WO2000076516A1 - Il-8 receptor antagonists - Google Patents

Il-8 receptor antagonists Download PDF

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Publication number
WO2000076516A1
WO2000076516A1 PCT/US2000/016813 US0016813W WO0076516A1 WO 2000076516 A1 WO2000076516 A1 WO 2000076516A1 US 0016813 W US0016813 W US 0016813W WO 0076516 A1 WO0076516 A1 WO 0076516A1
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Prior art keywords
optionally substituted
alkyl
4alkyl
heterocyclic
aryl
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PCT/US2000/016813
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English (en)
French (fr)
Inventor
Deborah L. Bryan
John G. Gleason
Katherine L. Widdowson
Gregory Martin Benson
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Smithkline Beecham Corporation
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Publication date
Priority to EP00942933A priority Critical patent/EP1191934A4/en
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to NZ515232A priority patent/NZ515232A/xx
Priority to PL00352218A priority patent/PL352218A1/xx
Priority to IL14621400A priority patent/IL146214A0/xx
Priority to BR0010985-1A priority patent/BR0010985A/pt
Priority to AU57482/00A priority patent/AU766086B2/en
Priority to KR1020017016140A priority patent/KR20020009635A/ko
Priority to JP2001502849A priority patent/JP2003501471A/ja
Priority to MXPA01013287A priority patent/MXPA01013287A/es
Priority to CA002377397A priority patent/CA2377397A1/en
Publication of WO2000076516A1 publication Critical patent/WO2000076516A1/en
Priority to NO20016065A priority patent/NO20016065D0/no
Priority to HK02106332.2A priority patent/HK1044716A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
    • C07D317/66—Nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/28—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to cyano groups, e.g. cyanoguanidines, dicyandiamides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to novel guanidine containing compounds, pharmaceutical compositions, processes for their preparation, and use thereof in treating IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , ENA-78, and NAP-2 mediated diseases.
  • Interleukin-8 Interleukin-8
  • NAP-1 neutrophil attractant/activation protein- 1
  • MDNCF monocyte derived neutrophil chemotactic factor
  • NAF neutrophil activating factor
  • T-cell lymphocyte chemotactic factor 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 ⁇ , IL-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 IL-8 these chemokines have also been referred to by different names. For instance GRO ⁇ , ⁇ , ⁇ have been referred to as MGSA ⁇ , ⁇ and ⁇ respectively (Melanoma Growth Stimulating Activity), see Richmond et al, J. Cell Physiology
  • IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ and NAP-2 stimulate a number of functions in vitro. They have all been shown to have chemoattractant properties for neutrophils, while IL-8 and GRO ⁇ have demonstrated T-lymphocytes, and basophiles chemotactic activity.
  • IL-8 can induce histamine release from basophils from both normal and atopic individuals
  • GRO- ⁇ and IL-8 can in addition, induce lysozomal enzyme release and respiratory burst from neutrophils.
  • IL-8 has also been shown to increase the surface expression of Mac- 1 (CD 1 lb/CD 18) on neutrophils without de novo protein synthesis. This may contribute to increased adhesion of the neutrophils to vascular endothelial cells.
  • 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.
  • IL-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 IL-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.
  • IL-8 receptor represents a promising target for the development of novel anti-inflammatory agents.
  • Two high affinity human IL-8 receptors (77% homology) have been characterized: IL-8R ⁇ , which binds only IL-8 with high affinity, and IL-8R ⁇ , which has high affinity for IL-8 as well as for GRO- ⁇ , GRO ⁇ , GRO ⁇ and NAP-2.
  • IL-8R ⁇ Two high affinity human IL-8 receptors (77% homology) have been characterized: IL-8R ⁇ , which binds only IL-8 with high affinity, and IL-8R ⁇ , which has high affinity for IL-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).
