WO2000072840A1 - Antagonistes du recepteur de l'il-8 - Google Patents

Antagonistes du recepteur de l'il-8 Download PDF

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WO2000072840A1
WO2000072840A1 PCT/US2000/014660 US0014660W WO0072840A1 WO 2000072840 A1 WO2000072840 A1 WO 2000072840A1 US 0014660 W US0014660 W US 0014660W WO 0072840 A1 WO0072840 A1 WO 0072840A1
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alkyl
optionally substituted
alkenyl
aryl
4alkyl
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PCT/US2000/014660
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Michael R. Palovich
Katherine L. Widdowson
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Smithkline Beecham Corporation
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Priority to HU0201302A priority Critical patent/HUP0201302A3/hu
Priority to IL14605300A priority patent/IL146053A0/xx
Priority to KR1020017015176A priority patent/KR20020016806A/ko
Priority to EP00936368A priority patent/EP1180025A4/fr
Priority to CA002374295A priority patent/CA2374295A1/fr
Priority to MXPA01012267A priority patent/MXPA01012267A/es
Priority to PL00351947A priority patent/PL351947A1/xx
Priority to JP2000620952A priority patent/JP2003500443A/ja
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to BR0010863-4A priority patent/BR0010863A/pt
Priority to NZ514728A priority patent/NZ514728A/en
Priority to AU51690/00A priority patent/AU766999B2/en
Publication of WO2000072840A1 publication Critical patent/WO2000072840A1/fr
Priority to NO20015774A priority patent/NO20015774L/no
Priority to HK02105335.1A priority patent/HK1045256A1/zh

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    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
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    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/18—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 carbon atoms of six-membered aromatic rings
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/88—Nitrogen atoms, e.g. allantoin

