WO2011095772A2 - Novel iminosugar therapeutics - Google Patents

Abstract

Compounds of formula (Ia) or (Ib) find application in treating or preventing: (a) infection; (b) immune disorders; (c) neoplasia; (d) an energy utilization disease; (e) a proteostatic disease; or (f) a lysosomal storage disorder.

Description

NOVEL IMINOSUGAR THERAPEUTICS

Field of the Invention The present invention relates to carbon-branched iminosugars, to compositions (including pharmaceutical compositions) containing them and to methods of treatment and prophylaxis using the compounds and compositions.

Background to the Invention

Around 200 natural products are known that may be described as carbohydrate mimics in which the ring oxygen of a sugar is replaced by nitrogen - but all of them has a linear carbon chain. The pyrrolidine iminosugar DAB, isolated from Arachniodes standishii and Angylocalyx boutiqueanus, shows strong inhibition of a-glucosidases and weaker inhibition of several other glycosidases. Synthetic enantiomers of iminosugars are frequently powerful glycosidase inhibitors; the unnatural enantiomer of DAB (LAB) is a more potent and more specific inhibitor of α-glucosidases. Two N-alkyl derivatives of deoxynojirimycin (DNJ), a naturally occurring a-glucosidase inhibitor, are drugs and have potential for the treatment of a number of diseases. In particular, N-butyl-DNJ (miglustat, Zavesca®, Λ/Β- DNJ partially rescues the defective F508del-CFTR function in CF-KM4 cells and is therefore of interests for the chemotherapeutic treatment of cystic fibrosis.

Carbon branching of iminosugars usually removes the glycosidase inhibition properties; an exception is that a C6 methyl group branch in L-swainsonine which increases the inhibition of naringinase by an order of magnitude in comparison to the parent indolizidine, L- swainsonine (Hakansson et al. (2008) Tetrahedron Lett. 49: 179-184). In contrast to the a- glucosidase inhibition by DNJ and its alkyl derivatives, the branched analogue isofagomine 7 is a potent β-glucosidase inhibitor (Jesperson et al. (1994) Angew. Chem. Int. Ed. 33: 1778-1779; lchikawa et al. (1998) J. Am. Chem. Soc. 120: 3007-3018; Li ef al. (2009) Tetrahedron 65: 3717-3727; Liu et al. (2004) J. Carbohydr. Chem. 23: 223-238.) whereas the ga/acfo-analogue 8 inhibits β-galactosidases (lchikawa et al. (1995) Tetrahedron Lett. 36: 4585-4586; Sohoel et al. (2001 ) J. Chem. Soc, Perkin Trans. 1 : 1584-1585).

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Summary of the Invention

The present inventors have developed an efficient synthesis of various carbon-branched iminosugars, including carbon-branched azetidine and pyrrolidine iminosugars such as the carbon-branched pyrrolidine iminosugar isoDAB [1 ,4-dideoxy-2-hydroxymethyl-1 ,4-imino- D-threitol].

IsoDAB is a potent and specific inhibitor of a number of a-glucosidases and provides the first example of a carbon branched iminosugar pyrrolidine showing significant glycosidase inhibition. DAB is an excellent inhibitor of glycogen phosphorylase and a moderate inhibitor of glycoprotein processing glucosidases, but isoDAB showed no inhibition of these enzymes. The combination of potency and specificity of isoDAB finds application in various methods of treatment, and in particular isoDAB and related carbon-branched iminosugar pyrrolidines are likely to exhibit an improved protective/therapeutic index compared with known pyrrolidine iminosugar therapeutics.

Therefore, in a first aspect of the present invention, there is provided a compound of formula la or lb:

la

wherein n is 0 or 1 ; p is 0 or 1 ;

X is selected from H; OH and F;

Y is selected from H and CH₂X;

R¹ is selected from H; linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl and aralkyi and wherein the optional substitution may be with one or more groups independently selected from: -OH; -F; -CI; -Br; -I; -NH₂; alkylamino;

dialkylamino; linear or branched alkyl, alkenyl, alkynyl and aralkyi; aryl; heteroaryl; linear or branched alkoxy; aryloxy; aralkoxy; -(alkylene)oxy(alkyl); -CN; -N0₂; - COOH; -COO(alkyl); -COO(aryl); -C(0)NH(alkyl); -C(0)NH(aryl); sulfonyl;

alkylsulfonyl; arylsulfonyl; sulfamoyl; alkylsulfamoyl; alkylthio; alkylsulfonamide; arylsulfonamide; -NHNH₂; and -NHOH; or a bioisostere, pharmaceutically acceptable salt or derivative thereof.

In preferred embodiments, R¹ is selected from H, C_1-18 alkyl (for example, d_-9 alkyl, e.g. d. 6 alkyl), C₂.₁₈ alkenyl (for example, C₂-g alkenyl, e.g. C_2-6 alkenyl) and C₂.₁₈ alkynyl (for example, C₂.₉ alkynyl, e.g. C₂.₆ alkynyl). For example, R may be -H and R¹ selected from C_1-18 alkyl (for example, C_1-g alkyl, e.g. C_1-6 alkyl), C_2-18 alkenyl (for example, C₂._g alkenyl, e.g. C_2-6 alkenyl) and C_2-18 alkynyl (for example, C_2-9 alkynyl, e.g. C_2-6 alkynyl). In preferred embodiments, R¹ represents H; C1-15 alkyl, C1-15 alkenyl or C1 -15 alkynyl, optionally substituted with one or more R²; oxygen or an oxygen containing group such that the compound is an N-oxide; C(0)OR³; C(0)NR³R⁴; S0₂NR³; OH, OR³, or formyl. In other embodiments, R¹ may represent C1-9 alkyl, optionally substituted with up to 6 OH, NR³R⁴, aryl, 0-C1-3 alkyl, 0-C1-3 alkenyl, C0₂H, NH(NH)NH₂, CONR³R⁴; C(0)OR³;

C(0)NR³R⁴; or S0₂NR³.

The compounds of formula IE and IG (below) have been described by Bols et al. (1996) Tetrahedron Letters 37: 2097-2100:

Other aspects of the invention are as defined in the claims attached hereto. Detailed Description of the Invention

Definitions and general preferences

Where used herein and unless specifically indicated otherwise, the following terms are intended to have the following meanings in addition to any broader (or narrower) meanings the terms might enjoy in the art:

Unless otherwise required by context, the use herein of the singular is to be read to include the plural and vice versa. The term "a" or "an" used in relation to an entity is to be read to refer to one or more of that entity. As such, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein.

As used herein, the term "comprise," or variations thereof such as "comprises" or

"comprising," are to be read to indicate the inclusion of any recited integer (e.g. a feature, element, characteristic, property, method/process step or limitation) or group of integers (e.g. features, element, characteristics, properties, method/process steps or limitations) but not the exclusion of any other integer or group of integers. Thus, as used herein the term "comprising" is inclusive or open-ended and does not exclude additional, unrecited integers or method/process steps. As used herein, the term "treatment" or "treating" refers to an intervention (e.g. the administration of an agent to a subject) which cures, ameliorates or lessens the symptoms of a disease or removes (or lessens the impact of) its cause(s). In this case, the term is used synonymously with the term "therapy". Additionally, the terms "treatment" or "treating" refers to an intervention (e.g. the administration of an agent to a subject) which prevents or delays the onset or progression of a disease or reduces (or eradicates) its incidence within a treated population. In this case, the term treatment is used synonymously with the term "prophylaxis". The term "subject" (which is to be read to include "individual", "animal", "patient" or

"mammal" where context permits) defines any subject, particularly a mammalian subject, for whom treatment is indicated. Mammalian subjects include, but are not limited to, humans, primates, domestic animals, farm animals, pet animals and rodents such as mice, rats, hamsters and guinea pigs. In preferred embodiments, the subject is a human.

The term "proteostatic disease" is a term of art used to define a set of diseases mediated, at least in part, by deficiencies in proteostasis. The term therefore covers aggregative and misfolding proteostatic diseases, including in particular neurodegenerative disorders (e.g. Parkinson's disease, Alzheimer's disease and Huntington's disease), lysosomal storage disorders, diabetes, emphysema, cancer and cystic fibrosis.

The term "metabolic syndrome" is used herein to define conditions characterized by the presence of three or more of the following symptoms: central obesity (waist measurement of more than 40 inches for men and more than 35 inches for women); high levels of triglycerides (150 mg/dL or higher); low levels of HDL (below 40 mg/dL for men and below 50 mg/dL for women) and high blood pressure (130/85 mm Hg or higher).

The term therefore includes conditions defined in accordance with the definition of metabolic syndrome by the World Health Organization: (a) fasting plasma glucose above 6.1 mmol/L; (b) blood pressure above140/90 mm Hg; and (c) one or more of the following: (i) plasma triglycerides above 1.7mmol/L; (ii) HDL below 0.9 and 1.0 mmol/L (for men and women, respectively); (iii) a body mass index above 30 kg/m².

References herein to the treatment of metabolic syndrome are to be interpreted to include the treatment of any or all of the disorders associated with metabolic syndrome, including in particular obesity (e.g. central obesity) and elevated serum triglycerides.

References herein to the treatment of type 1 or type 2 diabetes are to be interpreted to include the treatment of type 1 and type 2 diabetes per se as well as pre-diabetes (incipient diabetes) and insulin resistance.

