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WO2003082862A1 - Derives de morpholine-acetamide anti-inflammatoires - Google Patents

Derives de morpholine-acetamide anti-inflammatoires Download PDF

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Publication number
WO2003082862A1
WO2003082862A1 PCT/EP2003/003347 EP0303347W WO03082862A1 WO 2003082862 A1 WO2003082862 A1 WO 2003082862A1 EP 0303347 W EP0303347 W EP 0303347W WO 03082862 A1 WO03082862 A1 WO 03082862A1
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Prior art keywords
methyl
formula
compound
morpholin
dichlorobenzyl
Prior art date
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Ceased
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PCT/EP2003/003347
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English (en)
Inventor
Rachael Ann Ancliff
Caroline Mary Cook
Colin David Eldred
Paul Martin Gore
Lee Andrew Harrison
Martin Alistair Hayes
Simon Teanby Hodgson
Duncan Bruce Judd
Suzanne Elaine Keeling
Xiao Qing Lewell
Gail Mills
Graeme Michael Robertson
Stephen Swanson
Andrew John Walker
Mark Wilkinson
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Glaxo Group Ltd
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Glaxo Group Ltd
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Priority to AU2003216907A priority Critical patent/AU2003216907A1/en
Priority to JP2003580327A priority patent/JP2005527564A/ja
Priority to EP03712119A priority patent/EP1487827A1/fr
Publication of WO2003082862A1 publication Critical patent/WO2003082862A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P17/00—Drugs for dermatological disorders
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    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to novel compounds, processes for their preparation, pharmaceutical formulations containing them and their use in therapy.
  • Inflammation is a primary response to tissue injury or microbial invasion and is characterised by leukocyte adhesion to the endothelium, diapedesis and activation within the tissue.
  • Leukocyte activation can result in the generation of toxic oxygen species (such as superoxide anion), and the release of granule products (such as peroxidases and proteases).
  • Circulating leukocytes include neutrophils, eosinophils, basophils, monocytes and lymphocytes.
  • Different forms of inflammation involve different types of infiltrating leukocytes, the particular profile being regulated by the profile of adhesion molecule, cytokine and chemotactic factor expression within the tissue.
  • leukocytes The primary function of leukocytes is to defend the host from invading organisms, such as bacteria and parasites. Once a tissue is injured or infected, a series of events occurs which causes the local recruitment of leukocytes from the circulation into the affected tissue. Leukocyte recruitment is controlled to allow for the orderly destruction and phagocytosis of foreign or dead cells, followed by tissue repair and resolution of the inflammatory infiltrate. However in chronic inflammatory states, recruitment is often inappropriate, resolution is not adequately controlled and the inflammatory reaction causes tissue destruction.
  • bronchial inflammation which is characteristic of asthma represents a specialised form of cell-mediated immunity, in which cytokine products, such as IL-4 and IL-5 released by T-helper 2 (Th2) lymphocytes, orchestrate the accumulation and activation of granulocytes, in particular eosinophils and to a lesser extent basophils.
  • Th2 T-helper 2
  • eosinophils generate mucosal damage and initiate mechanisms that underlie bronchial hyperreactivity. Therefore, blocking the recruitment and activation of Th2 cells and eosinophils is likely to have anti-inflammatory properties in asthma.
  • eosinophils have been implicated in other disease types such as rhinitis, eczema, irritable bowel syndrome and parasitic infections.
  • Chemokines are a large family of small proteins which are involved in trafficking and recruitment of leukocytes (for review see Luster, New Eng. J. Med., 338, 436-445 (1998)). They are released by a wide variety of cells and act to attract and activate various cell types, including eosinophils, basophils, neutrophils, macrophages, T and B lymphocytes. There are two major families of chemokines, CXC- ( ⁇ ) and CC- ( ⁇ ) chemokines, classified according to the spacing of two conserved cysteine residues near to the amino terminus of the chemokine proteins.
  • Chemokines bind to specific cell surface receptors belonging to the family of G-protein-coupled seven transmembrane-domain proteins (for review see Luster, 1998). Activation of chemokine receptors results in, amongst other responses, an increase in intracellular calcium, changes in cell shape, increased expression of cellular adhesion molecules, degranulation and promotion of cell migration (chemotaxis).
  • CCR-3 CC-chemokine receptor-3
  • RANTES RANTES
  • MCP-3 and MCP-4 are known to recruit and activate eosinophils.
  • eotaxin and eotaxin-2 which specifically bind to CCR-3.
  • the localization and function of CCR-3 chemokines indicate that they play a central role in the development of allergic diseases such as asthma.
  • CCR- 3 is specifically expressed on all the major cell types involved in inflammatory allergic responses.
  • Chemokines that act at CCR-3 are generated in response to inflammatory stimuli and act to recruit these cell types to sites of inflammation, where they cause their activation (e.g. Griffiths et al., J. Exp. Med., 179, 881-887 (1994), Lloyd et al., J. Exp. Med., 191 , 265-273 (2000)).
  • anti-CCR-3 monoclonal antibodies completely inhibit eotaxin interaction with eosinophils (Heath, H. et al, J. Clin. Invest.
  • chemokines and their receptors also play a role in infectious disease.
  • Mammalian cytomegaloviruses, herpes viruses and pox viruses express chemokine receptor homologues, which can be activated by human CC chemokines such as RANTES and MCP-3 receptors (for review see Wells and Schwartz, Curr. Opin. Biotech., 8, 741-748, 1997).
  • human chemokine receptors such as CXCR-4, CCR-5 and CCR-3, can act as co-receptors for the infection of mammalian cells by microbes such as human immunodeficiency viruses (HIV).
  • chemokine receptor antagonists including CCR-3 antagonists, may be useful in blocking infection of CCR-3 expressing cells by HIV or in preventing the manipulation of immune cellular responses by viruses such as cytomegaloviruses.
  • WO 01/24786 discloses certain aryl and heteroaryl derivatives for treating diabetes.
  • WO 00/69830 discloses certain diazacyclic compounds, and libraries containing them, for biological screening.
  • WO 00/18767 discloses certain piperazine derivatives as dopamine D4 receptor antagonists.
  • United States Patent 6,031,097 and WO 99/21848 discloses certain aminoisoquinoline derivatives as dopamine receptor ligands.
  • WO 99/06384 discloses piperazine derivatives useful for the treatment of neuromuscular dysfunction of the lower urinary tract.
  • WO 98/56771 discloses certain piperazine derivatives as anti- inflammatory agents.
  • WO 97/47601 discloses certain fused heterocyclic compounds as dopamine D-receptor blocking agents.
  • WO 96/39386 discloses certain piperidine derivatives as neurokinin antagonists.
  • WO 96/02534 (Byk Gulden Lomberg Chemische Fabrik GmbH) discloses certain piperazine thiopyridines useful for controlling helicobacter bacteria.