  • Compounds of Formula (I) useful in the present invention are represented by the structure:
  • Z is cyano, OR u , C(O)NR 15 R ⁇ 6 , Rig, C(O)R n , C(O)OR ⁇ , or S(0) 2 R ⁇ 7 ;
  • 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 Ci-io alkyl; Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CRgRg)q S(O)(R4; hydroxy; hydroxy C ⁇ - alkyl; aryl; aryl Ci-4 alkyl; aryloxy; aryl Ci-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic C ⁇ -4alkyl; heteroaryl C1.4 alkyloxy; aryl C
  • R4 and R5 are independently hydrogen, optionally substituted C1-.4 alkyl, optionally substituted aryl, optionally substituted aryl C ⁇ -4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C ⁇ _4--lkyl, heterocyclic, heterocyclic Ci-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;
  • Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10 alkenyl; C i-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CRgRg)q S(O)tR-4; hydroxy; hydroxyC ⁇ -4alkyl; aryl; aryl C1-.4 alkyl; aryloxy; arylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C1-.4 alkyloxy; heterocyclic, heterocyclic C ⁇ -4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CRgRg)q NR4R5; C2-10 alkenyl C(O)NR4R5; (CRgRg)q C(O)NR4R 5
  • NR4C(O)Rn (CRgRg)q NHS(O) 2 Rd.
  • (CRgRg)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; n is an integer having a value of 1 to 3; m is an integer having a value of 1 to 3;
  • R6 and R7 are independently hydrogen or a C1-.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 selected from oxygen, nitrogen or sulfur;
  • Rg is independently selected from hydrogen or Cj-4 alkyl
  • RlO is C MO alkyl C(O)2Rg
  • Rl l is hydrogen, C1-.4 alkyl, optionally substituted aryl, optionally substituted aryl C ⁇ -4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi -4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 _4alky 1 ;
  • Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl;
  • Rl3 and R 14 are independently hydrogen, optionally substituted Ci-4 alkyl or one of R13 and R14 may be optionally substituted aryl;
  • Rj5 and R are independently hydrogen, optionally substituted C 1-.4 alkyl, optionally substituted aryl, optionally substituted aryl C ⁇ -4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC ⁇ -4alkyl, optionally substituted heterocyclic, optionally substituted heterocyclicC i-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, NR 5R16, ORn , optionally substituted aryl, optionally substituted aryl Ci_4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 _4alkyl;
  • Ri is optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC i-4alkyl;
  • Rl9 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or heterocyclicC i-4alkyl, wherein the all of these moieties may be optionally substituted;
  • Rd is NR6R7, alkyl, arylC ⁇ - alkyl, arylC 2.4 alkenyl, heteroaryl, hetroaryl-C i-4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclicC 1.4 alkyl, wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl
  • the E' containing ring is optionally selected from
  • the E containing ring is optionally selected from
  • 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 IL-8 or other chemokines which bind to the IL-8 ⁇ and ⁇ receptors.
  • Chemokine mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted herein in the Methods of Treatment section.
  • (*) may optionally be present. If if it is not present the ring is a phenyl moiety which is substituted by the Ri terms as shown.
  • the E ring may be substituted by the R moiety in any ring, saturated or unsaturated, and is shown for purposes herein substituted only in the unsaturated ring(s).
  • 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, -SR2.-OR2, -NH-C(O)R a , -C(O)NR6'R7', a substituted sulfonamides of the formula -NHS(O)2Rb, -S(O)2NHR c , NHC(X 2 )NHRb, or a tetrazolyl; wherein X2 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 SR2 or OR2. More preferably R is OH, SH, or NHS(O)2Rb-
  • R2 is a substituted aryl, heteroaryl, or heterocyclic moiety which ring has the functional moiety providing the ionizable hydrogen having a pKa of 10 or less.
  • R6' and R7' are hydrogen, C1-.4 alkyl, aryl, arylCi-4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylC ⁇ _4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic Ci-4alkyl, heterocyclic C2-4alkenyl moiety , 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; Ci-4 alkoxy, such as methoxy; NR9C(O)R a ; C(O)NR6R7; S(O)3H; or C(O)OCi-4 alkyl, provided that only one of R6' and R7' are hydrogen, but not both.
  • 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 which heteroatom is selected from oxygen, nitrogen or sulfur. This heteroring may be optionally substituted as defined herein.
  • R a is an aryl, arylC ⁇ _4alkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or a heterocyclic Ci-4alkyl moiety, all of which may be optionally substituted, as defined herein below.
  • R is a NR6R7 .
  • Rb is preferably an optionally substituted phenyl, benzyl, or styryl.
