Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/40—Oxygen atoms
  • C07D211/44—Oxygen atoms attached in position 4
  • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • 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
• • A—HUMAN NECESSITIES
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  • 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
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
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  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/16—Masculine contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • 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
  • A61P25/08—Antiepileptics; Anticonvulsants
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • 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
• • 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
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
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  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/06—Antianaemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to a novel piperidine derivative useful as an inhibitor of glucosylceramide synthase (GCS; UDP-glucose:ceramide glucosyltransferase, UDP-glucose:N- acylsphingosine D-glucosyltransferase, EC 2.4.1.80), methods for its preparation and its use in medicine, specifically in the treatment and prevention of disease states mediated by GCS.
• GCS glucosylceramide synthase
• the compound finds use in the treatment of glycolipid storage diseases, diseases associated with glycolipid accumulation, cancers in which glycolipid synthesis is abnormal, infectious diseases caused by microorganisms which use cell surface glycolipids as receptors, infectious diseases in which synthesis of glucosylceramide is essential or important, diseases in which excessive glycolipid synthesis occurs, neuronal disorders and neuronal injury.
• GCS is an intracellular enzyme that catalyzes the assembly of uridine diphosphate-glucose and ceramide into the glycolipid, glucosylceramide.
• the role of GCS in regulating ceramide levels has been explored, since this molecule can induce apoptotic cell death (J. Biol. Chem., 2000, 275(10), 7138-43).
• GCS is considered to be a target for treating certain human diseases.
• Glucosylceramide and structurally related glycolipids are stored in the lysosomes of patients with genetic diseases, which result from a mutation in one of the essential glycolipid-degrading enzymes (e.g. Gaucher, Tay Sachs, Sandhoffs, GMl gangliosidosis and Fabry diseases).
• Glycolipid storage also occurs as a secondary effect in some tissues (e.g. neuronal tissue) with genetic storage diseases such as Niemann-Pick C disease, mucopolysaccharidoses, mucolipidosis type IV (Proc. Natl. Acad. Sci.
• GCS inhibitors may be applied to reduce the rate of glycolipid synthesis in diseased cells so that there is less glycolipid present to be stored, a treatment approach termed substrate deprivation. Studies have demonstrated that GCS inhibitors can be used to reduce the glycolipid accumulation seen in cell and animal models of glycolipid storage disorders (Proc. Natl. Acad. Sci. USA, 1999, 96(11), 6388-93; Science, 1997, 276(5311), 428-31; J. CHn. Invest., 2000, 105(11), 1563-71).
• GCS inhibitors such as, N-butyldeoxynojirimycin (NB-DNJ) are useful in treating human patients with Gaucher disease (Lancet, 2000, 355(9214), 1481-5).
• the use of the imino sugar NB-DNJ as a GCS inhibitor is disclosed in EP-A-0698012.
• EP-A-0536402 and EP-A-0698012 disclose that N-alkyl derivatives of deoxygalactonojirimycin, e.g. N-butyldeoxygalactonojirimycin (NB-DGJ), may also be of use in the treatment of glycolipid storage disorders.
• NB-DGJ N-butyldeoxygalactonojirimycin
• EP-A-0698012 also discloses that the corresponding N-butyl derivatives of mannose (NB-DMJ), fucose (NB-DFJ) and N-acetylglucosamine (NB-NAG) do not act as inhibitors of glycolipid biosynthesis.
• NB-DMJ mannose
• NB-DFJ fucose
• NB-NAG N-acetylglucosamine
• tumour shed and cell surface bound tumour gangliosides can influence tumour host cell interactions such as cell-cell contacts or adhesion (Methods Enzymol., 2000, 312, 447-58), cell motility (MoI. Chem. Neuropathol., 1995, 24(2-3), 121-35), growth factor signalling events (J. Biol. Chem., 2000, 275(44), 34213-23), tumour stimulated angiogenesis (Acta.
