WO2010029313A1

WO2010029313A1 - Antiinfective compounds

Info

Publication number: WO2010029313A1
Application number: PCT/GB2009/002190
Authority: WO
Inventors: Francis Xavier Wilson; Robert James Nash; Graeme Horne; Richard Storer
Original assignee: Summit Corporation Plc.; Tinsley, Jonathan, Mark; Roach, Alan, Geoffrey
Priority date: 2008-09-11
Filing date: 2009-09-10
Publication date: 2010-03-18

Abstract

Described are various compounds and methods for the treatment of infections. In particular, alkaloids and imino sugars with antiviral activity are described, including those with activity against HCV and RSV.

Description

ANTIINFECTIVE COMPOUNDS

Field of the Invention

This invention relates to certain compounds, in particular iminosugars, for the treatment of infections.

Background of the Invention

Diseases caused by infection with various classes of infectious agent (including bacteria, viruses, fungi, protozoa and metazoan parasites) are a significant cause of human and animal death and morbidity, typically accounting for about a quarter of all annual deaths worldwide. In addition, pandemics occur periodically which can kill vast numbers of people over a wide geographical area: the last global pandemic (the influenza pandemic of 1918) killed about 2% of the world population (about 50 million people).

Moreover, the risks of a new pandemic are increasing as a result of certain human activities which lead to the emergence and spread of new diseases. These include colonization of previously uninhabited regions, mass migration, changes in agricultural practice, the destruction of rain forests, urbanization, modern transport and climate change.

Thus, the development of new antiinfective agents is of paramount importance.

Although many bacterial infections are now effectively treated with antibiotics and prevented with vaccines, bacterial infection still remain a major cause of death (particularly in developing countries). The increased prevalence of multi-drug resistant bacterial infections has made the need for alternative means of treatment more pressing and the number of nosocomial infections due to antibiotic resistant bacteria has recently increased sharply. Methiciilin-resistant Staphylococcus aureus (MRSA) has emerged as one of the main causative agents. MRSA infections are presently treated with the glycopeptide antibiotic vancomycin but continued use of vancomycin to treat MRSA infections is likely to ultimately give rise to a fully glycopeptide resistant population of Staphylococcus aureus.

The demand for new antibacterials is primarily driven by the dramatic increase in resistance rates - approximately 70% of infections are now resistant to at least one drug. Although Staphylococcus aureus and Enterococcus spp. are well publicised pathogens of concern, resistance in Pseudomonas spp., Klebsiella spp. and E. coll is a growing concern. Moreover, not only is resistance to established pathogens an issue but new bacteria are emerging as important pathogens, including Clostridium difficile and Acinetobacter baumannii.

Clostridium difficile causes Costridium difficile associated diseases (CDAD) and there ahs been a ten fold increase in the number of cases within the last 10 years, with hyper-virulent and drug resistant strains are now becoming endemic. Recent HPA figures show there were 55,681 cases of C. difficile infection in patients aged 65 years and above in England in 2006 (up 8% on the previous year). Perhaps most worrying are the cases of CDAD with no underlying antibiotic use now being reported.

Until recently, Acinetobacter baumannii was regarded as a community pathogen of very little concern. However, it is now becoming endemic in hospitals and is naturally resistant to most antibiotics. MDR strains are now becoming common with only polymixins being effective.

Nosocomial infections are also becoming increasingly problematic. In the US and EU, 5 to 10% of all hospital patients will develop a nosocomial infection with the incidence of infection in ICU patients now as high as 50%. In the US, 2 million cases result in 90,000 deaths per annum, while in the EU 2 million cases result in 175,000 deaths per annum. Th rise in nosocomial infections is at least partially attributable to the ever increasing number of immunocompromised patients and of indwelling medical devices.

Example Resistant Nosocomial Pathogens in USA 2002

Pathogen Resistance Rate (%) Cases

S. aureus Methicillin 57.1 102,000

Other staphylococci spp. Methicillin 89.1 130,000

Enterococci Vancomycin 27.5 26,000

P. aeruginosa Ceftazidime 30.2 12,000

P. aeruginosa lmipenem 22.3 16,000

K. pneumoniae Ceftazidime 14.0 11 ,000

In addition to the obvious personal and health issues associated with nosocomial infection, there is a significant finical burden imparted on healthcare systems. Resistance has been estimated to cost the US economy $5 billion per annum and a nosocomial infection is estimated to quadruple average hospital patient costs from $44,367 to $173,206 for a given underlying morbidity of equal severity. The overall bill to the UK NHS for nosocomial infections is almost £1 billion per annum.

Although there is an obvious medical need for agents to treat these infections, there is a very empty pipeline for new antibacterials. Of all approvals in the last 30 years, there have been only 3 new classes approved and the overall number of new agents approved has fallen dramatically in the last 30 years.

Malaria and other protozoal diseases continue to pose serious health problems world-wide. Resistance of the malaria parasites, Plasmodium spp., to drugs such as chloroquine (and, more lately, quinine) occurs with increasing frequency and underlies the necessity to develop new agents for malaria chemotherapy. In the case of diseases caused by species of Leishmania and Trypanosoma there has always been a paucity of effective drugs, particularly those with a wide safety margin and minimal or no undesirable side effects. Novel drugs are required to help alleviate morbidity and mortality and to contribute to the world-wide control of theses diseases, in part by helping to reduce the reservoirs of infection.

With regard to fungal pathogens, the incidence of infections and mycoses has increased significantly in the past two decades mainly due to the growing number of immunocompromised patients (including cancer patients, transplant patients and AIDS patients) as well as the widespread use of cytotoxic and/or antibacterial drugs which alter the normal bacterial flora.

However, viral infections are among the greatest causes of human morbidity, with an estimated 60% or more, of all episodes of human illness in developed countries resulting from a viral infection. In addition, viruses infect virtually every organism in nature, with high virus infection rates occurring among all mammals, including humans, pets and livestock.

Viruses exhibit an extensive diversity in structure and life cycle. Virus particles are obligate parasites, and have evolved to transfer genetic material between cells and encode sufficient information to ensure their propagation. In a most basic form, a virus consists of a small segment of nucleic acid encased in a simple protein shell. The broadest distinction between viruses is the enveloped and nonenveloped viruses, i.e., those that do or do not contain, respectively, a lipid-bilayer membrane.

Glycosylation and viral infectivitv

A number of viral pathogens display heavily glycosylated envelope proteins on their surface. These glycosylated envelope proteins are central to the initial binding event between the virus particle and the target cell. In addition, the glycosylated envelope proteins are often centrally involved in the post-binding membrane fusion event required for a productive infection.

The plasma membrane of eukaryotic cells acts as a barrier against invading viruses. Thus, in order to infect a eukaryotic cell, an invading virus must first bind to the target host cell and then transport its genome and accessory proteins across its plasma membrane. In the case of enveloped viruses, entry into the host cell typically involves three steps: (i) attachment (typically to one or more host cell virus receptors); (W) co-receptor binding and (iii) membrane fusion. Specificity for one or more virus receptors may give rise to cell tropism. For example, viruses typically restrict the host cefls they infect by targeting receptors which are restricted to particular compartments, for example the gut (coronaviruses) or immune cells (HIV-1). .

Membrane fusion may occur by two different general mechanisms: (1) fusion of viral envelope and host cell plasma membrane; and (2) fusion of endosomal membrane with viral envelope following virus internalization by receptor-mediated host cell endocytosis. In both cases, membrane fusion is mediated by specific viral surface glycoproteins. Thus, many viral pathogens display heavily glycosylated envelope proteins on their surface.

Glycosylated envelope proteins are central to the initial binding event between the virus particle and the target cell. In addition, the glycosylated envelope proteins are often centrally involved in the post-binding membrane fusion event required for a productive infection. Viral fusion proteins undergo structural reorganization, changing from a nonfusogenic to fusogenic conformation.

Viral fusion glycoproteins are type I integral membrane proteins comprising a large ectodomain, a single transmembrane sequence and a small C-terminal endodomain. They contain N-linked carbohydrates and form oligomers at high density in the viral membrane. The particular segment involved in membrane fusion is known as the fusion peptide.

At least two classes of viral fusion peptide can be recognized on the basis of structural criteria. Class I fusion proteins are trimeric and have a predominantly α-helical secondary structure. The fusion peptide is located at the N-terminus. Class I fusion proteins are found in many important pathogens, for example retroviruses (including HIV, SIV, MoLV, HTLV-1), orthomyxoviruses (including influenza viruses), paramyxoviruses (including Sendai, SV5 and HRSV) and filoviruses (including Ebola). Class Il fusion proteins are dimeric and have a predominantly β-sheet secondary structure. The fusion peptide is located internally. Class Il fusion proteins are also found in important pathogens, including for example alphaviruses (including SFV) and flaviviruses (including dengue and TBE).

Despite their structural differences, both class I and class Il fusion proteins are believed to function by an essentially identical mechanism: the proteins exist in a metastable, prefusion conformation in the isolated virus particle and an irreversible transition to the post-fusion conformation provides the energy required for membrane fusion. A third class of fusion proteins (exemplified by the rhabdovirus fusion glycoprotein) has recently been recognized and is thought to function in a completely different manner from the class I and- class Il fusion peptides described above.

Flaviviruses

The fiavivirus group (family Flaviviridae) comprises the genera Flavivirus, Pestivirus and Hepacivirus and includes the causative agents of numerous human diseases and a variety of animal diseases which cause significant losses to the livestock industry.

The family Flaviviridae (members of which are referred to herein as flaviviruses) include the genera Flavivirus (e.g. yellow fever virus, dengue viruses, Japanese encephalitis virus, Murray Valley encephalitis virus, West Nile fever virus, Rocio virus, St. Louis encephalitis virus, Louping ill virus, Powassan virus, Omsk hemorrhagic fever virus, Kyasanur forest disease virus and tick-borne encephalitis virus), Pestivirus (e.g. bovine viral diarrhoea virus, rubella virus, classical swine fever virus, hog cholera virus and border disease virus), Hepacivirus (hepatitis C virus) and currently unclassified members of the Flaviviridae (e.g. GB virus types A, B and C). The full list of members of the Flaviviridae are defined in detail by the International Committee on Taxonomy of Viruses (the currently accepted taxanomic definition is described in: Virus Taxonomy: The Classification and Nomenclature of Viruses. The Seventh Report of the International Committee on Taxonomy of Viruses (M. H. V. van Regenmortel, CM. Fauquet, D. H. L. Bishop, E. B. Carstens, M. K. Estes, S. M. Lemon, J. Maniloff, M.A. Mayo, D.J. McGeoch, CR. Pringle, R.B. Wickner (2000). Virus Taxonomy, Vllth report of the ICTV. Academic Press, SanDiego), the content of which relating to the constitution of the family Flaviviridae is hereby incorporated by reference.

One particularly important flavivirus is the hepatitis C virus (HCV). HCV is an enveloped plus-strand RNA virus belonging to the Flaviviridae family, but classified as a distinct genus Hepacivirus. It was first identified in 1989 and it has since become clear that this virus is responsible for most cases of post-transfusion non-A, non-B hepatitis. Indeed, HCV is now recognised as one of the commonest infections causing chronic liver disease and the

World Health Organisation estimates that 170 million people are chronically infected. HCV infection results in a chronic infection in 85% of infected patients and approximately 20- 30% of these will progress to cirrhosis and end stage liver disease, frequently complicated by hepatocellular carcinoma.

The hepatitis C virus species is classified into six genotypes (1 to 6). Each genotype is further subclassified into distinct subtypes (represented by letters). These subtypes are then further broken down into quasispecies based on genetic characteristics. The preponderance and distribution of HCV genotypes varies globally. For example, in North America, genotype 1a predominates followed by 1 b, 2a, 2b, and 3a. In Europe, genotype 1 b is predominant followed by 2a, 2b, 2c, and 3a. Genotypes 4 and 5 are found almost exclusively in Africa.

The HCV genome consists of a single long open reading frame which encodes a -3000 amino acid residue polyprotein. This polyprotein is processed co- and post translationally into at least 10 different products including two N-linked glycosylated proteins E1 and E2. The genome carries at the 5' and 3' ends non-translated regions (NTRs) that form stable secondary and tertiary structures. The 5' NTR carries an internal ribosome entry site (IRES) permitting the direct binding of ribosomes in close proximity to the start codon of the ORF. Thus translation of HCV RNA is mediated by the IRES, rather than the CAP- dependent mechanism typically used by cellular mRNA.

Within the polyprotein, cleavage products are ordered as follows: core (C), envelope protein 1 (E1), E2, p7, non-structural protein 2 (NS2), NS3, NS4A, NS4B, NS5A and NS5B. The core protein is a highly basic RNA binding protein forming the major constituent of the nucleocapsid. The envelope proteins E1 and E2 are highly glycosylated type 1 membrane proteins anchored through the carboxy-terminal region. They are embedded into the lipid envelope of the virus particle and associate to form stable heterodimers. The cleavage product p7 is a small hydrophobic peptide of unknown function. The non-structural proteins are involved in viral replication and possess protease (NS2/NS3), helicase (NS3) and RNA polymerase activities (NS5B). Binding to the host cell probably requires the interaction of E2 or the E1/E2 complex with a receptor that is present on the cell surface.

The study of HCV has been hampered by the inability to propagate the virus efficiently in cell culture. However, in the absence of a suitable cell culture system able to support replication of human HCV, bovine diarrhoea virus (BVDV) is an accepted cell culture model. HCV and BVDV share a significant degree of local protein homology, a common replication strategy and probably the same subcellular location for viral envelopment. Such studies have suggested a model wherein initial virion morphogenesis occurs by budding into intracellular vesicles from the endoplasmic reticulum (ER). It is thought that mature E1-E2 heterodimers do not leave the ER, and ER retention signals have been identified in the C-terminal regions of both E1 and E2. In this case,the virus would be exported via the constitutive secretory pathway. In agreement with this assumption, complex N-linked glycans were found on the surface of partially purified virus particles suggesting that the virus transits through the Golgi.

Until recently, interferon-α (IFN-α) was the only therapy with proven benefit for the treatment of HCV infection. Using IFN-α up to 50% of patients show a response to treatment, but this is not sustainable in the majority of patients and there are considerable associated side effects. More recently, a combination of pegylated IFN-α (Pegasys™ and PEG-lntron™) and the antiviral drug ribavirin have been used. However, this treatment is associated with severe side effects, including anaemia, cardiovascular events and psychiatric problems. There is therefore a need for improved anti-viral drugs in general, and anti-HCV drugs in particular.

Glycoproteins and viral development

Glycoproteins are classified into two major classes according to the linkage between sugar and amino acid of the protein. The most common and extensively studied is N-glycosidic linkage between an asparagine of the protein and an N-acetyl-D-glucosamine residue of the oligosaccharide. N-linked oligosaccharides, following attachment to a polypeptide backbone, are processed by a series of specific enzymes in the endoplasmic reticulum (ER) and this processing pathway has been well characterised.

In the ER, α-glucosidase I is responsible for the removal of the terminal α-1 ,2 glucose ■residue from the precursor oligosaccharide and α-glucosidase Il removes the two remaining α-1,3 linked glucose residues, prior to removal of mannose residues by mannosidases and further processing reactions involving various transferases. These oligosaccharide "trimming" reactions enable glycoproteins to fold correctly and to interact with chaperone proteins such as calnexin and calreticulin for transport through the Golgi apparatus.

Inhibitors of key enzymes in this biosynthetic pathway, particularly those blocking α- glucosidases and α-mannosidase, have been shown to prevent replication of several enveloped viruses. Such inhibitors may act by interfering with the folding of the viral envelope glycoprotein, so preventing the initial virus-host cell interaction or subsequent fusion. They may also prevent viral duplication by preventing the construction of the proper glycoprotein required for the completion of the viral membrane.

For example, it has been reported that the nonspecific glycosylation inhibitors 2-deoxy-D- glucose and β-hydroxy-norvaline inhibit expression of HIV glycoproteins and block the formation of syncytia (Blough et al., Biochem., (1986), Biophys. Res; Comm., 141 (1), 33- 38). Viral multiplication of HIV-infected cells treated with these agents is stopped, presumably because of the unavailability of glycoprotein required for viral membrane formation. In another report, the glycosylation inhibitor 2-deoxy-2-fluoro-D-mannose was found to exhibit antiviral activity against influenza infected cells by preventing the glycosylation of viral membrane protein (McDowell et al., (1985), Biochemistry, 24(27), 8145-8152). This report also studied the antiviral activity of 2-deoxyglucose and 2-deoxy-2-fluoroglucose and found that each inhibits viral protein glycosylation by a different mechanism.

Lu et al. (1995) presented evidence that N-linked glycosylation is necessary for hepatitis B virus secretion (Virology, (1995) 213: 660-665) while Block et al. (1994) showed that secretion of human hepatitis B virus is inhibited by the iminosugar N-butyldeoxynojirimycin (Proc. Nat. Acad. ScL₁ (1994), 91 : 2235-2239). See also WO9929321 for further studies.

Taylor et al. (1988) demonstrated the loss of cytomegalovirus infectivity after treatment with castanospermine or other plant alkaloids and related this to abberant glycoprotein synthesis (Antiviral Res., (1988), 10: 1 1-26). See also US patent 5,004,746.

Taylor et al. (1994) showed that inhibition of α-glucosidase I of the glycoprotein processing enzymes by 6-0-butanoyl castanospermine has consequences in human immunodeficiency virus-infected T-cells (Antimicrob. Agents Chemother., (1994), 38: 1780-1787) while Sunkara et al. (1989) described anti-HIV activity of castanospermine analogues (Lancet, (1989), Il 1206). See also US patent 5,004,746.

US patent 5,385,911 discloses anti-herpes activity in certain castanospermine esters.

However, many other known glycosylation inhibitors have been found to have no antiviral activity. Thus the antiviral activity against enveloped viruses, in general, and the anti-viral activity, specifically, of glycosylation inhibitors is quite unpredictable.

Iminosugar glvcosidase inhibitors

It has long been recognized that many iminosugars are pharmacologically active, and humans have been using iminosugars (typically in the form of plant extracts) as poisons, narcotics, stimulants and medicines for thousands of years. The therapeutic applications of polyhydroxylated alkaloids have been comprehensively reviewed by Watson and colleagues (Watson et al., (2001 ), Phytochemistry, 56: 265-295) and these applications include cancer therapy, stimulation of the immune system, diabetes, infectious diseases (especially viral infections), glycosphingolipid lysosomal storage diseases and autoimmune disorders (such as arthritis and sclerosis).

It is also known that certain iminosugars, such as deoxynojirimycin (DNJ) and castanospermine, are ER α-glucosidase inhibitors and both potently inhibit the early stages of glycoprotein processing. However, their effects differ substantially depending on the system to which they are applied and they may exhibit quite different specificities, castanospermine being relatively specific for α-glucosidase I.

Branza-Nichita et al., (2001) J. Virol., 75(8): 3527-3536 showed that the iminosugar N- butyldeoxynojirimycin has an antiviral effect against the pestivirus BVDV. However, the authors make clear that while treatment with α-glucosidase inhibitors may affect the life cycles of this and other enveloped viruses, it is not possible to generalize to other viruses since the effects may depend crucially on the particular folding pathway used by the viral proteins.

Courageot et al., (2000) J. Virol., 74(1): 564-572 reported that the α-glucosidase inhibitors castanospermine and DNJ reduced dengue virus production in an in vitro mouse neuroblastoma model.

WO 99/29321 discloses the use of various iminosugar α-glucosidase inhibitors in the treatment of inter alia HCV infections.

The use of iminosugars containing the glucose analogue DNJ as antiviral agents against different viruses has been suggested since the late 1980s. While the action of DNJ and N- butyl DNJ (NB-DNJ) has been extensively described in the literature, the discovery of the antiviral action of a longer alkyl chain derivative of DNJ, N-nonyl DNJ (N-DNJ), was reported only relatively recently (see Zitzmann et al., (1999), Proc. Nat. Acad. Sci. 96: 11878-11882).

