted
  • Ci-4 alkyl optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC i-4alkyl, optionally substituted heterocyclic, optionally substituted heterocyclicCi-4alkyl, or
  • R 5 and R ⁇ may together with the nitrogen to which they are attached form a 5 to 7 member ring optionally containing an additional heteroatom selected from oxygen, nitrogen, or sulfur.
  • R 17 is C 1.4 alkyl, OR - optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC i-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicCi-4alkl; wherein the optional substituents are as defined herein.
  • R ⁇ 8 is suitably hydrogen, halogen, cyano, optionally substituted Ci-4 alkyl, halo substituted Cj-4 alkyl, C(O)NRj5R ⁇ ,5, optionally substituted aryl, optionally substituted aryl C i-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC i-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicCi-4alkyl; wherein the optional substituents are as defined herein.
  • the X ring is denoted by its point of attachment through the asterix.
  • the X ring may be substituted by the Rj moiety or both the phenyl ring and the X ring may be substituted independently by (R ) m .
  • the nitrogen containing X rings are preferably substituted on the nitrogen moiety by an amide functionality such as C(O)NR4R5, preferably where one of R4 or R5 is an optionally substituted aryl, such as phenyl.
  • the larger saturated nitrogen containing ring may also be substituted by an aryl ring.
  • R 2 Q is Wj, an optionally substituted heteroaryl, an optionally substituted C5_ 8 cylcoalkyl, an optionally substituted C ⁇ _ ⁇ o alkyl, an optionally substituted C 2 _ ⁇ o alkenyl, or an optionally substituted C 2 -io lkynyl.
  • Wj is or
  • the E' containing ring is optionally selected from
  • the E' containing ring may optionally be present. If not present the ring is a phenyl moiety which is substituted by the Y terms as shown.
  • the E ring may be substituted by a (Y) n moiety in any ring, saturated or unsaturated, and is shown for purposes herein substituted only in the unsaturated ring(s).
  • R20 is an optionally substituted C5_ 8 cycloalkyl ring
  • the ring may be substituted by (Y) n as defined above.
  • R 2 o is an optionally substituted Cj.io alkyl, an optionally substituted C2-10 alkenyl, or an optionally substituted C2-10 alkynyl
  • these moieties may be optionally substituted one or more times independently by halogen; nitro; cyano; halosubstituted C i-io alkyl, such as trifluoromethyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; S(O)tR4; hydroxy; hydroxy Ci-4alkyl; aryloxy; arylCj-4 alkyloxy; heteroaryloxy; heteroaryl Cj-4 alkyloxy; heterocyclic, heterocyclic Ci-4alkyl; heterocyclic-oxy; heterocyclic C .4 alkyloxy; NR4R5;
  • R 2 o i an optionally substituted C2-10 alkenyl, or an optionally substituted C 2 .
  • JO alkynyl these moieties may also, in addition to those moieties noted above, may also be optionally substituted with aryl, aryl C1.4 alkyl, heteroaryl, and heteroarylalkyl.
  • R 2 when R 2 is a heteroaryl (HET) ring, it is suitably a heteroaryl ring or ring system. If the HET moiety is a multi ring system, the ring containing the heteroatom does not need to be directly attached to the urea moiety. All the rings in this ring system may be optionally substituted as defined herein.
  • the HET moiety is a pyridyl, which may be 2-, 3- or 4-pyridyl. If the ring is a multi system ring it is preferably benzimidazole, dibenzothiophene, or an indole ring.
  • Other heterocyclic rings of interest include, but are not limited to thiophene, furan, pyrimidine, pyrrole, pyrazole, quinoline, isoquinoline, quinazolinyl, pyridine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
  • the HET ring may be optionally substituted independently one to three times by Y, i.e. (Y(n) )• wherein n is an integer having a value of 1 to 3.
