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WO2007014054A2 - Inhibiteur benzenesulfonamide de recepteur de chimiokine ccr2 - Google Patents

Inhibiteur benzenesulfonamide de recepteur de chimiokine ccr2 Download PDF

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Publication number
WO2007014054A2
WO2007014054A2 PCT/US2006/028419 US2006028419W WO2007014054A2 WO 2007014054 A2 WO2007014054 A2 WO 2007014054A2 US 2006028419 W US2006028419 W US 2006028419W WO 2007014054 A2 WO2007014054 A2 WO 2007014054A2
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WO
WIPO (PCT)
Prior art keywords
group
methyl
optionally substituted
phenyl
chloro
Prior art date
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Ceased
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PCT/US2006/028419
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WO2007014054A3 (fr
Inventor
Carl Brooks
Pamela A. Cleary
Krista B. Goodman
Simon Peace
Joanne Philp
Clark A. Sehon
Christian Smethurst
Stephen Paul Watson
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Glaxo Group Ltd
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Glaxo Group Ltd
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Priority claimed from GB0515194A external-priority patent/GB0515194D0/en
Priority claimed from GB0519492A external-priority patent/GB0519492D0/en
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of WO2007014054A2 publication Critical patent/WO2007014054A2/fr
Publication of WO2007014054A3 publication Critical patent/WO2007014054A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Definitions

  • the present invention relates to novel compounds, pharmaceutical compositions containing them and their use in therapy, as modulators of chemokine receptors, particularly as CCR2 antagonists, as well as to processes for their preparation, and intermediates used in these processes.
  • Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, that are released by a wide variety of cells to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils (reviewed in: Luster, New Eng. J. Med. 1998, 338, 436-445 and Rollins, Blood 1997, 90, 909-928).
  • CXC chemotactic cytokines
  • CC chemotactic cytokines, of molecular weight 6-15 kDa, that are released by a wide variety of cells to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils (reviewed in: Luster, New Eng. J. Med. 1998, 338, 436-445 and Rollins, Blood 1997, 90, 909-928).
  • CXC single amino acid
  • CC adjacent
  • the CXC chemokines such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils and T lymphocytes, whereas the CC chemokines, such as RANTES, MIP-Ia, MlP- ⁇ , the monocyte chemotactic proteins (MCP-1 , MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1 and -2) are chemotactic for, among other cell types, macrophages, T lymphocytes, eosinophils, dendritic cells, and basophils.
  • IL-8 interleukin-8
  • NAP-2 neutrophil-activating protein-2
  • MGSA melanoma growth stimulatory activity protein
  • lymphotactin-1 lymphotactin-1
  • lymphotactin-2 both C chemokines
  • fractalkine a CX 3 C chemokine
  • chemokines bind to specific cell-surface receptors belonging to the family of G- protein-coupled seven-transmembrane-domain proteins (reviewed in: Horuk, Trends Pharm. Sci. 1994, 15, 159-165) which are termed "chemokine receptors.”
  • chemokine receptors On binding their cognate ligands, chemokine receptors transduce an intracellular signal through the associated trimeric G proteins, resulting in, among other responses, a rapid increase in intracellular calcium concentration, changes in cell shape, increased expression of cellular adhesion molecules, degranulation, and promotion of cell migration.
  • CCR-1 or "CKR-1 " or "CC-CKFM ”
  • MIP-1 ⁇ , MCP-3, MCP-4, RANTES Ben-Barruch, et al., ce// 1993, 72, 415-425, and Luster, New Eng. J. Med.
  • CCR2A and CCR2B (or "CKR-2AVCKR-2B” or "CC-CKR-2ATCC-CKR-2B") [MCP-1 , MCP-2, MCP-3, MCP-4, MCP-5] (Charo, et al., Proc. Natl. Acad. ScL USA 1994, 91 , 2752-2756 Luster, New Eng. J Med. 1998, 338, 436-445); CCR-3 (or "CKR-3” or "CC-CKR-3”) [eotaxin-1 , eotaxin-2, RANTES, MCP-3, MCP-4] (Combadiere, et al., J. Biol. Chem.
