WO2008070758A1 - Composés de liaison à un récepteur de chimiokine - Google Patents

Composés de liaison à un récepteur de chimiokine Download PDF

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WO2008070758A1
WO2008070758A1 PCT/US2007/086588 US2007086588W WO2008070758A1 WO 2008070758 A1 WO2008070758 A1 WO 2008070758A1 US 2007086588 W US2007086588 W US 2007086588W WO 2008070758 A1 WO2008070758 A1 WO 2008070758A1
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mmol
compound
methyl
alkyl
dimethyl
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Elyse Bourque
Markus Metz
Ian R. Baird
Wen Yang
Gary Bridger
Renato T. Skerlj
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Genzyme Corporation
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Priority to EP07865277A priority patent/EP2088860A4/fr
Publication of WO2008070758A1 publication Critical patent/WO2008070758A1/fr

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Definitions

  • This invention generally relates to novel compounds, pharmaceutical compositions and their use. More specifically, these novel compounds are modulators of chemokine receptor activity, in particular modulators of chemokine receptor CCR5, further demonstrate protective effects against infection in target cells by a human immunodeficiency virus (HIV). In another aspect, the compounds in the present invention are useful in the treatment and prevention of various inflammatory and autoimmune diseases.
  • modulators of chemokine receptor activity in particular modulators of chemokine receptor CCR5
  • HAV human immunodeficiency virus
  • the compounds in the present invention are useful in the treatment and prevention of various inflammatory and autoimmune diseases.
  • chemokines that function at least in part, by modulating a complex and overlapping set of biological activities important for the movement of lymphoid cells and extravasation and tissue infiltration of leukocytes in response to inciting agents (See, for example: Ponath, P., Exp. Opin. Invest. Drugs (1998) 7:1-18).
  • These chemotac ⁇ c cytokines, or chemokines constitute a family of proteins, approximately 8-10 kDa in size, that are released by a wide variety of cells, to attract macrophages, T cells, eosinophils, basophils, and neutrophils to sites of inflammation and also play a role in the maturation of cells of the immune system.
  • Chemokines appear to share a common structural motif that consists of 4 conserved cysteines involved in maintaining tertiary structure. There are two major subfamilies of chemokines: the "CC” or ⁇ -chemokines and the “CXC” or ⁇ -chemokines, depending on whether the first two cysteines are separated by a single amino acid, i.e., CXC or are adjacent, i.e., CC.
  • chemokines bind specifically to cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane proteins which are referred to as "chemokine receptors", and mediate biological activity through these receptors.
  • the chemokine receptor is classified based upon the chemokine that constitutes the receptor's natural ligand. Chemokine receptors of the ⁇ -chemokines are designated "CCR”; while those of the ⁇ -chemokines are designated "CXCR.”
  • CCR Chemokine receptors of the ⁇ -chemokines
  • CXCR those of the ⁇ -chemokines
  • These chemokine receptors include but are not limited to CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CXCR3 and CXCR4 (see for a complete review, Murphy, et al. Pharmacol. Rev. (2000) 52:145-176).
  • Chemokines are considered to be principal mediators in the initiation and maintenance of inflammation (see Chemokines in Disease published by Humana Press (1999), Edited by C. Herbert; Murdoch, et al, Blood (2000) 95:3032-3043). More specifically, chemokines have been found to play an important role in the regulation of endothelial cell function, including proliferation, migration and differentiation during angiogenesis and re-endothelialization after injury (Gupta, et al. , /. Biolog. Chem. (1998) 7:4282-4287). Both chemokine receptors CXCR4 and CCR5 have been implicated in the etiology of infection by human immunodeficiency virus (HIV).
  • HAV human immunodeficiency virus
  • HIV initially binds via its gpl20 envelope protein to the CD4 receptor of the target cell.
  • HIV-I isolates arising subsequently in the infection bind to the CXCR4 chemokine receptor.
  • the observed binding of another related retrovirus, feline immunodeficiency virus, to a chemokine receptor without needing to bind first to the CD4 receptor suggests that chemokine receptors may be the primordial obligate receptors for immunodeficiency retroviruses.
  • virus -cell fusion results which is mediated by members of the chemokine receptor family, with different members serving as fusion cofactors for macrophage-tropic (M-tropic) and T cell line-tropic (T-tropic) isolates of HIV-I
  • M-tropic macrophage-tropic
  • T-tropic T cell line-tropic isolates of HIV-I
  • the M-tropic viral phenotype correlates with the virus' ability to enter the cell following binding of the CCR5 receptor, while the T-tropic viral phenotype correlates with viral entry into the cell following binding and membrane fusion with the CXCR4 receptor.
  • CCR5 and CXCR4 appear to be the only physiologically relevant coreceptors used by a wide variety of primary clinical HIV-I strains (Zhang, et al, J. Virol. (1998) 72:9307-9312; Zhang, et al, J. Virol. (1999) 73:3443-3448; Simmonds, et al, J. Virol. (1988) 72:8453-8457). Fusion and entry of T-tropic viruses that use CXCR4 are inhibited by the natural CXC-chemokine stromal cell-derived factor- 1 (SDF-I).
  • SDF-I CXC-chemokine stromal cell-derived factor- 1
  • M-tropic viruses that use CCR5 are inhibited by the natural CC-chemokines namely, Regulated on Activation Normal T-cell Expressed and Secreted (RANTES or CCL5) and Macrophage Inflammatory proteins (MIP-I alpha and MIP-I beta or CCL3 and CCL4, respectively).
  • SDF-I is known as CXCL12 or Pre B-cell stimulating factor (PBSF).
  • CXCR4 or SDF-I knock-out mice exhibit cerebellar, cardiac and gastrointestinal tract abnormalities and die in utero (Zou, et al, Nature (1998) 393:591-594; Tachibana, et al, Nature (1998) 393:591-594; Nagasawa, et al, Nature (1996) 382:635-638).