The term "pre-diabetes" or "incipient diabetes" defines conditions in which elevated levels of glucose or glycosylated haemoglobin are present in the absence of diabetes. The term pharmacoperone is a term of art (from "pharmacological chaperone") used to define a class of biologically active small molecules (sometimes also referred to in the art as "chemical chaperones") that serve as molecular scaffolds, causing otherwise misfolded mutant proteins to fold and route correctly within the cell. As used herein, the term Λ/Β-DNJ is used sensu stricto to cover N-butyldeoxynojirimycin (a.k.a. Miglustat, Λ/Β-DNJ and Zavesca®), as well as its pharmaceutically acceptable salts and derivatives. However, the term is also used sensu lato to cover various derivatives and analogues of deoxynojirimycin (DNJ) which can restore CFTR function, including for example those described in WO2005/046672 and WO2007/123403 (the disclosure of which relating to the structure of the DNJ derivatives is hereby incorporated by reference). Such DNJ derivatives may have glucosidase inhibitory activity.

As used herein, an effective amount of a compound or composition defines an amount that can be administered to a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, but one that is sufficient to provide the desired effect, e.g. the treatment or prophylaxis manifested by a permanent or temporary improvement in the subject's condition. The amount will vary from subject to subject, depending on the age and general condition of the individual, mode of administration and other factors. Thus, while it is not possible to specify an exact effective amount, those skilled in the art will be able to determine an appropriate "effective" amount in any individual case using routine experimentation and background general knowledge. A therapeutic result in this context includes eradication or lessening of symptoms, reduced pain or discomfort, prolonged survival, improved mobility and other markers of clinical improvement. A therapeutic result need not be a complete cure.

As used herein, the term "combination", as applied to two or more compounds and/or agents (also referred to herein as the components), is intended to define material in which the two or more compounds/agents are associated. The terms "combined" and

"combining" in this context are to be interpreted accordingly.

The association of the two or more compounds/agents in a combination may be physical or non-physical. Examples of physically associated combined compounds/agents include:

• compositions (e.g. unitary formulations) comprising the two or more

compounds/agents in admixture (for example within the same unit dose);

• compositions comprising material in which the two or more compounds/agents are chemically/physicochemically linked (for example by crosslinking, molecular agglomeration or binding to a common vehicle moiety);

• compositions comprising material in which the two or more compounds/agents are chemically/physicochemically co-packaged (for example, disposed on or within lipid vesicles, particles (e.g. micro- or nanoparticles) or emulsion droplets);

• pharmaceutical kits, pharmaceutical packs or patient packs in which the two or more compounds/agents are co-packaged or co-presented (e.g. as part of an array of unit doses);

Examples of non-physically associated combined compounds/agents include:

• material (e.g. a non-unitary formulation) comprising at least one of the two or more compounds/agents together with instructions for the extemporaneous association of the at least one compound/agent to form a physical association of the two or more compounds/agents;

• material (e.g. a non-unitary formulation) comprising at least one of the two or more compounds/agents together with instructions for combination therapy with the two or more compounds/agents; • material comprising at least one of the two or more compounds/agents together with instructions for administration to a patient population in which the other(s) of the two or more compounds/agents have been (or are being) administered;

• material comprising at least one of the two or more compounds/agents in an

amount or in a form which is specifically adapted for use in combination with the other(s) of the two or more compounds/agents.

As used herein, the term "combination therapy" is intended to define therapies which comprise the use of a combination of two or more compounds/agents (as defined above). Thus, references to "combination therapy", "combinations" and the use of

compounds/agents "in combination" in this application may refer to compounds/agents that are administered as part of the same overall treatment regimen. As such, the posology of each of the two or more compounds/agents may differ: each may be administered at the same time or at different times. It will therefore be appreciated that the compounds/agents of the combination may be administered sequentially (e.g. before or after) or

simultaneously, either in the same pharmaceutical formulation (i.e. together), or in different pharmaceutical formulations (i.e. separately). Simultaneously in the same formulation is as a unitary formulation whereas simultaneously in different pharmaceutical formulations is non-unitary. The posologies of each of the two or more compounds/agents in a

combination therapy may also differ with respect to the route of administration.

As used herein, the term "pharmaceutical kit" defines an array of one or more unit doses of a pharmaceutical composition together with dosing means (e.g. measuring device) and/or delivery means (e.g. inhaler or syringe), optionally all contained within common outer packaging. In pharmaceutical kits comprising a combination of two or more

compounds/agents, the individual compounds/agents may unitary or non-unitary formulations. The unit dose(s) may be contained within a blister pack. The pharmaceutical kit may optionally further comprise instructions for use. As used herein, the term "pharmaceutical pack" defines an array of one or more unit doses of a pharmaceutical composition, optionally contained within common outer packaging. In pharmaceutical packs comprising a combination of two or more compounds/agents, the individual compounds/agents may unitary or non-unitary formulations. The unit dose(s) may be contained within a blister pack. The pharmaceutical pack may optionally further comprise instructions for use. In its broadest aspect, the present invention contemplates all optical isomers, racemic forms and diastereoisomers of the compounds described herein. Those skilled in the art will appreciate that, owing to the asymmetrically substituted carbon atoms present in the compounds of the invention, the compounds may be produced in optically active and racemic forms. If a chiral centre or another form of isomeric centre is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereoisomers, are intended to be covered herein. Compounds of the invention containing a chiral centre (or multiple chiral centres) may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. Thus, references to the compounds (e.g. iminosugars) of the present invention encompass the products as a mixture of diastereoisomers, as individual diastereoisomers, as a mixture of enantiomers as well as in the form of individual enantiomers.

Therefore, the present invention contemplates all optical isomers and racemic forms thereof of the compounds of the invention, and unless indicated otherwise (e.g. by use of dash-wedge structural formulae) the compounds shown herein are intended to encompass all possible optical isomers of the compounds so depicted. In cases where the

stereochemical form of the compound is important for pharmaceutical utility, the invention contemplates use of an isolated eutomer.

The term bioisostere (or simply isostere) is a term of art used to define drug analogues in which one or more atoms (or groups of atoms) have been substituted with replacement atoms (or groups of atoms) having similar steric and/or electronic features to those atoms which they replace. The substitution of a hydrogen atom or a hydroxyl group with a fluorine atom is a commonly employed bioisosteric replacement. Sila-substitution (C/Si-exchange) is a relatively recent technique for producing isosteres. This approach involves the replacement of one or more specific carbon atoms in a compound with silicon (for a review, see Tacke and Zilch (1986) Endeavour, New Series 10: 191 -197). The sila-substituted isosteres (silicon isosteres) may exhibit improved pharmacological properties, and may for example be better tolerated, have a longer half-life or exhibit increased potency (see for example Englebienne (2005) Med. Chem., 1 (3): 215-226). Similarly, replacement of an atom by one of its isotopes, for example hydrogen by deuterium, may also lead to improved pharmacological properties, for example leading to longer half-life (see for example Kushner et al (1999) Can J Physiol Pharmacol. 77(2):79-88). In its broadest aspect, the present invention contemplates all bioisosteres (and specifically, all silicon bioisosteres) of the compounds of the invention. The term pharmaceutically acceptable derivative as applied to the compounds of the invention define compounds which are obtained (or obtainable) by chemical derivatization of the parent compounds of the invention. The pharmaceutically acceptable derivatives are therefore suitable for administration to or use in contact with mammalian tissues without undue toxicity, irritation or allergic response (i.e. commensurate with a reasonable benefit/risk ratio). Preferred derivatives are those obtained (or obtainable) by alkylation, esterification or acylation of the parent compounds of the invention. The derivatives may be active per se, or may be inactive until processed in vivo. In the latter case, the derivatives of the invention act as prodrugs. Particularly preferred prodrugs are ester derivatives which are esterified at one or more of the free hydroxyls and which are activated by hydrolysis in vivo. Other preferred prodrugs are covalently bonded compounds which release the active parent drug according to general formula (I) after cleavage of the covalent bond(s) in vivo.

The term pharmaceutically acceptable salt as applied to the inhibitors of the invention defines any non-toxic organic or inorganic acid addition salt of the free base which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and which are commensurate with a reasonable benefit/risk ratio. Suitable pharmaceutically acceptable salts are well known in the art. Examples are the salts with inorganic acids (for example hydrochloric, hydrobromic, sulphuric and phosphoric acids), organic carboxylic acids (for example acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4- hydroxybenzoic, anthranilic, cinnamic, salicylic, 2-phenoxybenzoic, 2-acetoxybenzoic and mandelic acid) and organic sulfonic acids (for example methanesulfonic acid and p- toluenesulfonic acid).

The term substantially pure as applied to compositions containing the compounds of the invention defines compositions in which the compound of the invention is at least 90% pure, preferably at least 95% pure and most preferably at least 99% pure. In the present specification the term "alkyl" defines a straight or branched saturated hydrocarbon chain. The term "Ci-C₆ alkyl" refers to a straight or branched saturated hydrocarbon chain having one to six carbon atoms. Examples include methyl, ethyl, n- propyl, isopropyl, t-butyl, n-hexyl. The term "d-Cg alkyl" refers to a straight or branched saturated hydrocarbon chain having one to nine carbon atoms. The term "Ci-C₁₅ alkyl" refers to a straight or branched saturated hydrocarbon chain having one to fifteen carbon atoms. The alkyl groups of the invention may be optionally substituted by one or more halogen atoms. Thus, the term alkyl may define the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl groups, alkyl substituted cycloalkyl groups and cycloalkyl substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C Cso for straight chain, C₃-C₃₀ for branched chain), and more preferably up to 20, 15, 12, 10, 8 or 6. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.

The term aralkyl defines an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group). ^uCi-C₄ alkyl" has a similar meaning except that it contains from one to four carbon atoms.

"C₂-C₆ alkenyl" refers to a straight or branched hydrocarbon chain having from two to six carbon atoms and containing at least one carbon-carbon double bond. Examples include ethenyl, 2-propenyl, and 3-hexenyl. The term "C C₆ haloalkyl" refers to a C^e alkyl group as defined above substituted by one or more halogen atoms.

