Compounds for neurodegenerative diseases

Abstract

The invention relates to an iminosugar prodrug compound of General Formula (I) or General Formula (II): Compounds and compositions comprising the same exhibit low toxicity and are efficacious against Lysosomal Storage Disorders (LSDs), neurodegenerative disorders and Down Syndrome. Further, by masking the iminosugar API, well documented adverse effects associated with iminosugar APIs, including diarrhoea and other gut-related issues can be minimized or even eliminated. The invention also relates to methods of treating LSDs, neurodegenerative disorders or Down Syndrome using the compounds of General Formula (I) or General Formula (II).

Description

[0001] COMPOUNDS FOR NEURODEGENERATIVE DISEASES

[0002] Field of the Invention

[0003] The invention relates to an iminosugar prodrug compound and a pharmaceutical composition comprising same that exhibits excellent bioavailability, likely due to improved blood-brain barrier penetrance, activity, and / or low toxicity compared to the corresponding active pharmaceutical ingredient (API). Moreover, the addition of phosphate-derived masking groups markedly reduces known off-target adverse effects associated with iminosugar derived APIs. The compound is converted to the API in vivo by enzymatic and / or chemical reactions, so the compound and composition are for use in the treatment of numerous conditions for which iminosugar APIs are administered.

[0004] In particular, iminosugar APIs have been shown to be a potent inhibitor of Glucosylceramide Synthase (GCS), an enzyme that catalyses the first step in synthesis of glycosphingolipids (GSLs) and may be approved for use to reduce the accumulation of GSLs in lysosomal storage disorders, where both primary or secondary accumulation of GSL occurs. Therefore, the prodrug compound and composition are for use in the treatment of lysosomal storage disorders, particularly Gaucher type 1 and 3, Niemann-Pick type C, Dehydrodolichyl diphosphate synthase (DHDDS) syndrome, and the neuronal ceroid lipofuscinoses group of diseases. Further, evidence demonstrates that the prodrug compound and composition also find utility in the treatment of neurodegenerative disorders, particularly Huntington’s disease, Alzheimer’s disease, Spinocerebellar ataxia (SCA) and Parkinson’s disease, and / or Down Syndrome, where GSL accumulation has been identified. Also provided are methods of treating such disorders, comprising the use of the compound or composition according to the invention.