  • CXCR4-deficient mice also display hematopoietic defects (Nagasawa, et al, Nature (1996) 382:635-638). Furthermore, the migration of CXCR4 expressing leukocytes and hematopoietic progenitors to SDF-I appears to be important for maintaining B-cell lineage and localization of CD34 + progenitor cells in bone marrow (Bleul, et al, J. Exp. Med. (1998) 187:753-762; Viardot, et al, Ann. Hematol. (1998) 77:195-197; Auiti, et al, J. Exp. Med.
  • the signal provided by SDF- 1 on binding to CXCR4 may also play an important role in tumor cell proliferation and regulation of angiogenesis associated with tumor growth (See Chemokines and Cancer, published by Humana Press (1999); Edited by B. J. Rollins; Arenburg, et al, J. Leukocyte Biol. (1997) 62:554-562; Moore, et al, J. Invest. Med. (1998) 46:113-120; Moore, et al, Trends cardiovasc. Med. (1998) 8:51-58; Seghal, et al, J. Surg. Oncol. (1998) 69:99-104).
  • angiogenic growth factors VEG-F and bFGF up-regulated levels of CXCR4 in endothelial cells, and SDF-I can induce neovascularization in vivo (Salcedo, et al, Am. J. Pathol. (1999) 154:1125- 1135).
  • leukemia cells that express CXCR4 migrate and adhere to lymph nodes and bone marrow stromal cells that express SDF-I (Burger, et al, Blood (1999) 94:3658-3667; Arai, et al, Eur. J. Haematol. (2000) 64:323-332; Bradstock, et al, Leukemia (2000) 14:882-888).
  • SDF- 1 The binding of SDF- 1 to CXCR4 has also been implicated in the pathogenesis of atherosclerosis (Abi-Younes, et al, Circ. Res. (2000) 86:131-138), renal allograft rejection (Eitner, et al, Transplantation (1998) 66:1551-1557), asthma and allergic airway inflammation (Yssel, et al, Clinical and Experimental Allergy (1998) 28: 104- 109; Nagase, H, et al, J. Immunol. (2000) 164:5935-5943; Gonzalo, et al, J. Immunol.
  • Alzheimer's disease Xia, et al, J. Neurovirology (1999) 5:32-41) and arthritis (Nanki, et al, J. Immunol. (2000) 164:5010-5014).
  • Platelets have also been shown to secrete the chemokine RANTES upon activation, and that the presence of RANTES on the endothelium promotes the arrest of monocytes on the inflamed endothelium, an important step in atherogenesis as the conversion of macrophages into foam cells in the subendothelium is a central process in atheroma formation (Tan, et al, Expert Opin. Investig. Drugs (2003) 12:1765-1776). Hence, the inhibition or prevention of the binding of RANTES, directly or indirectly, to the CCR5 receptor could potentially attenuate the development of atherosclerosis. For example, Met- RANTES has also been shown to inhibit the binding of monocytes to the activated endothelium (Tan, et al, supra).
  • CCR5 blocking agents include monoclonal antibodies, some which selectively block HIV coreceptor activity but not chemokine binding, and chemokine derivatives, such as truncated versions of RANTES, Met-RANTES, and AOP-RANTES and the viral chemokine KSHV vMIP-II, all which block both chemokine and HIV interaction with CCR5 but are not selective (reviewed by Murphy, et al, Pharmacol. Rev. (2000) 52:145-176).
  • bicyclam dose-dependently inhibits binding of 1251-labeled SDF-I to CXCR4 and the signal transduction (indicated by an increase in intracellular calcium) in response to SDF-I.
  • the bicyclam also functioned as an antagonist to the signal transduction resulting from the binding of stromal derived factor or SDF- l ⁇ , the natural chemokine to CXCR4.
  • Bicyclams also inhibited HIV gpl20 (envelope) -induced apoptosis in non-HIV infected cells (Blanco, et al, Antimicrobial Agents and Chemother. (2000) 44:51-56).
  • CAV cardiac allograft vasculopathy
  • CCR5 cardiac allograft vasculopathy
  • antagonism of the chemokine receptors CCRl and CCR5 with Met-RANTES attenuated CAV development by reducing mononuclear cell recruitment to the transplanted heart.
  • Met-CCL5 an antagonist of CCRl and CCR5 had been tested and shown to inhibit the growth of breast tumors (Robinson, S. C, et al, Cancer Res. (2003) 63:8360-8365).
  • Chemokines play an important role and are implicated in a wide variety of human disease such as in autoimmune disease, allograft rejection, infection, allergies, neoplasia, and vascular abnormalities.
  • the chemokine receptor CCR5 has been associated with diseases such as the inflammatory demyelinating diseases of the central nervous system, including multiple sclerosis and experimental autoimmune encephalomyelitis, rheumatoid arthritis, intestinal inflammation, allograft rejection, asthma, and cardiovascular disease (reviewed in Gerard, et al., Natl. Immunol. (2001) 2:108-115, and Luster, A., N. Eng. J. Med. (1998) 338:436-445).
  • the CCR5 receptor is expressed on T- lymphocytes, and macrophages and reports of CCR5 on neurons, astrocytes, capillary endothelial cells, epithelium, vascular smooth muscle, and fibroblast have been published.
  • the natural ligands that bind to the CCR5 receptor are monocyte chemoattractant protein 2 (MCP-2 or CCL8).
  • these compounds antagonize the binding, signaling and chemotactic effects of the natural ligand for CXCR4, the chemokine stromal cell-derived factor l ⁇ (SDF-I). Furthermore, these compounds demonstrate protective effects against HIV infection of target cells by binding in vitro to the CCR5 receptor.
