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EP1492537A1 - Derives de morpholine comprenant un groupe acetamide substitue en position 2 utilises en tant qu'antagonistes de ccr-3 dans le traitement de maladies inflammatoires - Google Patents

Derives de morpholine comprenant un groupe acetamide substitue en position 2 utilises en tant qu'antagonistes de ccr-3 dans le traitement de maladies inflammatoires

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Publication number
EP1492537A1
EP1492537A1 EP03745299A EP03745299A EP1492537A1 EP 1492537 A1 EP1492537 A1 EP 1492537A1 EP 03745299 A EP03745299 A EP 03745299A EP 03745299 A EP03745299 A EP 03745299A EP 1492537 A1 EP1492537 A1 EP 1492537A1
Authority
EP
European Patent Office
Prior art keywords
methyl
morpholin
dichlorobenzyl
acetamide
phenyl
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Withdrawn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
EP03745299A
Other languages
German (de)
English (en)
Inventor
Rachael Ann GlaxoSmithKline ANCLIFF
Caroline Mary GlaxoSmithKline COOK
Colin David GlaxoSmithKline Eldred
Paul Martin GlaxoSmithKline GORE
Lee Andrew GlaxoSmithKline HARRISON
Martin Alistair GlaxoSmithKline HAYES
Simon Teanby GlaxoSmithKline HODGSON
Duncan Bruce GlaxoSmithKline JUDD
Suzanne Elaine GlaxoSmithKline KEELING
Xiao Qing GlaxoSmithKline LEWELL
Gail GlaxoSmithKline MILLS
Graeme Michael GlaxoSmithKline ROBERTSON
Stephen GlaxoSmithKline SWANSON
Andrew John GlaxoSmithKline WALKER
Mark GlaxoSmithKline 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
Original Assignee
Glaxo Group Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of EP1492537A1 publication Critical patent/EP1492537A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • 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
    • A61P37/08—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
    • 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
    • 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
    • C07D413/06—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 carbon chain containing only aliphatic carbon atoms
    • 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

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-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 aryl
  • X represents -O- or a bond
  • Y represents -(CR na Rnb)n-
  • R na and R nb are each independently hydrogen or d- 6 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 h alky!
  • R 10 represents hydrogen or C ⁇ alkyl
  • salts and solvates thereof with the proviso that the following compounds are excluded;
  • Examples of the aryl group, R 1 include phenyl.
  • R 1 When R 1 is substituted aryl, suitable substituents include G*- 6 alkylsulphonyl; d-ealkylthio; unsubstituted or substituted heteroaryl; C 3 - ⁇ cycloalkylsulphonylamino; d- 6 alkylaminocarbonylamino; C
  • R 4 R 5 NC(O)- wherein R 4 and R 5 may each independently represent hydrogen or C-
  • R 1 is aryl substituted with unsubstituted or substituted heteroaryl
  • examples of such a heteroaryl group include pyrazolyl, oxadiazolyl, and triazolyl.
  • Suitable substituents for such a heteroaryl group include C ⁇ . 6 alkyl.
  • R is unsubstituted or substituted phenyl.
  • suitable substituents include d-
  • R 4 R 5 NC(O)- wherein R 4 and R 5 may each independently represent hydrogen or d- 6 alkyl, or R 4 and R 5 may represent a -(CH 2 ) P - group wherein p is an integer from 3 to 7 so that, together with the nitrogen atom to which they are attached, a 4 to 8- membered heterocyclyl ring is formed; d- 6 alkoxycarbonyl; aminosulphonyl; aminocarbonyl; halo; or carboxy.
  • R 1 is unsubstituted phenyl or phenyl substituted with 4- (methanesulphonyl), 4-(methylcarbonylamino), 2,4,6-(trifluoro), 3-(methylthio), 2,5-(difluoro), 4-(pyrazol-1-yl), 3-(methanesulphonyl), 3-(2-methyl-1 ,3,4- oxadiazol-5-yl), 3-(1 ,3,4-oxadiazol-5-yl), 3-(2-methyl-1 ,3,4-triazol-5-yl), 4- (ethylcarbonylamino), 4-(methylaminocarbonyl), 4-(carboxy), 3-(/so- propanesulphonylamino), 3-(cyclopropanesulphonylamino), 3- (ethanesulphonylamino), 4-(methylaminocarbonylamino), 4-methanesulphonyl-2- methanesulphonylamino), 4-(ethylcarbon
  • R na and R nb are both hydrogen.