  • CCR-4 or "CKR-4" or "CC-CKR-4" [TARC, MDC] (Power, et al., J. Biol. Chem. 1995, 270, 19495- 19500, and Luster, New Eng. J. Med. 1998, 338, 436-445); CCR-5 (or "CKR-5" or "CC- CKR-5") [MIP-1 ⁇ , RANTES, MIP-1 B] (Sanson, et al., Biochemistry 1996, 35, 3362-3367); CCR-6(or "CKR-6” [LARC] (Baba, et al., J. Biol.
  • CCR-7 or “CKR-7” or “CC-CKR-7" [ELC] (Yoshie et al., J. Leukoc. Biol. 1997, 62, 634-644); CCR-8 (or “CKR-8” or “CC-CKR-8”) [1 -309] (Napolitano et al., J. Immunol., 1996, 157, 2759-2763); CCR-10 (or “CKR-IO” or "CC-CKR-IO”) [MCP-1 , MCP-3] (Bonini, et al., DNA and Cell Biol. 1997, 16, 1249-1256); and CCR-11 [MCP-1 , MCP-2, and MCP-4] (Schweickert, et al., J. bid. Chem. 2000, 275, 90550).
  • mammalian chemokine receptors In addition to the mammalian chemokine receptors, mammalian cytomegaloviruses, herpe's viruses and poxviruses have been shown to express, in infected cells, proteins with the binding properties of chemokine receptors (reviewed in: Wells and Schwartz, Curr. Opin. Biotech. 1997, 8, 741-748).
  • Human CC chemokines such as RANTES and MCF-3, can cause rapid mobilization of calcium via these virally encoded receptors. Receptor expression may be permissive for infection by allowing for the subversion of normal immune system surveillance and response to infection.
  • human chemokine receptors such as CXCR4, CCR2, CCR3, CCR5 and CCR8, can act as co- receptors for the infection of mammalian cells by microbes as with, for example, the human immunodeficiency viruses (HIV).
  • HAV human immunodeficiency viruses
  • chemokines and their cognate receptors have been implicated as being important mediators of inflammatory, infectious, and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis (reviewed in: F. H. Carter, Current Opinion in Chemical Biology 2002, 6, 510; Trivedi, et al, Ann. Reports Med. Chem. 2000, 35, 191 ; Saunders and Tarby, Drug Disc. Today 1999, 4, 80; Fremack and Schall, Nature Medicine 1996, 2, 1174).
  • the chemokine monocyte chemoattractant-l (MCP-1) and its receptor CC Chemokine Receptor 2 (CCR2) play a pivotal role in attracting leukocytes to sites of inflammation and in subsequently activating these cells.
  • MCP-1 monocyte chemoattractant-l
  • CCR2 Chemokine Receptor 2
  • MCP-1 -/- mice had normal numbers of leukocytes and macrophages, but were unable to recruit monocytes into sites of inflammation after several different types of immune challenge (Bao Lu, et al., J. Exp. Med. 1998, 187, 601). Likewise, CCR2 -/- mice were unable to recruit monocytes or produce interferon- ⁇ when challenged with various exogenous agents; moreover, the leukocytes of CCR2 null mice did not migrate in response to MCP-1 (Landin Boring, et al., J. Clin. Invest. 1997, 100, 2552), thereby demonstrating the specificity of the MCP-1/CCR2 interaction.
  • MCP-1 is upregulated in patients with rheumatoid arthritis (Alisa Koch, et al., J. CHn. Invest. 1992, 90, 772 - 779). Moreover, several studies have demonstrated the potential therapeutic value of antagonism of the MCP-1 /CCR2 interaction in treating rheumatoid arthritis. A DNA vaccine encoding MCP-1 was shown recently to ameliorate chronic polyadjuvant-induced arthritis in rats (Sawsan Youssef, et al., J. Clin. Invest. 2000, 106, 361).
  • MCP-1 collagen-induced arthritis
  • streptococcal cell wall-induced arthritis Roseptococcal cell wall-induced arthritis
  • MCP-1 a peptide antagonist of MCP-1 , MCP-1 (9-76)1 was shown both to prevent disease onset and to reduce disease symptoms (depending on the time of administration) in the MRL-1pr mouse model of arthritis (Jiang-Hong Gong, et al., J. Exp. Med. 1997, 186, 131).