DNJ and its N-alkylated derivatives have been shown to inhibit α-glucosidase I and/or α- glucosidase II, so preventing the interaction of calnexin (CNX) and/or calreticulin (CRT) with folding glycoproteins. N-alkylation of DNJ has been shown to increase its inhibitory potency: N-nonyl-DNJ (NN-DNJ), a 9-carbon alkyl derivative of DNJ, has been found to be at least 20 times more potent than the non-alkylated DNJ in inhibiting hepatitis B virus (HBV) and BVDV in cell based assays. Other N-substituted DNJ derivatives (including N- methoxy-nonyl-DNJ and N-butyl-cyclohexyl DNJ) have also been shown to have improved potency (the N-methoxy analogue being the most potent, exhibiting micromolar antiviral activity).

However, ER α-glucosidase inhibition does not correlate precisely with antiviral activity: the less active NB-DNJ is a more effective ER α-glucosidase inhibitor than NN-DNJ. Moreover, the short-chain N-butyl-DGJ (NB-DGJ) exhibits no antiviral activity, whereas its long-chain derivative NN-DGJ is a potent antiviral. Thus, an additional mechanism of action may appear to be associated with the length of the N-alkyl side chain, and it has recently been suggested that this may be based on the inhibition of an ion channel formed by the HCV p7 protein (Pavlovic et al., (2003), Proc. Nat. Acad. Sci. 100(10): 6104-6108; see also WO2004/047719). However, further studies (Mehta et al., (2004) Antimicrob. Agents Chemother., 48(6): 2085-2090) have shown that at least one alkovir (N-9- oxadecyl-6-methyl-DGJ) inhibits HCV under conditions where p7 is not present, suggesting that p7 inhibition may not be the sole mechanism of alkoviral activity.

lminosugars mediating an antiviral effect via α-glucosidase inhibition (for example, DNJ and NB-DNJ) have been dubbed glucovirs, whereas those (such as NN-DGJ and Λ/-7- oxanonyl-6-deoxy-DGJ) mediating an antiviral effect independently of α-glucosidase inhibition (for example by interfering with viral p7 protein as described infra) have been dubbed alkovirs (see Block and Jordan, (2001), Antivir. Chem. Chemother. 12(6): 317- 325).

The use of current iminosugar α-glucosidase inhibitors in general (and DNJ and other piperidine derivatives in particular) as antiviral drugs is limited by toxicity arising from the subsequent inhibition of gastrointestinal α-glycosidases at the concentrations required for therapeutic effects. There is therefore much interest in alkovirs, since toxicity arising from co-inhibition of gastrointestinal α-glycosidases may be avoided by members of this class. Indeed, the N-substituted iminosugar Λ/-7-oxanonyl-6-deoxy-DGJ (Λ/-7-oxanonyl-6- methyldeoxygalactonojirimycin; Λ/-7-oxanonyl-6-MeDGJ) was entered into phase I clinical studies (as UT 231 -B) in 2002. The present inventors have now surprisingly discovered that certain iminosugars exhibit antiviral activity. Moreover, they have found that the therapeutic index is unexpectedly superior to that exhibited by known α-glucosidase inhibitors of the iminosugar class.

Summary of the Invention

According to a first aspect of the present invention there is provided a compound of Formula (1)

in which

n represents an integer from 1 to 7, provided that where n>1 the ring may also contain at least one unsaturated C-C bond

z represents an integer from 1 to (n+2)

y represents 1 or 2

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(O)OR³; C(O)NR³R⁴; SO₂NR³; OH, OR³, or formyl

R² represents OH; OR³; =0; NH₂; N₃; SH; SO_xR³; halo; CN; NO₂; NR³R⁴; (NR³)NR³R⁴; NH(NR³)NR³R⁴; CO₂R⁴; OC(O)R³; CONR³R⁴; NR⁴C(O)R³; NR⁴SO₂R³;

P(O)(OR³)₂; C1-15 alkyl or alkenyl optionally substituted with one or more OH, OR³, =0, NH₂, N₃, SH, SO_xR³, halo, CN, NO_2, NR³R⁴, (NR³)NR³R⁴, NH(NR³)NR³R⁴, CO₂R⁴, OC(O)R³, CONR³R⁴, NR⁴C(O)R³, NR⁴SO₂R³, P(O)(OR³)₂, aryl or carbocyclyl groups; carbocyclyl or aryl, either of which is optionally substituted with one or more OH, OR³, =O, NH₂, N₃, SH, SO_xR³, halo, CN, NO₂, NR³R⁴,

(NR³)NR³R⁴, NH(NR³)NR³R⁴, CO₂R⁴, OC(O)R³, CONR³R⁴, NR⁴C(O)R³, NR⁴SO₂R³, P(O)(OR³)₂, C1-9 alkyl optionally substituted with one or more OH, OR³, =0, NH₂, N₃, halo, CN, NO₂, NR³R⁴, CO₂R⁴, CONR³R⁴, aryl or carbocyclyl groups; O- glycosyl; C-glycosyl; O-sulfate; O-phosphate or a group which together with the endocyclic carbon forms a spiro ring, with the provisos that: (a) two OH groups may not be attached to the same endocyclic carbon atom; (b) where there is only one R² substituent it contains an oxygen atom directly bonded to an endocyclic carbon atom; and (c) where z>1 any two R² substituents may together form an optionally heterocyclic ring (for example a carbocycle, cyclic ether or acetal)

R³ represents H; C 1-6 alkyl, optionally substituted with one or more OH; aryl or C1- 3 alkyl optionally substituted with aryl; SiR⁴ ₃ and

R⁴ represents H; C1-6 alkyl, optionally substituted with one or more OH

R³ and R⁴ may optionally form a 4 to 8 membered ring, containing one or more O, SO_x or NR³ groups

x represents an integer from O to 2

or a pharmaceutically acceptable salt or derivative thereof, for the treatment of infection with, or a disease caused by, an infectious agent.

In a second aspect, the invention provides a compound of Formula (2)

in which

p represents an integer from 1 to 2

z represents an integer from 1 to (p+7) y represents 1 or 2

the broken line represents a bridge containing 2 or 3 carbon atoms between any two different ring carbon atoms, any or all of which bridge or bridgehead carbon atoms being optionally substituted with R²

R¹ represents H; C1-15 alky!, 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(O)OR³; C(O)NR³R⁴; SO₂NR³; OH, OR³, or formyl

R² represents OH; OR³; =0; NH₂; N₃; SH; SO_xR³; halo; CN; NO₂; NR³R⁴; (NR³)NR³R⁴; NH(NR³)NR³R⁴; CO₂R⁴; OC(O)R³; CONR³R⁴; NR⁴C(O)R³; NR⁴SO₂R³; P(O)(OR³)₂; C1-15 alkyl or alkenyl optionally substituted with one or more OH, OR³, =0, NH₂, N₃, SH, SO_xR³, halo, CN, NO₂, NR³R⁴, (NR³)NR³R⁴, NH(NR³)NR³R⁴, CO₂R⁴, OC(O)R³, CONR³R⁴, NR⁴C(O)R³, NR⁴SO₂R³, P(O)(OR³)₂, aryl or carbocyclyl groups; carbocyclyl or aryl, either of which is optionally substituted with one or more OH, OR³, =0, NH₂, N₃, SH, SO_xR³, halo, CN, NO₂, NR³R⁴, (NR³)NR³R⁴, NH(NR³)NR³R⁴, CO₂R⁴, OC(O)R³, CONR³R⁴, NR⁴C(O)R³, NR⁴SO₂R³, P(0)(OR³)₂, C1-9 alkyl optionally substituted with one or more OH, OR³, =0, NH₂, N₃, halo, CN, NO₂, NR³R⁴, CO₂R⁴, CONR³R⁴, aryl or carbocyclyl groups; O- glycosyl; C-glycosyl; O-sulfate; O-phosphate or a group which together with the endocyclic carbon forms a spiro ring, with the provisos that: (a) two OH groups may not be attached to the same endocyclic carbon atom; (b) where there is only one R² substituent it contains an oxygen atom directly bonded to an endocyclic carbon atom; and (c) where z>1 any two R² substituents may together form an optionally heterocyclic ring (for example a carbocycle, cyclic ether or acetal)

R³ represents H; C1-6 aikyl, optionally substituted with one or more OH; aryl or C1- 3 alkyl optionally substituted with aryl; SiR⁴ ₃ and

R⁴ represents H; C1-6 alkyl, optionally substituted with one or more OH

R³ and R⁴ may optionally form a 4 to 8 membered ring, containing one or more O, SO_x or NR³ groups x represents an integer from 0 to 2

or pharmaceutically acceptable salt or derivative thereof, for the treatment of infection with, or a disease caused by, an infectious agent.

In a third aspect, the invention provides a compound of Formula (3)

(3)

in which

n represents an integer from 1 to 7, for example 1 to 5, provided that where n>1 the ring may also contain at least one unsaturated C-C bond

m represents an integer from 1 to 3 and the ring may also contain at least one unsaturated C-C bond

z represents an integer from 0 to (n+2), provided that where z = 0 then y ≥ 1

y represents an integer from 0 to (m+2), provided that where y = 0 then z > 1

the endocyclic nitrogen atom may be bonded to an oxygen or an oxygen containing group such that the compound is an N-oxide,

R² represents OH; OR³; =0; NH₂; N₃; SH; SO_xR³; halo; CN; NO₂; NR³R⁴;

(NR³)NR³R⁴; NH(NR³)NR³R⁴; CO₂R⁴; OC(O)R³; CONR³R⁴; NR⁴C(O)R³; NR⁴SO₂R³; P(O)(OR³)₂; C1-15 alkyl or alkenyl optionally substituted with one or more OH, OR³, =0, NH₂, N₃, SH, SO_xR³, halo, CN, NO₂, NR³R⁴, (NR³)NR³R⁴, NH(NR³)NR³R⁴, CO₂R⁴, OC(O)R³, CONR³R⁴, NR⁴C(O)R³, NR⁴SO₂R³, P(O)(OR³)₂, aryl or carbocyclyl groups; carbocyclyl or aryl, either of which is optionally substituted with one or more OH, OR³, =0, NH₂, N₃, SH, SO_xR³, halo, CN, NO₂, NR³R⁴, (NR³)NR³R⁴, NH(NR³)NR³R⁴, CO₂R⁴, OC(O)R³, CONR³R⁴, NR⁴C(O)R³, NR⁴SO₂R³, P(O)(OR³)₂, C1-9 alkyl optionally substituted with one or more OH₁ OR³, =0, NH₂, N₃, halo, CN, NO₂, NR³R⁴, CO₂R⁴, CONR³R⁴, aryl or carbocyclyl groups; O- glycosyl; C-glycosyl; O-sulfate; O-phosphate or a group which together with the endocyclic carbon forms a spiro ring, with the provisos that: (a) two OH groups may not be attached to the same endocyclic carbon atom; (b) where there is only one R² substituent it contains an oxygen atom directly bonded to an endocyclic carbon atom; and (c) where z>1 any two R² substituents may together form an optionally heterocyclic ring (for example a carbocycle, cyclic ether or acetal)

R³ represents H; C1-6 alkyl, optionally substituted with one or more OH; aryl or C1- 3 alkyl optionally substituted with aryl; SiR⁴ ₃ and

R⁴ represents H; C1-6 alkyl, optionally substituted with one or more OH

x represents an integer from O to 2

optionally wherein the compound has three, four or more rings

In a further aspect, the invention provides an iminosugar as herein defined for the treatment of infection with, or a disease caused by, an infectious agent.

In a yet further aspect, the invention provides a compound selected from compounds \ to 892 of Table 1 , or a pharmaceutically acceptable salt or derivative thereof, for the treatment of infection with, or a disease caused by, an infectious agent.

Other aspects and preferred embodiments of the invention are defined and described in the claims set out below. The invention also contemplates adjunctive use of the compounds of the invention with various adjunctive agents. The adjunctive agent may comprise any of the agents described below in Section G.

In preferred embodiments, the adjunctive agent is an antiviral compound, for example an anti-HCV drug. Particularly preferred are adjunctive therapeutics comprising interferon-α and/or ribavirin.

Thus, in another aspect, the invention provides a composition comprising a compound of the invention in combination with the various adjunctive agents described herein, including for example: (a) compounds which inhibit the binding to and/or infection of cells by HCV. These include antibodies (e.g. monoclonal antibodies) against, for example, HCV E1 and/or E2 proteins) and glucosaminoglycans (such as heparan sulphate and suramin); (b) compounds which inhibit the release of viral RNA from the viral capsid or the function of HCV gene products, including inhibitors of the IRES, protease (e.g. serine protease) inhibitors, helicase inhibitors and inhibitors of the viral polymerase/replicase; (c) compounds which perturb cellular functions involved in or influencing viral replication, including inhibitors of inosine monophosphate dehydrogenase (e.g. Ribavirin, mycophenolic acid and VX497) and inhibitors of glycoprotein processing such as DNJ and its derivatives; (d) compounds which act to alter immune function (e.g. thymosin alpha and interferons such as α interferons and β interferons) and (e) compounds which act to modulate the symptoms and effects of HCV infection (e.g. antioxidants such as the flavinoids).

In addition the invention provides a composition comprising a compound of the invention in combination with compounds used in the treatment of frequently found co-infections (such as hepatitis B virus and the human retroviruses such as human immunodeficiency viruses types 1 and 2 and human T-cell lymphotrophic viruses types 1 and 2). Examples of such compounds include nucleotide/nucleoside RT inhibitors (e.g. Lamivudine (3TC), zidovudine, stavudine, didanosine, adefovir dipivoxil and abacavir), non-nucleoside RT inhibitors (e.g. nevirapine) and and protease inhibitors (e.g. saquinavir, indinavir and ritonavir). Preferably, the interferon is interferon-α (IFN-α), though other interferons may also be used (for example an interferon produced by expression of a cloned human interferon gene).

In another aspect, the invention provides a pharmaceutical kit of parts comprising a compound of the invention in combination with the various adjunctive agents described herein, including for example: (a) compounds which inhibit the binding to and/or infection of cells by HCV; (b) compounds which inhibit the release of viral RNA from the viral capsid or the function of HCV gene products; (c) compounds which perturb cellular functions involved in or influencing viral replication; (d) compounds which act to alter immune function, and (e) compounds which act to modulate the symptoms and effects of HCV infection, as described above.

The kit may also further comprise instructions for use in the treatment of an infectious disease (for example in the flaviviral diseases described herein).

In the compositions of the invention the compound of the invention and the various adjunctive agents described herein may act in a complementary or synergistic fashion. Particularly preferred are compositions and methods comprising both the compound of the invention and interferon which act in a synergistic fashion in the treatment of HCV infection.

Detailed Description of the Invention

All publications, patents, patent applications and other references mentioned herein are hereby incorporated by reference in their entireties for all purposes as if each individual publication, patent or patent application were specifically and individually indicated to be incorporated by reference and the content thereof recited in full.

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.

The phrase "consisting essentially of" is used herein to require the specified integer(s) or steps as well as those which do not materially affect the character or function of the claimed invention.

As used herein, the term "consisting" is used to indicate the presence of the 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) alone.

As used herein, the term "flavivirus" refers to any virus of the family Flaviviridae, including in particular any virus of the genera Flavivirus, Pestivirus and Hepacivirus and so including in particular the hepatitis C virus (HCV).

The term Gram-positive bacterium is a term of art defining a particular class of bacteria that are grouped together on the basis of certain cell wall staining characteristics.

The term low G+C Gram-positive bacterium is a term of art defining a particular subclass class of evolutionarily related bacteria within the Gram-positives on the basis of the composition of the bases in the DNA. The subclass includes Streptococcus spp.,

Staphylococcus spp., Listeria spp., Bacillus spp., Clostridium spp., Enterococcus spp. and Lactobacillus spp.).

The term high G+C Gram-positive bacterium is a term of art defining a particular subclass class of evolutionarily related bacteria within the Gram-positives on the basis of the composition of the bases in the DNA. The subclass includes actinomycetes (actinobacteria) including Actinomyces spp., Arthrobacter spp., Corynebacteήum spp., Frankia spp., Micrococcus spp., Micromonospora spp., Mycobacterium spp,, Nocardia spp., Propionibacterium spp. and Streptomyces spp.

As used herein, the term "disease" is used to define any abnormal condition that impairs physiological function and is associated with specific symptoms. The term is used broadly to encompass any disorder, illness, abnormality, pathology, sickness, condition or syndrome in which physiological function is impaired irrespective of the nature of the aetiology (or indeed whether the aetiological basis for the disease is established). It therefore encompasses conditions arising from infection, trauma, injury, surgery, radiological ablation, poisoning or nutritional deficiencies.

As used herein, the term "infectious disease" refers to any disease that involves (e.g. is caused, exacerbated, associated with or characterized by the presence of) an infectious agent residing and/or replicating in the body and/or cells of a subject.

As used herein, the term "infection" is used to define a condition in which a subject is infected with an infectious agent. The infection may be symptomatic or asymptomatic. In the latter case, the subject may be identified as infected on the basis of various tests, including for example serological analyses (e.g. using antibodies and/or antigens).

The term "infectious" as used herein in relation to various diseases pathogens, organisms and agents is used to indicate the potential for direct or indirect transmission between subjects. The term does not imply any particular degree of infectivity on the part of the infectious organism, pathogen or agent, nor does it imply any particular degree of contagiousness or infectiousness when applied to a disease.

The term "infectious agent" is used to define any pathogen, organism or agent which can cause infectious disease in a subject. The term therefore covers microbial infectious agents (and in particular viral, bacterial and fungal infectious agents) as well as prion particles and metazoan organisms. In the latter case, the metazoan organism may be a parasite which can give rise to a transmissable infestation in a subject. As used herein, the term "viral disease" refers to any disease that involves (e.g. is caused, exacerbated, associated with or characterized by the presence of) a virus residing and/or replicating in the cells (or within the body) of a subject.

As used herein, the term "viral infection" is used to define a condition in which a subject is infected with a virus. The infection may be symptomatic or asymptomatic. In the latter case, the subject may be identified as infected on the basis of various tests, including for example serological analyses (e.g. using viral antibodies and/or antigens).

As used herein, the term "bacterial disease" refers to any disease that involves (e.g. is caused, exacerbated, associated with or characterized by the presence of) a bacterium residing and/or replicating in the body and/or cells of a subject.

As used herein, the term "bacterial infection" is used to define a condition in which a subject is infected with a bacterium. The infection may be symptomatic or asymptomatic. In the latter case, the subject may be identified as infected on the basis of various tests, including for example biochemical tests, serological tests, microbiological culture and/or microscopy.

As used herein, the term "fungal infection" is used to define a condition in which a subject is infected with a fungus. The infection may be symptomatic or asymptomatic. In the latter case, the subject may be identified as infected on the basis of various tests, including for example including for example microbiological culture or microscopy.

As used herein, the term "fungal disease" refers to any disease that involves (e.g. is caused, exacerbated, associated with or characterized by the presence of) a fungus residing and/or replicating in the body and/or cells of a subject.

As used herein, the term "protozoal disease" refers to any disease that involves (e.g. is caused, exacerbated, associated with or characterized by the presence of) a protozoan residing and/or replicating in the body and/or cells of a subject.

As used herein, the term "protozoal infection" is used to define a condition in which a subject is infected with a protozoan. The infection may be symptomatic or asymptomatic. In the latter case, the subject may be identified as infected on the basis of various tests, including for example microscopy.

As used herein, the term "metazoan disease" refers to any disease that involves (e.g. is caused, exacerbated, associated with or characterized by the presence of) a metazoan residing and/or replicating within the body of a subject.

As used herein, the term "metazoal infection" (or "metazoal infestation") is used to define a condition in which a subject is infected or infested with a metazoan. The infection may be symptomatic or asymptomatic. In the latter case, the subject may be identified as infected on the basis of various tests, including for example microscopy (e.g. using stool samples).

As used herein, the term "prion disease" refers to any disease that involves (e.g. is caused, exacerbated, associated with or characterized by the presence of) a prion residing and/or replicating in the cells (or within the body) of a subject.

As used herein, the term "prion infection" is used to define a condition in which a subject is infected with a prion. The infection may be symptomatic or asymptomatic. In the latter case, the subject may be identified as infected on the basis of various tests, including for example serological analyses (e.g. using prion antibodies and/or antigens).

As used herein, the term "flaviviral disease" refers to any disease that involves (e.g. is caused, exacerbated, associated with or characterized by the presence of) a virus of the family Flaviviridae residing and/or replicating in the cells (or within the body) of a subject.