  • n is 1 , 2, or 3.
  • R 10 is hydrogen or methyl.
  • R 10 is hydrogen
  • R 3 is hydrogen
  • R 2 is aryl
  • examples include phenyl.
  • R 2 is substituted aryl
  • suitable substituents include cyano, perhalod- 6 alkyl, amido, halo, d- 6 alkyl, d. 6 alkoxycarbonyl, mono- and di-(d- 6 alkyl)aminocarbonyl, d- 6 alkoxy, nitro, d-ealkylsulphonyl, hydroxy, C 1 . 6 alkoxyC ⁇ - 6 alkyl, d- 6 alkylthio-, mono- and-di-(C ⁇ alkyl)amino, and d. 6 alkylcarbonylamino.
  • R 2 is heteroaryl
  • examples include thiophenyl and pyridinyl.
  • R 2 is substituted heteroaryl
  • suitable substituents include cyano, perhaloCi- 6 alkyl, amido, halo, d- 6 alkyl, d. 6 alkoxycarbonyl, mono- and di-(d- 6 alkyl)aminocarbonyl, d- 6 alkoxy, nitro, d- 6 alkylsulphonyl, hydroxy, C 1 . 6 alkoxyC 1 - 6 alkyl, d- 6 alkylthio-, mono- and-di-(C 1 . 6 alkyl)amino, and C ⁇ -6alkylcarbonylamino.
  • R 2 is unsubstituted or substituted phenyl, unsubstituted or substituted thiophenyl, or unsubstituted or substituted pyridinyl.
  • R 2 is substituted phenyl suitable substituents include halo.
  • R 2 is phenyl substituted with chloro or fluoro, thiophenyl substituted with chloro, or pyridinyl.
  • R 2 is 3-fluorophenyl, 4-fluorophenyl, 2,5-dichlorophenyl, 3- chlorophenyl, 3-(trifluoromethyl)phenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3,4- difluorophenyl, 3-chloro-4-fluoro-phenyl, 2-chlorothiophen-5-yl, or pyridin-3-yl.
  • R 1 represents substituted or unsubstituted aryl
  • X represents -O- or a bond
  • Y represents -(CR na R nb ) n -
  • R na and R n b are each independently hydrogen or d-ealkyl
  • 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- 6 alkyl; and salts and solvates thereof; with the proviso that the following compounds are excluded;
  • R 1A is a moiety of formula (M)
  • R 6 represents d- 6 alkylthio, unsubstituted or substituted heteroaryl, C 3 - scycloalkylsulphonylamino; N,N-di(C 1 - 6 alkyl)aminosulphonyl, R 8 R 9 NC(O)- wherein R 8 and R 9 may each independently represent hydrogen or Ci-ealkyl or R 8 and R 9 may represent a -(CH 2 ) q - group wherein q is an integer from 3 to 7 so that, together with the nitrogen atom to which they are attached, a 4 to 8- membered heterocyclyl ring is formed; unsubstituted heteroaryl; heteroaryl substituted with d- 6 alkyl, halo, C ⁇ - 8 a!koxy, or hydroxy; C 3 - 8 cycloalkylaminosulphonyl; C 3 . 8 cycloalkylcarbonyl; aminosulphonyl; carboxy; mono-and di-(
  • R 7 represents cyano, perhalod- 6 alkyl, hydrogen, C* ⁇ - 6 alkyl, halo, d-ealkoxy, or hydroxy;
  • Y, R 2 , R 3 , and R 10 are as hereinbefore defined for formula (I); and the following compounds are excluded;
  • R 6 is d- 6 alkylsulphonylamino, C 3 . 8 cycloalkylcarbonyl, Ci-
  • R 7 is hydrogen.
  • Suitable groups R 1A include phenyl substituted with 3-methylthio, 3- methanesulphonyl, 3-(2-methyl-1 ,3,4-oxadiazol-5-yl), 3-(1 ,3,4-oxadiazol-2-yl), 3-
  • R 1A is phenyl substituted with 3-methylthio, 3- methanesulphonyl, 3-(2-methyl-1 ,3,4-oxadiazol-5-yl), 3-(1 ,3,4-oxadiazol-2-yl), 3-
  • R 1A is a moiety of formula (M)
  • R 6 represents R 8 R 9 NC(O)- wherein R 8 and R 9 may each independently represent hydrogen or C ⁇ - 6 alkyl or R 8 and R 9 may represent a -(CH 2 ) q - group wherein q is an integer from 3 to 7 so that, together with the nitrogen atom to which they are attached, a 4 to 8-membered heterocyclyl ring is formed; unsubstituted heteroaryl; heteroaryl substituted with C ⁇ . 6 alkyl, halo, d.