  • WO 95/32196 (Merck Sharp & Dohme Limited) discloses certain piperazine, piperidine, and tetrahydropyridine derivatives as 5-HT1 D-alpha antagonists.
  • United States Patent 5,389,635 (E.I. Du Pont de Nemours and Company) discloses certain substituted imadazoles as angiotensin-ll antagonists.
  • European Patent Application publication number 0 306 440 (Schering Aktiengesellschaft) discloses certain imidazole derivatives as cardiovascular agents.
  • CCR-3 antagonists A novel group of compounds has now been found which are CCR-3 antagonists. These compounds block the migration/chemotaxis of eosinophils and thus possess anti-inflammatory properties. These compounds are therefore of potential therapeutic benefit, especially in providing protection from eosinophil, basophil mast cell and Th2-cell-induced tissue damage in diseases where such cell types are implicated, particularly allergic diseases, including but not limited to bronchial asthma, allergic rhinitis and atopic dermatitis.
  • R 1 represents substituted or unsubstituted heteroaryl
  • Y represents -(CR na R n b)n-;
  • R na and R nt> are each independently hydrogen or C ⁇ alkyl; n is an integer from 1 to 5;
  • R 2 represents unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl
  • R 3 represents hydrogen or C ⁇ alkyl; and salts and solvates thereof; with the provisos that;
  • R 1 is not oxazolyl; R 1 is not substituted by phenyl, and; the following compounds are excluded;
  • heteroaryl group examples include imidazolyl, triazolyl, oxadiazolyl, thiazolyl, thiophenyl, isoxadiazolyl, isoxathiazolyl, pyridinyl, furanyl, isoxazolyl, tetrazolyl and pyrazolyl.
  • suitable substituents include C ⁇
  • heterocyclyl group examples include piperidinyl.
  • heteroaryl group examples include pyrazinyl, oxadiazolyl, triazolyl, imidazolyl, thiadizolyl, isoxazolyl, thiazolyl and thiophenyl.
  • R 1 is unsubstituted or substituted imidazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted oxadiazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted thiophenyl, unsubstituted or substituted isoxadiazolyl, unsubstituted or substituted isoxathiazolyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted furanyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted tetrazolyl and unsubstituted or substituted pyrazolyl.
  • R When R is substituted furanyl, suitable substituents include carboxy, d. 6 alkoxycarbonylhydrazinocarbonyl, hydrazinocarbonyl, substituted heteroaryl, mono- and di ⁇ C ⁇ alky aminocarbonyl, C ⁇ alkoxycarbonyl, and C 3 . ⁇ cycloalkylaminocarbonyl.
  • suitable substituents include d.
  • R 1 is substituted triazolyl
  • suitable substituents include C ⁇ alkyl and amino.
  • R 1 When R 1 is substituted oxadiazolyl, suitable substituents include ⁇ alkyl, C ⁇ alkoxycarbonyl, amino, and mono- and di-(d ⁇ alkyl)aminocarbonyl.
  • R 1 is substituted thiazolyl
  • suitable substituents include d ⁇ alkyl, and unsubstituted or substituted heteroaryl.
  • R 1 When R 1 is substituted isoxadiazolyl, suitable substituents include d. 6 alkyl. When R 1 is substituted pyrazolyl, suitable substituents include amino, d.
  • R 1 When R 1 is substituted tetrazolyl, suitable substituents include unsubstituted heterocyclyl, for example piperidinyl, and ⁇ alkyl. When R 1 is substituted isoxazolyl, suitable substituents include d.
  • R 1 is 3-(tert-butoxycarbonylamino)pyrazol-5-yl, 3- (amino)pyrazol-5-yl, 3-(acetamido)pyrazol-5-yl, 3-(propionamido)pyrazol-5-yl, 3- (/so-propylcarbonylamino)pyrazol-5-yl, furan-2-yl, 4-(ethoxycarbonyl)-5- methylimidazol-1-yl, 5-(bromo)imidazol-1-yl, 5-methyl-1 ,3,4-triazol-2-yl, 3-methyl- 1 ,2,4-oxadiazol-5-yl, 3-ethoxycarbonyl-1 ,2,4-oxadiazol-5-yl, 4-(carboxy)furan-2- yl, 2,4-dimethylthiazol-5-yl, 3-(tert-butyl)isoxazol-5-yl, thiophen-2-yl, 3- me
  • R na and R nb are both hydrogen.
  • n is 1 or 2.
  • R 3 is hydrogen.
  • R 2 is aryl
  • examples include phenyl.
  • R 2 is substituted aryl
  • suitable substituents include cyano, perhaloC ⁇ alkyl, amido, halo, C ⁇ alkyl, d-ealkoxycarbonyl, mono- and di-(d. 6 alkyl)aminocarbonyl, d ⁇ alkoxy, nitro, d-ealkylsulphonyl, hydroxy, d-ealkoxyd- 6 alkyl, C ⁇ alkylthio, mono- and-di-(d-6alkyl)amino, and Ci-ealkylcarbonylamino.
  • R 2 is heteroaryl
  • examples include thiophenyl.
  • R 2 is substituted heteroaryl
  • suitable substituents include cyano, perhalod-ealkyl, amido, halo, mono- and di-(d. 6 alkyl)aminocarbonyl, 6 alkyl, d_5alkylthio, mono- and-di-(C 1 ⁇ alkyl)amino, and C ⁇ alkylcarbonylamino.
  • R 2 is unsubstituted or substituted phenyl or unsubstituted or substituted thiophenyl.
  • R 2 is substituted phenyl suitable substituents include halo.
  • R 2 is substituted thiophenyl
  • suitable substituents include halo. More suitably, R 2 is phenyl substituted with chloro or fluoro, or thiophenyl substituted with chloro.
  • R 2 is 3-fluorophenyl, 3-(trifluoromethyl)phenyl, 2- chlorothiophen-4-yl, 3-chlorophenyl, 3,4-difluorophenyl or 3,4-dichlorophenyl.
  • R 1 represents substituted or unsubstituted heteroaryl
  • Y represents -(CR na Rnb)n-;
  • R na and R réelle b are each independently hydrogen or d ⁇ alkyl; n is an integer from 1 to 5;
  • R 2 represents unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl
  • R 3 represents hydrogen or d ⁇ alkyl; and salts and solvates thereof; with the provisos that;
  • R 1 is not oxazolyl; R 1 is not substituted by phenyl, and; the following compounds are excluded;
  • R 1' is unsubstituted or substituted heteroaryl, and; R 2' is phenyl substituted with halo.
  • R 1' is pyrazolyl substituted with thiophenyl, thiazolyl, formyl, d- 6 alkoxycarbonyl, C ⁇ alkyl, or perhaloC ⁇ alkyl; unsubstituted tetrazolyl or tetrazolyl substituted with piperidinyl or d ⁇ alkyl; or isoxazolyl substituted with d- 5 6 alkyl.
