EP1492537A1 - Morpholine derivatives with a substituted acetamide group in the 2-position for use as ccr-3 antagonists for the treatment of inflammatory diseases - Google Patents

Morpholine derivatives with a substituted acetamide group in the 2-position for use as ccr-3 antagonists for the treatment of inflammatory diseases

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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Withdrawn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)
French (fr)
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
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Glaxo Group Ltd
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Filing date
Publication date
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of EP1492537A1 publication Critical patent/EP1492537A1/en
Withdrawn legal-status Critical Current

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    • 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

Certain compounds of formula (I); wherein R1 represents substituted or unsubstituted aryl; X represents -O- or a bond; Y represents -(CRna,Rnb) n-; Rna and Rnb are each independently hydrogen or C1-6alkyl; n is an integer from 1 to 5; R2 represents unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl; R3 represents hydrogen or C1-6alkyl; R10 represents hydrogen or C1-6alkyl; and salts and solvates thereof are CCR3 antagonists and are therefore indicated to be useful in therapy of inflammatory conditions.

Description

MORPHOLINE DERIVATIVES WITH A SUBSTITUTED ACETAMIDE GROUP IN THE 2-POSITION FOR USE AS CCR-3 ANTAGONISTS FOR THE TREATMENT OF INFLAMMATORY DISEASES
Novel Compounds
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
10 products (such as peroxidases and proteases). Circulating leukocytes include neutrophils, eosinophils, basophils, monocytes and lymphocytes. Different forms of inflammation involve different types of infiltrating leukocytes, the particular profile being regulated by the profile of adhesion molecule, cytokine and chemotactic factor expression within the tissue.
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,
20 followed by tissue repair and resolution of the inflammatory infiltrate. However in chronic inflammatory states, recruitment is often inappropriate, resolution is not adequately controlled and the inflammatory reaction causes tissue destruction.
There is increasing evidence that the bronchial inflammation which is characteristic of asthma represents a specialised form of cell-mediated immunity,
25 in which cytokine products, such as IL-4 and IL-5 released by T-helper 2 (Th2) lymphocytes, orchestrate the accumulation and activation of granulocytes, in particular eosinophils and to a lesser extent basophils. Through the release of cytotoxic basic proteins, pro-inflammatory mediators and oxygen radicals, eosinophils generate mucosal damage and initiate mechanisms that underlie
30 bronchial hyperreactivity. Therefore, blocking the recruitment and activation of Th2 cells and eosinophils is likely to have anti-inflammatory properties in asthma. In addition, 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
35 trafficking and recruitment of leukocytes (for review see Luster, New Eng. J. Med., 338, 436-445 (1998)). They are released by a wide variety of cells and act to attract and activate various cell types, including eosinophils, basophils, neutrophils, macrophages, T and B lymphocytes. There are two major families of chemokines, CXC- ( ) and CC- (β) chemokines, classified according to the
40 spacing of two conserved cysteine residues near to the amino terminus of the chemokine proteins. Chemokines bind to specific cell surface receptors belonging to the family of G-protein-coupled seven transmembrane-domain proteins (for review see Luster, 1998). Activation of chemokine receptors results in, amongst other responses, an increase in intracellular calcium, changes in cell shape, increased expression of cellular adhesion molecules, degranulation and promotion of cell migration (chemotaxis).
To date a number of CC chemokine receptors have been identified and of particular importance to the current invention is the CC-chemokine receptor-3 (CCR-3), which is predominantly expressed on eosinophils, and also on basophils, mast cells and Th2 cells. Chemokines that act at CCR-3, such as RANTES, MCP-3 and MCP-4, are known to recruit and activate eosinophils. Of particular interest are 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. Thus, 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)). In addition, anti-CCR-3 monoclonal antibodies completely inhibit eotaxin interaction with eosinophils (Heath, H. et al., J. Clin. Invest. 99 (2), 178-184 (1997)), while an antibody for the CCR-3 specific chemokine, eotaxin, reduced both bronchial hyperreactivity and lung eosinophilia in an animal model of asthma (Gonzalo et al., J. Exp. Med., 188, 157-167 (1998). Thus, many lines of evidence indicate that antagonists at the CCR-3 receptor are very likely to be of therapeutic use for the treatment of a range of inflammatory conditions.
In addition to a key role in inflammatory disorders, 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). In addition, 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). Thus, 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.
International Patent Application publication number WO 01/24786 (Shionogi & Co. Ltd.) discloses certain aryl and heteroaryl derivatives for treating diabetes. WO 00/69830 (Torrey Pines Institute for Molecular Studies) discloses certain diazacyclic compounds, and libraries containing them, for biological screening. WO 00/18767 (Neurogen Corporation) discloses certain piperazine derivatives as dopamine D4 receptor antagonists. United States Patent 6,031,097 and WO 99/21848 (Neurogen Corporation) discloses certain aminoisoquinoline derivatives as dopamine receptor ligands. WO 99/06384 (Recordati Industria Chimica) discloses piperazine derivatives useful for the treatment of neuromuscular dysfunction of the lower urinary tract. WO 98/56771 (Schering Aktiengesellschaft) discloses certain piperazine derivatives as anti- inflammatory agents. WO 97/47601 (Yoshitomi Pharmaceutical Industries Ltd.) discloses certain fused heterocyclic compounds as dopamine D-receptor blocking agents. WO 96/39386 (Schering Corporation) 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.
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.
Thus, according to one aspect of the invention, there are provided compounds of formula (I):
wherein:
R1 represents substituted or unsubstituted aryl;
X represents -O- or a bond; Y represents -(CRnaRnb)n-;
Rna and Rnb are each independently hydrogen or d-6alkyl; n is an integer from 1 to 5; R2 represents unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl;
R3 represents hydrogen or Chalky!; R10 represents hydrogen or C^alkyl; and salts and solvates thereof; with the proviso that the following compounds are excluded;
2-(4-chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-phenylacetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-phenoxyacetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-methoxyphenyl)acetamide; 2-(3-Chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylthio)-
-phenyljacetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(dϊmethylamino)-
-phenyljacetamide compound with formic acid (1 :1 ); N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(dimethylamino)-
-sulfonyl]phenyl}acetamide compound with formic acid (1 :1);
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methyIsulfonyl)-
-phenyljacetamide compound with formic acid (1 :1)
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(3-fluorophenyl)acetamide; 2-[3,5-bis(trifluoromethyl)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]-
-methyljacetamide;
2-(2-chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-fluoro-2-methylphenyl)-
-acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(3,4-difluorophenyl)-
-acetamide;
4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-
-benzamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(trifluoromethyl)- -phenyljacetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-methylphenyl)acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,4-dichlorophenyl)-
-acetamide;
N-{[4-(3,4-dichIorobenzyl)morpholin-2-yl]methyl}-2-(4-fluorophenyl)acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(3,4-dichlorophenyl)- -acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,5-dichlorophenyl)-
-acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,6-dichlorophenyl)- -acetamide;
2-(4-chlorophenyl)-N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}-
-acetamide trifluoroacetate;
2-[3-(acetylamino)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-
-acetamide; 2-(4-acetylphenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide trifluoroacetate;
2-(4-acetylphenyl)-N-([4-(3,4-dichlorobenzyl)morpholin-2-yljmethyl}acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-isobutyrylphenyl)acetamide trifluoroacetate; methyl 4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-
-benzoate trifluoroacetate; methyl 4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-
-benzoate;
2-(4-cyanophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide trifluoroacetate;
2-(4-cyanophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide;
2-(4-chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}propanamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(3-fluoro-4-hydroxyphenyl)-
-acetamide trifluoroacetate; N-{[(2R)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl)-
-phenyljacetamide;
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl)- phenyljacetamide;
N-{[4-(3,4-dichlorobenzyl)morphoIin-2-yl]methyl}-2-{4-[(4-methylpiperazin- -1 -yl)carbonyl]phenyl}acetamide;
4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-
-[2-(dimethylamino)ethyl]benzamide;
4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-
-N,N-dimethylbenzamide; 4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-
-ethylbenzamide;
4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-
-(2-hydroxyethyl)benzamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yI]methyI}-2-[4-(morpholin-4-yl- -carbonyl)phenyl]acetamide; N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(dimethylamino)-
-sulfonyl]phenyl}acetamide;
N-{[(2R)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(dimethylamino)-
-sulfonyl]phenyl}acetamide; N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(dimethylamino)-
-sulfonyl]phenyl}acetamide;
4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-
-methylbenzamide;
4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N- -isopropylbenzamide;
N-cyclopropyl-4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-
-oxoethyljbenzamide;
4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyll-N-(2-
-methoxyethyl)benzamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-nitrophenyl)acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(3-nitrophenyl)acetamide; methyl 3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-
-benzoate;
2-[3-(acetylamino)phenyl]-N-{[4-(3-fluorobenzyl)morpholin-2-yl]methyl}- -acetamide;
N-{[4-(3-fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)-
-amino]phenyl}acetamide;
2-[3-(acetylamino)phenyl]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-
-acetamide; N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)-
-amino]phenyl}acetamide;
2-[4-(acetylamino)phenyl]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]-
-methyljacetamide;
N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-2-{3-[(methylsulfonyl)- -amino]phenyl}acetamide;
N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)-
-phenyljacetamide;
N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl)-
-phenyljacetamide; N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)-
-phenyljacetamide;
2-[3-(acetylamino)phenyl]-N-{[4-(4-fluorobenzyl)morpholin-2-yl]methyl}acetamide;
N-{[4-(4-fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)amino]-
-phenyljacetamide; 2-[4-(acetylamino)phenyl]-N-{[4-(4-fluorobenzyl)morpholin-2-yl]methyl}acetamide; N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl)-
-phenyljacetamide;
2-[3-(acetylamino)phenyl]-N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}-
-acetamide; N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)-
-amino]phenyl}acetamide;
N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-{[(methylamino)-
-carbonyl]amino}phenyl)acetamide;
N-({4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-[4-(methylsulfonyl)- -phenyljacetamide;
2-[3-(acetylamino)phenyl]-N-({4-[(5-chlorothien-2-yl)methyl]morpholin-2-
-yl}methyl)acetamide;
N-({4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{4-[(methylsulfonyl)-
-amino]phenyl}acetamide; N-({4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3-[(methylsulfonyl)-
-amino]phenyl}acetamide;
2-[3-(acetylamino)phenyl]-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-
-acetamide;
N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)- -amino]phenyl}acetamide;
2-[4-(acetylamino)phenyl]-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-
-acetamide;
N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-2-(4-{[(methylamino)carbonyl]-
-amino}phenyl)acetamide; 2-[4-(acetylamino)phenyl]-N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]-
-methyl}acetamide;
N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)-
-phenyljacetamide;
2-[4-(aminosulfonyl)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2- -yl]methyl}acetamide;
2-[2-(acetylamino)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-
-yl]methyl}acetamide;
2-(3-cyanophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2-fluorophenyl)acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,3-difluorophenyl)-
-acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,4-difluorophenyl)-
-acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,5-difluorophenyl)- -acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,6-difluorophenyl)-
-acetamide;
N-cyclopropyI-3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-
-oxoethyljbenzamide; 3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-(2-
-methoxyethyl)benzamide;
3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-
-ethylbenzamide;
3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N,N- dimethylbenzamide;
3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-[2-
(dimethylamino)ethyl]benzamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(4-methylpiperazin-1-
-yl)carbonyl]phenyl}acetamide; 2-(3-aminophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide;
2-(4-aminophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide;
2-[4-(acetylamino)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-
-acetamide;
N-{4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]- -phenyl}2-methylpropanamide;
N-{3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-
-phenyl}2-methylpropanamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(methylsulfonyl)-
-amino]phenyl}acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)-
-amino]phenyl}acetamide;
N-{3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-
-phenyl}-2-(dimethylamino)acetamide;
2-{4-[bis(methylsulfonyl)amino]phenyl}-N-{[4-(3,4-dichlorobenzyl)morpholin-2- yl]methyl}acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)-
-phenyljacetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl)-2-
-nitrophenyljacetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2-hydroxyphenyl)acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[methyl(methyisulfonyl)-
-amino]phenyl}acetamide;
N-{[4-(3,4-dichIorobenzyl)morpholin-2-yl]methyl}-2-{3-[methyl(methylsulfonyl)-
-amino]phenyl}acetamide; 2-[2-amino-4-(methylsulfonyl)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2- -yl]methyl}acetamide;
N-({(2S)-4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3-
-[(methylsulfonyl)amino]phenyl}acetamide;
N-({(2R)-4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3- -[(methylsulfonyl)amino]phenyl}acetamide;
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylamino)-
-sulfonyl]phenyl}acetamide;
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-r(ethylamino)-
-sulfonyl]phenyl}acetamide; 2-[3-(aminosulfonyl)phenyl]-N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-
-yl]methyl}acetamide;
2-{3-[(cyclopropylamino)sulfonyl]phenyl}-N-{[(2S)-4-(3,4-dichlorobenzyl)-
-morpholin-2-yl]methyl}acetamide;
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(ethylamino)- -sulfonyl]phenyl}acetamide;
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(methylamino)-
-sulfonyl]phenyl}acetamide;
N-{[(2S)-4-(4-fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)-
-amino]phenyl}acetamide; N-{[(2R)-4-(4-fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)-
-amino]phenyl}acetamide;
2-[4-(aminosulfonyl)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-
-yl]methyl}acetamide;
2-{4-[(cyclopropylamino)sulfonyl]phenyl}-N-{[4-(3,4-dichlorobenzyl)morpholin-2- -yl]methyl}acetamide;
N-cyclopropyl-3-[2-({[(2S)-4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-
-oxoethyljbenzamide;
3-{2-[({(2S)-4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)amino]-2-
-oxoethyl}-N-cyclopropylbenzamide; N-cyclopropyl-3-[2-({[(2S)-4-(4-fluorobenzyl)morpholin-2-yl]methyl}amino)-2-
-oxoethyljbenzamide;
3-[2-({[(2S)-4-(3-chlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-
-cyclopropylbenzamide;
N-cyclopropyl-3-[2-({[(2S)-4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}amino)-2- -oxoethyljbenzamide, and;
N-cyclopropyl-3-[2-({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-
-oxoethyljbenzamide.