  • MCP-1 is upregulated in atherosclerotic lesions, and it has been shown that circulating levels of MCP-1 are reduced through treatment with therapeutic agents, plays a role in disease progression (Abdolreza Rezaie-Majd, et al, Arterioscler. Thromb. Vase. Biol. 2002, 22, 1194 - 1199).
  • Four key studies have demonstrated the potential therapeutic value of antagonism of the MCP-1 /CCR2 interaction in treating atherosclerosis. For example, when MCP-1 -/- mice are mated with LDL receptor- deficient mice, an 83% reduction in aortic lipid deposition was observed (Long Gu, et al., MoI. Cell 1998, 2, 275).
  • mice which already overexpressed human apolipoprotein B were protected from atherosclerotic lesion formation relative to the MCP-1 +/+ apoB control mice (Jennifa Gosling, et al., J. Clin. Invest. 1999, 103, 773).
  • CCR2 -/- mice are crossed with apolipoprotein E -/- mice, a significant decrease in the incidence of atherosclerotic lesions was observed (Landin Boring, et al, Nature 1998, 394, 894).
  • MCP-1 is upregulated in human multiple sclerosis, and it has been shown that effective therapy with interferon b-lb reduces MCP-1 expression in peripheral blood mononuclear cells, suggesting that MCP-1 plays a role in disease progression (Carla larlori, et al., J. Neuroimmunol. 2002, 123, 170 - 179).
  • Other studies have demonstrated the potential therapeutic value of antagonism of the MCP-1 /CCR2 interaction in treating multiple sclerosis; all of these studies have been demonstrated in experimental autoimmune encephalomyelitis (EAE), the conventional animal model for multiple sclerosis.
  • EAE experimental autoimmune encephalomyelitis
  • MCP-1 is upregulated in patients who develop bronchiolitis obliterans syndrome after lung transplantation (Martine Reynaud-Gaubert, et al., J. of Heart and Lung Transplant, 2002, 21, 721 - 730; John Belperio, et al., J. Clin. Invest. 2001, 108, 547 - 556).
  • bronchiolitis obliterans syndrome administration of an antibody to MCP-1 led to attenuation of airway obliteration; likewise, CCR2 -/- mice were resistant to airway obliteration in this same model (John Belperio, et al., J. Clin. Invest. 2001, 108, 547 - 556).
  • MCP-1 -/- mice with induced nephrotoxic serum nephritis showed significantly less tubular damage than their MCP-1 +/+ counterparts (Gregory H. Tesch, et al.7 J. Cur. Invest. 1999, 103, 73).
  • MCP-1 is overexpressed in various disease states not mentioned above. These reports provide correlative evidence that MCP-1 antagonists could be useful therapeutics for such diseases.
  • Two reports describe the overexpression of MCP-1 rats with induced brain trauma (J. S. King, et al., J. Neuroimmunol. 1994, 56, 127, and Joan W.
  • MCP-1 is overexpressed in the brains and cerebrospinal fluid of patients with HIV-associated dementia (Alfredo Garzino-Demo, WO 99/46991).
  • CCR2 has been implicated as a co-receptor for some strains of HIV (B. J. Doranz, et al., Cell 1996, 85, 1149). It has also been determined that the use of CCR2 as an HIV co-receptor can be correlated with disease progression (Ruth I.
