EP1495020A1 - Derives de n-(morpholin-2yl) methyle acetamide servant d'antagonistes de ccr-3 et utilises dans le traitement de maladies inflammatoires - Google Patents

Derives de n-(morpholin-2yl) methyle acetamide servant d'antagonistes de ccr-3 et utilises dans le traitement de maladies inflammatoires

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Publication number
EP1495020A1
EP1495020A1 EP03745300A EP03745300A EP1495020A1 EP 1495020 A1 EP1495020 A1 EP 1495020A1 EP 03745300 A EP03745300 A EP 03745300A EP 03745300 A EP03745300 A EP 03745300A EP 1495020 A1 EP1495020 A1 EP 1495020A1
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EP
European Patent Office
Prior art keywords
formula
compound
piperidin
substituted
unsubstituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03745300A
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German (de)
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
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glaxo Group Ltd
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Glaxo Group Ltd
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Filing date
Publication date
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Publication of EP1495020A1 publication Critical patent/EP1495020A1/fr
Withdrawn legal-status Critical Current

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    • 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
    • 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
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • 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
    • A—HUMAN NECESSITIES
    • 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
    • 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
    • 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

Definitions

  • This invention relates to novel compounds, processes for their preparation, pharmaceutical formulations containing them and their use in 5 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
  • 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 15 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,
  • cytokine products such as IL-4 and IL-5 released by T-helper 2 (Th2) lymphocytes
  • Th2 T-helper 2
  • eosinophils Through the release of cytotoxic basic proteins, pro-inflammatory mediators and oxygen radicals, 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
  • chemokines There are two major families of chemokines, CXC- ( ⁇ ) and CC- ( ⁇ ) chemokines, classified according to the
  • 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-HT1D-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 heterocyclyl
  • Y represents -(CR na Rnb)n-;
  • R na and R n 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 proviso that the following compound is excluded; N- ⁇ [4-(3,4-dichlorobenzyl)morpholin-2-yl]methyi ⁇ -2-(1,1-dioxidothiomorpholin-4- yl)acetamide.
  • heterocyclyl group, R 1 examples include uracilyl, pyrandionyl, piperazinyl, hydantoinyl and piperidinyl.
  • R 1 is substituted heterocyclyl
  • suitable substituents include aminocarbonyl, C 3 . 8 cycloalkylaminocarbonyl, C ⁇ alkylsulphonylamino, d. 6 alkyIcarbonyl , C 3 . 8 cycloalkylcarbonyl, mono- and di-(C 1 . 6 alkyI)aminocarbonyl, d- 6 alkoxycarbonyl, C ⁇ alkylsulphonyl, d- ⁇ alkoxyd-ealkyl, d-ealkylcarbonylamino, and C ⁇ . 6 alkyl.
  • R 1 is unsubstituted or substituted pyrandionyl, unsubstituted or substituted uracilyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted hydantoinyl, or unsubstituted or substituted piperazinyl.
  • R 1 is substituted piperidinyl
  • suitable substituents include aminocarbonyl, C ⁇ alkylsulphonylamino, d-ealkylcarbonylamino, C 3 _ scycloalkylcarbonyl, mono- and di-(C 1 . 6 alkyl)aminocarbonyl, C ⁇ . 6 alkylcarbonyl, d- 6 alkoxycarbonyl, d. 6 alkylcarbonylamino, cycloalkylaminocarbonyl, and d. 6 alkylsuIphonyl.
  • R 1 When R 1 is substituted uracilyl, suitable substituents include C ⁇ alkyl.
  • R 1 is pyran-3,4-dion-6-yl, 4-methyluracil-6-yl, 1- (methylcarbonyl)piperidin-4-yl, piperidin-4-yl, 1-(aminocarbonyl)piperidin-4-yl, 1- (cyclopropylaminocarbonyl)piperidin-4-yl, 1 -(fert-butoxycarbonyl)piperidin-4-yl, 4- (methanesulphonylamino)piperidin-l-yl, 4-(methylcarbonylamino)piperidin-1-yl, 1-(cyclopropylcarbonyl)piperidin-4-yl, 1-(ethylaminocarbonyl)piperidin-4-yl, 1-(/so- propylaminocarbonyl)piperidin-4-yl, 1-(/so-propylcarbonyl)piperidin-4-yl, 1- (ethoxycarbonyl)piperidin-4-yl, 1
  • R na and R n are both hydrogen.