Examples of the aryl group, R1, include phenyl.
When R1 is substituted aryl, suitable substituents include G*- 6alkylsulphonyl; d-ealkylthio; unsubstituted or substituted heteroaryl; C3- βcycloalkylsulphonylamino; d-6alkylaminocarbonylamino; C|. 6alkylaminosulphonyl; Cι-6alkylsulphonylaminoCι-6alkyl; amino; C3. 8cycloalkylaminocarbonyl; Cι-6aIkylcarbonyl; C3.8cycloalkylcarbonyl; d_ 6alkylsulphonylamino; d -ealkylcarbonylamino; C3-8cycloalkylcarbonylamino; R4R5NC(O)-, wherein R4 and R5 may each independently represent hydrogen or C-|.6alkyl, or R4 and R5 may represent a -(CH2)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; Cι-6alkoxycarbonyl; cyano; aminosulphonyl; aminocarbonyl; halo; carboxy; C-|.6alkyl, hydroxy, nitro, d- 6alkoxy, mono-and di-(d-6alkyl)amino.
When R1 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 Cι.6alkyl. Suitably, R is unsubstituted or substituted phenyl. When R1 is substituted phenyl, suitable substituents include d-
6alkylsulphonyl; d.6alkylthio; unsubstituted pyrazolyl; unsubstituted and substituted oxadiazolyl; substituted triazolyl; C3-8cycloalkylsulphonylamino; Ci- 6alkylaminocarbonyIamino; C-*-6alkylaminosulphonyl; d-βalkylsulphonylaminod- 6alkyl; cyano; amino; C3-8cycloalkylaminocarbonyl; C3.8cycloalkylcarbonyl; d- 6alkylcarbonyl; d-6alkylsulphonylamino; d-6alkylcarbonylamino; R4R5NC(O)-, wherein R4 and R5 may each independently represent hydrogen or d-6alkyl, or R4 and R5 may represent a -(CH2)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-6alkoxycarbonyl; aminosulphonyl; aminocarbonyl; halo; or carboxy.
More suitably, R1 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-(ethylaminocarbonyl), 3-(N,N- dimethylaminosulphonyl), 4-(methanesulphonylaminomethyl), 3- (methanesulphonylamino), 3-(cyclopropylcarbonyl), 3-(methyIcarbonyl), 3- (methoxycarbonyl), 3-(aminosulphonyl), 4-(methanesulphonylamino), 3- (methylaminocarbonyl), 3-(dimethylaminocarbonyl), 3-(/so-propylaminocarbonyl), 3-(/so-propylmethylaminocarbonyl), 4-(fluoro), 3-(amino), 4- (methylcarbonylamino), 3-(cyclopropylaminocarbonyl), 3-(methylcarbonylamino), 3-(ethylaminocarbonyl), 4-(piperidin-1-ylcarbonyl), 3-(ethoxycarbonyl), 4-cyano, 4-(aminosulphonyl), 4-(amido), 4-(chIoro), or 3-(carboxy).
Suitably, Rna and Rnb are both hydrogen.
Suitably, n is 1 , 2, or 3. Suitably, R10 is hydrogen or methyl.
More suitably, R10 is hydrogen.
Suitably, R3 is hydrogen.
When R2 is aryl, examples include phenyl.
When R2 is substituted aryl, suitable substituents include cyano, perhalod-6alkyl, amido, halo, d-6alkyl, d.6alkoxycarbonyl, mono- and di-(d- 6alkyl)aminocarbonyl, d-6alkoxy, nitro, d-ealkylsulphonyl, hydroxy, C1.6alkoxyCι- 6alkyl, d-6alkylthio-, mono- and-di-(Cι^alkyl)amino, and d.6alkylcarbonylamino.
When R2 is heteroaryl, examples include thiophenyl and pyridinyl.
When R2 is substituted heteroaryl, suitable substituents include cyano, perhaloCi-6alkyl, amido, halo, d-6alkyl, d.6alkoxycarbonyl, mono- and di-(d- 6alkyl)aminocarbonyl, d-6alkoxy, nitro, d-6alkylsulphonyl, hydroxy, C1.6alkoxyC1- 6alkyl, d-6alkylthio-, mono- and-di-(C1.6alkyl)amino, and Cι-6alkylcarbonylamino.
Suitably, R2 is unsubstituted or substituted phenyl, unsubstituted or substituted thiophenyl, or unsubstituted or substituted pyridinyl. When R2 is substituted phenyl suitable substituents include halo.
More suitably, R2 is phenyl substituted with chloro or fluoro, thiophenyl substituted with chloro, or pyridinyl.
Preferably, R2 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.
A group of compounds of formula (I) which may be mentioned is that of formula (Ii)
wherein:
R1 represents substituted or unsubstituted aryl; X represents -O- or a bond; Y represents -(CRnaRnb)n-; Rna and Rnb are each independently hydrogen or d-ealkyl; n is an integer from 1 to 5;
R2 represents unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl; R3 represents hydrogen or d-6alkyl; and salts and solvates thereof; with the proviso that the following compounds are excluded;
2-(4-chlorophenyl)-N-{[4-(3,4-dichlorobenzyI)morpholin-2-yl]methyl}acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-phenylacetamide; N-{[4-(3,4-dichIorobenzyl)morpholin-2-yl]methyl}-2-phenoxyacetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-methoxyphenyl)acetamide;
2-(3-Chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylthio)-
-phenyljacetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(dimethylamino)-
-phenyljacetamide compound with formic acid (1 :1 );
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(dimethylamino)-
-sulfonyl]phenyI}acetamide compound with formic acid (1 :1);
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl)- -phenyljacetamide compound with formic acid (1 :1)
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(3-fluorophenyl)acetamide;
2-[3,5-bis(trifluoromethyl)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]-
-methyljacetamide;
2-(2-chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-fluoro-2-methylphenyl)-
-acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(3,4-difluorophenyl)-
-acetamide;
4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]- -benzamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(trifluoromethyl)-
-phenyljacetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-methylphenyl)acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,4-dichlorophenyl)- -acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-fluorophenyl)acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(3,4-dichlorophenyl)-
-acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,5-dichlorophenyl)- -acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,6-dichlorophenyl)-
-acetamide;
2-(4-chlorophenyl)-N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}-
-acetamide trifluoroacetate; 2-[3-(acetylamino)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-
-acetamide;
2-(4-acetylphenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide trifluoroacetate;
2-(4-acetylphenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-isobutyrylphenyl)acetamide trifluoroacetate; methyl 4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-
-benzoate trifluoroacetate; methyl 4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]- -benzoate;
2-(4-cyanophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide trifluoroacetate;
2-(4-cyanophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide;
2-(4-chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}propanamide; N-{[4-(3,4-dichIorobenzyl)morpholin-2-yl]methyl}-2-(3-fluoro-4-hydroxyphenyl)-
-acetamide trifluoroacetate;
N-{[(2R)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl)-
-phenyljacetamide;
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl)- phenyljacetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(4-methylpiperazin-
-1-yl)carbonyl]phenyl}acetamide;
4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-
-[2-(dimethylamino)ethyl]benzamide; 4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-
-N,N-dimethylbenzamide;
4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-
-ethylbenzamide;
4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N- -(2-hydroxyethyl)benzamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(morpholin-4-yl-
-carbonyl)phenyl]acetamide;
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(dimethylamino)-
-sulfonyl]phenyl}acetamide; N-{[(2R)-4-(3,4-dichIorobenzyl)morpholin-2-yl]methyl}-2-{4-[(dimethylamino)- -suIfonyl]phenyl}acetamide;
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]rnethyl}-2-{4-[(dimethylamino)-
-sulfonyl]phenyl}acetamide;
4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N- -methylbenzamide;
4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-ylJmethyl}amino)-2-oxoethyl]-N-
-isopropylbenzamide;
N-cyclopropyI-4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-
-oxoethyljbenzamide; 4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-(2-
-methoxyethyl)benzamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-nitrophenyl)acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(3-nitrophenyl)acetamide; methyl 3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]- -benzoate;
2-[3-(acetylamino)phenyl]-N-{[4-(3-fluorobenzyl)morpholin-2-yl]methyl}-
-acetamide;
N-{[4-(3-fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)-
-amino]phenyl}acetamide; 2-[3-(acetylamino)phenyl]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-
-acetamide;
N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)-
-amino]phenyl}acetamide;
2-[4-(acetylamino)phenyl]-N-{[4-(3,4-difIuorobenzyl)morpholin-2-yl]- -methyljacetamide;
N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-2-{3-[(methylsulfonyl)-
-amino]phenyl}acetamide;
N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)-
-phenyljacetamide; N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl)-
-phenyljacetamide;
N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)-
-phenyljacetamide;
2-[3-(acetylamino)phenyl]-N-{[4-(4-fluorobenzyI)morpholin-2-yl]methyl}acetamide; N-{[4-(4-fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)amino]-
-phenyljacetamide;
2-[4-(acetylamino)phenyl]-N-{[4-(4-fluorobenzyl)morpholin-2-yl]methyl}acetamide;
N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl)-
-phenyljacetamide; 2-[3-(acetylamino)phenyl]-N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}- -acetamide;
N-{[4-(2,3-dichIorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)-
-amino]phenyl}acetamide;
N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-{[(methylamino)- -carbonyl]amino}phenyl)acetamide;
N-({4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-[4-(methylsulfonyl)-
-phenyljacetamide;
2-[3-(acetylamino)phenyl]-N-({4-[(5-chlorothien-2-yl)methyl]morpholin-2-
-yl}methyl)acetamide; N-({4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{4-[(methylsulfonyl)-
-amino]phenyl}acetamide;
N-({4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3-[(methylsulfonyl)-
-amino]phenyl}acetamide;
2-[3-(acetylamino)phenyl]-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}- -acetamide;
N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)-
-amino]phenyl}acetamide;
2-[4-(acetylamino)phenyl]-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-
-acetamide; N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-2-(4-{[(methylamino)carbonyl]-
-amino}phenyl)acetamide;
2-[4-(acetylamino)phenyl]-N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]-
-methyljacetamide;
N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)- -phenyljacetamide;
2-[4-(aminosuIfonyl)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-
-yl]methyl}acetamide;
2-[2-(acetylamino)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-
-yl]methyl}acetamide; 2-(3-cyanophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2-fluorophenyl)acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,3-difluorophenyl)-
-acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,4-difluorophenyl)- -acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,5-difluorophenyl)-
-acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yljmethyl}-2-(2,6-difluorophenyl)-
-acetamide; N-cyclopropyl-3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2- -oxoethyljbenzamide;
3-[2-({[4-(3,4-dichlorobenzyI)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-(2-
-methoxyethyl)benzamide;
3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N- -ethylbenzamide;
3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N,N- dimethylbenzamide;
3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-[2-
(dimethylamino)ethyl]benzamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(4-methylpiperazin-1-
-yl)carbonyl]phenyl}acetamide;
2-(3-aminophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide;
2-(4-aminophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide;
2-[4-(acetylamino)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}- -acetamide;
N-{4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-
-phenyl}2-methylpropanamide;
N-{3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-
-phenyl}2-methylpropanamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(methylsulfonyl)-
-amino]phenyl}acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)-
-amino]phenyl}acetamide;
N-{3-[2-({[4-(3,4-dichlorobenzyl)morphoNn-2-yl]methyl}amino)-2-oxoethyl]- -phenyl}-2-(dimethylamino)acetamide;
