WO2001034141A1 - Antagonistes du recepteur de il-8 - Google Patents

Antagonistes du recepteur de il-8 Download PDF

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Publication number
WO2001034141A1
WO2001034141A1 PCT/US2000/030668 US0030668W WO0134141A1 WO 2001034141 A1 WO2001034141 A1 WO 2001034141A1 US 0030668 W US0030668 W US 0030668W WO 0134141 A1 WO0134141 A1 WO 0134141A1
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alkyl
amino
optionally substituted
carbonyl
aryl
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PCT/US2000/030668
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Brent W. Mccleland
Katherine L. Widdowson
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Smithkline Beecham Corporation
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Priority to JP2001536141A priority Critical patent/JP2003513919A/ja
Priority to EP00978419A priority patent/EP1237548A4/fr
Priority to AU15885/01A priority patent/AU1588501A/en
Publication of WO2001034141A1 publication Critical patent/WO2001034141A1/fr

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Definitions

  • This invention relates to novel sulfonamide substituted diphenyl urea compounds, pharmaceutical compositions, processes for their preparation, and use thereof in treating IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2, and ENA-78 mediated diseases.
  • Interleukin-8 such as neutrophil attractant/activation protein- 1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor.
  • 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.
  • nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL-1 ⁇ , IL-1 ⁇ 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 IL-8 B receptor (CXCR2).
  • CXCR2 IL-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 basophilic 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 (CD1 lb/CDl 8) 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 IL-8 ⁇ receptor (CXCR2). Thomas et al., J. Biol. Chem. 266. 14839 (1991); and Holmes et al., Science 253. 1278 (1991).
  • CXCR2 IL-8 ⁇ receptor
  • IL-8R ⁇ which binds only IL-8 with high affinity
  • IL-8R ⁇ 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-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 a or b 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).
  • the present invention also provides for the novel compounds of Formula (I), and pharmaceutical compositions comprising a compound of Formula (I), and a pharmaceutical carrier or diluent.
  • R represents R 6 , C(0)OR a ', COR a * , or S(0) 2 R a *;
  • A represents heteroaryl, heterocyclic, aryl or a covalent bond
  • n represents an integer from 1 to 8;
  • R a is an alkyl, aryl, arylC i _4alkyl, heteroaryl, heteroaryl C ⁇ _4alkyl, heterocyclic or a heterocyclic C ⁇ _4alkyl moiety, all of which moieties may be optionally substituted;
  • m is an integer having a value of 1 to 3;
  • m' is 0, or an integer having a value of 1 or 2;
  • n' is an integer having a value of 1 to 3;
  • 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;
  • Rl is independently selected from hydrogen, halogen, nitro, cyano, Cl-io alkyl, halosubstituted Ci-io alkyl, C2-10 alkenyl, C _ ⁇ o alkoxy, halosubstituted Ci-ioalk
  • NR C(NR5)R j 1, or two Y moieties together may form 0-(CH2)s-0 or a 5 to 6 membered saturated or unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted;
  • R 8 is hydrogen or Cj-4 alkyl
  • R9 is hydrogen or a C 1 -4 alkyl; Rio is C1.10 alkyl C(0) Rs;
  • Rl 1 is hydrogen, optionally substituted Ci- 4 alkyl, optionally substituted aryl, optionally substituted aryl C 1 -4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCl-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 _ 4 alkyl;
  • R13 is suitably C ⁇ _ 4 alkyl, aryl, aryl Ci ⁇ alkyl, heteroaryl, heteroarylCi _4alkyl, heterocyclic, or heterocyclicC i ⁇ alkyl; or a pharmaceutically acceptable salt thereof.
  • 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.
  • Rl is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C i-io alkyl, such as CF3, Ci-io alkyl, such as methyl, ethyl, isopropyl, or n- propyl, C2-10 alkenyl, Ci-io alkoxy, such as methoxy, or ethoxy; halosubstituted Cj-io alkoxy, such as trifluoromethoxy, azide, (CR 8 R 8 )q S(0) 1 R 4 , wherein t is 0, 1 or 2, hydroxy, hydroxy Ci- 4 alkyl, such as methanol or ethanol, aryl, such as phenyl or naphthyl, aryl C ⁇ - alkyl, such as benzyl, aryloxy, such as phenoxy, aryl Cl-4 alkyloxy, such as benzyloxy; heteroaryl, heteroarylalkyl,
  • aryl, heteroaryl, and heterocyclic-containing moieties may be optionally substituted as defined herein below.
  • the term "the aryl, heteroaryl, and heterocyclic containing moieties” refers to both the ring and the alkyl, or if included, the alkenyl rings, such as aryl, arylalkyl, and aryl alkenyl rings.
