EP1487455A1 - Morpholine derivatives substituted at the 2-position by an arylalkylurea group for use as ccr-3 antagonists in the treatment of inflammatory conditions - Google Patents

Morpholine derivatives substituted at the 2-position by an arylalkylurea group for use as ccr-3 antagonists in the treatment of inflammatory conditions

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Publication number
EP1487455A1
EP1487455A1 EP03745296A EP03745296A EP1487455A1 EP 1487455 A1 EP1487455 A1 EP 1487455A1 EP 03745296 A EP03745296 A EP 03745296A EP 03745296 A EP03745296 A EP 03745296A EP 1487455 A1 EP1487455 A1 EP 1487455A1
Authority
EP
European Patent Office
Prior art keywords
methyl
dichlorobenzyl
morpholin
amino
urea
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Withdrawn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
EP03745296A
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 EP1487455A1 publication Critical patent/EP1487455A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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 unsubstituted or substituted aryl
  • Y represents -(CR na Rnb)n-;
  • R na and R nb are each independently hydrogen or C h alky!; n is an integer from 1 to 5;
  • R 2 represents unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl
  • R 3 and R 4 each independently represent hydrogen or d- 6 alkyl; and salts and solvates thereof; with the proviso that the following compounds are excluded;
  • substituents for R 1 include perhaloalkyl, aminosulphonyl; carboxy; mono-and di-(alkyl)aminosulphonyl; alkylsulphonylamino; alkylcarbonyl; cycloalkylaminocarbonyl; aminocarbonyl; alkyl; alkoxycarbonyl; mono- and di-
  • alkyl alkylaminocarbonyl; unsubstituted heteroaryl; heteroaryl substituted with alkylsulphonylamino, alkylcarbonyl, alkyl, alkoxycarbonyl, mono- and di-
  • R 1 When R 1 is substituted aryl, suitable substituents include aminosulphonyl; carboxy; mono-and di-(alkyl)aminosulphonyl; C L ⁇ alkylsulphonylamino; C ⁇
  • R 1 When R 1 is substituted with unsubstituted or substituted heteroaryl, examples of said heteroaryl group include oxadiazolyl and triazolyl.
  • R 1 is unsubstituted or substituted phenyl.
  • suitable substituents include carboxy, halo, Ci-ealkylsulphonyl, C ⁇ - 6 alkylsulphonylamino, mono-and di-(C ⁇ - 6 alkyl)aminosulphonyl, aminosulphonyl, C 3 ⁇ cycloalkylaminocarbonyl, mono- and di-(C 1 .
  • R 1 is phenyl substituted with 4-(3-methyl-1 ,2,4-oxadiazol-
  • R na and R nb are both hydrogen.
  • n is 1.
  • R 3 and R 4 are both hydrogen.
  • R 2 is aryl
  • examples include phenyl.
  • suitable substituents include cyano, perhaloC ⁇ - 6 alkyl, amido, halo, d- 6 alkyl, C ⁇ alkoxycarbonyl, mono- and di-(C ⁇ - 6 alkyl)aminocarbonyl, d- ⁇ alkoxy, nitro, C ⁇ . 6 alkylsulphonyl, hydroxy, 6 alkyl, C ⁇ - 6 alkylthio-, mono- and-di-(C ⁇ - 6 alkyl)amino, and d. 6 alkylcarbonylamino.
  • R 2 When R 2 is heteroaryl, examples include thiophenyl.
  • suitable substituents include cyano, perhaloCi-ealkyl, amido, halo, dialkyl, Ci- ⁇ alkoxycarbonyl, mono- and di-(C ⁇ . 6 alkyl)aminocarbonyl, C ⁇ . 6 alkoxy, nitro, Ci-ealkylsulphonyl, hydroxy, 6 alkyl, C ⁇ - 6 alkylthio-, mono- and-di-(C ⁇ - 6 alkyl)amino, and C ⁇ alkylcarbonylamino.
  • R 2 is unsubstituted or substituted phenyl or unsubstituted or substituted thiophenyl.
  • R 2 is substituted phenyl or thiophenyl suitable substituents include halo. More suitably, R 2 is phenyl or thiophenyl substituted with chloro or fluoro. Preferably, R 2 is 3,4-dichlorophenyl, 3,4-difluorophenyl or 2-chloro- thiophen-5-yl.
  • R 1A is a moiety of the formula (M)
  • R 5 represents C 3 - 8 cycloalkylaminosulphonyl
  • R 7 R 8 NC(O)- wherein R 7 and R 8 may each independently represent hydrogen or C ⁇ - 6 alkyl or R 7 and R 8 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; aminosulphonyl; carboxy; mono-and di-(C ⁇ . 6 alkyl)aminosulphonyl; d- 6 alkylsulphonylamino; d.
  • R 6 represents cyano, perhaloC ⁇ alkyl, hydrogen, d- 6 alkyl, halo, C ⁇ - 6 alkoxy, or hydroxy, and; R 2 , R 3 , and R 4 are as hereinbefore defined for formula (I); and salts and solvates thereof; with the proviso
  • heteroaryl group examples include oxadiazolyl and triazolyl.
  • R 5 is carboxy, halo, C ⁇ . 6 alkylsulphonyl, C ⁇ - 6 alkylsulphonylamino, mono-and di-(C ⁇ . 6 alkyl)aminosulphonyl, aminosulphonyl, C 3 . scycloalkylaminocarbonyl, mono- and di-(C ⁇ . 6 alkyl)aminocarbonyl, unsubstituted heteroaryl, heteroaryl substituted with C ⁇ - 6 alkyl, C ⁇ - 6 alkylcarbonylamino, Ci-
  • R 6 is hydrogen or halo. More suitably, R 1A is phenyl substituted with 3-(5-methyl-1 ,3,4-triazol-2- yl), 3-(2-methyl-1 ,3,4-triazol-5-yl), 3-(/so-propylaminocarbonyl), 3-(3-methyl-
  • R r is a moiety of formula (M)
  • R 5 represents C ⁇ - 6 alkylaminocarbonyl, substituted heteroaryl, Ci- 6 alkylcarbonylamino, halo, d. 6 alkoxycarbonyl, amido, C 3 - ecycloalkylaminocarbonyl, carboxy, d- 6 alkylsulphonyl, or Ci- 6 alkylsulphonylamino;
  • R 6' is H or halo; and R 2' is phenyl substituted by halo.
  • M' represents 3-(5-methyl-1 ,3,4-triazol-2-yl)phenyl, 3-(/so- propylaminocarbonyl)phenyl, 3-(3-methyl-1 ,2,4-oxadiazol-5-yl)phenyl, 3- (methylcarbonylamino)phenyl, 4-fluoro-3-(methoxycarbonyl)phenyl, 3- amidophenyl, 4-fluoro-3-(ethylaminocarbonyl)phenyl, 4-fluoro-3-
  • R 2' is 3,4-dichlorophenyl, 3,4-difluorophenyl or 3-chloro-4- fluorophenyl.
  • the stereochemistry at the position marked ' * ' is (S). Accordingly, there is provided a compound of formula (I') or a salt or solvate thereof.
  • R 1 is phenyl substituted at the 4-position by substituted heteroaryl, Ci- 6 alkylsulphonylamino, N,N-diC ⁇ - 6 alkylaminosulphonyl, aminosulphonyl, or amido; and;
  • R 2" is phenyl substituted by halo or thiophenyl substituted by halo.
  • R 1" is 4-(3-methyl-1 ,2,4-oxadiazol-5yl)phenyl, 4- (methanesulphonylamino)phenyl, 4-(N,N-dimethylaminosulphonyl)phenyl, 4- (aminosulphonyl)phenyl or 4-amidophenyl.
  • R 2 is 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-chloro-4- fluorophenyl or 2-chloro-thiophen-5-yl.
  • the stereochemistry at the position marked ' * ' is (S). Accordingly, there is provided a compound of formula (I") or a salt or solvate thereof.
  • R 9 is mono- or di-(C 1 . 6 alkyl)aminocarbonyl or C 3 . scycloalkylaminocarbonyl.
  • R 9 is ethylaminocarbonyl, cyclopropylaminocarbonyl, or dimethylaminocarbonyl.
  • R 9 is 4-ethylaminocarbonyl, 3-cyclopropylaminocarbonyl, or 3- dimethylaminocarbonyl. Accordingly, there is provided a compound of formula (IB) or a salt or solvate thereof.
  • Suitable compounds of the invention are Examples 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 31 , 33, 34, and 35.
  • Preferred compounds of the invention are Examples 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 18, 20, 22, 28, 31 , 33, 34, and 35.
  • More preferred compounds of the invention are Examples 1 , 2, 3, 4, 5, 6, 7, 12, 22, 28, 31 , 33 and 34.
  • Especially preferred compounds of the invention are Examples 1 , 2, 12,
  • 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.
  • 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 heterocyclylcarbonyl; cycloalkylaminosulphonyl; aminosulphonyl; carboxy; mono-and di- (alkyl)aminosulphonyl; alkylsulphonylamino; alkylcarbonyl; cycloalkylaminocarbonyl; aminocarbonyl; alkyl; alkoxycarbonyl; mono- and di- (alkyl)aminocarbonyl; unsubstituted heteroaryl; heteroaryl substituted with alkyl, halo, alkoxy, hydroxy; halo; alkoxy; nitro; alkylsulphonyl; hydroxy; alkoxyalkyl; alkylthio; mono- and-di-(alkyl)amino; alkylcarbonylamino; hydrogen; cyano; perhaloalkyl; and amido.
  • references to 'heteroaryl' refer to monocyclic heterocyclic aromatic rings containing 1-4 heteroatoms selected from nitrogen, oxygen and sulphur.