• glycolipids also have roles in infectious disease, serving as receptors for the binding of pathogenic bacteria (APMIS, 1990, Dec, 98(12), 1053-60, Review), fungi (Infect. Immun., 1990 JuI, 58(7), 2085-90) and viruses (FEBS Lett., 1984, May 7, 170(1), 15-8).
• glycolipids on the surface of cells are bound by bacterial toxins (Methods Enzymol., 2000, 312, 459-73) for instance, the B subunit of cholera toxin (ganglioside GMl) and verocytotoxin (globotriaosylceramide GB3) (J. Infect. Dis., 2001, suppl. 70-73, 183).
• GCS inhibitors may also be appropriate in a number of other clinical indications which are associated with abnormalities in glycolipid synthesis.
• Atherosclerotic lesions of human aorta have a higher ganglioside content than unaffected regions of the aorta and serum ganglioside concentrations in atherosclerotic patients are higher than in normal individuals (Lipids, 1994, 29(1), 1-5).
• Tissue derived from the kidneys of patients with polycystic kidney disease contains high levels of both glucosylceramide and lactosylceramide (J. Lipid. Res., 1996, Jun, 37(6), 1334-44). Renal hypertrophy in an animal model of diabetes is associated with increases in glycolipid synthesis, (J. Clin. Invest., 1993, Mar, 91(3), 797-803).
• Glycolipid metabolism also plays a critical role in neuronal disorders, such as Alzheimer's disease and epilepsy.
• Niemann-Pick C (NPC) patient neurons present with fibrillar tangles reminiscent of the morphology seen in Alzheimer's disease.
• GMl ganglioside binding by amyloid beta-protein induces conformational changes that support its formation of fibrous polymers, and the fibrillar deposition of this protein is an early event in Alzheimer's disease (Yanagisawa et al., 1995, Nat. Med. 1, 1062-6; Choo-Smith et al., 1997, Biol. Chem., 272, 22987-90).
• GCS inhibitors e.g. NB-DNJ
• Parkinson's disease, stroke and spinal cord injuries seem to improve by treating patients with GMl ganglioside (Alter, (1998), Ann. NY Acad. Sci., 845, 391-4011; Schneider, 1998, Ann. NY. Acad. Sd., 845, 363-73; Geisler, (1998), Ann. NY. Acad. Sci., 845, 374-81).
• GCS inhibitors like NB-DNJ would limit patient-specific inconsistencies by blocking their neuronal glycolipid synthesis.
• inhibiting glucosylceramide synthesis would limit the metabolism of administered glycolipids into other, perhaps unproductive, forms.
• the ability to modulate glucosylceramide synthesis with GCS inhibitors may be useful in the treatment of a wide variety of neuronal disorders.
• imino sugars can reversibly induce male sterility and can, therefore, be used as male contraceptives.
• GCS inhibitors could be used for the treatment of obesity.
• an inflammatory agent e.g. bacterial endotoxin
• an inflammatory agent e.g. bacterial endotoxin
• serine palmitoyltransferase and glucosylceramide synthase are key to the de novo synthesis of glycolipids, see Memon, R.A. et al., J Biol Chem, 1999, 274(28), 19707-13; Memon, R.A. et al., J Lipid Res, 2001, 42(3), 452-9.
• glycolipids are further supported by the demonstration of changes in glycolipid expression in animals with genetic defects which result in hyper- or hyposensitive responses to inflammatory stimuli.
• endotoxin treatment in C3H/HeJ mice which have a toll-like receptor 4 mutation and are hypo-responsive to bacterial endotoxin
• recruited macrophages were found to lack ganglioside G M i b , which is a major ganglioside found in recruited macrophages in normal mice, see Yohe, H.C. et al., Immunol, 1991, 146(6), 1900-8; Yohe, H.C. et al., Immunol, 1986, 137(12), 3921-7.
• GCS inhibitors may be useful in the treatment of inflammatory diseases and other disorders associated with macrophage recruitment and activation, including, but not limited to, rheumatoid arthritis, Crohn's disease, asthma and sepsis.
