Classifications

• • 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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• 2002
  • 2002-03-28 GB GBGB0207436.7A patent/GB0207436D0/en not_active Ceased
• 2003
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  • 2003-03-27 EP EP03745296A patent/EP1487455A1/en not_active Withdrawn
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