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EP1487454A1 - Derives de morpholine substitues en position 2 par un groupe heterocyclylalkylurea, destines a etre utilises en tant qu'antagonistes du recepteur ccr3 dans le traitement d'etats inflammatoires - Google Patents

Derives de morpholine substitues en position 2 par un groupe heterocyclylalkylurea, destines a etre utilises en tant qu'antagonistes du recepteur ccr3 dans le traitement d'etats inflammatoires

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Publication number
EP1487454A1
EP1487454A1 EP03745197A EP03745197A EP1487454A1 EP 1487454 A1 EP1487454 A1 EP 1487454A1 EP 03745197 A EP03745197 A EP 03745197A EP 03745197 A EP03745197 A EP 03745197A EP 1487454 A1 EP1487454 A1 EP 1487454A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
piperidin
group
substituted
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Withdrawn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
EP03745197A
Other languages
German (de)
English (en)
Inventor
Rachael Ann GlaxoSmithKline ANCLIFF
Caroline Mary GlaxoSmithKline COOK
Colin David GlaxoSmithKline Eldred
Paul Martin GlaxoSmithKline GORE
Lee Andrew GlaxoSmithKline HARRISON
Martin Alistair GlaxoSmithKline HAYES
Simon Teanby GlaxoSmithKline HODGSON
Duncan Bruce GlaxoSmithKline JUDD
Suzanne Elaine GlaxoSmithKline KEELING
Xiao Qing GlaxoSmithKline LEWELL
Gail GlaxoSmithKline MILLS
Graeme Michael GlaxoSmithKline ROBERTSON
Stephen GlaxoSmithKline SWANSON
Andrew John GlaxoSmithKline WALKER
Mark GlaxoSmithKline WILKINSON
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glaxo Group Ltd
Original Assignee
Glaxo Group Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of EP1487454A1 publication Critical patent/EP1487454A1/fr
Withdrawn legal-status Critical Current