As used herein, the term "flaviviral infection" is used to define a condition in which a subject is infected with a virus of the family Flaviviridae (i.e. is infected with a flavivirus as hereinbefore defined). The infection may be symptomatic or asymptomatic. In the latter case, the subject may be identified as infected on the basis of various tests, including for example serological analyses (e.g. using HCV antibodies and/or antigens).

The terms pathostatic and pathocidal are terms of art used to define the ability to prevent (or reduce the rate of) pathogen growth or replication and to mediate (directly or indirectly) the cellular destruction of pathogenic agents, respectively. The terms are not mutually exclusive, and many agents exert both pathostatic and pathocidal effects (in some cases in a dose-specific or target-specific manner). In general, pathocidal agents yield better therapeutic results and are preferred.

The terms virostatic and virocidal are terms of art used to define the ability to prevent (or reduce the rate of) viral replication and to mediate (directly or indirectly) the cellular destruction of viral particles, respectively. The terms are not mutually exclusive, and many antiviral agents exert both virostatic and virocidal effects (in some cases in a dose-specific or target-specific manner). In general, virocidal compounds yield better therapeutic results and are preferred.

The terms bacteriostatic and bacteriocidal are terms of art used to define the ability to prevent (or reduce the rate of) bacterial growth and to mediate (directly or indirectly) the cellular destruction of bacterial cells, respectively. The terms are not mutually exclusive, and many antimycotic agents ^'exert both bacteriostatic and bacteriocidal effects (in some cases in a dose-specific or target-specific manner). In general, bacteriocidal agents yield better therapeutic results and are preferred.

The terms fungistatic and fungicidal are terms of art used to define the ability to prevent (or reduce the rate of) fungal growth and to mediate (directly or indirectly) the cellular destruction of fungal cells, respectively. The terms are not mutually exclusive, and many antimycotic agents exert both fungistatic and fungicidal effects (in some cases in a dose- specific or target-specific manner). In general, fungicidal antimycotics yield better therapeutic results and are preferred.

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) (for example, the causitive pathogen in the case of infectious diseases). In this case, the term is used synonymously with the term "therapy". Thus, the treatment of infection according to the invention may be characterized by the (direct or indirect) pathostatic and/or pathocidal action of the compounds of the invention.

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 "intervention" is a term of art used herein to define any agency which effects a physiological change at any level. Thus, the intervention may comprise the induction or repression of any physiological process, event, biochemical pathway or cellular/biochemical event. The interventions of the invention typically effect (or contribute to) the treatment (i.e. therapy or prophylaxis as herein defined) of a disease and typically involve the administration of an agent to a subject.

In this context "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, domestic animals, farm animals, zoo animals, sport animals, pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows; primates such as apes, monkeys, orangutans, and chimpanzees; canids such as dogs and wolves; felids such as cats, lions, and tigers; equids such as horses, donkeys, and zebras; food animals such as cows, pigs, and sheep; ungulates such as deer and giraffes; rodents such as mice, rats, hamsters and guinea pigs; and so on. In preferred embodiments, the subject is a human.

As used herein, an effective amount or a therapeutically effective amount of a compound 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, a "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

The term "adjunctive" as applied to the use of the compounds of the invention in therapy or prophylaxis defines uses in which the compound is administered together with one or more other drugs, interventions, regimens or treatments (such as surgery and/or irradiation). Such adjunctive therapies may comprise the concurrent, separate or sequential administration/application of the materials of the invention and the other treatment(s). Thus, in some embodiments, adjunctive use of the materials of the invention is reflected in the formulation of the pharmaceutical compositions of the invention. For example, adjunctive use may be reflected in a specific unit dosage, or in formulations in which the compound of the invention is present in admixture with the other drug(s) with which it is to be used adjunctively (or else physically associated with the other drug(s) within a single unit dose). In other embodiments, adjunctive use of the compounds or compositions of the invention may be reflected in the composition of the pharmaceutical kits of the invention, wherein the compound of the invention is co-packaged (e.g. as part of an array of unit doses) with the other drug(s) with which it is to be used adjunctively. In yet other embodiments, adjunctive use of the compounds of the invention may be reflected in the content of the information and/or instructions co-packaged with the compound relating to formulation and/or posology.

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.

As used herein, the term "patient pack" defines a package, prescribed to a patient, which contains pharmaceutical compositions for the whole course of treatment. Patient packs usually contain one or more blister pack(s). Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient's supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in patient prescriptions. The inclusion of a package insert has been shown to improve patient compliance with the physician's instructions.

The combinations of the invention may produce a therapeutically efficacious effect relative to the therapeutic effect of the individual compounds/agents when administered separately.

The term iminosugar defines a saccharide analogue in which the ring oxygen is replaced by a nitrogen. The term is used herein sensu lato to include isoiminosugars, these being aza-carba analogues of sugars in which the C-1 carbon is replaced by nitrogen and the ring oxygen is replaced by a carbon atom, as well as azasugars in which an endocyclic carbon is replaced with a nitrogen atom. 1 -Azasugars (with the N in the anomeric position) in which the ring oxygen is substituted with a carbon atom are isoiminosugars (as herein defined), but 1-azasugars in which the ring oxygen remains unsubstituted (oxazines) or is substituted with a nitrogen atom (hydrazines) are also of particular importance. In all cases, one or more endocyclic carbon atoms may be substituted with a sulphur, oxygen or nitrogen atom.

As used herein, the term glycosylation modulator encompasses any agent which alters relinked or O-linked oligosaccharide structures on viral envelope glycoproteins. Preferably the glycosylation modulator is a glucosidase I or glycosidase I inhibitor. Particularly preferred glycosylation inhibitors are glycovirs. Most preferred glycosylation inhibitors are glucovirs.

The term alkovir ls a term of art (see Block and Jordan, (2001), Antivir. Chem. Chemother. 12(6): 317-325) and is used herein to define a family of iminosugars which exert antiviral activity independently of ER α-glucosidase inhibition. Alkovirs therefore include iminosugars which act to inhibit antiviral activity by mechanisms which are wholly independent of ER α-glucosidase inhibition (such alkovirs not being ER α-glucosidase inhibitors), as well as iminosugars which exert antiviral activity by a combination of ER α- glucosidase inhibition and one or more other modes of action (for example, interference with viral p7 protein or by immunomodulatory activity).

The term glucovir is a term of art (see Block and Jordan, (2001), Antivir. Chem. Chemother. 12(6): 317-325) and is used herein to define a family of iminosugars which exert antiviral activity, at least in part, by ER α-glucosidase inhibition. Glucovirs therefore include iminosugars which act to inhibit antiviral activity by ER α-glucosidase inhibition, as well as iminosugars which exert antiviral activity by a combination of ER α-glucosidase inhibition and one or more other modes of action (for example, interference with viral p7 protein or by immunomodulatory activity). Thus, the alkovir and glucovir iminosugar families as herein defined partially overlap.

The analogous term glycovir is used herein as a more generic term than glucovir (as defined above) to define a class of iminosugars which exert antiviral activity, at least in part, by glycosidase inhibition. Thus, glucovirs form a subclass of the broader glycovir class of antiviral iminosugars. Thus, glycovirs and glucovirs suitable for use according to the invention may be glycosylation modulators as herein defined. As used herein, the term polyhydroxylated iminosugar defines a class of oxygenated iminosugars. Typically these have at least 2, 3, 4, 5, 6 or 7 (preferably 3, 4 or 5) hydroxyl groups (or alkyl groups with one or more hydroxy substituent(s)) on the ring system nucleus.

The term iminosugar acid defines mono- or bicyclic sugar acid analogues in which the ring oxygen is replaced by a nitrogen. The term N-acid ISA defines an iminosugar acid in which the carboxylic acid group is located on the ring nitrogen.

Preferred ISAs are selected from the following structural classes: piperidine (including (poly)hydroxypipecolic acids); pyrroline; pyrrolidine (including (poly)hydroxyprolines); pyrrolidine; indolizidine and nortropane.

As used herein, the term polyhydroxylated as applied to iminosugar acids defines an ISA having at least 2 (preferably at least 3) hydroxyl groups (or alkyl groups with one or more hydroxy substituent(s)) on the ring system nucleus.

As used herein, the term bicyclic polyhydroxylated iminosugar defines a class of highly oxygenated iminosugars having a double or fused ring nucleus (i.e. having two or more cyclic rings in which two or more atoms are common to two adjoining rings). Typically, such iminosugars have at least 3, 4, 5, 6 or 7 (preferably 3, 4 or 5) free hydroxyl groups on the ring system nucleus.

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.

The term ligand as used herein in relation to the compounds of the invention is intended to define those compounds which can act as binding partners for a biological target molecule in vivo (for example, an enzyme or receptor, such as a pathogen-(or pattem-)recognition receptor (PRR)). Such ligands therefore include those which bind (or directly physically interact) with the target in vivo irrespective of the physiological consequences of that binding. Thus, the ligands of the invention may bind the target as part of a cellular signalling cascade in which the target forms a part. Alternatively, they may bind the target in the context of some other aspect of cellular physiology. In the latter case, the ligands may for example bind the target at the cell surface without triggering a signalling cascade, in which case the binding may affect other aspects of cell function. Thus, the ligands of the invention may bind the target and thereby effect an increase in the concentration of functional target at the cell surface (for example mediated via an increase in target stability, absolute receptor numbers and/or target activity). Alternatively, the iminosugar ligands may bind target (or target precursors) intracellular^, in which case they may act as molecular chaperones to increase the expression of active target.

The term PRR ligand as used herein in relation to the compounds for use according to the invention defines compounds which can act as binding partners for a PRR. Such compounds therefore include those which bind (or directly physically interact) with a PRR in vivo irrespective of the physiological consequences of that binding. Thus, the ligands of the invention may bind a PRR as part of a cellular signalling cascade in which the PRR forms a part. Alternatively, they may bind PRR in the context of some other aspect of cellular physiology. In the latter case, the ligands may for example bind PRR at the cell surface without triggering a signalling cascade, in which case the binding may affect other aspects of cell function. Thus, the ligands of the invention may bind PRRs and thereby effect an increase in the concentration of functional PRR at the cell surface (for example mediated via an increase in PRR stability, absolute receptor numbers and/or PRR activity). Alternatively, the ligands may bind PRR (or PRR precursors) intracellular^, in which case they may act as molecular chaperones to increase the expression of active PRR.

In preferred embodiments, the PRR ligands of the invention are PRR agonists. The term agonist is used herein in relation to the PRR ligands of the invention to define a subclass of ligands which productively bind PRR to trigger the cellular signalling cascade of which the PRR forms a part.

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.

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 terms derivative and pharmaceutically acceptable derivative as applied to the compounds of the invention define compounds which are obtained (or obtainable) by chemical derivatization of the parent compound of the invention. The pharmaceutically acceptable derivatives are therefore suitable for administration to or use in contact with the tissues of humans 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.

The pharmaceutically acceptable derivatives of the invention may retain some or all of the biological activities described herein. In some cases, the biological activity (e.g. chaperone activity) is increased by derivatization. The derivatives may act as pro-drugs, and one or more of the biological activities described herein (e.g. pharmacoperones activity) may arise only after in vivo processing. Particularly preferred pro-drugs are ester derivatives which are esterified at one or more of the free hydroxyls and which are activated by hydrolysis in vivo. Derivatization may also augment other biological activities of the compound, for example bioavailability and/or glycosidase inhibitory activity and/or glycosidase inhibitory profile. For example, derivatization may increase glycosidase inhibitory potency and/or specificity and/or CNS penetration (e.g. penetration of the blood-brain barrier).

The term pharmaceutically acceptable salt as applied to the iminosugars 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).

These salts and the free base compounds can exist in either a hydrated or a substantially anhydrous form. Crystalline forms, including all polymorphic forms, of the iminosugars of the invention are also contemplated and in general the acid addition salts of the compounds are crystalline materials which are soluble in water and various hydrophilic organic solvents and which in comparison to their free base forms, demonstrate higher melting points and an increased solubility. In the present specification the term "alkyl" defines a straight or branched saturated hydrocarbon chain. The term "C₁-C₆ alkyl" refers to a straight or branched saturated hydrocarbon chain having one to six carbon atoms. The term "C₁-C₉ alkyl" refers to a straight or branched saturated hydrocarbon chain having one to nine carbon atoms. The term "C₁-C₁₅ alkyl" refers to a straight or branched saturated hydrocarbon chain having one to fifteen carbon atoms. Preferred is Ci-C₆ alkyl. Examples include methyl, ethyl, n-propyl, isopropyl, t-butyl, n-hexyl. The alkyl groups of the invention may be optionally 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 "C₁-C₆ alkenyl" refers to a straight or branched unsaturated hydrocarbon chain having one to six carbon atoms. The term "C₁-Cg alkenyl" refers to a straight or branched unsaturated hydrocarbon chain having one to nine carbon atoms. The term "C₁-C₁₅ alkenyl" refers to a straight or branched unsaturated hydrocarbon chain having one to fifteen carbon atoms. Preferred is C₁-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 "C₁-C₆ alkynyl" refers to a straight or branched unsaturated hydrocarbon chain having one to six carbon atoms. The term "C₁-C₉ alkynyl" refers to a straight or branched unsaturated hydrocarbon chain having one to nine carbon atoms. The term "C₁-Ci₅ alkynyl" refers to a straight or branched unsaturated hydrocarbon chain having one to fifteen carbon atoms. Preferred is C₁-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.

As used herein, the term "carbocyclyl" means a mono- or polycyclic residue containing 3 or more (e.g. 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.

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 tricyclic 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. As used herein, the term "aryl" includes heteroaryls containing heteroatoms (e.g. nitrogen, sulphur and/or oxygen) being otherwise as defined above. The aryl groups of the invention may optionally be substituted by one or more halogen atoms. Examples of aromatic moieties are benzene, naphthalene, imidazole and pyridine.

In the present specification, "halo" refers to fluoro, chloro, bromo or iodo.

Compounds for use according to the invention

Certain compounds as described below (e.g. those compounds of Formula (1), (2) or (3) described in Section A(I) and/or the iminosugars described in Section A(II)) are novel.

According to the invention, those compounds which are novel are claimed as compounds perse, together with processes for their preparation, compositions containing them, as well as their use as pharmaceuticals (for example in any of the particular medical uses described herein).

Moreover, to the extent that certain of the compounds as described below (e.g. those compounds of Formula (1), (2) or (3) described in Section A(I) and/or the iminosugars described in Section A(II)) are known as such but not as pharmaceuticals, those compounds are claimed for use as pharmaceuticals (for example in any of the particular medical uses described herein).

A. Structural considerations

(I) Compounds of Formula (1), (2) or (3) The compounds for use according to the invention may comprise a nucleus selected from those shown below and numbered (1), (2) and (3):

(i) Compounds of Formula (1)

The compounds for use according to the invention may be of Formula (1)

in which

z represents an integer from 1 to (n+2)

y represents 1 or 2

R² represents OH; OR³; =0; NH₂; N₃; SH; SO_xR³; halo; CN; NO₂; NR³R⁴; (NR³)NR³R⁴; NH(NR³)NR³R⁴; CO₂R⁴; OC(O)R³; CONR³R⁴; NR⁴C(O)R³; NR⁴SO₂R³; P(O)(OR³)₂; C1-15 alkyl or alkenyl optionally substituted with one or more OH₁ OR³, =0, NH₂, N₃, SH, SO_xR³, halo, CN, NO₂, NR³R⁴, (NR³)NR³R⁴, NH(NR³)NR³R⁴, CO₂R⁴, OC(O)R³, CONR³R⁴, NR⁴C(O)R³, NR⁴SO₂R³, P(O)(OR³)₂, aryl or carbocyclyl groups; carbocyclyl or aryl, either of which is optionally substituted with one or more OH, OR³, =O, NH₂, N₃, SH, SO_xR³, halo, CN, NO₂, NR³R⁴,

(NR³)NR³R⁴, NH(NR³)NR³R⁴, CO₂R⁴, OC(O)R³, CONR³R⁴, NR⁴C(O)R³, NR⁴SO₂R³, P(O)(OR³)₂, C1-9 alkyl optionally substituted^'with one or more OH, OR³, =0, NH₂, N₃, halo, CN, NO₂, NR³R⁴, CO₂R⁴, CONR³R⁴, aryl or carbocyclyl groups; O- glycosyl; C-glycosyl; O-sulfate; O-phosphate or a group which together with the endocyclic carbon forms a spiro ring, with the provisos that: (a) two OH groups may not be attached to the same endocyclic carbon atom; (b) where there is only one R² substituent it contains an oxygen atom directly bonded to an endocyclic carbon atom; and (c) where z>1 any two R² substituents may together form an optionally heterocyclic ring (for example a carbocycle, cyclic ether or acetal)

R⁴ represents H; C1-6 alkyl, optionally substituted with one or more OH

x represents an integer from O to 2

or a pharmaceutically acceptable salt or derivative thereof.

In preferred embodiments, the compound of Formula (1) is selected from any one of the Formulae shown below:

wherein:

r represents an integer from 1 to (n+4)

s represents an integer from 1 to (n+4)

n represents an integer from O to 2

R¹ represents C1-9 alkyl, optionally substituted with up to 6 OH, NR³R⁴, aryl, O-C1- 3 alkyl, O-C1-3 alkenyl, CO₂H, NH(NH)NH₂, CONR³R⁴; C(O)OR³; C(O)NR³R⁴; SO₂NR³

R² represents =0; C1-9 alkyl, C1-9 alkenyl, aryl, optionally substituted with up to 6 OH, NR³R⁴, aryl, 0-C1-3 alkyl, CONR³R⁴, C(O)OR³; C(O)NR³R⁴; SO₂NR³; NH(NH)NH₂; NR⁴C(O)R³; NR⁴SO₂R³; N₃; F; Cl

R³ represents H; C1-6 alkyl, optionally substituted with up to 4 OH; aryl or C1-3 alkyl optionally substituted with aryl R⁴ represents H; C1-6 alkyl, optionally substituted with up to 4 OH

R³ and R⁴ may optionally form a 4 to 8 membered ring, containing 0 to 1 O, S or

NR³ groups.

(H) Compounds of Formula (2)

The compounds for use according to the invention may be of Formula (2)

in which

p represents an integer from 1 to 2

z represents an integer from 1 to (p+7)

y represents 1 or 2

R² represents OH; OR³; =0; NH₂; N₃; SH; SO_xR³; halo; CN; NO₂; NR³R⁴; (NR³)NR³R⁴; NH(NR³)NR³R⁴; CO₂R⁴; OC(O)R³; CONR³R⁴; NR⁴C(O)R³; NR⁴SO₂R³; P(O)(OR³)₂; C 1-15 alkyl or alkenyl optionally substituted with one or more OH, OR³, =0, NH₂, N₃, SH, SO_xR³, halo, CN, NO₂, NR³R⁴, (NR³)NR³R⁴, NH(NR³)NR³R⁴,

CO₂R⁴, OC(O)R³, CONR³R⁴, NR⁴C(O)R³, NR⁴SO₂R³, P(O)(OR³)₂, aryl or carbocyclyl groups; carbocyclyl or aryl, either of which is optionally substituted with one or more OH, OR³, =0, NH₂, N₃, SH, SO_xR³, halo, CN, NO₂, NR³R⁴, (NR³)NR³R⁴, NH(NR³)NR³R⁴, CO₂R⁴, OC(O)R³, CONR³R⁴, NR⁴C(O)R³, NR⁴SO₂R³, P(O)(OR³)₂, C1-9 alkyl optionally substituted with one or more OH, OR³, =0, NH₂, N₃, halo, CN, NO₂, NR³R⁴, CO₂R⁴, CONR³R⁴, aryl or carbocyclyl groups; O- glycosyl; C-glycosyl; O-sulfate; O-phosphate or a group which together with the endocyclic carbon forms a spiro ring, with the provisos that: (a) two OH groups may not be attached to the same endocyclic carbon atom; (b) where there is only one R² substituent it contains an oxygen atom directly bonded to an endocyclic carbon atom; and (c) where z>1 any two R² substituents may together form an optionally heterocyclic ring (for example a carbocycle, cyclic ether or acetal)

R⁴ represents H; C1-6 alkyl, optionally substituted with one or more OH

x represents an integer from O to 2

or pharmaceutically acceptable salt or derivative thereof.