[0005] Background of the Invention

[0006] Glycosphingolipids are a family of lipids, comprising a ceramide backbone (an amino alcohol amide linked to a fatty acid) with a sugar headgroup, that are essential for development, and normal functional of, amongst others, the brain, immune system and skin. Glycosphingolipids are made in the Golgi, starting on the cytosolic surface with glucosylceramide (GlcCer) synthesis which then flips to the inner leaflet for further complex GSL biosynthesis. GSLs are secreted from the Golgi to the plasma membrane where they form signaling microdomains and are then recycled by endocytosis or taken to the lysosome for hydrolysis in a step wise manner involving specific enzyme hydrolases and accessory proteins. However, any defect in these hydrolysis processes (resulting from, e.g., mutations in enzymes, accessory proteins, or transport proteins) leads to their accumulation within the lysosome. Lysosomal storage of sphingolipids and GSLs is observed throughout the family of disorders known collectively as lysosomal storage diseases (LSDs), either as a primary result of loss of hydrolysis / transport functionality or as secondary storage to a different primary material (which itself can then disrupt glycosphingolipid enzyme function) and may ultimately cause severe neurodegeneration. LSDs include ~60-70 individually rare and predominantly neurodegenerative diseases that as a group constitute the most common cause of childhood brain disease (incidence ~1:3,500 live births). All are life limiting and life shortening diseases and almost all are orphan diseases with no current therapy beyond symptom management. At the patient level the diseases are heterogeneous but most present with splenomegaly, failure to thrive, gait abnormalities, speech abnormalities, neurological impairment, visual impairment, sleeping difficulties, immune dysfunction. At the cellular level the diseases are predominantly characterized by the primary accumulation of GSLs due to a defective enzyme or transporter, but in almost all cases the presence of secondary accumulation of GSLs has been shown even when the primary mutated enzyme is not involved in GSL metabolism. Various treatment strategies for LSDs focus on gene therapy to re-introduce a normal copy of the defective gene (although this does not rescue any dysfunction caused by misfolded mutant proteins), protein chaperones, upregulation of mechanisms inducing lysosomal gene biosynthesis (e.g. nuclear translocation of TFEB / TFE3) or reduction of lysosomal storage material (a strategy referred to as substrate reduction therapy). Miglustat is an inhibitor (IC50= ~5-50 ^M) of Glucosylceramide Synthase (GCS), an enzyme that catalyses the first step in synthesis of GSLs, namely the production of glucosylceramide from ceramide and UDP-glucose on the outer leaflet of the Golgi (Figure 1). Miglustat is an iminosugar compound and, as such, is a natural product glucose mimetic. Due to its GCS inhibitory activity, it is approved for use to reduce the accumulation of glycosphingolipids in lysosomal storage disorders, including Gaucher’s disease (EMA and FDA) and Niemann-Pick C (EMA). Further, as DHDDS syndrome is caused by a loss of either subunit of dehydrolichyl diphosphate synthase and results in misprocessing of NPC2 and accumulation of cholesterol and ganglioside containing inclusions in cells analogous to Niemann-Pick C patients who have a genetic loss of NPC2, it is expected that miglustat would also be effective in the treatment of DHDDS syndrome. However, there are numerous well documented adverse effects associated with miglustat (and other iminosugar APIs), including diarrhoea and other gut-related issues in approximately 80% of patients due to inhibition of carbohydrate-metabolizing glucosidases in the GI-lumen. Additional reports of peripheral neuropathy in Gaucher patients (~10-15%) have also been reported and may be due to potent inhibition (IC50 = 15nM) of non-lysosomal glucosylceramidase (GBA2), mutations in which are associated with rare forms of Marinesco-Sjogren syndrome that manifests with a demyelinating peripheral neuropathy. Further, blood brain barrier (BBB) penetrance of miglustat is poor, with >10% of plasma miglustat crossing the BBB, and even then, with slow kinetics. In particular, experiments (Figure 2) show that it can take more than 6 months for the brain concentration (~ 1 to 2 ^M in Gaucher patients, 0.5 ^M estimated in one NPC patient cerebrospinal fluid sample) of miglustat to have a clinical effect in patient cells compared to just 1 month for the much higher peripheral plasma concentration (~ 5 to 10 ^M). Therefore, it is in an object of the present invention to design a safe and effective prodrug platform for iminosugar APIs, in particular miglustat, that imparts excellent bioavailability, activity and / or low toxicity, and also reduces off- target adverse effects associated with iminosugar APIs. Statements of Invention The present invention, in its various aspects, is as set out in the accompanying claims. According to a first aspect of the invention there is provided a compound according to General Formula (I) or General Formula (II), including all tautomers thereof: (II) wherein: R1 and R2 each independently represents an amino acid ester radical according to General Formula (III) or an aryloxy radical according to General Formula (IV): V) wherein R4represents H, or a saturated or unsaturated and optionally substituted C1-4alkyl group; R5represents a saturated or unsaturated and optionally substituted C1-4alkyl or C6-10aryl group; and R6represents an optionally substituted C6-18aryl or a 6 to 18 membered heteroaryl group; x is 0, 1, 2 or 3; y is 0, 1, 2, 3 or 4; R3represents H, an optionally substituted C1-20alkyl group; and R11represents H, an optionally substituted C1-4alkyl group or an optionally substituted C2-4acyl group. or any salt thereof. The compounds of General Formula (I) and General Formula (II) represent a novel prodrug approach for the intracellular delivery of iminosugar APIs, in which the iminosugar active moiety is masked by aryl and / or amino acid ester groups, which are enzymatically cleaved off inside cells to release the API. Further, compared with the corresponding APIs per se, such iminosugar prodrug compounds should demonstrate excellent bioavailability (both in the gut and in the brain). Moreover, these compounds demonstrate potent activity and / or low toxicity. Moreover, masking of the active moiety in this way has been shown to significantly reduce, and even substantially eliminate known undesirable off-target adverse effects associated with the iminosugar APIs. For example, miglutstat is known: (i) to inhibit gut disaccharidases and, as a consequence, water retention, resulting in osmotic diarrhea in 100% of patients; (ii) to inhibit the plasma membrane enzyme GBA2, the genetic cause of hereditary spastic paraplegia with associated neuropathy; (iii) not to penetrate the blood-brain barrier (BBB) sufficiently due to prolonged interaction with epithelial glycocalyx; and (iv) to be poorly absorbed by the body due to its polar nature, so requiring patients (who have swallowing issues) to frequently take multiple doses. Common side effects associated with iminosugars, in particular miglustat, include gastrointestinal effects (including osmotic diarrhea, stomach pain or bloating, gas, peripheral nerve pain). However, by adopting this prodrug approach, the inventors have likely improved the potency and permeability of miglustat, both in the gut and in the brain, thereby allowing the use of lower dosages and / or less frequent dosing regimens, thus reducing side effects such as diarrhoea and neuropathy. In addition, these side effects are further reduced by virtue of the aryl and / or amino acid ester groups negating the inhibitory activity of carbohydrate-metabolizing glucosidases in the GI-lumen and / or GBA2 associated with the active iminosugar compound per se. The term ‘C1-4 alkyl’ as used herein refers to a straight or branched saturated hydrocarbon chain containing from 1 to 4 carbon atoms. Examples include ethyl, n- propyl, isopropyl, n-butyl, s-butyl, and t-butyl. The tern ‘C2-4acyl’ as used herein refers to a C1-4alkyl group in which one carbon atom is double bonded to an oxygen atom to form a carbonyl, preferably a ketone or aldehyde, group. The term ‘C6-18aryl’ as used herein refers to any hydrocarbon group that contains 6 to 18 carbon atoms and includes one or more carbocyclic aromatic ring. More suitably aryl groups are C6-10and are preferably C6aryl groups. The term ‘heteroaryl’ as used herein refers to any hydrocarbon group that includes one or more aromatic ring that includes one or more heteroatom (e.g. N, O or S) as part of said ring. Particularly suitable examples of heteroaryl groups are pyridine, furan, thiophene and indole groups. A 6 to 18 membered heteroaryl group refers to a group in which the total number of rings forming atoms (carbon and heteroatom(s)) is from 6 to 18. Other alkyl, aryl and heteroaryl groups are as defined but have different numbers of carbon atoms. For example, C1-6alkyl has 1 to 6 carbon atoms. The alkyl, aryl, acyl and / or heteroaryl group may be optionally substituted with one or more substituents selected from OH, halo, nitro, C1-6alkyl, C1-6perfluoroalkyl, C1-6haloalkyl, -O( C1-6alkyl), -O(C1-6haloalkyl), NH2, NH(C1-6alkyl) or N(C1-6alkyl)2. Alternatively or additionally, the alkyl group may be optionally substituted by the independent replacement of one or more available -CH2- groups present in the alkyl chain with a group selected from -O- and an optionally substituted phenylene group. As used herein, any carbon number of an alkyl or aryl radical includes any carbon atoms present in substituents. Where substituted, the alkyl, aryl or heteroaryl radical is preferably substituted with one or more substituents selected from OH, halo and NH2. Salts of the compounds of General Formula (I) and / or General Formula (II) are suitably pharmaceutically or veterinary acceptable salts. Depending on the nature of R1 to R6, these may be basic addition salts such as sodium, potassium, calcium, aluminium, zinc, magnesium and other metal salts as well as choline, diethanolamine, ethanolamine, ethyl diamine, megulmine and other well-known basic addition salts as summarised in Paulekuhn et al., (2007) J. Med. Chem.50: 6665-6672 and / or known to those skilled in the art. Alternatively, when the compound of general formula (I) or (II) contains an amino group, this may be quaternised to form a salt with a counter ion such as halide, hydroxide, sulfate, nitrate, phosphate, formate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methane sulfonate and p-toluene sulfonate. As would be readily appreciated by the skilled reader, this prodrug technology could be introduced into any pharmaceutically active iminosugar compound. As such the structure of said iminosugar compound is not particularly limited. However, in preferred embodiments, the compound of the invention is a compound according to General Formula (I). Such piperidine iminosugar compounds represent hexose (e.g. glucose / galactose) sugar analogues, which were the first generation of iminosugars to reach the market. Examples of such first generation approved iminosugars include Miglitol (approved for use in the treatment of type II diabetes mellitus), Miglustat (approved for the treatment of LSDs) and Migalastat (approved for the LSD Fabry disease), each of which are shown in Figure 3 together with Sinbaglustat and Lucerastat, both of which are currently in human trials for the treatment of LSDs), and all are associated with significant adverse side-effects, mainly at the level of the digestive system. In a preferred subset of compounds according to General Formula (I) or General Formula (II), the iminosugar active compound is masked by an amino acid ester and an aryl group. Such compounds are of General Formula (V) and General Formula (VI), wherein x, y, R3, R4R5, R6and R11as defined above: VI) In some compounds of General Formula (I) or General Formula (V), y is 2 or 3, and is preferably 3. Similarly, in some compounds of General Formula (II) or General Formula (VI), x is 1 or 2, and is preferably 3. Alternatively or additionally, in some compounds of General Formula (I), (II), (V) or (VI), R3preferably represents an optionally substituted C1-12alkyl group, more preferably an optionally substituted C1-6alkyl group, and still more preferably a group selected from: pentyl, butyl, hydroxyethyl, or hydrogen. In particularly preferred embodiments the butyl group of R3is n-butyl. Alternatively or additionally, in some compounds of General Formula (I), (II), (V) or (VI), R11preferably represents H. By limiting the number of attached hydroxy groups (or protected derivatives thereof), and the nature of the R3group, the resultant iminosugar prodrug compounds are analogous to known iminosugar APIs. For example, in particularly preferred embodiments, the compound of the present invention is a compound of General Formula (VII), a prodrug of miglustat or the galactose derivative lucerastat; a compound of General Formula (VIII), a prodrug of migalastat; a compound of General Formula (IX), a prodrug of Miglitol; or a compound of General Formula (X), a prodrug of Sinbaglustat, wherein R4, R5, R6and R11 are as defined above. II) III)