  • Y is suitably independently selected from hydrogen; halogen; nitro; cyano; halosubstituted -io alkyl; Cj-io alkyl; C 2 -io alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CR R 8 )q S(O)tR4; hydroxy; hydroxyCi-4alkyi; aryl; aryl Ci-4 alkyl; aryloxy; arylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl Ci-4 alkyloxy; heterocyclic, heterocyclic Ci-4alkyl; aryl
  • Y moieties together may form O-(CH 2 ) s O- or a 5 to 6 membered saturated or unsaturated ring.
  • These aryl, heteroaryl, and heterocyclic containing moieties may also be optionally substituted as defined herein.
  • R d is NR.5R7, alkyl, arylCl-4alkyl, arylC 2 -4 alkenyl, heteroaryl, hetroaryl-C ⁇ .4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclicC ⁇ .4 alkyl, wherein the alkyl, aryl, heteroaryl, and heterocyclic, containing moieties may be optionally substituted as defined herein.
  • R20 i preferably optionally substituted phenyl, allyl, C ⁇ - ⁇ Q alkyl, ethoxy carbonyl ethyl, dimethylacetal, 2-methoxy isopropyl, or 2-methoxy ethyl.
  • halogen such as fluorine, chlorine, bromine or iodine
  • hydroxy such as methoxy or ethoxy
  • Ci-io alkoxy such as methoxy or ethoxy
  • S(O) m * Ci-io alkyl wherein m' is 0, 1 or 2, such as methyl thio, methyl sulfinyl or methyl sulfonyl
  • amino, mono & di-substituted amino such as in the NR4R5 group; NHC(O)R4; C(O)NR4R5; C(O)OH; S(O)2NR4R5; NHS(O)2R2I; Cl-10 alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl
  • halosubstituted Ci-io alkyl such CF3; an optionally
  • Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid.
  • pharmaceutically acceptable salts of compounds of Formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety.
  • Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
  • halo all halogens, that is chloro, fluoro, bromo and iodo.
  • cycloalkyl is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
  • alkenyl is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl and the like.
  • heteroaryl (on its own or in any combination, such as “heteroaryloxy”, or “heteroaryl alkyl”) - a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
  • heterocyclic (on its own or in any combination, such as “heterocyclicalkyl”) - a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine.
  • arylalkyl or heteroarylalkyl or “heterocyclicalkyl” is used herein to mean Cj-io alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated.
  • Ri moieties or two Y moieties may together form a 5 or 6 membered saturated or unsaturated ring
  • a napthylene ring system or a phenyl moiety having attached a 5 or 6 membered partially saturated or unsaturated ring such as a C6 cycloalkenyl, i.e hexene, or a C5 cycloalkenyl moiety, cyclopentene.
  • compounds of the present invention may exist as stereoisomers, regioisomers, or diastereiomers. These compounds may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are included within the scope of the present invention.
  • the compounds of Formula (I) may be obtained by applying synthetic procedures, some of which are illustrated in the Schemes below.
  • the synthesis provided for in these Schemes is applicable for the producing compounds of Formula (I) having a variety of different R, Rl, and Aryl groups which are reacted, employing optional substituents which are suitably protected, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, in those cases, then affords compounds of the nature generally disclosed.
  • further compounds of these formulas may be prepared by applying standard techniques for functional group interconversion, well known in the art.
  • R" represents (Ri3Ri4)y-R20 linkage, as defined in compounds of Formula (I).
  • Z is as defined in compounds of Formula (I).
  • the thio imidate can be synthesized be condensing electron-withdrawing substituted methylene compound 1 with a strong base such as LDA, alkyl lithium or potassium t-butoxide.
  • the resulting anion can then be reacted with a commercially available thioisocyanate (if the thioisocyanate is not commercially available it can be synthesized by reacting the desired amine with thiophosgene in the presence of a base like sodium bicarbonate).
  • the resulting thioanion can then be alkylated with an alkyl halide like methyl iodide to form 2.
  • Alternatively 2 can be synthesized by reacting the commercially available acid 3 with an amine in the presence of a coupling reagent like EDC (scheme 2).
  • a coupling reagent like EDC (scheme 2).