  • R 1' is 3-(thiazol-2-yl)pyrazol-1-yl, 5-(1-piperidinyl)tetrazol-2-yl, 5-(/so-propyl)tetrazol-2-yl, 2-methyltetrazol-5-yl, 4-methyl-3-(thiophen-2- yl)pyrazol-1-yl, 5-(/ ' so-propyl)tetrazol-1-yl, 5-methyl-3-(trifluoromethyl)pyrazol-1-yl, 5-(piperidin-1-yl)tetrazol-1-yl, 1-methyltetrazol-5-yl, tetrazol-5-yl, 3- 10 (methyl)isoxazol-5-yl, 3-(formyl)pyrazol-1-yl, 3-(methyl)pyrazol-1-yl, 3,5- dimethylpyrazol-1-yl, 4-(ethoxycarbonyl)pyrazol-1-yl, or 5-methylisoxazol-3
  • R 2 is phenyl substituted with chloro or fluoro.
  • R 2' is 3,4-dichlorophenyl or 3,4-difluorophenyl.
  • the stereochemistry at the position marked ' * ' is (S). 15 Accordingly, there is provided a compound of formula (I') or a salt or solvate thereof.
  • Suitable compounds of the invention are Examples 1 , 2, 3, 8, 12, 14, 16, 18, 19, 20, 21 , 23, 25, 27, 28, 30, 31 , 32, 34, 36, 40, 42, 45, 46, 48, 49, 50, 52, 53, 54, 55, 56, 58, 60, 63, 64, 65, 67, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 80, 20 81 , 82, 83, 87, 88, 89, 90, 91 , 93, 95, 97, 99, 100, 102, 104, 106, 108, 109, 110, and 111.
  • Preferred compounds of the invention are Examples 1 , 2, 3, 19, 23, 27, 32, 34, 36, 42, 45, 48, 50, 52, 54, 58, 63, 64, 65, 67, 71 , 75, 76, 78, 80, 89, 91 , 93, 97, 102, 104, and 106.
  • 25 More preferred compounds of the invention are Examples 1 , 23, 32, 34,
  • Suitable salts of the compounds of formula (I) include physiologically acceptable salts and salts which may not be physiologically acceptable but may be useful in the preparation of compounds of formula (I) and physiologically 30 acceptable salts thereof.
  • acid addition salts may be derived from inorganic or organic acids, for example hydrochlorides, hydrobromides, sulphates, phosphates, acetates, benzoates, citrates, succinates, lactates, tartrates, fumarates, maleates, 1-hydroxy-2-naphthoates, palmoates, methanesulphonates, formates or trifluoroacetates. 35 Examples of solvates include hydrates.
  • Certain of the compounds of formula (I) may contain chiral atoms and/or multiple bonds, and hence may exist in one or more stereoisomeric forms.
  • the present invention encompasses all of the stereoisomers of the compounds of formula (I), including geometric isomers and optical isomers, whether as 40 individual stereoisomers or as mixtures thereof including racemic modifications.
  • a compound of formula (I) is in the form of a single enantiomer or diastereoisomer.
  • Certain of the compounds of formula (I) may exist in one of several tautomeric forms. It will be understood that the present invention encompasses all of the tautomers of the compounds of formula (I) whether as individual tautomers or as mixtures thereof.
  • references to 'aryl' refer to monocyclic and bicyclic carbocyclic aromatic rings, for example naphthyl and phenyl, especially phenyl.
  • Suitable substituents for any aryl group include 1 to 5, suitably 1 to 3, substituents selected from the list consisting of cyano, perhaloalkyl, amido, halo, alkyl, alkoxycarbonyl, mono- and di-(alkyl)aminocarbonyl, alkoxy, nitro, alkylsulphonyl, hydroxy, alkoxyalkyl, alkylthio, mono- and-di-(alkyl)amino, and alkylcarbonylamino.
  • references to 'heteroaryl' refer to monocyclic heterocyclic aromatic rings containing 1-4 heteroatoms selected from nitrogen, oxygen and sulphur.
  • heterocyclic aromatic rings examples include imidazolyl, triazolyl, oxadiazolyl, isoxadiazolyl, isoxathiazolyl, pyridinyl, thiophenyl, furanyl, thiazolyl, pyrazinyl, tetrazolyl, triazolyl, oxadiazolyl, oxazolyl, isoxazolyl, and pyrazolyl especially imidazolyl, triazolyl, oxadiazolyl, thiophenyl, isoxadiazolyl, isoxathiazolyl, pyridinyl pyrazolyl, tetrazolyl, thiazolyl, and isoxazolyl.
  • Suitable substituents for any heteroaryl group include 1 to 5, suitably 1 to 3, substituents selected from the list consisting of alkoxycarbonylamino; amino; carboxy; hydrazinocarbonyl; alkoxycarbonylhydrazinocarbonyl; alkylsulphonylamino; alkylcarbonyl; aminocarbonyl; unsubstituted heterocyclyl; heterocyclyl substituted with alkyl, halo, alkoxy, or hydroxy; unsubstituted heteroaryl; heteroaryl substituted with alkyl, halo, alkoxy, or hydroxy; perhaloalkyl; alkyl; alkoxycarbonyl; mono- and di-(alkyl)aminocarbonyl; halo; alkoxy; nitro; alkylsulphonyl; hydroxy; alkoxyalkyl; alkylthio; mono- and-di- (alkyl)amino; cycloalkylaminocarbonyl
  • references to 'cycloalkyl' refer to saturated alicyclic rings suitably containing 3-8 carbon atoms. Suitable substituents for any cycloalkyl group include alkyl, halo, and hydroxy.
  • references to 'heterocyclyl' refer to monocyclic heterocyclic aliphatic rings containing 2 to 6, suitably 3 to 5, carbon atoms, and 1 to 3, heteroatoms selected from nitrogen, oxygen, and sulphur.
  • heterocyclic rings include piperidinyl.
  • Suitable substituents for any heterocyclyl group include alkyl, halo, alkoxy, or hydroxy.
  • references to 'halogen' or 'halo' refer to iodo, bromo, chloro or fluoro, especially fluoro and chloro.
  • the compounds of formula (I) and salts and solvates thereof may be prepared by the methodology described hereinafter, constituting a further aspect of this invention.
  • R 1 , Y, R 3 , and R 2 are as hereinbefore defined for formula (I) in the presence of an activating agent and a peptide coupling agent, and thereafter, if required, carrying out one or more of the following optional steps: (i) converting a compound of formula (I) to a further compound of formula (I); (ii) removing any necessary protecting group; (iii) preparing a salt or solvate of the compound so formed.
  • the activating agent is 1-hydroxybenzotriazole (HOBT).