• WO02/055498 discloses piperidine derivatives useful as GCS inhibitors.
• the invention provides the compound 3,4,5-piperidinetriol, 2-(hydroxymethyl)-l-[(4- (pentyloxy)phenyl)methyl]-, (2S,3S,4R,5S) and pharmaceutically acceptable salts and prodrugs thereof.
• the compound of the present invention can be used for the inhibition of GCS.
• the present invention provides the use of the compound of the invention in medicine.
• Suitable, pharmaceutically acceptable salts of the compound of the invention include, but are not limited to, salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate, or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, palmitate, salicylate, and stearate.
• inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate
• an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, palmitate, salicylate, and stearate.
• Suitable prodrugs of the compound of the invention include, but are not limited to, pharmaceutically acceptable esters such as Ci -6 alkyl esters.
• the compound of the invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed.
• This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. Since the compound of the invention is intended for use in pharmaceutical compositions it will readily be understood that it is preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis).
• Impure preparations of the compound may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compound should contain at least 1%, more suitably at least 5%, e.g. from 10 to 59%, of the compound of the invention or pharmaceutically acceptable derivative thereof.
• the compound of the invention can be prepared by art-recognized procedures from known or commercially available starting materials. If the starting materials are unavailable from a commercial source, their synthesis is described herein, or they can be prepared by procedures known in the art. Specifically, the compound of the invention may be prepared by a process comprising: (a) reacting a compound of formula (H):
• L which may be the same or different, are leaving groups, such as mesyl, and P is as defined for formula (DI), with 4-(pentyloxy)benzylamine, either neat or in a solvent, such as tetrahydrofuran.
• Compound (Wa), wherein L is mesyl and P is benzyl, may be prepared by reacting 2,3,4,6-tetra- O-benzyl-D-galactitol base such as pyridine.
• labile functional groups in the intermediate compounds e.g. hydroxy groups
• a comprehensive discussion of the ways in which various labile functional groups may be protected and methods for cleaving the resulting protected derivatives is given in for example Protective Groups in Organic Chemistry, T. W. Greene and P.G.M. Wuts, (Wiley-Merscience, New York, 2nd edition, 1991). Further details for the preparation of the compound of the invention are provided in the example.
• the pharmaceutically effective compound of the invention may be administered in conventional dosage forms prepared by combining the compound of the invention ("active ingredient") with standard pharmaceutical carriers, excipients or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising the compound of the invention, together with one or more pharmaceutically acceptable carriers, excipients and/or diluents.
• the active ingredient or pharmaceutical composition can be administered simultaneously, separately or sequentially with another treatment for the disorder to be treated.
• the active ingredient or pharmaceutical composition may be administered to a subject by any of the routes conventionally used for drug administration, for example they may be adapted for oral (including buccal, sublingual), topical (including transdermal), nasal (including inhalation), rectal, vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) administration to mammals including humans.
• routes conventionally used for drug administration for example they may be adapted for oral (including buccal, sublingual), topical (including transdermal), nasal (including inhalation), rectal, vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) administration to mammals including humans.
• the most suitable route for administration in any given case will depend on the particular compound or pharmaceutical composition, the subject, and the nature and severity of the disease and the physical condition of the subject.
• Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s), excipient(s) and/ or diluent(
• compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
• Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulfate.
• the tablets may be coated according to methods well known in normal pharmaceutical practice.
• 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 reconstitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl />-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
• suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate,
• compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, impregnated dressings, sprays, aerosols or oils and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
• Such applications include those to the eye or other external tissues, for example the mouth and skin and the compositions are preferably applied as a topical ointment or cream.
• the active ingredient may be employed with either a paraffinic or a water- miscible ointment base.
• the active ingredient may be formulated in a cream with an oil-in- water cream base or a water-in-oil base.