  • Rb is a heteroaryl preferably it is an optionally substituted thiazole, optionally substituted thienyl, or optionally substituted quinolinyl ring.
  • R9 is hydrogen or a C ⁇ _4 alkyl, preferably hydrogen.
  • R a is preferably an alkyl group, such as methyl.
  • R c is hydrogen, alkyl, aryl, arylCi-4alkyl, arylCi-4alkenyl, heteroaryl, heteroarylC ⁇ _4alkyl, heteroarylCi-4alkenyl, heterocyclic, heterocyclic Ci-4alkyl, or heterocyclic Ci-4alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen, nitro, halosubstituted Ci-4 alkyl, C1-4 alkyl, C1-4 alkoxy, NR9C(O)R a , C(O)NR6R7, S(O)3H, or C(O)OC ⁇ _4 alkyl, wherein R9 is hydrogen or a Ci-4 alkyl.
  • R c is an optionally substituted phenyl.
  • R is an OR2 or SR2 moiety it is recognized by one of skill in the art that the aryl ring must, therefore, contain the required ionizable hydrogen.
  • the aryl ring may also be additionally substituted, independently, by one to three groups, which groups may also contain an additional ionizable group, and which include but are not limited to, halogen, nitro, halosubstituted Ci-4 alkyl, C1-.4 alkyl, C1.4 alkoxy, hydroxy, SH, -C(O)NR6R7, -NH-C(O)R a , -NHS(O)2Rb, S(O)2NR6R7, C(O)ORg 5 or a tetrazolyl ring.
  • Rl is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl, such as CF3; C ⁇ o alkyl, such as methyl, ethyl, isopropyi, or n-propyl; C2-10 alkenyl; Ci-io alkoxy, such as methoxy, or ethoxy; halosubstituted Ci-io alkoxy, such as trifluoromethoxy; azide; (CRgRg)q S(O) ⁇ R4, wherein t is 0, 1 or 2; hydroxy; hydroxy C ⁇ _4alkyl, such as methanol or ethanol; aryl, such as phenyl or naphthyl; aryl C ⁇ 4 alkyl, such as benzyl; aryloxy, such as phenoxy; aryl C ⁇ _4 alkyloxy, such as benzyloxy; heteroaryl;
  • NHS(O)2Ri9, (CRgR )qS(O)2NR4R5; or two Rl moieties together may form O-(CH2)sO- or a 5 to 6 membered saturated or unsaturated ring; and s is an integer having a value of 1 to 3.
  • the aryl , heteroaryl, and heterocyclic containing moieites may be optionally substituted as defined herein below.
  • q is 0, or an integer having a value of 1 to 10.
  • Rl When Rl forms a dioxybridge, s is preferably 1. When Rl forms an additional saturated or unsaturated 5 to 6 membered ring, it is preferably 6 membered ring with unsaturation, resulting in a naphthylene ring system. These rings may be substituted independently, 1 to 3 times by the other Rl moieties as defined above.
  • R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Cj-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C ⁇ _4alkyl, heterocyclic, heterocyclicC 1-4 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.
  • Rg is suitably independently selected from hydrogen or Cj-4 alkyl.
  • RlO is suitably Ci-io alkyl C(O)2R8, such as CH2C(O)2H or CH 2 C(O) 2 CH 3 .
  • Rl 1 is suitably hydrogen, Ci-4 alkyl, aryl, aryl Cj-4 alkyl, heteroaryl, heteroaryl C ⁇ _4alkyl, heterocyclic, or heterocyclic C ⁇ _4alkyl.
  • Rl2 is suitably hydrogen, Cl-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl.
  • Rl9 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or heterocyclicC i-4alkyl, wherein the all of these moieties may be optionally substituted;
  • Rl is halogen, cyano, nitro, CF3, C(O)NR-4R5, alkenyl C(O)NR4R5, C(O) R4R10, alkenyl C(O)ORi2, heteroaryl, heteroarylalkyl , heteroaryl alkenyl, or S(O)NR4.R5, and preferably R4 and R5 are both hydrogen or one is phenyl.
  • a preferred ring substitution for Rj is in the 4-position of the phenyl ring.
  • R is OH, SH or NSO2Rb than Ri is preferably substituted in the 3- position, the 4- position or di substituted in the 3,4- position.