  • the present invention is a compound as represented in formula (I):
  • R 1 represents an aryl, a thienyl, a benzothienyl, an imidazolyl, a pyridyl, an isoquinolinyl, a piperonyl, a benzoxathiadiazolyl, or a benzoxadiazolyl group optionally substituted with one to three R 4 groups, wherein each R 4 group is independently selected from the group consisting of Ci_ 6 -alkyl, C ⁇ -haloalkyl, C ⁇ -alkoxy, C 1-6 -haloalkoxy, halo, -NH 2 , -OH, -CN, -NO 2 , CF 3 , phenyl, phenoxy, phenyl-C(O)-, isoxazolyl, and -C(O)NR 7 R 8 , wherein R 7 and R 8 each independently represent hydrogen or C 1-4 alkyl, or R 7 and R 8 together with the nitrogen atom to which they are attached form a 5- or
  • n 1 , 2, or 3; each R 2 is independently selected from the group consisting of halo, -CN, OCF 3 , and - CF 3 ,;
  • R 3 is a heteroaryl or a heterocycloalkyl group optionally substituted by up to three substituents independently selected from the group consisting of halo, hydroxy, hydroxy- d- 6 -alkyl-, C ⁇ alkoxy-d-ealkyl-, Ci -4 alkoxy-, C ⁇ thioalkoxy, amino, R 10 R 11 N-Ci. 4 alkyl-, heterocycloalkyl, heteroaryl, halogenated heteroaryl, phenyl, benzyl, halophenyl,
  • the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a combination thereof and a pharmaceutically acceptable carrier, diluent, or excipient or combination thereof.
  • the present invention is a method for treating a disease or condition mediated by CCR2 comprising administering to a patient in need thereof a pharmaceutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof or a combination thereof.
  • Compounds within the scope of the present invention have potential in the treatment of conditions wherein modulation, especially antagonism/inhibition, of the CCR2 receptor is thought to be beneficial.
  • the compounds may be effective in the treatment of diseases such as atherosclerosis, asthma, seasonal and perennial allergic rhinitis, sinusitis, conjunctivitis, food allergy, scombroid poisoning, pulmonary fibrosis, restenosis, including vascular restenosis, myocarditis, ulcerative colitis, psoriasis, urticaria, pruritis, eczema, atopic dermatitis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombotic disease, otis media, rheumatoid arthritis, nephritis (nephropathy), liver cirrhosis, multiple sclerosis and systemic sclerosis, lupus, erthematosis, hepatitis, pancreatitis, sarcoidosis, organ transplantation, Crohn's disease, endometriosis, cardiac disease, congestive heart failure, viral meningitis, cerebral infarction, neuropathy
  • CCR2 is also the receptor for the chemokines MCP-2, MCP-3, MCP-4, and MCP-5 (Luster, New Eng. J. Med. 1998, 338, 436-445). Since the new compounds of formula (I) described herein antagonize MCP-1 by binding to the CCR2 receptor, it may be that these compounds of formula (I) are also effective antagonists of the actions of MCP-2, MCP-3, MCP-4, and MCP-5 that are mediated by CCR2.
  • alkyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms.
  • C 1-6 alkyl means a straight or branched alkyl containing at 1 to 6 carbon atoms.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isobutyl, isopropyl, t-butyl and 1 ,1-dimethylpropyl.
  • alkoxy refers to a straight or branched alkoxy group containing the specified number of carbon atoms.
  • Ci -6 alkoxy means a straight or branched alkoxy group containing 1 to 6 carbon atoms.
  • alkoxy include, but are not limited to methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy or hexyloxy.
  • alkylthio refers to a straight or branched alkylthio group containing the specified number of carbon atoms.
  • C 1-4 alkylthio means a straight or branched alkylthio group containing 1 to 6 carbon atoms.
  • alkylthio as used herein include, but are not limited to methylthio, ethylthio, propylthio, prop-2-thio, butylthio, but-2-thio, 2-methylprop-1 -thio, 2-methylprop-2-thio.
  • C 3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
  • halogen or halo refers to fluoro, chloro, bromo and iodo.
  • heterocycloalkyl groups include, but are not limited to pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholino, thiomorpholino, piperazinyl, oxopiperidinyl, oxophenyltriazaspirodecyl, oxopyrazolidinyl, oxopyrazolyl, oxooxazolidinyl, oxoimidazolidinyl, dioxaazaspirodecyl groups.
  • Heteroaryl groups include, but are not limited to, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, furazanyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzthiazolyl, indazolyl, indolazinyl, benzimidazolyl, benzotriazolyl, purinyl, coumarinyl, isocoumarinyl, chromonyl, quinolinyl, isoquinolinyl, cinnolinyl, quin
  • C 6-10 aryl ring systems include: phenyl and naphthyl.