  • n is 1 or 2.
  • R 3 is hydrogen.
  • R 2 is aryl
  • examples include phenyl.
  • suitable substituents include cyano, perhalod-ealkyl, amido, halo, C h alky!, d-ealkoxycarbonyl, mono- and di-(d- 6 aIkyl)aminocarbonyl, d-ealkoxy, nitro, d. 6 aIkylsulphonyl, hydroxy, d-ealkoxyd- 6 alkyl, C ⁇ alkylthio, mono- and-di-(C 1 . 6 alkyl)amino, and d. 6 alkylcarbonylamino.
  • R 2 When R 2 is heteroaryl, examples include thiophenyl.
  • suitable substituents include cyano, perhalod. 6 alkyl, amido, halo, d ⁇ alkyl, d. 6 alkoxycarbonyl, mono- and di-(C 1 . 6 alkyl)aminocarbonyl, d-ealkoxy, nitro, d-ealkylsulphonyl, hydroxy, d ⁇ alkoxyd. 6 alkyl, d-ealkylthio, mono- and-di-(C 1 . 6 alkyl)amino, and d. 6 aIkylcarbonylamino.
  • R 2 is unsubstituted or substituted phenyl or unsubstituted or substituted thiophenyl.
  • R 2 is substituted phenyl suitable substituents include halo. More suitably, R 2 is phenyl substituted with chloro.
  • R 2 is 3,4-dichlorophenyl.
  • Suitable compounds of the invention are Examples 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 14, 15, 19, and 20.
  • Preferred compounds of the invention are Examples 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11.
  • 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 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.
  • solvates include hydrates.
  • R 1 is unsubstituted or substituted heterocyclyl, and; R 2' is phenyl substituted with halo.
  • heterocyclyl group examples include hydantoinyl, piperazinyl, and piperidinyl.
  • R 1' is unsubstituted hydantoinyl or hydantoinyl substituted with d-ealkyl, piperazinyl substituted with d-ealkyl, unsubstituted piperidinyl or piperidinyl substituted with C ⁇ cycloalkylcarbonyl, d. 6 alkylcarbonyl, d-
  • C 3 proposition 8 cycloalkylaminocarbonyl, d. 6 alkylsulphonylamino, or d-ealkylcarbonylamino.
  • R 1 is 1-(cyclopropylcarbonyl)piperidin-4-yl, 1- (ethylaminocarbonyl)piperidin-4-yl, 1-(/so-propylaminocarbonyl)piperidin-4-yl, 1- (/so-propyIcarbonyl)piperidin-4-yI, 1-(ethoxycarbonyl)piperidin-4-yl, 1- (methoxycarbonyl)piperidin-4-yl, 1-(ethylcarbonyl)piperidin-4-yl, 1- (ethanesulphonyl)piperidin-4-yl, 1-(methylaminocarbonyl)piperidin-4-yl, 1- (methanesulphonyl)piperidin-4-yl, 1-(diethylaminocarbonyl)piperidin-4-yl, 1- (methylcarbonyl)piperidin-4-yl, piperidin-4-yl, 1-(amido)piperidin-4-yl,
  • R 2' is phenyl substituted with chloro or fluoro.
  • R 2' is 3,4-dichlorophenyl.
  • the stereochemistry at the position marked '*' is (S).
  • a compound of formula (I") or a salt or solvate thereof 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 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 include thiophenyl.
  • Suitable substituents for any heteroaryl group include 1 to 5, suitably 1 to 3, substituents selected from the list consisting of hydroxy, alkoxy, mono- and di- (alkyl)amino, halo, 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 'alkyl' refer to both straight chain and branched chain aliphatic isomers of the corresponding alkyl, suitably containing up to six carbon atoms.
  • References to 'cycloalkyP 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, uracilyl, and pyrandionyl.