  • R 7 represents cyano, perhalod. 6 alkyl, hydrogen, d- 6 alkyl, halo, C ⁇ - 6 alkoxy, or hydroxy;
  • Y, R 2 . and R 3 are as hereinbefore defined for formula (I); and the following compounds are excluded;
  • Suitable compounds of the invention are Examples 1 , 2, 3, 4, 5, 8, 9, 10,
  • Preferred compounds of the invention are Examples 1 , 3, 4, 5, 8, 10, 11 , 12, 13, 14, 15, 16, 17, 29, 31 , 35, 41 , 43, 45, 47, 49, 51, 55, 57, 59, 61 , 63, 65,
  • 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 a moiety of formula (M 1 )
  • R 6' represents R 8 R 9 NC(O)-, where R 8 and R 9 are as previously defined; C ⁇ - 6 alkoxycarbonyl; d. 6 alkylcarbonyl; C 3 . 8 cycloalkylcarbonyl; d. ealkylsulphonylamino; carboxy; or aminosulphonyl; R 7' is hydrogen or halo, and; R 2' is phenyl substituted by halo.
  • R 1' is phenyl substituted with C3- 8 cycloalkylcarbonyl, d- 6 alkylcarbonyl, C ⁇ . 6 alkoxycarbonyl, aminosulphonyl, C ⁇ - 6 alkylsulphonylamino, carboxy, or mono-or di-(d- 6 alkyl)aminocarbonyl.
  • R 1' is 3-(cyclopropylcarbonyl)phenyl, 3- (methylcarbonyl)phenyl, 3-(methoxycarbonyl)phenyl, 3-(aminosulphonyl)phenyl, 3-carboxyphenyl, 3-(methylaminocarbonyl)phenyl, 3- (methylsulphonylamino)phenyl, 3-(dimethylaminocarbonyl)phenyl, 3- (ethylaminocarbonyl)phenyl), 3-( so-propylaminocarbonyl)phenyl, or 3-(/so- propyI(methyl)aminocarbonyl)phenyl.
  • R 2' is phenyl substituted by chloro of fluoro.
  • R 2' is 3,4-dichlorophenyl, 3,4-difluorophenyl or 3-chloro-4- fluorophenyl.
  • the stereochemistry at the position marked ' * ' is (S).
  • R 1" is substituted phenyl, and; R 2 is phenyl substituted with halo.
  • R 1" is phenyl substituted with C 3 - 8 cycloalkylaminocarbonyl, Ci- 6 alkylcarbonylamino, R 4 R 5 NCO (where R 4 and R 5 are as previously defined), Ci- 6 alkoxycarbonyl, carboxy, d- 6 alkylsulphonylamino, cyano, aminosulphonyl, aminocarbonyl, halo, or amino.
  • R " is 3-(cyclopropylaminocarbonyl)phenyl, 3-
  • R 2" is phenyl substituted with chloro.
  • R 2' is 3,4-dichlorophenyl.
  • the stereochemistry at the position marked ' * ' is (S). Accordingly, there is provided a compound of formula (I") or a salt or solvate thereof. There exists a further preferred subgroup of compounds of formula (I) being of formula (I" 1 )
  • R 1" is 4-substituted phenyl, and; R 2"' is phenyl substituted by halo.
  • R 1 "' is phenyl substituted at the 4- or para position with Ci. 6 alkylsulphonylaminoalkyl.
  • R 1 "' is 4-(methanesulphonylaminomethyl)phenyl.
  • R 2'" is phenyl substituted by chloro of fluoro.
  • R 2" is 3,4-difluorophenyl.
  • the stereochemistry at the position marked ' * ' is (S).
  • 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 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 alkylsulphonyl; alkylthio; unsubstituted or substituted heteroaryl; cycloalkylsulphonylamino; alkylaminocarbonylamino; alkylaminosulphonyl; perhaloalkyl; cycloalkylaminosulphonyl; heterocyclylcarbonyl; alkylsulphonylaminoalkyl; cyano; amino; cycloalkylcarbonyl; alkylcarbonyl; alkylsulphonylamino; cycloalkylaminocarbonyl; aminocarbonyl; halo; alkyl; alkoxycarbonyl; mono- and di-(alkyl)aminocarbonyl; alkoxy; nitro; alkylsulphonyl; hydroxy; alkoxyalkyl; alkylthio; mono-and di
  • references to 'heteroaryl' refer to heterocyclic aromatic rings containing 1-4 heteroatoms selected from nitrogen, oxygen and sulphur.