  • U.S. Pat. No. 6,365,583 discloses that these cyclic polyamine antiviral agents described in the above-mentioned patents/patent applications have the effect of enhancing production of white blood cells as well as exhibiting antiviral properties. Thus, these agents are useful for controlling the side-effects of chemotherapy, enhancing the success of bone marrow transplantation, enhancing wound healing and burn treatment, as well as combating bacterial infections in leukemia.
  • WO 02/34745 describe a series of heterocyclic compounds that exhibit anti-HIV activity by binding to the chemokine receptors CXCR4 and CCR5 expressed on the surface of certain cells of the immune system. This competitive binding thereby protects these target cells from infection by HIV which utilize the CXCR4 or CCR5 receptors for entry. In addition, these compounds antagonize the binding, signaling and chemotactic effects of the natural ligand for CXCR4, the chemokine stromal cell-derived factor l ⁇ (SDF-I) and/or the natural ligand for CCR5, the chemokine RANTES.
  • SDF-I chemokine stromal cell-derived factor l ⁇
  • the chemokine receptor, CXCR4 has been found to be associated with the vascularization of the gastrointestinal tract (Tachibana, et ah, Nature (1998) 393:591- 594) as well as in hematopoiesis and cerebellar development (Zou, et al, Nature (1998) 393:591-594). Interference with any of these important functions served by the binding of pre-B-cell growth- stimulating factor/stromal derived factor (PBSF/SDF-1) to the CXCR4 chemokine receptor results in lethal deficiencies in vascular development, hematopoiesis and cardiogenesis.
  • PBSF/SDF-1 pre-B-cell growth- stimulating factor/stromal derived factor
  • fetal cerebellar development appears to rely upon the effective functioning of CXCR4 in neuronal cell migration and patterning in the central nervous system.
  • This G-protein-coupled chemokine receptor appears to play an important role in ensuring the necessary patterns of migration of granule cells in the cerebellar strom.
  • the present invention provides novel compounds that modulate chemokine receptors, in particular CCR5 receptors, and interfere with the binding of the natural ligand thereto.
  • the compounds of the present invention are useful as agents demonstrating protective effects on target cells from HIV infection.
  • the compounds of the present invention are useful for the treatment and prevention of inflammatory and autoimmune diseases.
  • the invention compounds act as antagonists or agonists of chemokine receptors and are useful as agents capable of reconstituting the immune system by increasing the level of CD4 + cells; as antagonists to apoptosis in immune cells, such as CD8 + cells, and neuronal cells; and as antagonists to migration of human bone marrow B lineage cells to stromal-derived factor 1.
  • the invention provides a compound of formula (1)
  • each Ar 1 and Ar 2 is independently an optionally substituted carbocyclic or heterocyclic aromatic system; each Y is independently O, S or CHCN;
  • Z H or alkyl or is CH 2 coupled to X;
  • R 1 is H or a non-interfering substituent, but only one R 1 is a non-interfering substituent other than H or alkyl;
  • R 2 -R 4 are non-interfering substituents other than H;
  • each m or 1 is independently an integer of 0-4;
  • j is 0 or 1 ;
  • each n is independently 1-2; or a pharmaceutically acceptable salt or conjugate thereof.
  • R : -R 4 may be alkyl, alkenyl or alkynyl, including the straight chain, branched chain or cyclic forms thereof, or may be aromatic systems, each optionally containing one or more heteroatoms selected from O, N and S and optionally substituted by halo and/or other inorganic substituents and/or comprising organic functional groups, such as carboxylic acids, carboxylic esters, carboxylic amides, substituted amino groups, and the like.
  • R 1 may also be H.
  • Ar 1 and Ar 2 are aromatic systems of 5-12 ring members including heterocyclic ring members. Ar 1 and Ar 2 may also be substituted by the non-interfering substituents as defined above but cannot include more than one additional aromatic system.
  • the non-interfering substituent itself may be an inorganic moiety such as OH, NH 2 and/or an oxidized form thereof, SH and/or an oxidized form thereof, or oxidized forms of phosphorus.
  • R 1 -R 4 may also themselves include aryl or heteroaryl systems as defined above.
  • the systems included may themselves bear substituents as outlined above, other than including additional aromatic systems.
  • non-interfering substituent is meant a substituent that does not destroy the ability of the compound to modulate at least the CCR5 chemokine receptor.
  • Assay methods for modulating the CCR5 receptor are well known in the art, and the compounds containing any particular set of non-interfering substituents may readily be tested.
  • the present invention also provides pharmaceutical compositions comprising one or more compounds having formula (1), and a pharmaceutically acceptable carrier.
  • the present invention also provides methods for treating a CCR5 mediated disease in a cell, tissue or organ, comprising contacting one or more compounds having formula (1) with the system, thereby treating a CCR5-mediated disease.
  • the present invention also provides methods for treating a CCR5 mediated disease in a human or animal subject, comprising administering one or more compounds having formula (1) with the subject, thereby treating a CCR5 -mediated disease.
  • CCR5 -mediated diseases examples include but are not limited to HIV, an inflammatory demyelinating disease of the central nervous system, an autoimmune disease, multiple sclerosis, experimental autoimmune encephalomyelitis, psoriatic or rheumatoid arthritis, intestinal inflammation, allograft rejection, asthma, cardiovascular disease, atherosclerosis, allergic disease, allergic rhinitis, dermatitis, conjunctivitis, hypersensitivity lung disease, hypersensitivity pneumonitis, eosinophilic pneumonia, delayed-type hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis, dermatomyositis, systemic anaphylaxis, myastenia gravis, juvenile
  • HIV an inflammatory demyelinating disease
  • the compounds of formula (1) may form hydrates or solvates, and may be in any stereoisomeric forms and mixtures of stereoisomeric forms thereof. Racemate compounds may be separated into individual isomers using known separation and purification methods. Individual optical isomers and a mixture thereof, are included in the scope of the present invention.