  • heterocyclic aromatic rings include thiophenyl and oxadiazolyl.
  • Suitable substituents for any heteroaryl group include 1 to 5, suitably 1 to 3, substituents selected from the list consisting of cyano, perhaloalkyl, amido, halo, alkyl, alkoxycarbonyl, mono- and di-(alkyl)aminocarbonyl, alkoxy, nitro, alkylsulphonyl, hydroxy, alkoxyalkyl, alkylthio, mono- and-di-(alkyl)amino, and alkylcarbonylamino.
  • references to '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.
  • Suitable substituents for any cycloalkyl group include alkyl, halo, and hydroxy.
  • references to 'heterocyclyl' refer to monocyclic heterocyclic aliphatic rings containing 2 to 6, suitably 3 to 5, carbon atoms, and 1 to 3, heteroatoms selected from nitrogen, oxygen, and sulphur.
  • heterocyclic rings include piperidinyl.
  • Suitable substituents for any heterocyclyl group include 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.
  • R 1 , Y, R 3 , R 4 , and R 2 are as hereinbefore defined for formula (I) and U is a urea-forming group; and thereafter, if required, carrying out one or more of the following optional steps:
  • a urea-forming group is a group which is derived from a reagent which introduces a carbonyl group and a leaving group to an amino compound.
  • urea-forming groups are imidazolylcarbonyl and chlorocarbonyl, and, when R 4 is hydrogen, then 4-nitrophenoxycarbonyl may be used.
  • the reagents from which they are derived are 1 ,1'-carbonyldiimidazole, phosgene, and 4-nitrophenylchloroformate respectively.
  • a suitable urea-forming group is 4- nitrophenoxycarbonyl.
  • the compound of formula (II) and the compound of formula (III) in a suitable solvent are treated with a suitable base, such as a tertiary amine, e.g. triethylamine, at ambient temperature, such as 18 - 25 " C.
  • a suitable solvent such as an organic solvent, e.g. dichloromethane
  • a suitable base such as a tertiary amine, e.g. triethylamine
  • a compound of formula (III) may be prepared by reaction of a compound of formula (IV);
  • R 4 and R 2 are as hereinbefore defined for formula (I); with a compound of formula U-L wherein U is a urea-forming group as hereinbefore defined and L is a leaving group.
  • a suitable leaving group is a halo group such as chloro.
  • reaction between the compound of formula (IV) in the presence of a suitable base, such as a tertiary amine, e.g. triethylamine, and the compound U- L is performed in a suitable solvent, for example dichloromethane, at a suitable temperature, for example those in the range of -5°C to +5°C over a suitable period of time, for example 3-5 hours.
  • a suitable solvent for example dichloromethane
  • a compound of formula (IV) wherein R 4 is hydrogen may be prepared either by Reaction (a) or Reaction (c).
  • the S-enantiomer of a compound of formula (IV) may be prepared by Reaction (b).
  • R 2 is as hereinbefore defined for formula (I) and A is a protected amino group, suitably phthalimido, followed by deprotection of the amino group to give a compound of formula (IV) wherein R 4 is hydrogen i.e. a compound of formula (IVR)
  • R 2 is as hereinbefore defined, and optionally resolution of the resulting enantiomers of a compound of formula (IVR); or;
  • R 2 is as hereinbefore defined.
  • T is trifluoroacetyl
  • R 4 and R 2 are as hereinbefore defined for formula (I), and optionally resolution of the resulting enantiomers of a compound of formula (IV).
  • a suitable azo compound suitably diisopropylazodicarboxylate, is then added over a period of time, suitably, 10 -15 minutes, while maintaining the temperature at ⁇ 7°C.
  • the mixture is allowed to stand for a period of time, suitably 2 - 3 hours, then allowed to warm, suitably to 20 - 25°C. After a further period of standing, suitably 4 - 6 hours, further
  • 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
  • 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 (IVR) or formula (IVE) respectively.
  • the removal of the protecting group from the product is typically carried out as follows.
  • 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 is as hereinbefore defined for formulae (VI) and (VIA) and R 2 is as hereinbefore defined for formula (I); is isolated.
  • a mixture of the compound of formula (V) and a compound of formula (VI) or formula (VIA) in a suitable solvent, such as tetrahydrofuran is stirred, suitably for 20 - 24 hours at a suitable temperature, suitably the reflux temperature of the solvent, under an inert atmosphere, suitably an atmosphere of nitrogen.
  • a suitable temperature suitably the reflux temperature of the solvent, under an inert atmosphere, suitably an atmosphere of nitrogen, for a suitable period of time, suitably 3-6 hours.
  • reaction mixture is then cooled, suitably to 20 - 25°C, and the compound precipitated by means of addition of a suitable co- solvent, suitably diisopropyl ether.
  • a suitable co- solvent suitably diisopropyl ether.
  • the compound of formula (IVBR) or formula (IVBE) respectively is isolated by filtration, washed with further co-solvent and dried in vacuo.
  • a protected form of the compound of formula (IVR) or formula (IVE) may then be prepared from a compound of formula (IVBR) or formula (IVBE) under similar conditions to those of the reaction between a compound of formula (V) and formulae (VI) or (VIA) as hereinbefore described, but omitting the reflux 5 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 (VII) 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 - 10 25°C for a suitable time, for example 16 - 20 hours followed by removal of the organic solvent was 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 15 and evaporation of the solvent in vacuo.
  • the crude product is then purified by flash chromatography.
  • the resolution of the compound of formula (IVE) from the racemic product i.e. the compound of formula (IVR) may be undertaken using techniques well known to those skilled in the art, for example preparative chiral high 20 performance liquid chromatography (chiral HPLC) or by fractional crystallisation of diastereoisomeric salts.
  • a compound of formula (VII) may be prepared by reaction of a compound of formula (VIII) with a compound of formula (IX)
  • T, R 4 and R 2 are as hereinbefore defined for formula (VII) and L 2 is a leaving group.
  • a suitable leaving group, L 2 is a halo group such as chloro.
  • reaction between a compound of formula (VIII) and a compound of formula (IX) is typically carried out by stirring a solution of the compound of formula (VIII) 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,
  • a suitable solvent for example N,N-dimethylformamide
  • an inert atmosphere for example an atmosphere of nitrogen
  • 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.
  • 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 (VIII) may be prepared by reaction of a compound of formula (X) with a compound of formula (XI);
  • R 4 and T are as hereinbefore defined for formula (VII) and R x is an alkyl group, suitably ethyl.
  • the reaction between a compound of formula (X) and a compound of formula (XI) is typically carried out by stirring a solution of a compound of formula (X) 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 (XI) 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.
  • Compounds of formula (II) may be prepared from other compounds of formula (II) by a procedure comprising appropriate steps of protection, reaction, and deprotection.
  • An example of such a procedure is protection of the amino function of a compound of formula (II) wherein Y is -CH 2 - and R 1 is 3-carboxy-4- fluorophenyl, and R 3 is hydrogen.
  • a suitable protecting group is tBoc.
  • the carboxy function is then alkylated, for example with (trimethylsilyl)diazomethane, and the tBoc group is then removed.
  • the above mentioned conversion of a compound of formula (I) into another compound of formula (I) includes any conversion which may be effected using conventional procedures, but in particular the said conversions include converting one group R 1 into another group R 1 .
  • Suitable protecting groups in any of the above mentioned reactions are those used conventionally in the art.
  • the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected, for example those methods discussed in standard reference texts of synthetic methodology such as P J Kocienski, Protecting Groups, (1994), Thieme.
  • the absolute stereochemistry of compounds may be determined using conventional methods, such as X-ray crystallography.
  • the salts and solvates of the compounds of formula (I) may be prepared and isolated according to conventional procedures.
  • 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 (2.5 ⁇ 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.- hydroxy be nzoates or sorbic acid.
  • the preparations may also contain buffer salts, flavouring, colouring and/or sweetening agents (e.g. mannitol) as appropriate.
  • 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.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • a suitable vehicle e.g. sterile, pyrogen-free water
  • 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 100mg/kg body weight, and at any appropriate frequency e.g. 1 to 4 times daily.
  • the precise dosing regimen will of course depend on factors such as the therapeutic indication, the age and condition of the patient, and the particular route of administration chosen.
  • Mass directed automated preparative high performance liquid chromatography was carried out using an LCABZ+ 5 ⁇ m (5cm x 10mm internal diameter) column, employing gradient elution using two solvent systems, (A) 0.1% formic acid in water, and (B) 95% acetonitrile and 0.5% formic acid in water, at a flow rate of 8ml min "1 .
  • Mass spectrometry was carried out using a VG Platform Mass
  • Thermospray Mass Spectra used a micromass spectrometer, with electrospray ionisation mode, positive and negative ion switching, mass range 80-1000 a.m.u. Thermospray Mass Spectra
  • Thermospray Mass Spectra were determined on a HP 5989A engine mass spectrometer, +ve thermospray, source temperature 250°C, probe temperatures
  • SCX' refers to Isolute Flash SCX-2 sulphonic acid solid phase extraction cartridges.
  • 'Hydrophobic frit' refers to a Whatman polypropylene filter tube fitted with a PTFE frit, pore size 5.0 ⁇ m.
  • Description 3 r4-(3.4-Dichlorobenzyl)morpholin-2-yllmethylamine
  • methanol 15ml
  • water 5ml
  • potassium carbonate 5.53g
  • the mixture was stirred at 22°C for 18h before the methanol was removed in vacuo.
  • Water 25ml
  • 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.
  • 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
  • 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).