  • peptide coupling agents are 1 ,3-dicyclohexylcarbodiimide (DCC); 2-ethoxy-1-ethoxycarbonyl-1 ,2-dihydroquinoline (EEDQ) and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide, or a salt thereof.
  • the peptide coupling agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • a suitable solvent such as a polar organic solvent, e.g. N,N- dimethylformamide are treated with a peptide coupling agent at ambient temperature, such as about 18 - 25 ° C.
  • the reaction mixture is stirred at ambient temperature for an appropriate time period, such as about 12 - 20 hours.
  • a compound of formula (III) wherein R 3 is hydrogen may be prepared either by Reaction (a) or Reaction (c).
  • the S-enantiomer of a compound of formula (III) may be prepared by Reaction (b).
  • Reaction (a) Reaction of the compound of formula (IV) with a compound of formula (V)
  • R 2 is as hereinbefore defined for formula (I) and A is a protected amino group, suitably phthalimido, followed by deprotection of the amino group to give a compound of formula (III) wherein R 3 is hydrogen i.e. a compound of formula (IIIR)
  • R 2 is as hereinbefore defined, and optionally resolution of the resulting enantiomers of a compound of formula (IIIR); or;
  • T is trifluoroacetyl
  • R 3 and R 2 are as hereinbefore defined for formula (I), and optionally resolution of the resulting enantiomers of a compound of formula (III).
  • the cyclisation of the intermediate diols (IIIBR) and (IIIBE) in the reaction between the compound of formula (IV) and a compound of formula (V) or (VA) is typically carried out under the Mitsunobu conditions as follows: Typically, a mixture of the compound of formula (IV) and the compound of formula (V) or formula (VA) in a suitable solvent, such as tetrahydrofuran, is stirred, suitably for 20-24 hours at a suitable temperature, suitably the reflux temperature of the solvent, under an inert atmosphere, suitably an atmosphere of nitrogen. Further solvent is then added and the mixture cooled, suitably to 0- 5°C.
  • a suitable solvent such as tetrahydrofuran
  • a suitable phosphine suitably triphenyl phosphine
  • a suitable azo compound suitably diisopropylazodicarboxylate
  • the mixture is allowed to stand for a period of time, suitably 2-3 hours, then allowed to warm, suitably to 20-25°C.
  • further phosphine and azo compound are added.
  • the reaction mixture is concentrated to near dryness.
  • a suitable alcohol suitably propan-2-ol
  • the concentration step repeated; the alcohol addition and concentration step is then repeated.
  • Further alcohol is then added and the mixture heated to a temperature suitably between 65-75°C.
  • a suitable period suitably 20-45 minutes
  • the resultant slurry is cooled, suitably to 20-25°C, and then allowed to stand, suitably for 1.5 - 3 hours, after which time the product is isolated by filtration.
  • the filter bed is washed with more alcohol and then dried in vacuo at 35-45°C to yield the protected form of the of formula (IIIR) or formula (HIE) respectively.
  • the mixture was then heated at elevated temperature, suitably the reflux temperature of the solvent, for a suitable period of time, suitably 20-24 hours, after which the reaction mixture was cooled to 20-25°C and then treated with a suitable apolar solvent, suitably dichloromethane.
  • a base suitably 0.880 ammonia solution, is then added dropwise, maintaining the temperature between 20-25°C.
  • A is as hereinbefore defined for formulae (V) and (VA) and R 2 is as hereinbefore defined for formula (I); is isolated.
  • a mixture of the compound of formula (IV) and a compound of formula (V) or formula (VA) in a suitable solvent, such as tetrahydrofuran is stirred, suitably for 20-24 hours at a suitable temperature, suitably the reflux temperature of the solvent, under an inert atmosphere, suitably an atmosphere of nitrogen.
  • a suitable temperature suitably the reflux temperature of the solvent, under an inert atmosphere, suitably an atmosphere of nitrogen, for a suitable period of time, suitably 3-6 hours.
  • reaction mixture is then cooled, suitably to 20- 25°C, and the compound precipitated by means of addition of a suitable co- solvent, suitably diisopropyl ether.
  • a suitable co- solvent suitably diisopropyl ether.
  • the compound of formula (IIIBR) or formula (IIIBE) respectively is isolated by filtration, washed with further co-solvent and dried in vacuo.
  • a protected form of the compound of formula (IIIR) or formula (HIE) may then be prepared from a compound of formula (IIIBR) or formula (IIIBE) under similar conditions to that of the reaction between a compound of formula (IV) and formulae (V) or (VA) as hereinbefore described, but omitting the reflux period prior to the addition of the phosphine and azo compounds.
  • Reaction (c) is typically carried out by stirring a solution of the compound of formula (VI) in a suitable solvent, for example a mixture of methanol and water, and adding a suitable base, for example potassium carbonate.
  • the mixture is stirred at a suitable temperature, for example those in the range 20- 25°C for a suitable time, for example 16-20 hours followed by removal of the organic solvent in vacuo.
  • a suitable temperature for example those in the range 20- 25°C for a suitable time, for example 16-20 hours followed by removal of the organic solvent in vacuo.
  • Water is then added and the mixture extracted with a suitable organic solvent, for example ethyl acetate.
  • the combined organic phases are washed with water and saturated aqueous sodium chloride solution before drying over a suitable drying agent, for example sodium sulphate, filtering and evaporation of the solvent in vacuo.
  • the crude product is then purified by flash chromatography.
  • the resolution of the compound of formula (HIE) from the racemic product i.e. the compound of formula (IIIR) may be undertaken using techniques well known to those skilled in the art, for example preparative chiral high performance liquid chromatography (chiral HPLC) or by fractional crystallisation of diastereoisomeric salts.
  • a compound of formula (VI) may be prepared by reaction of a compound of formula (VII) with a compound of formula (VIII)
  • T, R 3 and R 2 are as hereinbefore defined and L 2 is a leaving group.
  • a suitable leaving group, L 2 is a halo group such as chloro.
  • the reaction between a compound of formula (VII) and a compound of formula (VIII) is typically carried out by stirring a solution of the compound of formula (VII) in a suitable solvent, for example N,N-dimethylformamide, under an inert atmosphere, for example an atmosphere of nitrogen, with the addition of a suitable base, for example potassium carbonate, and a suitable activating agent such as sodium iodide.
  • a solution of a compound of formula (VIII) in a suitable solvent, such as N,N-dimethylformamide is added dropwise to the mixture.
  • the mixture is then stirred at a suitable temperature, for example a temperature in the range of 20-25°C, for a suitable period of time, for example 16-20 hours before removing the volatile components in vacuo.
  • a suitable temperature for example a temperature in the range of 20-25°C
  • a suitable period of time for example 16-20 hours before removing the volatile components in vacuo.
  • the residue is partitioned between a suitable organic solvent, for example dichloromethane, and a saturated aqueous base, for example saturated aqueous sodium carbonate solution.