  • ring systems covered by the definitions in this specification are those which are stable enough to be effective for the intended purpose. This stability is with reference to the preparation and storage of the compound containing said ring system and not with reference to in vivo metabolism.
  • pharmaceutically acceptable means suitable for pharmaceutical use.
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include water, methanol, ethanol, and acetic acid.
  • the compounds of formula (I) as defined above contain a basic grouping and may also contain an acidic grouping and therefore may form salts with physiologically acceptable acids or bases.
  • Physiologically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a physiologically acceptable anion or cation.
  • physiologically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example benzenesul, in
  • Certain of the compounds of the invention may form acid addition salts with one or more equivalents of the acid. Certain of the compounds of the invention may form acid addition salts with less than one equivalent of the acid.
  • the present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.
  • Certain compounds of formula (I) may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms).
  • the individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention.
  • the present invention also covers the individual isomers of the compounds represented by formula (I) as mixtures with isomers thereof in which one or more chiral centres are inverted.
  • compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.
  • the invention provides a method for treating a disease or condition mediated by CCR2 comprising administering to a patient in need thereof a pharmaceutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof or a combination thereof.
  • a compound of the invention may be administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a combination thereof and a pharmaceutically acceptable carrier, diluent, or excipient or a combination thereof.
  • the carrier, diluent and/or excipient must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.
  • the compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers, diluents or excipients according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, buccal, topical, inhalation or insufflation, implant, rectal or parenteral administration to mammals including humans.
  • compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, sugar, microcystalline cellulose, maize-starch, calcium phosphate, glycine or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch or sodium starch glycollate, or wetting agents such as sodium lauryl sulphate.
  • binding agents for example, syrup, acacia, gelatin, sorbitol, tragacanth, muci
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; solubilizers such as surfactants for example polysorbates or other agents such as cyclodextrins; and preservatives, for example, methyl or propyl p-hydroxybenzoates or ascorbic acid; and, if desired, conventional flavouring or colouring agents.
  • the compositions may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides
  • composition may take the form of tablets or lozenges formulated in conventional manner.
  • composition according to the invention may be formulated for parenteral administration by injection or continuous infusion.
  • Formulations for injection may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • the dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • a compound of the invention required for use in treatment will vary with the nature of the condition being treated, the route of administration and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician. In general however doses employed for adult human treatment will typically be in the range of 1 to 10OOmg per day, dependent upon the route of administration.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • each unit will typically contain from 1 -1000 mg of the active ingredient.
  • Suitable protecting groups for use according to the present invention are well known to those skilled in the art and may be used in a conventional manner. See, for example, "Protective groups in organic synthesis” by T.W. Greene and P.G.M. Wuts (John Wiley & sons 1991) or "Protecting Groups” by P.J. Kocienski (Georg Thieme Verlag 1994).
  • suitable amino protecting groups include acyl type protecting groups (e.g.
  • aromatic urethane type protecting groups e.g. benzyloxycarbonyl (Cbz) and substituted Cbz
  • aliphatic urethane protecting groups e.g. 9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl
  • alkyl type protecting groups e.g. benzyl, trityl, chlorotrityl.
  • oxygen protecting groups may include for example alkyl silyl groups, such as trimethylsilyl or tert-butyldimethylsilyl; alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters such as acetate.
  • alkyl silyl groups such as trimethylsilyl or tert-butyldimethylsilyl
  • alkyl ethers such as tetrahydropyranyl or tert-butyl
  • esters such as acetate.
  • the compounds of formula (I), wherein the R 3 group is attached to the methylene linker via a nitrogen atom, may in general be prepared by the reaction of a compound of formula (II):
  • R 3 is as defined above;
  • Suitable leaving groups L include chloro or bromo.
  • L may represents a sulfonyloxy group such C alkylsulfonyloxy (for example methanesulfonyloxy), C 1 4 alkylsulfonyloxy or haloC ⁇ alkylsulfonyloxy (for example trifluoromethanesulfonyloxy); or arylsulfonyloxy for example para-toluenesulfonyloxy.
  • such a reaction may be carried out by dissolving the compound of formula (III) in a suitable solvent, for example 1 ,4-dioxane, in the presence of an appropriate crown ether, for example 18-crown-6-ether, and then reacting it with a deprotonating agent such as potassium tert-butoxide, and then reacting the resulting solution with the compound of formula (II).