  • Triethylamine (0.09ml) was added to solution of Description 3 (0.150g. 0.545mmol) in dichloromethane (3ml) with stirring at 20°C under nitrogen. The solution was cooled to 0°C and a solution of 4-nitrophenyl chloroformate (0.121g) in dichloromethane (1ml) was added drop-wise. The resultant mixture was stirred for 4h at 0°C. The solution was allowed to warm to 20°C, washed with brine (4ml), dried (MgSO 4 ), and concentrated in vacuo.
  • Description 9 was prepared in an analogous manner to Description 8 from Description 5 (0.225g) and 4-nitrophenylchloroformate (0.182g) to yield the title compound (0.2g).
  • Description 11 was prepared in an analogous manner to Description 9 from Description 10 and 4-nitrophenylchloroformate.
  • Example 16 A solution of Example 16 (0.626g) in N,N-dimethylformamide (5.5ml) was treated with 1-hydroxybenzotriazole (0.174g), 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (0.283g), t-butyl carbazate (0.120g) and N,N- diisopropylethylamine (0.174ml), and the mixture stirred at room temperature for seventeen hours. The solution was then diluted with dichloromethane (30ml) and washed successively with saturated aqueous sodium hydrogen carbonate (25ml) and dilute aqueous sodium chloride (2 x 25ml).
  • Example 5 To a solution of Example 5 (0.21 Og) in methanol (5ml) was added 2N sodium hydroxide (1 ml). The solution was stirred at 20° for 2h. The solvent was removed in vacuo. The residue was dissolved in water (5ml) and acidified to pH1 using 2H hydrochloric acid. The suspension was applied onto sulphonic acid ion exchange cartridges (2x1 Og Isolute SCX, pre-treated with water). The cartridges were eluted with water followed by 5% triethylamine in methanol; evaporation of the basic fraction in vacuo gave the title compound as a colourless oil (0.246g). LC/MS R, 2.42min m/z 470[MH + ].
  • Example 15 To a solution of Example 15 (0.043g) in N,N-dimethylformamide (2ml) was added N,N-diisopropylethylamine (0.026ml), 1-hydroxybenzotriazole (0.013g), and 1-(3- dimethylaminopropyl)-3-ethylcabodiimide hydrochloride (0.017g). The solution was stirred at 20° for 5min and then treated with ethylamine hydrochloride (0.036g). After 0.75h, the solution was treated with further N,N- diisopropylethylamine (0.026ml) and stirred in a sealed vial for 18h.
  • Triethyl orthoacetate (0.54ml) was added to Description 14 (0.047g) and the mixture heated to 160° for eighteen hours. After cooling, the mixture was diluted with methanol (2ml) and loaded directly onto an SCX (2g) ion exchange cartridge, which had been pre-treated with methanol and which was then eluted with methanol followed by 10% 0.880 ammonia/methanol. The basic fractions were combined and evaporated to give a pale yellow film which was purified by chromatography on silica gel (Varian Bond-Elut cartidge, 1g), eluting with 0%, 5%, and 10% methanol/ethyl acetate to yield 2 impure clear colourless films.
  • Ethyl acetimidate hydrochloride (0.011g) was treated with sodium hydroxide (0.112ml of a solution of 0.0915g in methanol (2.86ml)) and the mixture shaken for two minutes then left to stand for ten minutes. The supernatant liquid was then transferred by syringe to a thick walled sealed vial (ReactivialTM) containing Description 14 (0.039g); the mixture was heated at reflux for one and a quarter hours, and allowed to cool to give an orange gum.
  • ReactivialTM thick walled sealed vial
  • Example 23 1 - ⁇ (2S)-4-(3.4-Difluorobenzyl)morpholin-2-ylmethyll-3-(3- n .3,41oxadiazol-2-yl-benzyl)urea
  • Example 15 is the triethylammonium salt +
  • Example 16 is the hydrochloride salt Table 2

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Abstract

Certain compounds of formula (I); wherein R1 represents unsubstituted or substituted aryl; Y represents -(CRnaRnb)n-; Rna and Rnb are each independently hydrogen or C1-6 alkyl; n is an integer from 1 to 5; R2 represents unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl; R3 and R4 each independently represent hydrogen or C1-6 alkyl; and salts and solvates thereof are CCR3-antagonists and are thus indicated to be useful in therapy of inflammatory conditions.

Description

MORPHOLINE DERIVATIVES SUBSTITUTED AT THE 2-POSITION BY AN ARYLALKYLUREA GROUP FOR USE AS CCR-3 ANTAGONISTS IN THE TREATMENT OF INFLAMMATORY CONDITIONS
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- (α) 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 unsubstituted or substituted aryl; Y represents -(CRnaRnb)n-;
Rna and Rnb are each independently hydrogen or Chalky!; n is an integer from 1 to 5;
R2 represents unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl;
R3 and R4 each independently represent hydrogen or d-6alkyl; and salts and solvates thereof; with the proviso that the following compounds are excluded;
N-benzyl-N'-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}urea; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(2-phenylethyl)urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(4-methoxybenzyl)urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(2-methylbenzyl)urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(3-methylbenzyl)urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(4-methylbenzyl)urea; N-(4-chlorobenzyl)-N'-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}urea;
N-(3-chlorobenzyl)-N'-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}urea;
N-(2-chlorobenzyl)-N'-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}urea;
N-[3-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]-
-amino}methyl)phenyl]acetamide formate; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[4-(methylsulfonyl)-
-benzyljurea;
4-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]amino}-
-methyl)benzenesulfonamide;
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(4-methoxybenzyl)urea; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(3,4-dimethoxybenzyl)urea;
N-(3-cyanobenzyl)-N'-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(3-methoxybenzyl)urea;
4-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]amino}-
-methyl)benzamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[3-(trifluoromethoxy)-
-benzyljurea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[4-(trifluoromethyl)-
-benzyljurea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[4-(1 ,2,3-thiadiazol- -4-yl)benzyl]urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[4-(trifluoromethoxy)-
-benzyljurea;
N-(3,5-dichlorobenzyl)-N'-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[3-(trifluoromethyl)- -benzyljurea N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(2,4-difluorobenzyl)urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(3,4-difluorobenzyl)urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(3-fluorobenzyl)urea;
N-(3,4-dichlorobenzyl)-N'-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}urea; 3-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-
-carbonyl]amino}methyl)-N-methylbenzamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[2-
-(trifluoromethoxy)benzyl]urea;
Methyl 3-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)- -carbonyl]amino}methyl)benzoate;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[2-(trifluoromethyl)-
-benzyljurea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(4-fluorobenzyl)urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(2-fluorobenzyl)urea; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(4-isopropoxybenzyl)urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(2,4-dimethoxybenzyl)urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[2-(4-methoxyphenyl)-
-ethyljurea;
N-[2-(4-tert-butoxyphenyl)ethyl]-N'-{[4-(3,4-dichlorobenzyl)morpholin-2- -yl]methyl}urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[3-
(dimethylamino)benzyl]urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[2-(methylthio)benzyl]urea;
N-(4-cyanobenzyl)-N'-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}urea; N'-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N-(4-methoxybenzyl)-N-
-methylurea; methyl 4-({[({[4-(3,4-dichlorobenzyl)morpholin-2-
-yl]methyl}amino)carbonyl]amino}methyl)benzoate;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[1-(4-fluorophenyl)ethyl]urea; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(1-methyl-1-phenylethyl)urea;
4-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]amino}-
-methyl)-N-(1,3-thiazol-2-yl)benzenesulfonamide;
4-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]amino}-
-methyl)-benzoic acid compound with N,N,N-triethylamine (1 :1 ); 4-({[({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]-
-amino}methyl)benzamide hydrochloride;
4-({[({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]-
-amino}methyl)benzamide;
4-({[({[(2R)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]- -amino}methyl)benzamide; 3-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]-
-amino}methyl)-N,N-dimethylbenzamide;
3-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]-
-amino}methyl)-N-ethylbenzamide; N-cyclopropyl-3-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-
-carbonyl]amino}methyl)benzamide;
4-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]-
-amino}methyl)-N-methylbenzamide;
4-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]- -amino}methyl)-N,N-dimethylbenzamide;
4-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]-
-amino}methyl)-N-ethylbenzamide;
N-cyclopropyl-4-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-
-carbonyl]amino}methyl)benzamide; 4-(2-{[({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-
-carbonyl]amino}ethyl)benzenesulfonamide;
3-({[({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-
-carbonyl]amino}methyl)-N-methylbenzamide;
N-cyclopropyl-3-({[({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)- -carbonyl]amino}methyl)benzenesulfonamide;
N-cyclopropyl-4-({[({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-
-carbonyl]amino}methyl)benzenesulfonamide;
4-({[({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)- carbonyl]amino}methyl)-N-methylbenzamide, and; N-cyclopropyl-4-({[({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2- yl]methyl}amino)carbonyl]amino}methyl)benzamide. Examples of the aryl group, R1 include phenyl. Examples of substituents for R1 include perhaloalkyl, aminosulphonyl; carboxy; mono-and di-(alkyl)aminosulphonyl; alkylsulphonylamino; alkylcarbonyl; cycloalkylaminocarbonyl; aminocarbonyl; alkyl; alkoxycarbonyl; mono- and di-
(alkyl)aminocarbonyl; unsubstituted heteroaryl; heteroaryl substituted with alkylsulphonylamino, alkylcarbonyl, alkyl, alkoxycarbonyl, mono- and di-
(alkyl)aminocarbonyl, halo, alkoxy, nitro, alkylsulphonyl, hydroxy, alkoxyalkyl, d-
6alkylthio-, mono- and-di-(alkyl)amino, or alkylcarbonylamino; halo; alkoxy; nitro; alkylsulphonyl; hydroxy; alkoxyalkyl; alkylthio-; mono- and-di-(alkyl)amino; and alkylcarbonylamino.