Definitions

  • IL-8 RECEPTOR ANTAGONISTS FIELD OF THE INVENTION This invention relates to a novel group of cyclicguanidine compounds, processes for the preparation thereof, the use thereof in treating IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ . NAP-2, and ENA-78 mediated diseases and pharmaceutical compositions for use in such therapy.
  • Interleukin-8 Interleukin-8
  • NAP-1 neutrophil attractant activation protein- 1
  • MDNCF monocyte derived neutrophil chemo tactic 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.
  • 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 129, 375 (1986) and Chang et al, J. Immunol 148, 451 (1992). All of the chemokines of the ⁇ -family which possess the ELR motif directly preceding the CXC motif bind to the EL-8 B receptor.
  • IL-8, Gro ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 and ENA-78 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. In addition 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.
  • 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).
  • 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).
  • B-receptor Thomas et al., J. Biol. Chem. 266. 14839 (1991)
  • Holmes et al. Science 253, 1278 (1991).
  • 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-8RB, which has high affinity for IL-8 as well as for GRO- ⁇ , GRO ⁇ , GRO ⁇ and NAP-2.
  • IL-8R ⁇ which binds only IL-8 with high affinity
  • IL-8RB 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).
  • R is OH, SH, NHSO 2 Rd ;
  • R f j is NRgR , alkyl, arylC ⁇ _4alkyl, arylC 2-4 alkenyl, heteroaryl, hetroaryl-C ⁇ alkyl, heteroarylC2_4 alkenyl, heterocyclic, heterocyclicC ⁇ _4 alkyl, wherein the aryl, heteoaryl and heterocyclic rings may all be optionally substituted;
  • 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 is selected from oxygen, nitrogen or sulfur, and which ring may be optionally substituted;
  • 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) j 4, hydroxy, hydroxy Ci-4alkyl, aryl, aryl Ci-4 alkyl, aryloxy, aryl C1-.4 alkyloxy, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclic C ⁇ -4alkyl, heteroaryl C1-.4 alkyloxy, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CR 8 R )qNR4R5, C2-10 alkenyl C(O)NR4R5, (CR 8 R 8 )q C(O)NR4R 5 , (CR 8
  • (CR 8 R 8 )q S(O) 2 NR 4 R 5 , or two Ri moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring; q is 0, or an integer having a value of 1 to 10; t is 0, or an integer having a value of 1 or 2; s is an integer having a value of 1 to 3;
  • R4 and R5 are independently hydrogen, optionally substituted C1-.4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C ⁇ -4alkyl, heterocyclic, heterocyclicC ⁇ -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;
  • R2 is independently selected from C2-5 alkyl and C2-5 alkenyl all of which moieties may be optionally substituted one to three times independently by halogen; nitro; halosubstituted C i -.4 alkyl; Cj-4 alkyl; amino, mono or di-C ⁇ .4 alkyl substituted amine; hydroxy; C1-.4 alkoxy; NR9C(O)R a ; S(O) m R a ; C(O)NR6R7; C(O)OH; C(O)OR a ; S(O)2NR6R7; NHS(O)2R a ; and optionally containing, in addition to carbon, independently, 1 to 3 NR9, O, C(O), S, SO, or SO2 moities; Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10 alkeny
  • R 8 is hydrogen or C1-.4 alkyl
  • R9 is hydrogen or Cl-4alkyl; Rio is C MO alkyl C(O)2R8;
  • Rl 1 is hydrogen, C ⁇ _4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi_4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC -4alky 1 ;
  • R12 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl;
  • Rl7 is C ⁇ _4alkyl, aryl, arylalkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or heterocyclicCi-4alkyl, wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted; and
  • R a is an alkyl, aryl, arylCi-4alkyl, heteroaryl, heteroaryl Ci-4alkyl, heterocyclic, or a heterocyclic C ⁇ _4alkyl moiety, all of which moieties may be optionally substituted.
  • 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-8RA and RB 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.
  • Exemplified compounds of Formula (I) include: 4-[[l-(2-bromophenyl)-4,5-dihydro-5-oxo-lH-imidazol-2-yl]amino]-3- hy droxybenzonitrile ,
  • N-(4-cyano-2-hyroxyphenyl)-N'-(2-bromophenyl)-N"-(chloromethanesulfonyl) guanidine N-(4-cyano-2-hyroxyphenyl)-N'-(2-bromophenyl)-N"-(2,2-dimethoxyethyl) guanidine,
  • 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.
  • C2-5alkyl or “alkyl” both straight and branched chain moieties of 2 to 5 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl. n- pentyl and the like.
  • alkenyl is used herein at all occurrences to mean straight or branched chain moieties 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 Ci-io alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated.
  • Methods of Preparation 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 producing compounds of Formula (I) having a variety of different R, R ⁇ , and aryl groups which are reacted, employing optional substituents which are suitably protected, to achieve compatibility with the reactions outlined herein.
  • the desired aniline 6-scheme-l can be prepared from the commercially available benzoxazolinone 1 -scheme- 1.
  • Bromide 2-scheme-l can be prepared from benzoxazolinone 1 -scheme- 1 using standard bromination conditions such as bromine and sodium acetate in acetic acid.
  • Bromide 2-scheme- 1 can be converted to the cyanide 3-scheme-l using standard procedures such as copper (I) cyanide in refluxing DMF.
  • the amide 3-scheme-l can be converted to the BOC protected compound 4-scheme-l using standard conditions such as BOC anhydride and triethylamine with a catalytic amount of dimethylaminopyridine in methylene chloride or another suitable organic solvent.
  • the oxazolinone 4-scheme-l can be converted to the desired aniline 6-scheme-l by first hydrolysis to the phenol 5; scheme- 1 using standard conditions such as potassium carbonate in methanol followed by removal of the BOC protecting group using standard conditions such as trifluoroacetic acid in methylene chloride or another suitable organic solvent to give the aniline 6-scheme-l.
  • Scheme 2
  • the desired thiourea 3-scheme-2 can be prepared as outlined in scheme 2.
  • the aniline l-scheme-2 can be coupled with a commercially available isothiocyanate or with an isothiocyanate made from condensing a commercially available amine with thiophosgene or a thiophosgene equivalent to give the thiourea 2-scheme-2.