  • the substituent group is suitably an electron withdrawing moiety.
  • R is OH, SH or NSO2Rb . than Rj is nitro, halogen, cyano. trifluoromethyl group, C(O)NR4R5.
  • Ri is preferably hydrogen, or Ri is preferably substituted in the 4-position, more preferably substituted by trifluoromethyl or chloro.
  • R13 and R 14 are independently hydrogen, optionally substituted C ⁇ _4 alkyl which may be straight or branched as defined herein, or one of R 3 and R 14 are an optionally substituted aryl; v is 0, or an integer having a value of 1 to 4.
  • R 3 or R14 are an optionally substituted alkyl
  • the alkyl moiety may be 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 Ci-io alkoxy, S(O)tR4; aryl; NR4R5; NHC(O)R4; C(O)NR-4R5; or C(O)ORg.
  • Wj is suitably
  • the E containing ring denoted by its point of attachment through the asterix (*) may optionally be present. If if it is not present the ring is a phenyl moiety which is substituted by the Y terms as shown herein.
  • the E ring may be substituted by the Y moiety in any ring, saturated or unsaturated, and is shown for purposes herein substituted only in the unsaturated ring(s).
  • Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10 alkenyl; Ci- o alkoxy; halosubstituted Ci-io alkoxy; azide; (CRgRg)q S(O)tR-4; hydroxy; hydroxyC ⁇ _4alkyl; aryl; aryl C1-.4 alkyl; aryloxy; arylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl Ci-4 alkyloxy; heterocyclic, heterocyclic C ⁇ _4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CRgRg)q NR4R5; C2-10 alkenyl C(O)NR4R 5 ; (CRgRg)q C(O)NR4R
  • s is preferably 1.
  • Y forms an additional saturated or unsaturated ring, it is preferably 6 membered ring resulting in a naphthylene ring system.
  • This naphthylene ring may be substituted 1 to 3 times by other Y moieties as defined above.
  • the aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclic, heterocyclicalkyl, and heterocyclicalkenyl moieties noted above may all be optionally substituted as defined herein.
  • Rd is a NR6R7, alkyl, aryl C -.4 alklyl, arylC 2-4 alkenyl, heteroaryl, hetroaryl-C 1.4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclicC j -.4 alkyl, or heterocyclic C 2-4 alkenyl moiety, wherein the aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclic, and heterocyclicalkyl, and heterocyclicalkenyl moieties noted above may all be optionally substituted as defined herein.
  • Y is preferably a halogen, Ci-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-substituted halogen, disubstituted halogen, mono- substituted alkoxy, disubstituted 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
  • Y is preferably mono-substituted in the 2'-position or 3'- position, with the 4'- preferably being unsubstituted; more preferably R is OH, SH, or NSO2Rb- If the ring is disubstituted, preferably when R is OH, SH, or NSO2Rb. then the substituents are preferably in the 2' or 3' position of a monocyclic ring.
  • Ri and Y can both be hydrogen, it is prefered that at least one of the rings be substituted, preferably both rings are substituted.
  • W is phenyl
  • R is OH
  • v is 0, and W is a phenyl, than (Y) n , wherein n is 1 or 2, is not mono substituted in the 3' position or di-substituted in the 3 '-5 ' position of the phenyl ring with halogen, trifluromethyl, OCF3, C(O)2H, C(O) 2 alkyl, C(O)2aryl, C(O)amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl, amino, aryloxy, alkylcarbonyl, arylcarbonyl, alkylcarbonyloxy, or arylcarbonyloxy.
  • n 1, is other than a 2-substituted arylalkyl, or arylalkenyl moiety (optionally substituted by alkyl).
  • Z is suitably cyano, ORn, C(O)NRi5R ⁇ g,
  • R15 and R16 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, optionally substituted heterocyclicC ⁇ _4alkyl, or Rl5 and Ri6 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.
  • R17 is Ci-4 alkyl, NR15R16, ORn, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 _4alkyl .
  • Rig is optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi_4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 -4alkyl.