In preferred embodiments, the compound of Formula (2) is selected from any one of the Formulae shown below:

wherein:

r represents an integer from 1 to (n+4)

s represents an integer from 1 to (n+4)

p represents an integer from 1 to 2

R¹ represents C1-9 alky!, optionally substituted with up to 6 OH, NR³R⁴, aryl, O-C1- 3 alkyl, O-C1-3 alkenyl, CO₂H₁ NH(NH)NH₂, CONR³R⁴; C(O)OR³; C(O)NR³R⁴; SO₂NR³

R² represents =0; C1-9 alkyl, C1-9 alkenyl, aryl, optionally substituted with up to 6

OH, NR³R⁴, aryl, 0-C1-3 alkyl, CONR³R⁴, C(O)OR³; C(O)NR³R⁴; SO₂NR³; NH(NH)NH₂; NR⁴C(O)R³; NR⁴SO₂R³; N₃; F; Cl

R³ represents H; C1-6 alkyl, optionally substituted with up to 4 OH; aryl or C1-3 alkyl optionally substituted with aryl

R⁴ represents H; C 1-6 alkyl, optionally substituted with up to 4 OH R³ and R⁴ may optionally form a 4 to 8 membered ring, containing 0 to 1 O, S or NR³ groups.

(iii) Compounds of Formula (3)

The compounds for use according to the invention may be of Formula (3)

in which

z represents an integer from 0 to (n+2), provided that where z = 0 then y ≥ 1

y represents an integer from 0 to (m+2), provided that where y = 0 then z ≥ 1

R² represents OH; OR³; =O; NH₂; N₃; SH; SO_xR³; halo; CN; NO₂; NR³R⁴;

(NR³)NR³R⁴; NH(NR³)NR³R⁴; CO₂R⁴; OC(O)R³; CONR³R⁴; NR⁴C(O)R³; NR⁴SO₂R³; P(O)(0R³)₂; C1-15 alkyl or alkenyl optionally substituted with one or more OH₁ OR³, =O, NH₂, N₃, SH, SO_xR³, halo, CN, NO₂, NR³R⁴, (NR³)NR³R⁴, NH(NR³)NR³R⁴, CO₂R⁴, OC(O)R³, CONR³R⁴, NR⁴C(O)R³, NR⁴SO₂R³, P(O)(OR³)₂, aryl or carbocyclyl groups; carbocyclyl or aryl, either of which is optionally substituted with one or more OH, OR³, =O, NH₂, N₃, SH, SO_xR³, halo, CN, NO₂, NR³R⁴, (NR³)NR³R⁴, NH(NR³)NR³R⁴, CO₂R⁴, OC(O)R³, CONR³R⁴, NR⁴C(O)R³, NR⁴SO₂R³, P(O)(OR³)₂, C1-9 alkyl optionally substituted with one or more OH, OR³, =O, NH₂, N₃, halo, CN, NO₂, NR³R⁴, CO₂R⁴, CONR³R⁴, aryl or carbocyclyl groups; O- glycosyl; C-glycosyl; O-sulfate; O-phosphate or a group which together with the endocyclic carbon forms a spiro ring, with the provisos that: (a) two OH groups may not be attached to the same endocyclic carbon atom; (b) where there is only one R² ^' substituent it contains an oxygen atom directly bonded to an endocyclic carbon atom; and (c) where z>1 any two R² substituents may together form an optionally heterocyclic ring (for example a carbocycle, cyclic ether or acetal)

R⁴ represents H; C1-6 alkyl, optionally substituted with one or more OH

, x represents an integer from O to 2

optionally wherein the compound has three, four or more rings

or pharmaceutically acceptable salt or derivative thereof.

In preferred embodiments, trie compound of Formula (3) is selected from any one of the Formulae shown below:

wherein:

r represents an integer from 1 to (n+m+4)

s represents an integer from 1 to (n+m+4)

n represents an integer from 1 to 3

m represents an integer from 1 to 3

R² represents =0; C1-9 alkyl, C1-9 alkenyl, aryl, optionally substituted with up to 6 OH, NR³R⁴, aryl, O-C1-3 alkyl, CONR³R⁴, C(O)OR³; C(O)NR³R⁴; SO₂NR³;

NH(NH)NH₂; NR⁴C(O)R³; NR⁴SO₂R³; N₃; F; Cl

R⁴ represents H; C1-6 alkyl, optionally substituted with up to 4 OH

R³ and R⁴ may optionally form a 4 to 8 membered ring, containing O to 1 O, S or

NR³ groups the endocyclic nitrogen atom may be bonded to an oxygen or an oxygen containing group such that the compound is an N-oxide.

In all of the above compounds, one or more endocyclic carbon atoms may be substituted with a sulphur, oxygen or nitrogen atom.

It will be appreciated that the compounds of Formula (1), (2) and (3) may comprise compounds having three, four or more rings.

Preferred are compounds of Formula (1), (2) or (3) which are polyhydroxylated, having 2, 3 or more hydroxyl residues on the ring system nucleus.

Also preferred are oligomers (e.g. dimers, trimers etc.) of the above-defined compounds. Such compounds may be di- and/or oligosaccharide mimetics (as described below), and they may be linked, for example, at C6 and C2, 3 or 4. Oligomers of the above-defined compounds are preferably imino-C-disaccharides and analogues as described in Section ll(b)(vi), below.

Certain compounds of Formula (1), (2) or (3) are novel. According to the invention, those compounds of Formula (1), (2) or (3) which are novel are claimed as compounds perse, together with processes for their preparation, compositions containing them, as well as their use as pharmaceuticals (for example in any of the particular medical uses described herein).

Moreover, to the extent that certain of the compounds falling within the scope of Formula (1), (2) or (3) are known, as such, but not as pharmaceuticals, those compounds are claimed for use as pharmaceuticals (for example in any of the particular medical uses described herein).

The compounds of Formula (1), (2) or (3) may be, but not necessarily are, iminosugars as defined in Section A(II) (below).

(II) Iminosugars The compounds for use according to the invention may be iminosugars, as hereinbefore defined.

Thus, the compounds for use according to the invention may be selected from:

• iminosugars sensu stricto, being saccharide analogues in which the ring oxygen is replaced by a nitrogen; or

• isoiminosugars, being aza-carba analogues of sugars in which the C-1 carbon is replaced by nitrogen and the ring oxygen is replaced by a carbon atom; and • azasugars in which an endocyclic carbon is replaced with a nitrogen atom.

In embodiments where the iminosugar for use according to the invention is an azasugar as defined above, then the iminosugar may be selected from:

• 1 -Azasugars in which the N is in the anomeric position;

• oxazines in which the ring oxygen remains unsubstituted; and

• hydrazines in which the ring oxygen is substituted with a nitrogen atom.

In all of the above iminosugars, one or more endocyclic carbon atoms may be substituted with a sulphur, oxygen or nitrogen atom.

The iminosugars for use according to the invention may be of Formula (1), (2) or (3) as defined in Section A(I) (above).

The iminosugars as defined above for use according to the invention may be of any structural class or subclass, including the classes described below:

(a) Principal structural iminosugar classes

The compounds for use according to the invention may be an iminosugar (as herein defined). The iminosugars for use according to the invention may be of a structural class selected from:

(a) a piperidine; (b) a pyrroline; (c) a pyrrolidine;

(d) a pyrrolizidine;

(e) an indolizidine;

(f) a quinolizidine; (g) a nortropane;

(h) ring-open iminosugars; (i) 5,7 fused; G) an azepane; (k) an azetidine; (I) mixtures of any two or more of (a) to (k).

The iminosugars of any of the foregoing structural classes may be polyhydroxylated, as hereinbefore defined. As used herein, the term polyhydroxylated piperidine iminosugar defines an oxygenated iminosugar (e.g. having at least 2 (preferably at least 3) free hydroxyl groups (or alkyl groups with one or more OH substituents) on the ring system nucleus) that comprises the nucleus:

As used herein, the term polyhydroxylated pyrrolidine iminosugar defines an oxygenated iminosugar (e.g. having at least 2 (preferably at least 3) free hydroxyl groups (or alkyl groups with one or more OH substituents) on the ring system nucleus) that comprises the nucleus:

As used herein, the term polyhydroxylated pyrrolizidine iminosugar defines an oxygenated iminosugar (e.g. having at least 3, 4, 5, 6 or 7 (preferably 3, 4 or 5) free hydroxyl groups (or alkyl groups with one or more OH substituents) on the ring system nucleus) that comprises the nucleus:

V-N^/ As used herein, the term polyhydroxylated indolizidine iminosugar defines an oxygenated iminosugar (e.g. having at least 3, 4, 5, 6 or 7 (preferably 3, 4 or 5) free hydroxyl groups (or alkyl groups with one or more OH substituents) on the ring system nucleus) that comprises the nucleus:

As used herein, the term polyhydroxylated quinolizidine iminosugar defines an oxygenated iminosugar (e.g. having at least 3, 4, 5, 6 or 7 (preferably 3, 4, 5 or 6) free hydroxyl groups (or alkyl groups with one or more OH substituents) on the ring system nucleus) that comprises the nucleus:

In each of the above iminosugar nuclei, it is to be understood that one or more endocyclic carbon atoms may be substituted with a sulphur, oxygen or nitrogen atom.

(i) Piperidine iminosugars

Piperidine iminosugars comprise the nucleus:

Preferred are polyhydroxylated piperidine iminosugars as hereinbefore defined comprising the above nucleus and having at least 2 (preferably at least 3) hydroxyl groups (or alkyl groups with one or more hydroxy substituent(s)) on the ring system nucleus.

(ii) Pyrroline iminosugars

Pyrroline iminosugars comprise one of the following three nuclei: Ni=/ N_^-V N

Preferred are polyhydroxylated pyrroline iminosugars as hereinbefore defined having at least 2 hydroxyl groups (or alkyl groups with one or more hydroxy substituent(s)) on the ring system nucleus.

(iii) Pyrrolidine iminosugars

Pyrrolidine iminosugars comprise the nucleus:

Preferred are polyhydroxylated pyrrolidine iminosugars as hereinbefore defined comprising the above nucleus and having at least 2 (for example at least 3) hydroxyl groups (or alkyl groups with one or more hydroxy substituent(s)) on the ring system nucleus.

(iv) Pyrrolizidine iminosugars

Pyrrolidine iminosugars comprise the nucleus:

Preferred are polyhydroxylated pyrrolizidine iminosugars as hereinbefore defined comprising the above nucleus and having at least 2, 3, 4, 5, 6 or 7 (preferably 3, 4 or 5) hydroxyl groups (or alkyl groups with one or more hydroxy substituent(s)) on the ring system nucleus.

(v) Indolizidine iminosugars

Indolizidine iminosugars comprise the nucleus:

Preferred are polyhydroxylated indolizidine iminosugars as hereinbefore defined comprising the above nucleus and having at least 2, 3, 4, 5, 6 or 7 (preferably 3, 4 or 5) hydroxyl groups (or alkyl groups with one or more hydroxy substituent(s)) on the ring system nucleus.

(vi) Quinolizidine iminosugars

Quinolizidine iminosugars comprise the nucleus:

Preferred are polyhydroxylated quinolizidine iminosugars as hereinbefore defined comprising the above nucleus and having at least 2, 3, 4, 5, 6 or 7 (preferably 3, 4, 5 or 6) hydroxyl groups (or alkyl groups with one or more hydroxy substituent(s)) on the ring system nucleus.

(vii) Nortropanes

Nortropane iminosugars comprise the nucleus:

wherein the dotted line represents a bridge containing 2 or 3 carbon atoms between any two different ring carbon atoms.

Preferred are polyhydroxylated nortropane iminosugars as hereinbefore defined comprising the above nucleus and having at least 3 (preferably at least 4) hydroxyl groups (or alkyl groups with one or more hydroxy substituent(s)) on the ring system nucleus. A preferred class of nortropane iminosugar for use according to the invention are calystegines. These are polyhdroxylated nor-tropanes which have been reported to inhibit β-glucosidases, β-xylosidases and α-galactosidases (Asano et al., (1997), Glycobiol., 7: 1085-1088). The calystegines are common in foods belonging to the Solanaceae family of plants that includes potatoes and aubergines (egg plant). The calystegines have been shown to inhibit mammalian glycosidases including human, rat and bovine liver enzymes. Attaching sugars to the calystegines such as in 3-0-β-D-glucopyranoside of 1α,2β,3α,6α- tetrahydroxy-/7or-tropane (Calystegine B₁) (Griffiths et al., (1996), Tetrahedron Lett. 37: 3207-3208) can alter the glycosidase inhibition to include α-glucosidases and β- galactosidases.

(viii) 5-7 fused

These iminosugars comprise the nucleus:

Preferred are polyhydroxylated 5-7 fused iminosugars as hereinbefore defined comprising the above nucleus and having at least 2, 3, 4, 5, 6 or 7 (preferably 3, 4 or 5) hydroxyl groups (or alkyl groups with one or more hydroxy substituent(s)) on the ring system nucleus.

(ix) Azepanes

Azepane iminosugars comprise the nucleus:

Preferred are polyhydroxylated azepane iminosugars as hereinbefore defined comprising the above nucleus and having at least 2 (preferably at least 3 or 4) hydroxyl groups (or alkyl groups with one or more hydroxy substituent(s)) on the ring system nucleus. In each of the above iminosugar nuclei described in subsections (i) to (ix), it is to be understood that one or more endocyclic carbon atoms may be substituted with a sulphur, oxygen or nitrogen atom.

It will also be appreciated that iminosugars comprising the various nuclei described in subsections (i) to (ix) may comprise compounds having three, four or more rings.

(x) Ring-open iminosugars

Also considered are amino sugars acids formed by the opening of the imino ring such as compound P1 and P2 (found in Cucurbita spp.) and P3. Such compounds may also be the biological precursors of the iminosugar acids.

(b) Iminosugar structural subclasses

The principal structural classes described above can be further categorized into various subclasses, for example on the basis of the presence of various functional groups, as described below.

The iminosugars for use according to the invention may therefore be further characterized on the basis of their structural subclass, for example being selected from:

(i) Iminosugar acids

The iminosugar acids (ISAs) are mono- or bicyclic analogues of sugar acids in which the ring oxygen is replaced by a nitrogen. Although iminosugars are widely distributed in plants (Watson et al. (2001) Phytochemistry 56: 265-295), the iminosugar acids are much less widely distributed.

Iminosugar acids can be classified structurally on the basis of the configuration of the N- heterocycle. Examples include piperidine, pyrroline, pyrrolidine, pyrrolizidine, indolizidine and nortropanes iminosugar acids (see Figs. 1-7 of Watson et al. (2001), the disclosure of which is incorporated herein by reference).

Particularly preferred are iminosugar acids selected from the following structural classes:

(a) piperidine ISAs (including (poly)hydroxypipecolic acids) ;

(b) pyrroline ISAs;

(c) pyrrolidine ISAs (including (poly)hydroxyprolines);

(d) pyrrolizidine ISAs; (e) indolizidine ISAs; and

(T) nortropane ISAs.

The ISAs for use according to the invention may be N-acid ISAs (as hereinbefore defined).

ISA mixtures or combinations containing two or more different ISAs representative of one or more of the classes listed above may also be used.

Preferred are polyhydroxylated ISAs. Particularly preferred are ISAs having a small molecular weight, since these may exhibit desirable pharmacokinetics. Thus, the ISA may have a molecular weight of 100 to 400 Daltons, preferably 150 to 300 Daltons and most preferably 200 to 250 Daltons.

Also preferred are ISAs, which are analogues of hydroxymethyl-substituted iminosugars in which one or more hydroxymethyl groups are replaced with carboxyl groups.

Exemplary piperidine iminosugar acids

The ISA of the invention may be a piperidine ISA having at least 3 free hydroxyl (or hydroxyalkyl) groups on the ring system nucleus. Exemplary piperidine ISAs are hydroxypipecolic acids. Particularly preferred hydroxypipecolic acids are polyhydroxypipecolic acids having at least two (e.g. 3) free hydroxyl (or hydroxyalkyl) groups on the ring system nucleus.

Exemplary pyrrolidine iminosugar acids The ISA of the invention may be a pyrrolidine ISAs having at least 2 (preferably at least 3) free hydroxyl (or hydroxyalkyl) groups on the ring system nucleus. Preferred pyrrolidine ISAs are hydroxyprolines. Particularly preferred hydroxyprolines are polyhydroxyprolines having at least two (e.g. at least 3) free hydroxyl (or hydroxyalkyl) groups on the ring system nucleus.

Exemplary pyrrolidine iminosugar acids

The ISA of the invention may be a pyrrolidine ISA having at least 2 (preferably at least 3,

4 or 5) free hydroxyl (or hydroxyalkyl) groups on the ring system nucleus.

Exemplary indolizidine iminosugar acids

The ISA of the invention may be an indolizidine ISA having at least 2 (preferably at least 3, 4 or 5) free hydroxyl (or hydroxyalkyl) groups on the ring system nucleus.

Exemplary nortropane iminosugar acids The ISA of the invention may be a nortropane ISA having at least 2 (preferably at least 3) free hydroxyl (or hydroxyalkyl) groups on the ring system nucleus.

(ii) 1-Λ/-iminosugars (isoiminosugars)

Isoiminosugars are carbohydrate mimics in which the anomeric carbon is replaced by a nitrogen atom and the ring oxygen is repaced by a carbon atom (for example, a methylene group in the case of monocyclic piperidine and pyrrolidine compounds).

(iii) Iminosugar conjugates

Carbohydrates are often conjugated to other biomolecules in vivo, including lipids, proteins, nucleosides and phosphate groups. Thus, of particular interest as a subclass of the various principal classes of iminosugar described above is iminosugar conjugates. These include: • Iminosugar-based glycopeptide analogues

• Imiπosugar phosphonate analogues

• lminosugar nucleotide analogues and oligomers thereof

• lminosugar glycolipid analogues (e.g. C- or N-alkyl iminosugar derivatives)

(iv) lminosugar C-glycosides

Imino-analogues of glycosides in which an aglycone moiety is attached to the anomeric (C- 1) carbon via an O-glycosidic bond are of limited utility as drugs due to the lability of the N,O-acetal function. Replacement of the oxygen atom of the N,O-acetal by a methylene group yields iminosugar C-glycosides, which are stable analogues of glycoconjugates. The endocyclic nitrogen is preferably unsubstituted in such C-glycosides, so that the compounds may comprise a nucleus selected from those listed below:

lminosugars of this structural subclass are described by Compain (2007) in "Iminosugars: From synthesis to therapeutic applications", Wiley ISBN 978-0-470-03391-3; Gompain and Martin. (Eds.) pp 63-86 (the disclosure of which is hereby incorporated by reference).

(v) N-substituted iminosugars

N-substituted iminosugars may be considered as analogues of the iminosugar C- glycosides described above in which the aglycone moiety is positioned on the endocyclic nitrogen rather than the "anomeric" C-1 carbon atom.

(vi) Imino-C-disaccharides and analogues

Imino-C-disaccharides and analogues for use according to the invention may fall into any one of the three structural subclasses described by Vogel et a/. (2007) in "Iminosugars: From synthesis to therapeutic applications", Wiley ISBN 978-0-470-03391-3; Compain and Martin (Eds.) 87-130 the disclosure of which is hereby incorporated herein by reference. For example, they may be: (a) linear (1→1)-C-linked; (b) linear (1→ ω)-C-linked; or (c) branched (I→n)-C-Iinked (see Fig. 5.1 of Vogel et al. (2007), op. cit).

(vii) lminosugar lactams

lminosugar lactams for use according to the invention may for example comprise a nucleus selected from:

in which the =O group may be on both rings of the bicyclic nuclei.

In each of the above iminosugar lactam nuclei, it is to be understood that one or more endocyclic carbon atoms may be substituted with a sulphur, oxygen or nitrogen atom.

(viii) Branched iminosugars

The iminosugars for use according to the invention may be a branched iminosugar. Branched iminosugars are as defined in sections (i) to (x) (above) but are distinguished by the presence of two non-H substituents (e.g. two alkyl groups, two hydroxyalkyl groups, a hydroxy and hydroxyalkyl group or a hydroxy and alkyl group) on any one or more endocyclic carbon atom.

It will be appreciated that iminosugars with features characteristic of two or more of the foregoing subclasses (i) to (x) may also find application according to the invention.