In the present specification the term "alkenyl" defines a straight or branched hydrocarbon chain having containing at least one carbon-carbon double bond. The term "Ci-C₆ alkenyl" refers to a straight or branched unsaturated hydrocarbon chain having one to six carbon atoms. The term "C C₉ alkenyl" refers to a straight or branched unsaturated hydrocarbon chain having one to nine carbon atoms. The term "C C ₅ alkenyl" refers to a straight or branched unsaturated hydrocarbon chain having one to fifteen carbon atoms. Preferred is C C₆ alkenyl. Examples include ethenyl, 2-propenyl, and 3-hexenyl. The alkenyl groups of the invention may be optionally substituted by one or more halogen atoms. In the present specification the term "alkynyl" defines a straight or branched hydrocarbon chain having containing at least one carbon-carbon triple bond. The term "C C₆ alkynyl" refers to a straight or branched unsaturated hydrocarbon chain having one to six carbon atoms. The term "Ci-C₉ alkynyl" refers to a straight or branched unsaturated hydrocarbon chain having one to nine carbon atoms. The term "C1-C15 alkynyl" refers to a straight or branched unsaturated hydrocarbon chain having one to fifteen carbon atoms. Preferred is C C₆ alkynyl. Examples include ethynyl, 2-propynyl, and 3-hexynyl. The alkynyl groups of the invention may be optionally substituted by one or more halogen atoms.

The term "heterocyclyl" defines a saturated or partially saturated 3 to 14 membered ring system (except when alternative numbers of ring atoms are specified) similar to cycloalkyl but in which at least one of the carbon atoms has been replaced by N, O, S, SO or S0₂. Examples include piperidine, piperazine, morpholine, tetrahydrofuran and pyrrolidine.

As used herein, the term "carbocyclyl" means a mono- or polycyclic residue containing 3 or more (e.g. 3-14, 3-10 or 3-8) carbon atoms. The carbocyclyl residues of the invention may be optionally substituted by one or more halogen atoms. Mono- and bicyclic carbocyclyl residues are preferred. The carbocyclyl residues can be saturated or partially unsaturated and include fused bicyclic or tricyclic systems. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and also bridged systems such as norbornyl and adamantyl.

Saturated carbocyclyl residues are preferred and are referred to herein as "cycloalkyls" and the term "cycloalkyl" is used herein to define a saturated 3 to 14 membered carbocyclic ring including fused bicyclic or tricyclic systems. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and also bridged systems such as norbornyl and adamantyl. The cycloalkyl residues of the invention may be optionally substituted by one or more halogen atoms.

In the present specification the term "aryl" defines a 5-14 (e.g. 5-10) membered aromatic mono-, bi- or tricyclic group at least one ring of which is aromatic. Thus, bicyclic aryl groups may contain only one aromatic ring. Examples of aromatic moieties are benzene, naphthalene, imidazole and pyridine. The term also includes bicyclic or tricyclic systems in which one or more of the rings has aromatic character. Indane is an example of this type of system.

As used herein, the term "heteroaryl" are aryl moieties as defined above which contain heteroatoms (e.g. nitrogen, sulphur and/or oxygen). The term also includes systems in which a ring having aromatic character is fused to a saturated or partially saturated ring. Examples include pyridine, pyrimidine, furan, thiophene, indole, isoindole, indoline, benzofuran, benzimidazole, benzimidazoline quinoline, isoquinoline,

tetrahydroisoquinoline, quinazoline, thiazole, benzthiazole, benzoxazole, indazole and imidazole ring systems. Unless otherwise indicated, the term "aryl" is to be interpreted to include heteroaryl groups as defined above.

The aryl and heteroaryl groups of the invention may optionally be substituted by one or more halogen atoms. In the present specification, "halo" refers to fluoro, chloro, bromo or iodo.

N-alkylation

N-alkyl derivates of the compounds of formula la and lb may be prepared by techniques known to those skilled in the art. Typical approaches involve: (a) reductive amination by hydrogenantion of the amine in the presence of palladium with an aldehyde; (b) reductive amination by sodium cyanoborohydride of the amine with an aldehyde; (c) reductive amination by sodium triacetoxyborohydride of the amine with an aldehyde; and (d) N- alkylation of the amine with an akyl halide or other leaving group such as a tosylate, etc. (all of the preceding in water, alcohols or other suitable solvents).

Exemplary techniques and reaction schemes which may be adapted for use in the synthesis of compounds of formula (I) are described for example in: (a) Rawlings et al. (2009) Chembiochem 10: 1101-1105; (b) Mellor et al. (2002) Biochem. J. 366: 225-233; (c) WO2001/010429; and (d) Butters et al. (2000) Tetrahedron Asymm. 11 : 113-125.

CFTR protein rescue

Preferred compounds of the invention are able to rescue mutant CFTR activity. The ability of the compounds of the invention to rescue mutant CFTR activity may be determined by routine assays known to those skilled in the art (an example of which is described in the Exemplification section (Example 3), below). Preferred are compounds which can rescue the activity of the mutant AF508 CFTR polypeptide.

Without wishing to be bound by any theory, it is thought that the compounds of the invention act as CFTR pharmacoperones, restoring mutant CFTR function via a

pharmacological chaperone mechanism. Thus, preferred compounds of the invention are CFTR pharmacoperones. Such compounds find application in the treatment of CF.

Some or all of the observed CFTR rescue activity may arise from other mechanisms. For example, the compounds may act as an indirect chaperone of CFTR via a chaperone effect attendant on binding to a protein (e.g. enzyme) which itself acts as a chaperone or co- chaperone of CFTR. For example, the compounds of the invention may bind to (or otherwise inhibit) chaperone proteins such as calnexin and so influence protein trafficking through the Golgi apparatus. Thus, compounds of the invention may prevent the interaction of mutant CFTR polypeptides (e.g. the AF508 CFTR polypeptide) to the chaperone calnexin.

Thus, preferred compounds of the invention inhibit the interaction of calnexin with CFTR polypeptide. Glycosidase inhibition

The ability to inhibit various glycosidases underpins the therapeutic utility of a number of known iminosugar therapeutics (see for example Cox et al. (2007) Medicinal use of iminosugars, in Iminosugars From Synthesis to Therapeutic Applications: Compain, Philippe / Martin, Olivier R. (eds.) ISBN-13: 978-0-470-03391 -3 - John Wiley & Sons, pages 318-319); Asano, N. (2009) Cell. Mol. Life Sci. 66: 1479-1492).

Thus, preferred compounds of the invention are glycosidase inhibitors (i.e. compounds which inhibit one or more glycosidase enzymes). Preferred are specific inhibitors of a- glucosidases (i.e. compounds which inhibit one or more a-glucosidase enzymes but which are inactive against members of other classes of glycosidases).

Posology

The compounds of the present invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), nasal, rectal, vaginal and topical (including buccal and sublingual) administration. Preferred is oral administration.

The amount of the compound administered can vary widely according to the particular dosage unit employed, the period of treatment, the age and sex of the patient treated, the nature and extent of the disorder treated, and the particular compound selected. The desired dose is preferably presented as a single dose for daily administration.

However, two, three, four, five or six or more sub-doses administered at appropriate intervals throughout the day may also be employed. These sub-doses may be

administered in unit dosage forms, for example, containing 0.001 to 100 mg, preferably 0.01 to 10 mg, and most preferably 0.5 to 1.0 mg of active ingredient per unit dosage form.

In determining an effective amount or dose, a number of factors are considered by the attending physician, including, but not limited to, the potency and duration of action of the inhibitors used, the nature and severity of the illness to be treated, as well as the sex, age, weight, general health and individual responsiveness of the patient to be treated, and other relevant circumstances. Those skilled in the art will appreciate that dosages can also be determined with guidance from Goodman & Goldman's The Pharmacological Basis of Therapeutics, Ninth Edition (1996), Appendix II, pp. 1707-1711.

The effectiveness of a particular dosage of the compound of the invention can be determined by monitoring the effect of a given dosage on the progression of the disease or its prevention.

Compositions of the invention may be delivered to the respiratory tract and lungs by inhalation. They may be delivered systemically by oral administration. Formulation

Illustrative pharmaceutically acceptable salts are prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic,

ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, b-hydroxybutyric, galactaric and galacturonic acids.

Suitable pharmaceutically-acceptable base addition salts include metallic ion salts and organic ion salts. Metallic ion salts include, but are not limited to, appropriate alkali metal (group la) salts, alkaline earth metal (group I la) salts and other physiologically acceptable metal ions. Such salts can be made from the ions of aluminium, calcium, lithium, magnesium, potassium, sodium and zinc. Organic salts can be made from tertiary amines and quaternary ammonium salts, including in part, trimethylamine, diethylamine, N, N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of the above salts can be prepared by those skilled in the art by conventional means from the corresponding compound.

Pharmaceutical compositions can include stabilizers, antioxidants, colorants and diluents. Pharmaceutically acceptable carriers and additives are chosen such that side effects from the pharmaceutical compound are minimized and the performance of the compound is not compromised to such an extent that treatment is ineffective.