[0007] IX) X) As would be readily appreciated, each of General Formula (VII) to (X) are directed to prodrugs that are not limited to any particular iminosugar stereochemical configuration. However, in preferred embodiments, the compounds of General Formula (VII) to (X) are selected from: D-gluco configured prodrugs according to General Formula (VII-A) to (X-A); L-ido configured prodrugs according to General Formula (VII-B) to (X-B); or D-galacto configured prodrugs according to General Formula (VII-C) to (X-C), wherein R4R5, R6and R11 are as defined above. A) (VIII-C) (IX-C) CH3R4O O P N R5N O H O O R6R11O OR11OR11(X-C) The compounds of General Formulae (I), (II), (V) to (X), (VII-A) to (X-A), (VII-B) to (X- B) and (VII-C) to (X-C) are prodrugs in which the active iminosugar compound is masked by an aryloxy and / or an amino acid ester group, which are both enzymatically cleaved off inside cells to release the pharmaceutically active species. Suitable amino acid ester masking groups include a wide variety of amino acid sidechain (R4) groups. Typically, R4represents is a sidechain, preferably a nonpolar sidechain, of a proteinogenic amino acid. Particularly preferred R4groups include hydrogen (glycine), methyl (alanine), propyl, in particular isopropyl (valine), and butyl, in particular isobutyl (leucine) or sec-butyl (isoleucine). Compounds derived from glycine, alanine or leucine, i.e. compounds in which R4represents hydrogen, methyl or isobutyl, are particularly suitable. As noted above, R5is a saturated or unsaturated and optionally substituted C1-4alkyl or C6-10aryl group. Preferably, R5is a C2-3alkyl or a C6aryl group. In particularly preferred embodiments R5is selected from: benzyl; ethyl; and propyl, more preferably isopropyl. In exemplary embodiments, the R5is a benzyl group. Suitable aryloxy masking groups include a wide variety of aryl (R6) groups, including ring systems with aromatic character containing a single or multiple fused rings. Where an aryl group contains multiple fused rings, both rings need not be fully aromatic in character. Examples of suitable aromatic moieties are phenyl, naphthyl, anthracyl and tetracyl. A preferred substituted aromatic moiety is 5,6,7,8-tetrahydro- 1-napthyl. However, R6typically represents a monocyclic aryl group, and in exemplary embodiments, R6is a phenyl group. Without wishing to be bound by theory, compounds according to any of General Formulae (I), (II) or (V) to (IX) comprising a benzyl (R5) ester and / or a phenyl (R6) group have a higher rate of degradation and improved lipophilicity (and thus improved cell uptake) in comparison with aliphatic ester-based prodrug compounds. Exemplary compounds of General Formula (I) include: , and D- gluco, L-ido or D-galacto configured derivatives thereof. The iminosugar prodrug compounds of the first aspect of the invention may be prepared in a single step Grignard addition process as set out schematically in Figure 4. This method for the preparation of said compounds itself represents the second aspect of the invention. In said method, a compound of General Formula (XI) is reacted with an iminosugar compound of General Formula (XII) or General Formula (XIII) in the presence of a Grignard reagent of General Formula (XIV) to prepare a compound of General Formula (I) or General Formula (II) (XI) (XII) (XIII) R21-Mg-R22 (XIV) wherein each of R1, R2, R3and R11 are as defined above; R12 is a halo group, preferably chloro; R21 is an alkyl or aryl group; and R22 is a halo group, preferably chloro. In preferred embodiments the Grignard reagent of General Formula (XIV) is tert- butylmagnesium chloride. Many compounds of General Formulae (XI), (XII), (XIII) and (XIV) are well known and readily available. In particular, there is a vast array of pharmaceutically active iminosugar compounds of General Formula (XII) or (XIII) that are well known and commercially available. Other examples of compounds of General Formulae (XI), (XII), (XIII) and (XIV) can readily be synthesised by a person of skill in the art using standard methods. It will be appreciated that the compounds of the first aspect of the invention will generally be administered as part of a pharmaceutical composition. Therefore, according to a third aspect of the invention there is provided a pharmaceutical composition comprising a compound of the first aspect of the invention and a pharmaceutically acceptable excipient or carrier. Suitable pharmaceutical excipients are well known to those of skill in the art. Pharmaceutical compositions may be formulated for administration by any suitable route, for example oral, rectal, nasal, bronchial (inhaled), topical (including eye drops, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration and may be prepared by any methods well known in the art of pharmacy. The composition may be prepared by bringing into association the compound of the first aspect of the invention with the carrier. In general, the formulations are prepared by uniformly and intimately bringing into association said compound with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. Formulations for oral administration in the present invention may be presented as: discrete units such as capsules, sachets or tablets each containing a predetermined amount of the compound; as a powder or granules; as a solution or a suspension of the compound in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; or as a bolus etc. For compositions for oral administration (e.g. tablets and capsules), the term “acceptable carrier” includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, glycerol stearate, stearic acid, silicone fluid, talc waxes, oils and colloidal silica. Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring and the like can also be used. It may be desirable to add a colouring agent to make the dosage form readily identifiable. Tablets may also be coated by methods well known in the art. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent. Other formulations suitable for oral administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier. Parenteral formulations will generally be sterile. For topical application to the skin, the composition may be made up into a cream, ointment, jelly, solution or suspension etc. Cream or ointment formulations that may be used for the drug are conventional formulations well known in the art, for example, as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia. In a preferred embodiment of this aspect of the invention the composition is formulated for oral delivery. The precise amount of a composition as defined herein which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art. Such amounts will depend, of course, on the particular condition being treated, the severity of the condition, the individual patient parameters including age, physical condition, size and weight, the duration of the treatment, the nature of concurrent therapy (if any), the specific route of administration and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is generally preferred that a maximum dose of the individual components or combinations thereof be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art, however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons. The doses of the compound or composition according to the invention administered to a subject can be chosen in accordance with different parameters, in particular in accordance with the mode of administration used and the state of the subject. Other factors include the desired period of treatment. In the event that a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. As discussed above, the compounds of the first aspect of the invention represent prodrugs of pharmaceutically active iminosugar compounds. Therefore, according to a fourth aspect of the invention, there is provided a compound according to the first aspect or a composition according to the third aspect of the invention for use in medicine. In particular, and as already indicated above, the compounds of the first aspect of the or the compositions according to the third aspect of the invention are for use in in the treatment of lysosomal storage disorders (LSDs). In preferred embodiments, the LSDs are selected from: Niemann–Pick C1; Niemann-Pick type C2; Niemann-Pick types A and B; neuronal ceroid lipofuscinoses (NCL aka Batten disease); mucolipidoses (e.g. I cell, MLIV); mucopolysaccharidoses (e.g. Hunter or Hurler