  • the organic phase is then washed with additional saturated aqueous base and water before drying over a suitable drying agent, for example magnesium sulphate, filtering and evaporation of the solvent in vacuo to yield the crude product.
  • the crude product is purified by flash chromatography.
  • a compound of formula (VII) may be prepared by reaction of a compound of formula (IX) with a compound of formula (X);
  • R 3 and T are as hereinbefore defined and R x is an alkyl group, suitably ethyl.
  • the reaction between a compound of formula (IX) and a compound of formula (X) is typically carried out by stirring a solution of a compound of formula (IX) in a suitable organic solvent, for example methanol, under an inert atmosphere, for example an atmosphere nitrogen, and then adding a solution of a compound of formula (X) in a suitable organic solvent, for example ether.
  • a suitable organic solvent for example methanol
  • the mixture is then stirred for a suitable period of time, for example 20-40 minutes at a suitable temperature, for example a temperature in the range of 20-25°C and the volatile components removed in vacuo.
  • the residue is then dissolved in a suitable organic solvent, for example methanol, and the volatile components removed in vacuo.
  • (XII) is an unsubstituted or substituted heteroaryl group
  • L 2 is a leaving group
  • R 3 and R 2 are as hereinbefore defined for formula (I), and thereafter, if required, carrying out one or more of the following optional steps:
  • Suitable leaving groups are halo groups, preferably bromo.
  • the reaction between a compound of formula (XII) and a compound of formula (XIII) will be conducted in a suitable organic solvent, such as for example dichloromethane, N,N-dimethylformamide of a mixture thereof, suitably at ambient temperature, e.g. 18 - 25 ' C for an appropriate time period, e.g. 4 - 10h.
  • a suitable base such as an alkali or alkaline earth metal carbonate, e.g. potassium carbonate, is then added.
  • a compound of formula (XIII) may be prepared by reaction of a compound of formula (III) with a compound of formula (XIV)
  • L 2 is as hereinbefore defined for formula (XIII), in the presence of a peptide coupling reagent.
  • peptide coupling agents are 1 ,3- dicyclohexylcarbodiimide (DCC); 2-ethoxy-1-ethoxycarbonyl-1 ,2-dihydroquinoline (EEDQ) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, or a salt thereof.
  • the peptide coupling agent is 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride.
  • reaction between a compound of formula (III) and a compound of formula (XIV) is conducted at low temperature, e.g. 0 - 5°C, in a suitable organic solvent such as a haloalkane e.g.dichloromethane, for a suitable time period e.g. 20 - 60 mins.
  • a suitable organic solvent such as a haloalkane e.g.dichloromethane
  • the above mentioned conversion of a compound of formula (I) into another compound of formula (I) includes any conversion which may be effected using conventional procedures, but in particular the said conversions include converting one group R 1 into another group R 1 .
  • Suitable protecting groups in any of the above mentioned reactions are those used conventionally in the art.
  • the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected, for example those methods discussed in standard reference texts of synthetic methodology such as P J Kocienski, Protecting Groups, (1994), Thieme.
  • the absolute stereochemistry of compounds may be determined using conventional methods, such as X-ray crystallography.
  • the salts and solvates of the compounds of formula (I) may be prepared and isolated according to conventional procedures.
  • Compounds of the invention may be tested for in vitro biological activity in accordance with the following assays: (a) CCR-3 Binding Assay
  • a CCR-3 competition binding SPA was used to assess the affinity of novel compounds for CCR-3.
  • Membranes prepared from K562 cells stably expressing CCR-3 (2.5 ⁇ g/well) were mixed with 0.25mg/well wheat-germ agglutinin SPA beads (Amersham) and incubated in binding buffer (HEPES 50 mM, CaCI 2 1 mM, MgCI 2 5 mM, 0.5% BSA) at 4°C for 1.5 hr.
  • the compounds of the Examples were tested in the CCR-3 binding assay.
  • the compounds of the Examples tested in the CCR-3 binding assay possessed plC 50 values in the range 5.5 - 8.6.
  • Eosinophils were purified from human peripheral blood by standard CD16 cell depletion using a Miltenyi cell separation column and a magnetic Super Macs magnet as previously described (Motegi & Kita, 1998;
  • the agonist eotaxin (an EC 8 o concentration) was added to the lower chamber of a 96 well chemotaxis plate (5 ⁇ m filter: Receptor Technologies). Eosinophils (50 ⁇ l of 2 million/ml cells) were added to the top chamber of the filter plate and incubated at 37°C for 45 mins. Cells remaining on top of the chemotaxis filter were removed and the number of eosinophils which had migrated were quantified by reading the plate on a fluorescent plate reader. Inhibition curves for the effect of compounds on eosinophil chemotaxis were analysed by fitting the data with a four parameter logistic equation. Functional pKj values (fpKj) were generated using the equation below (Lazareno & Birdsall, 1995. Br.J. Pharmacol 109: 1110- 9).
  • the compounds of the Examples were tested in the CCR-3 binding and/or eosinophil chemotaxis assays (assays (a) and (b)).
  • the compounds of the Examples tested in the CCR-3 binding assay possessed plC50 values in the range 6.6 - 9.1.
  • the compounds of the Examples tested in the CCR-3 eosinophil chemotaxis assay possessed fpKi values such as those given in the table below:
  • diseases of the respiratory tract such as bronchitis (including chronic bronchitis), bronchiectasis, asthma (including allergen-induced asthmatic reactions), chronic obstructive pulmonary disease (COPD), cystic fibrosis, sinusitis and rhinitis.
  • diseases of the gastrointestinal tract such as intestinal inflammatory diseases including inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis) and intestinal inflammatory diseases secondary to radiation exposure or allergen exposure.
  • compounds of the invention may be used to treat nephritis; skin diseases such as psoriasis, eczema, allergic dermatitis and hypersensitivity reactions; and diseases of the central nervous system which have an inflammatory component (eg. Alzheimer's disease, meningitis, multiple sclerosis), HIV and AIDS dementia.
  • skin diseases such as psoriasis, eczema, allergic dermatitis and hypersensitivity reactions
  • diseases of the central nervous system which have an inflammatory component (eg. Alzheimer's disease, meningitis, multiple sclerosis), HIV and AIDS dementia.
  • Compounds of the present invention may also be of use in the treatment of nasal polyposis, conjunctivitis or pruritis.
  • cardiovascular conditions such as atherosclerosis, peripheral vascular disease and idiopathic hypereosinophilic syndrome.
  • Compounds of the invention may be useful as immunosuppressive agents and so have use in the treatment of auto-immune diseases such as allograft tissue rejection after transplantation, rheumatoid arthritis and diabetes.
  • Compounds of the invention may also be useful in inhibiting metastasis.
  • Diseases of principal interest include asthma, COPD and inflammatory diseases of the upper respiratory tract involving seasonal and perennial rhinitis.