2-{4-[bis(methylsulfonyl)amino]phenyl}-N-{[4-(3,4-dichlorobenzyl)morpholin-2- yl]methyl}acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)-
-phenyljacetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl)-2-
-nitrophenyljacetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2-hydroxyphenyl)acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[methyl(methylsulfonyl)-
-amino]phenyl}acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[methyl(methylsulfonyl)-
-amino]phenyl}acetamide;
2-[2-amino-4-(methylsulfonyl)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-
-yl]methyl}acetamide;
N-({(2S)-4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3- -[(methylsuIfonyl)amino]phenyl}acetamide; N-({(2R)-4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3-
-[(methylsulfonyl)amino]phenyl}acetamide;
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylamino)-
-sulfonyl]phenyl}acetamide; N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(ethylamino)-
-sulfonyl]phenyl}acetamide;
2-[3-(aminosulfonyl)phenyl]-N-{[(2S)-4-(3,4-dichlorobenzyl)morphoIin-2-
-yl]methyl}acetamide;
2-{3-[(cyclopropylamino)sulfonyl]phenyl}-N-{[(2S)-4-(3,4-dichlorobenzyl)- -morpholin-2-yl]methyl}acetamide;
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(ethylamino)-
-sulfonyl]phenyl}acetamide;
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(methylamino)-
-sulfonyl]phenyl}acetamide; N-{[(2S)-4-(4-fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)-
-amino]phenyl}acetamide;
N-{[(2R)-4-(4-fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)-
-amino]phenyl}acetamide;
2-[4-(aminosulfonyl)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2- -yl]methyl}acetamide;
2-{4-[(cyclopropylamino)sulfonyl]phenyl}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-
-yl]methyl}acetamide;
N-cyclopropyl-3-[2-({[(2S)-4-(2,3-dichlorobenzyl)morphoIin-2-yl]methyl}amino)-2-
-oxoethyljbenzamide; 3-{2-[({(2S)-4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)amino]-2-
-oxoethyl}-N-cyclopropylbenzamide;
N-cyclopropyl-3-[2-({[(2S)-4-(4-fluorobenzyl)morpholin-2-yl]methyl}amino)-2-
-oxoethyljbenzamide;
3-[2-({[(2S)-4-(3-chlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N- -cyclopropylbenzamide;
N-cyclopropyl-3-[2-({[(2S)-4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}amino)-2-
-oxoethyljbenzamide, and;
N-cyclopropyl-3-[2-({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-
-oxoethyljbenzamide. There exists a subgroup of compounds of formula (1) being of formula (IA)
wherein
R1A is a moiety of formula (M)
wherein R6 represents d-6alkylthio, unsubstituted or substituted heteroaryl, C3- scycloalkylsulphonylamino; N,N-di(C1-6alkyl)aminosulphonyl, R8R9NC(O)- wherein R8 and R9 may each independently represent hydrogen or Ci-ealkyl or R8 and R9 may represent a -(CH2)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-6alkyl, halo, Cι-8a!koxy, or hydroxy; C3- 8cycloalkylaminosulphonyl; C3.8cycloalkylcarbonyl; aminosulphonyl; carboxy; mono-and di-(d.6alkyl)aminosulphonyl; d-6alkylsulphonylamino; Ci-
6alkylcarbonyl; C3-8cycloalkylaminocarbonyl; aminocarbonyl; d-6alkoxycarbonyl;
Cι-6alkylsulphonyl; or d-6alkylcarbonylamino;
R7 represents cyano, perhalod-6alkyl, hydrogen, C*ι-6alkyl, halo, d-ealkoxy, or hydroxy;
Y, R2, R3, and R10 are as hereinbefore defined for formula (I); and the following compounds are excluded;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-phenoxyacetamide;
2-[3-(acetylamino)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]- -methyljacetamide;
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(dimethylamino)-
-sulfonyl]phenyl}acetamide; methyl 3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-
-oxoethyljbenzoate; 2-[3-(acetylamino)phenyl]-N-{[4-(3-fluorobenzyl)morpholin-2-yl]methyl}acetamide; 2-[3-(acetylamino)phenyl]-N-{[4-(3,4-difluorobenzyl)morphoIin-2-yl]methyl}-
-acetamide;
N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-2-{3-[(methylsulfonyl)-
-amino]phenyl}acetamide; N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)-
-phenyljacetamide;
N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)-
-phenyljacetamide;
2-[3-(acetylamino)phenyl]-N-{[4-(4-fluorobenzyl)morpholin-2-yl]methyl}acetamide; 2-[3-(acetylamino)phenyl]-N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]-
-methyljacetamide;
2-[3-(acetylamino)phenyl]-N-({4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}-
-methyl)acetamide;
N-({4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3-[(methylsulfonyl)- -amino]phenyl}acetamide;
2-[3-(acetylamino)phenyl]-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-
-acetamide;
N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)-
-phenyljacetamide; N-cyclopropyl-3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-
-oxoethyljbenzamide;
3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-
-ethylbenzamide;
3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N,N- -dimethylbenzamide;
N-{3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]phenyl}-
-2-methylpropanamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(methylsulfonyl)-
-amino]phenyl}acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)-
-phenyljacetamide;
N-({(2S)-4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3-
-[(methylsulfonyl)amino]phenyl}acetamide;
N-({(2R)-4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3- -[(methylsulfonyl)amino]phenyl}acetamide;
2-[3-(aminosulfonyl)phenyl]-N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]-
-methyljacetamide;
2-{3-[(cyclopropylamino)sulfonyl]phenyl}-N-{[(2S)-4-(3,4-dichlorobenzyl)-
-morpholin-2-yl]methyl}acetamide; N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(ethylamino)- -sulfonyljphenyljacetamide;
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(methylamino)-
-suIfonyl]phenyl}acetamide;
N-cyclopropyl-3-[2-({[(2S)-4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2- -oxoethyljbenzamide;
3-{2-[({(2S)-4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)amino]-2-
-oxoethyl}-N-cyclopropylbenzamide;
N-cyclopropyl-3-[2-({[(2S)-4-(4-fluorobenzyl)morpholin-2-yl]methyl}amino)-2- oxoethyljbenzamide; 3-[2-({[(2S)-4-(3-chlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-
-cyclopropylbenzamide;
N-cyclopropyl-3-[2-({[(2S)-4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}amino)-2-
-oxoethyljbenzamide, and;
N-cyclopropyl-3-[2-({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2- oxoethyljbenzamide.
Suitably, R6 is d-6alkylsulphonylamino, C3.8cycloalkylcarbonyl, Ci-
6alkylcarbonyl, d.6alkoxycarbonyl, aminosulphonyl, carboxy, or mono- and di-
(Cι-6alkyl)aminocarbonyl.
Suitably, R7 is hydrogen. Suitable groups R1A 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-
(2-methyl-1 ,3,4-triazol-5-yl), 3-(methylaminocarbonyl), 3-(/so- propylsulphonylamino), 3-(cyclopropylsulphonylamino), 3-(ethylsulphonylamino),
3-(/so-propylaminosulphonyl), 3-(methylsulphonylamino), 3- (cyclopropylcarbonyl), 3-(methylcarbonyl), 3-(methoxycarbonyl), 3-
(aminosulphonyl), 4-(methylsulphonylaminomethyl), 3-(methylaminocarbonyl), 3-
(dimethylaminocarbonyl), 3-(/so-propylaminocarbonyl), 3-(iso- propylmethylaminocarbonyl), 4-(fluoro), 3-(amino), 4-(methyIcarbonylamino), 3-
(cyclopropylaminocarbonyl), 3-(methylcarbonylamino), 3-(ethylaminocarbonyl), 4- (piperidin-1-ylcarbonyl), 3-(ethoxycarbonyl), 4-cyano, 4-(aminosulphonyl), 4-
(amido), 4-(chloro) and 3-(carboxy).
More suitably, R1Ais phenyl substituted with 3-methylthio, 3- methanesulphonyl, 3-(2-methyl-1 ,3,4-oxadiazol-5-yl), 3-(1 ,3,4-oxadiazol-2-yl), 3-
(2-methyl-1 ,3,4-triazol-5-yl), 3-(methylaminocarbonyl), 3-(iso- propylsulphonylamino), 3-(cyclopropylsulphonylamino), 3-(ethylsulphonylamino),
3-(/so-propylaminosuIphonyl), 3-(cyclopropylcarbonyl), 3-(methylcarbonyl), 3-
(methoxycarbonyl), 3-(aminosulphonyl), 3-(methylaminocarbonyl), 3-
(dimethylaminocarbonyl), 3-( so-propylaminocarbonyl), 3-(iso propylmethylaminocarbonyl), 3-(ethylaminocarbonyl), 3-(methylsulphonylamino, or 3-(carboxy). A subgroup of compounds of formula (Ii) which may be mentioned is that of formula (lAi)
wherein
R1A is a moiety of formula (M)
wherein R6 represents R8R9NC(O)- wherein R8 and R9 may each independently represent hydrogen or Cι-6alkyl or R8 and R9 may represent a -(CH2)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 Cι.6alkyl, halo, d.6alkoxy, or hydroxy; C3-8cycloalkylaminosulphonyl; C3-8cycloalkylcarbonyl; aminosulphonyl; carboxy; mono-and di-(d-6alkyl)aminosulphonyl; d-6alkylsulphonylamino; d-
6alkylcarbonyl; C3-8cycloalkylaminocarbonyl; aminocarbonyl; d-6alkoxycarbonyl;
Cι-6alkylsulphonyl; or d-6alkylcarbonyIamino; R7 represents cyano, perhalod. 6alkyl, hydrogen, d-6alkyl, halo, Cι-6alkoxy, or hydroxy;
Y, R2. and R3 are as hereinbefore defined for formula (I); and the following compounds are excluded;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-phenoxyacetamide;
2-[3-(acetylamino)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]- -methyljacetamide;
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(dimethylamino)-
-sulfonyl]phenyl}acetamide; methyl 3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-
-oxoethyljbenzoate; 2-[3-(acetylamino)phenyl]-N-{[4-(3-fluorobenzyl)morpholin-2-yl]methyl}acetamide; 2-[3-(acetylamino)phenyl]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-
-acetamide;
N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-2-{3-[(methylsulfonyl)-
-amino]phenyl}acetamide; N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)-
-phenyljacetamide;
N-{[4-(3-chIorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)-
-phenyljacetamide;
2-[3-(acetylamino)phenyl]-N-{[4-(4-fluorobenzyl)morpholin-2-yl]methyl}acetamide; 2-[3-(acetylamino)phenyl]-N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]-
-methyljacetamide;
2-[3-(acetylamino)phenyl]-N-({4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}-
-methyl)acetamide;
N-({4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3-[(methylsulfonyl)- -amino]phenyl}acetamide;
2-[3-(acetylamino)phenyl]-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-
-acetamide;
N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)-
-phenyljacetamide; N-cyclopropyl-3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-
-oxoethyljbenzamide;
3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-
-ethylbenzamide;
3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N,N- -dimethylbenzamide;
N-{3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]phenyl}-
-2-methylpropanamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(methylsulfonyl)-
-amino]phenyl}acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)-
-phenyljacetamide;
N-({(2S)-4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3-
-[(methylsulfonyl)amino]phenyl}acetamide;
N-({(2R)-4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3- -[(methylsulfonyl)amino]phenyl}acetamide;
2-[3-(aminosulfonyl)phenyl]-N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]-
-methyljacetamide;
2-{3-[(cyclopropylamino)sulfonyl]phenyl}-N-{[(2S)-4-(3,4-dichlorobenzyl)-
-morpholin-2-yl]methyl}acetamide; N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(ethylamino)- -sulfonyl]phenyl}acetamide;
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(methylamino)-
-sulfonyl]phenyl}acetamide;
N-cyclopropyl-3-[2-({[(2S)-4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2- -oxoethyljbenzamide;
3-{2-[({(2S)-4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyI)amino]-2-
-oxoethyl}-N-cyclopropylbenzamide;
N-cyclopropyl-3-[2-({[(2S)-4-(4-fluorobenzyl)morpholin-2-yl]methyl}amino)-2- oxoethyljbenzamide; 3-[2-({[(2S)-4-(3-chlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-
-cyclopropylbenzamide;
N-cyclopropyl-3-[2-({[(2S)-4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}amino)-2-
-oxoethyljbenzamide, and;
N-cyclopropyl-3-[2-({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2- oxoethyljbenzamide.
Suitable compounds of the invention are Examples 1 , 2, 3, 4, 5, 8, 9, 10,
11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 24, 25, 28, 29, 30, 31 , 35, 39, 41, 43,
45, 47, 49, 51 , 53, 55, 57, 59, 61 , 63, 65, 77, 81, 82, 83, 85, 87, 88, 89, and 90. 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,
77, 85, 87, 88, 89, and 90.
More preferred compounds of the invention are Examples 13, 88, 14, 1 ,
4, 35, 29, 43, 45, 47, 49, 51 , 55, 57, 59, 85, and 87.