  • a suitable solvent for example 1 ,4-dioxane
  • an appropriate crown ether for example 18-crown-6-ether
  • a deprotonating agent such as potassium tert-butoxide
  • the compounds of formula (I) may be prepared by the reaction of a compound of formula (IV):
  • L' is a suitable leaving group, and R 1 is as defined above;
  • Suitable leaving groups L' include chloro, bromo or pentafluorophenoxy.
  • L' represents chloro
  • such a reaction may be carried out by dissolving the compound of formula (IV) in a suitable solvent, for example pyridine optionally mixed with a second solvent, such as chloroform or tetrahydrofuran, and reacting it with the compound of formula (V) also in a suitable solvent, for example pyridine.
  • a catalytic quantity of dimethylaminopyridine may also be used.
  • the reaction would generally be carried out at elevated temperature in the region of 80-250 s C, for example at about 200 9 C, for a period of 30 minutes to 1 hour or at 8O 0 C for a period of 5-24 hours.
  • this ring system may be formed de novo by methods well-known to the person skilled in the art.
  • n is a group capable of being converted by reaction with appropriate reagents into the group R 3 or a protected derivative thereof;
  • a suitable scheme to generate de novo a pyridazinone ring system would suitably involve reacting a compound of formula (II) wherein L represents chloro with tert- butyl carbazat ⁇ in a suitable solvent, for example DMF. Typically such a reaction would be carried out at ambient temperature for between 3 and 8 hours. The resulting product may then be dissolved in a suitable solvent containing 50% trifluoroacetic acid, for example dichloromethane, and stirred for a suitable time, typically 2 to 3 hours, at ambient temperature. Subsequent to the removal of the solvent the residue may be reacted with ethyl levulinate and glacial acetic acid, typically at elevated temperature in the region of 100 9 C for between 30 and 60 minutes. The final product will represent a compound of formula (I) wherein R 3 represents a 3-methyl-6-oxo-5,6-dihydro-1 (4H)- pyridazinyl group.
  • the compound of formula (IV), wherein the group R 3 is joined to the methylene linker by a nitrogen atom, may be prepared by reacting a compound of formula (VII):
  • such compounds may be prepared by de novo generation of a hetero-aryl ring, for example by the general process outlined in Scheme 6.
  • Generation of a di-acyl hydrazine of the type shown may be achieved by, for example, activation of a carboxylic acid to the acid chloride with oxalyl chloride in the presence of a catalytic quantity of dimethylformamide or dimethylacetamide and subsequent reaction with the appropriate acyl hydrazine.
  • Dehydration of the diacylhydrazine intermediate may be achieved with an appropriate reagent such as Burgess' reagent.
  • Reduction of the nitro-arene to the corresponding aniline (IV) may be achieved by hydrogenation with platinum or palladium catalysis in a suitable solvent, for example ethanol.
  • Substituted triazolyl examples may be constructed as outlined by the general method provided in Scheme 7.
  • Preparation of the intermediate azides may be achieved by treatment of relevant alcohol with an azidinating reagent such as diphenylphosphoryl azide in the presence of an appropriate base, such as 1 ,8-diazabicyclo[5.4.0]undec-7- ene.
  • the triazole products may be prepared by reaction of appropriately substituted acetylenes catalysed by, for example, copper sulfate in the presence of sodium ascorbate.
  • the compounds of formula (I), wherein the R 3 group is a dihydropyridazinone or a dihydropyrazolone may be prepared from a compound of formula (II) by a process analogous to that set out in Scheme 8. Direct displacement of the chloride with f-butyl carbazate followed by removal of the protecting group provides the hydrazine which can be cyclized upon treatment with a ketoester.
  • 1 ,2,4-Triazole examples may be constructed as by the general procedure illustrated in Scheme 10. Treatment with f-butyl carbazate, followed by a borane reduction and removal of the protecting group provides the hydrazine. Addition of 1 ,3,5-triazine yields the triazole.
  • 1 ,2,4-triazoles of formula (IV) may be constructed by the general methods shown in Scheme 11 and Scheme 12.