  • thio amide can then be synthesized by reacting the amide with Lawesson's reagent. Finally the thio imidate can be synthesized by deprotonation with a base like lithium diisopropylamide (LDA) or sodium hexamethyldisilazane followed by alkylation with methyl iodide to form 2.
  • LDA lithium diisopropylamide
  • methyl iodide sodium hexamethyldisilazane
  • the thio imidate can then be reacted with ortho functionalized aniline to form the title compound 5_.
  • the reaction could be accelerated by the addition of metal salt with a high affinity for sulfur like mercuric oxide or silver acetate or by oxidation of the sulfur with dimethyloxirane to form a better leaving group.
  • the title compound (5, scheme 4) could be synthesized by reaction of the thiourea or urea with the anion ZCH"R'(formed from reaction of ZCH2R' with a base such as LDA).
  • the thiourea or urea is synthesized as described
  • the carbodiimide 8. scheme 5 can then be reacted with ZCH2R' in the presence of a base such as triethyl amine or sodium hydride to form 9.
  • a base such as triethyl amine or sodium hydride
  • This compound can then be deprotected by standard conditions such as Pd(PPh3)4, sodium borohydride and morpholine in a polar solvent such as THF to form the desired 1 , 1 diamino ethylene 10.
  • a solution of nitromethane (2.26 mmol) in dry DMF (2.4 ml) can be added dropwise under argon to a suspension of sodium hydride (1.24 mmol) in DMF (1.2 ml). After 30 min stirring at room temperature , a solution of carbodimide (1.13 mmol) in DMF (2.2 ml) can be added. The reaction mixture can be stirred at 100 °C for one hour.
  • compositions of Formula (I) may be obtained in known manner, for example by treatment thereof with an appropriate amount of acid or base in the presence of a suitable solvent.
  • the compounds of Formula (I), or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human, or other mammal, which is exacerbated or caused by excessive or unregulated LL-8 cytokine production by such mammal's cell, such as but not limited to monocytes and/or macrophages, or other chemokines which bind to the LL-8 ⁇ or ⁇ receptor, also referred to as the type I or type II receptor.
  • the present invention provides a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an LL-8 ⁇ or ⁇ receptor and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the chemokines are LL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , ENA-78, or NAP-2.
  • the compounds of Formula (I) are administered in an amount sufficient to inhibit cytokine function, in particular LL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , ENA-78, or NAP-2, such that they are biologically regulated down to normal levels of physiological function, or in some case to subnormal levels, so as to ameliorate the disease state.
  • Abnormal levels of LL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , ENA-78, or NAP-2 for instance in the context of the present invention constitute: (i) levels of free LL-8 greater than or equal to 1 picogram per mL; (ii) any cell LL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , ENA-78, or NAP-2 above normal physiological levels; or (iii)the presence of IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , ENA-78, or NAP-2 above basal levels in cells or tissues in which LL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , ENA-78, or NAP-2 respectively, is produced.
  • Chemokine mediated diseases include psoriasis, atopic dermatitis, arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, stroke, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, graft vs. host reaction, alzheimers disease, allograft rejections, malaria, restinosis, angiogenesis or undesired hematopoietic stem cells release.
  • the ⁇ -chemokines but particularly, GRO ⁇ , GRO ⁇ , GRO ⁇ or NAP-2, working through the IL-8 type I or II receptor can promote the neovascularization of tumors by promoting the directional growth of endothelial cells. Therefore, the inhibition of LL-8 induced chemotaxis or activation would lead to a direct reduction in the neutrophil infiltration.
  • the present invention also provides for a means of treating, in an acute setting, as well as preventing, in those individuals deemed susceptible to, CNS injuries by the chemokine receptor antagonist compounds of Formula (I).
  • CNS injuries as defined herein include both open or penetrating head trauma, such as by surgery, or a closed head trauma injury, such as by an injury to the head region. Also included within this definition is ischemic stroke, particularly to the brain area.
  • Ischemic stroke may be defined as a focal neurologic disorder that results from insufficient blood supply to a particular brain area, usually as a consequence of an embolus, thrombi, or local atheromatous closure of the blood vessel.