(c) lminosugar carbohydrate mimetics

As described above, the iminosugars for use according to the invention may be of any structural class and/or subclass, including the classes and subclasses described above in Sections ll(a) and ll(b). In addition to this structural classification, the iminosugars for use according to the invention may also be further structurally and/or functionally defined by reference to the carbohydrate(s) they mimic, as described below:

(i) General considerations

An iminosugar carbohydrate mimetic is an iminosugar that mimics one or more carbohydrates (for example, a mono- or disaccharide) through replication of one or more structural motifs of the carbohydrate scaffold. Thus, iminosugar carbohydrate mimetics share absolute/relative stereochemical motifs with the carbohydrate(s) they mimic.

This structural mimicry may be associated with functional mimicry: the shared absolute/relative stereochemical motifs may give rise to shared functional attributes. In such cases the compound may be defined as a functional sugar mimetic (as discussed in more detail in Section B, below). However, since the sugar mimics of the carbohydrate may also contain new functional groups, a new scaffold, or both, they may also exhibit functional attributes which are distinct from those of the carbohydrate(s) mimicked.

Thus, iminosugar carbohydrate mimetics correspond structurally to one or more carbohydrates and this structural mimicry may be accompanied by functional mimicry (e.g. at the level of interaction with a biological target in vivo) or other functional attributes related to, but distinct from, those of the carbohydrate they mimic (for example, the ability to competitively inhibit an enzyme for which the carbohydrate mimicked is a substrate in vivo).

For example, and considering the following pentose (3 contiguous chiral centres) and hexose (4 contiguous chiral centres) stereochemistries (Scheme 1 , below):

3 contiguous chiral centres 4 contiguous chiral centres

D-arabino or D-lyxo L-gluco orD-gulo D-gOco orL-gul

D-altro or D-taio L-altro or L-IaIo

D-manno L-mεnno

D- σ L-allo D- orL-galacto

Scheme 1. Relative Carbohydrate Stereochemistry

The above analysis is non-limiting, and intended to be illustrative only of a wider principle. A similar analysis can readily be extended to lower sugars (e.g. tetroses) and higher sugars (e.g. heptoses), as well as to ketoses and the like.

An iminosugar can be considered as being a structural mimetic of a particular reference monosaccharide, disaccharide or oligosaccharide unit when stereochemical comparisons between the iminosugar and the relative carbohydrate stereochemistry exhibited by the carbohydrate scaffold reveal shared stereochemical motifs. For the purposes of the analysis, the stereochemical comparison relates to consideration of contiguous C-het stereocentres (these being C-O, C-N etc.)

For example in the case of two simple monocyclic iminosugars IS1 and IS2 (shown below) the relative stereochemical relationship to the reference monosaccharide units (D- arabinose and D-glucose respectively) can be seen:

IS1 D-arabinσse IS2 D-glucoss

Thus, IS1 is a D-arabinose mimetic while IS2 is a D-glucose mimetic.

However, as monosaccharides can exist in both acyclic and several cyclic forms, the relative stereochemical relationship between the iminosugar and the parent monosaccharide is not necessarily fixed to one structural class or type or to the contiguous sequence depicted.

For example, D-arabinose can exist in the following cyclic forms:

D-aratafnofuraπose D-arabinopyranose

Exemplary iminosugar mimetics include the iminosugars IS1 and IS3, respectively, as shown below:

IS1 IS3

Note that unlike their monosaccharide counterparts these compounds generally cannot interconvert and are chemically distinct from each other. Thus, IS1 is a D-arabinofuranose mimetic while IS3 is a D-arabinopyranose mimetic. However, in the case of IS3 the stereochemistry represents that not just of D- arabinopyranose but also that of D-lyxose:

D-a rabino pyra nose D-lyκopyrancs.e

This is a consequence of the stereochemical sequence overlap that exists amongst carbohydrate sequences. For these purposes the carbon backbone with the most contiguous chiral centres is selected primarily. When considering cyclic iminosugars the ring nitrogen is included amongst the primary contiguous chiral centres.

For example, the iminosugar IS4 exhibits the following stereochemical sequences:

IS4 D-manno configuration L-altro configuration

1 _-talo configuration L-talo configuration

The iminosugar IS5 exhibits the following stereochemical sequences:

IS5 D-gluco configuration L-gluco configuration L-gulo configuration D-gulo configuration

The iminosugar IS6 exhibits the following stereochemical sequences:

D-altro configuration D-gluco configuration

D- talo configuration L-gulo configuration

L-altro configuration L-g!ucσ configuration

L-talo configuration D-gulo configuration

However, although an iminosugar may present more than one stereochemical sequence it is not necessarily a carbohydrate mimetic for each and every stereochemical sequence exhibited.

For example, the 2,5-imino pyrrolidine IS7 exhibits both D-gluco and L-gulo stereochemistry and can be considered as both a glucose and gulose mimetic:

D-giucosβ D-glaco L-gulo L-gulose

Note that an alternative, but chemically distinct isomer of IS7, not the 2,5-pyrrolidine but the 1 ,4-pyrrolidine IS8, also exhibits both D-gluco and L-gulo stereochemistries but is considered a D-glucose mimetic only. This is by virtue of the structural constraints enforced by the cyclic nature of IS8 leading to presentation of the structural motifs of D-glucose only. Note that in chemical terms IS7 and IS8 are distinct and cannot interconvert.

D-glucofuranose D-ghico L-gulo L-guIofuranose

(ii) Deoxysugar mimetics and further substitution

Where an iminosugar mimics a deoxy sugar, this may also be considered as mimicry (albeit partial) of the cognate (fully oxygenated) monosaccharide. For example, the mimetic properties of iminosugar IS9 can be analysed as follows: D-manno D-manno

D-aftro p-^a'f°

D-talo ^D-^fato

Moreover, replacement of hydroxyl groups with hydroxyl isosteres (e.g. similarly sized atoms or groups such as Me, Cl and F) may also generates iminosugars which are mimetics of a monosaccaride. For example, IS10 is a D-arabinofuranose mimetic, as shown below:

D-arabino D-arabinofuranose

However, it should be noted that where the stereochemical configuration of the iminosugar matches one or more monosaccharides, but the group is not OH or an isostere (e.g. OBn, CO₂H or N₃) this would also be considered a mimetic for the purposes of the present invention. For example, the iminosugar IS11 is considered to be a mimetic of D- arabinofuranose, as shown below:

D-arabino D-arabinofuranose

(iii) Quaternary Centres Where these are present only the stereochemical^ defined groups on adjacent carbon atoms are considered when assigning matches, as shown below in the case of iminosugar IS12:

D-arabinσf uraπ os e

(iv) Disaccharides and oligosaccharides

Appropriately substituted iminosugars may also be considered as mimics of di- or oligosaccharides. In the case the same general principles described above are applied, with the caveat being that the iminosugar must contain two or more non-overlapping carbohydrate mimics.

IS13 D-arabino configuration L-arabino configuration D-arabino configurat

+ L-arabino configurati

(v) D- and L-sugar mimicry

Iminosugars may mimic either D- or L- forms of sugars. In the example below it can be seen that IS14 is a mimic of D-glucose, whereas its enantiomer IS15 is a mimic of L- i glucose. This principle is generally applicable.

5-triol

Thus, the iminosugars for use according to the invention may be of any structural class and/or subclass, including the classes and subclasses described above in Sections ll(a) and ll(b), and may be further characterized on the basis of the stereochemical configuration as follows:

• Iminosugars of D- or L-gluco configuration; • Iminosugars of D- or L-galacto configuration;

• Iminosugars of D- or L-manno configuration;

• Iminosugars of D- or L-allo configuration;

• Iminosugars of D- or L-altro configuration;

• Iminosugars of D- or L-ido configuration; • Iminosugars of D- or L-gulo configuration;

• Iminosugars of D- or L-talo configuration;

• Iminosugars of D- or L-arabino configuration;

• Iminosugars of D- or L-ribo configuration;

• Iminosugars of D- or L-xylo configuration; and/or • Iminosugars of D- or L-lyxo configuration. Alternatively, or in addition, the iminosugars for use according to the invention may be classified according to their stereochemical configuration in combination with other structural characteristics by reference to the sugars mimicked, as follows:

• D- or L-glucose;

• D- or L-galactose;

• D- or L-mannose;

• D- or L-allose;

• D- or L-altrose; • D- or L-idose;

• D- or L-gulose;

• D- or L-talose;

• D- or L-arabinose;

• D- or L-ribose; • D- or L-deoxyribose;

• D- or L-xylose;

• D- or L-lyxose;

• D- or L-psicose;

• D- or L-fructose; • D- or L-sorbose;

• D- or L-tagatose;

• D- or L-ribulose;

• D- or L-xylulose;

• D- or L-fucose; • D- or L-fuculose;

• D- or L-rhamnose;

• D- or L-seduheptulose;

• Sucrose;

• Lactose; • Trehalose;

• Maltose;

• Acarbose;

• Raffinose;

• Melezitose; • Maltotriose;

• Stachyose;

• Glycogen;

• Cellulose; • Chitin;

• Starch;

• Dextrin;

• Glucan;

• Glycosaminoglycans; and/or • Other oligosaccharides.

B, Functional considerations

The compounds for use according to the invention (including the compounds having the general formulae defined in section A(I) and the iminosugars described in section A(II), above) may have various functional properties. Any such functional properties may or may not contribute to the claimed in vivo activity, therapeutic activity or mode of action.

Thus, in some cases the compound for use according to the present invention may have one or more of the functional characteristics described below, wherein the functional characteristic(s) do not contribute to the claimed therapeutic activity and are purely incidental. In other cases, the compound for use according to the present invention may have one or more of the functional characteristics described below, wherein the functional characteristic(s) are responsible, wholly or partly, for the claimed therapeutic activity.

(I) Glvcosidase ligands

The compounds for use according to the invention may act as a ligand for one or more enzyme(s) of the following glycosidase classes in vitro and/or in vivo:

• α-glucosidases;

• β-glucosidases;

• α-galactosidases;

• β-galactosidases; • α-mannosidases; • α-fucosidases; or

• α-iduronidases; or

• β-glucuronidases; or

• β-mannosidases; or • hexosaminidases; or

• α-N-acetylglucosaminidases; or

• α-N-acetylgalactosaminidases; or

• β-N-acetylglucosaminidases; or

• β-N-acetylgalactosaminidases; or • sialidases; or

• heparinases; or

• neuraminidases; or

• hyaluronidase; or

• amylases; or • two or more of the foregoing enzyme classes.

The glycosidase ligands for use according to the invention may function as:

• Inhibitors (competitive or non-competitive) of the target enzyme (e.g. by binding to the catalytic site of the enzyme);

• Activators (e.g. by binding to an allosteric site of the enzyme);

• Allosteric site ligands (e.g. acting as inhibitors or activators of enzyme activity);

• Catalytic site ligands (e.g. acting as competitive inhibitor);

• Pharmacoperones for the target enzyme, for example by binding to: (i) the catalytic site; (ii) an allosteric site; (iii), a site outside the catalytic site; and/or (d) a site outside an allosteric site (see also Section III, below); or

• Two or more of the foregoing.

The compounds for use according to the invention preferably do not inhibit enzymes involved in metabolism of xenobiotics as this could lead to drug-drug interactions. Thus, the compounds of the invention preferably do not inhibit one or more of the following enzymes: CYP3A3/4 (most abundant isoenzyme in humans and responsible for metabolism of widest range of drugs), CYP1A, CYP2D6, CYP2C9/10 and CYP2C19. The compounds for use according to the invention preferably do not inhibit digestive disaccharidases (unless such inhibition is desirable in order to, for example, modify sugar metabolism in the treatment of metabolic disorders).

Preferred compounds are glycosylation modulators. Glycosylation modulators may be identified by standard enzymological assays. Preferred are compounds which specifically inhibit ER α-glucosidases (for example, which specifically inhibit ER α-glucosidase I and/or ER α-glucosidase II, relative to other mammalian glycosidase enzymes). Most preferably, the compounds of the invention inhibit ER α-glucosidase I and/or ER α-glucosidase Il with a degree of specificity such that gastrointestinal toxicity wa'disaccharidase inhibition on administration at antiviral concentrations in humans is absent (or present at clinically acceptable or subtoxic levels).

(II) Glvcosyltransferase ligands

The compounds for use according to the invention may act as a ligand for a glycosyltransferase. Such compounds may act as a ligand for any glycosyltransferase, but preferred are compounds which are ligands for one or more enzyme(s) of the following glycosyltransferase enzyme classes in vitro and/or in vivo:

• Fucosyltransferase;

• Chitin synthetase;

• Ceramide glucosyltransferase;

• β-1 ,4-galactosyltransferase; • α-1 ,3-galactosyltransferase;

• arabinofuranosyl transferase;

• galactofuranosyltransferase; or

• two or more of the foregoing enzyme classes.

The glycosyltransferase ligands for use according to the invention may function as:

• Inhibitors (competitive or non-competitive) of the target enzyme (e.g. by binding to the catalytic site of the enzyme); • Activators (e.g. by binding to an allosteric site of the enzyme);

• Allosteric site ligands (e.g. acting as inhibitors or activators of enzyme activity); • Catalytic site ligands (e.g. acting as competitive inhibitor);

• Pharmacoperones for the target enzyme, for example by binding to: (i) the catalytic site; (ii) an allosteric site; (iii), a site outside the catalytic site; and/or (d) a site outside an allosteric site (see also Section III, below); or • Two or more of the foregoing.

(Ill) Other enzyme ligands

The compounds for use according to the invention may act as a ligand for one or more enzyme(s) of the following classes in vitro and/or in vivo:

• Matrix metalloproteinases;

• Nucleoside processing enzymes; • UDP GaI mutases;

• Glycogen phosphorylases;

• ATPases;

• GTPases;

• Kinases (e.g. protein kinases, for example selected from serine/threonine specific, tyrosine specific, receptor tyrosine, histidine specific, aspartic acid/glutamic acid specific and mixed protein kinase classes);

• Phosphatases;

• Enzymes involved in nucleic acid synthesis; and

• Two or more of the foregoing.

The above enzyme ligands for use according to the invention may function as:

• Catalytic site ligands (e.g. acting as competitive inhibitor);

• Two or more of the foregoing. The compounds for use according to the invention may act as a ligand for one or more G- protein coupled receptor(s) in vitro and/or in vivo.

(IV) PRR ligands

The innate immune response has evolved to recognize a few, highly conserved structures present in diverse groups of microorganisms. These highly conserve structures are known as pathogen-associated molecular patterns (PAMPs). They are recognized by a class of receptors known as pathogen-(orpattern~)recognition receptors (PRRs), which are expressed on various effector cells of the innate immune system, including the professional antigen-presenting cells, macrophages and dendritic cells.

The best-studied class of PRR is the Toll-like receptor class (TLRs). Mammalian TLRs comprise at least 10 members, designated TLR1-10, and may be expressed as homodimers or heterodimers (TLR1 plus TLR2 or TLR6 plus TLR2). It seems that different classes of pathogen are recognized by different TLRs. For example, TLR4 appears to be responsible for the detection of Gram-negative bacteria, its cognate PAMP being lipopolysaccharide (LPS). TLR2 appears to have several ligands, including peptidogiycan of Gram-positive bacteria, lipoproteins from Mycobacterium tuberculosis, and certain components of Saccharomyces cerevisiae zymosan, as well as highly purified

Porphyromonas gingivalis LPS. TLR3 recognizes dsRNA, while TLR5 binds flagellin and TLR6 cooperates with TLR2 in detecting a subset of bacterial peptidogiycan. TLR7 can be triggered by imidazoquinolines, as well as ssRNA, and may thus be involved in the detection of viral infection. TLR9 detects bacterial and viral DNA sequences containing unmethylated cytosine-guanosine dinucleotides (CpGs). Other members of the mammalian TLR family may be specific for PAMPs characteristic of other classes of pathogens such as fungi (mannan, glucan and mycobacteria (via lipoarabinomannan and/or muramyldipeptide as cognate PAMPs)).

Another major class of PRR are the C-type lectins (reviewed by Figdor et a/. (2002) Nat. Rev. Immunol. 2: 77-84). These PRRs share a conserved domain (the carbohydrate recognition domain or CRD) which was first characterized in animal lectins and which appears to function as a calcium-dependent carbohydrate-recognition domain. This consists of about 110 to 130 residues and contains four cysteines which are involved in two disulfide bonds. This domain may be present in multiple copies in some C-type lectin PRRs (for example, the mannose receptor contains eight CRDs).

Examples of C-type lectins include DC-SIGN (Dendritic Cell Specific ICAM-3 Grabbing Nonintegrin, or CD209), which can signal in response to Mycobacterium tuberculosis, synergising with LPS to induce IL-10 production by monocyte-derived DCs. The mannose receptor (MR) is involved in recognition of mycobacteria, fungi and protozoa. Dectin-1 acts as a PRR for β-glucan. Other C-type lectins are expressed in DCs (e.g. blood dendritic cell antigen-2 (BDCA-2), dendritic cell immunoactivating receptor (DCAR) and can also act as signalling receptors, though their role in PAMP recognition has yet to be established.

Preferred compounds for use according to the invention are PRR ligands (as defined herein). Such PRR ligands may be readily identified by screening assays which detect: (a) binding to a PRR (for example, TLR, C-type lectin or NOD-protein); and/or (b) the stimulation of PRR (for example, TLR, C-type lectin or NOD-protein) signalling. In the former case, the assays may involve competitive binding assays using an isolated PRR and a known cognate PAMP ligand as test reagents. Such competitive binding assays are routine in the art, and those skilled in the art will readily be able to identify appropriate conditions and formats for such assays. In the latter case, assays for PRR (for example C- type lectin) signalling activity may involve the use of PRR (for example C-type lectin)- bearing immune cells (typically DCs) as test reagent. Those skilled in the art will readily be able to identify appropriate conditions and formats for such assays, including inter alia the nature and number of the dendritic cells, the relative concentrations of compound and cells, the duration of stimulation with the compound and the methods used to detect signalling (for example by immunoassay for cytokine release).

The PRR ligands of the invention may bind any PRR, including any TLR, C-type lectin or NOD-protein. Preferably, the compounds for use according to the invention bind to PRRs displayed on/expressed by neutrophils, though they may bind to PRRs in, on or secreted by other cells including other cells of the innate immune system as well as to PRRs in, on or secreted by, for example, DCs, macrophages and/or T-cells. (a) NOD-protein ligands

The NOD-proteins (also known as the caterpillar family and NOD-LRR family) are cytosolic proteins that have a role in various innate and adaptive immune responses to cytosolic pathogens. Particularly preferred NOD-protein ligands for use according to the invention are NOD1 and/or NOD2 ligands. These latter proteins bind structures derived from peptidoglycan that are not TLR ligands.

NOD-protein PRRs comprise C-terminal leucine-rich repeats (LRRs), a central nucleotide- binding oligomerization domain (NOD), and N-terminal protein-protein interaction motifs, such as caspase recruitment domains (CARDs), pyrin domains or a TIR domain.

(b) Toll-like receptor (TLR) ligands

The PRR ligands of the invention may bind to any TLR receptor. Thus, the PRRs of the invention may bind to one or more of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10 and TLR11.

Preferably, the TLR ligands for use according to the invention bind to:

(a) a TLR coupled with the MyD88 adaptor signalling pathway; and/or

(b) a TLR coupled with the TRIF adaptor signalling pathway; and/or

(c) a cell-surface TLR; and/or

(d) an endosomal TLR (e.g. TLR7, TLR8 and/or TLR9); (e) an intracellular TLR (e.g. TLR3).

Particularly preferred are TLR9 or TLR4 ligands.

(c) Lectin ligands

As used herein, the term "lectin" defines a proteins which specifically binds (or crosslinks) a carbohydrate. Many lectins are multivalent carbohydrate-binding proteins or glycoproteins (excluding enzymes and antibodies). Preferred compounds for use according to the invention are ligands for C-type lectins. However, the compounds for use according to the invention may bind to any lectin, for example to any of the lectins described in Figdor et al. (2002) Nat. Rev. Immunol. 2: 77-84 (the disclosure of which relating to the identification of various lectins is incorporated herein by reference). Thus, the compounds of the invention may be ligands for type I and/or type Il C-type lectins.

The compounds of the invention may be ligands for lectins selected from:

(a) MMR (CD206, macrophage mannose receptor); and/or .