  • heterocyclic aromatic rings include thiophenyl, pyrazolyl, oxadiazolyl, and triazolyl.
  • Suitable substituents for any heteroaryl group include 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 'cycloalkyl' refer to saturated alicyclic rings suitably containing 3-8 carbon atoms, for example cyclopropyl.
  • 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 cycloalkylcarbonyl, aminocarbonyl, alkylsulphonylamino, alkylcarbonyl, cycloalkylaminocarbonyl, alkyl, alkoxycarbonyl, alkylaminocarbonyl, halo, alkoxy, nitro, alkylsulphonyl, hydroxy, alkoxyalkyl, alkylthio, mono- and di-(alkyl)amino, and alkylcarbonylamino.
  • 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. Accordingly, there is provided a process for the preparation of a compound of formula (I) which process comprises the reaction of a compound of formula (II) with a compound of formula (III);
  • R ⁇ X, Y, R 3 , R 10 , and R 2 are as hereinbefore defined for formula (I) in the presence of a peptide coupling agent, and, if necessary, an activating 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-dimethylaminopropyI)-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).
  • R 2 and R 10 are 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 (I MR)
  • R 2 and R 10 are as hereinbefore defined, and optionally resolution of the resulting enantiomers of a compound of formula (IIIR); or;
  • 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.
  • An 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 compounds 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 65-75°C.
  • 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 between 20-25°C.
  • 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 those 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)
  • T, R 3 , R 10 , and R 2 are as hereinbefore defined for formula (VI) and L 2 is a leaving group.
  • 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.
  • 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.
  • 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 , R 10 , and T are as hereinbefore defined for formula (VI) 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 of 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.
  • a compound of formula (I) may be prepared by reaction of a compound of formula (XI) with a compound of formula
  • L 2 is a leaving group
  • R 1 , X, and Y 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.
  • a suitable solvent such as a polar organic solvent, e.g. acetonitrile
  • a suitable base such as an alkali or alkaline earth metal carbonate, e.g. potassium carbonate
  • a suitable temperature such as ambient temperature, e.g. 18 - 25 ° C for a suitable time period, e.g. 2 - 4 hours.
  • 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 conversions of one group R 1 into another group R 1 include: (a) converting a group R 1 which represents an aryl group substituted with an alkoxycarbonyl group into a group R 1 which represents an aryl group substituted with a carboxy group; such a conversion may be carried out using an appropriate conventional hydrolysis procedure, for example treating an appropriately protected compound of formula (I) with an appropriate base;
  • 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.
  • conventional methods of heating and cooling may be employed, for example electric heating mantles and ice/salt baths respectively.
  • Conventional methods of purification, for example crystallisation and column chromatography may be used as required. Where appropriate individual isomeric forms of the compounds of formula
  • (I) may be prepared as individual isomers using conventional procedures such as the fractional crystallisation of diastereoisomeric derivatives or chiral high performance liquid chromatography (chiral HPLC).
  • 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 assay: (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 plC50 values in the range 6.0 to 8.7.
  • 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 80 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. 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.
  • compounds of formula (I) are useful as therapeutic agents.
  • 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.
  • 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) eg.
  • 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 10Omg/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.
  • 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.
  • 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 0.7mins; A+B mixtures, gradient profile 0 - 100% B over 3.5mins; hold at 100%B for 1.1mins; return to 100% A over 0.2mins.
  • the LC/MS system used a micromass spectrometer, with electrospray ionisation mode, positive and negative ion switching, mass range 80-1000 a.m.u. Thermosprav Mass Spectra
  • Thermospray Mass Spectra were determined-on a HP 5989A engine mass spectrometer, +ve thermospray, source temperature 250°C, probe temperatures
  • SCX' refers to Isolute Flash SCX-2 sulphonic acid solid phase extraction cartridges.
  • Organic/Agueous phase separation with hydrophobic frits 'Hydrophobic frit' refers to a Whatman polypropylene filter tube fitted with a PTFE frit, pore size 5.0 ⁇ m.
  • 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).