  • the compounds of the invention may also be in the form of pharmaceutically acceptable salts or conjugates, such as PEGylated forms, or can be provided in a form coupled to targeting agents or additional desired moieties.
  • the invention provides compounds having formula (1) described above, which are modulators of chemokine receptors.
  • the compounds may bind chemokine receptors and interfere with the binding of the natural ligand thereto, and demonstrate protective effects on target cells from HIV infection.
  • the compounds are useful as antagonists or agonists of chemokine receptors, and are thus capable of reconstituting the immune system by increasing the level of CD4 + cells; as antagonist agents of apoptosis in immune cells, such as CD8 + cells and neuronal cells; as antagonist agents of migration of human bone marrow B lineage cells to stromal-derived factor 1.
  • Chemokine antagonists that interfere in the binding of a chemokine to its receptor are useful to reconstitute the immune system by increasing the level of CD4 + cells (Biard-Piechaczyk, et al, Immunol.
  • Chemokine receptor antagonist agents also inhibit the migration of human bone marrow B lineage cells to stromal-derived factor 1 (See, e.g., Fedyk, E., et al, J of Leukocyte Biol. (1999) 66:667-783).
  • the invention includes pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of formula (1) along with at least one excipient, and methods of treating diseases of the human body or the bodies of other mammals with such compositions.
  • therapeutically effective amount refers to the amount of one or more compounds of formula (1) that will elicit a desired response of a cell, tissue, organ, system, animal or human that is being sought by the researcher, veterinarian, medical doctor, or other clinician.
  • the invention provides a method for blocking or interfering with the binding by a chemokine receptor with its natural ligand, comprising contacting of the chemokine receptor with an effective amount of the one or more compounds of formula (1).
  • the present invention also provides methods of protecting target cells possessing chemokine receptors, which binding to a pathogenic agent results in disease or pathology, comprising administering to a mammalian subject a pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds of formula (1).
  • the invention provides the use of a compound of formula (1) in the manufacture of a medicament for the treatment of a disease in which blocking or interfering with binding of a chemokine receptor with its natural ligand is advantageous.
  • the compound is formulated into a composition in an amount corresponding to a therapeutically effective amount of a compound of formula (1).
  • each Ar 1 and Ar 2 is independently an optionally substituted carbocyclic or heterocyclic aromatic system; each Y is independently O, S or CHCN;
  • Z H or alkyl or is CH 2 coupled to X;
  • X O and k is 0 or 1 ;
  • R 1 is H or a non-interfering substituent, but only one R 1 is a non-interfering substituent other than H or alkyl;
  • R 2 -R 4 are non-interfering substituents other than H; each m or 1 is independently an integer of 0-4; j is 0 or 1; and each n is independently 1-2; or a pharmaceutically acceptable salt or conjugate thereof.
  • alkyl, alkenyl and alkynyl include straight-chain, branched-chain and cyclic monovalent hydrocarbyl radicals, and combinations of these, which contain only C and H when they are unsubstituted. Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylethyl, 2-propenyl, 3-butynyl, and the like. Typically, these substituents include up to 10 carbon atoms, or up to 8 carbon atoms or up to 6 carbon atoms or up to 4 carbon atoms.
  • Heteroalkyl, heteroalkenyl or heteroalkynyl are defined in a manner similar to alkyl, alkenyl and alkynyl except that they include one or more heteroatoms selected from N, O and S in place of one or more carbon atoms of the alkyl, alkenyl or alkynyl group. No more than two contiguous carbon atoms are replaced by heteroatoms. Where N is present, it is understood that it is trivalent and must be suitably substituted according to commonly understood principles of chemical stability.
  • Halo refers to any of the halogens, typically including F, Cl, Br and I.
  • aromatic refers either to a polyunsaturated, aromatic hydrocarbon substituent containing at least one aromatic ring that does not have a heteroatom as a ring member, or to a heteroaromatic substituent which is an aromatic group containing at least one heteroatom as a ring member. More than one heteroatom may be present as ring members in a heteroaryl group, provided that not more than two contiguous ring atoms are heteroatoms.
  • the aromatic structures encompass compounds having monocyclic, bicyclic or multiple ring systems, and thus they may include a mixture of aryl and heteroaryl groups. At least one ring system must be aromatic or heteroaromatic. The number of ring members is typically 5-12.
  • Exemplary non- limiting substituents of aromatic or heteroaromatic systems include cyclic or acyclic alkyl, alkenyl, alkynyl, halogen, CN, CHO, CF 3 , OCF 3 , NO 2 , OH, NHC(0)(Ci_6 acyclic or C 3 _ 6 cyclic alkyl), NHC(O)CF 3 , NHSO 2 (Ci_ 6 alkyl), NHC(O)NH 2 , NHC(0)(Ci_6 alkyl), C(O)NH 2 , C(O)NHC 6 H 5 , C(O)C 6 H 4 C(O)OH, C(0)N(0Ci_6 alkyl)(Ci_ 6 alkyl), C(O)NHCH 2 C(O)O(Ci_ 6 alkyl), C(O)(C 1-6 alkyl), C(O)O(Ci_6 alkyl), C(O)(non-aromatic heterocyclic ring),
  • inorganic substituent refers to substituents that do not contain carbon.
  • examples of inorganic substituents include but are not limited to nitro, halogen, azido, and groups such as sulfonates, sulfinates, phosphates, and phosphonates, as either their acid forms or as simple C1-C4 esters, e.g., a dimethyl phosphonate.
  • Specific embodiments of formula (1) are represented by formulas (2)-(5):
  • X, Y, Z, Ar 1 , Ar 2 , and R 1 -R 4 are as defined with respect to formula (1), as are j-n.
