EP1490345A2 - Novel compound - Google Patents
Novel compoundInfo
- Publication number
- EP1490345A2 EP1490345A2 EP03745295A EP03745295A EP1490345A2 EP 1490345 A2 EP1490345 A2 EP 1490345A2 EP 03745295 A EP03745295 A EP 03745295A EP 03745295 A EP03745295 A EP 03745295A EP 1490345 A2 EP1490345 A2 EP 1490345A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- formula
- mixture
- suitably
- solvent
- 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- Withdrawn
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Classifications
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
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- 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]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Definitions
- This invention relates to a novel compound, a process for its preparation, pharmaceutical formulations containing it and its 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. 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-HT1D-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 compound has now been found which is a CCR-3 antagonist.
- This compound blocks the migration/chemotaxis of eosinophils and thus possesses anti-inflammatory properties.
- This compound is 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.
- Suitable salts of the compound 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, l-hydroxy-2-naphthoates, pamoates, methanesulphonates, formates or trifluoroacetates.
- inorganic or organic acids for example hydrochlorides, hydrobromides, sulphates, phosphates, acetates, benzoates, citrates, succinates, lactates, tartrates, fumarates, maleates, l-hydroxy-2-naphthoates, pamoates, methanesulphonates, formates or trifluoroacetates.
- solvates include hydrates.
- the compound of formula (I) and salts and solvates thereof may be prepared by the methodology described hereinafter, constituting a further aspect of this invention.
- a process according to the invention for the preparation of the compound of formula (I) comprises coupling of a compound of formula (II) or a salt thereof with ethylamine:
- the coupling of the compound of formula (II) is carried out in any suitable solvent, for example a polar organic solvent such as a mixture of tetrahydrofuran and N,N-dimethylformamide in the presence of a suitable dehydrating agent such as a carbodiimide reagent e.g. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and optionally a suitable activating agent, e.g. an activated hydroxy compound such as 1-hydroxybenzotriazole, and optionally in the presence of a base such as a tertiary amine, e.g. N,N-diisopropylethylamine, under conventional coupling conditions at any temperature providing a suitable rate of formation of the required product, over a suitable reaction time, for example 12 - 24 hours.
- a suitable dehydrating agent such as a carbodiimide reagent e.g. 1-(3-dimethylamin
- Suitable reaction temperatures include those in the range of 18°C to 25°C.
- the reaction products are isolated and purified using conventional methods.
- the compound of formula (II) may be prepared by hydrolysis of the compound of formula (III):
- the hydrolysis is carried out in a suitable solvent, for example an aqueous alcohol such as a mixture of water and methanol, in the presence of a suitable catalyst, for example an aqueous base such as sodium hydroxide, at a suitable temperature, for example those in the range of 18°C to 25°C over a suitable period of time, for example 12 -24 hours.
- a suitable solvent for example an aqueous alcohol such as a mixture of water and methanol
- a suitable catalyst for example an aqueous base such as sodium hydroxide
- the reaction between the compound of formula (IV) and the compound of formula (V) is performed in a suitable solvent, such as a polar organic solvent, for example N,N-dimethylformamide and a suitable base, for example a tertiary amine such as N,N-diisopropy!ethylamine, at a suitable temperature, for example those in the range of 18°C to 25°C over a suitable period of time, for example 60 - 100 hours.
- a suitable solvent such as a polar organic solvent, for example N,N-dimethylformamide and a suitable base, for example a tertiary amine such as N,N-diisopropy!ethylamine
- the compound of formula (IV) may be prepared from the compound of formula (VI)
- the reaction between the compound of formula (VI) and 4-nitrophenyl chloroformate is performed in a suitable solvent, for example an inert organic solvent such as dichloromethane, in the presence of a suitable base, for example a tertiary amine such as triethylamine, 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 an inert organic solvent such as dichloromethane
- a suitable base for example a tertiary amine such as triethylamine
- a compound of formula (VI) may be prepared by either by Reaction (a), Reaction (b), or Reaction (c).
- A is a protected amino group, suitably phthalimido, followed by deprotection of the amino group to give a compound of formula (VIR)
- a mixture of the compound of formula (IX) and the compound of formula (X) or formula (XA) in a suitable solvent 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 compound 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 65-75C°. 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 (VIR) or formula (VI) respectively.
- the mixture was 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 was 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 (X) and (XA); is isolated.
- a mixture of the compound of formula (IX) and a compound of formula (X) or formula (XA) 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 (IX) 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.
- 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 (VIBR) or formula (VIB) respectively is isolated by filtration, washed with further co-solvent and dried in vacuo.