  • halogen such as fluorine, chlorine, bromine or iodine
  • hydroxy hydroxy substituted Ci-ioalkyl
  • Cj-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)2R21, Cl-10 alkyl, such as methyl, ethyl, propyl, isopropyi, or t-butyl
  • halosubstituted Ci-io alkyl such CF3; an optionally substituted Ci-io alkyl, such CF3; an optionally substituted
  • R21 is suitably Ci-4 alkyl, aryl, aryl C ⁇ _4alkyl, heteroaryl, heteroarylC ⁇ _4alkyl, heterocyclic, or heterocyclicC ⁇ _4alkyl.
  • 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.
  • i-ioalkyl or "alkyl” - both straight and branched chain radicals of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, w ⁇ -propyl, n-butyl, sec-butyl, iso-butyl, tert- butyl, n-pentyl and the like.
  • 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 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.
  • Exemplified compounds of Formula (I) include: N-(2-Hydroxy-4-nitrophenyl)-N'-(2-chlorophenyl)-N"-cyanoguanidine N-(2-Hydroxy 4-nitro phenyl) N'-(2-chloro phenyl)-N"-cyanoguanidine N-(4-Cyano-2-hydroxyphenyl)-N'-(phenyl)cyanoguanidine
  • N-(2-Bromophenyl) N'-(4-cyano-2-hydroxyphenyl) N"-cyanoguanidine N-(4-Cyano-2-hydroxyphenyl)-N'-(2,3-dichlorophenyl)-N"-cyanoguanidine
  • N-(2-Bromophenyl)-N'-(4-cyano-2-hydroxy-3 -isobutylphenyl)-N"- cyanoguanidine N-(2-Bromophenyl)-N'-(4-cyano-2-hydroxy-3 -isobutylphenyl)-N"- cyanoguanidine
  • N-(2-Bromophenyl)-N'-(3-bromo-4-cyano-2-hydroxyphenyl)-N"-cyanoguanidine N-(4-Cyano-2-hydroxy-3-propylphenyl)-N'-(2,3-dichlorophenyl)-N"- cyanoguanidine; and N-(3-Bromo-4-cyano-2-hydroxyphenyl)-N'-(2,3-methylenedioxyphenyl)-N"- cyanoguanidine N-(2-Chlorophenyl)-N'-(4-cyano-2-hydroxy-3-propylphenyl)-N"-cyanoguanidine; and
  • N-(2-Bromophenyl)-N'-(4-cyano-2-hydroxy-3-methoxycarbonylphenyl)- N " -cyanoguanidine 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 thiouronium salt(2. Scheme 1) can be synthesized by reacting sodium cyanamide with a commercially available isothiocyanate X (if the isothiocyanate 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 thiouronium salt (2) can then be condensed with the appropriate substituted aniline in the presence of a coupling reagent like EDC ⁇ C1 or acidified to form the cyanothiourea and then reacted.
  • Alternatively 4 can be synthesized by reacting the commercially available (Aldrich Chem. Co.), diphenyl cyanocarboimidate (5, Scheme 2) with an amine to form an intermediate O-phenylisourea 6_which then reacts with the appropriately substituted aniline in the presence of trimethyl aluminum by the method of Atwal. (Atwal, K. S., Tetrahedron Lett, 35, 8085 (1994).).
  • Compounds wherein R' is alkyl may be prepared by heating with the appropriately substituted alkylamine, but without the presence of catalyst.
  • the title compound can be synthesized using a protected ortho- substituted aniline (8, Scheme 3, See synthesis as described in US provisional application USSN 60/020655 filed June 27, 1996, Attorney Docket No.: P50467P; WO96/25157 filed 22 August 1996, Widdowson et al. (Attorney Docket No.: P50324-1); and USSN 08/701,299 filed 21 August 1996 (Attorney Docket No.: P50324-2) whose disclosures are incorporated herein by reference in their entireties.
  • An ortho-substituted aniline (7, Scheme 3) is first protected (ie.
  • tert-butyl dimethyl silyl, allyl, benzyl, mom or other suitable protecting group by reacting the ortho- substituted aniline with the appropriate alkyl or silyl halide in the presence of a suitable base (ie. cesium carbonate, potassium carbonate or imidazole) in an aprotic solvent.