  • Carbon linked 1 ,2,4-triazoles of formula (IV) may be prepared by the method in Scheme 13.
  • Treatment of the nitrile with acetyl chloride provides the imine which is converted to the formyl hydrazone.
  • Addition of an amine allows for ring closure to the triazole.
  • Polymer supported isocyanate is added to capture any excess amine. Reduction of the nitrobenzene then provides the aniline.
  • Imidazoles of formula (I) may be constructed from the hydrazines in formed in Scheme 10 by the general procedure outlined in Scheme 14. Treatment of the hydrazine with a 3-substituted 3-oxoproanenitrile affords the imidazole.
  • Interconversion reactions between compounds of formula (I) may be performed using methods well known in the art. Included are conversions of the substituent(s) within the group R 3 and/or conversions within groups R 2 and R 1 for example: (i) converting an acid to an acid amide;
  • DMEM Dulbecco Minimal Essential Medium GDP: Guanosine Diphosphate
  • Mass spectra were obtained using either a Waters ZQ mass spectrometer or Micromass Platform 2 mass spectrometer and use electro-spray ionisoation to observe either MH+ or M-.
  • Proton Nuclear Magnetic Resonance ( 1 H-NMR) spectra were recorded at 400 MHz unless otherwise stated, chemical shifts are reported in ppm downfield from M ⁇ 4Si, used as internal standard, and are assigned as singlets (s), doublets (d), doublets of doublets (dd), triplets (t), doublet of triplets (dt), quartets (q) multiplets (m) or are otherwise described in full.
  • the prefix "br” refers to a broad peak; for example, a broad single may appear as br.s (or br s).
  • Methyl 2- ⁇ [(4-chlorophenyl)sulfonyl]amino ⁇ -4-(trifluoromethyl)benzoate (460 mg, 1.17 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to 0 0 C.
  • Diisobutylaluminum hydride (1.5 M in toluene, 1.95 mL, 2.93 mmol) was added dropwise and then the reaction stirred at room temperature for 12 hours. A further portion of diisobutylaluminum hydride was added (1.17 mL, 1.76 mmol) and the solution allowed to stir for an additional 5 hours. The reaction was quenched with water and concentrated to dryness.
  • the resulting solid was dissolved in IMS (2.5 ml_) and water (30 mL) to which was added a 5M sodium hydroxide solution (1.5 mL). The mixture was then heated to reflux under argon overnight. The mixture was concentrated and the residue taken up in DCM (70 mL) and water (30 mL). The organic phase was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was re-dissolved in IMS (2.5 mL) and water (30 mL) to which was added a 5M sodium hydroxide solution (1.5 mL) and the mixture heated to reflux under argon overnight. The mixture was concentrated and the residue taken up in DCM (70 mL) and water (30 mL).
  • Nitric acid was added slowly to a mixture of 1 ,2-dichloro-4-methylbenzene (10 g) in sulfuric acid at 0 °C, keeping the temperature below 10 0 C.
  • the mixture was allowed to warm to room temperature, stirred for 10 minutes, poured over ice (250 g) and stirred for 10 further minutes.
  • the solid was filtered, washed with water (50 mL) and dissolved in DCM (150 mL). The resulting solution was washed with water (120 ml_) and brine (100 mL), dried over magnesium sulfate and concentrated. To the resulting solid at 150 0 C was added bromine (3.4 mL).