disease), monosaccharidoses (e.g. fucosidosis) or lipidoses (e.g. Wolman and Tangier disease), DHDDS syndrome, and sphingolipidoses such as Gaucher disease, Fabry disease and Tay-Sachs disease. In Exemplary embodiments the LSD is selected from Niemann–Pick C1; Batten disease; and Gaucher disease. Alternatively or additionally, the compounds of the first aspect or the compositions of the third aspect of the invention are for use in the treatment of a neurodegenerative disorder. In preferred embodiments, the neurodegenerative disorders are selected from: Huntington’s disease; Alzheimer’s disease; Spinocerebellar ataxia (SCA); or Parkinson’s disease, preferably forms of PD associated with lysosomal associated risk genes such as GBA1-associated Parkinson’s disease. Alternatively or additionally, the compounds of the first aspect or the compositions of the third aspect of the invention are for use in the treatment of Down Syndrome. According to a fifth aspect, the invention provides the use of a compound according to the first aspect or a composition according to the third aspect in the preparation of an agent for the treatment of a LSD, a neurodegenerative disorder, or Down Syndrome. Preferred LSDs and neurodegenerative disorders are as described in connection with the fourth aspect of the invention. According to a sixth aspect, the invention extends to a method for treating a LSD, a neurodegenerative disorder or Down Syndrome, the method comprising administering to a subject in need of such treatment an effective amount of a compound according to the first aspect or a composition according to the third aspect of the invention. Again, preferred LSDs and neurodegenerative disorders are as described in connection with the first aspect of the invention. In a preferred embodiment of this aspect of the invention, said subject is a mammal. Ideally said mammal is human. Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of the words, for example “comprising” and “comprises”, mean “including but not limited to” and do not exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise. All references, including any patent or patent application, cited in this specification are hereby incorporated by reference. No admission is made that any reference constitutes prior art. Further, no admission is made that any of the prior art constitutes part of the common general knowledge in the art. Preferred features of each aspect of the invention may be as described in connection with any of the other aspects. Other features of the present invention will become apparent from the following examples. Generally speaking, the invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including the accompanying claims and drawings). Thus, features, integers, characteristics, compounds or chemical moieties described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. Moreover, unless stated otherwise, any feature disclosed herein may be replaced by an alternative feature serving the same or a similar purpose. The Invention will now be described by way of example only with reference to the Examples below and to the following Figures wherein: Figure 1: Schematic representation of a portion of the glycosphingolipid synthetic pathway, demonstrating the GCS catalyzed step that is inhibited by Miglustat (IC50 = 5-50 µM). Figure 2: Patient plasma (A, 6 ^M) and cerebrospinal fluid (B, 0.6 ^M) concentrations of miglustat take 2-4 weeks and 6-12 months respectively to rescue endocytic ganglioside GM1 transport defects. Transport from the endolysomes to Golgi was measured with cholera toxin B subunit (CtxB) in live cells, in immortalised NPC1 null astrocytes CtxB is trapped in punctate lysosomes, whereas in healthy cells it is transported to the perinuclear crescent shaped Golgi. (A) With plasma concentration (6 ^M), ganglioside GM1 levels are reduced at 2 weeks post-treatment with lysotracker fluorescence showing a concomitant decrease in lysosomal volume. Endocytosis (CtxB live) is normalised 4 weeks after treatment with visible peri-nuclear Golgi staining (white arrows) similar to the wild-type control and in contrast to the punctate staining network observed in the untreated NPC1 null astrocytes. However, no reduction in cholesterol storage is observed with either concentration at any timepoint. (B) With cerebrospinal fluid concentration (0.6 ^M), the cerebrospinal fluid concentration does not improve endocytosis of CtxB at 6 months post-treatment but does normalise trafficking to the perinuclear Golgi in immortalised NPC null astrocytes at 12 months. Again, there is no impact on cholesterol storage. Figure 3: Market Approved and in trial iminosugar APIs. Miglustat (i), approved for the treatment of severe LSDs, i.e. Gaucher and Niemann-Pick type C diseases; (ii) Migalastat, approved for the treatment of Fabry disease; Miglitol (iii), approved for the treatment of type II diabetes mellitus;Sinbaglustat (iv), under clinical trial for the treatment of LSDs; and Lucerastat (v), under clinical trial for the treatment of LSDs. Figure 4: Synthesis of Miglustat Prodrugs (4a-d). Reagents and conditions: THF, room temperature, 12-14 hrs under Ar(g). Yields: 4a: 18%; 4b: 9%; 4c: 5%; 4d: 13%. Figure 5: Toxicity of Miglustat Prodrugs (4a-d). Resazurin assay demonstrating untreated control and NPC1 mutant human fibroblasts alongside those treated with 1, 10, 25 and 50 µM of miglustat prodrug 4a (MGO1) for 7 days. Data is displayed as averages ± SEM and was analysed using two-way ANOVA. N = 3. Figure 6: Inhibition of GBA1 and GBA2 in control human fibroblast homogenate by migulstat and prodrugs of miglustat. Compound 4a (‘MG01’) and compound 4c (Pro-Mig M3 / MGO3), avoid GBA2 inhibition (measured using 4MU substrate with and without CBE) caused by the parental miglustat molecule. Miglustat inhibits GBA2 at 100nM, 1 ^M, 10 ^M, 25 ^M and 50 ^M whereas prodrugs of miglustat Pro-Mig M3 or MGO1 have no effect on either GBA1 or GBA2. Figure 7: Miglustat prodrugs reduce ganglioside (GSL) and globoside Gb3 / Gb4 storage in NPC1 patient skin fibroblasts at 10-50µM after 3 days incubation. (A) Ganglioside GM1 measured in fixed cells with cholera toxin following incubation with Compound 4a. (B) Miglustat has no beneficial effect on NPC1 patient skin cells at these concentrations at this timepoint on either ganglioside GM1 measured using cholera toxin or on globoside Gb3 / Gb4 storage ((C) & (D)) measured using Shiga toxin. ((E) & (F)) prodrug compound 4a (MGO1) reduces globoside Gb3 / Gb4 storage in NPC1 patient skin cells at 20 and 30 ^M over a 3 day incubation. Figure 8. Lysosomal volume, measured using Lysotracker (A), is reduced back to healthy control levels following a 3-day incubation with Compound 4a (B). Elevated lysotracker in NPC1 patient fibroblasts is not reduced by miglustat treatment (10- 30 ^M, 3 days, (C) & (D)). Figure 9. Miglustat prodrugs 4c and 4d (all other prodrugs behave analagously) do not inhibit gut dissacharidases at in vivo concentrations, in stark contrast to miglustat per se. Figure 10. Effect of Miglustat and miglustat prodrug treatment on Batten Disease (CLN3) 1kb deletion cells. Cells were stained with Lysotracker, CytoID, Magic Red – Cathepsin B and CtxB following treatment with 20 µM miglustat or Miglustat Prodrug 4c (‘Pro-M3’). Data analysed using one-way ANOVA Dunnett’s post-hoc test (vehicle comparison). Error bars represent SD. Figure 11. Effect of Miglustat and miglustat prodrug treatment on Batten Disease (CLN2) fibroblasts. Cells were stained with Lysotracker, CytoID, and Magic Red – Cathepsin B following treatment with 20 µM Miglustat Prodrug 4a (‘Pro-M1’). Figure 12. Effect of Miglustat and Pro-Miglustat treatment on PD / GBA1 mutant heterozygous patient cell line. Cells were stained with Lysotracker and CytoID following treatment with 20 µM Miglustat or Pro Miglustat 4a. Figure 13. Effect of Miglustat and Pro-Miglustat treatment on HD ST14A Q120 cells. Cells were stained with Lysotracker and CytoID following treatment with 20 µM Miglustat or Pro Miglustat 4a. Figure 14. Effect of Miglustat and Pro-Miglustat treatment on CH0066 (WT) and CH0067 (HD) fibroblast cells. Cells were stained with Lysotracker and CytoID following treatment with 20 µM Miglustat or Pro Miglustat 4a. Figure 15. Effect of Miglustat and Pro-Miglustat treatment on WT and Alzheimer’s Disease (APP v717, PSEN1) cells. Cells were stained with LysoTracker, CytoID and Cathepsin