  • a suitable base ie. cesium carbonate, potassium carbonate or imidazole
  • the protected ortho-substituted aniline may also be synthesized from an ortho-substituted nitrobenzene (9 ) by reacting it with a protecting group under conditions well known in the art (see Greene, T Protecting Groups in Organic Synthesis, Wiley&Sons, New York, 1981) This protected ortho-substituted nitro compound is then reduced to the corresponding aniline using SnCl2 in EtOH or alternately H2 Pd or LiAlH4 in an aprotic solvent.
  • This protected ortho-substituted aniline (8) can then be converted into an isothiocyanate using thiophosgene and then reacted with the anion ZNH " (formed from reaction of ZNH2 with a base such as NaH).
  • Z is as defined in compounds of
  • the thioimidate (10, Scheme 5) can be converted to the title compound 4 by reaction with the amine RNH2- This reaction can be accelerated by the addition of metal salt with a high affinity for sulfur such as mercuric oxide or silver acetate or by oxidation of the sulfur with dimethyloxirane to form a better leaving group. Finally the phenol protection is removed by standard methods to form the title compound 4.
  • a protected carbodiimide X X_, Scheme 6
  • the anion NH-Z formed from reaction of NH2Z with a base such as NaH
  • NH2Z neutral species
  • a tertiary amine base
  • Suitable bases for use herein include, secondary amine, such as pyridine, and amino substituted pyridine derivatives.
  • Suitable solvents for use herein when Z is cyano include various aprotic solvents, such as acetonitrile; halogenated solvents, such as chloroform and methylene chloride; ethyl gylcol-dimethyl ether (monoGLYME), dioxane, DMF and DMSO; or mixtures thereof, preferably acetonitrile. It is recognized by the skilled artisan that the limiting feature fo use of solvents herein will be the solubility of the cyano derivatived compound. For compounds wherein Z is other than cyano, while aprotic solvents are prefered, it is recognized by the skilled artisan that other suitable solvents, such as protic solvents, i.e. alcohols, may be used.
  • reaction (when Z is cyano) temperature is from about -10° to about 100°, preferably about 10° to about 50°, more preferably around room temperature, i.e. 20 to 30 °C.
  • the protected R" moiety may be suitably deprotected using art recognized techniques.
  • the deprotection is by deallylation catalyzed by palladium (O) when the protecting group is an allyl derivative.
  • the carbodiimide 11 is prepared from the thiourea (12a, Scheme 7) by treatment with phosgene and a tertiary amine base or from the thiourea (12a) or urea (12b) by reaction with triphenylphosphine, carbon tetrachloride and triethylamine.
  • the carbodiimide may also be prepared by reaction of the thiourea (12b) with an excess, such as 2 or more equivalents of methanesulfonyl chloride and a tertiary amine base, such as Hunig's base (diisopropylethylamine), triethylamine, tri- isopropylethylamine, N,N-dimethylbenzylamine, or N,N-dimethylisopropylamine, preferably triethylamine.
  • the reaction may use any halogenated solvent, such as methylene chloride, chloroform, or tetrachloroethylene, etc.; suitable reaction temperatures are from about.
  • the thiourea or urea is synthesized as described in the US provisional application USSN 60/020655 filed June 27, 1996, Attorney Docket No.: P50467P and Attorney Docket No.: P50324-2, whose disclosure is incorporated herein by reference.
  • the thiourea (12a, Scheme 8) may also be prepared by reaction of the protected ortho-substituted aniline and two equivalents of an appropriate base such as NaH, KH, calcium hydride, and reacting this anion with a commercially available isothiocyanate (Wj-NCS, wherein Wj is as defined for compounds of Formula (I)).
  • reaction make take place in any suitable aprotic solvent or halogenated solvent, preferably dimethyl formamide. Suitable reaction temperatures for this reaction are from about -10° to about 50°. If the desired isothiocyanate is not commercially available, it may be prepared by reaction of a corresponding aniline with thiophosgene and a suitable base such as sodium bicarbonate.