The compound of the invention can be administered parenterally, for example

subcutaneously, intravenously, or intramuscularly, or by infusion techniques, in the form of sterile injectable aqueous or oleaginous suspensions. Such suspensions can be formulated according to known art using suitable dispersing or wetting agents and suspending agents such as those mentioned above or other acceptable agents. A sterile injectable preparation can be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1 ,3- butanediol. Among acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed, including synthetic mono-or diglycerides. In addition, omega-3 polyunsaturated fatty acids can find use in preparation of injectables. Administration can also be by inhalation, in the form of aerosols or solutions for nebulizers, or rectally, in the form of suppositories prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary

temperature, but liquid at rectal temperature and will therefore, melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. Also encompassed by the present invention is buccal and sub-lingual administration, including administration in the form of lozenges, pastilles or a chewable gum comprising the inhibitors set forth herein. The inhibitors can be deposited in a flavoured base, usually sucrose, and acacia or tragacanth.

Preservatives are optionally employed to prevent microbial growth prior to or during use. Suitable preservatives include polyquaternium-1 , benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, edetate disodium, sorbic acid, or other agents known to those skilled in the art. Typically, such preservatives are employed at a level of about 0.001% to about 1.0% by weight of a pharmaceutical composition.

Solubility of components of the present compositions can be enhanced by a surfactant or other appropriate cosolvent in the composition. Such cosolvents include polysorbates 20,60 and 80, polyoxyethylene/polyoxypropylene surfactants (e. g., Pluronic F-68, F-84 and P-103), cyclodextrin, or other agents known to those skilled in the art. Typically, such cosolvents are employed at a level of about 0.01 % to about 2% by weight of a

pharmaceutical composition.

Pharmaceutically acceptable excipients and carriers encompass all the foregoing and the like. The above considerations concerning effective formulations and administration procedures are well known in the art and are described in standard textbooks. See for example Remington: The Science and Practice of Pharmacy, 20th Edition (Lippincott, Williams and Wilkins), 2000; Lieberman et al., ed. , Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y. (1980) and Kibbe et al., ed. , Handbook of Pharmaceutical Excipients (3rd Edition), American Pharmaceutical Association, Washington (1999).

The compounds and compositions of the invention are preferably formulated for oral delivery in tablet form. Formulations for delivery to the respiratory tract

The compounds of the invention can be formulated into a solution and/or a suspension of particles in a carrier appropriate for inhalation into the respiratory tract and the lungs.

A wide range of suitable carriers are known to those skilled in the art. In general, powders, mists or aerosols with particle sizes of 0.5 to 1 micron may be delivered to the respiratory tract. Such particle size ranges are commonly achieved by micronisation or spray drying and such delivery methods are described for example in Remington: The Science and Practice of Pharmacy, 20th Edition (Lippincott, Williams and Wilkins), 2000; Lieberman et al., ed. , Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y. (1980) and Kibbe et a/., ed. , Handbook of Pharmaceutical Excipients (3rd Edition), American Pharmaceutical Association, Washington (1999).

In a preferred formulation for inhalation, the compound of the invention forms part of a powdered composition within a gelatin capsule, blister pack and a multi-dose metering device. The capsule or blister is ruptured within the device enabling the powder to be inhaled.

Powdered compositions typically comprise the compounds of the invention blended or mixed with an inert carrier. Usually the inert carrier has a mean particle size substantially larger than that of the drug. This provides, among other advantages, an improvement in the flow properties and dispensing accuracy of the composition. Suitable carriers include calcium carbonate and sugars.

In other embodiments, the compound of the invention is formulated as an aerosol, for example by preparing a suspension of the compound as a finely divided powder in a liquefied propellant gas. Alternatively, a solution can be prepared which may contain solubilizers and co-solvents. Pressurized metered dose inhalers (pMDI) are normally used to dispense such formulations to a patient. Suitable propellents include

chlorofluorocarbons, fluorocarbons and hydrofluoroalkanes.

Inhalation devices, such as inhalers (including dry powder inhaler and metered dose inhalers (MDIs)) and nebulizers (also known as atomizers) may be used to deliver the compounds of the invention to the respiratory tract and/or lungs. Metered dose inhalers are designed to deliver a fixed unit dosage of medicament per actuation. Exemplary nebulizers for delivering an aerosolized solution include the AERx™ (Aradigm), the

Ultravent® (Mallinkrodt), the Pari LC Plus™ or the Pari LC Star™ (Pari GmbH, Germany), the DeVilbiss Pulmo-Aide, and the Acorn II® (Marquest Medical Products).

Exemplification

The invention will now be described with reference to specific Examples. These are merely exemplary and for illustrative purposes only: they are not intended to be limiting in any way to the scope of the monopoly claimed or to the invention described. These examples constitute the best mode currently contemplated for practicing the invention.

Example 1 : Preparation of isoDAB

Reaction scheme summary

1D isoDAB 16L 1SL 14 Scheme 1 : (i) CH₂0, K₂C0₃, MeOH, H₂0 (ii) NaBH₄, H₂0 (iii) Nal0₄, MeOH, H₂0, 84% (from 9) (iv) Br₂, BaC0₃, H₂0, 0^°C to RT, 90% (v) (CF₃S0₂)₂0, pyridine, CH₂CI₂, -30 ^°C; then NaN_3> DMF, 67% (vi) DIBALH, CH₂CI₂, -78 ^°C, 93% (vii) Dowex (50W-X8 hT form) H₂0:1 ,4-dioxane, 4:1 , 75 °C, 100% (viii) Pd/C (10%), H₂, H₂0:AcOH, 9: 1 , 71 %. IsoDAB was synthesized from D-ribose [Scheme 1]. The protected azido-L-apiose 15L was the key intermediate for the synthesis of isoDAB 1 D. Reaction of the D-ribose acetonide 9 with formaldehyde and potassium in the presence of potassium carbonate introduced the branching hydroxymethyl group via a Ho crossed aldol reaction gave a mixture of the protected D-hamamelose 10 together with the tetraol 11 , resulting from a crossed Cannizzaro reaction; the mixture was treated by sodium borohydride in water to afford pure 11. Oxidation of the tetraol 11 with sodium periodate which cleaved the 1 ,2-diol to afford the L-apiose acetonide 12 [mp. 70-72 °C; [a]_D +37.8 (c, 1.29). mp. 74 °C; [a]_D +39 (c, 1.7)] in 84% yield from 9. The only chromatography was the final purification of 12, which may conveniently be prepared from 9 on a multi gram scale. Treatment of the lactol 12 with bromine water gave the L-apionolactone 13 [mp. 90-92 ^°C; [a]_D +70.5 (c, 0.95)] in 90% yield. Esterification of the free alcohol in 13 with triflic (trifluoromethanesulfonic) anhydride in dichloromethane in the presence of pyridine gave the corresponding triflate which on reaction with sodium azide in DMF gave the L-azidolactone 14 [mp. 62-64 "C; [a]_D +104.5 (c, 1.3)] in 67% yield. Reduction of the lactone 14 with diisobutylaluminum hydride (DIBALH) in dichloromethane afford the L-azidolactol 15L [oil; [a]_D +109.9 (c, 0.94)] in 97% yield. The isopropylidene protecting group in 15L was removed quantitatively by hydrolysis by Dowex acid ion exchange resin to give 3-C-azidomethyl-L-erythrose 16L [oil [a]_D -1.9 (c 1.37, MeOH)] as a mixture of furanose anomers. Hydrogenation of the azidolactol 16L in the presence of palladium (10% on carbon) caused reduction of the azide to the corresponding amine followed by an intramolecular reductive amination to give the target isoDAB 1D [oil, [cc]_D -39.7 (c 0.17, H₂0)] in 71 % yield. The overall yield of isoDAB 1D from the acetonide 9 was 37% over eight steps. 2,3-O-lsopropylidene-L-apiose

A solution of 2,3-O-isopropylidine-D-ribose (9.68 g, 50.9 mmol) in methanol (100 mL) was stirred with potassium carbonate (7.74 g, 56.0 mmol) and 39.5% formaldehyde solution (50 mL) at reflux for 6 h. TLC analysis (EtOAc) showed the complete consumption of starting material (R_f 0.64) and the formation of major (R_f 0.33) and minor products (R_f 0.10). The reaction mixture was cooled to RT, neutralised with 2M HCI, filtered through Celite^® and concentrated under reduced pressure to afford crude 2,3-O-isopropylidene-D-hamamelose (11.2 g). Without further purification, the mixture was dissolved in water (400 mL) and stirred with sodium borohydride (3.86 g, 102 mmol) at RT. TLC analysis (EtOAc) after 80 min showed the complete consumption of the hamamelose derivative (R_f 0.33). The solution was neutralised with glacial acetic acid, and stirred with sodium metaperiodate (13.4 g, 56.0 mmol) at RT for 1 h, after which TLC analysis (EtOAc) showed the formation of a major product (R_f 0.62). The solution was then concentrated to dryness under reduced pressure and triturated exhaustively with EtOAc. The organic extracts were concentrated under reduced pressure and purified by flash column chromatography (1 :1 to 4:1 EtOAc/cyclohexane) to afford 2,3-O-isopropylidene-L-apiose (8.09 g, 84%) as a white crystalline solid, in a 7:1 ratio of anomers .