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. If appropriate, 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. Examples of solvates include hydrates. There exists a preferred subgroup of compounds of formula (I) being of formula (I1)
wherein:
R1' is a moiety of formula (M1)
wherein R6' represents R8R9NC(O)-, where R8 and R9 are as previously defined; Cι-6alkoxycarbonyl; d.6alkylcarbonyl; C3.8cycloalkylcarbonyl; d. ealkylsulphonylamino; carboxy; or aminosulphonyl; R7' is hydrogen or halo, and; R2' is phenyl substituted by halo.
Suitably, R1' is phenyl substituted with C3-8cycloalkylcarbonyl, d- 6alkylcarbonyl, Cι.6alkoxycarbonyl, aminosulphonyl, Cι-6alkylsulphonylamino, carboxy, or mono-or di-(d-6alkyl)aminocarbonyl.
Preferably, R1' 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.
Suitably, R2' is phenyl substituted by chloro of fluoro. Preferably, R2' is 3,4-dichlorophenyl, 3,4-difluorophenyl or 3-chloro-4- fluorophenyl. Preferably, the stereochemistry at the position marked '*' is (S).
Accordingly, there is provided a compound of formula (I1) or a salt or solvate thereof.
There exists a further preferred subgroup of compounds of formula (I) being of formula (I")
wherein;
R1" is substituted phenyl, and; R2 is phenyl substituted with halo.
Suitably, R1" is phenyl substituted with C3-8cycloalkylaminocarbonyl, Ci- 6alkylcarbonylamino, R4R5NCO (where R4and R5 are as previously defined), Ci- 6alkoxycarbonyl, carboxy, d-6alkylsulphonylamino, cyano, aminosulphonyl, aminocarbonyl, halo, or amino. Preferably, R " is 3-(cyclopropylaminocarbonyl)phenyl, 3-
(methylcarbonylamino)phenyl. 3-(ethylaminocarbonyl)phenyl, 3- (ethoxycarbonyl)phenyl, 3-carboxyphenyl, 3-(methanesulphonylamino)phenyl, 3 (methylaminocarbonyl)phenyl, 4-(methylcarbonylamino)phenyl, 4-(piperidin-1 - ylcarbonyl)phenyl or 3-aminophenyl. Suitably, R2" is phenyl substituted with chloro.
Preferably, R2' is 3,4-dichlorophenyl. Suitably, 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)
wherein:
R1" is 4-substituted phenyl, and; R2"' is phenyl substituted by halo. Suitably, R1 "' is phenyl substituted at the 4- or para position with Ci. 6alkylsulphonylaminoalkyl.
Preferably, R1 "' is 4-(methanesulphonylaminomethyl)phenyl.
Suitably, R2'" is phenyl substituted by chloro of fluoro. Preferably, R2" is 3,4-difluorophenyl.
Preferably, the stereochemistry at the position marked '*' is (S).
Accordingly, there is provided a compound of formula (I'") or a salt or solvate thereof.
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.
Generally it is preferred that 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-(alkyl)amino; and alkylcarbonylamino.
References to 'heteroaryl' refer to heterocyclic aromatic rings containing 1-4 heteroatoms selected from nitrogen, oxygen and sulphur. Examples of 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. Examples of 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);
wherein;
R\ X, Y, R3, R10, and R2 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.
Suitably, the activating agent is 1 -hydroxybenzotriazole (HOBT).
Examples of 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. Suitably, the peptide coupling agent is 1-(3-dimethylaminopropyI)-3-ethylcarbodiimide hydrochloride. Typically, the compound of formula (II) and the compound of formula (III) in 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 R3 is hydrogen may be prepared either by Reaction (a) or Reaction (c). The S-enantiomer of a compound of formula (III) may be prepared by Reaction (b).
Reaction (a). Reaction of the compound of formula (IV) with a compound of formula (V)
wherein R2 and R10 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 R3 is hydrogen i.e. a compound of formula (I MR)
wherein R2 and R10 are as hereinbefore defined, and optionally resolution of the resulting enantiomers of a compound of formula (IIIR); or;
Reaction (b). Reaction of a compound of formula (IV) as hereinbefore defined with a compound of formula (VA)
wherein A is as hereinbefore defined for formula (V), followed by deprotection of the amino group to give the corresponding enantiomer of a compound of formula (III) wherein R3 is hydrogen i.e. a compound of formula (HIE)
wherein R2 and R10 are as hereinbefore defined. Reaction (c). Hydrolysis of a compound of formula (VI);
wherein T is trifluoroacetyl, and R3, R10, and R2 are as hereinbefore defined for formula (I), and optionally resolution of the resulting enantiomers of a compound of formula (111). For both reactions (a) and (b), the reaction between the compound of formula (IV) and a compound of formula (V) or (VA) is typically carried out under the Mitsonobu conditions as follows:
Typically, a mixture of the compound of formula (IV) and the compound of formula (V) or formula (VA) in a suitable solvent, such as tetrahydrofuran, is stirred, suitably for 20-24 hours at a suitable temperature, suitably the reflux temperature of the solvent, under an inert atmosphere, suitably an atmosphere of nitrogen. Further solvent is then added and the mixture cooled, suitably to 0- 5°C. A suitable 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. After a suitable period, suitably 20 - 45 minutes, the resultant slurry is cooled, suitably to 20-25°C, and then allowed to stand, suitably for 1.5 - 3 hours, after which time the product is isolated by filtration. The filter bed is washed with more alcohol and then dried in vacuo at 35-45°C to yield the protected form of the compound of formula (IIIR) or formula (HIE) respectively.
The removal of the protecting group from the product is typically carried out as follows. A slurry of the protected form of the compound of formula (IIIR) or formula (HIE) in an appropriate polar solvent, suitably water, is heated to elevated temperature, suitably 70-75°C and then treated dropwise with a concentrated mineral acid, suitably concentrated sulphuric acid. 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. Further apolar solvent is then added, the aqueous phase then being separated and extracted with further apolar solvent. The combined organic phase is washed with water and then evaporated to dryness. The residue is redissolved and the apolar solvent evaporated to give the compound of formula (IIIR) or formula (HIE).
The process for the preparation of the protected form of the compound of formula (IIIR) or formula (HIE) described above may also be undertaken in two stages, in which an intermediate compound of formula (IIIBR) or of formula (IIIBE) respectively;
(IIIBR) (IIIBE)
wherein A is as hereinbefore defined for formulae (V) and (VA) and R2 and R10 are as hereinbefore defined for formula (I); is isolated.
Typically, 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. Further 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. The mixture is stirred at a suitable temperature, for example those in the range 20- 25°C for a suitable time, for example 16-20 hours followed by removal of the organic solvent in vacuo. Water is then added and the mixture extracted with a suitable organic solvent, for example ethyl acetate. The combined organic phases are washed with water and saturated aqueous sodium chloride solution before drying over a suitable drying agent, for example sodium sulphate, filtering and evaporation of the solvent in vacuo. The crude product is then purified by flash chromatography. The resolution of the compound of formula (HIE) from the racemic product i.e. the compound of formula (IIIR) may be undertaken using techniques well known to those skilled in the art, for example preparative chiral high performance liquid chromatography (chiral HPLC) or by fractional crystallisation of diastereoisomeric salts. A compound of formula (VI) may be prepared by reaction of a compound of formula (VII) with a compound of formula (VIII)
wherein;
T, R3, R10, and R2 are as hereinbefore defined for formula (VI) and L2 is a leaving group. A suitable leaving group, L2 is a halo group such as chloro. The reaction between a compound of formula (VII) and a compound of formula (VIII) is typically carried out by stirring a solution of the compound of formula (VII) in a suitable solvent, for example N,N-dimethylformamide, under an inert atmosphere, for example an atmosphere of nitrogen, with the addition of a suitable base, for example potassium carbonate, and a suitable activating agent such as sodium iodide. A solution of a compound of formula (VIII) in a suitable solvent, such as N,N-dimethylformamide, is added dropwise to the mixture. The mixture is then stirred at a suitable temperature, for example a temperature in the range of 20-25°C, for a suitable period of time, for example 16-20 hours before removing the volatile components in vacuo. 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);
wherein R3, R10, and T are as hereinbefore defined for formula (VI) and Rx 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. 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.
Additionally, and in a further aspect, a compound of formula (I) may be prepared by reaction of a compound of formula (XI) with a compound of formula
(in);
wherein L2 is a leaving group, and R1, X, and Y 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;
(iii) preparing a salt or solvate of the compound so formed.
Suitable leaving groups are halo groups, preferably bromo. Typically, the reaction between a compound of formula (III) and a compound of formula (XI) is carried out in a suitable solvent, such as a polar organic solvent, e.g. acetonitrile, in the presence of a suitable base, such as an alkali or alkaline earth metal carbonate, e.g. potassium carbonate, at a suitable temperature, such as ambient temperature, e.g. 18 - 25°C for a suitable time period, e.g. 2 - 4 hours.
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), and (XI) are known, commercially available compounds, 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), and (IIIBE) are considered to be novel. Accordingly, there is provided a compound of formula (IIIBE).
There is also provided a compound of formula (IIIBR). 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 R1 into another group R1.
The above mentioned conversion may be carried out using any appropriate method under conditions determined by the particular groups chosen. Thus, suitable conversions of one group R1 into another group R1 include: (a) converting a group R1 which represents an aryl group substituted with an alkoxycarbonyl group into a group R1 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;
(b) converting a group R1 which represents an aryl group substituted with a carboxy group into a group R1 which represents an aryl group substituted with an amido group; such a conversion may be carried out using an appropriate conventional amination procedure, for example treating an appropriately protected compound of formula (I) with a suitable amine in the presence of a suitable peptide coupling agent and, if required, a suitable activating agent;
(c) converting a group R1 which represents an aryl group substituted with an alkoxycarbonylamino group into a group R1 which represents an aryl group substituted with amino group; such a conversion may be carried out using an appropriate conventional deprotection procedure, for example treating an appropriately protected compound of formula (I) with a suitable mineral acid, and;
(d) converting a group R1 which represents an aryl group substituted with a amino group into a group R1 which represents an aryl group substituted with alkylsulphonylamino group; such a conversion may be carried out using an appropriate conventional sulphonylation procedure, for example treating an appropriately protected compound of formula (I) with a suitable alkylsulphonyl halide in the presence of a suitable base. The above mentioned conversions may as appropriate be carried out on any of the intermediate compounds mentioned herein.
The above mentioned conversions may as appropriate be carried out on any of the intermediate compounds mentioned herein.
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. For any of the hereinbefore described reactions or processes, 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 (scintillation proximity assay) was used to assess the affinity of novel compounds for CCR-3. Membranes prepared from K562 cells stably expressing CCR-3 (2.5μg/well) were mixed with 0.25mg/well wheat-germ agglutinin SPA beads (Amersham) and incubated in binding buffer (HEPES 50 mM, CaCI2 1 mM, MgCI25 mM, 0.5% BSA) at 4°C for 1.5 hr. Following incubation, 20 pM of [125l] eotaxin (Amersham) and increasing concentrations of compound (1 pM to 30μM) were added and incubated in a 96 well plate for 2 hr at 22°C then counted on a Microbeta plate counter. The total assay volume was 100 μl. Competition binding data were analysed by fitting the data with a four parameter logistic equation. Data are presented as the mean plC50 values (negative logarithm of the concentration of compound which inhibits [125l]eotaxin binding by 50%) from at least two experiments.
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. (b) Eosinophil Chemotaxis Assay.
Compounds were evaluated for their inhibitory effect on eosinophil chemotaxis. 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;
J. Immunology. 161 :4340-6). Cells were re-suspended in RPMI 1640/10% FCS solution and incubated with calcein-AM (Molecular Probes) at 37°C for 30 mins. Following incubation, the eosinophils were centrifuged at 400g for 5 min and re- suspended in RPMI/FCS at 2.2 million/ml. Cells were then incubated in the presence of increasing concentration of compounds (1 pM to 30 μM) at 37°C for 30 mins. For control responses cells were incubated with RPMI/FCS only. The agonist eotaxin (an EC80 concentration) was added to the lower chamber of a 96 well chemotaxis plate (5 μm filter: Receptor Technologies). Eosinophils (50 μl 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).
IC. fpKi =- 50
[Agonist]
1 +
EC 5.0
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:
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. Also included are 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.
Furthermore, 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.
Further examples of disease states in which compounds of the invention have potentially beneficial effects include 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. As mentioned above, compounds of formula (I) are useful as therapeutic agents.
There is thus provided as a further aspect of the invention a compound of formula (I) or a physiologically acceptable salt or solvate thereof for use as an active therapeutic agent. There is also therefore provided 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.
According to another aspect of the invention, there is provided the use of 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.
In a further or alternative aspect there is provided a method for the treatment of a human or animal subject suffering from or susceptible to an inflammatory condition e.g. asthma or rhinitis, which method 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.
There is thus further provided a pharmaceutical 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.