  • a compound of formula (I) or a physiologically acceptable salt or solvate thereof for use as an active therapeutic agent.
  • a compound of formula (I), or a physiologically acceptable salt or solvate thereof for use in the treatment of inflammatory conditions, e.g. asthma or rhinitis.
  • a compound of formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of inflammatory conditions, eg. asthma or rhinitis.
  • a method for the treatment of a human or animal subject suffering from or susceptible to an inflammatory condition e.g. asthma or rhinitis comprises administering an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof.
  • the compounds according to the invention may be formulated for administration in any convenient way.
  • composition comprising a compound of formula (I), or a physiologically acceptable salt or solvate thereof, and optionally one or more physiologically acceptable diluents or carriers.
  • the compounds according to the invention may, for example, be formulated for oral, inhaled, intranasal, buccal, parenteral or rectal administration, preferably for oral administration.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, cellulose or polyvinyl pyrrolidone; fillers, for example, lactose, microcrystalline cellulose, sugar, maize- starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in the art.
  • 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, hydroxymethyl cellulose, 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; or preservatives, for example, methyl or propyl p_- hydroxybenzoates or sorbic acid.
  • the preparations may also contain buffer salts, flavouring, colouring and/or sweeten
  • the compounds may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds according to the invention may also be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form, for instance as ampoules, vials, small volume infusions or pre-filled syringes, or in multidose containers with an added preservative.
  • the compositions may take such forms as solutions, suspensions, or emulsions in aqueous or non-aqueous vehicles, and may contain formulatory agents such as anti-oxidants, buffers, antimicrobial agents and/or tonicity adjusting agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • the dry solid presentation may be prepared by filling a sterile powder aseptically into individual sterile containers or by filling a sterile solution aseptically into each container and freeze-drying.
  • compositions according to the invention may also be used in combination with other therapeutic agents, for example anti-inflammatory agents such as corticosteroids, e.g. fluticasone propionate, beclomethasone dipropionate, mometasone furoate, triamcinolone acetonide or budesonide; or non-steroidal anti-inflammatory drugs (NSAIDs) eg.
  • corticosteroids e.g. fluticasone propionate, beclomethasone dipropionate, mometasone furoate, triamcinolone acetonide or budesonide
  • NSAIDs non-steroidal anti-inflammatory drugs
  • beta adrenergic agents such as salmeterol, salbutamol, formoterol, fenoterol or terbutaline and salts thereof; or antiinfective agents e.g. antibiotic agents and antiviral agents.
  • Compounds of the invention may conveniently be administered in amounts of, for example, 0.001 to 500mg/kg body weight, preferably 0.01 to 500mg/kg body weight, more preferably 0.01 to 100mg/kg body weight, and at any appropriate frequency e.g. 1 to 4 times daily.
  • the precise dosing regimen will of course depend on factors such as the therapeutic indication, the age and condition of the patient, and the particular route of administration chosen.
  • the word 'comprise', and variations such as 'comprises' and 'comprising' will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps.
  • Mass Directed Automated Preparative HPLC column, conditions and eluent Mass directed automated preparative high performance liquid chromatography was carried out using an LCABZ+ 5 ⁇ m (5cm x 10mm internal diameter) column, employing gradient elution using two solvent systems, (A) 0.1% formic acid in water, and (B) 95% acetonitrile and 0.5% formic acid in water, at a flow rate of
  • Mass spectrometry was carried out using a VG Platform Mass Spectrometer, with an HP1100 Diode Array Detector and Accurate Flow Splitter.
  • This system used an 3 ⁇ m ABZ+PLUS (3.3cm x 4.6mm internal diameter) column, eluting with solvents:A - 0.1%v/v formic acid + 0.077% w/v ammonium acetate in water; and B - 95:5 acetonitrile:water + 0.05%v/v formic acid, at a flow rate of 3 ml per minute.
  • the following gradient protocol was used: 100% A for OJmins; A+B mixtures, gradient profile 0 - 100% B over 3.5mins; hold at 100%B for 1.1 mins; return to 100% A over 0.2mins. 5
  • the LC/MS system used a micromass spectrometer, with electrospray ionisation mode, positive and negative ion switching, mass range 80-1000 a.m.u. Thermospray Mass Spectra
  • Thermospray Mass Spectra were determined on a HP 5989A engine mass spectrometer, +ve thermospray, source temperature 250°C, probe temperatures
  • Solid phase extraction (ion exchange) 'SCX' refers to Isolute Flash SCX-2 sulphonic acid solid phase extraction
  • 'Hydrophobic frit' refers to a Whatman polypropylene filter tube fitted with a PTFE frit, pore size 5.0 ⁇ m.
  • Description 17 was prepared in an analogous manner to that of Description 3.
  • tert-Butyl(diethylphosphono)acetate (1.65g) in THF (5ml) was added dropwise to a suspension of 60% sodium hydride (0.262g) in THF (5ml) stirred at 0°C under nitrogen. The mixture was stirred at room temperature for 45mins then re-cooled using an ice bath. A solution of ethyl 5-formylfuran 3-carboxylate (1.0g) in THF (10ml) was added dropwise to the mixture. The stirred mixture was heated to 60°C for 2hr then left at room temperature overnight. The mixture was poured into 1 :1 ethyl acetate/5% aqueous sodium bicarbonate solution (100ml), was shaken, and the layers separated.
  • the solution was then diluted with dichloromethane (30ml) and washed successively with saturated aqueous sodium hydrogen carbonate (30ml) and dilute aqueous sodium chloride (2 x 30ml).
  • the organic phase was separated using three hydrophobic frits (12ml) and drained directly onto an SCX (10g) ion exchange cartridge, which had been pre-treated with methanol and which was then eluted with methanol and 10% 0.880 ammonia/methanol.
  • Example 33 N-r4-(3.4-Dichlorobenzyl)morpholin-2-ylmethyl12-pyridin-3-yl- acetamide; compound with formic acid
  • Example 84 N-f(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-ylmethyl1-3-r2-(5- methyl-isoxazol-3-yl)thiazol-4-v ⁇ propionamide; compound with formic acid
  • the organic phase was separated using a hydrophobic frit and applied directly onto a sulphonic acid ion exchange cartridge (2g, Isolute SCX, pretreated with methanol). Four column volumes of methanol were eluted and discarded. Two column volumes of 10% 0.880 ammonia/methanol was eluted, collected and evaporated to dryness under a stream of nitrogen to give a brown gum. The gum was further purified by mass-directed preparative HPLC to give, after evaporation of the solvents under a stream of nitrogen, the title compound (O.OO ⁇ g) as a colourless film.
  • 3,5-Dimethyl-4-formyl phenoxyethoxymethyl polystyrene aldehyde resin (1.Og @ 0.9mmol/g loading) was swollen with the minimum quantity of a solution of 1% acetic acid in N,N-dimethylformamide to form a slurry.