  • the role of inflammatory cytokines in this are has been emerging and the present invention provides a mean for the potential treatment of these injuries. Relatively little treatment, for an acute injury such as these has been available.
  • TNF- ⁇ is a cytokine with proinflammatory actions, including endothelial leukocyte adhesion molecule expression.
  • Leukocytes infiltrate into ischemic brain lesions and hence compounds which inhibit or decrease levels of TNF would be useful for treatment of ischemic brain injury. See Liu et al., Stoke, Vol. 25., No. 7, pp 1481-88 (1994) whose disclosure is incorporated herein by reference.
  • the compounds of Formula (I) are administered in an amount sufficient to inhibit LL-8, binding to the LL-8 alpha or beta receptors, from binding to these receptors, such as evidenced by a reduction in neutrophil chemotaxis and activation.
  • the discovery that the compounds of Formula (I) are inhibitors of LL-8 binding is based upon the effects of the compounds of Formulas (I) in the in vitro receptor binding assays which are described herein.
  • the compounds of Formula (I) have been shown, in some instances, to be dual inhibitors of both recombinant type I and type II LL-8 receptors.
  • the compounds are inhibitors of only one receptor, more preferably Type II.
  • LL-8 mediated disease or disease state refers to any and all disease states in which LL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , ENA-78, or NAP-2 plays a role, either by production of IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , ENA-78, or
  • NAP-2 themselves, or by LL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , ENA-78, or NAP-2 causing another monokine to be released, such as but not limited to IL- 1 , IL-6 or TNF.
  • IL-8 a disease state in which, for instance, IL- 1 is a major component, and whose production or action, is exacerbated or secreted in response to LL-8, would therefore be considered a disease stated mediated by IL-8.
  • chemokine mediated disease or disease state refers to any and all disease states in which a chemokine which binds to an LL-8 ⁇ or ⁇ receptor plays a role, such as but not limited IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , ENA-78, or NAP-2. This would include a disease state in which, LL-8 plays a role, either by production of IL-8 itself, or by LL-8 causing another monokine to be released, such as but not limited to LL-1, LL-6 or TNF.
  • cytokine refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response.
  • a cytokine includes, but is not limited to, monokines and lymphokines, regardless of which cells produce them.
  • a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte.
  • Lymphokines are generally referred to as being produced by lymphocyte cells.
  • cytokines include, but are not limited to, Interleukin-1 (LL-1), Interleukin-6 (LL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF- ⁇ ) and Tumor Necrosis Factor beta (TNF- ⁇ ).
  • chemokine refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response, similar to the term “cytokine” above.
  • a chemokine is primarily secreted through cell transmembranes and causes chemotaxis and activation of specific white blood cells and leukocytes, neutrophils, monocytes, macrophages, T-cells, B-cells, endothelial cells and smooth muscle cells.
  • chemokines include, but are not limited to, LL-8, GRO- ⁇ , GRO- ⁇ , GRO- ⁇ , ENA-78, NAP-2, IP- 10, MlP-l ⁇ , MlP- ⁇ , PF4, and MCP 1, 2, and 3.
  • a pharmaceutical composition comprising an effective, non- toxic amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent.
  • Compounds of Formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions incorporating such may conveniently be administered by any of the routes conventionally used for drug administration, for instance, orally, topically, parenterally or by inhalation.
  • the compounds of Formula (I) may be administered in conventional dosage forms prepared by combining a compound of Formula (I) with standard pharmaceutical carriers according to conventional procedures.
  • the compounds of Formula (I) may also be administered in conventional dosages in combination with a known, second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • the form and character of the pharmaceutically acceptable character or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the pharmaceutical carrier employed may be, for example, either a solid or liquid.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent may include time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25mg. to about lg.
  • the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
  • Compounds of Formula (I) may be administered topically, that is by non- systemic administration. This includes the application of a compound of Formula (I) externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the Formulation. It may however comprise as much as 10% w/w but preferably will comprise less than 5% w/w, more preferably from 0.1% to 1% w/w of the Formulation.
  • Lotions according to the present invention include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base.