When R1 is substituted aryl, suitable substituents include aminosulphonyl; carboxy; mono-and di-(alkyl)aminosulphonyl; CLβalkylsulphonylamino; C^
6alkylcarbonyl; C3.8cycloalkylaminocarbonyl; aminocarbonyl; Ci-ealkyl; Ci- 6alkoxycarbonyl; mono- and di-(C1.6alkyl)aminocarbonyl; unsubstituted heteroaryl; heteroaryl substituted with Cι-6alkylsulphonylamino, Ci-ealkylcarbonyl, Cι-6alkyl, Ci-ealkoxycarbonyl, mono- and di-(Cι^alkyl)aminocarbonyl, halo, d- 6alkoxy, nitro, Ci-ealkylsulphonyl, hydroxy, Cι-6alkoxyCι-6alkyl, d-6alkylthio-, mono- and-di-(Cι-6alkyl)amino, or Ci-βalkylcarbonylamino; halo; Ci-βalkoxy; nitro; Ci-ealkylsulphonyl; hydroxy; d-ealkoxyCi-ealkyl; d-βalkylthio-; mono- and-di-(Cι- 6alkyl)amino; and Cι-6alkylcarbonylamino.
When R1 is substituted with unsubstituted or substituted heteroaryl, examples of said heteroaryl group include oxadiazolyl and triazolyl. Suitably, R1 is unsubstituted or substituted phenyl. When R1 is substituted phenyl, suitable substituents include carboxy, halo, Ci-ealkylsulphonyl, Cι-6alkylsulphonylamino, mono-and di-(Cι- 6alkyl)aminosulphonyl, aminosulphonyl, C3^cycloalkylaminocarbonyl, mono- and di-(C1.6alkyl)aminocarbonyl; heteroaryl substituted with Cι-6alkyl, Ci- 6alkylcarbonylamino, d.6alkoxycarbonyl, and aminocarbonyl. More suitably, R1 is phenyl substituted with 4-(3-methyl-1 ,2,4-oxadiazol-
5yl), 4-(methanesulphonylamino), 4-(N,N-dimethylaminosulphonyl), 4- (aminosulphonyl), 3-(/so-propylaminocarbonyl), 3-(3-methyl-1 ,2,4-oxadiazol-5-yl), 3-(methylcarbonylamino), 4-fluoro-3-(methoxycarbonyl), 3-amido, 4-fluoro-3- (ethylaminocarbonyl), 4-fluoro-3-(methylaminocarbonyl), 3-(methoxycarbonyl), 3- amido-4-fluoro, 3-(cyclopropylaminocarbonyl), 3-(ethylaminocarbonyl), 3-
(methylaminocarbonyl), 3-carboxy-4-fluoro, 3-carboxy, 3-(methanesulphonyl), 3- (methanesulphonylamino), 4-amido, 3-(5-methyl-1 ,3,4-oxadiazol-2-yl), 3-(5- methyl-1 ,3,4-triazol-2-yl) or 3-(1 ,3,4-oxadiazol-2-yl). Suitably, Rna and Rnb are both hydrogen. Suitably, n is 1.
Suitably, R3 and R4 are both hydrogen. When R2 is aryl, examples include phenyl. When R2 is substituted aryl, suitable substituents include cyano, perhaloCι-6alkyl, amido, halo, d-6alkyl, C^alkoxycarbonyl, mono- and di-(Cι- 6alkyl)aminocarbonyl, d-βalkoxy, nitro, Cι.6alkylsulphonyl, hydroxy, 6alkyl, Cι-6alkylthio-, mono- and-di-(Cι-6alkyl)amino, and d.6alkylcarbonylamino. When R2 is heteroaryl, examples include thiophenyl. When R2 is substituted heteroaryl, suitable substituents include cyano, perhaloCi-ealkyl, amido, halo, dialkyl, Ci-βalkoxycarbonyl, mono- and di-(Cι. 6alkyl)aminocarbonyl, Cι.6alkoxy, nitro, Ci-ealkylsulphonyl, hydroxy, 6alkyl, Cι-6alkylthio-, mono- and-di-(Cι-6alkyl)amino, and C^alkylcarbonylamino.
Suitably, R2 is unsubstituted or substituted phenyl or unsubstituted or substituted thiophenyl.
When R2 is substituted phenyl or thiophenyl suitable substituents include halo. More suitably, R2 is phenyl or thiophenyl substituted with chloro or fluoro. Preferably, R2 is 3,4-dichlorophenyl, 3,4-difluorophenyl or 2-chloro- thiophen-5-yl.
There exists a subgroup of compounds of formula (I) being of formula (IA)
wherein;
R1A is a moiety of the formula (M)
wherein R5 represents C3-8cycloalkylaminosulphonyl, R7R8NC(O)- wherein R7 and R8 may each independently represent hydrogen or Cι-6alkyl or R7 and R8 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; aminosulphonyl; carboxy; mono-and di-(Cι. 6alkyl)aminosulphonyl; d-6alkylsulphonylamino; d.6alkylcarbonyl; C3- βcycloalkylaminocarbonyl; aminocarbonyl; Ci-ealkyl; Cι-6alkoxycarbonyl; unsubstituted heteroaryl; heteroaryl substituted with Ci-ealkyl, halo, C^alkoxy, or hydroxy; halo; Ci-ealkoxy; nitro; Ci-ealkylsulphonyl; hydroxy; Cι-6alkoxyC1-6alkyl; Cι-6alkylthio-; mono- and-di-(Cι-6alkyl)amino; or Cι-6alkylcarbonylamino; R6 represents cyano, perhaloC^alkyl, hydrogen, d-6alkyl, halo, Cι-6alkoxy, or hydroxy, and; R2, R3, and R4 are as hereinbefore defined for formula (I); and salts and solvates thereof; with the proviso that the following compounds are excluded; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(3-methylbenzyl)urea; N-(3-chlorobenzyl)-N'-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}urea; N-[3-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]- -amino}methyl)phenyl]acetamide formate;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(3,4-dimethoxybenzyl)urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(3-methoxybenzyl)urea;
N-(3,5-dichlorobenzyl)-N'-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}urea; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(3,4-difluorobenzyl)urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(3-fluorobenzyl)urea;
N-(3,4-dichlorobenzyl)-N'-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}urea;
3-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]-
-amino}methyl)-N-methylbenzamide; methyl 3-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]-
-amino}methyl)benzoate;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[3-(dimethylamino)-
-benzyljurea;
3-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]- -amino}methyl)-N,N-dimethylbenzamide;
3-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]-
-amino}methyl)-N-ethylbenzamide;
N-cyclopropyl-3-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-
-carbonyl]amino}methyl)benzamide, and; 3-({[({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]-
-amino}methyl)-N-methylbenzamide.
When R5 is unsubstituted or substituted heteroaryl, examples of said heteroaryl group include oxadiazolyl and triazolyl.
Suitably, R5 is carboxy, halo, Cι.6alkylsulphonyl, Cι-6alkylsulphonylamino, mono-and di-(Cι.6alkyl)aminosulphonyl, aminosulphonyl, C3. scycloalkylaminocarbonyl, mono- and di-(Cι.6alkyl)aminocarbonyl, unsubstituted heteroaryl, heteroaryl substituted with Cι-6 alkyl, Cι-6 alkylcarbonylamino, Ci-
6alkoxycarbonyl or aminocarbonyl.
Suitably, R6 is hydrogen or halo. More suitably, R1A is phenyl substituted with 3-(5-methyl-1 ,3,4-triazol-2- yl), 3-(2-methyl-1 ,3,4-triazol-5-yl), 3-(/so-propylaminocarbonyl), 3-(3-methyl-
1 ,2,4-oxadiazol-5-yl), 3-(methylcarbonylamino), 4-fluoro-3-(methoxycarbonyl), 3- amido, 4-fluoro-3-(ethylaminocarbonyl), 4-fluoro-3-(methylaminocarbonyl), 3-
(methoxycarbonyl), 3-amido-4-fluoro, 3-(cyclopropylaminocarbonyl), 3- (ethylaminocarbonyl), 3-(methylaminocarbonyl), 3-carboxy-4-fluoro, 3-carboxy, 3-
(methanesulphonyl), 3-(methanesulphonylamino), 3-(5-methyl-1 ,3,4-oxadiazol-2- yl) or 3-(1,3,4-oxadiazol-2-yl).
There exists a preferred subgroup of compounds of formula (I) being of formula (I')
wherein;
Rr is a moiety of formula (M")
Wherein R5 represents Cι-6alkylaminocarbonyl, substituted heteroaryl, Ci- 6alkylcarbonylamino, halo, d.6alkoxycarbonyl, amido, C3- ecycloalkylaminocarbonyl, carboxy, d-6alkylsulphonyl, or Ci- 6alkylsulphonylamino;
R6' is H or halo; and R2' is phenyl substituted by halo. Suitably, M' represents 3-(5-methyl-1 ,3,4-triazol-2-yl)phenyl, 3-(/so- propylaminocarbonyl)phenyl, 3-(3-methyl-1 ,2,4-oxadiazol-5-yl)phenyl, 3- (methylcarbonylamino)phenyl, 4-fluoro-3-(methoxycarbonyl)phenyl, 3- amidophenyl, 4-fluoro-3-(ethylaminocarbonyl)phenyl, 4-fluoro-3-
(methylaminocarbonyl)phenyl, 3-(methoxycarbonyl)phenyl, 3-amido-4- fluorophenyl, 3-(cyclopropylaminocarbonyl)phenyl, 3- (ethylaminocarbonyl)phenyl, 3-(methylaminocarbonyl)phenyl, 3-carboxy-4- fluorophenyl, 3-carboxyphenyl, 3-(methanesulphonyl)phenyl, 3- (methanesulphonylamino)phenyl, 3-(5-methyl-1 ,3,4-oxadiazol-2-yl)phenyl or 3- (1 ,3,4-oxadiazol-2-yl)phenyl.