(b) DEC-205; and/or

(c) Dectin 1 ; and/or (d) Dectin 2; and/or

(e) Langerin; and/or

(f) DC-SIGN; and/or

(g) BDCA-2; and/or (h) DCIR; and/or (i) DLEC; and/or

G) CLEC; and/or

(k) a rhamnose-binding C-type lectin; and/or

(I) asialoglycoprotein receptor; and/or

(m)collectins; and/or (n) selectins; and/or

(o) galectins; and/or

(p) annexins; and/or

(q) lecticans; and/or

(r) l-type lectins (for example, siglecs (sialic acid-binding immunoglobulin superfamily lectins); and/or

(s) P-type lectins.

The PRR or lectin (for example C-type lectin) ligands (as defined herein) may be identified by assays for PRR/lectin (for example C-type lectin) binding. These may involve competitive binding assays using an isolated PRR/lectin (for example C-type lectin) and a known cognate PAMP ligand as test reagents. Such competitive binding assays are routine in the art, and those skilled in the art will readily be able to identify appropriate conditions and formats for such assays. (V) Pharmacoperones

It has recently been discovered that certain small molecules can serve as molecular scaffolds and cause otherwise-misfσlded mutant proteins to fold and route correctly within the cell. Such molecules have been dubbed "chemical chaperones", "pharmaceutical chaperones", "pharmacological chaperones" or "pharmacoperones".

The compounds of the invention may be pharmacoperones as defined above.

In particular, it has been recognised that certain iminosugars can act as competitive inhibitors of the mutant enzymes implicated in various lysosomal storage disorders can, at subinhibitory concentrations, act as "Active-Site-Specific Chaperones" or ASSCs by either inducing or stabilizing the proper conformation of the mutant enzyme by specific binding to the catalytic site (see Fan (2007) Iminosugars as active-site-specific chaperones for the treatment of lysosomal storage disorders, in Iminosugars From Synthesis to Therapeutic Applications: Compain, Philippe / Martin, Olivier R. (eds.) ISBN-13: 978-0-470-03391-3 - John Wiley & Sons, pages 225-247). Thus, the compounds for use according to the invention may be ASSCs as defined above.

(VI) lmmunomodulators

(a) General considerations

The compounds of the invention may be immunomodulatory. The term immunomodulatory is used in this context in relation to the compounds for use according to the invention to define a compound (e.g. a compound as described in section A(I) above or an iminosugar as described in Section A(II), above) which can stimulate and/or suppress one or more components or activities of the immune system (e.g. the mammalian immune system) in vivo or in vitro. Preferred immunomodulatory compounds for use according to the invention are capable of stimulating the activity of one or more cytokine(s) in a PRR- bearing cell. Such alkaloids are said to exhibit a cytokine stimulation profile in that PRR- bearing cell. Typically, the immunomodulatory alkaloids of the invention are capable of stimulating the activity of one or more cytokines in macrophages and/or dendritic cells. This stimulatory activity may be observable in vitro and/or in vivo. The stimulation may occur directly or indirectly via any mechanism and at any level (e.g. at the level of transcription, translation, post-transiational modification, secretion, activation, shedding, stabilization or sequestration). Typically, the stimulation comprises an increase in the production of the cytokine(s) by the PRR-bearing cell. Typically, the one or more cytokine(s) stimulated by the immunomodulatory alkaloids for use according to the invention comprise one or more Th1 cytokines (as herein defined and described). Particularly preferred are immunomodulatory alkaloids that stimulate IL-2 and/or IL-12 in dendritic cells and/or macrophages (in vivo and/or in vitro).

Immunomodulatory compounds for use according to the invention may be readily identified by screening assays designed to detect the induction of one or more cytokine(s) (for example, IL-12 production in dendritic cells) in vitro. Such assays conveniently involve immune assays or microarray analysis (the latter being especially useful in embodiments where immunomodulatory compounds which stimulate a large number of different cytokines or which differentially stimulate a specific subclass of cytokines (e.g. Th1 cytokines) are to be selected). Those skilled in the art will readily be able to identify appropriate conditions for such assays, including inter alia the nature, source and number of the PRR-bearing cell (e.g. macrophages or dendritic cells), the relative concentrations of compound and cells, the duration of stimulation with the compound and the methods used to detect the induction of the cytokine(s).

Immunomodulatory activity may be determined by in vitro cytokine release assays (for example using one or more immune cells, e.g. macrophage, dendritic or spleen cells). Preferred immunomodulatory compounds of the invention stimulate the release of one or more cytokines (e.g. IL-12) in vitro (for example, in spleen cells, macrophages and/or dendritic cells). They may act as PRR ligands, a term used herein in relation to certain , preferred compounds for use according to the invention to define compounds which can act as binding partners for a PRR. Such immunomodulatory compounds therefore include those which bind (or directly physically interact) with a PRR in vivo irrespective of the physiological consequences of that binding. Thus, the PRR ligands of the invention may bind a PRR as part of a cellular signalling cascade in which the PRR forms a part. Alternatively, they may bind PRR in the context of some other aspect of cellular physiology. In the latter case, the ligands may for example bind PRR at the cell surface without triggering a signalling cascade, in which case the binding may affect other aspects of cell function. Thus, the ligands of the invention may bind PRRs and thereby effect an increase in the concentration of functional PRR at the cell surface (for example mediated via an increase in PRR stability, absolute receptor numbers and/or PRR activity). Alternatively, the ligands may bind PRR (or PRR precursors) intracellularly, in which case they may act as molecular chaperones to increase the expression of active PRR.

(b) PRR agonists

As used herein, the term PRR-bearing cell defines any cell which expresses one or more pathogen-(or pattern-) recognition receptors (PRRs). The term PRR is a term of art used to define a class of receptors which are expressed on various cells (e.g. epithelial cells and effector cells of the innate immune system, including the professional antigen-presenting cells, macrophages and dendritic cells) and which recognize a few, highly conserved structures present in diverse groups of microorganisms known as pathogen-associated molecular patterns (PAMPs). Thus, PRR-bearing cells as described herein may comprise epithelial cells, macrophages, neutrophils, dendritic cells or other effector cells of the innate immune system. In preferred embodiments, the PRR-bearing cell for use in relation to the invention are dendritic cells and/or macrophages. Thus, those functional attributes of the immunomodulatory compounds of the invention that are defined by reference to inter alia a PRR-bearing cell are to be understood to relate to any of a wide variety of different PRR- bearing cells of diverse cytological properties and biological functions, including inter alia epithelial cells, dendritic cells, macrophages, various APCs, natural killer (NK) cells and other cells of the innate immune system (including e.g. neutrophils, granulocytes and monocytes). Preferably, however, the PRR-bearing cells described herein (and used for example to define a parameter of the reference conditions under which the functional properties of the immunomodulatory compound are manifest) are macrophages or dendritic cells.

The term cytokine stimulatory is used herein to define a subclass of immunomodulatory compounds for use according to the invention which are capable of stimulating the activity of one or more cytokine(s) in a PRR-bearing cell. Such compounds are said to exhibit a cytokine stimulation profile in that PRR-bearing cell. Typically, the immunomodulatory compounds of the invention are capable of stimulating the activity of one or more cytokines in macrophages and/or dendritic cells. This stimulatory activity may be observable in vitro and/or in vivo. The stimulation may occur directly or indirectly via any mechanism and at any level (e.g. at the level of transcription, translation, post-translational modification, secretion, activation, shedding, stabilization or sequestration). Preferred cytokine stimulatory compounds for use according to the invention are PRR ligands (as herein defined). Typically, the stimulation comprises an increase in the production of the cytokine(s) by the PRR-bearing cell. Typically, the one or more cytokine(s) stimulated by the immunomodulatory compounds for use according to the invention comprise one or ^■ more Th1 cytokines (as herein defined and described). Particularly preferred are immunomodulatory compounds that stimulate IL-2 and/or IL-12 in dendritic cells and/or macrophages (in vivo and/or in vitro).

Some iminosugars have immunomodulatory activity that is independent of any glycosidase inhibitory activity. Examples of such compounds are described, for example, in WO2004/064715, WO2005/070415 and WO2005/070418. It is thought that this immunomodulatory activity may arise from the stimulation of secretion of various cytokines (e.g. IL-12 and/or IL-2) by immune cells (e.g. dendritic cells and/or macrophages). As described in WO2004/064715, WO2005/070415 and WO2005/070418 (the content of which relating to the structure of the various compounds described and their biological activity is hereby incorporated herein by reference), the immunomodulatory activity of such compounds can itself confer antiviral activity.

(c) Cytokine stimulation

The compounds for use according to the invention may be cytokine stimulatory compounds capable of stimulating the activity of one or more cytokine(s) in a PRR-bearing cell. In preferred embodiments, the compound may stimulate one or more Th1 cytokine(s) in a PRR-bearing cell, for example IL-12 and/or IL-2.

IL-2 is a Th 1 cytokine involved in mediating type-1 responses. It appears to be involved not only in T cell activation but also in the activation of inter alia NK cells, so functioning to regulate and link innate and adaptive immunity. Thus, the induced expression of IL-2 by the compounds for use according to the invention may directly potentiate a Th1 response and so increase the Th1:Th2 response ratio. The induced expression of IL-2 may also indirectly potentiate a Th1 response (and so increase the Th1 :Th2 response ratio) by stimulating the activity of endogenous dendritic cells, which cells then trigger responses by other classes of lymphocytes (CTL, B, NK, and NKT cells) and also elicit T cell memory (a critical goal of vaccination).

The induced expression of IL-2 may also indirectly potentiate a TM response (and so increase the Th1 :Th2 response ratio) by stimulating the activity of endogenous dendritic cells, which cells then trigger responses by other classes of lymphocytes (CTL, B, NK, and NKT cells) and also elicit T cell memory (a critical goal of vaccination).

The compounds for use according to the invention may stimulate the expression of IL-12 in PRR-bearing cells (for example in dendritic cells and/or macrophages). IL-12 is the primary mediator of type-1 immunity (the Th1 response). It induces natural killer (NK) cells to produce IFN-γ as part of the innate immune response and promotes the expansion of CD4⁺ Th1 cells and cytotoxic CD8⁺ cells which produce IFN-γ. It therefore increases T-cell invasion of tumours as well as the susceptibility of tumour cells to T-cell invasion.

Thus, without wishing to be bound by any theory, the immunomodulatory activity of certain preferred compounds for use according to the invention may arise from the stimulation of one or more cytokines (for example one or more TM cytokines, e.g. IL-12 and/or IL-2) in PRR-bearing cells (e.g. neutrophils, macrophages or dendritic cells). This leads to the stimulation of NK cells to produce IFN-γ and induces the development of CD4⁺ TM cells. The induced Th1 cells then produce IFN- y and IL-2. The stimulated cytokine(s) (e.g. IL-12 and/or IL-2) then enhances further proliferation of TM cells and the differentiation of pathogen (e.g. tumour and virus) -specific CD8⁺ T cells. The cytokine(s) also stimulate the cytolytic activity of NK cells of the innate immune system. The term cytokine stimulation profile is used herein to define a functional attribute of certain immunomodulatory compounds for use according to the invention which is characterized by reference to the identity of one or more cytokines stimulated (and optionally the identity of one or more cytokines unstimulated) in a PRR-bearing cell when contacted with the relevant immunomodulatory compound. Preferably, the cytokine stimulation profile is characterized by reference to the presence or absence of stimulation of two or more cytokines, more preferably four or more. Even more preferably, the cytokine stimulation profile is characterized by reference to the presence or absence of stimulation of one or more TM cytokines and/or one or more Th2 cytokines. Alternatively, or in addition, the stimulation profiles which functionally define the immunomodulatory compounds may be characterized by the degree of stimulation of one or more reference cytokine(s) (or classes thereof). The degree of stimulation may be expressed as an induction ratio with respect to: (a) the levels of the reference cytokine(s) (or markers thereof, such as encoding nucleic acids) in the PRR-bearing cell in the absence of the relevant test immunomodulatory compound; and/or (b) the level of one or more other cytokine(s) (or classes thereof) also present in the PRR-bearing cell (whether stimulated or not by the immunomodulatory compound). The cytokine stimulation profile of the immunomodulatory compounds for use according to the invention is preferably characterized by the stimulation of one or more Th1 cytokines (and optionally the absence of stimulation of one or more Th2 cytokines).

The term Th1 cytokine (or Type-1 cytokine) is a term of art used to define those cytokines produced by Th1 T-helper cells. Th1 cytokines include, for example, IL2, IFN-γ, IFN-α/β, IL12, IL-18, IL-27 and TNF-β. The term Th2 cytokine (or Type-2 cytokine) is a term of art used to define those cytokines produced by Th2 T-helper cells. Th2 cytokines include, for example, IL-4, IL-5, IL-9, IL-13, IL-25 and TSLP. The term Treg cytokine is a term of art used to define those cytokines produced by regulatory T-cells. Treg cytokines include, for example, IL-10, TGF-β and TSP1.

Immunomodulatory compounds for use according to the invention are preferably cytokine stimulatory compounds capable of stimulating the activity of one or more cytokine(s) in a PRR-bearing cell. In preferred embodiments, the compound may stimulate one or more Th1 cytokine(s) in a PRR-bearing cell, for example IL-12 and/or IL-2.

Immunomodulatory compounds for use according to the invention may also be able to reduce the overproduction of Th 1 cytokines such as IFN-γ via regulating production of IL-2 W 2

80

or IL-12 directly or by stimulating production of Th 2 cytokines such as IL-4. The compounds of the invention may also affect the production of glucosylated cytokines such as IFN-Y such that any overproduction is reduced or IFN-γ produced becomes less active or inactive as proposed for deoxynojirimycin and Λ/-methyl-deoxynojirimycin in isolated splenocyte studies by Kosuge et al. (2000) Biol. Pharm. Bull. 23 (1): 1-5. Therapeutic improvements to iminosugars for therapeutic applications involving reduction of overproduction of IFN-γ would be increased glycosidase specificity to avoid inhibition of off- target glucosidases caused by DNJ and N-methyl-DNJ.

(VII) Functional sugar mimicry

(a) General considerations

As described in Section A(ll)(c) (above), the iminosugars for use according to the invention may be structural sugar mimetics and in many cases this structural mimicry is reflected in shared functional properties. Such functional sugar mimetics, as defined above, are compounds which share some or all of the functional properties of the sugar mimicked. For example, functional sugar mimetics may share some of the binding properties of the sugar mimicked in vivo (without necessarily sharing all of the attendant functional properties thereof).

Certain sugar mimetics may be identified by assays for saccharase inhibitory activity. Such enzyme assays are routine in the art, and those skilled in the art will readily be able to identify appropriate conditions and formats for such assays. For example, many polyhydroxylated iminosugars are potent and highly selective glycosidase inhibitors. These compounds can mimic the number, position and configuration of hydroxyl groups present in pyranosyl or furanosyl moieties and so bind to the active site of a cognate glycosidase, thereby inhibiting it. This area is reviewed in Legler (1990) Adv. Carbohydr. Chem. Biochem. 48: 319-384 and in Asano et al. (1995) J. Med. Chem. 38: 2349-2356.

In yet other embodiments, the functional sugar mimetic binds to a sugar receptor PRR. Such binding perse need not necessarily trigger a sugar receptor-mediated signalling pathway (i.e. initiate the cellular signalling cascade in which the sugar receptor forms a part): other co-stimulatory events may be required. Moreover, the binding may occur in the context of some other aspect of cellular physiology. In the latter case, the compounds of the invention may act as ligands as hereinbefore defined and may for example bind a sugar receptor at the cell surface without triggering a signalling cascade, in which case the binding may affect other aspects of cell function. Thus, the functional sugar mimetics of the invention may bind to a sugar receptor and thereby effect an increase in the concentration of functional sugar receptor at the cell surface (for example mediated via an increase in receptor stability, absolute receptor numbers and/or receptor activity).

Alternatively, the function sugar mimetics may bind a sugar receptors (or a sugar receptor precursor) intracellular^, in which case they may act as molecular chaperones to increase the expression of active PRR.

(b) Glucose mimetics

The compounds for use according to the invention may be glucose mimetics. Such compounds may share some or all of the binding properties of glucose in vivo (without necessarily sharing all of the attendant functional properties thereof).

Such glucose mimetics may be identified by assays for glucosidase inhibitory activity. Such enzyme assays are routine in the art, and those skilled in the art will readily be able to identify appropriate conditions and formats for such assays.

Examples of such compounds are described in e.g. WO9929321 (the disclosure of which relating to specific piperidine iminosugars and their structure is hereby incorporated by reference). An example of such a glucose mimetic the iminosugar designated 1 ,5-dideoxy- 1 ,5-imino-D-glucitol (alternately designated deoxynojirimycin), hereinafter "DNJ." Numerous DNJ derivatives have been described. DNJ and its alkyl derivatives are potent inhibitors of the N-linked oligosaccharide processing enzymes, alpha-glucosidase I and alpha-glucosidase Il (Saunier et al. (1982) J Biol Chem 257:14155-14161 ; Elbein (1987) Ann Rev Biochem 56:497534). These glucosidases are associated with the endoplasmic reticulum of mammalian cells. The N-butyl and N-nonyl derivatives of DNJ may also inhibit glucosyltransferases associated with the Golgi.

(c) Man nose and/or rhamnose mimetics

For example, the compounds of the invention may be mannose and/or rhamnose mimetics. Such compounds may share some or all of the binding properties of mannose and/or rhamnose in vivo (without necessarily sharing all of the attendant functional properties thereof).

Such sugar mimetics may be identified by assays for mannosidase and/or rhamnosidase inhibitory activity. Such enzyme assays are routine in the art, and those skilled in the art will readily be able to identify appropriate conditions and formats for such assays.

Thus, preferred rhamnose mimetics for use according to the invention are iminosugars which exhibit inhibitory activity against one or more rhamnosidase enzyme(s). Similarly, preferred mannose mimetics for use according to the invention are iminosugars which exhibit inhibitory activity against one or more mannosidase enzyme(s).

In yet other embodiments, preferred iminosugars may be rhamnose mimetics which bind to the rhamnose receptor PRR (see Grillon et al., (1990) Glycobiol., 1 (1): 33-8). Such binding perse need not necessarily trigger the rhamnose receptor-mediated signalling pathway (i.e. initiate the cellular signalling cascade in which the rhamnose receptor forms a part): ^■ other co-stimulatory events may be required. Moreover, the binding may occur in the context of some other aspect of cellular physiology. In the latter case, the iminosugars may act as ligands as hereinbefore defined and may for example bind rhamnose receptor at the cell surface without triggering a signalling cascade, in which case the binding may affect other aspects of cell function. Thus, the rhamnose mimetics of the invention may bind to the rhamnose receptor and thereby effect an increase in the concentration of functional rhamnose receptor at the cell surface (for example mediated via an increase in receptor stability, absolute receptor numbers and/or receptor activity). Alternatively, the rhamnose mimetics may bind rhamnose receptors (or rhamnose receptor precursors) intracellular^, in which case they may act as molecular chaperones to increase the expression of active PRR.

Similarly, other preferred iminosugars may be mannose mimetics which bind to the mannose receptor PRR. Again, such binding perse need not necessarily trigger the mannose receptor-mediated signalling pathway (i.e. initiate the cellular signalling cascade in which the mannose receptor forms a part): other co-stimulatory events may be required.

Moreover, the binding may occur in the context of some other aspect of cellular physiology.

In the latter case, the iminosugars may act as ligands as hereinbefore defined and may for example bind mannose receptor at the cell surface without triggering a signalling cascade, in which case the binding may affect other aspects of cell function. Thus, the mannose mimetics of the invention may bind to the mannose receptor and thereby effect an increase in the concentration of functional mannose receptor at the cell surface (for example mediated via an increase in receptor stability, absolute receptor numbers and/or receptor activity). Alternatively, the mannose mimetics may bind mannose receptors (or mannose receptor precursors) intracellular^, in which case they may act as molecular chaperones to increase the expression of active PRR.

(VIII) Glycosylation modulators, alkovirs and glycovirs

The compounds for use according to the invention may be glycosylation modulators, alkovirs and/or glycovirs, as hereinbefore defined.

Preferred glycosylation modulators can alter (e.g. eliminate, truncate, uncouple or debranch) N-linked or O-linked oligosaccharide structures on viral envelope glycoproteins. Preferred glycosylation modulators are glycosylation inhibitors. The glycosylation inhibitors of the invention may eliminate, truncate or debranch / uncouple oligosaccharide structures on viral envelope proteins.