HRMS (ESI +ve): found 213.0725; (M+Na⁺) requires 213.0733; [a]_D ¹⁹ +37.8 (c 1.70, CHCI₃) [a]_D ^T +39 (c 1.7, CHCI₃)]; m.p. 70-72°C [m.p. 74°C]; v_max (thin film): 3423 (s, br, OH); δ_Η (CDCI₃, 400 MHz): 1.40, 1.49 (2 x 3H, s, CH₃ ^A), 1.47, 1.57 (2 x 3H, s, CH₃ ^B), 2.48 (1 H, t, OH3^,B, JOH3', 3· 6.1 ), 2.84 (1 H, t, OH3^,A, J_0H3\ ₃. 5.6), 3.56, 3.90 (2 x 1 H, d, H4^B, J_GEM 10.6), 3.72 (2H, d, H3^,B, J₃.,₀H3' 6.3), 3.81 (2H, d, H3'^A, J_{3 ,0}H3_' 5.3), 3.84 (1 H, d, OH1^A, J₀HI_,I 4.3), 3.97, 4.04 (2 x 1 H, d, H4^A, J_GEM 10.1 ), 4.08 (1 H, d, OH1 ^B, ₀HI _,I 11 4), 4.35 (1 H, s, H2^A), 4.37 (1 H, d, H2^B, J₂ 3.5), 5.07 (1 H, dd, H1 ^B, J_1i0Hi 11.2, J ₂ 3.3), 5.41 (1 H, d, H1^A, _1i0Hi 4.0); δ₀ (CDCI₃, 100 MHz): 27.3, 27.5 (C(CH₃)₂ ^A), 27.6, 27.8 (C(CH₃)₂ ^B), 63.6 (C3'^B), 64.1 (C3^,A), 70.5 (C4^B), 74.2 (C4^A), 81.1 (C2^B), 86.8 (C2^A), 91.6 (C3^A), 91.7 (C3^B), 97.8 (C1 ^B), 101.5 (C1^A), 113.4 (C(CH₃)₂ ^A), 114.8 (C(CH₃)₂ ^B); m/z (ESI -ve): 249 (100% M+AcO ).

2,3-0-lsopropylidene-L-apiono-1 ,4-lactone

To a suspension of barium carbonate (3.02 g, 15.3 mmol) in aqueous 2,3-O- isopropylidene-L-apiose (1.92 g, 10.2 mmol in 25 mL) was added bromine (0.79 mL, 15.3 mmol) dropwise at 0°C in a covered flask. The mixture was stirred at 0°C for 1 h and then at RT for a further 2 h. TLC analysis (EtOAc) showed the complete consumption of starting material (R_f 0.62) and formation of a major product (R_f 0.70). The reaction was quenched with saturated sodium thiosulfate solution and the aqueous extracted with EtOAc (6 x 25 mL). The combined organic fractions were concentrated under reduced pressure. Purification of the crude by flash column chromatography (1 :1 EtOAc/cyclohexane) afforded 2, 3-0-isopropylidene-L-apiono-1 ,4-lactone (1.72 g, 90%) as a white crystalline solid.

Found: C, 50.79, H, 6.33; C₈H₁₂0₅ requires: C, 51.06, H, 6.43; HRMS (ESI +ve): found 211.0576 (M+Na⁺); C₈H₁₂0₅Na requires 211.0577; [a]_D ²² +70.5 (c 0.95, CHCI₃); m.p. 90- 92°C; v_max (thin film): 3500 (br, s, OH), 1774 (s, C=0); δ_Η (CDCI₃, 400 MHz): 1.49, 1.44 (2 x 3H, s, CH₃), 2.53 (1 H, br, s, OH), 3.75 (1 H, d, H3'a, J_gem 11.4), 3.80 (1 H, d, H3'b, J_gem 11.4), 4.42 (1H, d, H4a, J_gem 10.6), 4.48 (1 H, d, H4b, J_gem 10.6), 4.69 (1 H, s, H2); 5_C (CDCI₃, 100 MHz): 27.4, 28.1 (C(CH₃)₂), 62.9 (C3'), 73.3 (C4), 76.4 (C2), 86.4 (C3), 114.6 (C(CH₃)₂), 174.7 (C1 ); m/z (ESI +ve): 211 (100% M+Na⁺).

3-C-Azidomethyl-2,3-0-isopropylidene-L-erythrono-1 ,4-lactone

Triflouromethanesulfonic anhydride (1 .75 mL, 10.3 mmol) was added dropwise to a solution of 2, 3-0-isopropylidene-L-apiono-1 ,4-lactone (1.29 g, 6.86 mmol) in DCM (30 mL) and pyridine (1.66 mL, 20.6 mmol) at -30°C. TLC analysis (1 :1 EtOAc/cyclohexane) after 1 h showed the complete consumption of starting material (R_f 0.70) and formation of a major product (R_f 0.77). The crude mixture was partitioned between 2 M aqueous HCI (60 mL) and DCM (60 mL), and the aqueous layer extracted with DCM (3 x 60 mL). The combined organic fractions were concentrated under reduced pressure to yield the triflate derivative which was dissolved in DMF (15 mL) without further purification and stirred with sodium azide (670 mg, 10.3 mmol) at RT for 24 h. TLC analysis (1 : 1 EtOAc/cyclohexane) showed a major product (R_f 0.77). The reaction mixture was concentrated under reduced pressure, partitioned between water (60 mL) and EtOAc (60 mL), and the aqueous extracted with EtOAc. The combined organic fractions were dried (MgS0₄), filtered and concentrated under reduced pressure. Purification of the crude by flash column chromatography (1 :4 EtOAc/cyclohexane) afforded 3-C-azidomethyl-2,3-0-isopropylidene-L-erythrono-1 ,4- lactone (982 mg, 67%) as a white crystalline solid.

HRMS (ESI -ve): found 230.0774 (M+OH ); C₈H₁₂N₃O_s requires 230.0771 ; [a]_D ¹⁷ +104.5 (c 1.18, CHCI₃); m.p. 62-64°C; v_maK (thin film): 2103 (s, N₃), 1778 (s, C=0); δ_Η (CDCI₃, 400 MHz): 1.44, 1.53 (2 x 3H, s, CH₃), 3.56 (1 H, d, H3'a, J_gem 12.9), 3.60 (1 H, d, H3'b, J_gem 12.9), 4.33 (1 H, d, H4a, J_gem 10.6), 4.45 (1 H, d, H4b, J_gerT1 10.9), 4.62 (1 H, s, H2); δ₀ (CDCI₃, 100 MHz): 27.4, 28.0 (C(CH₃)₂), 53.7 (C3¹), 73.4 (C4), 76.8 (C2), 85.4 (C3), 115.2 (C(CH₃)₂), 173.6 (C1); m/z (ESI -ve): 230 (100% M+OH^').

3-C-Azidomethyl-2,3-0-isopropylidene-L-erythrose

Diisobutylaluminium hydride solution (1.5M in toluene, 5.0 mL, 7.5 mmol) was added dropwise to a solution of 3-C-azidomethyl-2,3-0-isopropylidene-L-erythrono-1 ,4-lactone (1.28 g, 6.01 mmol) in DCM (10 mL) at -78°C and stirred for 1 h. TLC analysis (1 :1 EtOAc/cyclohexane) showed the complete consumption of starting material (R_f 0.77) and formation of a major product (R_f 0.70). Excess diisobutylaluminium hydride was quenched with methanol, and the mixture allowed to warm to RT. DCM (10 mL) and saturated aqueous potassium sodium tartrate solution (20 mL) were added, and the mixture stirred until a biphasic system was obtained (4 h). The organic phase was collected and the aqueous layer extracted with DCM (2 x 20 mL). The combined organic fractions were dried (MgS0₄), filtered and concentrated under reduced pressure. Purification by flash column chromatography (1 :4 - 1 :2 EtOAc/cyclohexane) afforded 3-C-azidomethyl-2,3-0- isopropylidene-L-erythrose (1.21 g, 93%) in a 10:1 ratio of anomers, as a colourless oil. HRMS (ESI -ve): found 214.0817 [M-H]^"; C₈H₁₂N₃0₄ requires 214.0822; [c ]_D ²¹ +109.9 (c 0.94, CHCI₃); v_max (thin film): 3425 (br, w, OH), 2106 (s, N₃); δ_Η (CDCI_3> 400 MHz) major anomer only: 1.47, 1.50 (2 x 3H, s, C(CH₃)₂), 2.78 (1 H, d, OH1 , J₀HI .I 3.0), 3.54 (1 H, d, H3'a J_gem 12.9), 3.62 (1 H, d, H3'b, J_gem 12.9), 3.98 (1 H, d, H4a, J_gem 10.1), 4.04 (1H, d, H4b, J_gem 9.9), 4.34 (1 H, s, H2), 5.44 (1 H, d, H1 , J_{1 0H1} 3.0); 6_C (CDCI₃, 100 MHz) major anomer only: 27.3, 27.6 (C(CH₃)₂), 55.0 (C3'), 75.0 (C4), 87.1 (C2), 97.6 (C3), 101.8 (C1), 114.2 (C(CH₃)₂); m/z (ESI -ve): 214 (100% [M-HV).

3-C-Azidomethyl-L-erythrose

Dowex^® (50W-X8, H⁺) (5 g) was added to a solution of 3-C-azidomethyl-2,3-0- isopropylidene-L-erythrose (1.21 g, 5.63 mmol) in 4.1 water: 1 ,4-dioxane (10 mL) and stirred at 75°C. TLC analysis (1 :1 EtOAc/cyclohexane) after 5 h showed the absence of starting material (R_f 0.70), and a single product (R_f 0.17). The crude mixture was filtered and concentrated under reduced pressure to afford 3-C-azidomethyl-L-erythrose (980 mg, quant.) as a pale yellow oil, in a 2:1 ratio of anomers.