  • the base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel.
  • the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100 C. for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol
  • Compounds of formula (I) may be administered parenterally, that is by intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration.
  • the subcutaneous and intramuscular forms of parenteral administration are generally preferred.
  • Appropriate dosage forms for such administration may be prepared by conventional techniques
  • Compounds of Formula (I) may also be administered by inhalation, that is by intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler may be prepared by conventional techniques.
  • the daily oral dosage regimen will preferably be from about 0 01 to about 80 mg/kg of total body weight.
  • the daily parenteral dosage regimen about 0001 to about 80 mg/kg of total body weight.
  • the daily topical dosage regimen will preferably be from 0.1 mg to 150 mg, administered one to four, preferably two or three times daily.
  • the daily inhalation dosage regimen will preferably be from about 001 mg/kg to about 1 mg/kg per day.
  • the optimal quantity and spacing of individual dosages of a compound of Formula (I) or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • LL-8, and GRO- ⁇ chemokine inhibitiory effects of compounds of the present invention were determined by the following in vitro assay: Receptor Binding Assays:
  • [125l] LL-8 (human recombinant) is obtained from Amersham Corp., Arlington Heights, IL, with specific activity 2000 Ci/mmol. Gro- ⁇ is obtained from NEN- New England Nuclear. All other chemicals are of analytical grade. High levels of recombinant human LL-8 type ⁇ and ⁇ receptors were individually expressed in Chinese hamster ovary cells as described previously (Holmes, et al, Science, 1991, 253, 1278). The Chinese hamster ovary membranes were homogenized according to a previously described protocol (Haour, et al, J Biol Chem., 249 pp 2195-2205 (1974)).
  • homogenization buffer is changed to lOmM Tris-HCL, lmM MgS04, 0.5mM EDTA (ethylene-diaminetetra- acetic acid), lmMPMSF ( ⁇ -toluenesulphonyl fluoride), 0.5 mg/L Leupeptin, pH 7.5.
  • Membrane protein concentration is determined using Pierce Co. micro-assay kit using bovine serum albumin as a standard. All assays are performed in a 96-well micro plate format.
  • Each reaction mixture contains H$l LL-8 (0.25 nM) or 1251 Gro- ⁇ and 0.5 ⁇ g/mL of IL-8R ⁇ or 1.0 ⁇ g/mL of IL-8R ⁇ membranes in 20 mM Bis- Trispropane and 0.4 mM Tris HC1 buffers, pH 8.0, containing 1.2 mM MgSO4, 0.1 mM EDTA, 25 mM NaCl and 0.03% CHAPS.
  • drug or compound of interest ss added which has been pre-dissolved in DMSO so as to reach a final concentration of between O.OlnM and 100 uM.
  • the assay is initiated by addition of 12 l-LL-8.
  • the plate is harvested using a Tomtec 96-well harvester onto a glass fiber filtermat blocked with 1 % polyethylenimine /0.5% BSA and washed 3 times with 25 mM NaCl, 10 mM TrisHCl, 1 mM MgSO4,
  • the filter is then dried and counted on the Betaplate liquid scintillation counter.
  • the recombinant LL-8 R ⁇ , or Type I, receptor is also referred to herein as the non-permissive receptor and the recombinant LL-8 R ⁇ , or Type II, receptor is referred to as the permissive receptor.
  • the in vitro inhibitory properties of these compounds are determined in the neutrophil chemotaxis assay as described in Current Protocols in Immunology, vol I, Suppl 1, Unit 6.12.3., whose disclosure is incorporated herein by reference in its entirety.
  • Neutrophils where isolated from human blood as described in Current Protocols in Immunology Vol I, Suppl 1 Unit 7.23.1, whose disclosure is incorporated herein by reference in its entirety.
  • the chemoattractants IL-8, GRO- ⁇ , GRO- ⁇ , GRO- ⁇ and NAP-2 are placed in the bottom chamber of a 48 multiwell chamber (Neuro Probe, Cabin John, MD) at a concentration between 0.1 and 100 nM. The two chambers are separated by a 5um polycarbonate filter.