B following treatment with 20 µM Miglustat or Pro Miglustat 4a. Figure 16. Effect of Miglustat and Pro-Miglustat treatment on WT and Down Syndrome (DS) fibroblasts. Fibroblasts were stained with LysoTracker, CytoID and Cathepsin B following treatment with 20 µM Miglustat or Pro Miglustat 4c (‘ProMig3’) for 72 hours. Figure 17. Effect of Miglustat and Pro-Miglustat treatment on SCA (SCA1 and SCA3) cells. Cells were stained with LysoTracker and CytoID following treatment with 20 µM Miglustat or Pro Miglustat 4a. Figure 18. Pro-miglustat 4c activates nuclear translocation of TFE3 - Effect of Miglustat and Compound 4c on WT human fibroblasts. Cells were stained with TFE3 antibody and Hoechst nuclear counterstain following treatment with 50 µM Miglustat or Pro-Miglustat 4c for 72 hours. Figure 19. Pro-Miglustat 4c activates nuclear translocation of TFE3 at ~10-40 fold lower concentration compared to miglustat. Human fibroblast control cells were grown in presence of indicated concentrations of either miglustat or pro-Miglustat 4c (‘pro- mig 3’) for 72h prior to fixation and staining with initially anti-TFE3 antibody followed by Alexa Fluor 488 secondary antibody and Hoechst nuclear counterstain. Table 1: Summary of pharmacodynamic properties of Miglustat and Miglustat Prodrugs 4a, 4b, 4c and 4d. MATERIALS AND METHODS All reagents and solvents were of general purpose or analytical grade and were purchased from Sigma-Aldrich Ltd., Fisher Scientific, Fluorochem or Acros.31P,1H and13C NMR data were recorded on a Bruker Avance DPX500 spectrometer operating at 202, 500 and 125 MHz. Chemical shifts (δ) are quoted in ppm, and J values are quoted in Hz. In reporting spectral data, the following abbreviations were used: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), td (triplet of doublets), and m (multiplet). All reactions were carried out under nitrogen atmosphere and were monitored with analytical thin layer chromatography (TLC) on pre-coated silica plates (kiesel gel 60 F254, BDH). Compounds were visualized by illumination under UV light (254 nm) or using KMnO4stain followed by heating. Flash column chromatography was performed with silica gel 60 (230−400 mesh) (Merck). Analytical HPLC was performed on a Thermo Fisher Spectra system 4000 using a RP C-18 column Varian Pursuit, 150 mm × 4.6 mm, 5.0 μm with detection wavelength was 220 nm Mobile phases: Eluent A = H2O (+ 0.1% HClO4), Eluent B = Acetonitrile, gradient [time (min.) / % eluent B]: (0 / 50, 20 / 85, 22 / 85, 24 / 100, 25 / 100, 28 / 50), flow rate: 0.8 mL / min.Mass spectra (HRMS) were determined as a service by the School of Chemistry at Cardiff University. Example 1: Synthesis of aryloxy and amino acid ester masked Miglustat prodrug compounds (4a, 4b, 4c, 4d) Miglustat-based Prodrug compounds of General Formula (V) in which R11 is H, y is 3 and R3represents n-butyl were prepared by a synthetic Grignard method. In particular, the synthesis of Compounds 4a, 4b, 4c and 4d which is summarised schematically in Figure 4, was achieved by the addition of 1M tertbutylMgCl 2 and a phospochloridate (amino acid ester) 3a, 3b, 3c or 3d to the commercially available LSD therapeutic Miglustat 1. The product of this reaction yielded Prodrugs 4a, 4b, 4c and 4d in moderate yields (5-18%). A phenol motif was chosen for the aryloxy masking group during the synthesis of each of prodrug Compounds 4a, 4b, 4c and 4d. L-alanine was used as the amino acid of choice in the synthesis of Prodrugs 4a and 4b, whereas glycine and leucine were used in Prodrugs 4c and 4d, respectively. The phenol motif was chosen for the aryloxy masking group for all prodrug Compounds. Four different ester motifs were chosen in the synthesis of the miglustat Prodrugs – 4a: benzyl; 4b: isopropyl (iPr); 4c: methyl; and 4d: ethyl. Further details of the above synthesis can be found in the appendix. Example 2: Toxicity study of Miglustat Prodrug Compounds in NPC1 Patient Cells The effect of Miglustat Prodrugs on cellular toxicity was assessed using the standard resazurin cell viability assay, to fluorescently quantify the viability of control and compound heterozygous NPC human patient fibroblasts, following 7-day treatment with from 1 to 50 µM of a Miglustat Prodrug. The results for using Compound 4a are provided in Figure 5. No substantive variation in results was observed for Compounds 4b, 4c or 4d. These results clearly demonstrate that the Miglustat Prodrugs are non-toxic in both control and NPC patient cells. Further, as shown in Figure 6, the Prodrugs, as exemplified using Compound 4a (‘MG01’), avoid GBA2 inhibition caused by the parental miglustat molecule. This therefore, shows that the prodrug passes through the plasma membrane, where GBA2 is localised, before releasing the API (confirmed by proof of target engagement to lower GSL by inhibition of GlcCer synthase, Fig 7A & E). Accordingly, it is expected that delivering iminosugar APIs in this prodrug form will result in improved BBB penetrance due to a reduced interaction with the glycocalyx. Example 3: Proof of mechanism and proof of concept of Miglustat Prodrug Compounds in Nieman Pick C (NPC1) cells on glycosphingolipid (GSL) storage The data presented in Figures 7 and 8 clearly demonstrate that Miglustat prodrugs reduce ganglioside and globoside (GSL) storage and faciliate a return to normal lysosomal volume in NPC1 patient skin fibroblasts at 10-50µM after 3 days incubation, significantly outperforming miglustat per se, which takes 5 days at a 50µM dose, to achieve a comparable effect (te Vruchte et al 2004) and as shown here has no effect at 10-30 ^M over 3 days incubation. Example 4: Miglustat Prodrugs reduce Off-target adverse effects associated with iminosugar APIs As shown in Figure 9, the prodrug Compounds 4c (‘MG03’) and 4d (‘MG04’) clearly do not inhibit gut disaccharidases at typical in vivo concentrations (NB the typical gut concentration of miglustat in a treated subject is 25-50 µM). This is in stark contrast to miglustat, which at 50 µM is shown to inhibit these enzymes down to 15-50% of the untreated control. Accordingly, it is expected that delivering iminosugar APIs in this prodrug form will substantially reduce, and most likely eliminate, the occurrence of undesirable side effects, in particular osmotic diarrohea and other gut-related side effects which are observed in approximately 80% of patients and are attributable to the inhibition of these carbohydrate-metabolizing glucosidases in the GI-lumen. Example 5: Additional proof of concept / Therapeutic Efficacies of Miglustat Prodrug Compounds (Batten Disease) Batten disease (also known as neuronal ceroid lipofuscinoses; NCL) constitutes a family of devastating LSDs that collectively represent the most common inherited paediatric neurodegenerative disorders worldwide. These disorders are phenotypically characterised by visual impairment and blindness, cognitive and motor decline, seizures and premature death. In terms of pathology, they are characterised by lysosomal accumulation of lipid material, glial reactivity and neuronal loss. The data shown in Figure 10 clearly demonstrates that Batten Disease (CLN3) 1kb deletion cells (n=3 / treatment) showed a significant 8.3-fold increase in LysoTracker staining compared to WT vehicle. However, this was reduced to only 2-fold WT levels following Pro-Miglustat (Compound 4c) treatment and 4.5-fold following Miglustat treatment. Autophagy regulation, as evidenced using Cyto-ID Autophagy detection kit, appeared unaffected by treatment with either Miglustat or Pro-Miglustat (4c) and remained between 3.2-3.4-fold higher than WT vehicle cells. Cathepsin B staining showed a gradual increase in this lysosomal cysteine protease occurs following Miglustat treatment(1.7-fold higher vs WT Vehicle), with a significant 2.4-fold increase compared to WT Vehicle observed upon treatment with Pro- Miglustat 4c. In consideration with the data shown in figure 10, it is clear that the elevated cathepsin B activity and unaffected autophagy is likely due to activation of transcription of lysosomal and autophagic vacuole genes, which is confirmed in figure 19 by the induction of nuclear translocation of TFE3. Further, ganglioside GM1 levels (CtxB) are increased 1.7-fold in CLN31kb deletion cells compared to normal controls. However, this increase appeared to reduce back to control levels following both Miglustat and Pro-Miglustat (4c) treatment. The data shown in Figure 