  • Suitable substituents for any heterocyclyl group include alkylcarbonylamino, aminocarbonyl, cycloalkylaminocarbonyl, alkylsulphonylamino, alkylcarbonyl, cycloalkylcarbonyl, mono- and di- (alkyl)aminocarbonyl, alkoxycarbonyl, alkylsulphonyl, alkoxyalkyl, and alkyl.
  • 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 a base and an activating agent and optionally a peptide coupling agent, and thereafter, if required, carrying out one or more of the following optional steps:
  • the activating agent is 1-hydroxybenzotriazole (HOBT) or O-(7- azabenzotriazol-1-yl)-N,N,N 1 ,N 1 -tetramethylammonium hexafluorophosphate.
  • peptide coupling agents are 1 ,3-dicyclohexyIcarbodiimide (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
  • a suitable base such as a tertiary amine, e.g. N,N-diisopropylethylamine and an activating agent e.g. O-(7-azabenzotriazol-1-yl)-N,N,N 1 ,N 1 -tetramethylammonium hexafluorophosphate, followed by a compound of formula (II).
  • reaction is conducted at ambient temperature, e.g. 18-25 ° C, for a suitable time period e.g. 12 - 20 h.
  • 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 (IV) may be prepared by Reaction (b).
  • 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 (MR)
  • R 2 is as hereinbefore defined, and optionally resolution of the resulting enantiomers of a compound of formula (IIIR); or;
  • R 2 is as hereinbefore defined.
  • T is trifluoroacetyl
  • R 3 and R 2 are as hereinbefore defined, 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:
  • 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 phosphine suitably triphenyl phosphine, is added and the mixture stirred until all the solid is dissolved.
  • a suitable azo compound suitably diisopropylazodicarboxylate, is then added over a period of time, suitably, 10-15 minutes, while maintaining the temperature at ⁇ 7°C.
  • the mixture is allowed to stand for a period of time, suitably 2-3 hours, then allowed to warm, suitably to 20-25°C. After a further period of standing, suitably 4-6 hours, further phosphine and azo compound are added. After a further period of standing, suitably 20-24 hours, the reaction mixture is concentrated to near dryness.
  • a suitable alcohol suitably propan-2-ol, is added and 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 65-75C 0 .
  • 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 compound of formula (IIIR) or formula (HIE) respectively.
  • the mixture is 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 is 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 to 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.
  • compound of formula (IV) is added and the mixture heated at 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.
  • the 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.
  • 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 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.
  • 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.
  • a compound of formula (VI) may be prepared by reaction of a compound of formula (VII) with a compound of formula (VIII)
  • 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 suitable solvent for example N,N-dimethylformamide
  • a suitable solvent such as N,N-dimethylformamide
  • the residue is partitioned between a suitable organic solvent, for example dichloromethane, and a saturated aqueous base, for example saturated aqueous sodium carbonate solution.
  • a suitable organic solvent for example dichloromethane
  • 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.
  • a suitable drying agent for example magnesium sulphate
  • 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.
  • 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
  • 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-
  • (XII) is an unsubstituted or substituted heterocyclyl 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: (i) converting a compound of formula (I) to a further compound of formula (I); (ii) removing any necessary protecting group;
  • Suitable leaving groups are halo groups, preferably bromo.
  • 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 or 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) and L 3 is a leaving group which is more labile than L 2 , in the presence of a suitable base such as potassium carbonate.
  • a suitable base such as potassium carbonate.
  • the leaving group, L 3 include halo.
  • L 2 and L 3 are both bromo.
  • reaction between a compound of formula (III) and a compound of formula (XIV) is conducted atlow 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 compounds of formulae (II), certain compounds of formula (III), certain compounds of formula (IV), (V), certain compounds of formula (VI), certain compounds of formula (VII), (VIII), (IX), (X), (XII), and (XIV) are known, commercially available compounds, and/or may be prepared by analogy with known procedures, for examples those disclosed in standard reference texts of synthetic methodology such as J. March, Advanced Organic Chemistry, 3rd Edition (1985), Wiley Interscience.