Suitably, R2' is 3,4-dichlorophenyl, 3,4-difluorophenyl or 3-chloro-4- fluorophenyl.
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 subgroup of compounds of formula (I) being of formula (I")
wherein;
R1 is phenyl substituted at the 4-position by substituted heteroaryl, Ci- 6alkylsulphonylamino, N,N-diCι-6alkylaminosulphonyl, aminosulphonyl, or amido; and;
R2" is phenyl substituted by halo or thiophenyl substituted by halo. Suitably, R1" is 4-(3-methyl-1 ,2,4-oxadiazol-5yl)phenyl, 4- (methanesulphonylamino)phenyl, 4-(N,N-dimethylaminosulphonyl)phenyl, 4- (aminosulphonyl)phenyl or 4-amidophenyl.
Suitably, R2 is 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-chloro-4- fluorophenyl or 2-chloro-thiophen-5-yl.
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 subgroup of compounds, being of formula (IB)
wherein;
R9 is mono- or di-(C1.6alkyl)aminocarbonyl or C3. scycloalkylaminocarbonyl.
Suitably, R9 is ethylaminocarbonyl, cyclopropylaminocarbonyl, or dimethylaminocarbonyl. Preferably, R9 is 4-ethylaminocarbonyl, 3-cyclopropylaminocarbonyl, or 3- dimethylaminocarbonyl. Accordingly, there is provided a compound of formula (IB) or a salt or solvate thereof.
Suitable compounds of the invention are Examples 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 31 , 33, 34, and 35.
Preferred compounds of the invention are Examples 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 18, 20, 22, 28, 31 , 33, 34, and 35.
More preferred compounds of the invention are Examples 1 , 2, 3, 4, 5, 6, 7, 12, 22, 28, 31 , 33 and 34. Especially preferred compounds of the invention are Examples 1 , 2, 12,
22, 28, 31 , 33, and 34.
Suitable salts of the compounds of formula (I) include physiologically acceptable salts and salts which may not be physiologically acceptable but may be useful in the preparation of compounds of formula (I) and physiologically 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.
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 heterocyclylcarbonyl; cycloalkylaminosulphonyl; aminosulphonyl; carboxy; mono-and di- (alkyl)aminosulphonyl; alkylsulphonylamino; alkylcarbonyl; cycloalkylaminocarbonyl; aminocarbonyl; alkyl; alkoxycarbonyl; mono- and di- (alkyl)aminocarbonyl; unsubstituted heteroaryl; heteroaryl substituted with alkyl, halo, alkoxy, hydroxy; halo; alkoxy; nitro; alkylsulphonyl; hydroxy; alkoxyalkyl; alkylthio; mono- and-di-(alkyl)amino; alkylcarbonylamino; hydrogen; cyano; perhaloalkyl; and amido.
References to 'heteroaryl' refer to monocyclic heterocyclic aromatic rings containing 1-4 heteroatoms selected from nitrogen, oxygen and sulphur. Examples of heterocyclic aromatic rings include thiophenyl and oxadiazolyl.
Suitable substituents for any heteroaryl group include 1 to 5, suitably 1 to 3, substituents selected from the list consisting of cyano, perhaloalkyl, amido, halo, alkyl, alkoxycarbonyl, mono- and di-(alkyl)aminocarbonyl, alkoxy, nitro, alkylsulphonyl, hydroxy, alkoxyalkyl, alkylthio, mono- and-di-(alkyl)amino, and alkylcarbonylamino.
References to '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.
Suitable substituents for any cycloalkyl group include alkyl, halo, and hydroxy.
References to 'heterocyclyl' refer to monocyclic heterocyclic aliphatic rings containing 2 to 6, suitably 3 to 5, carbon atoms, and 1 to 3, heteroatoms selected from nitrogen, oxygen, and sulphur. 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;
R1, Y, R3, R4, and R2 are as hereinbefore defined for formula (I) and U is a urea-forming group; 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. A urea-forming group is a group which is derived from a reagent which introduces a carbonyl group and a leaving group to an amino compound.
Examples of urea-forming groups are imidazolylcarbonyl and chlorocarbonyl, and, when R4 is hydrogen, then 4-nitrophenoxycarbonyl may be used. The reagents from which they are derived are 1 ,1'-carbonyldiimidazole, phosgene, and 4-nitrophenylchloroformate respectively. A suitable urea-forming group is 4- nitrophenoxycarbonyl.
Typically, the compound of formula (II) and the compound of formula (III) in a suitable solvent, such as an organic solvent, e.g. dichloromethane are treated with a suitable base, such as a tertiary amine, e.g. triethylamine, at ambient temperature, such as 18 - 25"C.
A compound of formula (III) may be prepared by reaction of a compound of formula (IV);
wherein;
R4 and R2 are as hereinbefore defined for formula (I); with a compound of formula U-L wherein U is a urea-forming group as hereinbefore defined and L is a leaving group. A suitable leaving group is a halo group such as chloro.
The reaction between the compound of formula (IV) in the presence of a suitable base, such as a tertiary amine, e.g. triethylamine, and the compound U- L is performed in a suitable solvent, for example dichloromethane, at a suitable temperature, for example those in the range of -5°C to +5°C over a suitable period of time, for example 3-5 hours. A compound of formula (IV) wherein R4 is hydrogen may be prepared either by Reaction (a) or Reaction (c). The S-enantiomer of a compound of formula (IV) may be prepared by Reaction (b).
Reaction (a). Reaction of the compound of formula (V) with a compound of formula (VI)
wherein R2 is as hereinbefore defined for formula (I) and A is a protected amino group, suitably phthalimido, followed by deprotection of the amino group to give a compound of formula (IV) wherein R4 is hydrogen i.e. a compound of formula (IVR)
wherein R2 is as hereinbefore defined, and optionally resolution of the resulting enantiomers of a compound of formula (IVR); or;
Reaction (b). Reaction of a compound of formula (V) as hereinbefore defined with a compound of formula (VIA)
wherein A is as hereinbefore defined for formula (VI), followed by deprotection of the amino group to give the corresponding enantiomer of a compound of formula (IV) wherein R4 is hydrogen i.e. a compound of formula (IVE)
wherein R2 is as hereinbefore defined.
Reaction (c). Hydrolysis of a compound of formula (VII);
wherein T is trifluoroacetyl, and R4 and R2 are as hereinbefore defined for formula (I), and optionally resolution of the resulting enantiomers of a compound of formula (IV).
10 For both reactions (a) and (b), the cyclisation of the intermediate diols
(IVBR) and (IVBE) in the reaction between the compound of formula (V) and a compound of formula (VI) or (VIA) is typically carried out under the Mitsunobu conditions as follows:
Typically, a mixture of the compound of formula (V) and the compound of
15 formula (VI) or formula (VIA) 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
20 mixture stirred until all the solid is dissolved. A suitable azo compound, suitably diisopropylazodicarboxylate, is then added over a period of time, suitably, 10 -15 minutes, while maintaining the temperature at <7°C. The mixture is allowed to stand for a period of time, suitably 2 - 3 hours, then allowed to warm, suitably to 20 - 25°C. After a further period of standing, suitably 4 - 6 hours, further
25 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
30 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 (IVR) or formula (IVE) 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 (IVR) or formula (IVE) 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 re-evaporated to give the compound of formula (IVR) or formula (IVE).
The process for the preparation of the protected form of the compound of formula (IVR) or formula (IVE) described above may also be undertaken in two stages, in which an intermediate compound of formula (IVBR) or of formula (IVBE) respectively;
wherein A is as hereinbefore defined for formulae (VI) and (VIA) and R2 is as hereinbefore defined for formula (I); is isolated. Typically, a mixture of the compound of formula (V) and a compound of formula (VI) or formula (VIA) 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 (V) 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 (IVBR) or formula (IVBE) respectively is isolated by filtration, washed with further co-solvent and dried in vacuo. A protected form of the compound of formula (IVR) or formula (IVE) may then be prepared from a compound of formula (IVBR) or formula (IVBE) under similar conditions to those of the reaction between a compound of formula (V) and formulae (VI) or (VIA) as hereinbefore described, but omitting the reflux 5 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 (VII) 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 - 10 25°C for a suitable time, for example 16 - 20 hours followed by removal of the organic solvent was 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 15 and evaporation of the solvent in vacuo. The crude product is then purified by flash chromatography.
The resolution of the compound of formula (IVE) from the racemic product i.e. the compound of formula (IVR) may be undertaken using techniques well known to those skilled in the art, for example preparative chiral high 20 performance liquid chromatography (chiral HPLC) or by fractional crystallisation of diastereoisomeric salts.
A compound of formula (VII) may be prepared by reaction of a compound of formula (VIII) with a compound of formula (IX)
wherein;
T, R4 and R2 are as hereinbefore defined for formula (VII) and L2 is a leaving group. A suitable leaving group, L2 is a halo group such as chloro.
30 The reaction between a compound of formula (VIII) and a compound of formula (IX) is typically carried out by stirring a solution of the compound of formula (VIII) 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,
35 such as sodium iodide. A solution of a compound of formula (IX) 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 (VIII) may be prepared by reaction of a compound of formula (X) with a compound of formula (XI);
wherein R4 and T are as hereinbefore defined for formula (VII) and Rx is an alkyl group, suitably ethyl.
The reaction between a compound of formula (X) and a compound of formula (XI) is typically carried out by stirring a solution of a compound of formula (X) 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 (XI) 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.