  • the compounds of this invention are tested for their ability to prevent Elastase release from human neutrophils.
  • Neutrophils are isolated from human blood as described in Current Protocols in Immunology Vol I, Suppl 1 Unit 7.23.1.
  • PMNs 0.88 x 10 6 cells suspended in Ringer's Solution (NaCl 118, KC1 4.56, NaHCO3 25, KH2PO4 1.03, Glucose 1 1.1 , HEPES 5 mM, pH 7.4) are placed in each well of a 96 well plate in a volume of 50 ul.
  • test compound (0.001 - 1000 nM) in a volume of 50 ul, Cytochalasin B in a volume of 50 ul (20ug/ml) and Ringers buffer in a volume of 50 ul. These cells are allowed to warm (37 °C, 5% CO2, 95% RH) for 5 min before LL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ or NAP-2 at a final concentration of 0.01 - 1000 nM was added. The reaction is allowed to proceed for 45 min before the 96 well plate is centrifuged (800 xg 5 min) and 100 ul of the supernatant removed. This suppernatant is added to a second 96 well plate followed by an artificial elastase substrate (MeOSuc-Ala-Ala-Pro-Val-
  • the present assay provides for examination of the expression of tumor necrosis factor mRNA in specfic brain regions which follow experimentally induced lateral fluid-percussion traumatic brain injury (TBI) in rats.
  • TBI experimentally induced lateral fluid-percussion traumatic brain injury
  • LC left (injured) parietal cortex
  • RC contralateral right cortex
  • LA cortex adjacent to injured parietal cortex
  • RA right cortex
  • RH right hippocampus
  • TNF- ⁇ mRNA expression is observed in LH ( 104 ⁇ 17% of positive control, p ⁇ 0.05 compared with sham), LC (105 ⁇ 21%, p ⁇ 0.05) and LA (69 ⁇ 8%, p ⁇ 0.01) in the traumatized hemisphere 1 hr. following injury.
  • An increased TNF- ⁇ mRNA expression is also observed in LH (46 ⁇ 8%, p ⁇ 0.05), LC (30 ⁇ 3%, p ⁇ 0.01) and LA (32 ⁇ 3%, p ⁇ 0.01) at 6 hr. which resolves by 24 hr. following injury.
  • TNF- ⁇ mRNA In the contralateral hemisphere, expression of TNF- ⁇ mRNA is increased in RH (46 ⁇ 2%, p ⁇ 0.01), RC (4 ⁇ 3%) and RA (22 ⁇ 8%) at 1 hr. and in RH (28 ⁇ 1 1%), RC (7 ⁇ 5%) and RA (26 ⁇ 6%, p ⁇ 0.05) at 6 hr. but not at 24 hr. following injury. In sham (surgery without injury) or naive animals, no consistent changes in expression of TNF- ⁇ mRNA are observed in any of the 6 brain areas in either hemisphere at any times.
  • TNF- ⁇ is able to induce nerve growth factor (NGF) and stimulate the release of other cytokines from activated astrocytes, this post-traumatic alteration in gene expression of TNF- ⁇ plays an important role in both the acute and regenerative response to CNS trauma.
  • NGF nerve growth factor
  • This assay characterizes the regional expression of interleukin- l ⁇ (IL-l ⁇ ) mRNA in specific brain regions following experimental lateral fluid-percussion traumatic brain injury (TBI) in rats.
  • TBI lateral fluid-percussion traumatic brain injury
  • LC left (injured) parietal cortex
  • RC contralateral right cortex
  • LA cortex adjacent to injured parietal cortex
  • RA right cortex
  • LH left hippocampus
  • RH right hippocampus

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Abstract

L'invention concerne des nouveaux composés de la formule (I), des compositions pharmaceutiques, ainsi que l'utilisation de ceux-ci dans le traitement d'états maladifs induits par la chimiokine, interleukine-8 (IL-8).
EP97937142A 1996-08-06 1997-08-06 Antagonistes du recepteur d'il-8 Withdrawn EP0948330A4 (fr)

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