  • tert-Butyl carbazate (0.08 g, 0.63 mmol) was added to a solution of 3,4-dichloro- ⁇ /-(5- chloro-2-formylphenyl)benzenesulfonamide (0.19 g, 0.52 mmol) in hexane (8 ml_) and the reaction mixture was heated under reflux for 1 hour. A solution of 1 M BF 3 THF (2 ml_) was added and the reaction was stirred at room temperature for 14 minutes. The reaction was then treated with HCI (1 N in dioxane, 2 ml_) for 18 hours and concentrated. The residue was taken up in THF and filtered. The filtrate was concentrated to afford the titled product (0.15 g, 76%)
  • Example 2 1 -(r2-(r(4-chlorophenyl)sulfonyllamino)-4-(trifluoromethyl)phenyl1methyl)-5- r(methylamino)carbonyll-1 H-pyrazole-3-carboxylic acid
  • Example 36 ⁇ /-l2-r(5-cylopropyl-1 H-tetrazole-1 -vDmethyli-4-f luorophenyll-2.11.3- benzoxadiazole-4-sulfonamide
  • Example 74 3.4-Dichloro- ⁇ /-(5-chloro-2-r(3-oxo ⁇ .2.41triazolor4.3-alPyridin-2(3HV yl)methvnphenyl ⁇ benzenesulfonamide
  • Example 78 3.4-Dichloro- ⁇ /-l5-chloro-2-lY1 -methyl-1 H-tetrazol-5- vDnnethyliphenyllbenzenesulfonamicle
  • Example 145 3.4-dichloro- ⁇ /-l5-fluoro-2-IT4-propyl-1 H- 1.2.3-triazol-1 - vDmethyliphenyDbenze ⁇ esulfonamide
  • the aqueous layer was removed using a hydrophobic frit and washed with DCM (2 x 1 mL) and the combined DCM layers concentrated.
  • the title compound was retained on an isolute SCX ion-exchange column and eluted in 2M ammonia in methanol to give 40 mg upon removal of solvent.
  • Example 159 ⁇ /-r2-r(5-cyclopropyl-1 H-tetrazol-1 -yl)methyll-5-(trifluoromethyl)phenyl]- 2,1.3-benzoxadiazole-4-sulfonamide
  • Example 160 ⁇ /-r4.5-dichloro-2-(1 HA ,2.3-triazol-1 -ylmethvnphenv ⁇ -3- (trifluoromethvObenzenesulfonamide
  • Example 184 4-chloro- ⁇ /-l5-chloro-2-r(3,3-difluoro-1- pyrrolidinyl)methvnphenyl>benzenesulfonannide
  • Example 323 3.4-Dichloro- ⁇ /-r5-chloro-2-(1 H-1.2.4-triazol-1 - ylmethvDphenyllbenzenesulfonamide trifluoroacetate
  • 3-Pyrrolidinol (0.02 g, 0.23 mmol) was added to a solution of 3,4-dichloro- ⁇ /-(5-chloro-2- formylphenyl)benzenesulfonamide (0.07 g, 0.19 mmol) in anhydrous THF (2 mL) at room temperature. After stirring for 10 minutes, sodium cyanoborohydride (0.24 g, 0.38 mmol) and acetic acid (0.1 mL) were added. The resulting reaction mixture was stirred at room temperature for additional 12 hours until the starting material was consumed completely. Saturated K 2 CO 3 aqueous solution (4 ml_) was added to quench the reaction.
  • Example 360 2.3-Dichloro- ⁇ /-r2-((5-r3-(methyloxybhenyll-2H-tetrazol-2-yl>methvn-5-
  • Acetonitrile (2.75 ml_) was added to 5-[3-(methyloxy)phenyl]-1 /-/-tetrazole (0.0145 g, 0.0825 mmol) and polymer supported BEMP (0.150 g, 0.33 mmol).
  • a solution of trif luoromethyl2,3-dichloro- ⁇ /-[2-(chloromethyl)-5-()phenyl]benzenesulfonamide (0.0314 g, 0.075 mmol) in N-methyl pyrrolidinone (0.5 ml_) was also added and the reaction was stirred at 120 0 C in a Biotage microwave.
  • Example 379 ⁇ /-r2-r(5-amino-3-phenyl-1 H-pyrazol-1 -yl)methvn-5- (trifluoromethyl)phenyll-4-chlorobenzenesulfonamide
  • Example 380 1 -(r2-(r(4-chlorophenyl)sulfonyllamino)-4-(trif luoromethvDphenylimethyl)- ⁇ /-methyl-3-(2-thienylH H-pyrazole-5-carboxamide

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Abstract

L'invention concerne des composés de formule (I): ou un sel acceptable sur le plan pharmaceutique, un solvate ou une combinaison de ceux-ci, ainsi que des compositions de procédés d'utilisation de ces composés, R1, R2, R3 et m y étant décrits.
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