  • Example 2(b) The compound of Example 2(b) (47 mg, 0.146 mmol) was dissolved in ethyl acetate (20 mL), treated with 6 N HC1 (10 mL) and stirred at rt for 3 h . Then 6 N HC1 (5 mL) was added and stirring continued for 2 more h. The mixture was diluted with ethyl acetate and brine and the aqueous portion extracted further with ethyl acetate (X5). The combined organic portions were dried over sodium sulfate and evaporated in vacuo to give the title compound (64 mg) which was recrystallized from t-butyl-O-methylether to give the title compound as a white solid (2 mg,
  • Example 2(b) The compound prepared in Example 2(b) (1.88 g, 1.29 mmol) was treated with N,N-dimethylaniline (20 mL) under Ar and was kept for 3.5 h at 175° (oil bath temperature). The solvent was removed in vacuo and the residue was recrystallized from methyl-t-butylether with 10-20% of each methylene chloride and hexane to afford the title compound as a clear solid (1.67 g, 89%). MS(ES+) m/e 175 [M+H]+;
  • 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 IL-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 IL-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 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 chemokines are IL-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 IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , ENA-78 or
  • Abnormal levels of IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , ENA-78 or NAP-2 for instance in the context of the present invention constitute: (i) levels of free IL-8 greater than or equal to 1 picogram per mL; (ii) any cell IL-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 IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , ENA-78 or NAP-2 respectively, is produced.
  • Chemokine mediated diseases 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, atherosclerosis, osteoporosis, gingivitis or undesired hematopoietic stem cells release.
  • the present compounds are also useful for the treatment of diseases caused by respiratory viruses, including but not limited to rhinovirus and influenza virus, herpesviruses, including but not limited to herpes simplex I and II, and hepatitis viruses, including but not limited to Hepatitis B and Hepatitis C virus.
  • respiratory viruses including but not limited to rhinovirus and influenza virus
  • herpesviruses including but not limited to herpes simplex I and II
  • hepatitis viruses including but not limited to Hepatitis B and Hepatitis C virus.
  • IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ or NAP-2 has the unique property of promoting neutrophil chemotaxis, enzyme release including but not limited to elastase release as well as superoxide production and activation.
  • 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 IL-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 IL-8, binding to the IL-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 IL-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 IL-8 receptors.
  • the compounds are inhibitors of only one receptor, more preferably Type II.
  • IL-8 mediated disease or disease state refers to any and all disease states in which IL-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 IL-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.
  • chemokine mediated disease or disease state refers to any and all disease states in which a chemokine which binds to an IL-8 ⁇ or ⁇ receptor plays a role, such as but not limited IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , ENA-78 or NAP-2.
  • IL-8 plays a role, either by production of IL-8 itself, or by IL-8 causing another monokine to be released, such as but not limited to IL-1, IL-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.
  • mononuclear cell such as a macrophage and/or monocyte.
  • monokines such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epideral keratinocytes and B -lymphocytes.
  • Lymphokines are generally referred to as being produced by lymphocyte cells.
  • cytokines include, but are not limited to, Interleukin- 1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF- ⁇ ) and Tumor Necrosis Factor beta (TNF- ⁇ ).
  • IL-1 Interleukin-1
  • IL-6 Interleukin-6
  • IL-8 Interleukin-8
  • TNF- ⁇ Tumor Necrosis Factor-alpha
  • TNF- ⁇ Tumor Necrosis Factor beta
  • TNF- ⁇ Tumor Necrosis Factor beta
  • 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, IL-8, GRO- ⁇ , GRO- ⁇ , GRO- ⁇ , ENA-78, NAP-2, IP-10, MlP-l ⁇ , MlP- ⁇ , PF4, and MCP 1, 2, and 3.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof in therapy it will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice.
  • This invention also relates to 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 0.001 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 0.01 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.
  • BIOLOGICAL EXAMPLES The IL-8, and Gro- ⁇ chemokine inhibitiory effects of compounds of the present invention were determined by the following in vitro assay: Receptor Binding Assays:
  • [125 ⁇ ] iL-8 (human recombinant) was obtained from Amersham Corp., Arlington Heights, IL, with specific activity 2000 Ci/mmol. Gro- ⁇ was obtained from NEN- New England Nuclear. All other chemicals were of analytical grade. High levels of recombinant human IL-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)).
  • the homogenization buffer was 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 was determined using Pierce Co. micro-assay kit using bovine serum albumin as a standard. All assays were performed in a 96-well micro plate format.
  • Each reaction mixture contained 125j IL_ ⁇ (0.25 nM) or 25 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 was added which had been pre-dissolved in DMSO so as to reach a final concentration of between 0.0 InM and 100 uM.