There is also provided 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 sweetening agents (e.g. mannitol) as appropriate. For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
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. Alternatively, 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. sodium cromoglycate, nedocromil sodium, PDE-4 inhibitors, leukotriene antagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine 2a agonists; or beta adrenergic agents such as salmeterol, salbutamol, formoterol, fenoterol or terbutaline and salts thereof; or antiinfective agents e.g. antibiotic agents and antiviral agents. It will be appreciated that when the compounds of the present invention are administered in combination with other therapeutic agents normally administered by the inhaled or intranasal route, that the resultant pharmaceutical composition may be administered by the inhaled or intranasal route.
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. Throughout the description and the claims which follow, unless the context requires otherwise, 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 invention is illustrated by reference to, but is in no way limited by, the following Examples.
For the avoidance of doubt, the free bond on the R1 groups as presented in the Tables signifies the point of attachment of the R1 groups to the residue of the molecule.
It should be noted that, for clarity, compounds of the Descriptions and the Examples are referred to by number, for example "Description 3" and "Example 5". The structures of the compounds so referred to are given in Tables 1 to 4 for the Examples and Tables 5 to 7 for the Descriptions.
General experimental details LC/MS System
The following Liquid Chromatography Mass Spectroscopy (LC/MS) System was used:
This system used an 3μm 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
120°C (stem), 190°C (tip), detection mass range 100-850 a.m.u. Compounds were injected in 10μl of a mixture of solvents comprising 65% methanol and 35% 0.05M aqueous ammonium acetate, at a flow rate of 0.7ml/min.
Solid phase extraction (ion exchange)
'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 5.0μm.
All temperatures are in °C
Descriptions
Description 1 : 2.2.2-Trifluoro-N-(morpholin-2-ylmethyl)acetamide To a stirred solution of morpholin-2-ylmethylamine (3.1 g) in methanol (70ml) under nitrogen was added an ethereal solution of ethyl-α,α,c.-trifluoroacetate (5ml in 20ml ether) which had been washed with saturated aqueous sodium bicarbonate, water and brine, and dried. The mixture was stirred for 30 min at 22°C before removal of all volatiles in vacuo. The residue was dissolved in methanol (10ml) and the volatiles again removed in vacuo to give the title compound as a white crunchy foam (4.9g). Thermospray Mass Spectrum m/z 213 [MH+].
Description 2: N-(r4-(3,4-Dichlorobenzyl)morpholin-2-vπmethyl)-2,2,2- trifluoroacetamide
To a stirred solution of Description 1 (3.3g) in N,N-dimethylformamide (50ml) under nitrogen was added potassium carbonate (2.46g) and sodium iodide (2.12g). A solution of 3,4-dichlorobenzyl chloride (2ml) in N,N- dimethylformamide (10ml) was added dropwise to the mixture. The mixture was stirred at 22°C for 18h before the volatiles were removed in vacuo. The residue was partitioned between dichloromethane (100ml) and saturated aqueous sodium carbonate solution (50ml). The organic phase was subsequently washed with additional saturated aqueous sodium carbonate solution (2 x 50ml) and water (50ml) before drying over magnesium sulphate, filtering and evaporation of the solvent in vacuo to give a pale yellow oil. The oil was purified by Biotage flash chromatography on a 90g silica cartridge eluting with 25% ethyl acetate in cyclohexane, to give the title compound as a colourless oil (2.97g). 5 LC/MS Rt 2.63 min, Mass Spectrum m/z 371 [MH+].
Description 3: f4-(3.4-Dichlorobenzyl)morpholin-2-yl1methylamine
To a stirred solution of Description 2 (2.97g) in methanol (15ml) and water (5ml) was added potassium carbonate (5.53g). The mixture was stirred at 22°C for
10 18h before the methanol was removed in vacuo. Water (25ml) was added and the mixture extracted with ethyl acetate (3 x 30ml). The combined organic phases were washed with water (5ml) and saturated aqueous sodium chloride solution (10ml) before drying over sodium sulphate, filtering and evaporation of the solvent in vacuo to give a pale yellow oil. The oil was purified by Biotage
15 flash chromatography on a 90g silica cartridge eluting with 75:8:1 dichloromethane/ethanol/0.880 ammonia solution. The required fractions were combined and the solvent evaporated in vacuo to give the title compound as a colourless oil (1.85g). LC/MS Rt 1.77 min, Mass Spectrum /z 275 [MH+].
20
Description 4: r4-(3.4-Dichlorobenzyl)morpholin-2-vnmethylamine (alternative synthesis)
A mixture of 2-[(3,4-dichlorobenzyl)amino]ethanol (Chem Abs No. 40172-06-3,
0.980g) and 2-(oxiran-2-ylmethyl)-1 H-isoindole-1 ,3(2H)-dione (1.1 Og) was
25 heated at 80°C under nitrogen for 3h. The resulting solid mass was treated with concentrated sulphuric acid (1.5ml) then stirred at 150°C for 24h. The mixture was treated with water (100ml) then washed with ethyl acetate (2x100ml). The dark aqueous phase was basified to ~pH 12 using 5M aqueous sodium hydroxide, then extracted with ethyl acetate (2x100ml). The combined organic
30 extracts were washed with water and brine, dried (Na2SO ) and concentrated under vacuum to give the title compound as a brown oil (1.02g). Mass spec, m/z 275 (MH+).
Description 5: 1 -F(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-vπmethylamine 35 Description 3 (racemic mixture, 8g) was separated into its single enantiomers by preparative chiral-HPLC. The separation was carried out using a 2" x 22cm Chiralpak AD 20μm column, Merck self pack DAC system, eluting with 95:5:0.1 (v/v) heptane : absolute ethanol: diethylamine (flow rate: 55ml/min over 40min, UV detection 225nm); sample load preparation: 400mg sample in 20ml 3:2 (v/v) 40 absolute ethanol: system eluent. The title compound (2.49g) was obtained as follows: preparative HPLC retention time 23.0 min.
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 6: 1-[(2S)-4-(3.4-Dichlorobenzyl)morpholin-2-vnmethanamine salt with D-tartaric acid 1 :1
Description 3 (0.613g) was dissolved in methanol (12.3ml). D-Tartaric acid
(0.335g) was added and the slurry was heated to reflux for 50min. The mixture was allowed to cool to 0-5°C and the precipitate isolated by filtration to give the title compound as a white solid (0.4g). ee: 76%ee
Chiral analytical HPLC (Chiralpak AD column, 4.6 x 250mm, eluent 50:50:0.1
MeOH: EtOH: Butylamine, flow rate 0.5ml/min, UV detection at 220nm), Rt
8.9min.
Description 7: 2-r4-(3,4-Dichloro-benzyl)-morpholin-2-ylmethvn-isoindole-1 ,3- dione
A mixture of 2-[(3.4-dichlorobenzyl)amino]ethanol (2.038 g) and (S)-2-(oxiran-2- ylmethyl)-1 H-isoindole-1 ,3(2H)-dione (2.032g) in tetrahydrofuran (3.3ml) was stirred and heated at reflux under nitrogen. After 21.5h more tetrahydrofuran (12.5ml) was added and the mixture was cooled to 3°. Triphenyl phosphine (2.793g) was added and the mixture was stirred until all the solid had dissolved. Diisopropylazodicarboxylate (2.1ml) was then added over 12min maintaining the temperature at <7°. After 2.25h the mixture was allowed to warm to 22°. After 5.3h more triphenylphosphine (121mg) and diisopropylazodicarboxylate (0.09ml) were added. After 22.5h the reaction mixture was concentrated to near dryness. Propan-2-ol (12ml) was added and the concentration repeated, this was repeated once more. More propan-2-ol (12ml) was added and the mixture was heated to 70°. After 0.5h the slurry was cooled to 22° and then after a further 2h the product was collected. The bed was washed with propan-2-ol (2x4ml) and then dried in vacuo at 40° to give the product, (2.622g).
Description 8: f(2S)-4-(3.4-difluorobenzyl)morpholin-2-vnmethylamine Description 8 was made in an analogous manner to that of Description 5. Preparative HPLC retention time 28.3min
Description 10: r3-((IY2S)-4-(3.4-Dichlorobenzyl)morpholin-2- ylmethvπcarbamoyl)methoxy)phenvπcarbamic acid tert-butyl ester
To a stirred solution of (3-tert-butoxycarbonylamino-phenoxy)-acetic acid (0.1 OOg) (WO 9708193), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.1043g) and 1-hydroxybenzotriazoIe (0.0597g) in N,N- dimethylformamide (3ml) was added a solution of Description 5 (0.0936g) in N,N- dimethylformamide (1 ml). N,N-diisopropylethylamine (0.119ml) was added to the mixture which was then stirred at 20° for 19.5h. The mixture was diluted with methanol (ca. 2ml) and applied to a 10g SCX ion-exchange cartridge (preconditioned with methanol). The cartridge was eluted with methanol and 10% 0.880 ammonia solution in methanol. The first ammonia fraction was evaporated in vacuo and the residue further purified by Biotage™ flash chromatography on silica gel, eluting with 300:8:1 dichloromethane/ethanol/0.880 ammonia solution. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (0.1256g) as a colourless glass. LC/MS: Rt = 3.14min, m/z 524,526 [MH+]
Method G
Example 27: 2-(3-Amino-phenoxy)-N-r4-(3.4-dichlorobenzyl)morpholin-2- ylmethyllacetamide
To a stirred solution of Description 10 (0.120g) in methanol (3ml) was added a 4.0M solution of hydrogen chloride in 1 ,4-dioxane (1 ml). The mixture was stirred at 20° for 6h and then left to stand for 16h. The solvent was evaporated in vacuo to give a residue which was re-dissolved in methanol and evaporated to dryness under a stream of nitrogen to give the title compound (0.114g) as a light brown gum. LC/MS: R, = 2.30min, m/z 424,426 [MH+]
Description 12: C-f(2S)-4-(3-Chloro-4-fluorobenzyl)morpholin-2-yllmethylamine
A solution of Description 17 (0.36g) in dichloromethane (1ml) was treated with trifluoroacetic acid (1 ml) and allowed to stand for 1 hr. The mixture was concentrated in vacuo and the residue partitioned between dichloromethane and aqueous sodium bicarbonate; the phases were separated and the organic phase dried (MgSO ), filtered and the solvent evaporated in vacuo to give the title compound (0.25g) as a colourless gum.
LC-MS : Rt = 0.70min. Mass Spectrum m/z 259 [MH+]
5 Description 13: 3-Ethoxycarbonylmethoxy-benzoic acid ethyl ester
To a stirred mixture of ethyl 3-hydroxybenzoate (1.66g) and anhydrous 10 potassium carbonate (1.38g) in N,N-dimethylformamide (20ml) at room temperature was added ethylbromoacetate (1.67g). The mixture was stirred overnight before evaporation of the solvent in vacuo and the resultant thick white paste was partitioned between water and ethyl acetate (two portions, total 50ml). The combined organic extracts were washed with 2% aqueous sodium hyrdoxide 15 (100ml) and brine (2x50ml), dried over sodium sulphate, filtered and the solvent evaporated in vacuo. The residue was further purified by flash column chromatography on silica gel, eluting with 4:1 cyclohexane/ethyl acetate. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (2.18g) as a colourless oil. 20 1H nmr (250MHz, CDCI3) 7.70δ (I H, br.d, CH); 7.575 (IH, br.d, CH); 7.38δ (l±I, t, CH); 7.15δ (IH, br. dd, CH); 4.68δ (2H, s, CH2); 4.40-4.205 (4H, 2xq, 2xCH2); 1.39δ (3H, t, CH3);1.30δ (3H, t, CH3)
Description 14: 3-Carboxymethoxy-benzoic acid ethyl ester
25
To a stirred solution of Description 13 (0.397g) in methanol (7ml) and water (3ml) was added potassium carbonate (0.217g). The mixture was stirred at 20°C for 30 18h before the methanol was evaporated in vacuo. The pH of the resulting solution was adjusted to approximately 1 by addition of 2M aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate (3x15ml). The combined organic extracts were washed with brine (10ml), dried over magnesium sulphate, filtered and the solvent evaporated in vacuo to give the title compound (0.329g) as a white solid.