Compounds of formula (II) may be prepared from other compounds of formula (II) by a procedure comprising appropriate steps of protection, reaction, and deprotection. An example of such a procedure is protection of the amino function of a compound of formula (II) wherein Y is -CH2- and R1 is 3-carboxy-4- fluorophenyl, and R3 is hydrogen. A suitable protecting group is tBoc. The carboxy function is then alkylated, for example with (trimethylsilyl)diazomethane, and the tBoc group is then removed.
The compounds of formulae (II), certain compounds of formula (IV), certain compounds of formula (V), (VI), certain compounds of formula (VII), certain compounds of formula (VIII), (IX), (X), and (XI) are either known, commercially available compounds, and/or may be prepared by analogy with known procedures, for examples those disclosed in standard reference texts of synthetic methodology such as J. March, Advanced Organic Chemistry, 3rd Edition (1985), Wiley Interscience.
The compounds of formulae (III), (IVBR), and (IVBE) are considered to be novel. Accordingly, there is provided a compound of formula (III).
There is also provided a compound of formula (IVBR).
There is also provided a compound of formula (IVBE).
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 1 ,2,4-oxadiazol-5-yl group; such a conversion may be carried out using an appropriate conventional ring formation procedure, for example treating an appropriately protected compound of formula (I) with an appropriate hydroxyamidine;
(b) 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 a suitable aqueous base;
(c) converting a group R1 which represents an aryl group substituted with a carboxy group into a group R which represents an aryl group substituted with an amide 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;
(d) 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 a 2-alkyl-1,3,4-oxadiazol-5-yl group; such a conversion may be carried out by forming a first intermediate by reaction of a suitably protected compound of formula (I) with an alkyl carbazate, then forming a second intermediate by hydrolysis of the first intermediate with a mineral acid, followed by ring formation with a suitable orthoester, and; (e) 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 a 2-alkyl-1 ,3,4-triazol-5-yl group; such a conversion may be carried out by forming a first intermediate by reaction of a suitably protected compound of formula (I) with an alkyl carbazate, then forming a second intermediate by hydrolysis of the first intermediate with a mineral acid, followed by ring formation with a suitable carboximidate ester.
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 assays:
(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, MgCI2 5 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.
(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 EC8o 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 pK, values (fpK,) were generated using the equation below (Lazareno & Birdsall, 1995. Br.J. Pharmacol 109: 1110- 9).
fpKi = ICso
[Agonist]
EC50
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:
Example No. fpKi
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.- hydroxy be nzoates 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 100mg/kg body weight, and at any appropriate frequency e.g. 1 to 4 times daily. The precise dosing regimen will of course depend on factors such as the therapeutic indication, the age and condition of the patient, and the particular route of administration chosen.
Throughout the description and the claims which follow, unless the context requires otherwise, the word 'comprise', and variations such as 5 '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. 10 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 15 26". The structures of the compounds so referred to are given in Tables 1 to 3 for the Examples and Tables 4 to 5 for the Descriptions.
General experimental details
Mass Directed Automated Preparative HPLC column, conditions and eluent
20 Mass directed automated preparative high performance liquid chromatography was carried out using an LCABZ+ 5μm (5cm x 10mm internal diameter) column, employing gradient elution using two solvent systems, (A) 0.1% formic acid in water, and (B) 95% acetonitrile and 0.5% formic acid in water, at a flow rate of 8ml min"1. Mass spectrometry was carried out using a VG Platform Mass
25 Spectrometer, with an HP1100 Diode Array Detector and Accurate Flow Splitter. 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)
30 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 1.1 mins; return to 100% A over 0.2mins.
35 The LC/MS system used a micromass spectrometer, with electrospray ionisation mode, positive and negative ion switching, mass range 80-1000 a.m.u. Thermospray Mass Spectra
Thermospray Mass Spectra were determined on a HP 5989A engine mass spectrometer, +ve thermospray, source temperature 250°C, probe temperatures
40 120°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/Aqueous 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 (3.1g) in methanol (70ml) under nitrogen was added an ethereal solution of ethyl-α,α,α-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-{f4-(3,4-Dichlorobenzyl)morpholin-2-yllmethyl)-2.2.2- trifluoroacetamide
To a stirred solution of Description 1 (3.3q) 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). LC/MS/Rt 2.63 min, Mass Spectrum m/z 371 [MH+].
Description 3: r4-(3.4-Dichlorobenzyl)morpholin-2-yllmethylamine 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 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 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 m/z 275 [MH+].
Description 4: [4-(3.4-Dichlorobenzyl)morpholin-2-yllmethylamine (alternative synthesis)
A mixture of 2-[(3,4-dichlorobenzyl)amino]ethanol (Chem Abs No. 40172-06-3, 0.980g) and 2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione (1.10g) was 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 extracts were washed with water and brine, dried (Na2SO4) and concentrated under vacuum to give the title compound as a brown oil (1.02g). Mass Spec, m/z 275 [MH+].
Description 5: 1 -r(2S)-4-(3.4-Dichlorobenzyl)morpholin-2-yllmethylamine
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) 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-r(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-vHmethanamine 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-ylmethyl1-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 (121 mg) 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: 4-Nitrophenyl r4-(3,4-dichlorobenzyl)morpholin-2- yllmethylcarbamate
Triethylamine (0.09ml) was added to solution of Description 3 (0.150g. 0.545mmol) in dichloromethane (3ml) with stirring at 20°C under nitrogen. The solution was cooled to 0°C and a solution of 4-nitrophenyl chloroformate (0.121g) in dichloromethane (1ml) was added drop-wise. The resultant mixture was stirred for 4h at 0°C. The solution was allowed to warm to 20°C, washed with brine (4ml), dried (MgSO4), and concentrated in vacuo. Purification by Biotage flash chromatography on silica gel, eluting with 35% ethyl acetate in cyclohexane, gave the title compound (0.2g). LC-MS Rt 3.1 mins. Mass Spectrum m/z 441 [MH+].
Description 9: 4-Nitrophenyl r(2S)-4-(3.4-dichlorobenzyl)morpholin-2- yllmethylcarbamate
Description 9 was prepared in an analogous manner to Description 8 from Description 5 (0.225g) and 4-nitrophenylchloroformate (0.182g) to yield the title compound (0.2g).
LC-MS Rt 3.1mins. Mass Spectrum m/z 441 [MH+].
Description 10: r(2S)-4-(3,4-difluorobenzyl)morpholin-2-yllmethylamine Description 10 was made in an analogous manner to that of Description 5. Preparative HPLC retention time 28.3min
Description 11 : 4-Nitrophenyl r(2S)-4-(3,4-difluorobenzyl)morpholin-2- yllmethylcarbamate
Description 11 was prepared in an analogous manner to Description 9 from Description 10 and 4-nitrophenylchloroformate.
LC-MS Rt 2.52mins. Mass Spectrum m/z 408 [MH+].
Description 12: 4-Nitrophenyl f(2S)-4-(3,4-difluorobenzyl)morpholin-2- yllmethylcarbamate Description 12 was made in an analogous manner to that of Example 5. Mass Spectrum m/z 466 [MH+],
Description 13: N'-(3-(3-r(2S)-4-(3.4-Difluorobenzyl)morpholin-2- ylmethvHureidomethyl)benzoyl)hydrazinecarboxylic acid tert-butyl ester
A solution of Example 16 (0.626g) in N,N-dimethylformamide (5.5ml) was treated with 1-hydroxybenzotriazole (0.174g), 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (0.283g), t-butyl carbazate (0.120g) and N,N- diisopropylethylamine (0.174ml), and the mixture stirred at room temperature for seventeen hours. The solution was then diluted with dichloromethane (30ml) and washed successively with saturated aqueous sodium hydrogen carbonate (25ml) and dilute aqueous sodium chloride (2 x 25ml). The organic phase was separated using a hydrophobic frit (12ml) and drained directly onto an SCX (10g) ion exchange cartridge, which had been pre-treated with methanol and which was then eluted with methanol and 10% 0.880 ammonia/methanol. The basic fractions were combined and evaporated to give the title compound (0.480q) as a yellow film. LC-MS : Rt = 2.22 min.
Description 14: 1 -f (2S)-4-(3.4-Difluorobenzyl)morpholin-2-ylmethyll-3-(3- hydrazinocarbonyl-benzvDurea
Description 13 (0.480g) was treated with 4M hydrogen chloride in dioxane (10ml) at room temperature, followed after half an hour by methanol (3ml). After a further two and a half hours at room temperature, the solution was concentrated to dryness and the residue loaded directly and equally onto two SCX (10g) ion exchange cartridges, which had been pre-treated with methanol and which were then eluted with methanol and 10% 0.880 ammonia/methanol. All basic fractions were combined and evaporated to give the title compound (0.374g) as a yellow glassy film. LC-MS : Rt = 1.78 min.
Description 15: r(2S)-4-(3-Chloro-4-fluorobenzyl)morpholin-2-ylmethvHcarbamic acid 4-nitro-phenyl ester
A solution of 4-nitrophenyl chloroformate (0.102g) in anhydrous dichloromethane (5ml) at 0° was treated, dropwise, with a solution of Description 17 (0.13g) and triethylamine (0.070ml) in anhydrous dichloromethane (2ml). After stirring at room temperature for 18hrs the mixture was concentrated in vacuo. Chromatographic purification on silica gel (Varian Bond-Elut cartridge, 5g), eluting with a gradient of ethyl acetate/cyclohexane gave the title compound (0.19g) as a colourless oil. LC-MS : Rt = 2.66min. Mass Spectrum m/z 424 [MH+]
Description 16: {(2S)-4-r(5-chlorothien-2-yl)methyl1morpholin-2-yl)methylamine
Description 16 was made in an analogous manner to that of Description 5.