- a protected form of the compound of formula (VIR) or formula (VI) may then be prepared from a compound of formula (VIBR) or formula (VIB) under similar conditions to those of the reaction between a compound of formula (IX) and formulae (X) or (XA) 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 (VI) from the racemic product i.e. the compound of formula (VIR) 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.
- the compound of formula (VII) may be prepared by reaction of the compound of formula (VIII)
- the compound of formula (VIII) is prepared by treating a solution of morpholin-2-ylmethylamine in a suitable organic solvent, for example methanol, under an inert atmosphere, for example an atmosphere nitrogen, with a solution of ethyl- ⁇ , ⁇ , -trifluoroacetate 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 compound of formula (V) is known and may be prepared by conventional means, for example those disclosed in Eur. J. Med. Chem. (1993), 28(7-8), 625-32.
- Ethylamine, 4-nitrophenyl chloroformate, 2-[(3,4- dichlorobenzyl)amino]ethanol, 2-(oxiran-2-ylmethyl)-1 H-isoindole-1 ,3(2H)-dione, 3,4-dichlorobenzyl chloride, morpholin-2-ylmethylamine, 2-[(3,4- dichlorobenzyl)amino]ethanol and ethyl- ⁇ , ⁇ , ⁇ -trifluoroacetate are known, commercially available compounds or may be prepared by analogy with known procedures, for example those disclosed in standard reference texts of synthetic methodology such as J. March, Advanced Organic Chemistry, 3rd Edition (1985), Wiley Interscience.
- 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 salts and solvates of the compounds of formula (I) may be prepared from the compound of formula (I) or suitable salts or solvates thereof and isolated according to conventional procedures.
- the compounds of the invention may be tested for in vitro biological activity in accordance with the following assays:
- CCR-3 competition binding SPA sintillation proximity assay
- Eosinophils were purified from human peripheral blood by standard CD16 cell depletion using a Miltenyi cell separation column and a magnetic Super Macs magnet as previously described (Motegi & Kita, 1998;
- the agonist eotaxin (an EC 80 concentration) was added to the lower chamber of a 96 well chemotaxis plate (5 ⁇ m filter: Receptor Technologies). Eosinophils (50 ⁇ l of 2 million/ml cells) were added to the top chamber of the filter plate and incubated at 37°C for 45 mins. Cells remaining on top of the chemotaxis filter were removed and the number of eosinophils which had migrated were quantified by reading the plate on a fluorescent plate reader. Inhibition curves for the effect of compounds on eosinophil chemotaxis were analysed by fitting the data with a four parameter logistic equation. Functional pKj values (fpKj) were generated using the equation below (Lazareno & Birdsall, 1995. Br. J.Pharmacol 109: 1110- 9).
- the compound of the invention was tested in the CCR-3 binding and/or eosinophil chemotaxis assays (assays (a) and (b)).
- the compound of the invention was tested in the CCR-3 binding assay and possessed a plC50 value of 9.2.
- the compound of the invention tested in the CCR-3 eosinophil chemotaxis assay possessed an fpKi value of 10.0.
- 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.
- the compound 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.
- the 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.
- the compound of the invention may be useful as an immunosuppressive agents and so has use in the treatment of auto-immune diseases such as allograft tissue rejection after transplantation, rheumatoid arthritis and diabetes.
- the compound of the invention may also be useful in inhibiting metastasis.
- the compound of formula (I) is useful as a therapeutic agent.
- the compound of formula (I), or a physiologically acceptable salt or solvate thereof for use in 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 eg. asthma or rhinitis comprises administering an effective amount of the compound of formula (I) or a physiologically acceptable salt or solvate thereof.
- the compound according to the invention may be formulated for administration in any convenient way.
- a pharmaceutical composition comprising the compound of formula (I), or a physiologically acceptable salt or solvate thereof, and optionally one or more physiologically acceptable diluents or carriers.
- 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 compound according to the invention may, for example, be formulated for oral, inhaled, intranasal, buccal, parenteral or rectal administration, preferably for oral administration.
- Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, cellulose or polyvinyl pyrrolidone; fillers, for example, lactose, microcrystalline cellulose, sugar, maize- starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate.
- the tablets may be coated according to methods well known in the art.
- Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl p_- hydroxybenzoates or sorbic acid.
- the preparations may also contain buffer salts, flavouring, colouring and/or sweeten
- compositions may take the form of tablets or lozenges formulated in conventional manner.
- the compound may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
- the compound 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 compound 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 furcate, 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.