• the composition may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
• compositions adapted for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
• Pharmaceutical compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
• compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
• the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318, (1986).
• compositions adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
• Suitable compositions wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
• compositions adapted for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators.
• compositions adapted for rectal administration may be presented as suppositories or enemas.
• Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
• compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray compositions.
• compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
• the compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
• Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
• fluid unit dosage forms are prepared utilizing the active ingredient and a sterile vehicle, e.g. water .
• a sterile vehicle e.g. water
• the active ingredient depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
• the active ingredient can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
• agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
• the composition can be frozen after filling into the vial and the water removed under vacuum.
• the dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
• Parenteral suspensions are prepared in substantially the same manner except that the active ingredient is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
• the active ingredient can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
• a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active ingredient.
• the pharmaceutical compositions according to the invention are preferably adapted for oral administration.
• compositions may also include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents. They may also contain therapeutically active agents in addition to the compounds of the present invention. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
• compositions may contain from 0.1% by weight, e.g. 10-60% by weight, of the active material, depending on the method of administration.
• compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per dose.
• a unit may contain for example 0. lmg/kg to 750mg/kg, more preferably 0. lmg/kg to 10mg/kg, depending on the condition being treated, the route of administration and the age, weight and condition of the patient.
• Preferred unit dosage compositions are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient.
• the optimal quantity and spacing of individual dosages of active ingredients will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular subject being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e. the number of doses of the active ingredients given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
• the compound of the invention is useful in that it is capable of inhibiting glucosylceramide synthase.
• the compound of the invention can be used in the treatment of various glycolipid storage diseases such as Gaucher' s disease, Sandhoff s disease, Tay-Sachs disease, Fabry disease, GMl gangliosidosis, etc.
• the compound can also find use in the treatment of conditions in which glycolipid accumulation occurs such as Niemann-Pick disease, mucopolysaccharidoses (MPS I, MPS IUA, MPS IHB, MPS VI and MPS VII 5 preferably MPS I), mucolipidosis type IV and ⁇ -mannosidosis.
• the compound of the present invention can also be used in the treatment of cancer in which glycolipid synthesis is abnormal such as brain tumours, neuroblastoma, malignant melanoma, renal adenocarcinoma and multi-drug resistant cancers in general.
• the compound of the present invention can also be used in the treatment of diseases caused by infectious microorganisms which use cell surface glycolipids as receptors for either the infectious organism itself or for a toxin produced by the infectious organism (e.g. for attachment and/or invasion onto/into the host cell).
• the compound of the present invention can also be used in the treatment of disease caused by infectious microorganisms for which the synthesis of glucosylceramide is an essential or important process, e.g. the pathogenic fungus Cryptococcus neoformans.
• the compound of the present invention can also be used in the treatment of disease in which excessive glycolipid synthesis occurs, such as, but not limited to, atherosclerosis, polycystic kidney disease and diabetic renal hypertrophy.
• the compound of the present invention can also be used in the treatment of neuronal disorders, such as Alzheimer's disease and epilepsy; and neuronal degenerative disease, such as, Parkinsons' disease
• neuronal injury such as spinal cord injuries or stroke.
• the compound of the present invention can also be used in the treatment of obesity.
• the compound of the present invention can also be used in the treatment of inflammatory diseases or disorders associated with macrophage recruitment and activation, including, but not limited to, rheumatoid arthritis, Crohn's disease, asthma and sepsis.
• the present invention provides:
• glycolipid storage disease examples include, but are not limited to, Gaucher disease, Sandhoff s disease, Tay-Sachs disease, Fabry disease or GMl gangliosidosis, (iii) use of the compound of the invention in the manufacture of a medicament for the treatment of Niemann-Pick disease, types A and C.
• a method for the treatment of a glycolipid storage disease e.g. Gaucher's disease, Sandhoff s disease, Tay-Sachs disease or GMl gangliosidosis, which comprises the step of administering to a patient an effective amount of the compound of the invention.