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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]
    • 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 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 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.
  • leukocytes 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, 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.
  • bronchial inflammation which is characteristic of asthma represents a specialised form of cell-mediated immunity, 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.
  • Th2 T-helper 2
  • 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 trafficking and recruitment of leukocytes (for review see Luster, New Eng. J. Med., 338, 436-445 (1998)). They are released by a wide variety of cells and act to attract and activate various cell types, including eosinophils, basophils, neutrophils, macrophages, T and B lymphocytes. There are two major families of chemokines, CXC- ( ⁇ ) and CC- ( ⁇ ) chemokines, classified according to the 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).
  • 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. er a/., 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 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 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 Neurogen Corporation 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 (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.
  • CCR-3 antagonists A novel group of compounds has now been found which are CCR-3 antagonists. These compounds block the migration/chemotaxis of eosinophils and thus possess anti-inflammatory properties. These compounds are therefore of potential therapeutic benefit, especially in providing protection from eosinophil, basophil mast cell and Th2-cell-induced tissue damage in diseases where such cell types are implicated, particularly allergic diseases, including but not limited to bronchial asthma, allergic rhinitis and atopic dermatitis.
  • R 1 represents substituted or unsubstituted heterocyclyl
  • Y represents -(CR na R n b)n-;
  • R na and R nb are each independently hydrogen or C-i-ealkyl; 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 C h alky!; and salts and solvates thereof; with the proviso that the following compounds are excluded; N- ⁇ [4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl ⁇ -N'-[2-(2-oxoimidazolidin-1- yl)ethyl]urea; tert-butyl 4-( ⁇ [( ⁇ [4-(3,4-dichlorobenzyl)morpholin-2- yl]methyl ⁇ amino)carbonyl]amino ⁇ methyl)piperidine-1-carboxylate; N- ⁇ [1-(cyclopropylcarbonyl)piperidin-4-yl]methyl ⁇ -N'- ⁇ [(2S)-4-(3,4- -dichlorobenzyl)morpholin-2-yl]methyl ⁇ urea, and; N- ⁇ [(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl ⁇
  • heterocyclyl group, R 1 examples include piperidinyl.
  • R 1 is substituted heterocyclyl
  • suitable substituents include C- 3 - scycloalkylaminocarbonyl, C-*. 6 alkoxycarbonyl, mono- and di-(C-*- 6 alkyl)aminocarbonyl, d- ⁇ alkylsulphonyl, and
  • R 1 is unsubstituted or substituted piperidinyl.
  • R 1 is selected from substituted piperidinyl
  • suitable substituents include C 3-3 cycloalkylaminocarbonyl, mono- and di-(C ⁇ - 6 alkyl)aminocarbonyl; C-*. 6 alkoxycarbonyl, and aminocarbonyl.
  • R 1 is selected from 1-(methylaminocarbonyl)piperidin-4-yl, 1-(diethylaminocarbonyl)piperidin-4-yl, 1-(methoxycarbonyl)piperidin-4-yl, 1- (cyclopropylaminocarbonyl)piperidin-4-yl, 1-(ethylaminocarbonyl)piperidin-4-yl, 1- (/so-propylaminocarbonyl)piperidin-4-yl, 1-(ethoxycarbonyl)piperidin-4-yl, 1-(tert- butoxycarbonyl)piperidin-4-yl and 1-(aminocarbonyl)piperidin-4-yl.
  • R na and R réelleb are both hydrogen.
  • n 1
  • R 3 and R 4 are both hydrogen.
  • R 2 is aryl
  • examples include phenyl.
  • R 2 is substituted aryl
  • suitable substituents include cyano, perhaloC-i-ealkyl, amido, halo, C-i-ealkyl, d-ealkoxycarbonyl, mono- and di-(C**. 6 alkyl)aminocarbonyl, d ⁇ alkoxy, nitro, C-*. 6 alkylsulphonyl, hydroxy, d-ealkoxyC-*. 6 alkyl, C ⁇ alkylthio, mono- and-dKCi-ealkylJamino, and Ci-ealkylcarbonylamino.
  • R 2 When R 2 is heteroaryl, examples include thiophenyl.
  • suitable substituents include cyano, perhaloCi-ealkyl, amido, halo, C-i-ealkyl, C ⁇ alkoxycarbonyl, mono- and di-(C ⁇ . 6 alkyl)aminocarbonyl, C ⁇ alkoxy, nitro, Ci-ealkylsulphonyl, hydroxy, d-ealkoxyd. 6 alkyl, d-ealkylthio, mono- and-di-(C 1 - 6 alkyl)amino, and d-ealkylcarbonylamino.
  • R 2 is unsubstituted or substituted phenyl.
  • R 2 is substituted phenyl suitable substituents include halo.
  • R 2 is phenyl substituted with chloro.
  • R 2 is 3,4-dichlorophenyl.
  • R 1' is unsubstituted or substituted heterocyclyl, and
  • R 2' is phenyl substituted with halo.
  • heterocyclyl group examples include piperidinyl.
  • R 1' is piperidin-4-yl substituted with mono- or di-(d. 6 alkyl)aminocarbonyl, d- ⁇ alkoxycarbonyl, C 3 -acycloalkylaminocarbonyl, or aminocarbonyl.
  • R 1 is 1-(methylaminocarbonyl)piperidin-4-yl, 1- (diethylaminocarbonyl)piperidin-4-yl, 1-(methoxycarbonyl)piperidin-4-yl, 1- (cyclopropylaminocarbonyl)piperidin-4-yl, 1 -(ethylaminocarbonyl)piperidin-4-yl, 1 - (/so-propylaminocarbonyl)piperidin-4-yl, 1-(ethoxycarbonyl)piperidin-4-yl, 1-(tert- butoxycarbonyl)piperidin-4-yl or 1 -(aminocarbonyl)piperidin-4-yl.
  • R 2' is phenyl substituted with chloro or fluoro.
  • R 2' is 3,4-dichlorophenyl.
  • the stereochemistry at the position marked '*' is (S).
  • Suitable compounds of the invention are Examples 1 , 2, 3, 6, 4, 5, 7, and 8.
  • 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 cyano, perhaloalkyl, amido, halo, alkyl, alkoxycarbonyl, mono- and di-(alkyl)aminocarbonyl, alkoxy, nitro, alkylsulphonyl, hydroxy, alkoxyalkyl, alkylthio, mono- and-di-(alkyl)amino, and alkylcarbonylamino.