11 indicates that CLN2 fibroblasts showed a similar pattern of events as observed in CLN3 1kb deletion cells following treatment with Pro- Migustat (4a). Notably, Pro-Miglustat (4a) treated CLN2 cells showed a 26% reduction in lysotracker staining compared to CLN2 vehicle-treated cells. However, it is also noted that there was a 1.5 fold increase in CytoID staining in Pro-Miglustat (4a) treated cells compared to CLN2 vehicle treated cells, which we further attribute to activation of TFE3 nuclear translocation incurred by the prodrug. Example 6: Additional Therapeutic Efficacies of Miglustat Prodrug Compounds (Gaucher Disease and GBA1 associated Parkinson Disease) Parkinson’s Disease is the second most common form of neurodegeneration worldwide, affecting 2-3% of the population over the age of 65. GBA mutations are the most common known genetic cause of Parkinson's disease (PD), present in 2-30% of PD patients. Further, its biological pathway may be important in idiopathic PD, since activity of the enzyme encoded by GBA1, is reduced even among PD patients without GBA1 mutations. Mutations of GBA1 are also associated with Gaucher’s disease, whereby Miglustat is already used as a treatment. Patient cells heterozygous for the N370S GBA1 mutation (+ / N370S) associated with PD, were used as model cells to test the potential effect of miglustat and the Pro- Miglustat compounds of the invention in the treatment of such GBA1 associated disorders. The data shown in Figure 12 indicates that the GBA-PD cells show a significant increase in both LysoTracker and CytoID staining compared to WT vehicle. However, this increase is dramatically reduced towards WT levels following Pro-Miglustat or Miglustat treatment. Example 7: Additional Therapeutic Efficacies of Miglustat Prodrug Compounds (Huntingdon’s Disease) Huntington's disease (HD) is a rare, inherited disease that causes progressive neurodegeneration and results in movement issues, cognitive decline and psychiatric issues. HD symptoms generally develop when people are in their 30s or 40s, however, early-onset (or juvenile) Huntington's disease can develop pre-20’s and progresses faster. Medications are available to help manage the symptoms of HD, but no treatments are currently available to prevent the physical, mental and behavioural decline associated with the condition. Rat striatal cell line bearing the Huntington disease gain of function mutation in Huntingtin carrying Q120 polyglutamine repeats were used initially as model cells to test the potential effect of miglustat and Pro-Miglustat 4a compounds of the invention in the treatment of HD. CH0066 (WT) and CH0067 (HD) patient fibroblast cells were also used in subsequent experiments. The data shown in Figures 13 and 14 demonstrate that both Q120 (HD) and CH0067 (HD) cells show a significant increase in both LysoTracker and CytoID staining compared to WT vehicle. However, this increase is substantially reduced towards WT levels following Pro-Miglustat (4a) or Miglustat treatment. Example 8: Additional Therapeutic Efficacies of Miglustat Prodrug Compounds (Alzheimer’s Disease) Alzheimer’s disease (AD) is an age related-disorder affecting 1:5 people over 65 and 1:3 over 80 years of age. It is clinically characterized by a gradual decline in cognitive function, loss of speech, motor co-ordination and results in total care required for the individual. Pathologically, AD is caused by the mis-processing of the amyloid precursor protein (APP) causing the generation of neurotoxic oligomeric β-amyloid (Aβ) and subsequential upregulation of neuroinflammation and dysregulation of tau phosphorylation. Lysosomal and autophagy dysregulation and GSL accumulation has also been reported in AD, believed to be caused by the accumulation of APP C- terminal fragments. Recent research in mouse models of AD have also suggested that inhibition of GlcCerSyn can alleviate pathology and behavioural impairments. APP v717 and PSEN cells were used as model cells to test the potential effect of miglustat and Pro-Miglustat 4a of the invention in the treatment of AD. The data shown in Figure 15 demonstrate that both APP v717 and PSEN cells show a significant increase in LysoTracker, CytoID and Cathepsin B staining compared to WT vehicle. However, each of these increases is substantially reduced towards WT levels following Pro-Miglustat (4a) or Miglustat treatment. Example 9: Additional Therapeutic Efficacies of Miglustat Prodrug Compounds (Down Syndrome) Down Syndrome (DS), which is caused by a triplication of Chromosome 21, which includes the gene encoding APP, occurs in around 1:1000 births in the UK. Disease symptoms include learning and memory problems, congenital heart defects, delayed speech and movement development and reduced life span (although 50% of patients now live to 50-60 years of age). Patient cells have been shown to present with lysosomal acidification defects and mis-trafficking of lipids in the endocytic system. There is currently no cure or pharmacological treatment targeting the disease mechanisms for Down Syndrome (DS) Fibroblasts obtained from a DS patient (2 yr old) were used as model cells to test the potential effect of miglustat and Pro-Miglustat Compound 4c in the treatment of Down Syndrome. The data shown in Figure 16 demonstrate that DS fibroblasts show a significant increase in LysoTracker, CytoID and Cathpesin B staining compared to WT vehicle. However, each of these increases is reduced towards WT levels following Miglustat treatment, with the reduction being far more pronounced following treatment with the Pro-Miglustat Compound 4c. Example 10: Additional Therapeutic Efficacies of Miglustat Prodrug Compounds (Spinocerebellar ataxia) The spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of autosomal dominantly inherited progressive disorders, the clinical hallmark of which is loss of balance and coordination accompanied by slurred speech, for which there is currently no effective treatment.12 forms of SCA are caused by dynamic repeat expansion mutations, 6 of these are caused by CAG repeats, including SCA3 and SCA6. Further, Autophagy dysregulation has been reported in SCA1 and is likely to occur in other forms of SCA. SCA1 and SCA3 patient cells were used as models to test the potential effect of miglustat and Pro-Miglustat 4a of the invention in the treatment of SCA. The data shown in Figure 17 demonstrate that both SCA1 and SCA3 cells show a significant increase in LysoTracker and CytoID staining compared to WT vehicle. However, each of these increases is substantially reduced towards WT levels following Pro-Miglustat (4a) or Miglustat treatment. Example 11: Activation of TFE3 nuclear Translocation by Miglustat Prodrug Compounds Lysosomal dysfunction is now an accepted feature / hallmark of a number of common neurodegenerative diseases with GSL storage observed in post-mortem human brain or in mouse model tissues. The above examples have shown that both miglustat and the Pro-Miglustat compounds of the present invention are able to rescue lysosomal dysfunction across a host of neurodegenerative diseases. However, the above data, in particular the increased cathepsin enzyme levels observed in treated CLN31kb deletion cells, could suggest that the Pro-Miglustat compounds could provide an alternative, or improved, mode of action compared to Miglustat per se. For example, noting that TFEB and the associated gene TFE3 encode transcription factors whose translocation into the nucleus in response to stress or other factors drives the transcription of lysosomal genes, it is hypothesized that such Prodrug compounds (as opposed to the active pharmaceutical per se) could induce TFEB or TFE3 nuclear translation, thus driving lysosomal gene transcription and, as a consequence, stimulate lysosomal function. To test this hypothesis, wild type human fibroblast cells were grown in the presence of Miglustat or Pro Miglustat 4c for 72 hours prior to fixation and staining with anti- TFE3 antibody followed by Alexa Fluor 488 secondary antibody and Hoechst nuclear counterstain. These results, which are shown in Figures 18 and 19, show that both Miglustat and Miglustat prodrugs can activate nuclear translocation of the transcription factor TFE3 at high (i.e. non-physiological) concentrations. Moreover, the data presented in Figure 19 compares the effect on TFE3 translocation at a concentration shown in the cerebrospinal fluid of a Niemann Pick