- the 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 word 'comprise', and variations such as 'comprises' and 'comprising' will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps.
- Thermospray Mass Spectra were determined on a HP 5989A engine mass spectrometer, +ve thermospray, source temperature 250°C, probe temperatures
- Solid phase extraction (ion exchange) 'SCX' refers to Isolute Flash SCX-2 sulphonic acid solid phase extraction
- Description 10 3-((f((r(2S)-4-(3.4-dichlorobenzyl)morpholin-2- yllmethyl>amino)carbonyllamino ⁇ methyl)benzoic acid
- 2M aqueous sodium hydroxide 0.85ml
- water 5ml
- the mixture was stirred at 20°C for 20h before the solvents were evaporated in vacuo to leave a white solid.
- the solid was re-dissolved in water and the pH of the solution was adjusted to approximately 6 by the addition of 2M aqueous hydrochloric acid.
- the mixture was applied to 2x1 Og SCX ion- exchange cartridges (1ST Isolute Flash SCX-2), pre-conditioned with methanol.
- the cartridges were eluted with methanol and 5% triethylamine in methanol.
- the product was found to have eluted in the first methanol fractions which were combined and the solvent evaporated in vacuo to recover the crude product.
- the solid was re-dissolved in water and the pH of the solution adjusted to approximately 1 by the addition of 2M aqueous hydrochloric acid.
- the mixture was applied to 2x1 Og SCX ion-exchange cartridges (1ST Isolute Flash SCX-2), pre-conditioned with methanol.
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Abstract
Description
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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GBGB0207447.4A GB0207447D0 (en) | 2002-03-28 | 2002-03-28 | Novel compounds |
GB0207447 | 2002-03-28 | ||
PCT/EP2003/003338 WO2003082834A2 (en) | 2002-03-28 | 2003-03-27 | Morpholine derivatives and intermediates therefor |
Publications (1)
Publication Number | Publication Date |
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EP1490345A2 true EP1490345A2 (en) | 2004-12-29 |
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EP03745295A Withdrawn EP1490345A2 (en) | 2002-03-28 | 2003-03-27 | Novel compound |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP1490345A2 (en) |
JP (1) | JP2006504626A (en) |
AR (1) | AR039176A1 (en) |
AU (1) | AU2003226758A1 (en) |
GB (1) | GB0207447D0 (en) |
TW (1) | TW200401771A (en) |
WO (1) | WO2003082834A2 (en) |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CZ284687B6 (en) * | 1986-04-30 | 1999-02-17 | Dainippon Pharmaceutical Co., Ltd. | Substituted benzamide derivative, process of its preparation and pharmaceutical composition based thereon |
CA2189964A1 (en) * | 1994-05-18 | 1995-11-23 | Haruhiko Kikuchi | Novel diaminomethylidene derivative |
BR9507666A (en) * | 1994-05-18 | 1997-09-23 | Nisshin Flour Milling Co | New pyrimidine derivatives |
US6207665B1 (en) * | 1997-06-12 | 2001-03-27 | Schering Aktiengesellschaft | Piperazine derivatives and their use as anti-inflammatory agents |
PL362984A1 (en) * | 2000-09-29 | 2004-11-15 | Glaxo Group Limited | Compounds useful in the treatment of inflammatory diseases |
-
2002
- 2002-03-28 GB GBGB0207447.4A patent/GB0207447D0/en not_active Ceased
-
2003
- 2003-03-26 TW TW092106774A patent/TW200401771A/en unknown
- 2003-03-27 AU AU2003226758A patent/AU2003226758A1/en not_active Abandoned
- 2003-03-27 AR ARP030101089A patent/AR039176A1/en unknown
- 2003-03-27 WO PCT/EP2003/003338 patent/WO2003082834A2/en not_active Application Discontinuation
- 2003-03-27 JP JP2003580302A patent/JP2006504626A/en active Pending
- 2003-03-27 EP EP03745295A patent/EP1490345A2/en not_active Withdrawn
Non-Patent Citations (1)
Title |
---|
See references of WO03082834A2 * |
Also Published As
Publication number | Publication date |
---|---|
AR039176A1 (en) | 2005-02-09 |
JP2006504626A (en) | 2006-02-09 |
AU2003226758A8 (en) | 2003-10-13 |
AU2003226758A1 (en) | 2003-10-13 |
WO2003082834A3 (en) | 2004-03-25 |
WO2003082834A2 (en) | 2003-10-09 |
TW200401771A (en) | 2004-02-01 |
GB0207447D0 (en) | 2002-05-08 |
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