  • R 1 when X is N, is H, alkyl or cycloalkyl, optionally substituted by a single substituent; R 3 is alkyl, preferably methyl, when j is 1.
  • Particularly preferred are compounds of formula (2) or (3) are those wherein 1 and m are 0 and Ar 1 is unsubstituted phenyl.
  • Preferred forms of formulas (4) and (5) are those wherein R 1 is alkyl, alkoxy, cycloalkyl, alkoxyalkoxy, or an oxidized 5-membered ring. More preferred embodiments of R 1 are methyl, methoxy, 2-oxo-oxazolidine, 2-methoxyethoxy, and cyclopropyl. If R 1 is as described above, the remaining embodiments of R 1 in formula (4) or (5) permitted when X is N or CH are H or alkyl, preferably H. Preferred embodiments of X are N or CH, and of Y are O or CHCN.
  • R 3 is alkyl, preferably methyl, and j is 0 or 1.
  • Ar 1 is preferably monovalent thiophene. In formulas (3) and (4), preferably one n is 1 and the other is 2, but it is emphasized that embodiments wherein both n are 1 are included within the scope of the invention.
  • Ar 1 and Ar 2 include phenyl, pyridinyl, thiazolyl, oxazolyl, pyrimidinyl, indolyl, indolinyl, imidazolyl, benzimidazolyl, theophyl, isoindolinyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, benzofuranyl, 2,3-dihydroxybenzofuranyl, phthalanyl, and the like.
  • the compounds of the present invention may be administered in the form of pharmaceutically acceptable salts that are non-toxic.
  • pharmaceutically acceptable salt as used herein means an active ingredient comprising compounds of the invention used in the form of a salt thereof, particularly where the salt form confers on the active ingredient improved pharmacokinetic properties as compared to the free form of the active ingredient or other previously disclosed salt form.
  • pharmaceutically acceptable salt encompasses all acceptable salts including but not limited to acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartarate, mesylate, borate, methylbromide, bromide, methylnitrite, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, ⁇ -methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutame, stearate, phosphat
  • Pharmaceutically acceptable salts of the compounds of the present invention can be used as a dosage for modifying solubility or hydrolysis characteristics, or can be used in sustained release or pro-drug formulations.
  • pharmaceutically acceptable salts of the compounds of this invention may include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.
  • All of the compounds of the invention contain at least one chiral center.
  • the invention includes mixtures of stereoisomers, individual stereoisomers, and enantiomeric mixtures, and mixtures of multiple stereoisomers.
  • the compound may be supplied in any desired degree of chiral purity.
  • preferred forms of compounds of formulas (2) and (3) are those wherein Ar 1 is substituted at the chiral carbon in the S-configuration.
  • the compounds may also be supplied coupled to, e.g., PEG, PEO, targeting agents such as antibodies or ligands specific for receptors or other targets.
  • the invention is directed to compounds of formula (1) that modulates chemokine receptor activity.
  • Chemokine receptors include but are not limited to CCRl, CCR2, CCR3, CCR4, CCR5, CXCR3, and CXCR4.
  • the invention provides compounds of formula (1) that may demonstrate protective effects on target cells from HIV infection by binding specifically to the chemokine receptor, thus affecting the binding of a natural ligand to the CCR5 and/or CXCR4 of a target cell.
  • the compounds of the present invention may be useful as agents which affect chemokine receptors, such as CCRl, CCR2, CCR3, CCR4, CCR5, CXCR3, CXCR4 where such chemokine receptors have been correlated as being important mediators of many inflammatory as well as immunoregulatory diseases.
  • chemokine receptors such as CCRl, CCR2, CCR3, CCR4, CCR5, CXCR3, CXCR4 where such chemokine receptors have been correlated as being important mediators of many inflammatory as well as immunoregulatory diseases.
  • chemokines include angiogenesis, and tumorigenesis such as brain, and breast tumors.
  • a compound that modulates the activity of such chemokine receptors is useful for the treatment or prevention of such diseases.
  • modulators and/or modulation encompass antagonist/antagonism, agonist/agonism, partial antagonist/partial antagonism, and or partial agonist/partial agonism, i.e., inhibitors, and activators.
  • the compounds of formula (1) described herein may possess biological activity such that they are able to modulate CCR5 chemokine receptor activity and consequent or associated pathogenic processes subsequently mediated by the CCR5 receptor and its natural ligands.
  • compounds of formula (1) demonstrate a protective effect against HIV infection by inhibiting the binding of HIV to a chemokine receptor of a target cell such as CCR5 and/or CXCR4.
  • modulation is obtained by a method which comprises contacting a target cell with an effective amount of the compound to inhibit the binding of the virus to the chemokine receptor.
  • modulation and/or modulation encompass modulating activity in all types and subtypes of CCR5 receptors of a target cell, in any tissues of a particular patient where they are found, and in any cell components comprising those tissues that the target cell may be located.
  • chemokine receptor activity and function may be used for the treatment of diseases that are associated with inflammation, including but not limited to, inflammatory or allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias, delayed-type hypersensitivity, atherosclerosis, interstitial lung disease (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies; autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myastenia gravis, juvenile onset diabetes; glomerular lung disease (
  • compounds that activate or promote chemokine receptor function are used for the treatment of diseases associated with immunosuppression, such as in individuals undergoing chemotherapy, radiation therapy, enhanced wound healing and burn treatment, therapy for autoimmune disease or other drug therapy (e.g., corticosteroid therapy) or combination of conventional drugs used in the treatment of autoimmune diseases and graft/transplantation rejection, which causes immunosuppression; or immunosuppression due to congenital deficiency in receptor function or other causes.