LC/MS: Rt = 2.81 min, m/z 225 [MH+]
Description 15: (3-Methanesulfonylamino-phenyl)acetic acid
To a stirred solution of 3-aminophenylacetic acid (3.2g) and sodium carbonate (5.44g) in de-ionised water (36ml) was added methanesulphonyl chloride (1.7 ml). The mixture was heated with stirring at 85° for 4h before being left to cool to room temperature, acidified to pH 2 with cone, hydrochloric acid and left to stand in a refrigerator at 4° overnight. The precipitated solid was filtered, washed with water and ether and the combined filtrate and washings were evaporated to dryness in vacuo. The resultant residue was dissolved in hot water and left to re- crystallise overnight whilst standing in a refrigerator at 4°C. The crystals were filtered, washed with a small quantity of cold water and dried in vacuo to give the title compound (0.417g) as colourless crystals. LC/MS : Rt = 2.00min, m/z 228 [MH-], m/z 247 [MNH4 +]
Description 16: (3-Cvclopropanecarbonyl-phenyl)acetic acid
A stirred suspension of cyclopropyl-m-tolylketone (J Org Chem (1993), 58(21), 5802-10; 16.0g) and N-bromosuccinimide (17.8g) in carbon tetrachloride (100ml) was heated slowly to reflux with a 150W electric lamp. After two hours at reflux, the solution was cooled in ice-water to yield a solid which was filtered off and washed with carbon tetrachloride (10ml). The filtrate and washings were combined and evaporated to give a yellow oil which was fractionally distilled using a Vigreux column. The fraction which distilled at 115 - 130°C at 0.1 mm mercury was collected and dissolved in anhydrous N,N-dimethylformamide (20ml). This solution was added dropwise over one hour to a stirred suspension of sodium cyanide (1.96g) in anhydrous N,N-dimethylformamide (40ml) at <10°C. Stirring was maintained at 10°C for a further hour, then at room temperature for 2 hours after which the mixture was poured into ice (140g) and extracted with ethyl acetate (3 x 60ml). The combined extracts were dried (MgSO4) and evaporated to give a brown oil which was then treated with 50% aqueous alcohol containing potassium hydroxide (3.36g). This mixture was heated under reflux for five hours then allowed to cool, washed with chloroform (2 x 50ml) and acidified to pH1 by addition of 5M hydrochloric acid (~15ml). The resulting yellow oil was extracted into ethyl acetate (2 x 75ml) and the combined extracts were washed with water (3 x 15ml), dried (MgSO4) and the solvent evaporated to give a yellow oil. This oil was extracted with hot petroleum ether (b.p. 60 - 80°C, 4 x 50ml) and the combined extracts evaporated to give a gummy oil. This was recombined with the residue which remained from the extraction, dissolved in 10% ethyl acetate/ether (200ml), and the resulting solution filtered, washed with water (3 x 20ml), dried (MgSO4) and evaporated to give an oil. This oil was purified by chromatography on silica gel (100g) eluting with ethyl acetate, and appropriate fractions were combined and evaporated to give a pale yellow oil which was then distilled under high vacuum. The material which distilled at 170°C at 0.1 mm mercury was collected to give the title compound (1.5g) as a dark cream solid. Analysis found C, 70.44%; H, 6.00% Analysis required C, 70.6%; H, 5.92%.
Description 17: r(2S)-4-(3-Chloro-4-fluorobenzyl)morpholin-2-ylmethvncarbamic acid tert-butyl ester
A solution of (2-morpholinylmethyl)-carbamic acid 1 ,1 -dimethyl ester [CAS 186202-57-3] (0.26g) in dichloromethane (5ml) was treated with triethylamine (0.167ml) and 3-chloro-4-fluorobenzyl bromide (0.27g). After stirring for 18hrs the mixture was purified by applying directly to an SCX ion exchange cartridge (10g), eluting with methanol followed by 10% 0.880 ammonia/methanol. The basic fraction was evaporated in vacuo to give the title compound (0.37g) as a colourless gum. LC-MS : Rt = 2.46min. Mass Spectrum m/z 359 [MH+] Description 18: r4-(3,4-Dichlorobenzyl)morpholin-2-ylmethvπmethylamine
A mixture of Description 29 (0.0755g) in 5:1 methanol/water (7ml) and potassium carbonate (0.27g) was stirred at room temperature under nitrogen for 5hr before leaving to stand for 65hr. The solvent was evaporated in vacuo and the residue re-dissolved in water (6ml). The aueous solution was extracted with dichloromethane (4x3ml) using a hydrophobic frittted cartridge to separate the phases. The combined organic extracts gave, after evaporation of the solvent, the title compound (0.0507g). LCMS m/z 289 [MH+]
Description 20: 4-(2-(r(2S)-4-(3.4-Dichlorobenzyl)morpholin-2- ylmethyllcarbamoyllethvPbenzoic acid tert-butyl ester
Prepared in an analogous manner to that used for Example 18 using Description 5_and 4-(2-carboxy-ethyl)benzoic acid tert-butyl ester. LCMS m/z 507 [MH+]
Description 21 : 4-(2-(r(2S)-4-(3.4-Dichlorobenzyl)morpholin-2- ylmethvπcarbamovPethvDbenzoic acid hydrochloride
To Description 20 (0.29g) was added a 4.0M solution of HCl in 1 ,4-dioxane (10ml). The mixture was stirred at 20°C for 3hr before the solvent was removed in vacuo to give the title compound as a brown solid. LCMS m/z 451 [MH+]
Description 22: 3-(4-Amino-phenyl)-N-f(2S)-4-(3.4-dichlorobenzyl)morpholin-2- ylmethvπpropionamide
Prepared in an analogous manner to that used for Example 18 using Description 5_and 3-(4-Aminophenyl)propionic acid. LCMS m/z 422 [MH+]
Description 23: 3-(3-Amino-phenyl)-N-[(2S)-4-(3.4-dichlorobenzyl)morpholin-2- ylmethvnpropionamide
Prepared in an analogous manner to that used for Example 18 using Description 5_and 3-(3-Aminophenyl)propionic acid. LCMS m/z 422 [MH+] Description 24: 4-((r(2S)-4-(3.4-Dichlorobenzyl)morpholin-2- ylmethvπcarbamoyllmethvDbenzoic acid methyl ester
Prepared in an analogous manner to that used for Example 18 using Description 5_and 4-(methoxycarbonyl)phenylacetic acid. LCMS m/z 451 [MH+]
Description 25: r3-(N'-tert-Butoxycarbonyl-hvdrazinocarbonyl)phenyl]acetic acid methyl ester
To a stirred solution of 3-methoxycarbonylmethyl-benzoic acid (2.0g) (for preparation see Journal of Chemical Research, Synopses (2000), (6), 282-283) in N,N-dimethylformamide (30ml) was added tert-butylcarbazide (1.358g), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.19g), 1- hydroxybenzotriazole (1.96g) and N,N-diisopropylethylamine (1.96ml). The mixture was stirred under nitrogen at 20°C for 42hr before being diluted with dichloromethane (250ml). The mixture was washed with dilute aqueous sodium bicarbonate solution (200ml) and aqueous brine solution (2x200ml) before passing the organic phase through a cartridge incorporating a hydropgobic frit. The organic solution was then equally applied directly onto 10 sulphonic acid ion exchange cartridges (10x10g, Isolute SCX, pre-washed with methanol) and the cartridges eluted with methanol (x3). The combined eluents were evaporated in vacuo to give the title compound as a colourless liquid. LCMS m/z 309 [MH+]
Description 26: r3-(N'-tert-Butoxycarbonyl-hvdrazinocarbonyl)phenvnacetic acid
Description 25 (5.01 g) in methanol (9ml) had 2M aqueous sodium hydroxide solution (9.1 ml) added to it and the mixture was stirred at room temperature for 5.75hr. 2M aqueous HCl (9.1 ml) was added to the mixture followed by 2M aqueous sodium hydroxide solution (approximately 1 ml) to adjust the pH of the solution to 7. The solvents were evaporated in vacuo to give the title compound (4.766g) as a colourless glass and as a mixture with inorganic salts. LCMS m/z 295 [MH+]
Description 27: N'-13-(fr(2S)-4-(3.4-Difluorobenzyl)morpholin-2- ylmethvncarbamoyllmethvDbenzovnhvdrazinecarboxylic acid tert-butyl ester
Prepared in an analogous manner to that used for Example 5 using Description 8 and Description 26. LCMS m/z 519 [MH+]
Description 28: N-r(2S)-4-(3.4-Difluorobenzyl)morpholin-2-ylmethvn-2-(3- hvdrazinocarbonyl-phenvOacetamide
To Description 27 (2.05g) was added a 4.0M solution of HCl in 1 ,4-dioxane (35ml) and anhydrous methanol (10ml). The mixture was stirred under nitrogen at room temperature for 17hr before the solvent was removed in vacuo. The residue was re-dissolved in methanol and the solution was then equally applied directly onto 8 sulphonic acid ion exchange cartridges (10x10g, Isolute SCX, pre- washed with methanol) and the cartridges eluted with methanol (x3) followed by 10% 0.880 ammonia in methanol (x2). The solvent was removed from the basic fractions in vacuo to give the title compound as an orange foam (1.246g). LCMS m/z 419 [MH+]
Description 29: N-f4-(3.4-Dichlorobenzyl)morpholin-2-ylmethvn-2.2.2-trifluoro-N- methylacetamide
A solution of Description 2 (0.0755g) in dichloromethane (5ml) was sealed in an Alltech™ tube (cartridge with integral frit at the bottom). BEMP resin (polymer bound 2-tert-butylimino-2-diethylamino-1 ,3-dimethylperhydro-1 ,3,2- diazaphosphorine) (0.65g @ 2.3mmol/g) was added followed by methyl iodide (0.168ml). The mixture was agitated on a flatbed shaker at room temperature. The mixture was poured onto a sulphonic acid ion exchange cartridge (10g, Isolute SCX, pre-washed with methanol) and the cartridge eluted with methanol followed by 10% 0.880 ammonia in methanol. The solvent was evaporated from the first basic fraction in vacuo. The residue was further purified by dissolving in dichloromethane and applying the solution to a silica solid phase extraction cartridge (10g, Varian Bondelut, pre-washed with dichloromethane) eluting sequentially with dichloromethane, chloroform, ether, ethyl acetate, acetone, acetonitrile and methanol. The solvent was evaporated from the ether fractions in vacuo to give the title compound (0.0755g). LCMS m/z 385 [MH+]
Examples
Synthetic Method A Example 18
To a stirred solution of Description 14 (0.328g) in N,N-dimethylformamide (6ml) was added a solution of Description 5 (0.366g) in N,N-dimethylformamide (5ml). A solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.408g) and 1 -hydroxybenzotriazole (0.234g) in N,N-dimethylformamide (9ml) was added to the mixture followed by N,N-diisopropylethylamine (0.463ml). The mixture was stirred at 22°C for 18.5h before being diluted with methanol (ca. 5ml). The mixture was applied to 4x1 Og SCX ion-exchange cartridges (pre- conditioned with methanol). The cartridges were eluted with methanol, followed by 10% 0.880 ammonia solution in methanol. The first ammonia fractions were combined and the solvent was evaporated in vacuo. The residue was further purified by Biotage™ flash chromatography on silica gel, eluting with 400:8:1 dichloromethane/ethanol/0.880 ammonia solution. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (0.508g) as a light brown gum. LC/MS: Rt = 2.90min, m/z 481 ,483 [MH+]
Method A Alternative procedure Example 38: 3-(4-Chlorophenyl)-N-f4-(3,4-dichlorobenzyl)morpholin-2- ylmethyllpropionamide: compound with trifluoroacetic acid
To 3-(4-chlorophenyl)propionic acid (0.037g) was added a portion (0.25ml) of a solution of Description 3 (1.292g) in dichloromethane (5.0ml) and the dichloromethane allowed to evaporate. The mixture had N-methylpyrrolidinone (1 drop) added to it before being subjected to heating in a microwave oven (4 minutes at full power) then allowed to cool. The sample was purified by mass- directed preparative HPLC and the solvent removed in vacuo to give the title compound (0.0187g). LCMS Rt 2.03min, m/z 394 [MH+]
Synthetic Method B Example 23 (Interconversion)
To a stirred solution of Example 18 (0.5038g) in methanol (10ml) was added 2M aqueous sodium hydroxide (1.05ml) and water (10ml). The mixture was stirred at 22°C for 14h and then left to stand for a further 18h. 2M aqueous hydrochloric acid (1.05ml) was added, and 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 (0.453g) as a brown gum. LC/MS: Rt = 2.49min, m/z 453,455 [MH+]
Example 14 (Interconversion)
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. 2ml) and applied to a 10g SCX ion-exchange cartridge (pre-conditioned with methanol). The cartridge was eluted with methanol followed by 10% 0.880 ammonia solution in methanol. The first ammonia fraction was evaporated in vacuo and the residue further purified by Biotage™ flash chromatography on silica gel, eluting with 200:8:1 dichloromethane/ethanol/0.880 ammonia solution. The required fractions were combined and the solvent evaporated in vacuo to give a residue which was further purified by Biotage™ flash chromatography on silica gel, eluting with 5% methanol/ethyl acetate. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (0.105g) as a colourless glass. LC/MS: Rt = 2.53min, m/z 492,494 [MH+]
Synthetic Method C Example 24
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. The first ammonia fraction was evaporated in vacuo and the residue further purified by Biotage™ flash chromatography on silica gel, eluting with a gradient from 600:8:1 to 200:8:1 dichloromethane/ethanol/0.880 ammonia solution. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (0.0087g) as a light brown glass. LC/MS: Rt = 2.55min, m/z 502,504 [MH+]
Synthetic Method D Example 5
To a stirred solution of 3-carboxymethyl-benzoic acid methyl ester (0.214g) (J. Med. Chem. 1999, 42(14), 2621-2632) in N,N-dimethylformamide (5ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.288g) and 1-hydroxybenzotriazole (0.162g) followed by a solution of Description 8 (0.242g) in N,N-dimethylformamide (5ml). N.N-diisopropylethylamine (0.348ml) was added to the mixture which was then stirred at 22° for 18h. The mixture was equally to 2x1 Og SCX ion-exchange cartridges (pre-conditioned with methanol). The cartridges were eluted with methanol and 10% 0.880 ammonia solution in methanol. The first ammonia fractions were combined and the solvent was evaporated in vacuo. The residue was further purified by Biotage™ flash chromatography on silica gel, eluting with 200:8:1 dichloromethane/ethanol/0.880 ammonia solution. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (0.301 g) as a cream solid. LC/MS: Rt = 2.36min, m/z 419 [MH+]
Synthetic Method E
Example 7 (interconversion)
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: Rt = 2.15min, m/z 405 [MH+]
Example 10
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). The cartridge was eluted with methanol followed by 10% 0.880 ammonia solution in methanol. The first ammonia fraction was evaporated in vacuo and the residue was further purified by Biotage™ flash chromatography on silica gel, eluting with 150:8:1 dichloromethane/ethanol/0.880 ammonia solution. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (0.0379g) as a white solid. LC/MS: Rt = 2.14min, m/z 432 [MH+]
Synthetic Method F Example 22
To a stirred solution of Description 5 (0.050g) in acetonitrile (1ml) was added potassium carbonate (0.025g). To the mixture was added (4-chloro-phenoxy)- acetyl chloride (0.037g) (Chem. Pharm. Bull. 1988, 36(11), 4426-34) and the mixture was stirred at 20° for 3h. The solvent was evaporated in vacuo and the residue partitioned between water (2ml) and dichloromethane (2ml). The phases were separated using a hydrophobic frit, and the organic phase was purified directly by Biotage™ flash chromatography on silica gel, eluting with 300:8:1 dichloromethane/ethanol/0.880 ammonia solution. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (0.0286g) as a white solid.