HRMS (ESI +ve): found 198.0483 (M+Na⁺); C₅H₉N₃0₄Na requires 198.0485; [a]_D ¹⁸ -1.9 (c 1.37, MeOH); v_max (thin film, Ge): 3384 (s, br, OH), 2111 (s, N₃); δ_Η ((CD₃)₂CO, 400 MHz): 3.36 (1 H, d, H3'a^B, J_gem 10.6), 3.43 (1 H, d, H3'b^B, J_gem 10.9), 3.46 (2H, s, H3^,A), 3.74 (1H, d, H4a^A, Jgem 9.6), 3.76-3.78 (1 H, m, H2^A), 3.79 (1 H, d, H4a^B, Jg_em9.6), 3.81-3.84 (1 H, m, H2^B), 3.85 (1H, d, H4b^A, J_gem 9.6), 3.94 (1H, d, H4b^B, J_gem 9.6), 4.25 (1H, s, OH3^B), 4.29 (1H, s, OH3^A), 4.34 (1 H, d, OH2^B, J_OH2,2 6.8), 4.88 (1 H, d, OH2^A, J₀H₂₂ 5.6), 5.20 (1 H, dd, H1^A, ^,_ΟΗ14.6, Ji_,22.3), 5.25 (1 H, dd, H1^B, ^_,0Ηι 6.1 , ,₂3.5), 5.40 (1 H, d, OH1 ^B, om.1 6.3), 5.50 (1 H, d, OH1^A, JOHI,I 4.6); 6_C ((CD₃)₂CO, 100 MHz): 56.5 (C3^,B), 56.6 (C3^,A), 73.1 (C2^B), 73.5 (C4^B), 74.2 (C4^A), 78.2 (C3^B), 78.6 (C2^A), 79.4 (C3^A), 97.0 (C1^B), 103.7 (C1^A); m/z (ESI - ve): 214 (100% M-H⁺). 1,4-Dideoxy-2-C-hydroxymethyl-1,4-imino-D-threitol (iso-DAB)

Pd (10% on C, 100 mg) was added to a solution of 3-C-azidomethyl-L-erythrose (980 mg, 5.60 mmol) in 9:1 water/AcOH (30 mL) and the vessel purged and charged with hydrogen. The reaction mixture was stirred under hydrogen at RT for 24 h after which TLC analysis (EtOAc) showed the complete consumption of starting material (R_f 0.48). The reaction mixture was filtered through Celite^®, concentrated to approx. 5 mL under reduced pressure and absorbed onto a column of Dowex^® (50W-X8, H⁺). The resin was washed with water before liberation of the amine with 2M aqueous ammonia. The ammoniacal fractions were concentrated under reduced pressure to afford 1 ,4-dideoxy-2-C-hydroxymethyl-1 ,4-imino- D-threitol (530 mg, 71%) as a brown oil. HRMS (ESI +ve): found 134.0808 (M+H⁺); C₅H₁₂N0₃ requires 134.0812; [a]_D ²⁵ -39.7 (c 0.17, H₂0); v_max (thin film, Ge): 3332 (s, br, OH); δ_Η (D₂0, 400 MHz): 2.84 (1 H, d, H4a, J_gern 12.8), 2.85 (1 H, d, M a, J_gem 12.5), 2.95 (1 H, d, M b, J_gem 12.5), 3.38 (1 H, dd, H4b, J_gem 12.8, J₄,3 4.7), 3.70 (1 H, d, H2'a, _gem 12.0), 3.82 (1 H, d, H2'b, J_gem 12.0), 4.09 (1 H, d, H3, J₃.4 4.7); 6c (D₂0, 100 MHz): 53.1 (C4), 53.3 (C1), 63.3 (C2'), 76.9 (C3), 83.8 (C2); m/z (ESI +ve): 192 (100% M+HCI+Na⁺).

The above exemplified synthesis starts from D-ribose, but those skilled in the art will recognize that isoDAB can also be prepared by routes from other sugars. Examples of the many suitable starting monosaccharides include (but are not restricted to) L-TAGATOSE L- lyxose, D-psicose, L-mannose, L-fructose and D-sorbose, , D-ribonolactone, D-gulose, L- lyxonolactone, D-gulonolactone, L-mannonolactone, and suitably protected derivatives of any of the foregoing. In the latter case, protection may be of cis-1 ,2-diols by acetone to acetonides, or any suitable ketone (such as cyclohexanone, pentan-3-one or other ketones) to its corresponding ketal.

Example 2: Syntheses of azetidine iminosuqars of formula lb from arabinose and glucose Reaction scheme 1

Scheme 1 : (i) EtSH, HCI, H₂0; then fert-BuPh₂SiCI, imidazole; then Me₂CO, anhydr.

CuS0₄ (ii) TBAF, THF (iii) (CF₃S0₂)₂0, pyridine, CH₂CI₂, -30^°C (iv) BnNH₂ (v) Et₂0:BF₃, Ac₂0 (vi) NaBH₄, eOH (vii) Pd/C (10%), H₂, H₂0 (viii) Nal0₄, AcOH; then NaBH₄, MeOH (ix) EtSH, HCI, H₂0; then tosyl chloride, pyridine; then Me₂CO, anhydr. CuS0₄ (x)

(CF₃S0₂)₂0, pyridine, CH₂CI₂, -30^*C; then NaN₃, DMF If D-arabinose is converted to its crystalline dithioacetal, terf-butyldiphenylsilyl chloride protects the primary alcohol and reaction with acetone and anhydrous copper sulfate give the furanoside acetal 1 (J Chem. Soc, Perkin Trans. 1 1989, 1065; Tetrahedron 1995, 51, 959-974). Removal of the silyl either in 1 by TBAF gives the diol 2. Esterification of the alcohol in 2 with triflic anhydride in the presence of pyridine affords the corresponding ditriflate 3 which with benzylamine displaces the primary triflate first and then cyclizes to the azetidine 4.

The key intermediate 4 can also be accessed by the initial preparation of the tosylate 10 which is prepared via direct tosylation of the dithioacetal and then acetonation.

Esterification of the secondary alcohol in 10 with triflic anhydride in the presence of pyridine gives the triflate-tosylate 3 ; again benzylamine affords the same azetidine intermediate 4. Acetolysis of 4 gives the diacetate 5 which on borohydride reduction forms the /V-benzyl imino sugar 6 from which the benzyl group can be removed by

hydrogenolysis to give 1 ,3-dideoxy-1 ,3-imino-D-arabinitol 7. The enantiomer of 7 would be formed from L-arabinose. This route allows degradation of the side side to give the D- threitol analogues 8 and 9.

As an alternative to ring closure by benzylamine, compound 12 is formed from 1 by a triflate azide reaction; dedprotection of 12 by TBAF and subsequent tosylation gives 13 which on hydrogenation forms 14.

Reaction scheme 2

Scheme 2: (i) PCC, molecular sieve, CH₂CI₂; then NaBH₄, MeOH (ii) (CF₃S0₂)₂0, pyridine, CH₂CI₂, -30^°C; then NaN₃, DMF (iii) MeCOOH, H₂0; then Nal0₄, AcOH; then NaBH₄, MeOH; then tosyl chloride, pyridine (iv) Pd/C (10%), H₂, H₂0; then BnBr (v) MeCOOH, H₂0; then Nal0₄, AcOH; then NaBH₄, MeOH (vi) (CF₃S0₂)₂0, pyridine, CH₂CI₂, -30 (vii) BnNH₂ (viii) Et₂0:BF₃, Ac₂0 (ix) NaBH₄, MeOH (x) Pd/C (10%), H_2| HCI, H₂0

A similar approach from diacetone glucose 15 is shown in Scheme 2. PCC oxidation of 15 followed by reduction of the resulting ketone with sodium borohydride give diacetone allose 16. Introduction of an azide by a triflate-azide sequence gives the gr/i/co-azide 17.

Hydrolysis of the terminal acetonide in 17 followed by borohydride reduction and tosylation gives 18. Hydrogenation of 18 gives cyclizations and subsequent benzylation gives the azetidine 19. A quicker approach to 19 involves the side chain adjustment to 16 to give the ribose 1 ,2- acetonide 20. Ditriflation to 21 followed by benzylamine forms 19. The approach to 22 and thus to 23 and 24 is the same as in scheme 1. Since L-glucose is readily available both enantiomers can be synthesised enantiospecifically.

Example 3: Syntheses of isoDMDP

Scheme 1 OH₂C OH_jC

I

isoDMDP 1 12 11 Scheme 1 : (i) Ph₂CN₂, toluene (ii) DIBALH, CH₂CI₂ (Hi) CH₂0, Na₂C0₃, H₂0 (iv) Br₂, BaC0₃, H₂0 (v) (CF₃S0₂)₂0, pyridine, CH₂CI₂, -30^°C; then NaN₃, DMF (vi) LiBH₄, THF (vii) TBDMSCI, imidazole (viii) (CH₃S0₂)₂0, pyridine (ix) CF₃COOH, H₂0 (x) Pd/C (10%), H₂, Et₃N or AcONa (xi) (CF₃S0₂)₂0, pyridine, CH₂CI₂

The 2,3-acetonide of L-lyxonolactone 1 is the starting material for the synthesis of isoDMDP. The primary alcohol in 1 was protected as the benzhydryl ether by heating with diphenyldiazomethane in toluene to give the full protected lactone 2 which was reduced with DIBALH to afford the lactol 3. A crossed aldol reaction of 3 with formaldehyde and sodium carbonate gave the branched sugar 4 which was oxidized to the corresponding lactone 5 with bromine water in the presence of barium carbonate. Esterification of the alcohol in 5 with triflic anhydride in the presence of pyridine afforded the corresponding trilfate which on treatment with sodium azide in DMF gave 6. Reduction of 6 to 7 by lithium borohydride followed by protection of the primary alcohol with TBDMS chloride gave 8. Reaction of 8 with mesyl chloride in pyridine gave 9 from which all the protecting groups were removed by aqueous trifluoroacetic acid to give the azido mesylate 10.