• a glycolipid storage disease e.g. Gaucher's disease, Sandhoff s disease, Tay-Sachs disease or GMl gangliosidosis
• (xviii) a method for the treatment of Niemann-Pick disease, types A and C, which comprises the step of administering to a patient an effective amount of the compound of the invention.
• (xix) a method for the treatment of mucopolysaccharidosis type I, mucopolysaccharidosis type ⁇ iA, mucopolysaccharidosis type HIB, mucopolysaccharidosis type VI or mucopolysaccharidosis type V ⁇ which comprises the step of administering to a patient an effective amount of the compound of the invention.
• (xx) a method for the treatment of ⁇ -mannosidosis or mucolipidosis type IV which comprises the step of administering to a patient an effective amount of the compound of the invention.
• (xxi) a method for the treatment of cancer in which glycolipid synthesis is abnormal, including but not limited to brain cancer, neuronal cancer, renal adenocarcinoma, malignant melanoma, multiple myeloma and multi-drug resistant cancers, which comprises the step of administering to a patient an effective amount of the compound of the invention.
• a method for the treatment of Parkinson's disease which comprises the step of administering to a patient an effective amount of the compound of the invention.
• a method for the treatment of spinal injury which comprises the step of administering to a patient an effective amount of the compound of the invention.
• a method for the treatment of diseases caused by infectious microorganisms e.g. pathogenic fungi, for which the synthesis of glucosylceramide is an essential or important process, such as, but not limited to, pathologies associated with Cryptococcus neoformans infection, which comprises the step of administering to a patient an effective amount of the compound of the invention.
• a method for the treatment of diseases associated with abnormal glycolipid synthesis including but not limited to polycystic kidney disease, diabetic renal hypertrophy and atherosclerosis, which comprises the step of administering to a patient an effective amount of the compound of the invention.
• a method for the treatment of a condition treatable by the administration of a ganglioside such as GMl ganglioside, which comprises the step of administering to a patient an effective amount of the compound of the invention.
• a ganglioside such as GMl ganglioside
• Examples of such conditions are Parkinson's disease, stroke and spinal cord injuries.
• (xxx) a method for the treatment of obesity, which comprises the step of administering to a patient an effective amount of the compound of the invention.
• (xxxi) a method for the treatment of inflammatory diseases or disorders associated with macrophage recruitment and activation, including, but not limited to, rheumatoid arthritis, Crohn's disease, asthma and sepsis which comprises the step of administering to a patient an effective amount of the compound of the invention.
• the invention also provides for the use of the compound of the invention for the treatment of the above mentioned diseases and conditions.
• the desired compound was then eluted using a solution of 2:2:1 methanol/water/ammonium hydroxide (100 ml). The resulting solution was concentrated to a small volume (1 ml) and freeze-dried to afford the title compound as a white solid (30 mg, 29%).
• the compound of the invention may be tested for biological activity in the following assays: Inhibition of GCS
• the assay for inhibition of non-lysosomal- ⁇ -glucocerebrosidase was essentially carried out as described in Overkleeft, H. S. et al., J. Biol. Chem., 1998, 273, 26522-26527, with the following differences: whole cell extracts of MCF7 (a human breast carcinoma cell line) was used as the source of the enzyme instead of splenic membrane suspensions; 5 mM instead of 3 mM, 4-MU ⁇ -glucoside was used as substrate and 0.2M citrate/phosphate (pH 5.8) was used instead of Mcllvaine buffer.
• Table I shows IC 50 data for the compound of the invention against human GCS and non- lysosomal- ⁇ -glucocerebrosidase enzymes.
• HPTLC High-Performance Thin Layer Chromatography
• chloroform methanol: 0.2% CaCl 2 ; 65:35:8
• Scion Image software was then used to quantify GlcCer in the samples relative to a GlcCer standard. This enabled a cell-based IC 50 to be calculated for the compound of the invention for GCS inhibition.

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