  • references to 'heteroaryl' refer to monocyclic heterocyclic aromatic rings containing 1-4 heteroatoms selected from nitrogen, oxygen and sulphur.
  • heterocyclic aromatic rings include thiophenyl.
  • Suitable substituents for any heteroaryl group include 1 to 5, suitably 1 to 3, substituents selected from the list consisting of 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 cycloalkylaminocarbonyl, alkylcarbonyl, aminocarbonyl, alkyl, alkoxycarbonyl, mono- and di-(alkyl)aminocarbonyl, alkylsulphonyl, and alkoxyalkyl.
  • references to 'halogen' or 'halo' refer to iodo, bromo, chloro or fluoro, especially 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- nitrophenoxy carbonyl.
  • 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);
  • 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.
  • 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 suitable solvent for example dichloromethane
  • 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.
  • Conventional methods of cooling may be employed, for example ice/salt baths.
  • the product is isolated by conventional means, such as washing with brine, drying with a suitable drying agent such as magnesium sulphate, followed by concentration in vacuo.
  • 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.
  • a mixture of the compound of formula (V) and the 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 solvent is then added and the mixture cooled, suitably to 0- 5°C.
  • a suitable phosphine suitably triphenyl phosphine, is added and the mixture stirred until all the solid is dissolved.
  • a suitable azo compound suitably diisopropylazodicarboxylate, is then added over a period of time, suitably, 10 -15 minutes, while maintaining the temperature at ⁇ 7°C.
  • the mixture is allowed to stand for a period of time, suitably 2 - 3 hours, then allowed to warm, suitably to 20 - 25°C. After a further period of standing, suitably 4 - 6 hours, further phosphine and azo compounds are added. After a further period of standing, suitably 20 -24 hours, the reaction mixture is concentrated to near dryness.
  • a suitable alcohol suitably propan-2-ol, is added and the concentration step repeated; the alcohol addition and concentration step is then repeated. Further alcohol is then added and the mixture heated to a temperature suitably between 65 - 75°C.
  • the resultant slurry is cooled, suitably to 20 - 25°C, and then allowed to stand, suitably for 1.5 - 3 hours, after which time the product is isolated by filtration.
  • the filter bed is washed with more alcohol and then dried in vacuo at 35 - 45°C to yield the protected form of the compound of formula (IVR) or formula (IVE) respectively.
  • the mixture is then heated at elevated temperature, suitably the reflux temperature of the solvent, for a suitable period of time, suitably 20 - 24 hours, after which the reaction mixture is cooled to 20 - 25°C and then treated with a suitable apolar solvent, suitably dichloromethane.
  • a base suitably 0.880 ammonia solution, is then added dropwise, maintaining the temperature between 20 - 25°C.
  • a mixture of the compound of formula (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.
  • 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 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- 25°C for a suitable time, for example 16-20 hours followed by removal of the organic solvent in vacuo.
  • Water is then added and the mixture extracted with a suitable organic solvent, for example ethyl acetate.
  • the combined organic phases are washed with water and saturated aqueous sodium chloride solution before drying over a suitable drying agent, for example sodium sulphate, filtering and evaporation of the solvent in vacuo.
  • the crude product is then purified by flash chromatography.
  • the resolution of the compound of formula (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 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.
  • 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, such as sodium iodide.
  • a suitable solvent for example N,N-dimethylformamide
  • a suitable solvent such as N,N-dimethylformamide
  • the residue is partitioned between a suitable organic solvent, for example dichloromethane, and a saturated aqueous base, for example saturated aqueous sodium carbonate solution.
  • a suitable organic solvent for example dichloromethane
  • a saturated aqueous base for example saturated aqueous sodium carbonate solution.
  • the organic phase is then washed with additional saturated aqueous base and water before drying over a suitable drying agent, for example magnesium sulphate, filtering and evaporation of the solvent in vacuo to yield the crude product.
  • a suitable drying agent for example magnesium sulphate
  • a compound of formula (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.
  • 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.
  • a CCR-3 competition binding SPA was used to assess the affinity of novel compounds for CCR-3.
  • Membranes prepared from K562 cells stably expressing CCR-3 (2.5 ⁇ g/well) were mixed with 0.25mg/well wheat-germ agglutinin SPA beads (Amersham) and incubated in binding buffer (HEPES 50 mM, CaCI 2 1 mM, MgCI 2 5 mM, 0.5% BSA) at 4°C for 1.5 hr.
  • the compounds of the Examples tested in the CCR-3 binding assay possessed plC 50 values in the range 7.3 - 8.1.
  • 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.
  • 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 the manufacture of a medicament for the treatment of inflammatory conditions, eg. asthma or rhinitis.