  • the phenol 2-scheme-2 can be protected as the TBS ether 3-scheme-2 using standard conditions such as TBSCl and imidazole in THF or another suitable organic solvent.
  • the amine l-scheme-2 can be converted to the isothiocyanate 5-Scheme-2 by first protecting the phenol l-Scheme-2 with a suitable protecting group such as the TBS ether 4-scheme-2 using standard conditions such as TBSCl and an amine base such as imidazole in THF or another suitable organic solvent.
  • the thiourea 5-scheme-2 can be made by condensing the amine 4-scheme 2 with thiophosgene in the presence of a base such as potassium carbonate.
  • the desired thiourea 3-scheme-2 can be prepared from the isothiocyanate 5-scheme-2 by condensing it with the desired amine in a suitable organic solvent such as ethanol or DMF.
  • the desired lactam 3-scheme-3 can be prepared as outlined in Scheme 3.
  • the carbodiimide 2-Scheme-3 can be prepared from the thiourea l-scheme-3 using standard conditions such as an excess amount of methane sulfonyl chloride and a suitable amine base such as triethylamine in an organic solvent preferably methylene chloride at room temperature.
  • the lactam 3-Scheme-3 can be prepared from the carbodiimide 2-Scheme-3 by first condensing the carbodiimide 2-Scheme-3 with the desired ⁇ -aminoester in a suitable organic solvent such as THF or acetonitrile followed by removal of the TBS group using standard conditions such as TBAF in THF at 0°C.
  • the desired dihydroimidazoyl guanidine 3-Scheme-4 can be prepared from the alcohol 2-Scheme-4 as outlined in Scheme-4.
  • the guanidine 2-Scheme-4 can be prepared from the carbodiimide 1 -Scheme-4 using standard canditions such as addition of the primary amine in a suitable organic solvent such as acetonitrile or THF followed by removal of the TBS group using standard procedures such as TBAF in THF at 0°C.
  • the cyclic guanidine 3-Scheme-4 can be prepared from the guanidine 2-Scheme-4 employing standard Mitsunobu conditons such as triphenylphosphine and DEAD in a suitable organic solvent such as THF.
  • the desired cyclicsulfonamide guanidine 3-Scheme-5 can be prepared from the chloride 2-Scheme-5 as outlined in Scheme 5.
  • the guanidine 2-Scheme-5 can be prepared from the carbodiimide l-Scheme-5 using the conditions outlined in schemes 3 and 4.
  • the cyclic guanidine 3-Scheme-5 can be prepared from the chloride 2-Scheme-5 using standard alkylation conditions such as NaH in a suitable organic solvent such as DMF at ambient room temperature or slight heating.
  • the imidazoyl guanidine 3-Scheme-6 can be prepared from the dimethyl acetal 2-Scheme-6 under standard acid conditions such as pTSA in a suitable organic solvent such as acetone.
  • the guanidine 2-Scheme-6 can be prepared form the carbodiimide l-Scheme-6 by the methods outline in schemes 3 and 4.
  • 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 ⁇ , NAP-2 or ENA-78.
  • the compounds of Formula (I) and (II) all have the same dosages, and formulations as that of Formula (I) are used interchangeably.
  • the compounds of Formula (I) are administered in an amount sufficient to inhibit cytokine function, in particular IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78, 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 IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 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 associated IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 above normal physiological levels; or (iii) the presence IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 above basal levels in cells or tissues in IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 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, atherosclerosis, osteoporosis, gingivitis or undesired hematopoietic stem cells release.
  • 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 area 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., Stroke, 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 binding to the IL-8 alpha or beta 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 ⁇ , NAP-2 or ENA-78 plays a role, either by production of IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 themselves, or by IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 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 ⁇ , NAP-2 or ENA-78.
  • 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
  • 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- ⁇ , NAP-2, ENA-78, 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. It will be appreciated that 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.
  • Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • Exemplary of 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. It will also be recognized by one of skill in the art that 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:
  • IL- 8 human recombinant
  • 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), ImMPMSF ( ⁇ -toluenesulphonyl fluoride), 0.5 mgL 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_ 8 (0.25 nM) or 125j 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 HCl 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 O.OlnM and 100 uM.
  • the assay was initiated by addition of 125j_iL-. 8 .
  • 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.
  • 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.
  • 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.
  • To this plate is added 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.
  • These cells are allowed to warm (37 °C, 5% CO2, 95% RH) for 5 min before IL-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- AMC, Nova Biochem, La Jolla, CA) to a final concentration of 6 ug/ml dissolved in phosphate buffered saline. Immediately, the plate is placed in a fluorescent 96 well plate reader (Cytofluor 2350, Millipore, Bedford, MA) and data collected at 3 min intervals according to the method of Nakajima et al J. Biol Chem 254 4027 (1979). The amount of Elastase released from the PMNs is calculated by measuring the rate of MeOSuc- Ala- Ala-Pro- Val-AMC degradation. TNF- ⁇ in Traumatic Brain Injury Assay
  • 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.
  • 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 une nouvelle application de phénylurées dans le traitement d'états pathologiques liés à la chimiokine interleukine-8 (IL-8).
PCT/US2000/014660 1999-05-28 2000-05-26 Antagonistes du recepteur de l'il-8 WO2000072840A1 (fr)