LC/MS: Rt = 2.90min, m/z 443,445 [MH+]
Method H
Example 37: N-[(2S)-4-(3,4-Difluorobenzyl)morpholin-2-ylmethyl]-2-[3-(5-methyl- [1 ,3,4]oxadiazol-2-yl)phenyl]acetamide
Description 28 (0.20g) had triethylorthoacetate (1.5ml) added to it and was heated in a 'Reacti-vial' at 160°C for 18hrs. After cooling, the volatiles were evaporated under a stream of nitrogen before the residue was re-dissolved in methanol and directly applied onto a sulphonic acid ion exhange cartridge (1 Og Isolute SCX, pre-washed with methanol). The cartridge was eluted with methanol followed by 10% 0.880 ammonia in methanol and the basic fractions concentrated in vacuo to give the title compound as a colourless gum (0.17g). LCMS R, 2.12 min, m/z 443 [MH+]
Method I
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
Description 28 (0.20g) had triethylorthoformate (1.5ml) added to it and was heated in a 'Reacti-vial' at 160°C for 18hrs. After cooling, the volatiles were 5 evaporated under a stream of nitrogen before the residue was re-dissolved in methanol and directly applied onto a sulphonic acid ion exhange cartridge (10g Isolute SCX, pre-washed with methanol). The cartridge was eluted with methanol followed by 10% 0.880 ammonia in methanol and the basic fractions concentrated in vacuo. The residue was further purified by mass-directed 10 preparative HPLC to give, after removal of the solvent in vacuo, the title compound as a colourless gum (0.021 g). LCMS Rt 2.05 min, m/z 429 [MH+]
Method J 15 Example 41 : N-r(2S)-4-(3.4-Dif luorobenzyl)morpholin-2-ylmethvn-2-r3-(5-methyl- 4H-M ,2.41triazol-3-yl)phenyl1acetamide: compound with formic acid
20 A solution of sodium hydroxide (0.0933g) in anhydrous methanol (2.91 ml) was prepared and a portion of the solution (0.596ml) added to ethyl acetimidate hydrochloride (0.059g). After shaking the mixture for 2min and leaving to stand for a further 5min, the supernatant of the mixture was transferred by syringe to a 'Reacti-vial' charged with Description 28 (0.20g). The mixture was heated at
25 90°C for 1 hrs before cooling to room temperature and concentrating under a stream of nitrogen. The residue was dissolved in a mixture of 5% methanol/chloroform and dichloromethane and was applied to a silica solid phase extraction cartridge (1 Og, Varian Bondelut, pre-washed with dichloromethane) eluting with 5% methanoi/chloroform. The solvent was evaporated from the required fractions in vacuo and the residue further purified by mass-directed preparative HPLC and the solvent removed in vacuo to give the title compound as a colourless gum (0.020g). LCMS Rt 2.01 min, m/z 442 [MH+]
Example 42: N-r(2R)-4-(3.4-Dichlorobenzyl)morpholin-2-ylmethvπ-2-(3- dimethylsulfamoyl-phenvDacetamide
To (4-dimethyIsulfamoyl-phenyl)acetic acid (0.049g) (containing a quantity of the isomeric 3-dimethylsulfamoyl-phenyl)acetic acid) was added a portion (0.25ml) of a solution of Description 3 (1.1g) in dichloromethane (4.0ml) and the dichloromethane allowed to evaporate. The mixture had N-methylpyrrolidinone (1 drop) added to it before being subjected to heating in a microwave oven (4 minutes at full power) then allowed to cool. The sample was purified by mass- directed preparative HPLC and the solvent evaporated under a stream of nitrogen. The residue, being a isomeric and racemic mixture, was separated on a Chiralpak AD preparative hplc column (25x2cm), eluted with 40% ethanol in n- heptane. The flow rate was 15ml/min and detection wavelength 215nm. Fractions containing the required product (first eluting product) were combined and evaporated to give the title compound (0.0017g). LCMS Rt 2.70min, m/z 500 [MH+]
Example 51 : N-r(2S)-4-(3.4-Dichloro-benzyl)morpholin-2-ylmethvπ-3-(4- propionylamino-phenvPpropionamide
To a solution of Description 22 (0.1 Og) in anhydrous dichloromethane (8ml) was added N,N-diisopropyIethylamine (0.062ml) followed by propionyl chloride (0.0329g). The mixture was stirred at room temperature for 22hr. The mixture was poured onto a sulphonic acid ion exchange cartridge (10g, Isolute SCX, pre- washed with methanol) and the cartridge eluted with methanol followed by 10% 0.880 ammonia in methanol. The solvent was evaporated from the basic fractions in vacuo to give the title compound (0.0936g). LCMS R, 2.45 min, m/z 478 [MH+]
Example 82: N-F4-(3,4-Dichlorobenzyl)morpholin-2-ylmethvπ-2-(3-methylsulfanyl- phenvDacetamide
A mixture of Description 3 (0.312g). 1-hydroxybenzotriazole (0.199g), N,N- diisopropylethylamine (0.387ml) and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (0.346g) were stirred in N,N-dimethylformamide (5ml) at 20°C for 7hr and then left to stand for 18hr. Thevolatiles were removed in vacuo and the residue re-dissolved in methanol. The mixture was equally applied directly onto two sulphonic acid ion exchange cartridges (2x1 Og, Isolute SCX, pre-washed with methanol) and the cartridges eluted with methanol followed by 10% 0.880 ammonia in methanol. The solvent was evaporated from the combined first basic fractions in vacuo. The residue was further purified by dissolving in dichloromethane and applying the solution equally to two silica solid phase extraction cartridges (2x1 Og, Varian Bondelut. pre-washed with dichloromethane) eluting sequentially with dichloromethane, chloroform, ether, ethyl acetate, acetone, acetonitrile and methanol. The solvent was evaporated from the combined acetone fractions in vacuo to give the title compound
(0.122g).
LCMS Rt 2.84 min, m/z 439 [MH+]
PG4788
Table 1
# (LC/MS) [M+H]+ of lowest mass isomer unless otherwise indicated PG4788
# (LC/MS) [M+H]+ of lowest mass isomer unless otherwise indicated
Example 7 is the triethylammonium salt Table 2
# (LC/MS) [M+H]+ of lowest mass isomer unless otherwise indicated
# (LC/MS) [M+H]+ of lowest mass isomer unless otherwise indicated
* Examples 23 is the triethylammonium salt ** Example 27 is a dihydrochloride Table 3
# (LC/MS) [M+H]+ of lowest mass isomer unless otherwise indicated
Table 4
Synthetic Method A was used for the preparation of Examples 35, 44, 46, 48, 52,
54, 56, 58, 62, 67, 68, 70, 75, 77, 81, 85, 86, 87, 88, 88, 89, 78, 80, 60, 66, and
82.
Synthetic Method A (alternative procedure) was used for the preparation of
Examples 30, 32, 34, 36, 72, 74, 76, 38, and 42.
Synthetic Method B was used for the preparation of Examples 65, 79, 73, 69, and 71.
Synthetic Method C was used for the preparation of Examples 45, 63, 59, 61 , 47,
84, and 43.
Synthetic Method D was used for the preparation of Examples 50, 64, 31 , 33, 83, and 90.
Synthetic Method E was used for the preparation of Example 40.
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.