Hydrogenation of 10 in the presence of 10% palladium on carbon, followed by treatment with sodium acetate, gave the target isoDMDP. Alternatively treatment of 8 with triflic anhydride gave 11 which on hydrogenation formed the frans-acetonide 12. Deprotection of 12 with trifluoroacetic acid gave isoDMDP. The enantiomer isoL-DMDP may be formed using the enantiomeric D-lyxonolactone as starting material. Scheme 2

Scheme 3: (i) PhCH₂Br, NaH, DMF (ii) MeCOOH, H₂0; then Nal0₄, AcOH (iii) CH₂0, Na₂C0₃, H₂0 (iv) CH₃S0₂CI, pyridine; then NaN₃, DMF (v) PhCH₂Br, NaH, DMF (vi) CF₃C0₂H, H₂0; then Br₂, BaC0₃, H₂0 (vii) (CF₃S0₂)₂0, pyridine, CH₂CI₂, -30°C; then Pd/C (10%), H₂, AcONa (viii) LiBH_4l THF (ix) Pd/C (10%), H₂, HCI, H₂0 An alternative approach to isoDMDP from diacetone glucose 13 is shown in Scheme 2. Benzylation of 13 with benzyl bromide and sodium hydride in DMF gave 14; hydrolysis of the primary acetonide in 14 gave the diol which with sodium periodate gave the aldehyde 15. Reaction of 15 with formaldehyde in the presence of sodium hydroxide gave a crossed aldol reaction followed by a cross Cannizarro reaction to afford 16; protection of the C3 in 15 is necessary to ensure there is no epimerization at C3 by a reversible aldol reaction. Activation of the least hindered primary alcohol on 16 by mesyl chloride, followed by displacement by azide in DMF gave the azide 17; again the C3 benzyl ether prevents oxetane formation. The remaining hydroxyl group in 17 was then protected as the benzyl ether 18. Acid hydrolysis of 18 to the lactol followed by bromine oxidation gave the lactone 19 in which only the C2 alcohol is unprotected. Estrification of the alcohol 19 with triflic anhydride, followed by hydrogenation of the azide afforded the corresponding amine which underwent spontaneous cyclizations to give the lactone 20. Reduction of 20 with sodium borohydride to give 21 , followed by removal of the benzyl ether groups by hydrogenolysis, gave isoDMDP.

It should be noted that hydrolysis of 18 followed by periodate cleavage and hydrogenation would also be a route isoDAB. Those skilled in the art will appreciate that the above schemes provide intermediates that can be used for the synthesis of other stereoisomers and afford many opportunities for making analogues.

Example 4: CFTR rescue activity

Materials and methods

Cell culture

The human tracheal gland serous epithelial cell line CF-KM4 is derived from a CF patient homozygous for the AF508 mutation. The details of the generation, characterization, and routine propagation have been described elsewhere (Kammouni et al. (1999) Resp. Cell Mol. Biol. 20(4): 684-91 ).

Functional analysis of CFTR activity

CFTR ion channel functions can be assessed by single-cell fluorescence imaging, using the potential-sensitive probe bis-(1 ,3-diethylthiobarbituric acid)trimethine oxonol

(DiSBAC₂(3); Molecular Probes, Eugene, OR), as previously reported (see Norez et al.

(2009) Am. J. Respir. Cell Mol. Biol. 41 (2): 217-225). Fluorescence intensity is recorded by confocal laser scanning microscopy using Bio-Rad MRC 1024 equipped with 15 mW Ar/Kr gas laser (Hemel Hempstead, UK). Maximal resolution is obtained with Olympus plan apo X60 oil, 1.4 NA, objective lens. Fluorescence signal collection can be performed through the control software Lasersharp 3.2 (Hemel Hempstead, UK). The resolution time is 30 s. Bis-oxonol slowly distributes across biological membrane according to the membrane potential and binds to hydrophobic cell components; since the quantum yield of the dye increases impressively upon the binding, the fluorescence of cells incubated in a medium containing bis-oxonol increases upon depolarization and, conversely, decreases with hyperpolarization (Dall'Asta et al. (1997) Exp. Cell Res. 231 : 260-268). CFTR-dependent current was stimulated by application of Forskolin + Genistein (Fsk+Gst), inducing a depolarization characterized by an increase of the fluorescence, while CFTR-dependent current is inhibited by application of CFTR_inh-1 2 characterized by a decrease of the fluorescence.

The CF-KM4 cells are treated 2 hours with 100μΜ of test compound and then CFTR proteins stimulated by a cocktail of forskolin (Fsk) + genistein (Gst).

Example 5: Glycosidase inhibitory profile

The CFTR-resuing activity of /VB-DNJ has been ascribed (at least in part) to its a- glucosidase inhibitory activity (Norez er al. (2006) FEBS Lett. 580: 2081-2086). Assays of compounds of the invention with various glycosidases were conducted to evaluate their glycosidase inhibitory profile (see Table 1 , below).

a- cQa d3se

250 {Κί a 14) 41<Ki o 4)

Yeast 0.15 Nl'

Rat intestinal mates 2 (Κί*δμΜ)

Rat intestine! isoroaitase 6.8 20

Rat intestinal sucrase 16 IS

IVGIuDosidasa

Almond 2S0 Nl

636 Nl

Ret intestinal cellobias* 7SS Ml

a-Gaiactosidsse

Coffee eans l Nl

Human (ysesome Nl Nl

p-Galaciosidase

Bo -ίη# live? Nl Nl

Rat intestinal lactase 323 Ml

-Wanno5idase

Jarfc beans 320 Nl

lM.lsnn$sida¾e

Snail Nl Nl

Nl

-L-Fuco¾idase

Bovine epididymis m Nl

Trehslase

Rat intestinal trehalase 61 Nl

*NJ : No iWwbition (^sthan 50H inhSbitioi* at 1030 μΜ).

The results show that isoDAB is a potent and specific a-glucosidase inhibitor. Further tests (data not shown) have established that it does not inhibit any cellular ER processing glucosidases. It constitutes the first example of a carbon branched iminosugar pyrrolidine showing significant glycosidase inhibition. It was also determined (data not shown) that isoDAB does not inhibit glycogen phosphorylase (unlike DAB, which is a potent inhibitor). Previous studies with the compounds IE and IG (see above) have indicated that these compounds also have no glycosidase inhibitory activity (Bols et al. (1996) Tetrahedron Letters 37: 2097-2 00).

Equivalents

The foregoing description details presently preferred embodiments of the present invention. Numerous modifications and variations in practice thereof are expected to occur to those skilled in the art upon consideration of these descriptions. Those modifications and variations are intended to be encompassed within the claims appended hereto.

Claims

CLAIMS:

1. A compound of formula la or lb:

la

wherein n is 0 or 1 ; p is 0 or 1 ;

X is selected from H; OH and F;

Y is selected from H and CH₂X;

R¹ is selected from H; linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl and aralkyi and wherein the optional substitution may be with one or more groups independently selected from: -OH; -F; -CI; -Br; -I; -NH₂; alkylamino;

diaikylamino; linear or branched alkyl, alkenyl, alkynyl and aralkyi; aryl; heteroaryl; linear or branched alkoxy; aryloxy; aralkoxy; -(alkylene)oxy(alkyl); -CN; -N0₂; - COOH; -COO(alkyl); -COO(aryl); -C(0)NH(alkyl); -C(0)NH(aryl); sulfonyl;

alkylsulfonyl; arylsulfonyl; sulfamoyl; alkylsulfamoyl; alkylthio; alkylsulfonamide; arylsulfonamide; -NHNH₂; and -NHOH; or a bioisostere, pharmaceutically acceptable salt or derivative thereof.

2. The compound of claim 1 of formula la wherein p is 0, having the formula: v OH

CH₂OH

I

R or a bioisostere, pharmaceutically acceptable salt or derivative thereof. 3. The compound of claim 2 wherein X is OH, having the formula:

HO ^0H

CH₂OH

I

R¹ or a bioisostere, pharmaceutically acceptable salt or derivative thereof. 4. The compound of claim 3 having a formula selected from:

or a bioisostere, pharmaceutically acceptable salt or derivative thereof.

5. The compound of claim 1 of formula la wherein p is 1 , n is 0 and X is OH, having the formula: HO ^0H

CH_jOH

HOHiC

I

R¹ or a bioisostere, pharmaceutically acceptable salt or derivative thereof. 6. The compound of claim 5 having a formula selected from:

or a bioisostere, pharmaceutically acceptable salt or derivative thereof.

The compound of claim 1 of formula lb wherein Y is CH₂OH having the formula:

8. The compound of any one of the preceding claims wherein R¹ is selected from H, CM₈ alkyl (for example, Ci_-g alkyl, e.g. Ci_-6 alkyl), C₂.is alkenyl (for example, C_2-9 alkenyl, e.g. C₂. ₆ alkenyl) and C₂-i₈ alkynyl (for example, C₂.₉ alkynyl, e.g. C₂.₆ alkynyl). For example, R¹ may be -H and R¹ selected from C_1-18 alkyl (for example, C_1-9 alkyl, e.g. d_-6 alkyl), C₂.₁₈ alkenyl (for example, C_2-9 alkenyl, e.g. C_2-6 alkenyl) and C₂.i₈ alkynyl (for example, C_2-9 alkynyl, e.g. C_2-e alkynyl).

9. The compound of any one of claims 1 to 7 wherein R¹ is selected from H; C1-15 alkyl, C1-15 alkenyl or C1-15 alkynyl, optionally substituted with one or more R²; oxygen or an oxygen containing group such that the compound is an N-oxide; C(0)OR³; C(0)NR³R⁴; S0₂NR³; OH, OR³, or formyl.