  • a method for the treatment of a human or animal subject suffering from or susceptible to an inflammatory condition e.g. asthma or rhinitis comprises administering an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof.
  • the compounds according to the invention may be formulated for administration in any convenient way.
  • composition comprising a compound of formula (I), or a physiologically acceptable salt or solvate thereof, and optionally one or more physiologically acceptable diluents or carriers.
  • the compounds according to the invention may, for example, be formulated for oral, inhaled, intranasal, buccal, parenteral or rectal administration, preferably for oral administration.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, cellulose or polyvinyl pyrrolidone; fillers, for example, lactose, microcrystalline cellulose, sugar, maize- starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl j hydroxybenzoates or sorbic acid.
  • the preparations may also contain buffer salts, flavouring, colouring and/or sweetening agents
  • 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.
  • 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.
  • the free bond on the R 1 groups as presented in the Tables signifies the point of attachment of the R 1 groups to the residue of the molecule.
  • Mass Directed Automated Preparative HPLC column, conditions and eluent Mass directed automated preparative high performance liquid chromatography was carried out using an LCABZ+ 5 ⁇ m (5cm x 10mm internal diameter) column, employing gradient elution using two solvent systems, (A) 0.1% formic acid in water, and (B) 95% acetonitrile and 0.5% formic acid in water, at a flow rate of 8ml min "1 .
  • Mass spectrometry was carried out using a VG Platform Mass Spectrometer, with an HP1100 Diode Array Detector and Accurate Flow Splitter.
  • This system used an 3 ⁇ m ABZ+PLUS (3.3cm x 4.6mm internal diameter) column, eluting with 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
  • 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 were determined on a HP 5989A engine mass spectrometer, +ve thermospray, source temperature 250°C, probe temperatures 120°C (stem), 190°C (tip), detection mass range 100-850 a.m.u. Compounds were injected in 10 ⁇ l of a mixture of solvents comprising 65% methanol and 35% 0.05M aqueous ammonium acetate, at a flow rate of 0.7ml/min.
  • SCX' refers to Isolute Flash SCX-2 sulphonic acid solid phase extraction cartridges.
  • Description 3 r4-(3,4-Dichlorobenzyl)morpholin-2-vHmethylamine 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.
  • Example 9 The compound of Example 9 was dissolved in dry 1 ,4-dioxane (6ml), and the stirred solution treated with 4M hydrogen chloride in 1 ,4-dioxane (6ml), giving a white precipitate. The mixture was stirred at room temperature for 16h, and the solvent was evaporated in vacuo to give the title compound hydrochloride as a white solid (0.518g).
  • LC/MS , Rt 1.83min, Mass Spectrum m/z 415 [MH + ]
  • the solid was dissolved in methanol and applied to an Isolute SCX ion exchange cartridge (10g, preatreated with methanol). Elution with methanol followed by 10% 880 ammonia in methanol, followed by evaporation of the methanol/ammonia fraction, gave the free base (0.221 g).
  • Example 10 A solution of Example 10 (0.037g) in a mixture of dichloromethane (2ml) and N,N-dimethylformamide (0.5ml) was treated with ethyl isocyanate (0.008ml), and the mixture was stirred at 22° under nitrogen for 16h.
  • the mixture was applied directly to an Isolute SCX ion exchange cartridge (2g, pretreated with methanol), and eluted with methanol followed by 10% 880 ammonia in methanol. Evaporation of the methanol/ammonia fraction gave a pale yellow gum (0.029g), which was purified by mass directed preparative HPLC to give the title compound (0.0147g).
  • LC/MS , Rt 2.24min, Mass Spectrum m/z 486 [MH + ]
  • Example 10 A solution of Example 10 (0.037g) and N,N-diisopropylethylamine (0.035ml) in dichloromethane (2ml) and N,N-dimethylformamide (0.5ml) was treated with 4- nitrophenyl N-methylcarbamate (Tetrahedron (1994), 50(34), 10367-70) (0.0195g), and the mixture was stirred at 22° under nitrogen for 16h. The mixture was applied directly to an Isolute SCX ion exchange cartridge (2g, pretreated with methanol), and eluted with methanol followed by 10% 880 ammonia in methanol.
  • Example 10 A solution of Example 10 (0.063g) in N,N-dimethylformamide (3ml) was added slowly to a solution of 1 ,1-carbonyldiimidazole (0.074g) in N,N- dimethylformamide (1ml) and the mixture was stirred under nitrogen at room temperature for 3 days.
  • 0.880 Ammonia (2ml) was then added and stirring continued for a further five hours.
  • a further portion of 0.880 ammonia (2ml) was added and stirring continued again for 16 hours after which time the solution was concentrated to dryness.
  • 0.880 Ammonia was added, the solution heated at 50°C in a thick walled sealed vial (Reacti-vialTM) for 3 hours then blown down to dryness.
  • Example 10 A solution of Example 10 (0.028g) in dichloromethane (1ml) and N,N- diisopropylethylamine (0.014ml) was treated with diethylcarbamyl chloride (0.010ml) and the reaction stirred for 16 hours at room temperature.
  • the solution was concentrated in vacuo, dissolved in methanol then loaded onto an SCX (1g) ion exchange cartridge, which had been pre-treated with methanol and which was then eluted with methanol and 10% 0.880 ammonia/methanol. Basic fractions were combined and concentrated to give the title compound (0.030g) as a clear gum.
  • LC-MS , Rt 2.55 min. Mass Spectrum m/z 514 [MH + ]