Table 5
Table 6

Claims

Claims
1. A compound of formula (I):
wherein:
R1 represents substituted or unsubstituted aryl;
X represents -O- or a bond;
Y represents -(CRnaRnb)n-;
Rna and Rn are each independently hydrogen or d-ealkyl; n is an integer from 1 to 5;
R2 represents unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl;
R3 represents hydrogen or Cι.6alkyl;
R10 represents hydrogen or Cι-6alkyl; and salts and solvates thereof; with the proviso that the following compounds are excluded; 2-(4-chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-phenylacetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-phenoxyacetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-methoxyphenyl)acetamide; 2-(3-Chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylthio)- -phenyl]acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyI}-2-[4-(dimethylamino)- -phenyl]acetamide compound with formic acid (1 :1); N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(dimethylamino)- -sulfonyl]phenyl}acetamide compound with formic acid (1 :1); N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl)- -phenyl]acetamide compound with formic acid (1 :1)
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(3-fluorophenyl)acetamide; 2-[3,5-bis(trifluoromethyI)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]- -methyljacetamide; 2-(2-chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide;
N-{[4-(3,4-dichlorobenzyI)morpholin-2-yI]methyI}-2-(4-fIuoro-2-methylphenyl)-
-acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(3,4-difluorophenyl)-
-acetamide;
4-[2-({[4-(3,4-dichIorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-
-benzamide;
N-{[4-(3,4-dichIorobenzyl)morpholin-2-yl]methyl}-2-[4-(trifluoromethyl)-
-phenyl]acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-methylphenyl)acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyI}-2-(2,4-dichlorophenyl)-
-acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-fluorophenyl)acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(3,4-dichlorophenyl)-
-acetamide;
N-{[4-(3,4-dichlorobenzyl)morphoIin-2-yl]methyl}-2-(2,5-dichlorophenyl)-
-acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,6-dichlorophenyl)-
-acetamide;
2-(4-chlorophenyl)-N-{[4-(2,3-dichlorobenzyl)morpholin-2-yI]methyl}-
-acetamide trifluoroacetate;
2-[3-(acetylamino)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyI}-
-acetamide;
2-(4-acetylphenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide trifluoroacetate;
2-(4-acetylphenyI)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-isobutyrylphenyl)acetamide trifluoroacetate; methyl 4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-
-benzoate trifluoroacetate; methyl 4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-
-benzoate;
2-(4-cyanophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide trifluoroacetate;
2-(4-cyanophenyl)-N-{[4-(3,4-dichlorobenzyI)morpholin-2-yl]methyl}acetamide;
2-(4-chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morphoIin-2-yl]methyl}propanamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(3-fluoro-4-hydroxyphenyl)-
-acetamide trifluoroacetate;
N-{[(2R)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl)-
-phenyljacetamide; N-{[(2S)-4-(3,4-dichlorobenzyl)morphoIin-2-yl]methyl}-2-[4-(methylsuIfonyl)- phenyljacetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(4-methylpiperazin-
-1-yl)carbonyl]phenyl}acetamide;
4-[2-({[4-(3,4-dichIorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyI]-N-
-[2-(dimethylamino)ethyl]benzamide;
4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-
-N , N-dimethylbenzamide;
4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-
-ethylbenzamide;
4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-
-(2-hydroxyethyl)benzamide;
N-{[4-(3,4-dichlorobenzyl)morphoIin-2-yl]methyl}-2-[4-(morpholin-4-yI-
-carbonyl)phenyl]acetamide;
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(dimethylamino)-
-sulfonyl]phenyl}acetamide;
N-{[(2R)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(dimethyIamino)-
-sulfonyl]phenyl}acetamide;
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(dimethylamino)-
-sulfonyl]phenyl}acetamide;
4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-
-methylbenzamide;
4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-
-isopropylbenzamide;
N-cyclopropyl-4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-
-oxoethyl]benzamide;
4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-(2-
-methoxyethyl)benzamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-nitrophenyl)acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(3-nitrophenyl)acetamide; methyl 3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-
-benzoate;
2-[3-(acetylamino)phenyl]-N-{[4-(3-fluorobenzyl)morpholin-2-yl]methyl}-
-acetamide;
N-{[4-(3-fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)-
-amino]phenyl}acetamide;
2-[3-(acetylamino)phenyl]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-
-acetamide;
N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)-
-amino]phenyI}acetamide; 2-[4-(acetylamino)phenyl]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]-
-methyljacetamide;
N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-2-{3-[(methylsulfonyl)-
-amino]phenyl}acetamide;
N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)-
-phenyl]acetamide;
N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl)-
-phenyljacetamide;
N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)-
-phenyl]acetamide;
2-[3-(acetylamino)phenyl]-N-{[4-(4-fluorobenzyl)morphoIin-2-yl]methyI}acetamide;
N-{[4-(4-fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)amino]-
-phenyljacetamide;
2-[4-(acetylamino)phenyl]-N-{[4-(4-fluorobenzyl)morpholin-2-yl]methyl}acetamide;
N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyi}-2-[4-(methylsulfonyl)-
-phenyl]acetamide;
2-[3-(acetylamino)phenyl]-N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyI}-
-acetamide;
N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)-
-amino]phenyl}acetamide;
N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-{[(methylamino)-
-carbonyl]amino}phenyI)acetamide;
N-({4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-[4-(methylsulfonyl)-
-phenyljacetamide;
2-[3-(acetylamino)phenyl]-N-({4-[(5-chlorothien-2-yl)methyl]morpholin-2-
-yl}methyl)acetamide;
N-({4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{4-[(methylsulfonyl)-
-amino]phenyl}acetamide;
N-({4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3-[(methylsulfonyl)-
-amino]phenyl}acetamide;
2-[3-(acetylamino)phenyl]-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyI}-
-acetamide;
N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)-
-amino]phenyl}acetamide;
2-[4-(acetylamino)phenyl]-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-
-acetamide;
N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-2-(4-{[(methylamino)carbonyl]-
-amino}phenyl)acetamide;
2-[4-(acetylamino)phenyl]-N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]-
-methyl}acetamide; N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}-2-[3-(methyIsuIfonyl)-
-phenyl]acetamide;
2-[4-(aminosulfonyl)phenyl]-N-{[4-(3,4-dichlorobenzyl)morphoIin-2-
-yl]methyl}acetamide;
2-[2-(acetylamino)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-
-yl]methyl}acetamide;
2-(3-cyanophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2-fluorophenyl)acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,3-difluorophenyl)-
-acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,4-difluorophenyl)-
-acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,5-difluorophenyl)-
-acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,6-difluorophenyl)-
-acetamide;
N-cyclopropyl-3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-
-oxoethyl]benzamide;
3-[2-({[4-(3,4-dichIorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-(2-
-methoxyethyl)benzamide;
3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-
-ethylbenzamide;
3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-ylJmethyl}amino)-2-oxoethyl]-N,N- dimethylbenzamide;
3-[2-({[4-(3,4-dichIorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-[2-
(dimethylamino)ethyl]benzamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(4-methylpiperazin-1-
-yl)carbonyl]phenyl}acetamide;
2-(3-aminophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide;
2-(4-aminophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide;
2-[4-(acetyIamino)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-
-acetamide;
N-{4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-
-phenyl}2-methylpropanamide;
N-{3-[2-({[4-(3,4-dichlorobenzyl)morphoIin-2-yl]methyI}amino)-2-oxoethyl]-
-phenyl}2-methylpropanamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(methylsulfonyl)-
-amino]phenyl}acetamide;
N-{[4-(3,4-dichlorobenzyl)morphoIin-2-yl]methyl}-2-{4-[(methylsulfonyl)-
-amino]phenyl}acetamide; N-{3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethylJ-
-phenyl}-2-(dimethylamino)acetamide;
2-{4-[bis(methylsulfonyl)amino]phenyl}-N-{[4-(3,4-dichlorobenzyl)morpholin-2- yl]methyl}acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[3-(methylsulfonyl)-
-phenyljacetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl)-2-
-n itrophenyl]acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyI}-2-(2-hydroxyphenyl)acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[methyl(methylsulfonyl)-
-amino]phenyl}acetamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[methyl(methylsulfonyl)-
-amino]phenyI}acetamide;
2-[2-amino-4-(methyIsulfonyl)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-
-yl]methyl}acetamide;
N-({(2S)-4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3-
-[(methylsulfonyl)amino]phenyl}acetamide;
N-({(2R)-4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3-
-[(methylsulfonyl)amino]phenyl}acetamide;
N-{[(2S)-4-(3,4-dichIorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylamino)-
-sulfonyl]phenyI}acetamide;
N-{[(2S)-4-(3,4-dichIorobenzyl)morpholin-2-yl]methyl}-2-{4-[(ethylamino)-
-sulfonyl]phenyl}acetamide;
2-[3-(aminosulfonyl)phenyl]-N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-
-yl] methyljacetamide;
2-{3-[(cyclopropylamino)sulfonyl]phenyl}-N-{[(2S)-4-(3,4-dichlorobenzyl)-
-morpholin-2-yl]methyl}acetamide;
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(ethylamino)-
-sulfonyl]phenyl}acetamide;
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yI]methyl}-2-{3-[(methylamino)-
-sulfonyl]phenyl}acetamide;
N-{[(2S)-4-(4-fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)-
-amino]phenyl}acetamide;
N-{[(2R)-4-(4-fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)-
-amino]phenyl}acetamide;
2-[4-(aminosulfonyl)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-
-yl] methyljacetamide;
2-{4-[(cyclopropylamino)sulfonyl]phenyl}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-
-yl]methyl}acetamide;
N-cyclopropyl-3-[2-({[(2S)-4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2- -oxoethyljbenzamide;
3-{2-[({(2S)-4-[(5-chlorothien-2-yl)methyl]morpholin-2-yl}methyl)amino]-2-
-oxoethyl}-N-cyclopropylbenzamide;
N-cyclopropyl-3-[2-({[(2S)-4-(4-fluorobenzyl)morphoIin-2-yl]methyl}amino)-2-
-oxoethyljbenzamide;
3-[2-({[(2S)-4-(3-chlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-
-cyclopropylbenzamide;
N-cyclopropyl-3-[2-({[(2S)-4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}amino)-2-
-oxoethyl]benzamide, and;
N-cyclopropyl-3-[2-({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-
-oxoethyl]benzamide.
2. A compound of formula (I) according to claim 1 wherein R is unsubstituted or substituted phenyl.
3. A compound of formula (I) according to claim 1 or claim 2 wherein R1 is unsubstituted phenyl or phenyl substituted with 4-(methanesulphonyl), 4- (methylcarbonylamino), 2,4,6-(trifluoro), 3-(methyIthio), 2,5-(difluoro). 4-(pyrazol- 1-yl), 3-(methanesuIphonyl), 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- (methylaminocarbonylamiήo), 4-methanesulphonyl-2-methanesulphonylamino), 4-(ethylaminocarbonyl), 3-(N,N-dimethylaminosulphonyl), 4- (methanesulphonylaminomethyl), 3-(methanesulphonylamino), 3- (cyclopropylcarbonyl), 3-(methylcarbonyl), 3-(methoxycarbonyl), 3- (aminosulphonyl), 4-(methanesulphonylamino), 3-(methyIaminocarbonyl), 3- (dimethylaminocarbonyl), 3-( so-propylaminocarbonyl), 3-(iso- propylmethylaminocarbonyl), 4-(fluoro), 3-(amino), 4-(methylcarbonylamino), 3- (cyclopropylaminocarbonyl), 3-(methylcarbonylamino), 3-(ethylaminocarbonyl), 4- (piperidin-1 -ylcarbonyl), 3-(ethoxycarbonyl), 4-cyano, 4-(aminosulphonyl), 4- (amido), 4-(chloro), or 3-(carboxy).
4. A compound of formula (I) according to any one of the preceding claims wherein Rna and Rnb are both hydrogen.
5. A compound of formula (I) according to any one of the preceding claims wherein n is 1 , 2, or 3.
6. A compound of formula (1) according to any one of the preceding claims wherein R10 is hydrogen or methyl.
7. A compound of formula (I) according to any one of the preceding claims wherein R10 is hydrogen.
8. A compound of formula (I) according to any one of the preceding claims wherein R3 is hydrogen.
9. A compound of formula (I) according to any one of the preceding claims wherein R2 is unsubstituted or substituted phenyl, unsubstituted or substituted thiophenyl, or unsubstituted or substituted pyridinyl.
10. A compound of formula (I) according to any one of the preceding claims wherein R2 is phenyl substituted with chloro or fluoro, thiophenyl substituted with chloro, or pyridinyl.
11. A compound of formula (I) according to any one of the preceding claims wherein R2 is 3-fluorophenyl, 4-fluorophenyl, 2,5-dichlorophenyI, 3-chlorophenyl, 3-(trifluoromethyl)phenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3,4-difIuorophenyl, 3-chloro-4-fluoro-phenyl, 2-chlorothiophen-5-yl, or pyridin-3-yl.
12. A compound of formula (I) according to claim 1 selected from the Examples.
13. A compound of formula (I) according claim 12 selected from Examples 1 ,
2, 3, 4, 5, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 24, 25, 28, 29, 30, 31 , 35, 39, 41 , 43, 45, 47, 49, 51 , 53, 55, 57, 59, 61 , 63, 65, 77, 81 , 82, 83, 85, 87, 88, 89, and 90.
14. A compound of formula (I) according claim 12 selected from 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, 77, 85, 87, 88, 89, and 90.
15. A compound of formula (I) according claim 12 selected from Examples 13, 88, 14, 1 , 4, 35, 29, 43, 45, 47, 49, 51 , 55, 57, 59, 85, and 87.
16. A process for the preparation of a compound of formula (I) as defined in claim 1 which process comprises the reaction of a compound of formula (II) with a compound of formula (III);
wherein;
R1, X, Y, R3, R10, and R2 are as hereinbefore defined for formula (I) in claim 1 , 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.
17. A process for the preparation of a compound of formula (I) which process comprises reaction of a compound of formula (XI) with a compound of formula
(iii);
wherein L2 is a leaving group, and R1, X, and Y are as hereinbefore defined for formula (I) in claim 1 , 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.
18. A compound of formula (IIIBE)
(IIIBE) wherein R2 and R10 are as defined for formula (I) in claim 1 and A is a protected amino group.
19. A compound of formula (IIIBR)
wherein R2 and R10 are as defined for formula (I) in claim 1 and A is a protected amino group.
20. A compound of formula (I) as defined in claim 1 or a physiologically acceptable salt or solvate thereof for use as an active therapeutic agent.
21. A compound of formula (I) as defined in claim 1 , or a physiologically acceptable salt or solvate thereof, for use in the treatment of inflammatory conditions, e.g. asthma or rhinitis.
22. Use of a compound of formula (I) as defined in claim 1 or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of inflammatory conditions, eg. asthma or rhinitis.
23. A method for the treatment of a human or animal subject suffering from or susceptible to an inflammatory condition e.g. asthma or rhinitis, which method comprises administering an effective amount of a compound of formula (I) as defined in claim 1 or a physiologically acceptable salt or solvate thereof.
24. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 , or a physiologically acceptable salt or solvate thereof, and optionally one or more physiologically acceptable diluents or carriers.
EP03745299A 2002-03-28 2003-03-27 Morpholine derivatives with a substituted acetamide group in the 2-position for use as ccr-3 antagonists for the treatment of inflammatory diseases Withdrawn EP1492537A1 (en)

Applications Claiming Priority (3)

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GB0207443 2002-03-28
GBGB0207443.3A GB0207443D0 (en) 2002-03-28 2002-03-28 Novel compounds
PCT/EP2003/003348 WO2003082294A1 (en) 2002-03-28 2003-03-27 Morpholine derivatives with a substituted acetamide group in the 2-position for use as ccr-3 antagonists for the treatment of inflammatory diseases

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AR (1) AR039174A1 (en)
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DK1801108T3 (en) 2004-09-08 2013-02-18 Mitsubishi Tanabe Pharma Corp Morpholine compounds for the treatment of inflammation.
JP2009501792A (en) * 2005-07-21 2009-01-22 アストラゼネカ・アクチエボラーグ N-benzyl-morpholine derivatives as modulators of chemokine receptors

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JP3593037B2 (en) * 1998-11-20 2004-11-24 エフ．ホフマン−ラ ロシュ アーゲー Pyrrolidine derivative CCR-3 receptor antagonist
KR20030031198A (en) * 2000-09-29 2003-04-18 글락소 그룹 리미티드 Morpholin-acetamide derivatives for the treatment of inflammatory diseases

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JP2006504625A (en) 2006-02-09
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GB0207443D0 (en) 2002-05-08
AU2003226762A1 (en) 2003-10-13

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