  • a solution of Description 3 (0.969g) in N,N-dimethylformamide (2ml) was added and the mixture shaken at room temperature for 100 min.
  • a solution of 1% acetic acid in N,N- dimethylformamide (10ml) was added, followed by sodium triacetoxyborohydride (0.333g).
  • reaction was shaken for 20 min before a further portion of sodium triacetoxyborohydride (0.30g) was added and the reaction shaken at room temperature for a further 18 hrs.
  • the reaction solution was removed by filtration and the resin washed with N,N-dimethylformamide (5 x 10ml), methanol (5 x 10ml), dichloromethane (5 x 10ml) and diethyl ether (3 x 10ml) before being dried in vacuo. A portion of the resin (0.1 Og) was swollen with dichloromethane and then drained.
  • a solution of potassium- terf-butoxide (50mg) and 4-bromo-1 H-imidazole (0.132g) in N,N- dimethylformamide (1ml) was prepared and stirred for 5 min before this was added to the resin.
  • the reaction mixture was heated to 60°C and shaken for 18 hrs.
  • the reaction solution was removed by filtration and the resin washed with N,N-dimethylformamide (5 x 1ml), methanol (5 x 1ml) and dichloromethane (5 x 1 ml).
  • a 1 :1 solution of trifluoroacetic acid/dichloromethane (1 ml) was added to the resin. The mixture was shaken for 90 min, before the reaction solution was collected by filtration.
  • the gum was purified on a 20g SPE cartridge, eluting initially with ethyl acetate and then with a (100:1 ) mixture of ethyl acetate/methanol. The product containg fractions were evaporated in vacuo to give the title compound (0.032g) as a pale brown gum.
  • Example 10 A stirred solution of Example 10 (0.038g) in dichloromethane (1.5ml) and methanol (0.5ml) was treated dropwise at room temperature with (trimethylsilyl)diazomethane (0.22ml of 10% solution in hexane). After 2 hours stirring at room temperature, acetic acid (0.1ml) was added and the solvent evaporated under a stream of nitrogen to dryness. The residue was loaded onto an SCX (2g) ion exchange cartridge, which had been pre-treated with methanol and which was then eluted with methanol and 10% 0.880 ammonia/methanol.
  • SCX (2g) ion exchange cartridge which had been pre-treated with methanol and which was then eluted with methanol and 10% 0.880 ammonia/methanol.
  • Example 59 (0.036g) in N,N-dimethylformamide (1ml) was added N,N- diisopropylethylamine (0.035ml) and propanoyl chloride (0.0086ml), and the mixture was stirred at 20°C for 5h.
  • the mixture was applied directly to a sulphonic acid ion exchange cartridge (1g, Isolute SCX), and eluted with methanol followed by 10% 880 ammonia in methanol. The methanol/ammonia fraction was evaporated to give the crude product. Purification by mass-directed preparative HPLC gave the title compound (0.0061g).
  • Example 100 2-(3-Acetylamino-isoxazol-5-yl)-N-r(2S)-4-(3.4- dichlorobenzyl)morpholin-2-ylmethyllacetamide; compound with formic acid
  • Example 98 To a solution of Example 98 (0.050g) in anhydrous dichloromethane (3.5ml) was added N,N-diisopropylethylamine (0.033ml) and acetyl chloride (0.0135ml). After stirring for 3hrs at 20°C, further N,N-diisopropylethylamine (0.022ml) and acetyl chloride (0.009ml) were added. The mixture was stirred at 20°C overnight before the solvent was removed under a stream of nitrogen. The residue was diluted with ethanol (4ml) and had 0.880 ammonia (0.1 ml) added to it before stirring at 20°C for 20mins.
  • Example 77 5-((f(2S)-4-(3.4-Dichlorobenzvnmorpholin-2- ylmethyllcarbamoyl)methyl)furan-2-carboxylic acid; compound with triethyl-amine
  • Example 75 To a solution of Example 75 (0.222g) in methanol (3ml) was added 2M aqueous sodium hydroxide solution (0.488ml) and water (3ml). The mixture was stirred at 20°C for 0.5h before being left to stand overnight. The mixture was concentrated in vacuo to give a gum, which was re-dissolved in water and the pH of the solution was adjusted to pH7 by the addition of 2M aqueous hydrochloric acid. The mixture was applied onto a sulphonic acid ion exchange cartridge (10g, Isolute SCX, pretreated with methanol) and the cartridge was eluted with water (x3) followed by 5% triethylamine in methanol (x2). The solvent was removed from the first basic fraction in vacuo. The residue was dissolved in acetonitrile and the solvent removed under a stream of nitrogen to give the title compound as a light brown gum (0.223g).
  • Example 75 To a solution of Example 75 (0.0642g) in ethanol (2ml) was added acetamidoxime (0.052g) (prepared according to Journal of Medicinal Chemistry (1986), 29(11 ), 2174-83) in ethanol (2ml). The suspension was treated with activated 4A powdered molecular sieves (0.240g) and stirred for 5mins. To the suspension was added 21% sodium ethoxide in ethanol (0.104ml) and the mixture heated at reflux for 4J5hrs. The mixture was cooled and allowed to stand overnight at room temperature.
  • Example 77 To a solution of Example 77 (0.084g) in N,N-dimethylformamide (3ml) was added 1-hydroxybenzotriazole (0.030g), and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (0.0525g). The mixture was stirred at 20°C for 10mins before tert-butylcarbazide (0.0226g) and N,N-diisopropylethylamine (0.0596ml) were added and the mixture stirred for a further 30mins at 20°C before being left to stand overnight.
  • Example 30 To a solution of Example 30 (0.0655g) in methanol (4ml) was added 4.0M HCl in 1 ,4-dioxane (1ml) and the mixture was stirred at 20°C for 3hrs. The volatiles were removed in vacuo and the residue re-dissolved in methanol and applied directly onto a sulphonic acid ion exchange cartridge (5g, Isolute SCX, pretreated with methanol). The cartridge was eluted with methanol (x3) followed by 10% 0.880 ammonia in methanol (x2). The solvent was removed from the first basic fraction in vacuo to give the title compound as a colourless glass (0.0532g).
  • Example 48 N-r(2S)-4-(3.4-Dichlorobenzyl)morpholin-2-ylmethyll-2-f5-(5- methyl-f1.3,4loxadiazol-2-yl)furan-2-yllacetamide
  • Example 46 A solution of Example 46 (0.0312g) in triethylorthoacetate (0.22ml) was heated in a 'Reacti-vial' at 160°C for 21 hrs. The mixture was diluted with methanol and directly applied onto a sulphonic acid ion exhange cartridge (5g Isolute SCX, pre- washed with methanol). The cartridge was eluted with methanol followed by 10% 0.880 ammonia in methanol and the first basic fraction concentrated in vacuo. The residue was further purified by mass-directed preparative HPLC to give, after removal of the solvent in vacuo, the title compound as a colourless gum (0.0117g).