  • diseases associated with immunosuppression such as in individuals undergoing chemotherapy, radiation therapy, enhanced wound healing and burn treatment, therapy for autoimmune disease or other drug therapy (e.g., corticosteroid therapy) or combination of conventional drugs used in the treatment of autoimmune diseases and graft/transplantation rejection, which causes immunosuppression; or immunosuppression due to congenital deficiency in receptor function or other causes.
  • helminth infections such as nematodes (round worms); Trichuriasis, Enterobiasis, Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis; trematodes; visceral worms, visceral larva migtrans (e.g., Toxocara), eosinophilic gastroenteritis (e.g., Anisaki spp., Phocanema ssp.), cutaneous larva migrans (Ancylostona braziliense, Ancylostoma caninum); the malaria-causing protozoan Plasmodium vivax, Human cytomegalovirus, Herpesvirus saimiri, and Kaposi's sarcoma herpesvirus, also known as human herpesvirus 8, and poxvirus Molus
  • Compounds of the present invention may be used in combination with any other active agents or pharmaceutical compositions where such combined therapy is useful to modulate chemokine receptor activity and thereby prevent and treat inflammatory and immunoregulatory diseases.
  • the compounds may be used in combination with one or more agents useful in the prevention or treatment of HIV.
  • agents useful in the prevention or treatment of HIV include:
  • nucleotide reverse transcriptase inhibitor such as tenofovir disoproxil fumarate; lamivudine/zidovudine; abacavir/lamivudine/zidovudine; emtricitabine; amdoxovir; alovudine; DPC-817; SPD-756; SPD-754; GS7340; ACH-126,443 (beta)-L-F d4C; didanosine, zalcitabine, stavudine, adefovir, adefovir dipivoxil, fozivudine todoxil, etc.;
  • non-nucleotide reverse transcriptase inhibitor including an agent having anti-oxidation activity such as immunocal, oltipraz, etc.
  • non-nucleotide reverse transcriptase inhibitor such as nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, TMC-125; DPC-083; capravarine; calanolide A; SJ-3366 series, etc.
  • protease inhibitors such as saquinavir, lopinavir/ritonavir, atazanavir, fosamprenavir, tipranavir, TMC- 114, DPC-684, indinavir, nelfinavir, amprenavir, palinavir, lasinavir, etc.
  • an agent having anti-oxidation activity such as immunocal, oltipraz, etc.
  • protease inhibitors such as saquinavir, lopinavir/riton
  • entry inhibitors such as T-20; T-1249; PRO-542; PRO-MO; TNX-355; BMS-806 series; and 5-Helix;
  • CCR5-receptor inhibitors such as Sch-C (or SCH351125); Sch-D (or SCH350634); TAK779; UK 427,857 and TAK 449; or CXCR4- receptor inhibitors such as T22, T134, T140, 18 amino acid analogs of polyphemusin II, ALX40-4C, ALK40- 4C, AMD3100 and AMD070; (6) Integrase inhibitors such as L-870,810; GW-810781 (S-1360); and
  • Budding inhibitors such as PA-344; and PA-457.
  • Combinations of compounds of the present invention with HIV agents are not limited to the above examples, but include the combination with any agent useful for the treatment of HIV.
  • Combinations the compounds of the invention and other HIV agents may be administered separately or in conjunction.
  • the administration of one agent may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • the compounds according to the present invention may be administered by oral, intramuscular, intraperitoneal, intravenous, intracisternal injection or infusion, subcutaneous injection, transdermal or transmucosal administration or by implant. They may also be administered by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • the compounds of the invention may be used to treat animals, including mice, rats, horses, cattle, sheep, dogs, cats, and monkeys. However, compounds of the invention can also be used in other species, such as avian species (e.g., chickens). The compounds of the invention may also be effective for use in humans.
  • the term "subject” or alternatively referred to herein as "patient” is intended to be referred to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. However, the compounds, methods and pharmaceutical compositions of the present invention may be used in the treatment of animals.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective amount of compound of formula (1).
  • the compounds may be administered alone or as a mixture with a pharmaceutically acceptable carrier (e.g., solid formulations such as tablets, capsules, granules, powders, etc.; liquid formulations such as syrups, injections, etc.).
  • a pharmaceutically acceptable carrier e.g., solid formulations such as tablets, capsules, granules, powders, etc.; liquid formulations such as syrups, injections, etc.
  • the compounds may be administered orally or non-orally. Examples of non-oral formulations include injections, drops, suppositories, pessaryies.
  • an appropriate dosage level will generally be about 0.01 to 500 mg per kg subject body weight per day, and can be administered in singe or multiple doses.
  • the dosage level will be about 0.1 to about 250 mg/kg per day. It will be understood that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound used, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the patient undergoing therapy.
  • a compound of formula (1) may be used in screening assays for compounds which modulate the activity of chemokine receptors, preferably CCR5 receptors.
  • the ability of a test compound to inhibit gpl20 and CD4/CCR5 -dependent cell-cell fusion may be measured using a cell fusion assay known in the art.
  • the compounds of formula (1) as disclosed herein may be useful for isolating receptor mutants, which can then be made into screening tools for the discovery of even more potent compounds, following procedures described herein and procedures known in the art.
  • the compounds of formula (1) may also be useful in establishing or characterizing the binding sites of other ligands, including compounds other than those of formula (1) to chemokine receptors, e.g., by competitive inhibition.
  • the compounds of the present invention may also be useful for the evaluation of putative specific modulators of various chemokine receptors.
  • COMPOUND 2 4-r4-((R)-3-Cvclohexyl-2-oxo-5-phenyl-imidazolidin-l-yl)- r 1 ,4'lbipiperidinyl- 1 '-carbonyll -benzoic acid
  • COMPOUND 1 57 mg, 0.10 mmol
  • 1OM NaOH 0.20 mL
  • COMPOUND 4 as a white foam (60 mg, 72%).