  • the compounds of formulae (IIIBR), (IIIBE), and (XIII) are considered to be novel.
  • 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.
  • 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 10 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.
  • 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 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 5.0 to 8.5.
  • the compounds of the Examples tested in the CCR-3 eosinophil chemotaxis assay possessed fpKi values such as those given in the table below:
  • Examples of disease states in which the compounds of the invention have potentially beneficial anti-inflammatory effects include 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 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.
  • 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.
  • 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. It will be appreciated by those skilled in the art that references herein to treatment or therapy extend to prophylaxis as well as the treatment of established conditions.
  • 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.
  • a process for preparing such a pharmaceutical formulation which comprises admixing the compound of formula (I) or a physiologically acceptable salt or solvate thereof with 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.
  • the compounds and pharmaceutical compositions according to the invention may also be used in combination with other therapeutic agents, for example antihistaminic agents, anticholinergic agents, 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) e.g.
  • 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 free bond on the R 1 groups as presented in the Tables signifies the point of attachment of the R 1 groups to the residue of the molecule.
  • 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 8ml min "1 .
  • 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 so!vents: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.
  • the LC/MS system used a micromass spectrometer, with electrospray ionisation 5 mode, positive and negative ion switching, mass range 80-1000 a.m.u.
  • Thermospray Mass Spectra were determined on a HP 5989A engine mass spectrometer, +ve thermospray, source temperature 250°C, probe temperatures 10 120°C (stem), 190°C (tip), detection mass range 100-850 a.m.u. Compounds were injected in 10 ⁇ l of a mixture of solvents comprising 65% methanol and 35% 0.05M aqueous ammonium acetate, at a flow rate of OJml/min.
  • Solid phase extraction (ion exchange) 15 'SCX' refers to Isolute Flash SCX-2 sulphonic acid solid phase extraction cartridges.
  • Description 5 (Alternative procedure) A slurry of Description 7 (1.00g) in water (8.5ml) was heated to 75° and then treated dropwise with concentrated sulphuric acid (2.5ml). The mixture was then heated at reflux. After 23h the reaction mixture was cooled to 22° and then treated with dichloromethane (6ml). 880 Ammonia solution (7ml) was then added dropwise with cooling. More dichloromethane (10ml) was added. The aqueous phase was separated and extracted with more dichloromethane (10ml). The combined organic phase was washed with water (5ml) and then evaporated to dryness. The residue was redissolved in dichloromethane and the solvent re- evaporated to give the product as an oil (662mg).
  • Description 8 (0.104g) was dissolved in 1 ,4-dioxane (3ml) and treated with 4M hydrogen chloride in 1 ,4-dioxane (3ml). The mixture was stirred at 22° for 18h, and evaporated in vacuo to give Description 9 as a colourless gum (0.078g).
  • Example 26 A solution of Example 26 (0.380g) in 1 ,4-dioxane (2ml) was treated with hydrogen chloride in 1,4-dioxane (4M, 4ml) and the resulting solution was stirred under nitrogen for two hours at room temperature, followed by concentration in vacuo to give a pale yellow solid. This was azeotroped with dichloromethane (10ml), triturated with ether (10ml) and concentrated in vacuo to give the title compound (0.342g) as a pale yellow solid.
  • LC-MS Rt 1.91 min, Mass Spectrum m/z 414 [MH + ]
  • Example 26 A solution of Example 26 (0.167g) in 1 ,4-dioxane (1 ml) was treated with hydrogen chloride in 1 ,4-dioxane (4M, 3ml) and the resulting solution was stirred under nitrogen for eighteen hours at room temperature then left to stand for two days. The mixture was concentrated in vacuo and the residue azeotroped with methanol followed by dichloromethane. The product was dissolved in methanol and loaded onto an SCX (5g) ion exchange cartridge, which had been pre- treated with methanol and which was then eluted with methanol and 10% 0.880 ammonia/methanol. The basic fractions were combined and concentrated in vacuo to give the title compound (0.127g). LC-MS: Rt 1.85 min, Mass Spectrum m/z 414 [MH + ] Example 12
  • Example 13 HCI salt, 0.055g
  • dichloromethane (2ml) was treated with N,N-diisopropylethylamine (0.06ml) followed by acetyl chloride (0.010ml) and the resulting solution was stirred at room temperature for three hours.