  • a solution of sodium hydroxide (0.102g) in anhydrous methanol (3ml) was prepared and a portion of the solution (0.142ml) added to ethyl acetimidate hydrochloride (0.015g). After stirring the mixture for 2min and leaving to stand for a further 5min, the supernatant of the mixture was transferred by syringe to a 'Reacti-vial' charged with Example 46 (0.0532g). The mixture was heated to 90°C for 3hrs before cooling to room temperature and concentrating under a stream of nitrogen. The concentrated mixture was purified by mass-directed preparative HPLC and the solvent removed in vacuo to give a colouriless gum.
  • the gum was further purified by dissolving in dichloromethane and applying the solution to a silica solid phase extraction cartridge (0.5g, Varian Bondelut, pre- washed with dichloromethane) eluting sequentially with dichloromethane, chloroform, ether, ethyl acetate, acetonitrile, acetone and methanol.
  • the solvent was evaporated from the acetone fractions in vacuo and the residue further purified by BiotageTM flash chromatography on silica gel (8g cartridge), eluting with 100:8:1 dichloromethane/ethanol/0.880 ammonia solution.
  • the solvents were evaporated from the required combined fractions to give the title compound as a colourless gum (0.0051 g).
  • Example 27 5-(2-(r(2S)-4-(3.4-Difluorobenzvnmorpholin-2- ylmethyl1carbamoyl)ethyl)-H ,2,41oxadiazole-3-carboxylic acid ethylamide; compound with formic acid
  • Description 8 (0.016g) in anhydrous N,N-dimethylformamide (2ml) was added Description 56 (0.0275g).
  • Description 56 (0.0275g)
  • 1- hydroxybenzotriazole (0.0107g)
  • N,N-diisopropylethylamine (0.024ml)
  • 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.015g).
  • the mixture was stirred at 20°C for 17h.
  • the mixture was applied onto a sulphonic acid ion exchange cartridge (2g, Isolute SCX, pretreated with methanol) and the cartridge eluted with methanol followed by 10% 0.880 ammonia in methanol.
  • Example 90 N-r(2S)-4-(3.4-Difluorobenzyl)morpho1in-2-ylmethyll-2-r4-methyl-2- (5-methyl-isoxazol-3-yl)thiazol-5-v ⁇ acetamide; compound with formic acid
  • Synthetic Method D was used for the preparation of Examples 61 , 65, and 63.
  • Synthetic Method E was used for the preparation of Examples 102, 104, 106,
  • Synthetic Method F was used for the preparation of Examples 22 and 77.
  • Synthetic Method H was used for the preparation of Example 67, 71 , and 69.
  • Synthetic Method J was used for the preparation of Examples 59 and 46.
  • Synthetic Method K was used for the preparation of Example 48.
  • Synthetic Method L was used for the preparation of Example 78.

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Abstract

L'invention concerne certains composés de formule (I), dans laquelle: R1 représente un hétéroaryle substitué ou non substitué; Y représente -(CRnaRnb)n-; Rna et Rnb représentent chacun indépendamment hydrogène ou C1-6alkyle; n représente un entier compris entre 1 et 5; R2 représente un aryle substitué ou non substitué ou un hétéroaryle substitué ou non substitué; R3 représente hydrogène ou C1-6alkyle. Ces composés et leurs sels et solvates sont CCR-3 antagonistes et sont donc indiqués pour être utilisés en thérapie.
PCT/EP2003/003347 2002-03-28 2003-03-27 Derives de morpholine-acetamide anti-inflammatoires Ceased WO2003082862A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU2003216907A AU2003216907A1 (en) 2002-03-28 2003-03-27 Anti-inflammatory morpholin-acetamide derivatives
JP2003580327A JP2005527564A (ja) 2002-03-28 2003-03-27 抗炎症性モルホリン−アセトアミド誘導体
EP03712119A EP1487827A1 (fr) 2002-03-28 2003-03-27 Derives de morpholine-acetamide anti-inflammatoires

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GBGB0208158.6A GB0208158D0 (en) 2002-03-28 2002-03-28 Novel compounds
GB0208158.6 2002-03-28

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006028284A1 (fr) 2004-09-08 2006-03-16 Mitsubishi Pharma Corporation Dérivé de morpholine
WO2007011292A1 (fr) * 2005-07-21 2007-01-25 Astrazeneca Ab Dérivés de n-benzyl-morpholine en tant que modulateurs du récepteur de chimiokine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0243959A1 (fr) * 1986-04-30 1987-11-04 Dainippon Pharmaceutical Co., Ltd. Dérivés substitués du benzamide, procédé pour leur préparation et compositions pharmaceutiques les contenant
WO2000071518A2 (fr) * 1999-05-25 2000-11-30 Sepracor, Inc. Composes heterocycliques analgesiques et procedes d'utilisation de ces derniers
WO2002026722A1 (fr) * 2000-09-29 2002-04-04 Glaxo Group Limited Derives de morpholine-acetamide permettant de traiter les maladies inflammatoires

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0243959A1 (fr) * 1986-04-30 1987-11-04 Dainippon Pharmaceutical Co., Ltd. Dérivés substitués du benzamide, procédé pour leur préparation et compositions pharmaceutiques les contenant
WO2000071518A2 (fr) * 1999-05-25 2000-11-30 Sepracor, Inc. Composes heterocycliques analgesiques et procedes d'utilisation de ces derniers
WO2002026722A1 (fr) * 2000-09-29 2002-04-04 Glaxo Group Limited Derives de morpholine-acetamide permettant de traiter les maladies inflammatoires

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KATO S ET AL: "NOVEL BENZAMIDES AS SELECTIVE AND POTENT GASTROKINETIC AGENTS 2. SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIPS OF 4-AMINO-5-CHLORO-2-ETHOXY-N-4-(4-FLUOROBENZYL)-2-MORPHOLINYL METHYLBENZAMIDE CITRATE (AS-4370) AND RELATED COMPOUNDS", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 34, no. 2, February 1991 (1991-02-01), pages 616 - 624, XP001037842, ISSN: 0022-2623 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006028284A1 (fr) 2004-09-08 2006-03-16 Mitsubishi Pharma Corporation Dérivé de morpholine
WO2007011292A1 (fr) * 2005-07-21 2007-01-25 Astrazeneca Ab Dérivés de n-benzyl-morpholine en tant que modulateurs du récepteur de chimiokine

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TW200402419A (en) 2004-02-16
AU2003216907A1 (en) 2003-10-13
GB0208158D0 (en) 2002-05-22
EP1487827A1 (fr) 2004-12-22
JP2005527564A (ja) 2005-09-15

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