  • COMPOUND 5 (R)-3-n'-(4,6-Dimethyl-pyrimidine-5-carbonyl)-4'-methyl- ri,4'lbipiperidinyl-4-yll-4-phenyl-oxazolidin-2-one
  • COMPOUND 7 (R)-l-fery-Butyl-3-n'-(4,6-dimethyl-pyrimidine-5-carbonyl)- 4'-methyl-ri,4'lbipiperidinyl-4-yll-4-phenyl-imidazolidin-2-one
  • COMPOUND 8 (R)-l-fery-butyl-3-n'-(6-chloro-2,4-dimethyl-pyridine-
  • COMPOUND 11 (R)-3-n'-(6-Chloro-2.4-dimethyl-pyridine-3-carbonyl)- 4'-methyl-ri,4'lbipiperidinyl-4-yll-l-methyl-4-phenyl-imidazolidin-2-one
  • COMPOUND 12 l-n'-(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-
  • COMPOUND 13 N-n'-(6-Cvano-2,4-dimethyl-l-oxy-pyridine-3-carbonyl)- 4'-methyl-ri,4'lbipiperidinyl-4-yll-2-(2-oxo-oxazolidin-3-yl)-N-thiophen- 3-ylmethyl-acetamide
  • COMPOUND 14 as a white foam (27 mg, 41%).
  • COMPOUND 15 N-n'-(6-Chloro-2,4-dimethyl-l-oxy-pyridine-3-carbonyl)-
  • N-(4'-methyl-[l,4']bipiperidinyl-4-yl)-2-(2-oxo-oxazolidin-3-yl)-N-thiophen-3-ylmethyl- acetamide (see EXAMPLE 13) (57 mg, 0.14 mmol), 6-chloro-2,4-dimethyl-l-oxy- nicotinic acid (30 mg, 0.15 mmol), EDCI (29 mg, 0.15 mmol), HOBT (20 mg, 0.15 mmol) and DIPEA (0.039 niL, 0.22 mmol) in DMF (6 niL) was stirred at room temperature overnight.
  • COMPOUND 15 as a white foam (10 mg, 12%).
  • COMPOUND 16 l-rr-(2,6-Dichloro-4-methyl-l-oxy-pyridine-3-carbonyl)- 4'-methyl-ri,4'lbipiperidinyl-4-yll-3-(2-methoxyethoxy)-l-thiophen-3-ylmethyl-urea
  • COMPOUND 17 l-n'-(6-Cvano-2,4-dimethyl-l-oxy-pyridine-3-carbonyl)-
  • COMPOUND 18 1-Fl '-(2.6-Dichloro-4-methyl- 1 -oxy-pyridine-3 -carbonylV 4'-methyl-ri,4'lbipiperidinyl-4-yll-3-methoxy-l-thiophen-3-ylmethyl-urea Following general procedure C: a solution of 3-methoxy-l-(4'-methyl-
  • COMPOUND 19 l-n'-(6-Cvano-2.4-dimethyl-pyridine-3-carbonyl)-4'-methyl- ri,4'lbipiperidinyl-4-yll-3-methoxy-l-thiophen-3-ylmethyl-urea
  • COMPOUND 20 l-n'-(6-Cvano-2,4-dimethyl-l-oxy-pyridine-3-carbonyl)- 4'-methyl-ri,4'lbipiperidinyl-4-yll-3-methoxy-l-thiophen-3-ylmethyl-urea
  • COMPOUND 21 1 - [ 1 '-(6-Chloro-2,4-dimethyl- 1 -oxy-pyridine-3 -carbonyl)- 4'-methyl-ri,4'lbipiperidinyl-4-yll-3-methoxy-l-thiophen-3-ylmethyl-urea
  • COMPOUND 22 5-r4-(3-Methoxy-l-thiophen-3-ylmethyl-ureido)-4'-methyl- ri,4'lbipiperidinyl-r-carbonyll-4,6-dimethyl-pyridine-2-carboxylic acid isopropylamide
  • COMPOUND 23 5-(3-n'-(6-Chloro-2.4-dimethyl-pyridine-3-carbonyl)-4'- methyl- [ 1 ,4'1bipiperidinyl-4-vH-3-thiophen-3-ylmethyl- ⁇ ireido j -pentanoic acid methyl ester
  • COMPOUND 23 52 mg, 0.084 mmol
  • MeOH MeOH
  • IN NaOH 1 mL
  • the mixture was concentrated under reduced pressure and the pH was adjusted to ⁇ 3 with HCl.
  • the aqueous was extracted with CH 2 CI 2 (6 x 15 mL) and the combined organic extracts were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to afford COMPOUND 24 as a white foam (36 mg, 71%).
  • COMPOUND 25 3-( n'-(6-Chloro-2.4-dimethyl-pyridine-3-carbonyl)-4'- methyl-ri,4'lbipiperidinyl-4-yll-thiophen-3-ylmethyl-aminol-3-methylamino- acrylonitrile To a solution of (6-chloro-2,4-dimethyl-pyridin-3-yl)- ⁇ 4'-methyl-4-[(thiophen-
  • COMPOUND 26 3- ⁇ rr-(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-4'-methyl-ri,4'lbipiperidinyl-4-yll- thiophen-S-ylmethyl-aminoj-S-cyclopropylamino-acrylonitrile
  • COMPOUND 27 l- ⁇ l-ri-(6-Cyano-2,4-dimethyl-pyridine-3-carbonyl)- azetidin-3-yll-piperidin-4-ylj-3-methoxy-l-thiophen-3-ylmethyl-urea
  • N-(4-nitrophenoxycarbonyl)methoxylamine (420 mg, 1.98 mmol) and DIPEA (0.57 mL, 5.9 mmol) in CH 2 Cl 2 (8 mL) was stirred at room temperature overnight. Standard work-up afforded the desired crude carbamate.