  • the term “moieties” and “rings” may be interchangeably used throughout.
  • R4 and R5 are independently hydrogen, optionally substituted Cj-4 alkyl, optionally substituted aryl, optionally substituted aryl C l _4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-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 and S.
  • R 8 is independently hydrogen or C ⁇ _4 alkyl.
  • R9 is hydrogen or a Ci-4 alkyl;
  • q is 0 or an integer having a value of 1 to 10.
  • Rio is C O alkyl C(0) 2 R8, such as CH2C(0)2H or CH2C(0)2CH3.
  • Rl l is hydrogen, Ci-4 alkyl, aryl, aryl C ⁇ _4 alkyl, heteroaryl, heteroaryl C 1 -4alkyl, heterocyclic, or heterocyclic C 1 -4alkyl.
  • R12 is hydrogen, C I_IQ alkyl, optionally substituted aryl or optionally substituted arylalkyl.
  • R13 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or heterocyclicC 1 -4alkyl, wherein all of the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted.
  • Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C i-io alkyl; Ci-io alkyl; C2-10 alkenyl; Cl-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CR 8 R 8 )q S(0)tR a ; hydroxy; hydroxyC ⁇ _4alkyl; aryl; aryl Ci_4 alkyl; aryloxy; arylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl Cl-4 alkyloxy; heterocyclic, heterocyclic Ci-4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CR 8 R 8 )q NR4R5; C2-IO alkenyl C(0)NR4Rs; (CR 8 R 8 )q C(0)NR4R5; (CR
  • s is an integer having a value of 1 to 3.
  • s is preferably 1.
  • Y forms an additional unsaturated ring, it is preferably 6 membered resulting in a naphthylene ⁇ ng system.
  • These ring systems may be substituted 1 to 3 times by other Y moieties as defined above.
  • Y is preferably a halogen, C i .4 alkoxy, optionally substituted aryl, optionally substituted aryloxy or arylalkoxy, methylene dioxy, NR4R5, thio C ⁇ _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'-pos ⁇ t ⁇ on.
  • n is preferably one While both Ri and Y can both be hydrogen, it is preferred that at least one of the rings is substituted, preferably both rings are substituted.
  • "optionally substituted” unless specifically defined shall mean such groups as halogen, such as fluorine, chlorine, bromine or iodine, hydroxy; hydroxy substituted Cl-ioalkyl, Ci-io alkoxy, such as methoxy or ethoxy, S(0) m ' Cj-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(0)R4, C(0)NR4R5, COOR4, S(0)tNR4R5, NHS(O) t R20, l-10 alkyl, such as methyl, ethoxy, hydroxy substituted Cl-ioalkyl, Ci-io al
  • R20 is suitably Ci- 4 alkyl, aryl, aryl C ⁇ _4alkyl, heteroaryl, heteroarylCi-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.
  • Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
  • the following terms, as used herein, refer to: • "halo" - all halogens, that is chloro, fluoro, bromo and iodo.
  • C ⁇ _ oalkyl or “alkyl” - both straight and branched chain moieties of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, wo-propyl, w-butyl, sec-butyl, iso-butyl, tert-b tyl, n-pentyl and the like.
  • cycloalkyl is used herein to mean cyclic moiety, 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 moiety of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1 -butenyl, 2-butenyl and the like.
  • heteroaryl (on its own or in any combination, such as “heteroaryloxy”, or “heteroaryl alkyl”) - a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, tetrazole, 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, thiomorpholine, or imidazolidine.
  • sulfur may be optionally oxidized to the sulfone or the sulfoxide.
  • arylalkyl or “heteroarylalkyl” or “heterocyclicalkyl” is used herein to mean Ci- 1 o alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated.
  • sulfinyl - the oxide S (O) of the corresponding sulfide
  • thio refers to the sulfide
  • sulfonyl refers to the fully oxidized S(0)2 moiety.
  • C5 cycloalkenyl moiety such as cyclopentene.
  • Illustrative compounds of Formula (I) include:
  • the anilines for the amide formation can be obtained as outlined below in scheme 1.
  • the commercially available ethyl amine 1 can be protected using tBoc anhydride.
  • the resulting nitrobenzene can then be reduced using standard procedures like Pd/C and hydrogen gas, SnCl2, or Zn to form the aniline 2.
  • the commercially available acid 3 is first converted to the acid chloride using standard procedures such as oxalyl chloride or thionyl chloride.
  • the resulting acid chloride is then coupled with the amines from scheme 1 to generate the dichloroamide 4.
  • Selective hydrolysis of the 2-C1 is accomplished with KOAc and 18-Crown-6 to yield the phenol 5.
  • the nitro is then reduced using SnCl2, and the resulting aniline is condensed with the desired isocyanate which can be purchased commercially.
  • the protected amine can then be deprotected by standard conditions such as triflouroacetic acid to form the urea 8.