The glycosylation modulators may modulate the activity of one or more glycosidase(s). Preferred are glycosylation inhibitors which inhibit the activity of one or more glycosidase(s). Particularly preferred are glycosylation modulators or inhibitors which modulate or inhibit the activity of glycosidase I (particularly glucosidase I).

Particularly preferred compounds are glycosylation inhibitors which are glycovirs, and more particularly glucovirs (as described and defined herein).

Glycosylation modulators may be identified by standard enzymological assay. Preferred are agents which specifically inhibit ER α-glucosidases (for example, which specifically inhibit ER α-glucosidase I and/or ER α-glucosidase II, relative to other mammalian glycosidase enzymes). Most preferably, the glycosylation modulators of the invention inhibit ER α-glucosidase I and/or ER α-glucosidase Il with a degree of specificity such that gastrointestinal toxicity via disaccharidase inhibition on administration at antiviral concentrations in humans is absent (or present at clinically acceptable or subtoxic levels). Preferred compounds for use according to the invention: (a) are glycosylate modulators as defined herein and described in the previous section; (b) are alkovirs, glycovirs or glucovirs as herein defined; and/or (c) have immunomodulatory activity (e.g. being an immunomodulatory or cytokine activating alkaloid as herein defined).

Glycosylation modulators, glucovirs and glycovirs may be identified by standard enzymological assay. Preferred are alkaloids which specifically inhibit ER α-glucosidases (for example, which specifically inhibit ER α-glucosidase I and/or ER α-glucosidase II, relative to other mammalian glycosidase enzymes). Most preferably, the compounds of the invention inhibit ER α-glucosidase I and/or ER α-glucosidase Il with a degree of specificity such that gastrointestinal toxicity via disaccharidase inhibition on administration at antiviral concentrations in humans is absent (or present at clinically acceptable or subtoxic levels).

(IX) Viral p7 protein inhibition and ion channel interference '

Alternatively, or in addition, the compounds may inhibit the activity of a viral p7 protein (for example, acting as viral ion channel blockers). Such compounds may be identified by the methods described for example in Pavlovic et al. (2003) Proc. Nat. Acad. Sci. 100(10): 6104-6108 (the relevant methodological disclosure of which is incorporated herein by reference).

In such embodiments, the compounds of the invention may not inhibit ER α-glucosidases at physiologically significant levels in vivo (and may not exhibit significant ER α-glucosidase I or Il inhibitory activity in vitro). Indeed, in such embodiments the compounds of the invention may exhibit poor glucosidase inhibitory activity (relative to castanospermine and DNJ as reference glucosidase inhibitors) and may therefore exhibit levels of glucosidase inhibition which are so low as to permit viral glycoprotein processing on administration at antiviral concentrations in humans (the antiviral activity in such embodiments being mediated independently of glucosidase inhibition).

Without wishing to be bound by any theory, it is thought that antiviral activity in such embodiments of the invention may arise from: (a) direct interaction of the compounds of the invention with viral p7molecules, either blocking the p7-derived ion channels or preventing them from forming and/or opening; and/or (b) effecting a change to the membrane bilayer (for example by accumulating therein), so preventing p7 molecules from assembling into channel-forming pores.

In this embodiment, the invention finds particular application in the treatment or prevention of any infection mediated by p7-viroporin viruses, which include pestiviruses and hepaciviruses (so including the treatment or prevention of infections involving members of the genera Pestivirus and Hepacivirus, including the HCV and BVDV viruses, as discussed infra).

(X) Other activities

Alternatively, or in addition, the compounds may exert antiviral activity independently of α- glucosidase inhibition or p7 interference. For example, the compounds of the invention may exert an antiviral effect mediated by an immunomodulatory activity (as proposed in Mehta et al., (2004), Antimicrob. Agents Chemother. 48(6): 2085-2090), for example by activating components of the innate immune system by a TLR-distinct or NF-κB- independent mechanism, by inducing interferon expression or by acting as interferon surrogates in vivo.

The compounds of the invention may exert an antiviral effect mediated by inhibition of other enzymes, for example viral enzymes involved or required for viral pathogenicity (for example neuraminidase).

C. General physicochemical considerations

The compounds for use according to the invention (including the compounds having the general formulae defined in section A(I) and the iminosugars described in section A(II), above) may have various physicochemical properties.

The compounds for use according to the invention are preferably crystalline materials. Also preferred are compounds which are water soluble, or which are soluble in pharmaceutically acceptable excipients and formulations used in oral or i.v. administration (e.g. those described below). Also preferred are compounds which are subject to efficient passive or active transport to the desired site of action in vivo. Preferred are iminosugars having a small molecular weight, since these may exhibit desirable pharmacokinetics. Thus, the iminosugar may have a molecular weight of 100 to 400 Daltons, preferably 150 to 300 Daltons and most preferably 200 to 250 Daltons.

Also preferred are non-metabolizable iminosugars. Such sugars may exhibit extended tissue residence durations, and so exhibit favourable pharmacokinetics.

D. Specific examples

Particular examples of compounds suitable for use according to the invention are listed in Table 1 (below). References to particular compound numbers herein refer to the numbers in this list.

Compound Chemical Name Compound Stereochemistry

# Class

Allose Altrose Arabinose Galactose Glucose Gulose ldose Lyxose Mannose Ribose Talose Xylose

1 (1 R,2R,3S,6S,7R,7aS)- pyrrol dine y y y y y

(hydroxymethyl)hexahy dro-1 H-pyrrolizine-

1 ,2,6,7-tetraol

CΛ 2 (2R,3R,4R)-2- pyrrolidine

C (hydroxymethyl)pyrrolιdι DO ne-3,4-dιol CΛ 3 (2R,3R,4R,5S)-2- pipeπdine

(hydroxymethyl)-i- methylpιperιdιne-3,4,5- tnol m 4 (3R,4R)-4-hydroxy-1 ,1- pyrrolidine OC

CΛ dιmethylpyrrolιdιnιum-3-

Z carboxylate m 5 (2R,3S,4S)-4-hydroxy- pyrrolidine m 2-(4- methoxybenzyl)pyrrolιdι n-3-yl acetate c 6 (2S,4R)-4-hydroxy-1 ,1- pyrrolidine dιmethylpyrrolιdιnιum-2- m carboxylate

7 (2S,3R,4R,5S)-3,4,5- piperidine trιhydroxypιpeπdιne-2- carboxylic acid

8 (1 R,5S,8R)-1 ,8- other dιhydroxy-6-oxa-3- azabιcyclo[3 2 1]octan-

2-one

9 (3R,4R,5S)-3- pipeπdine

(hydroxymethyl)pιpeπdι πe-3,4,5-trιol

10 (1S,2R,3S,4R,5S)-8- nortropane methyl-8- azabιcyclo[3 2 1]octane-

1 ,2,3,4-tetraol

11 (2R,3R,4R,5R)-2-((R)- pyσolidine

1 ,2-dιhydroxyethyl)-5-

(hydroxymethyl)pyrrolιdι ne-3,4-dιol

12 (1S,7S,8S,8aR)- indolizidine octahydroindolizine-

1 ,2,7,8-tetraol

13 (2R,3R,4R,5R)-2,5- pyrrolidine bιs(hydroxymethyl)pyrro lιdιne-3,4-dιol

14 (1 R 2R,3R,5R,7aR)-3- pyrrolizidine

(hydroxymethyl)-5- methylhexahydro-1 H- r/j pyrrolιzιne-1 2-dιol

15 (2R,3S,4R,5R,6R)-2,6- piperidine y

DO bιs(hydroxymethyl)pιperι

V) dιne-3,4,5-tnol

16 (2R,3R,4S,5S,6R)-2- piperidine y

(hydroxymethyl)-6-

C (((2R,3R,4S,5S,6R)-

H 3,4,5-tπhydroxy-6- m (hydroxymethyl)tetrahyd OC OC

C/) ro-2H-pyraπ-2-

Z yloxy)methyl)pιperιdιne- m m 3,4,5-tπol

17 (1R,2R,3R,7S,7aS)-3- pyrrolizidiπe

(hydroxymethyl)hexahy dro-1 H-pyrrolιzιne-1 ,2,7-

C tπol ι— (3aR,3a1 R,4R,5S,8aS)- pyrrolizidine m 18

5-(hydroxymethyl)-2,2-

N) dimethylhexahydro-

3aH-[1 ,3]dιoxιno[4,5,6- gh]pyrrolιzιn-4-ol

19 loline pyrrolizidine

20 (1 R,2S,3R,5R)-8- nortropane azabιcyclo[3 2 1]octane-

1 ,2,3-trιol

21 (1 R,2S,3R,4S,5R)-8- nortropaπe azabιcyclo[32 1]octane-

1 ,2,3,4-tetraol

22 (1R,2R,3R,5S,7S,7aR)- pyrrolizidine

3-(hydroxymethyl)-5- methylhexahydra-1 H- pyrolιzιne-1 ,2,7-tπol

23 (2S,3R,4S,5S,6S)-2- pipeπdine ethyl-6-

(hydroxymethyl)pιpeπdι ne-3,4,5-tπol

24 (1S,2R,3R,5R,6S,7R,7a pyrrohzidine R)-3-(hydroxymethyl)-5- methylhexahydro-1 H- pyrrolιzιne-1 , 2,6,7- tetraol

25 (2R,3R,4R,5R)-1-(2- pyrrolidine hydroxyethyl)-2,5- bιs(hydroxymethyl)pyrro lιdιne-3,4-dιol

J/) 26 (2R,3R,4R,5R)-2-(3- pyrrolidine

^ hydroxy-4- gg methoxyphenyl)-5-

C/) (hydroxymethyl)pyrrolιdι

H ne-3,4-dιol

H 27 (2R,3R,4R,5R)-2- pyrrolidine

C (hydroxymethyl)-5-(4-

H hydroxyphenyl)pyrrolιdι rπ ne-3,4-dιol OC

C/) 28 (1R,2R,3R,6S,7S,7aS)- pyrrolidine

X 3-(hydroxymethyl)-6- m (3,4,5-tπhydroxy-6-

^ (hydroxymethyl)tetrahyd

""" ro-2H-pyran-2- jQ yloxy)hexahydro-1H-

^ pyrrolιzιne-1 ,2,7-tπol

|— 29 (2S,3S,4R)-1-(2- pyrrolidine m hydroxyethyl)-2-

Ni (hydroxymethyl)pyrrolιdι

2 ne-3,4-dιol

30 (1 R,2S,6R,7R,8R,8aR)- indolizidine octahydroindolizine- 1 ,2,6,7,8-pentaol

31 (1R,2R,3R,7aR)-3- pyrrohzidine (hydroxymethyl)-5-

(3,10,11- tπhydroxyundecyl)hexa hydro-1 H-pyrrolizine-

1 ,2,6-tπol

32 (1S,6S,7R,8R,8aR)-8- indolizidine

(3,4,5-tπhydroxy-6-

(hydroxymethyl)tetrahyd ro-2H-pyraπ-2-

yloxy)octahydroιndolιzιn e-1 ,6,7-trιol

33 (1 R,2S,3R,4S,5R,6R)-8- nortropane azabιcyclo[3 2 1]octane-

1 ,2,3,4,6-pentaol

34 (2R,3R,4R,6R)-6-butyl- piperidine

2-

(hydroxymethyl)pιperιdι ne-3,4-dιol

35 (1 R,2R,3S,6S,7R,7aR)- pyrrolizidine

3-

(butyryloxymethyl)hexah ydro-1 H-pyrrolιzιne-

V) 1 ,2,6,7-tetrayl

C tetrabutyrate

DO 36 (1S,2R,8R,8aR)- indolizidine

C/) y octahydroindolizine-

—i 1 ,2,8-trιol

-\ 37 (1S,2R,6R,7S)- pyrrolizidine

C y hexahydro-1 H- m pyrrolιzιne-1 , 2,6,7- tetraol

C/) 38 (1R,2R,3S,6S,7R,7aR)- pyrrolizidine

X m 7-amιno-3- m (hydroxymethyl)hexahy dro-1H-pyrrolιzιne-1 ,2,6- tnol

73 39 (2R,3R,4R,5R)-2-((1 R)- pyrrolidine

C 2-(3,4-dιhydroxy-4- ι r~π (hydroxymethyl)tetrahyd m rofuran-2-yloxy)-1-

N) hydroxyethyl)-5- S)

(hydroxymethyl)pyrrolιdι ne-3,4-dιol

40 (2R,3R,4R)-2- piperidine

(hydroxymethyl)pιpeπdι ne-3,4-dιol

41 (1R,2S,6S,7R,8R,8aS)- indolizidine

2-(3,4,5-tnhydroxy-6-

(hydroxymethyl)tetrahyd ro-2H-pyran-2- yloxy)octahydroιndolιzιn e-1 ,6,7,8-tetraol

42 (2R,3R,4R,5R)-2-((Z)-5- pyrrolidine hydrazono-4- ιmιnopentyl)-5-

(hydroxymethyl)pyrrolιdι ne-3,4-dιol

43 (1S,2R,3S,5R)-8- nortropane azabιcyclo[3 2 1]octane-

1 ,2,3,6-tetraol

44 (1 S,3R,4R,5S)-8- nortropane azabιcyclo[3 2 1]octane-

1 ,3,4-trιol

45 (4R,5R,6S)-4,5- oxazilidme dιhydroxy-6-

(hydroxymethyl)morphol ιn-2-ιum

46 (1S,6S,7S,8R)-1 ,7,8- indolizidine

C/) trihydroxyoctahydroindo

C lιzιn-6-yl butyrate DO 47 (1 R,2R,3R,6S,7S,7aR)- pyrrolizidine C/) 3-

(acetoxymethyl)hexahy dro-1H-pyrrolιzιne-

1 ,2,6,7-tetrayl m tetraacetate

48 (2R,3R,4S)-2-((R)-1 ,2- pyrrolidine

C/) dιhydroxyethyl)-1-(2-

Z m hydroxyethyl)pyrrolιdιne m -3,4-dιol

49 (2R,3R,4R)-1-butyl-2- pyrrolidine (hydroxymethyl)pyrrolιdι ne-3,4-dιol c 50 2-((2R,3R,4R)-3- piperidine m hydroxy-2- (hydroxymethyl)pιperιdι n-4-yloxy)-6- (hydroxymethyi)tetrahyd ro-2H-pyran-3,4,5-trιol

51 (2R,3R,4R,5S,6R)-2- piperidine

(hydroxymethyl)-6- methylpιpeπdιπe-3,4,5- tπol

52 (2R,3R,4S,5S)-2,5- piperidine bιs(hydroxymethyl)pιpeπ dιne-3,4,5-tπol

53 2-((S)-2-((2S,3S,4S,5S)- pyrrolidine

3,4-dιhydroxy-5- (hydroxymethyl)pyrrolιdι n-2-yl)-2- hydroxyethoxy)tetrahydr

o-2H-pyran-3,4,5-trιol

54 (1S,2R,3R,7aR)-3- pyrrolizidiπe (hydroxymethyl)hexahy dro-1 H-pyrrolιzιne-1 ,2- diol

55 (1 R,2R,3R,6S,7S,7aR)- pyrrolizidinβ

3-((3,4,5-tπhydroxy-6- (hydroxymethyl)tetrahyd ro-2H-pyran-2- yloxy)methyl)hexahydro

-1 H-pyrrolιzιne-1 ,2,6,7- tetraol

C/) 56 (1 R,2R,3S,7S,7aR)- pyrrolizidme

C 1 ,2,7- OO tπhydroxyhexahydro- C/) 1H-pyrrolιzιne-3- carboxylic acid

57 (2R,3S)-2- pyrrolidine (hydroxymethyl)pyrrolιdι m n-3-ol

58 (3S,4S,5R,6S)-3,4,5- pipeπdine K.

C/) trιhydroxy-3,6-

Z m bιs(hydroxymethyl)pιperι m dιn-2-one

59 (1S,2R,3R,5S,7aR)-5- pyrrol dine

«1R)-1.3-

73 dιhydroxybutyl)-3- c (hydroxymethyl)hexahy m dro-1 H-pyrrolιzιne-1 ,2- diol

60 (2S,3S,4S,5S)-2-(4- pyrrolidine amιnopentyl)-5-

(hydroxymethyl)pyrrolιdι ne-3,4-dιol

61 4-((2S,3S,4R,5R)-3,4- piperidine dιhydroxy-2-

(hydroxymethyl)-5-

(3,4,5-tπhydroxy-6-

(hydroxymethyl)tetrahyd ro-2H-pyran-2- yloxy)pιpeπdιn-1- yl)butanoιc acid

62 (2R,3R,4R,5R)-2- pyrrolidine (hydroxymethyl)-5-((R)-

1-

hydroxypropyl)pyrrolιdιn e-3,4-dιol

63 (2R,3R,4R,5R)-2-((1R)- pyrrolidine

1 ,2-dιhydroxypropyl)-5-

(hydroxymethyl)pyrrolιdι ne-3,4-dιol

64 (2R,3R,4R,5R)-1-(2- pyrrolidine acetoxyethyl)-2,5- bιs(acetoxymethyl)pyrrol ιdine-3,4-dιyl diacetate

65 (2S,4R)-4-hydroxy-1- pyrrolidine methylpyrrolιdιne-2- carboxylic acid

V) 66 (1S,2R,3R,5R,6S,7aR)- pyrrol dine

C 5-(3-hydroxybutyl)-3-

DO (hydroxymethyl)hexahy

C/) dro-1 H-pyrrolιzιne-1 ,2,6-

—i tπol

-\ 67 (1S,2R,3R,5S,7aR)-5- pyrrolizidine

C (3-hydroxybutyl)-3-

H m (hydroxymethyl)hexahy

1 11 dro-1 H-pyrrolizιne-1 ,2-

C/) diol

Z 68 (1S,2R,3R,5S,7R,7aR)- pyrrol dine m m 3,5- bιs(hydroxymethyl)hexa

__, hydro-1 H-pyrrolιzιne-

Xl 1 ,2,7-tπol

C 69 (2S,3S,4S,5R,6S)-2- pipeπdme ι~ y y m (acetoxymethyl)-6- ethylpιpeπdιne-3,4,5-

N) O) tπyl tπacetate

70 (2S,3R,4S)-2-((R)-1 ,2- pyrrolidine dιhydroxyethyl)pyrrolιdιn e-3,4-dιol

71 (2R,3S)-3-hydroxy-1,1- pyrrolidine dιmethylpyrrolιdιnιum-2- carboxylate

72 (2S,3S,4S,5R)-2- pipeπdme ethylpιpeπdιne-3,4,5- tπol

73 (2S,3S,4R)-1-benzyl-2- pyrrolidine

((R)-1, 2- dihydroxyethyl)pyrrolidin e-3,4-dιol

74 (2S,3S,4R)-1-butyl-2- pyrrolidine (hydroxymethyl)pyrτolιdι ne-3,4-dιol 75 (2S,3R,4S)-2-(1 ,2- pyrrolidine dιhydroxypropyl)pyrrolιdι y ne-3,4-dιol 76 (2S,3S,4S,5S)-2-(3,6- pyrrolidine dιhydroxyheptyl)-5- y (hydroxymethyl)pyrrolιdι ne-3,4-dιol

77 (2S,3R,4R,5R,6R)-5- pipendine

(3,4-dιhydroxy-2,5- bιs(hydroxymethyl)tetra

C/) hydrofuran-2-yloxy)-2,6-

C bιs(hydroxymethyl)pιperι DO dιne-3,4-dιol C/) 78 (2R,3R,4R,5S)-2- pipeπdine

((3,4,5-tπhydroxy-6-

(hydroxymethyl)tetrahyd ro-2H-pyran-2- yloxy)methyl)pιperιdιne- m 3,4 5-tπol

C/) 79 2-((2R,3R,4R,5R)-4- pyrrolidine

Z hydroxy-2,5- m m bιs(hydroxymethyl)pyrro lιdιn-3-yloxy)-6-

(hydroxymethyl)tetrahyd ro2H-pyran-3,4,5-trιol

80 (2S,3R,4R)-3,4- pyrrolidine dιhydroxy-1 ,1- m dιmethylpyrrolιdιnιum-2- carboxylate