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Abstract

L'invention concerne certains composés de formule générale (I) dans laquelle: R1 représente hétérocyclyle substitué ou non substitué; Y représente -(CRnaRnb)n-; Rna et Rnb représentent chacun indépendamment hydrogène ou C1-6 alkyle; n est un nombre entier compris entre 1 et 5; R2 représente aryle substitué ou non substitué ou hétéroaryle substitué ou non substitué; R3 et R4 représentent chacun indépendamment hydrogène ou C1-6 alkyle; ainsi que des sels et des solvates de ceux-ci qui sont des antagonistes du récepteur CCR3 et qui sont ainsi destinés à être utilisés à des fins thérapeutiques d'états inflammatoires.
EP03745197A 2002-03-28 2003-03-27 Derives de morpholine substitues en position 2 par un groupe heterocyclylalkylurea, destines a etre utilises en tant qu'antagonistes du recepteur ccr3 dans le traitement d'etats inflammatoires Withdrawn EP1487454A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB0207439.1A GB0207439D0 (en) 2002-03-28 2002-03-28 Novel compounds
GB0207439 2002-03-28
PCT/EP2003/003349 WO2003082295A1 (fr) 2002-03-28 2003-03-27 Derives de morpholine substitues en position 2 par un groupe heterocyclylalkylurea, destines a etre utilises en tant qu'antagonistes du recepteur ccr3 dans le traitement d'etats inflammatoires

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EP1487454A1 true EP1487454A1 (fr) 2004-12-22

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EP (1) EP1487454A1 (fr)
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AR (1) AR039613A1 (fr)
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GB (1) GB0207439D0 (fr)
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WO2006028284A1 (fr) 2004-09-08 2006-03-16 Mitsubishi Pharma Corporation Dérivé de morpholine

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WO2000031032A1 (fr) * 1998-11-20 2000-06-02 F. Hoffmann-La Roche Ag Antagonistes du recepteur de derives de pyrrolidine-ccr-3
HUP0303107A2 (hu) * 2000-09-29 2004-03-01 Glaxo Group Ltd. Gyulladásos betegségek kezelésére alkalmazható vegyületek, eljárás az előállításukra és ezeket tartalmazó gyógyszerkészítmények

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AR039613A1 (es) 2005-03-02
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