  • the commercially available acid 3 is first converted to the acid chloride using standard procedures such as oxalyl chloride or thionyl chloride.
  • the resulting acid chloride is then coupled with commercially available Boc protected amines to generate the dichloro amide 9.
  • the amines are not commercially available they can be synthesized by coupling the desired diamine with 1 equiv. t-Boc anhydride. Selective hydrolysis of the 2-Cl is accomplished with KOAc and 18-Crown-6 to yield the phenol 10.
  • the nitro is then reduced using SnCl2, and the resulting aniline is condensed with the desired isocyanate which can be purchased commercially to form biaryl urea 12.
  • the Boc- amine can then be deprotected by standard conditions such as triflouroacetic acid to form the urea 13.
  • the desired isocyanate is not commercially available, it can be prepared in a variety of ways as shown below in scheme 4 and 5.
  • the aniline 14 can be reacted with a phosgene equivalent like triphosgene or carbonyl diimidazole in the presence of a base such as sodium bicarbonate to form the isocyanate 15 (or with thiophosgene to form the thioisocyanate).
  • This isocyanate can then be condensed with the desired amine which can either be synthesized as above or purchased commercially to form the urea 16.
  • isocyanate can be synthesized from the corresponding carboxylic acid using the Curtius rearrangement (dppa and triethyl amine, oxalyl chloride followed by sodium azide, scheme 5). This isocyanate can them be condensed with the desired amine to form the urea 18.
  • the present syntheses include the following novel intermediates represented by formulas (II), (III), (IV), (V), (VI) and (VII):
  • This compound was prepared from 6 (0.140g, 0.985mmol) in DMF (1.5mL) according to the procedure in General Method A.
  • the product was purified by precipitation from CH 2 C1 2 / hexane (1 equiv./ 20 equiv.) and filtering (0.133g, 65%).
  • This compound was prepared from 11 (0.253g, 0.656mmol) in DMF (2.2mL) according to the procedure in General Method A. The product was purified by precipitation from
  • the compounds of Formula (I), or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicine 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 comp ⁇ ses 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) 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: (1) levels of free IL-8 greater than or equal to 1 picogram per mL; (n) any cell associated IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 above normal physiological levels; or (in) the presence of IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 above basal levels in cells or tissues in which IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA- 78 respectively, is produced.
  • Chemokine mediated diseases include psoriasis, atopic dermatitis, osteo arthritis, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, stroke, septic shock, multiple sclerosis, endotoxic shock, gram negative sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, glomeruloneph ⁇ tis, thrombosis, graft vs.
  • the ⁇ -chemokines but particularly, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78, working through the IL-8 type I or II receptor can promote the neovascula ⁇ zation 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. Recent evidence also implicates the role of chemokines in the treatment of HIV infections, Littleman et al., Nature 381, pp. 661 (1996) and Koup et al., Nature 381, pp. 667 (1996).
  • 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.
  • 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 cytokmes 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 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) m the in vitro receptor binding assays which are described herein.
  • the compounds of Formula (I) have been shown to be inhibitors of type II IL-8 receptors.
  • 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.
  • a disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to IL-8, would therefore be considered a disease state mediated by IL-8.
  • chemokine mediated disease or disease state refers to any and all disease states in which a chemokine which binds to an IL-8 ⁇ or ⁇ receptor plays a role, such as but not limited to IL-8, GRO- ⁇ , GRO- ⁇ , GRO ⁇ , NAP-2 or ENA-78. This would include a disease state in which, 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, monokmes 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
  • a mononuclear cell such as a macrophage and/or monocyte
  • monokmes 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.
  • cytokmes include, but are not limited to, Interleuk ⁇ n-1 (IL-1), Interleuk ⁇ n-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF- ⁇ ) and Tumor Necrosis Factor beta (TNF- ⁇ ).