Type C patient (Lachmann et al, Neurobiology of Disease 2005) equivalent to 1.25 ^M and at a concentration that might be achievable in the periphery at a high oral dose (equivalent to 5 ^M). Surprisingly, Miglustat was found to reduce the nuclear staining of TFE3 at 1.25 ^M, presumably as it has a potent inhibitory effect on GBA2 at this concentration and no impact on GCS. However, in comparison, Pro-Miglustat Compound 4c was found to increase nuclear translocation of TFE3 at 1.25 ^M, and this effect which shown to persist with increasing concentration to 5 ^M. This indicates that the absence of GBA2 inhibition by Pro-Miglustat compounds such as Compound 4c allows a greater therapeutic effect via combined reduction in glycolipid biosynthesis and an increased lysosomal gene transcription elicited by nuclear translocation of TFE3. Summary We report the synthesis of novel iminosugar prodrug compounds. These prodrug compounds exhibited low toxicity and efficacy against LSDs, neurodegenerative disorders and Down Syndrome. Further, by masking the iminosugar API, well documented adverse effects associated with miglustat (and other iminosugar APIs), including diarrhea and other gut-related issues in approximately 80% of patients due to inhibition of carbohydrate-metabolizing glucosidases in the GI-lumen, can be minimized or even eliminated. This combination of properties makes them suitable for development as new therapeutics for treating a variety of conditions, including LSDs, neurodegenerative disorders and Down Syndrome. Table 1 Appendix: Synthesis and evaluation of Miglustat Prodrug Compounds 4a-d Phosphorochloridate Synthesis Standard Procedure To a stirred solution of the appropriate amino acid ester salt (1 equivalent) and the appropriate aryl dichlorophosphate (1 equivalent) in anhydrous CH2Cl2was added dropwise at -78 ^C anhydrous Et3N (2 equivalents). Following the addition, the reaction mixture was stirred at -78 ^C for 30 min and then at room temperature for 1 h. Formation of the desired compound and disappearance of the starting material was monitored by31PNMR. After this period the solvent was removed under reduced pressure to give an oil. Most of the aryl phosphorochloridate synthesised were purified by flash column chromatography on silica gel (eluting with hexane - ethyl acetate 70:30 v / v). benzyl (chloro(phenoxy)phosphoryl)-L-alaninate (for MG01) Followed the general procedure using 7 (0.35 mL, 3.32 mmol, 1 equiv.), Et3N (0.63 mL, 4.64 mmol, 2 equiv), and L-alanine benzyl ester hydrogen chloride (0.5 g, 2.32 mmol, 1 equiv) to give phosphorochloridate MG01 (0.505 g, 95%). δHNMR (300 MHz, CDCl3): 7.42–7.32 (m, 7H, Ph), 7.25–7.20 (m, 3H, Ph), 5.21 (2s, 2H, CH2), 4.34–4.15 (m, 2H, CH and N-H), 1.52 (dd, J = 6.6, 2.4 Hz, 3H, CH3). δCNMR (101 MHz, CDCl3): 172.52 (dd, J = 11.6, 8.7 Hz), 149.75 (dd, J = 11.6.8.7 Hz), 135.05 (d, J = 5.8 Hz, C- 10), 129.92, 128.68, 128.59, 128.33, 125.99, 120.57, 67.60, 50.67, 20.47 (t, J = 4.5 Hz). δP NMR (121 MHz, CDCl3): 7.49, 7.85. Isopropyl (Chloro(phenoxy)phosphoryl)-l-alaninate (for MG02) Colorless oil; 99%, 8.36 g. 31P NMR (202 MHz, CDCl3, mixture of Rp and Sp diastereoisomers, a / b): δP 8.09 (1P), 7.71 (0.9) ppm.1H NMR (500 MHz, CDCl3): δH7.39–7.36 (m, 2H, CH-Ph), 7.28–7.22 (m, 3H, CH-Ph), 5.10–5.05 (m, 1H, CH(CH3)2), 4.16–4.08 (m, 1H, NHCHCO), 1.50 (dd, 3H, J = 2.4, 7.1 Hz, NHCHCH3), 1.30–1.26 (m, 6H, CH(CH3)2) ppm. methyl (chloro(phenoxy)phosphoryl)glycinate (for MG03) Prepared according to Standard Procedure 1 with 78% yield as a mixture of two stereoisomers (SSp and SRp). Light yellow oil; 2.30 g.31P NMR (202 MHz, CDCl3): δP 9.08 ppm.1H NMR (500 MHz, CDCl3): δH 7.42–7.36 (m, 2H, CH-Ph), 7.09–6.81 (m, 3H, CH-Ph), 4.43−4.40 (br,1H, NH), 4.00 (dd, 2H, J = 4.2, 9.7 Hz, NHCH2CO), 3.80 (s, 3H,COOCH3) ppm. Ethyl (Chloro(phenoxy)phosphoryl)-l-leucinate (for MG04) Prepared according to Standard Procedure 1 with 98% yield as a mixture of two diastereoisomers (SSp and SRp). Colorless oil; 4.20 g.31P NMR (202 MHz, CDCl3CDCl3): δP 8.51 (1P), 8.27 (1P) ppm.1H NMR (500 MHz, CDCl3): δH 7.38–7.34 (m, 2H, CH-Ph), 7.27–7.21 (m, 3H, CH-Ph), 4.34–4.19 (m, 3H, NH, OCH2CH3), 4.14–4.02 (m, 1H, NHCHCO), 1.86 (spt, 0.5H, J = 6.6 Hz, CHa(CH3)2), 1.79 (spt, 0.5H, J = 6.6 Hz, CHb(CH3)2), 1.64–1.59 (m, 2H, CHCH2CH), 1.30–1.26 (m, 3 H, OCH2CH3), 0.96–0.93 (m, 6H, CH3CHCH3) ppm. Phosphoramidate Synthesis Using tBuMgCl Standard Procedure tBuMgCl (1 equivalent) was added dropwise to a solution of miglustat ((1 equivalent) in 5 anhydrous THF (7 ml) under anhydrous conditions and cooled to -20 degrees C. The mixture was stirred at room temperature for one hour. After this time the appropriate phosphorochloridate (1 equivalent) in anhydrous THF (2 ml) was added dropwise to the stirring reaction mixture. The reaction was left to stir for 24 hours and then the solvent was removed in vacuo and the desired product was dry-loaded to a column and isolated10 using flash chromatography (eluting with methanol – dichloromethane 0:100 v / v increasing to 10:90 v / v) benzyl(phenoxy(((2R,3R,4R,5S)-3,4,5-trihydroxy-1-propylpiperidin-2- yl)methoxy)phosphoryl)-L-alaninate.4a {MG 01(KS04)} Prepared according to the tBuMgCl standard procedure, from 50 mg of miglustat and obtained in 20% yield as a mixture of diastereoisomers (SSp and SRp). Colorless oil; 22 mg.31P (202MHz, CD3OD) dP3.89, 3.66 ppm;1H (500 MHz, CD3OD); dH7.26-7.20 (m, 7H, Ar), 7.11-7.05 (m, 3H, Ar), 5.12-5.11 (m, 2H, CH2Ph), 4.37-4.32 (m, CH2aOP), 4.27-4.24 (m, CH2bOP), 3.95-3.89 (m, 1H, H2), 3.40-3.35 (m, 2H, H4,H3), 3.08-3.04 (m, 1H, CHaa), 2.91 (dd, 1H, J = 4.3, 10.8 Hz, CH2aN), 2.71-2.65 (m, 1H, NCH2a), 2.47- 2.39 (m, 1H, NCH2b), 2.22-2.15 (m, 1H, CH2bN), 2.11-2.02 (m, 1H, H5), 1.35-1.14 (m, 7H, CH3aa; CH2CH2CH3), 0.82-0.79 (m, 3H, CH2CH2CH3). Isopropyl(phenoxy(((2R,3R,4R,5S)-3,4,5-trihydroxy-1-propylpiperidin-2- yl)methoxy)phosphoryl)-L-alaninate.4b {MG 02 (KS-09)} Prepared according to the tBuMgCl standard procedure, from 50 mg of miglustat and obtained in 10% yield as a mixture of diastereoisomers (SSp and SRp). Colorless oil; 11 mg;31P (202MHz, CD3OD) dP3.85, 3.70 ppm;1H (500 MHz, CD3OD); dH7.27-7.23 (m, 2H, Ph), 7.23-7.12 (m, 2H, Ph), 7.10-7.06 (m, 1H, Ph), 4.42-4.34 (m, CH2aOP), 4.30-4.23 (m, CH2bOP), 4.05-3.98 (m, 2H, CHaa, CH(CH3))3.81-3.74 (m, 1H, H2), 3.39- 3.34 (m, 1H, H4), 3.18 (1H overlap with solvent, H3), 3.07-3.03 (m, 2H, CH2aa), 2.90 (dd, 1H, J = 4.3, 10.8 Hz, CH2aN), 2.75-2.75 (m, 1H, NCH2a), 2.50-2.38 (m, 1H, NCH2b), 2.22-2.16 (m, 1H, CH2bN), 2.09-2.02 (m, 1H, H5), 1.52-1.31 (m, 2H, CH2CH2CH3), 1.23-1.17 (m, 2H, CH2CH2CH3), 1.15-1.11 (m, 3H, CHCH3), 0.85- 0.71(m, 9H, (CHCH3)2;CH2CH3). Methyl(phenoxy(((2R,3R,4R,5S)-3,4,5-trihydroxy-1-propylpiperidin-2- yl)methoxy)phosphoryl)glycinate.4c {MG 03- (KS-11)} Prepared according to the tBuMgCl standard procedure, from 50 mg of miglustat and obtained in 5% yield as a mixture of diastereoisomers (SSp and SRp). Colorless oil; 5 mg; 31P (202MHz, CD3OD) dP 4.97, 4.87 ppm;1H (500 MHz, CD3OD); dH 7.28-7.25 (m, 2H, Ph), 7.16-7.08 (m, 3H, Ph), 4.39 (d, 1H, J = 5 Hz, H6a), 4.38 (d, 1H, J = 5 Hz, H6b), 3.61, (s, 3H, OMe), 3.46-3.38 (m, 1H, H2), 3.30-3.23 (m, 1H, H4), 3.20 (1H overlap with solvent,H3), 3.13-3.07 (m, 2H, CH2aa), 3.00 (dd, 1H, J = 5.3, 11.6 Hz, CH2aN), 2.79-2.74 (m, 1H, NCH2a), 2.57-2.49 (m, 1H, NCH2b), 2.36-2.34 (m, 1H, CH2bN ), 2.26-2.10 (m, 1H,H5), 1.43-1.34 (m, 2H, CH2CH2CH3), 1.25-1.17 (m, 2H, CH2CH2CH3), 0.83 (t, 3H, J = 7.5 Mhz, CH2CH3). Ethyl(phenoxy(((2R,3R,4R,5S)-3,4,5-trihydroxy-1-propylpiperidin-2- yl)methoxy)phosphoryl)-L-leucinate.4d {MG04 (KS-12)} Prepared according to the tBuMgCl Standard Procedure, from 50 mg of miglustat and obtained in 13% yield as a mixture of diastereoisomers (SSp and SRp). Colorless oil; 16 mg;31P (202MHz, CD3OD) dP4.20, 3.90 ppm;1H (500 MHz, CD3OD); dH7.26-7.23 (m, 2H, Ph), 7.14-7.12 (m, 2H, Ph), 7.10-7.06 (m, 1H, Ph), 4.42-4.34 (m, CH2aOP), 4.30-4.23 (m, CH2bOP), 4.05-3.99 (m, 2H, CH2CH3), 3.81-3.71 (m, 1H, H2), 3.39-3.34 (m, 1H, H4), 3.21-3.02 (1H overlap with solvent, H3), 3.08-3.03 (m, 1H, CHaa), 2.90 (dd, 1H, J = 4.3, 10.8 Hz, CH2aN), 2.75-2.66 (m, 1H, NCH2a), 2.50-2.38 (m, 1H, NCH2b), 2.22-2.16 (m, 1H, CH2bN), 2.09-2.02 (m, 1H, H5), 1.69-1.64 (m,0.5H, CHCH2b, 1 diast.), 1.51-1.47 (m, 0.5H, CHCH2b, 1 diast.) 1.45-1.33 (m, 3H, CH2CH2CH3; CH(CH3)2; CHCH2a), 1.23-1.16 (m, 2H, CH2CH2CH3), 1.15-1.11 (m, 3H, CH2CH3), 0.85-0.71 (m, 9H, (CH(CH3)2; CH2CH3).