10. The compound of any one of claims 1 to 7 wherein R¹ is selected from C1-9 alkyl, optionally substituted with up to 6 OH, NR³R⁴, aryl, 0-C1-3 alkyl, 0-C1-3 alkenyl, C0₂H, NH(NH)NH₂, C0NR³R⁴; C(0)OR³; C(0)NR³R⁴; or S0₂NR³. 11. The compound of any one of claims 1 to 7 wherein R¹ is H.

12. The compound of any one of the preceding claims which: (a) is an an a-glucosidase inhibitor; or (b) is not an α-glucosidase inhibitor. 13. The compound of any one of the preceding claims which is not an a-glucosidase inhibitor.

14. The compound of any one of the preceding claims which does not inhibit cellular ER processing glucosidases.

15. The compound of any one of the preceding claims which exhibits less than 50% inhibition of cellular ER processing glucosidases at 1000 μΜ.

16. The compound of any one of the preceding claims which does not inhibit glucosylceramide synthase.

17. The compound of any one of the preceding claims which exhibits less than 50% inhibition of glucosylceramide synthase at 1000 μΜ. 18. The compound of any one of the preceding claims which does not inhibit disaccharidases, for example sucrase and/or maltase.

19. The compound of any one of the preceding claims which exhibits less than 50% inhibition of disaccharidases, for example sucrase and/or maltase, at 1000 μΜ.

20. The compound of any one of the preceding claims which does not inhibit lysosomal and/or non-lysosomal glucocerebrosidase.

21. The compound of any one of the preceding claims which exhibits less than 50% inhibition of lysosomal and/or non-lysosomal glucocerebrosidase at 1000 μΜ.

22. The compound of any one of the preceding claims which does not inhibit a- glucosidase I and/or II. 23. The compound of any one of the preceding claims which exhibits less than 50% inhibition of a-glucosidase I and/or II at 1000 μΜ.

24. The compound of any one of the preceding claims which does not exhibit inhibition of glycosidase activity sufficient to elicit gastric toxicity in humans.

25. The compound of any one of the preceding claims which does not inhibit the glycosidase enzymes listed in Table 1 herein.

26. The compound of any one of the preceding claims which exhibits less than 50% inhibition at 1000 μΜ of each of the glycosidase enzymes listed in Table 1 herein.

27. The compound of any one of the preceding claims which rescues mutant CFTR activity. 28. The compound of claim 13 which rescues AF508 CFTR activity.

29. The compound of any one of the preceding claims which is a CFTR pharmacoperone.

30. A composition comprising the compound of any one of the preceding claims.

The composition of claim 30 wherein the compound is substantially pure.

32. The composition of claims 30 or claim 31 which is a pharmaceutical composition.

33. The composition of claim 32 which further comprises a pharmaceutically acceptable excipient.

34. The composition of any one of claims 30 to 33 which is formulated for oral delivery.

35. The composition of any one of claims 30 to 34 which is formulated for delivery to the lung.

36. An inhalation device comprising the compound of any one of claims 1 to 29 or the composition of any one of claims 30 to 35.

37. The inhalation device of claim 36 wherein the compound or composition is present in the form of a solution, a suspension or a powder. 38. The inhalation device of claim 36 or 37 which is an MDI or nebulizer.

39. A composition comprising a compound of any one of claims 1 to 29 in combination with Λ Β-DNJ. 40. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 29 in combination with Λ/Β-DNJ.

41. A compound as defined in any one of claims 1 to 29 for use in combination therapy with Λ/Β-DNJ.

42. A combination comprising a compound as defined in any one of claims 1 to 29 and Λ/Β-DNJ.

43. The combination of claim 42 wherein the iminosugar and Λ/Β-DN J are physically associated.

44. The combination of claim 43 wherein the iminosugar and Λ/Β-DNJ are: (a) in admixture (for example within the same unit dose); (b) chemically/physicochemically linked (for example by crosslinking, molecular agglomeration or binding to a common vehicle moiety); (c) chemically/physicochemically co-packaged (for example, disposed on or within lipid vesicles, particles (e.g. micro- or nanoparticles) or emulsion droplets); or (d) unmixed but co-packaged or co-presented (e.g. as part of an array of unit doses).

45. The combination of claim 42 wherein the compound and Λ/Β-DNJ are non-physically associated.

46. The combination of claim 45 wherein the combination comprises: (a) at least one of the compound and Λ/Β-DNJ together with instructions for their extemporaneous association to form a physical association; or (b) at least one of the compound and Λ/Β-DNJ together with instructions for combination therapy with the compound and M3-DNJ; or (c) at least one of the compound and Λ/Β-DNJ together with instructions for administration to a patient population in which either the compound and Λ/Β-DNJ have been (or are being) administered; or (d) at least one of the compound and Λ/Β-DNJ in an amount or in a form which is specifically adapted for use in combination.

47. The combination as defined in any one of claims 42 to 46: (a) in the form of a pharmaceutical pack, kit or patient pack; (b) in a pharmaceutical excipient; or (c) in unit dosage form. 48. A pharmaceutical composition comprising the combination as defined in any one of claims 42 to 46.

49. The compound, composition or device of any one of the preceding claims for use in therapy or prophylaxis.

50. The compound, composition or device of claim 49 for use in a method of treating or preventing: (a) infection; (b) immune disorders; (c) neoplasia; (d) an energy utilization disease; (e) a proteostatic disease; or (f) a lysosomal storage disorder. 51. The compound, composition or device of claim 26(a) wherein the infection is selected from: (a) a viral infection; (b) a bacterial infection; (c) a fungal infection; or (d) a protozoal infection.

52. The compound, composition or device of claim 51(a) wherein the viral infection is selected from: (a) a flaviviral infection (for example, HCV infection); (b) a retroviral infection (for example, HIV) or (c) an influenza infection. 53. The compound, composition or device of claim 50(c) wherein the neoplasia is selected from benign, pre-cancerous and malignant neoplasia, hyperlasia, metaplasia and dysplasia.

54. The invention of claim 53 wherein the malignant neoplasia is: (I) selected from: (a) carcinoma; (b) blastoma; (c) leukemia; (d) lymphoma; (e) myeloma; (f) sarcoma and (g) cancers of mixed type; or (II) is a carcinoma selected from carcinoma of the: bladder, breast (e.g. primary breast tumours, node-negative breast cancer, invasive duct adenocarcinomas of the breast and non-endometrioid breast cancers), colon (e.g.

colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, epidermis (e.g. malignant melanoma), liver, lung (e.g. adenocarcinoma, adrenocortical, nasopharyngeal, small cell lung cancer and non-small cell lung carcinomas), oesophagus, gall bladder, ovary, pancreas (e.g. exocrine pancreatic carcinoma), stomach, cervix, thyroid, prostate, gastrointestinal system (e.g. gastrointestinal stromal tumours) or skin (e.g. squamous cell carcinoma).

55. The compound, composition or device of claim 50(d) wherein the energy utilization disease is selected from: (a) disorders of homeostasis; (b) metabolic diseases; (c) dysfunction of sugar metabolism; (d) appetite disorders; (e) insulin resistance; (f) diabetes (e.g. type 1 or type 2 diabetes); (g) pre-diabetes; (h) metabolic syndrome; (i) obesity; (j) wasting syndromes (for example, cancer associated cachexia); (k) myopathies; (I) gastrointestinal disease; (m) growth retardation; (n) hypercholesterolemia; (o)

atherosclerosis; (p) age-associated metabolic dysfunction; (q) hyperglycaemia; (r) glucose intolerance; (s) hyperinsulinaemia; (t) glucosuria; (u) metabolic acidosis; (v) cataracts; (w) diabetic neuropathy; (x) diabetic nephropathy; (y) diabetic retinopathy; (z) macular degeneration; (aa) glomerulosclerosis; (bb) diabetic cardiomyopathy; (cc) impaired glucose metabolism; (dd) arthritis; (ee) hypertension; (ff) hyperlipidemia; (gg) osteoporosis; (hh) osteopenia; (ii) bone loss; (jj) brittle bone syndromes; (kk) acute coronary syndrome; (II) infertility; (mm) short bowel syndrome; (nn) chronic fatigue; (oo) eating disorders; (pp) intestinal motility dysfunction; (qq) sugar metabolism dysfunction; (rr) fatty liver; (ss) polycystic ovarian syndrome; (tt) hemochromatosis; and (uu) acanthosis nigricans.

56. The compound, composition or device of claim 50(e) wherein the proteostatic disease is cystic fibrosis. 57. The compound, composition or device of claim 50(f) wherein the lysosomal storage disorder is selected from: (a) Pompe disease (including infantile and late-onset forms); (b) Gaucher disease (including Type 1 , Type 2 and Type 3 Gaucher disease); (c) Fabry disease; (d) GMI-gangliosidosis; (e) Tay-Sachs disease; (f) Sandhoff disease; (g)

Niemann-Pick disease; (h) Krabbe disease:; (i) Farber disease; (j) Metachromatic leukodystrophy; (k) Hurler-Scheie disease; (I) Hunter disease; (m) Sanfilippo disease A, B, C or D; (n) Morquio disease A or B; (o) Maroteaux-Lamy disease; (p) Sly disease; (q) alpha-Mannosidosis; (r) beta-Mannosidosis; (s) Fucosidosis; (t) Sialidosis; and (u)

Schindler-Kanzaki disease. 58. A method of treating a disease or disorder as defined in any one of claims 50 to 57 (for example, cystic fibrosis) comprising administering an effective amount of the compound as defined in any one of claims 1 to 15 or composition as defined in any one of claims 16 to 21 to a subject in need thereof. 59. A method of treating a disease or disorder as defined in any one of claims 50 to 57 (for example, cystic fibrosis) comprising administering an effective amount of the compound as defined in any one of claims 1 to 29 or the composition of any one of claims 30 to 35 to a subject in need thereof.