  • IL-1 Interleuk ⁇ n-1
  • IL-6 Interleuk ⁇ n-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- ⁇ , NAP-2, ENA-78, IP-10, MlP-l ⁇ , MlP- ⁇ , PF4, and MCP 1 , 2, and 3.
  • a pharmaceutical composition comp ⁇ sing 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.
  • 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.
  • 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.
  • IL-8, and GRO- ⁇ chemokine inhibitory effects of compounds of the present invention are determined by the following in vitro assay: Receptor Binding Assays:
  • 125 IL -8 human recombinant
  • Amersham Corp., Arlington Heights, IL with specific activity 2000 Ci/mmol.
  • GRO- ⁇ is obtained from NEN- New England Nuclear. All other chemicals are of analytical grade.
  • High levels of recombinant human 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 (1 74)).
  • homogenization buffer is changed to lOmM Tris-HCL, lmM MgS0 , 0.5mM EDTA (ethylene-diaminetetra- acetic acid), lmM PMSF ( ⁇ -toluenesulphonyl fluoride), 0.5 mg/L Leupeptin, pH 7.5.
  • Membrane protein concentration is determined using Pierce Co. micro-assay kit using bovine serum albumin as a standard. All assays are performed in a 96-well micro plate format.
  • Each reaction mixture contains 25 ⁇ L_ 8 (0.25 nM) or 125 ⁇ 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 MgS ⁇ 4, 0.1 mM EDTA, 25 mM Na and 0.03% CHAPS.
  • drug or compound of interest is added which has been pre-dissolved in DMSO so as to reach a final concentration of between O.OlnM and 100 uM.
  • the assay is initiated by addition of ⁇ I-IL-8.
  • the plate is harvested using a Tomtec 96-well harvester onto a glass fiber filtermat blocked with 1% polyethylenimine/ 0.5% BSA and washed 3 times with 25 mM NaCI, 10 mM TrisHCl, 1 mM MgS ⁇ 4, 0.5 mM EDTA, 0.03 % CHAPS, pH 7.4. The filter is then dried and counted on the Betaplate liquid scintillation counter.
  • 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.
  • Representative compounds of Formula (I), Examples 1 to 106 have exhibited positive inhibitory activity in this assay at IC50 levels ⁇ 30 uM.
  • 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 5 uM polycarbonate filter. When compounds of this invention are tested, they are mixed with the cells (0.001 - 1000 nM) just prior to the addition of the cells to the upper chamber.
  • the compounds of this invention are tested for their ability to prevent Elastase release from human neutrophils.
  • Neutrophils are isolated from human blood as desc ⁇ bed in Current Protocols in Immunology Vol. I, Suppl 1 Unit 7.23.1.
  • PMNs 0.88 x 10 6 cells suspended in Ringer's Solution (NaCI 1 18, KC1 4.56, NaHC0 3 25, KH 2 P0 1.03, Glucose
  • 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 supernatant 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, Mil pore, 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 specific brain regions, which follow experimentally, induced lateral fluid-percussion traumatic brain injury (TBI) in rats
  • TBI induced lateral fluid-percussion traumatic brain injury
  • LC left parietal cortex
  • RC contralateral right cortex
  • LA cortex adjacent to injured parietal cortex
  • RA left hippocampus
  • RH right hippocampus
  • TNF- ⁇ mRNA expression is observed in LH (104 ⁇ 17% of positive control, p ⁇ 0.05 compared with sham), LC (105 ⁇ 21%, p ⁇ 0.05) and LA (69 ⁇ 8%, p ⁇ 0.01) in the traumatized hemisphere 1 hr. following injury.
  • An increased TNF- ⁇ mRNA expression is also observed in LH (46 ⁇ 8%, p ⁇ 0.05), LC (30 ⁇ 3%, p ⁇ 0.01) and LA (32 ⁇ 3%, p ⁇ 0.01) at 6 hr which resolves by 24 hr following injury.
  • TNF- ⁇ mRNA In the contralateral hemisphere, expression of TNF- ⁇ mRNA is increased in RH (46 ⁇ 2%, p ⁇ 0.01), RC (4 ⁇ 3%) and RA (22 ⁇ 8%) at 1 hr and in RH (28 ⁇ 1 1%), RC (7 ⁇ 5%) and RA (26 ⁇ 6%, p ⁇ 0.05) at 6 hr but not at 24 hr following injury. In sham (surgery without injury) or naive animals, no consistent changes in expression of TNF- ⁇ mRNA are observed in any of the 6 brain areas in either hemisphere at any times.
  • TNF- ⁇ 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

Cette invention concerne des composés et des compositions obtenues à partir de ces composés, qui conviennent bien pour le traitement d'états pathologiques induites par la chémokine, Interleukine-8 (IL-8).
PCT/US2000/030668 1999-11-09 2000-11-08 Antagonistes du recepteur de il-8 WO2001034141A1 (fr)

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AU15885/01A AU1588501A (en) 1999-11-09 2000-11-08 Il-8 receptor antagonists

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US5780483A (en) * 1995-02-17 1998-07-14 Smithkline Beecham Corporation IL-8 receptor antagonists

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