Claims

CLAIMS 1. A compound according to General Formula (I) or General Formula (II), including all tautomers thereof:II) wherein: R1 and R2 each independently represents an amino acid ester radical according to General Formula (III) or an aryloxy radical according to General Formula (IV):V) wherein R4represents H, or a saturated or unsaturated and optionally substituted C1-4alkyl group; R5represents a saturated or unsaturated and optionally substituted C1-4alkyl or C6-10aryl group; and R6represents an optionally substituted C6-18aryl or a 6 to 18 membered heteroaryl group; x is 0, 1, 2 or 3; y is 0, 1, 2, 3 or 4; R3represents H or an optionally substituted C1-20 alkyl group; and R11 represents H, an optionally substituted C1-4 alkyl group or an optionally substituted C2-4 acyl group; or any salt thereof.

2. A compound according to claim 1, wherein said compound is of General Formula (V) or General Formula (IV), wherein x, y, R3, R4R5, R6and R11are as defined in claim 1: V)VI) 3. A compound according to claim 1 or claim 2, wherein y is 2 or 3 and / or x is 1 or 2.

4. A compound according to any of the preceding claims, wherein R3represents a group selected from: pentyl, butyl, hydroxyethyl or hydrogen.

5. A compound according to claim 4, wherein said compound is a compound of General Formula (VII), (VIII), (XI) or (X), wherein R4R5, R6and R11are as defined in claim 1: (VII)(VIII) (IX) (X) 6. A compound according to claim 5, wherein said compound is selected from: a D-gluco compound according to General Formula (VII-A) to (X-A); a L-ido compound according to General Formula (VII-B) to (X-B); and a D-galacto compound according to General Formula (VII-C) to (X-C), wherein R4, R5, R6and R11are as defined in claim 1:

7. A compound according to any of the preceding claims, wherein R4 represents a group selected from: hydrogen; methyl; propyl, preferably isopropyl; and butyl, preferably isobutyl or sec-butyl.

8. A compound according to any of the preceding claims, wherein R5represents a group selected from benzyl; ethyl; and propyl, preferably isopropyl.

9. A compound according to any of the preceding claims, wherein R6represents a C6aryl group, preferably phenyl.

10. A compound according to claim 1, selected from:and D-gluco, L-ido or D- galacto configured derivatives thereof11. A process for the preparation of a compound according to any one of the preceding claims, said process comprising reacting a compound of General Formula (XI) with an iminosugar compound of General Formula (XII) or General Formula (XIII) in the presence of a Grignard reagent of General Formula (XIV) to prepare a compound of General Formula (I) or General Formula (II):wherein each of R1, R2, R3and R11are as defined in any of the preceding claims;R12is a halo group; R21is an alkyl or aryl group; and R22is a halo group.

12. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 10 and a pharmaceutically acceptable excipient or carrier.

13. A pharmaceutical composition according to claim 12, formulated for oral administration.

14. A compound according to any one of claims 1 to 10, or a pharmaceutical composition according to claim 12 or claim 13, for use in medicine.

15. A compound or pharmaceutical composition for use according to claim 14, in the treatment of a lysosomal storage disorder.

16. A compound or pharmaceutical composition for use according to claim 15, wherein said lysosomal storage disorder is selected from: Niemann-Pick C1 ; Niemann-Pick type C2; Niemann-Pick types A and B; neuronal ceroid lipofuscinoses (NCL), i.e. Batten disease; mucolipidoses; mucopolysaccharidoses; monosaccharidoses; DHDDS syndrome; lipidoses; and sphingolipidoses such as, Gaucher disease, Fabry disease and Tay- Sachs disease.

17. A compound or pharmaceutical composition for use according to claim 14, in the treatment of a neurodegenerative disorder.

18. A compound or pharmaceutical composition for use according to claim 17, wherein said neurodegenerative disorder is selected from: Huntington’s disease; Alzheimer’s disease; Spinocerebellar ataxia (SCA); or Parkinson’s disease, preferably forms of Parkinsons disease associated with lysosomal risk genes such as GBA1 -associated Parkinson’s disease.

19. A compound or pharmaceutical composition for use according to claim 14, in the treatment of Down Syndrome.

20. Use of a compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 12 or claim 13 in the preparation of an agentfor the treatment of a lysosomal storage disorder, a neurodegenerative disorder, or Down Syndrome.21 . The use according to claim 20, wherein: said lysosomal storage disorder is selected from: Niemann-Pick C1 ; Niemann-Pick type C2; Niemann-Pick types A and B; neuronal ceroid lipofuscinoses (NCL), i.e. Batten disease; mucolipidoses; mucopolysaccharidoses; monosaccharidoses; DHDDS syndrome; lipidoses; and sphingolipidoses such as, Gaucher disease, Fabry disease and Tay- Sachs disease; and / or said neurodegenerative disorder is selected from: Huntington’s disease; Alzheimer’s disease; Spinocerebellar ataxia (SCA); or Parkinson’s disease, preferably GBA1 -associated Parkinson’s disease.

22. A method of treating a lysosomal storage disorder, a neurodegenerative disorder or Down Syndrome, the method comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of claims 1 to 10 or a pharmaceutical composition as defined in claim 12 or claim 13.

23. A method according to claim 22, wherein: said lysosomal storage disorder is selected from: Niemann-Pick C1 ; Niemann-Pick type C2; Niemann-Pick types A and B; neuronal ceroid lipofuscinoses (NCL), i.e. Batten disease; mucolipidoses; mucopolysaccharidoses; monosaccharidoses; DHDDS syndrome; lipidoses; and sphingolipidoses such as, Gaucher disease, Fabry disease and Tay- Sachs disease; and / or said neurodegenerative disorder is selected from: Huntington’s disease; Alzheimer’s disease; Spinocerebellar ataxia (SCA); or Parkinson’s disease, preferably GBA1 -associated Parkinson’s disease.

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