  • the assay was initiated by addition of l ⁇ i-H ⁇ g.
  • the recombinant IL-8 R ⁇ , or Type I, receptor is also referred to herein as the non- permissive receptor and the recombinant IL-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.
  • PMNs 0.88 x 10 6 cells suspended in Ringer's Solution (NaCl 118, KC1 4.56, NaHCO3 25, KH2PO4 1.03, Glucose 11.1, HEPES 5 mM, pH 7.4) are placed in each well of a 96 well plate in a volume of 50 ul.
  • the 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.
  • 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 ⁇ 11%), 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- ⁇ mRNA is altered in specific brain regions, including those of the non-traumatized hemisphere. Since 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.
  • CNS Injury model for IL- ⁇ mRNA This assay characterizes the regional expression of interleukin- 1 ⁇ (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
  • RNA Total RNA is isolated and Northern blot hybridization was performed and the quantity of brain tissue IL-l ⁇ mRNA is presented as percent relative radioactivity of IL-l ⁇ positive macrophage RNA which was loaded on same gel.
  • LH 24.5 ⁇ 0.9%, p ⁇ 0.05
  • LA 21.5 ⁇ 3.1%, p ⁇ 0.05

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PCT/US2000/016813 1999-06-16 2000-06-16 Il-8 receptor antagonists WO2000076516A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
AU57482/00A AU766086B2 (en) 1999-06-16 2000-06-16 IL-8 receptor antagonists
NZ515232A NZ515232A (en) 1999-06-16 2000-06-16 IL-8 receptor antagonists
PL00352218A PL352218A1 (en) 1999-06-16 2000-06-16 Il-8 receptor antagonists
IL14621400A IL146214A0 (en) 1999-06-16 2000-06-16 Il-8 receptor antagonists
BR0010985-1A BR0010985A (pt) 1999-06-16 2000-06-16 Antagonistas de receptor de il-8
EP00942933A EP1191934A4 (en) 1999-06-16 2000-06-16 ANTAGONISTS OF IL-8 RECEPTORS
KR1020017016140A KR20020009635A (ko) 1999-06-16 2000-06-16 Ｉｌ-8 수용체 길항제
CA002377397A CA2377397A1 (en) 1999-06-16 2000-06-16 Il-8 receptor antagonists
MXPA01013287A MXPA01013287A (es) 1999-06-16 2000-06-16 Antagonistas de receptor de interleucina 8.
JP2001502849A JP2003501471A (ja) 1999-06-16 2000-06-16 Ｉｌ−８受容体アンタゴニスト
NO20016065A NO20016065D0 (no) 1999-06-16 2001-12-12 IL-8-reseptor-antagonister
HK02106332.2A HK1044716A1 (zh) 1999-06-16 2002-08-27 Il-8受體拮抗劑

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6642215B2 (en) * 2001-05-24 2003-11-04 Leo Pharma A/S Method of modulating NF-kB activity

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0344425A2 (en) * 1988-03-30 1989-12-06 Warner-Lambert Company N-[[(2,6-disubstituted)phenyl]-N'- arylalkyl] ureas as antihypercholesterolemic and antiatherosclerotic agents
US5780483A (en) * 1995-02-17 1998-07-14 Smithkline Beecham Corporation IL-8 receptor antagonists

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AR008290A1 (es) * 1996-08-15 1999-12-29 Smithkline Beecham Corp Nuevos compuestos que contienen guanidina utiles como antagonistas de los receptores de il-8, composiciones farmaceuticas que los contienenprocedimiento para la preparacion de dichos compuestos y procedimiento para la preparacion de intermediarios.

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0344425A2 (en) * 1988-03-30 1989-12-06 Warner-Lambert Company N-[[(2,6-disubstituted)phenyl]-N'- arylalkyl] ureas as antihypercholesterolemic and antiatherosclerotic agents
US5780483A (en) * 1995-02-17 1998-07-14 Smithkline Beecham Corporation IL-8 receptor antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1191934A4 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6642215B2 (en) * 2001-05-24 2003-11-04 Leo Pharma A/S Method of modulating NF-kB activity

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NO20016065D0 (no) 2001-12-12
TR200103690T2 (tr) 2002-05-21

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