  • the solvent was then evaporated under a stream of nitrogen to dryness, and the residue dissolved in methanol and loaded onto an SCX (1g) ion exchange cartridge, which had been pre-treated with methanol and which was then eluted with methanol and 10% 0.880 ammonia/methanol.
  • Example 13 HCI salt, 0.055g
  • dichloromethane (2ml) was treated with N,N-diisopropyIethylamine (0.06ml) followed by methane sulphonyl chloride (0.010ml) and the resulting solution was stirred at room temperature for three hours.
  • the solvent was then evaporated under a stream of nitrogen to dryness, and the residue dissolved in methanol and 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.
  • Example 26 A solution of Example 26 (0.015g) in 1,4-dioxane (0.5ml) was treated with hydrogen chloride in 1,4-dioxane (4M, 1ml) and the solution stirred at room temperature for sixteen hours; the solvent was then evaporated under a stream of nitrogen to dryness. The resulting yellow solid was treated with dichloromethane (1.5ml) and N,N-diisopropylethyIamine (1.2ml) followed by diethylcarbamyl chloride (0.010ml). After stirring at room temperature under nitrogen for three hours, the solution was concentrated in vacuo and the residue dissolved in methanol.
  • Example 13 A solution of Example 13 (free base, 0.127g) in N,N-dimethyIformamide (2ml) was added dropwise to a solution of 1 ,1-carbonyldiimidazole in N,N- dimethylformamide (2ml) and the resulting mixture stirred at room temperature under nitrogen for five hours. The solution was then concentrated in vacuo to ca. 2ml and 0.880 ammonia solution (4ml) was added. After stirring at room temperature under nitrogen for sixteen hours, the mixture was concentrated in vacuo, redissolved in N,N-dimethylformamide (0J5ml) and 0.880 ammonia solution (4ml) was added.
  • Example 2 A solution of Example 13 (free base) (0.037g) in dichloromethane (2ml) and N,N- dimethylformamide (0.2ml) was treated with ethyl isocyanate (0.008ml) and the mixture was stirred at room temperature under nitrogen for 16h. The mixture was applied directly to an Isolute SCX ion exchange cartidge (2g) and eluted with methanol followed by 10% 0.880 ammonia in methanol. Evaporation of the methanol/ammonia fraction gave a gum (0.022g), which was purified by mass directed preparative HPLC to give the title compound as a colourless gum (0.0088g). LC/MS Rt 2.28min, Mass Spectrum m/z 485 [MH + ]
  • Example 24 A solution of Example 24 (0.039g) in acetonitrile (2ml) and N,N- dimethylformamide (0.5ml) was added to 2-tert-butylimino-2-diethylamino-1 ,3- dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (BEMP resin, 0.104g) and the mixture was shaken at room temperature for 0.5h. A solution of iodomethane (0.007ml) in acetonitrile (0.1ml) was added, and the mixture was shaken at 22° for 16h. The resin was filtered off and washed with acetonitrile (3x2ml) and methanol (3x2ml).
  • Example 13 is the hydrochloride salt
  • Example 27 is the trifluoroacetate salt Table 2

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Abstract

L'invention concerne des composés de formule (I), dans laquelle: R1 représente un hétérocyclyle substitué ou non substitué; Y représente -(CRnaRnb)n-; Rna et Rnb représentent chacun indépendamment hydrogène ou C1-6alkyle; n représente un nombre entier compris entre 1 et 5; R2 représente aryle substitué ou non substitué ou héteroaryle substitué ou non substitué; R3 représente hydrogène ou C1-6alkyle. Ces composés et leurs sels et solvates sont antagonistes de CCR-3 et sont donc indiqués pour être utilisés en thérapie.
EP03745300A 2002-03-28 2003-03-27 Derives de n-(morpholin-2yl) methyle acetamide servant d'antagonistes de ccr-3 et utilises dans le traitement de maladies inflammatoires Withdrawn EP1495020A1 (fr)

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