  • Example 23 A solution of Example 23 (0.148g) in N,N ⁇ dimethylformamide (1ml) was added to a stirred solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.081 g) and 1 -hydroxybenzotriazole (0.047g) in N,N- dimethylformamide (1m!) at 20°. Cyclopropylamine (0.0918ml) was added, followed by N,N-diisopropylethylamine (0.0923ml) and the mixture was stirred at 20° for 20h. The mixture was diluted with methanol (ca.
  • Example 27 To a stirred solution of Example 27 (0.0491 g) in dichloromethane (5ml) and acetonitrile (1 ml) at 20° was added N,N-diisopropylethylamine (0.0516ml) and methanesulphonyl chloride (0.0084ml). The mixture was stirred at 20° for 26h during which time a further portion of methanesulphonyl chloride (0.0031 ml) was added. The mixture was diluted with methanol (ca. 2ml) and applied to a 5g SCX ion-exchange cartridge (pre-conditioned with methanol). The cartridge was eluted with methanol and 10% 0.880 ammonia solution in methanol.
  • Example 5 To a stirred solution of Example 5 (0.2988g) in methanol (5ml) was added 2M aqueous sodium hydroxide (0.71 ml). The mixture was stirred at 22° for 66h before 2M aqueous hydrochloric acid (0.71 ml) was added. The mixture was applied to 2x1 Og SCX ion-exchange cartridges (pre-conditioned with methanol). The cartridges were eluted with methanol followed by 5% triethylamine in methanol. The first triethylamine fractions were combined and the solvent was evaporated in vacuo to give the title compound (0.353g) as a yellow gum.
  • LC/MS: R t 2.15min, m/z 405 [MH + ]
  • Example 7 To a stirred solution of Example 7 (0.057g) in N,N-dimethylformamide (1ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0325g) and 1-hydroxybenzotriazole (0.018g). N,N-diisopropylethylamine (0.039ml) was added followed by a 2M solution of ethylamine in tetrahydrofuran (0.140ml) and the mixture was stirred at 22° for 18h. The mixture was applied to a 5g SCX ion- exchange cartridge (pre-conditioned with methanol).
  • Example 39 N-r(2S)-4-(3.4-Difluorobenzyl)morpholin-2-ylmethyll-2-(3- f1 ,3.41oxadiazol-2-yl-phenyl)acetamide; compound with formic acid
  • Example 7 is the triethylammonium salt Table 2
  • Synthetic Method B was used for the preparation of Examples 65, 79, 73, 69, and 71.
  • Synthetic Method D was used for the preparation of Examples 50, 64, 31 , 33, 83, and 90.
  • Synthetic Method G was used for the preparation of Examples 49, 55, 57, 51 , and 53.
  • Synthetic Method H was used for the preparation of Example 37.
  • Synthetic Method I was used for the preparation of Example 39.
  • Synthetic Method J was used for the preparation of Example 41.

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Abstract

L'invention concerne certains composés de formule (I), dans laquelle R1 représente aryle substitué ou non substitué; X représente -O- ou une liaison; Y représente -(CRna,Rnb) n-; Rna et Rnb sont chacun indépendamment hydrogène ou C1-6alkyle; n représente un nombre entier compris entre 1 et 5; R2 représente aryle substitué ou non substitué ou hétéroaryle substitué ou non substitué; R3 représente hydrogène ou C1-6alkyle; R10 représente hydrogène ou C1-6alkyle. Ces composés et leurs sels et solvates sont antagonistes de CCR3 et sont donc indiqués pour être utilisés dans la thérapie d'états inflammatoires.
EP03745299A 2002-03-28 2003-03-27 Derives de morpholine comprenant un groupe acetamide substitue en position 2 utilises en tant qu'antagonistes de ccr-3 dans le traitement de maladies inflammatoires Withdrawn EP1492537A1 (fr)

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GBGB0207443.3A GB0207443D0 (en) 2002-03-28 2002-03-28 Novel compounds
PCT/EP2003/003348 WO2003082294A1 (fr) 2002-03-28 2003-03-27 Derives de morpholine comprenant un groupe acetamide substitue en position 2 utilises en tant qu'antagonistes de ccr-3 dans le traitement de maladies inflammatoires

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US20090118288A1 (en) * 2005-07-21 2009-05-07 Astrazeneca Ab N-Benzyl-Morpholine Derivatives as Modulators of the Chemokine Receptor

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