Chiral preparative HPLC retention time 25.2min
Description 17: 4-Nitrophenyl r(2S)-4-r(5-chlorothien-2-yl)methyllmorpholin-2- yllmethylcarbamate
Description 17 was prepared in an analogous manner to Description 9 from
Description 16 and 4-nitrophenylchloroformate. LC-MS Rt 2.58mins. Mass Spectrum m/z 412 [MH+].
Description 18: 5-(tert-Butoxycarbonylamino-methyl)-2-fluoro-benzoic acid methyl ester
To a solution of 5-[[[(1,1-dimethylethoxy)carbonyl]amino]methyl]-2-fluoro-benzoic acid (prepared as described in Tetrahedron Lett. (1993), 34(39), 6263-4) in a mixture of dichloromethane (4ml) and methanol (4ml) was added (trimethylsilyl)diazomethane (0.9M solution in hexanes, 4.8ml). The solution was stirred at room temperature for 1 h. The solvent was removed in vacuo. The residue was purified by chromatography on silica gel (10g Varian Bond-elut cartridge), eluting sequentially with 8:1 to 6:1 cyclohexane/ethyl acetate to give the title compound as a colourless oil (0.388g). LC/MS Rt 2.91 min m/z 301 [MNH4 +].
Description 19: 5-Aminomethyl-2-fluoro-benzoic acid methyl ester hydrochloride
Description 18 (0.60q) was dissolved in 4M hydrogen chloride in dioxane (8ml), and the solution stirred at 20° for 40min. The solvent was removed in vacuo to give the title compound as a white solid (0.435g). LC/MS R, 1.18 min m/z 184 [MH+].
Description 20: (3-Ethylcarbamoyl-benzyl)carbamic acid tert-butyl ester
To a solution of 3-[[[(1 ,1-dimethylethoxy)carbonyl]amino]methyl] benzoic acid (0.980g) in tetrahydrofuran (25ml) was added 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (0.750g) followed by triethylamine (0.543ml) with stirring under nitrogen, and the mixture was stirred at 22° for 1.5h. A 2M solution of ethylamine in tetrahydrofuran (6.0ml) was added, and the mixture was stirred for 18h at 20°. The mixture was evaporated to dryness and the residue partitioned between water and ethyl acetate. The organic layer was separated, dried (MgSO4) and evaporated in vacuo. The residue was purified by chromatography on silica gel, eluting with ethyl acetate containing 0.5% trethylamine, to give the title compound (0.345g). LC/MS Rt = 2.62min. Mass Spectrum m/z 296 [MNH4 +]
Description 21 : 3-Aminomethyl-N-ethyl-benzamide trifluoroacetic acid salt
.CF3COOH
To a solution of Description 20 in dichloromethane (1 ml) was added 5 trifluoroacetic acid (1ml) and the mixture was stirred at 22° until all starting material was consumed (by LC/MS). The mixture was evaporated to dryness, and toluene was added and re-evaporated twice. The residue was triturated with ether to form a white solid, and the ether evaporated in vacuo to give the title compound as the trifluoroacetate salt. 10 NMR (D6DMSO) 8.55(1 H,t,NH); 8.25(3H,bs,NH3 +); 8.0(1 H,bs,CH). 7.85(1 H.bd.CH); 7.6 (1 H,bd,CH); 7.53(1 H.dd.CH); 4.1 (2H,bs,CH2); 3.3(2H,m,CH2); 1.15(3H,t,CH3)
Description 22: r(2S)-4-(3-Chloro-4-fluoro-benzyl)-morpholin-2-ylmethyll- 15 carbamic acid tert-butyl ester
BocHN
A solution of (2-morpholinylmethyl)-carbamic acid 1 ,1 -dimethyl ester [CAS 20 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 25 colourless gum.
LC-MS : Rt = 2.46min. Mass Spectrum m/z 359 [MH+]
Description 23: C-f(2S)-4-(3-Chloro-4-fluorobenzyl)morpholin-2-yllmethylamine
A solution of Description 22 (0.36g) in dichloromethane (1ml) was treated with trifluoroacetic acid (1ml) 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 (MgSO4), 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+]
Description 24: 3-{3-f(2S)-4-(3.4-Dichlorobenzyl)morpholin-2- ylmethyllureidomethvDbenzoic acid; compound with triethylamine
Prepared in an analogous manner to that used for Example 15 using Description
12 and 4-(methoxycarbonyl)phenylacetic acid.
LCMS m/z452 [MH+]
Description 25: (4-Ethylcarbamoyl-benzyl)carbamic acid tert-butyl ester
Prepared in an analogous manner to that used for Description 20. LCMS m/z 279 [MH+]
Description 26: 4-Aminomethyl-N-ethyl-benzamide hydrochloride
Prepared in an analogous manner to that used for Description 21 but using 4.0M HCl in 1 ,4-dioxane instead of trifluoroacetic acid and dichloromethane. LCMS m/z 179 [MH+]
Examples
Synthetic Method A Example 5
To a solution of Description 9 (0.408g) in N,N-dimethylformamide (5ml) was added Description 19 (0.2g) and N,N-diisopropylethylamine (0.346ml). The solution was stirred at 20° for 18h. The mixture was applied to a sulphonic acid ion exchange cartridge (10g, Isolute SCX, pre-treated with methanol). The cartridge was eluted with methanol followed by 10% 0.880 ammonia in methanol; evaporation in vacuo of the basic fraction gave a yellow gum. The residue was dissolved in ethyl acetate (50ml) and the solution washed with 2N sodium hydroxide (30ml and 15ml x 2). The combined aqueous washings were extracted with ethyl acetate (30ml). The combined organic extracts were washed with water (20ml), dried (MgSO ) and concentrated in vacuo to give the title compound as an oil (0.377g). LC/MS R, 2.61 min m/z 484 [MH+].
Synthetic Method B Example 2
To a solution of Description 12 (0.047g) and N-hydroxy-ethanimidamide (0.037g) in absolute ethanol (1ml) was added sodium ethoxide (21% wt solution in ethanol, 0.1ml). To the solution was added pre-dried 4A powdered molecular sieves (0.230g). The suspension was heated under reflux for 5h. The suspension was filtered and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (10g Varian Bond-elut cartridge), eluting sequentially with cyclohexane/ethylacetate/5% methanol in chloroform to give the title compound as a white solid. LC/MS R, 2.65 min m/z 490 [MH+].
Synthetic Method C Example 15
To a solution of Example 5 (0.21 Og) in methanol (5ml) was added 2N sodium hydroxide (1 ml). The solution was stirred at 20° for 2h. The solvent was removed in vacuo. The residue was dissolved in water (5ml) and acidified to pH1 using 2H hydrochloric acid. The suspension was applied onto sulphonic acid ion exchange cartridges (2x1 Og Isolute SCX, pre-treated with water). The cartridges were eluted with water followed by 5% triethylamine in methanol; evaporation of the basic fraction in vacuo gave the title compound as a colourless oil (0.246g). LC/MS R, 2.42min m/z 470[MH+].
Synthetic Method D Example 7
To a solution of Example 15 (0.043g) in N,N-dimethylformamide (2ml) was added N,N-diisopropylethylamine (0.026ml), 1-hydroxybenzotriazole (0.013g), and 1-(3- dimethylaminopropyl)-3-ethylcabodiimide hydrochloride (0.017g). The solution was stirred at 20° for 5min and then treated with ethylamine hydrochloride (0.036g). After 0.75h, the solution was treated with further N,N- diisopropylethylamine (0.026ml) and stirred in a sealed vial for 18h. The mixture was applied onto a sulphonic acid ion exchange cartridge (5g Isolute SCX, pretreated with methanol). The cartridge was eluted with methanol followed by 10% 0.880 ammonia in methanol; evaporation of the basic fraction in vacuo gave an oil. The residue was purified by chromatography on silica gel (10g Varian Bond- elut cartridge), eluting sequentially with cyclohexane/ethyl acetate/5% methanol in dichloromethane to give the title compound (0.020g). LC/MS Rt 2.45 min m/z 497 [MH+].
Synthetic Method E Example 21
Triethyl orthoacetate (0.54ml) was added to Description 14 (0.047g) and the mixture heated to 160° for eighteen hours. After cooling, the mixture was diluted with methanol (2ml) and loaded directly onto an SCX (2g) ion exchange cartridge, which had been pre-treated with methanol and which was then eluted with methanol followed by 10% 0.880 ammonia/methanol. The basic fractions were combined and evaporated to give a pale yellow film which was purified by chromatography on silica gel (Varian Bond-Elut cartidge, 1g), eluting with 0%, 5%, and 10% methanol/ethyl acetate to yield 2 impure clear colourless films. These were recombined and purified using mass directed HPLC. Appropriate fractions were combined and evaporated to give the title compound (0.0021 g) as a clear colourless film. LC-MS : Rt = 2.07 min. Mass Spectrum m/z [MH+] 458
Synthetic Method F Example 22
Ethyl acetimidate hydrochloride (0.011g) was treated with sodium hydroxide (0.112ml of a solution of 0.0915g in methanol (2.86ml)) and the mixture shaken for two minutes then left to stand for ten minutes. The supernatant liquid was then transferred by syringe to a thick walled sealed vial (Reactivial™) containing Description 14 (0.039g); the mixture was heated at reflux for one and a quarter hours, and allowed to cool to give an orange gum. The gum was dissolved in methanol (1ml) and loaded directly onto an SCX (2g) ion exchange cartridge, which had been pre-treated with methanol and which was then eluted with methanol followed by 10% 0.880 ammonia/methanol. The basic fractions were combined and evaporated to give a clear colourless film which was further purified using mass directed HPLC. Appropriate fractions were combined and evaporated to give the title compound (0.0035g) as a clear colourless film. LC-MS : Rt = 2.02 min. Mass Spectrum m/z [MH+] 457
Synthetic Method G
Example 23: 1 -■(2S)-4-(3.4-Difluorobenzyl)morpholin-2-ylmethyll-3-(3- n .3,41oxadiazol-2-yl-benzyl)urea
Description 14 (0.114g) had triethylorthoformate (1.3ml) added to it and was heated at reflux under nitrogen for 18hrs. After cooling, the mixture was diluted with methanol and directly applied onto a sulphonic acid ion exhange cartridge
(5g Isolute SCX, pre-washed with methanol). The cartridge was eluted with methanol followed by 5% triethylamine in methanol and the basic fractions concentrated in vacuo. The residue was further purified by Biotage™ flash chromatography on silica gel (8g cartridge), eluting with 400:8:1 , then 300:8:1 , then 200:8:1 and then 100:8:1 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 gum (0.0025g)
LCMS R, 2.12 min, m/z 444 [MH+]
The further examples described in the following Tables were prepared according to or by analogy with the methods hereinbefore described.