Priority Applications (13)

Application Number Priority Date Filing Date Title
PL00351947A PL351947A1 (en) 1999-05-28 2000-05-26 Il-8 receptor antagonists
KR1020017015176A KR20020016806A (ko) 1999-05-28 2000-05-26 Ｉｌ-8 수용체 길항제
EP00936368A EP1180025A4 (fr) 1999-05-28 2000-05-26 Antagonistes du recepteur de l'il-8
CA002374295A CA2374295A1 (fr) 1999-05-28 2000-05-26 Antagonistes du recepteur de l'il-8
MXPA01012267A MXPA01012267A (es) 1999-05-28 2000-05-26 Antagonistas del receptor de interleucina-8.
HU0201302A HUP0201302A3 (en) 1999-05-28 2000-05-26 Il-8 receptor antagonists
JP2000620952A JP2003500443A (ja) 1999-05-28 2000-05-26 Ｉｌ−８受容体アンタゴニスト
IL14605300A IL146053A0 (en) 1999-05-28 2000-05-26 Il-8 receptor antagonists
BR0010863-4A BR0010863A (pt) 1999-05-28 2000-05-26 Antagonistas de receptores de il-8
NZ514728A NZ514728A (en) 1999-05-28 2000-05-26 IL-8 receptor antagonists
AU51690/00A AU766999B2 (en) 1999-05-28 2000-05-26 IL-8 receptor antagonists
NO20015774A NO20015774L (no) 1999-05-28 2001-11-27 IL-8 reseptorantagonister
HK02105335.1A HK1045256A1 (zh) 1999-05-28 2002-07-18 Il-8受體拮抗劑

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US60/136,665 1999-05-28

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WO2001007029A2 (fr) * 1999-07-21 2001-02-01 Kadmus Pharmaceuticals, Inc. Guanidines substitutees et utilisation correspondante
WO2001007029A3 (fr) * 1999-07-21 2001-08-23 Kadmus Pharmaceuticals Inc Guanidines substitutees et utilisation correspondante
EP1413302A2 (fr) * 1999-07-21 2004-04-28 Kadmus Pharmaceuticals, Inc. Guanidines substitutées et utilisation pour le traitement de douleurs
EP1413302A3 (fr) * 1999-07-21 2004-05-12 Kadmus Pharmaceuticals, Inc. Guanidines substitutées et utilisation pour le traitement de douleurs
US6875759B1 (en) 1999-07-21 2005-04-05 Kadmus Pharmaceuticals Substituted guanidines and the use thereof
DE10109204A1 (de) * 2001-02-26 2002-09-19 4Sc Ag Verbindungen zur Behandlung von Protozoen-Erkrankungen
US6949567B2 (en) 2001-02-26 2005-09-27 4Sc Ag Compounds for the treatment of protozoal diseases
US6998414B2 (en) 2003-05-01 2006-02-14 Roche Palo Alto Llc Substituted arylamides as IP antagonists
US7279498B2 (en) 2003-05-01 2007-10-09 Roche Palo Alto Llc Substituted aryl amides as IP antagonists

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EP1180025A1 (fr) 2002-02-20
CO5170528A1 (es) 2002-06-27
AR029361A1 (es) 2003-06-25
HUP0201302A2 (hu) 2002-12-28
HK1045256A1 (zh) 2002-11-22
AU766999B2 (en) 2003-10-30
NO20015774D0 (no) 2001-11-27
HUP0201302A3 (en) 2003-02-28
PL351947A1 (en) 2003-07-14
IL146053A0 (en) 2002-07-25
TR200103354T2 (tr) 2002-06-21
CN1352554A (zh) 2002-06-05
CZ20014246A3 (cs) 2002-05-15
EP1180025A4 (fr) 2002-08-28
NO20015774L (no) 2001-11-27
KR20020016806A (ko) 2002-03-06
MXPA01012267A (es) 2002-07-30
AU5169000A (en) 2000-12-18
BR0010863A (pt) 2002-02-19
CA2374295A1 (fr) 2000-12-07
NZ514728A (en) 2004-04-30
JP2003500443A (ja) 2003-01-07

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