  • COMPOUND 28 5- ⁇ 3-r4-(3-Methoxy-l-thiophen-3-ylmethyl-ureido)- piperidin- 1 - yli -azetidine- 1 -carbonyl j -4,6-dimethyl-pyridine-2-carboxylic acid isopropylamide
  • COMPOUND 30 5-(3-r4-(3-Methoxy-l-thiophen-3-ylmethyl-ureidoV piperidin- 1 - yli -azetidine- 1 -carbonyl j -4,6-dimethyl-pyridine-2-carboxylic acid (3-methyl-butvD-amide
  • COMPOUND 31 N- ⁇ l-ri-(6-Cvano-2,4-dimethyl-pyridine-3-carbonyl)- azetidin-3-yll-piperidin-4-yl)-2-(2-oxo-oxazolidin-3-yl)-N-thiophen-3-ylmethyl- acetamide
  • the assay measures the ability of a test compound to inhibit gpl20 and CD4/CCR5 -dependent cell-cell fusion.
  • the assay uses two cell lines, 1) CHO-tat cell line that expresses the viral gpl20 from a R5 using virus (JR-FL) and the HIV tat proteins, 2) P4-CCR5 cell line that expresses human CD4 and CCR5 on the surface and carries a ⁇ -galactosidase construct under the control of the retroviral promoter LTR. Once fusion of these two cell lines occurs, the tat protein from the CHO cell line trans-activates the reporter gene ⁇ -galactosidase in the P4-CCR5 cell line.
  • a concentration range of antagonist was incubated for 45 minutes at room temperature in binding buffer (50 mM HEPES, 5 mM MgCl 2 , 1 mM CaCl 2 , 0.2% BSA pH 7.4) with 8 ⁇ g of HEK293F.CCR5 cell membrane and 50 pM 125 I-RANTES (Perkin Elmer, 81400 GBq/mmol) in Milipore GF-B filter plates. Unbound 125 I-RANTES was removed by washing with cold 50 mM HEPES, 0.5 M NaCl pH 7.4. Compounds were tested at a concentration range of 10,000 - 0.6 nM. The 50% inhibitory concentration (IC 50 value) was defined as the concentration of test compound required to inhibit RANTES binding by 50% relative to untested controls.
  • PBMC from healthy donors were isolated by density gradient centrifugation and stimulated with PHA at 1 ⁇ g/ml (Sigma Chemical Co., Bornem, Belgium) for 3 days at 37°C.
  • the activated cells (PHA-stimulated blasts) were washed three times with PBS, and viral infections were performed.
  • the cells were seeded in 48-well plates (5 x 10 5 cells per well in 200 ⁇ L culture medium) and pre-incubated for 15 min with compounds at different concentrations. Then 500 pg p24 viral Ag/well of CCR5-using viruses was added.
  • the HIV-I R5 strains BaL, SF-162, ADA, and JR-FL were all obtained through the Medical Research Council AIDS reagent project (Herts, UK).
  • HIV-infected or mock- infected PHA-stimulated blasts were then further cultured in the presence of 25 U/ml of IL-2 and supernatant was collected at days 8-10, and HIV-I core antigen in the culture supernatant was analyzed by the p24 Ag ELISA kit from DuPont-Merck Pharmaceutical Co. (Wilmington, DE).

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Abstract

L'invention concerne des composés qui modulent l'activité de récepteurs de chimiokine, en particulier CCR5.
PCT/US2007/086588 2006-12-06 2007-12-06 Composés de liaison à un récepteur de chimiokine WO2008070758A1 (fr)

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JP2009540468A JP2010512340A (ja) 2006-12-06 2007-12-06 ケモカイン受容体結合性化合物
EP07865277A EP2088860A4 (fr) 2006-12-06 2007-12-06 Composés de liaison à un récepteur de chimiokine

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Cited By (2)

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WO2009013171A2 (fr) * 2007-07-24 2009-01-29 F. Hoffmann-La Roche Ag Composés antiviraux hétérocycliques
US9593106B2 (en) 2013-02-07 2017-03-14 Heptares Therapeutics Limited Piperidin-1-yl and azepin-1-yl carboxylates as muscarinic M4 receptor agonists

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040142920A1 (en) * 2001-04-09 2004-07-22 Rainer Albert Bipiperidinyl-derivatives and their use as chemokine receptors inhibitors
US20060229336A1 (en) * 2002-12-13 2006-10-12 Kazmierski Wieslaw M Ccr5 antagonists as therapeutic agents

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006077499A1 (fr) * 2005-01-20 2006-07-27 Pfizer Limited Composes chimiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040142920A1 (en) * 2001-04-09 2004-07-22 Rainer Albert Bipiperidinyl-derivatives and their use as chemokine receptors inhibitors
US20060229336A1 (en) * 2002-12-13 2006-10-12 Kazmierski Wieslaw M Ccr5 antagonists as therapeutic agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2088860A4 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009013171A2 (fr) * 2007-07-24 2009-01-29 F. Hoffmann-La Roche Ag Composés antiviraux hétérocycliques
WO2009013171A3 (fr) * 2007-07-24 2009-04-09 Hoffmann La Roche Composés antiviraux hétérocycliques
US9593106B2 (en) 2013-02-07 2017-03-14 Heptares Therapeutics Limited Piperidin-1-yl and azepin-1-yl carboxylates as muscarinic M4 receptor agonists
US10030012B2 (en) 2013-02-07 2018-07-24 Heptares Therapeutics Limited Piperidin-1-yl and azepin-1-yl carboxylates as muscarinic M4 receptor agonists

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EP2088860A1 (fr) 2009-08-19

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