Table 1
* Example 15 is the triethylammonium salt + Example 16 is the hydrochloride salt Table 2
Table 3
Table 4
Table 5
*Description 21 is the trifluoroacetate salt ** Description 19 is the hydrochloride salt

Claims

Claims
1. A compound of formula (I):
wherein:
R1 represents unsubstituted or substituted aryl; Y represents -(CRnaRnb)π-; Rna and Rnb are each independently hydrogen or Chalky!; n is an integer from 1 to 5; R2 represents unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl;
R3 and R4 each independently represent hydrogen or C^alkyl; and salts and solvates thereof; with the proviso that the following compounds are excluded;
N-benzyl-N'-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(2-phenylethyl)urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(4-methoxybenzyl)urea; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(2-methylbenzyl)urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(3-methylbenzyl)urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(4-methylbenzyl)urea;
N-(4-chlorobenzyl)-N'-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}urea;
N-(3-chlorobenzyl)-N'-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}urea; N-(2-chlorobenzyl)-N'-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}urea;
N-[3-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]-
-amino}methyl)phenyl]acetamide formate;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[4-(methylsulfonyl)-
-benzyl]urea; 4-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]amino}-
-methyl)benzenesulfonamide;
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(4-methoxybenzyl)urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(3,4-dimethoxybenzyl)urea;
N-(3-cyanobenzyl)-N'-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}urea; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(3-methoxybenzyl)urea;
4-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]amino}-
-methyl)benzamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[3-(trifluoromethoxy)- -benzyljurea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[4-(trifluoromethyl)-
-benzyl]urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[4-(1,2,3-thiadiazol-
-4-yl)benzyl]urea; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[4-(trifluoromethoxy)-
-benzyl]urea;
N-(3,5-dichlorobenzyl)-N'-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[3-(trifluoromethyl)-
-benzyl]urea N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(2,4-difluorobenzyl)urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(3,4-difluorobenzyl)urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(3-fluorobenzyl)urea;
N-(3,4-dichlorobenzyl)-N'-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}urea;
3-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)- -carbonyl]amino}methyl)-N-methylbenzamide;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[2-
-(trifluoromethoxy)benzyl]urea;
Methyl 3-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-
-carbonyl]amino}methyl)benzoate; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[2-(trifluoromethyl)-
-benzyl]urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(4-fluorobenzyl)urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(2-fluorobenzyl)urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(4-isopropoxybenzyl)urea; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(2,4-dimethoxybenzyl)urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[2-(4-methoxyphenyl)-
-ethyl]urea;
N-[2-(4-tert-butoxyphenyl)ethyl]-N'-{[4-(3,4-dichlorobenzyl)morpholin-2-
-yl]methyl}urea; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[3-
(dimethylamino)benzyl]urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[2-(methylthio)benzyl]urea;
N-(4-cyanobenzyl)-N'-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}urea;
N'-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N-(4-methoxybenzyl)-N- -methylurea; methyl 4-({[({[4-(3,4-dichlorobenzyl)morpholin-2-
-yl]methyl}amino)carbonyl]amino}methyl)benzoate;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-[1-(4-fluorophenyl)ethyl]urea;
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-N'-(1-methyl-1-phenylethyl)urea; 4-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]amino}-
-methyl)-N-(1 ,3-thiazol-2-yl)benzenesulfonamide;
4-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]amino}-
-methyl)-benzoic acid compound with N,N,N-triethylamine (1 :1);
4-({[({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]- -amino}methyl)benzamide hydrochloride;
4-({[({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]-
-amino}methyl)benzamide;
4-({[({[(2R)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]-
-amino}methyl)benzamide; 3-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]-
-amino}methyl)-N,N-dimethylbenzamide;
3-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]-
-amino}methyl)-N-ethylbenzamide;
N-cyclopropyl-3-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)- -carbonyl]amino}methyl)benzamide;
4-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]-
-amino}methyl)-N-methylbenzamide;
4-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]-
-amino}methyl)-N,N-dimethylbenzamide; 4-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]-
-amino}methyl)-N-ethylbenzamide;
N-cyclopropyl-4-({[({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-
-carbonyl]amino}methyl)benzamide;
4-(2-{[({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)- -carbonyl]amino}ethyl)benzenesulfonamide;
3-({[({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-
-carbonyl]amino}methyl)-N-methylbenzamide;
N-cyclopropyl-3-({[({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-
-carbonyl]amino}methyl)benzenesulfonamide; N-cyclopropyl-4-({[({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-
-carbonyl]amino}methyl)benzenesulfonamide;
4-({[({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)- carbonyl]amino}methyl)-N-methylbenzamide, and;
N-cyclopropyl-4-({[({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2- yl]methyl}amino)carbonyl]amino}methyl)benzamide.
2. A compound of formula (I) according to claim 1 wherein R1 is unsubstituted or substituted phenyl.
5 3. A compound of formula (I) according to claim 1 or claim 2 wherein R1 is phenyl substituted with 4-(3-methyl-1 ,2,4-oxadiazol-5yl), 4- (methanesulphonylamino), 4-(N,N-dimethylaminosulphonyl), 4-(aminosulphonyl), 3-(/so-propylaminocarbonyl), 3-(3-methyl-1 ,2,4-oxadiazol-5-yl), 3- (methylcarbonylamino), 4-fluoro-3-(methoxycarbonyl), 3-amido, 4-fluoro-3-
10 (ethylaminocarbonyl), 4-fluoro-3-(methylaminocarbonyl), 3-(methoxycarbonyl), 3- amido-4-fluoro, 3-(cyclopropylaminocarbonyl), 3-(ethylaminocarbonyl), 3- (methylaminocarbonyl), 3-carboxy-4-fluoro, 3-carboxy, 3-(methanesulphonyl), 3- (methanesulphonylamino), 4-amido, 3-(5-methyl-1 ,3,4-oxadiazol-2-yl), 3-(5- methyl-1 ,3,4-triazol-2-yl) or 3-(1 ,3,4-oxadiazol-2-yl).
15
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 20 wherein n is 1.
6. A compound of formula (I) according to any one of the preceding claims wherein R3 and R4 are both hydrogen.
25 7. A compound of formula (I) according to any one of the preceding claims wherein R2 is unsubstituted or substituted phenyl or unsubstituted or substituted thiophenyl.
8. A compound of formula (I) according to any one of the preceding claims 30 wherein R2 is phenyl or thiophenyl substituted with chloro or fluoro.
9. A compound of formula (I) according to any one of the preceding claims wherein R2 is 3,4-dichlorophenyl, 3,4-difluorophenyl or 2-chloro-thiophen-5-yl.
35 10. A compound of formula (IB)
wherein; 5 βcycloalkylaminocarbonyl; or a salt or solvate thereof.
11. A compound of formula (IB) according to claim 10 wherein R9 is ethylaminocarbonyl, cyclopropylaminocarbonyl, or dimethylaminocarbonyl.
10
12. A compound of formula (IB) according to claim 10 or claim 11 wherein R9 is 4-ethylaminocarbonyl, 3-cyclopropylaminocarbonyl, or 3- dimethylaminocarbonyl.
15 13. A compound according to claim 1 or claim 10 selected from the Examples.
14. A compound according to claim 1 or claim 10 selected from Examples 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 18, 19, 20, 21 , 22, 23, 24, 25, 26,
20 27, 28, 29, 31 , 33, 34, and 35.
15. A compound according to claim 1 or claim 10 selected from Examples 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 18, 20, 22, 28, 31 , 33, 34, and 35
25 16. A compound according to claim 1 or claim 10 selected from Examples 1 , 2, 3, 4, 5, 6, 7, 12, 22, 28, 31 , 33, and 34.
17. A compound according to claim 1 or claim 10 selected from Examples 1, 2, 12, 22, 28, 31 , 33, and 34.
30
18. 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, Y, R3, R4, and R2 are as hereinbefore defined for formula (I) in claim 1 and U is a urea-forming group; 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);
(ϋ) removing any necessary protecting group;
(iii) preparing a salt or solvate of the compound so formed.
19. A compound of formula (III)
wherein U is a urea-forming group and R2 and R4 are as defined for formula (I) in claim 1.
20. A compound of formula (IVBR)
wherein A is a protected amino group and R2 is as defined for formula (I) in claim 1.
21. A compound of formula (IVBE)
wherein A is a protected amino group and R2 is as defined for formula (I) in claim 1.
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.
EP03745296A 2002-03-28 2003-03-27 Morpholine derivatives substituted at the 2-position by an arylalkylurea group for use as ccr-3 antagonists in the treatment of inflammatory conditions Withdrawn EP1487455A1 (en)

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TW200400824A (en) 2004-01-16
AR039172A1 (en) 2005-02-09

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