2 81 (1 R,2R,3S,4R,6S,7R,7a pyrrolizidine R)-1 ,2,6,7-tetrahydroxy-

3-

(hydroxymethyl)octahyd ropyrrolizine 4-oxιde

82 (2S,3R,4S,5R)-2,3- pipeπdine dimethylpipeπdme-

3,4,5-tπol 83 (3R,4R,5S)-3,4,5- pipendine tπhydroxy-3- (hydroxymethyl)pιpeπdι n-2-one

84 (3R,4S)-2,2- pyrrolidine bιs(hydroxymethyl)pyrro

lιdιne-3,4-dιol

85 (2S,4S)-4- pyrrolidine

(hydroxymethyl)-i- methylpyrrolιdιne-2- carboxylic acid

86 (2R,3S,4R)-2-((S)-1 ,2- pyrrolidine dιhydroxyethyl)-4- methylpyrrolιdιne-3,4- diol

87 (3R,4R,5R)-3,4,5- pipeπdine trιhydroxypιperιdιne-3- carboxylic acid

C/) 88 (2R,3S,4S)-2-((S)-1- pyrrolidine y y

C hydroxyethyi)pyrrolιdιne

DO -3,4-dιol

C/) 89 (3S,4R)-1-(allyloxy)-2,2- pyrrolidine

—i bιs(hydroxymethyl)pyrro

-\ lιdιne-3,4-dιol

C 90 N-((1S,7aR)-hexahydro pyrrolizidine

—i m 1 H-pyrrolιzιn-1-yl)-2-

1 11 methylbutanamide 'J

C/) 91 (3S,4R)-2,2- pyrrolidine

Z bιs(hydroxymethyl)-1- m m propoxypyrrolιdιne-3,4- diol

__, 92 (2S,3S,4R)-2- pyrrolidine

7} (hydroxymethyl)-2-

C methylpyrrolιdιne-3,4- ι— diol m 93 (1R,2S,6S,8S,8aS)-6- indolizidine

N) m methyloctahydroindolizi ne-1 ,2,8-tπol

94 (2R,3R,4R)-3,4- pyrrolidine dιhydroxy-1-(2- hydroxyethyl)-2-

(hydroxymethyl)pyιτolιdι ne 1 -oxide

95 (2R,3R,4R)-1-butyl-3,4- pyrrolidine dιhydroxy-2-

(hydroxymethyl)pyrrolιdι ne 1 -oxide

96 (2S,3R,4S)-1-butyl-2- pyrrolidine

((S)-1 ,2- dιhydroxyethyl)pyrrolιdιn e-3,4-dιol

97 (S)-1-((3aS,4R,6aS)-6a- pyrrolidine

(hydroxymethyl)-2,2- dιmethyltetrahydro-3aH-

[1 ,3]dιoxolo[4,5-c]pyrrol-

4-yl)βthane-1 ,2-dιol

98 (2R,3S,4S)-2-((S)-1 ,2- pyrrolidine dιhydroxyethyl)-4-

(hydroxymethyl)pyrrolιdι ne-3,4-dιol

99 (2S,3S,4R)-1-(2- pyrrolidine hydroxyethyl)-2-

(hydroxymethyl)-2- methylpyrrolιdιne-3,4

C/) diol

C 100 (2S,3R,4S,5R)-1-butyl- pipeπdine

CD 2,3-dιmethylpιperιdιπe-

C/) 3,4 5-trιol

H 101 N-((3R,5R)-1-benzyl-5- pyrrolidine

H ((S)-I 2-

C dιhydroxyethyl)pyrrolιdιn

H -3-yl)acetamιde m 102 (3R 4S 5R)-5 6- pipeπdine

C/) dιmethyl-2,3,4 5-

Z tetrahydropyπdine- m 3,4,5-tπol m 103 (3R,4r,5S)-pιpeπdιne- piperidine

3,4,5-trιol

104 (1S,6S,7R,8R,8aR)- indolizidine

C octahydroindohzine- ι~ m 1 ,6,7,8-tetraol

105 (1 R,2S,3S,4S,5R)-4- nortropane

N) S) (3,4,5-tπhydroxy-6-

(hydroxymethyl)tetrahyd ro-2H-pyran-2-yloxy)-8- azabιcyclo[3 2 1]octane-

1 ,2,3-tπol

106 (1S,2S,3R,4S,5S)-5- nortropane methyl-8-oxa-6- azabιcyclo[3 2 1]octane-

2,3,4-tπol

107 (7aS,7a1R,10aR,18aR, pyrrolizidine

18bS)-

2,2,6,6,13,13,17,17- octamethyltetradecahyd robιs[1 ,5]dιoxeαno[2,3- b 2',3',4'-gh]pyrrolιzιne-

_SUB_{STI SHEET}

4,15(7aH,7a1 H)-dιone

108 (2S,3S,4R,5R,6R)-2- pipeπdine butyl-6- (hydroxymethyl)pιpeπdι ne-3,4,5-tπol

109 (2R,3R,4S,5R)-2- pipeπdine methylpιperιdιne-3,4,5- tπol

110 2-((2R,3R,4R,5S,6R)- piperidine

4,5-dιhydroxy-2,6- bιs(hydroxymethyl)pιperι dιn-3-yloxy)-6- (hydroxymethyl)tetrahyd ro-2H-pyraπ-3,4,5-tπol

111 1-((2S,3R,4R,5R)-3,4- pyrrolidine dιhydroxy-5- (hydroxymethyl)pyrrolιdι

H n-2-yl)-2-methoxy-1H- C ιmιdazole-4,5-dιol m 112 (3S,4S,5R,6R)-3,4,5- piperidine tπhydroxy-6- (hydroxymethyl)pιperιdι n-2-one

113 2-((1 S,5R,6R,7R,7aS)- pyrrolidine

6,7-dιhydroxy-5-

(hydroxymethyl)hexahy

73 dro1 H-pyrrolιzιn-1-

C r~ yloxy)-6- m (hydroxymethyl)tetrahyd ro-2H-pyran-3,4,5-triol

N) σ> 114 (2S,3S,4R,5R,6R)-2- piperidine pentyl-6-((3,4,5- trιhydroxytetrahydro-2H- pyran-2- yloxy)methyl)ριpeπdιne- 3,4,5-tπol

115 (2R,4R)-2- piperidine carboxypιpeπdιnιum-4-yl sulfate

116 (1S,2R,3R,5R,7aR)-3,5- pyrrolizidine bιs(hydroxymethyl)hexa hydro-1 H-pyrrolizine-

1 ,2-dιol

117 (2R,3R,4R,5R)-3,4- pyrrolidine dιhydroxy-2-methyl-1- oxo-5- phenylpyrrolidinium

118 (2R,3R,4R,5S)-1 -butyl- pipeπdine

2-

(hydroxymethyl)pιpeπdι ne-3,4,5-tπol

119 (2S,3S,4S,5R)-2- pyrrolidine (hydroxymethyl)-5- methylpyrrolιdιne-3,4- diol

120 2-((2R,3R,4R,5S)-3,5- piperidine

C/) dιhydroxy-2-

C (hydroxymethyl)pιpeπdι DO n-4-yloxy)-6- C/) (hydroxymethyl)tetrahyd ro-2H-pyran-3,4,5-trιol

121 2-((3S,4S,5R,6R)-4,5- piperidine dιhydroxy-6- (hydroxymethyl)pιperιdι m n-3 yloxy)-6- OC

C/) (hydroxymethyl)tetrahyd

Z ro-2H-pyran-3,4,5-tnol m m 122 2-((3S,4S,5R,6R)-4,5- piperidine dιhydroxy-6- (hydroxymethyl)-i - methylpιperιdιn-3- c yloxy)-6-

(hydroxymethyl)tetrahyd m ro-2H-pyran-3,4,5-tπol

123 2-((3R,4R,5R)-4- pyrrolidine hydroxy-5- (hydroxymethyl)pyrrolιdι n-3-yloxy)-6- (hydroxymethyl)tetrahyd ro-2H-pyran-3,4,5-tπol

124 (2R,3R,4R,5S,6R)-2,6- pipeπdine bιs(hydroxymethyl)-1 - methylpιpeπdιne-3,4,5- tπol

125 (3aR,6S,7R,7aS)- pipeπdine hexahydrospιro[[1 ,3]dιo xolo[4,5-b]pyrιdιne-2,1 '- cyciohexane]-6,7-dιol

126 (3S)-2,3-dιhydroxy-3- pyrrolidine

((2R,3R,4R)-2,3,4- trιhydroxypyrrolιdιn-2- yl)propanoιc acid

127 (1R,2R,3S,7S,7aR)-3- pyrrol izidine

(hydroxymethyl)hexahy dro-1 H-pyrrolιzιne-1 ,2,7- tnol

128 (1 R,2R,3R,7S,7aR)-3- pyrrolizidine

(hydroxymethyl)hexahy dro-1 H-pyrrolιzιne-1 ,2,7- tπol

129 (1 R,2R,3S,6S,7S,7aR)- pyrrolizidine

V) 3-

(hydroxymethyl)hexahy

DO dro-1 H-pyrrolizine-

V) 1 ,2,6,7-tetraol

130 (1 S,2S,6S,7S,8S,8aS)- indolizidine octahydroindolizine-

C 1 ,2,6,7,8-pentaol

H 131 (1 R,2R,3S 6R,7R,7aR)- pyrrolizidine m 3-

V) (hydroxymethyl)hexahy

Z dro-1 H-pyrroliZine- m m 1 ,2,6,7-tetraol

132 (1R,2R,3R,6S,7S,7aR)- pyrrolizidine

3-

(butyryloxymethyl)hexah

C ydro-1 H-pyrrolizine- ι— 1 ,2,6,7-tetrayl m tetrabutyrate

N) 133 (2R,3S,4S,5S,6R)-2- pipeπdine

(hydroxymethyl)-6- methylpιpeπdιπe-3,4,5- tπnl

134 (2R,3R,4R,5R,6S)-2- pipeπdine

(hydroxymethyl)-6- methylpιpeπdιne-3,4,5- tπol

135 (2S,3R,4S,5S)-2,5- pipeπdine y bιs(hydroxymethyl)pιperι dιne-3,4,5-tπol

136 (1R,2R,3S,6S,7S,7aR)- pyrrolizidine y

3-

(acetoxymethyl )hexahy dro-1 H-pyrrolizine-

1 ,2,6,7-tetrayl tetraacetate

137 (1R,2R,3R,6S,7S,7aR)- pyrrolidine

3-

(hydroxymethyl)hexahy dro-IH-pyrrolizine-

1 ,2,6,7-tetraol

138 (1 R,2R,3R,4S,5R)-8- nortropane azabιcyclo[3 2 1]octane-

1 ,2,3,4-tetraol

139 (1S,2R,3R,7S,7aR)-3- pyrrolizidine

(hydroxymethyl)hexahy dro-1 H-pyrrolιzιne-1 ,2,7-

C/) tπol

C 140 (2R,3R,4S)-2- pipeπdme

DO (hydroxymethyl)pιperιdι

C/) ne-3,4-dιol

^■H 141 (1 R,2S,3R,4R,5R)-8- nortropane y azabιcydo[3 2 1]octane-

1 ,2,3,4-tetraol

— I m 142 (2R,3R,4R)-1-(2- pyrrolidine y hydroxyethyl)-2- to (hydroxymethyl)pyrrolιdι

J- m ne-3,4-dιol m 143 (1S,2R,3R,5R,7R,7aR)- pyrrolizidine

3-(hydroxymethyl)-5- methylhexahydro-1 H-

7} pyrrolιzιne-1 ,2,7-tπol

C 144 (1 R,2R,3S,6S,7R,7aR)- pyrrolizidine m (acetoxymethyl)hexahy

N) dro-1 H-pyrrolιzιne- O)

1 ,2,6,7-tetrayl tetraacetate

145 (2R,3S,4R)-2-((S)-1 ,2- pyrrolidine dιhydroxyethyl)-1-(2- hydroxyethyl)pyrrolιdιne

-3,4-dιol

146 (1R,2R,3S,6S,7R,7aS)- pyrrolizidine

3-

(acetoxymethyl)hexahy dro-1 H-pyrrolιzιne-

1 ,2,6,7-tetrayl tetraacetate

147 (1S,2S,3S,6R,7R,7aS)- pyrrolizidine

3-

(hydroxymethyl)hexahy dro-1H-pyrrolιzιne-

1 ,2,6,7-tetraol

148 (1 S,2S,3S,6S,7S,7aS)- pyrrolizidine

(hydroxymethyl)hexahy dro-1H-pyrrolιzιne-

1 ,2,6,7-tetraol

149 (1S,2R,3R,5S,7R,7aR)- pyrrolidine

3-(hydroxymethyl)-5- methylhexahydro-1 H-

C/) pyrrolιzιne-1 ,2,7-trιol

C 150 (1S,2R,3R,5R,7aR)-3- pyrrolizidine

OO (hydroxymethyl)-5-

V) methylhexahydro-1 H-

H pyrrolιzιne-1 ,2-dιol

H 151 (1 R,2S,3R,5R,7aR)-3- pyrrolidine

C (hydroxymethyl)-5-

H methylhexahydro-1 H- m pyrrolιzιne-1 ,2-dιol

C/) 152 (1S,2R,3R,5S,6R,7S,7a pyrrolizidine

Z R)-3-(hydroxymethyl)-5- m methylhexahydro-1 H- m pyrrolιzιne-1 , 2,6,7-

-H tetraol

153 (1R,2S,8S,8aS)- indolizidine

C octahydromdolizine-

1 ,2,8-tπol m 154 (2R,3R,4S)-1-(2- pyrrolidine hydroxyethyl)-2-

(hydroxymethyl)pyrrolιdι ne-3,4-dιol

155 (2S,3R,4S)-2-((S)-1 ,2- pyrrolidine dιhydroxyethyl)pyrrolιdιπ e-3,4-dιol

156 (2S,3S,4R)-2-((R)-1 ,2- pyrrolidine dιhydroxyethyl)pyrrolιdιn e-3,4-dιol

157 (2S,3R,4R)-1-butyl-2- pyrrolidine

(hydroxymethyl)pyrrolιdι ne-3,4-dιol

158 (1R,2S,3R,5S,7S,7aR)- pyrrolizidine

3-(hydroxymethyl)-5- methylhexahydπ>1 H-

_STI

pyrrol ιzιne-1 ,2,7-tπol

159 (2S,3R,4S)-1-benzyl-2- pyrrolidine

((S)-1 ,2- dιhydroxyethyl)pyrrolιdιn e-3,4-dιol

160 (2S,3S,4S)-2- pyrrolidine y

(hydroxymethyl)pyrrolιdι ne-3,4-dιol

161 (2S,3S,4S)-1-(2- pyrrolidine y hydroxyethyl)-2- (hydroxymethyl)pyrrolιdι ne-3,4-dιol

C/) 162 (2S,3R,4S)-1 -butyl-2- pyrrolidine

C y (hydroxymethyl)pyrrolιdι

00 ne-3,4-dιol

163 (2S,3S,4S)-1-butyl-2- pyrrolidine y (hydroxymethyl)pyrrolidi

H ne-3,4-dιol C-_I 164 (1 S,2R,3S,5S,7S,7aR)- pyrrolidine m 3 (hydroxymethyl)-5- methylhexahydro-1 H-

C/)

Z pyrrolιzιne-1 ,2,7-trιol m 165 (1S,2R,3S,4S)-1 -butyl- pyrrolidine m 3,4-dιhydroxy-2- (hydroxymethyl)pyrrolιdι ne 1 -oxide

73 166 (2S,3S,4R)-2- pyrrolidine

C ^ (hydroxymethyl)pyrrolιdι

I™ m ne-3,4-dιol

167 (2S,3R,4S)-2- pyrrolidine σ> (hydroxymethyl)pyrrolιdι ne-3,4-dιol

168 (2R,3R,4S,5R)-1-(2- pyrrolidine hydroxyethyl)-2,5- bιs(hydroxymetnyl)pyrro lιdιne-3,4-dιol

169 (1R,2R,3R,6S,7S,7aR)- pyrrohzidine

1 ,2,6,7-tetrahydroxy-3-

(hydroxymethyl)octahyd ropyrrolizine 4-oxιde

170 (3R,4R,5R)-3,4,5- pipeπdine tnhydroxy-3-

(hydroxymethyl)pιpeπdι n-2-one

171 (2S,3R,4R)-2- pyrrolidine

(hydroxymethyl)pyrrolιdι ne-3,4-dιol

172 (1 R,2S,3S,7S,7aR)-3- pyrrol izidine

(hydroxymethyl)hexahy dro-1 H-pyrrolιzιne-1 ,2,7- tπol

173 (1 R,2S,3R,5R,7S,7aR)- pyrrolizidine

3-(hydroxymethyl)-5- methylhexahydro-1 H- pyrrolιzιne-1 ,2,7-tπol

174 (2S,4R)-4- pyrrolidine

(hydroxymethyl)-i-

C/) methylpyrrolιdιne-2-

C carboxylic acid

OO 175 (1R,2S,6R,8S,8aS)-6- indolizidine

V) methyloctahydroindolizi

H ne-1 ,2,8-tπol

H 176 (2S,3R,4S)-2-((S)-1 ,2- pyrrolidine

C dιhydroxyethyl)-1-(2-

H hydroxyethyOpyrrolidme m -3,4-dιol

C/) 177 (1 R,2R,3S,6S,7R,7aS)- pyrrolizidine O.

Z 1 ,2,6,7-tetrahydroxy-3- m (hydroxymethyl)octahyd m ropyrrolizine 4-oxιde

178 (1 R,2S,3R,4R)-1-butyl- pyrrolidine

3,4-dιhydroxy-2-

C (hydroxymethyl)pyrrolιdι ι— nβ 1 -oxide m 179 (2S,3S,4S)-2-((S)-1 ,2- pyrrolidine

N) dιhydroxyethyl)-4-

S) (hydroxymethyl)pyrrolιdι πe-3,4-dιol

180 (2S,3S,4R,5S)-2,3- pipeπdine dimethylpipeπdine-

3,4,5-tπol

181 (2R,3S,4R,5S)-2,3- pipeπdine dimethylpipeπdine-

3,4,5-trιol

182 (2R,3R,4S,5R)-2,3- piperidine y dimethylpipeπdme-

3,4,5-tπol

183 (2R,3R,4S,5R)-2,5- pyrrolidine y bιs(hydroxymethyl)pyrro lιdιne-3,4-dιoi

184 (2R,3R,4S,5R,6R)-2- pipeπdine

(hydroxymethyl)-6- methylpιperιdιne-3,4,5- tπol

185 (1 R,2R,3R 7R,7aR)-3- pyrrol dine

(hydroxymethyl)hexahy dro-1 H-pyrrolιzιne-1 ,2,7- tπol

186 (1S,6R,7R,8R,8aR)- indolizidine octahydroindoliziπe-

1 ,6,7 8-tetraol

187 (2R,3R,4S,5S)-2- pipeπdine

(hydroxymethyl)pιpeπdι r/j ne-3,4,5-trιol

C 188 (2R,3R,4R 5S,6S)-2- pipeπdine

OO (hydroxymethyl)-6-

V) methylpιperιdιne-3,4,5-

H tπol

H 189 (2R 3S 5S 6R)-2,6- piperidine

C bιs(hydroxymethyl)pιperι

H dιne-3 4 5-trιol m 190 (2R 3R 4R,5R)-2- pyrrolidine

C/) (hydroxymethyl)-5-

Z methylpyrrolιdιne-3,4- m diol m 191 (1 R,2R,3R,5R,7R,7aR)- pyrrolidine

3-(hydroxymethyl)-5- methylhexahydro-1 H- pyrrolιzιne-1 ,2,7-tπol ι— 192 (1 R 2R,3S,6S,7R,7aR)- pyrrol izidine m 3-

N) (hydroxymethyl)hexahy dro-1 H-pyrrolizine-

1 ,2,6,7-tetraol

193 (2R,3R,4R,5S)-2- piperidine

(hydroxymethyl)pιperιdι ne-3,4,5-tπol

194 (2R,3R,4R,5R)-2-(2- pyrrolidine hydroxyethyl)-5-

(hydroxymethyl)pyrrolιdι ne-3,4-dιol

195 (2S,3R,4R,5R)-2-(3- pyrrolidine hydroxy-4- methoxyphenyl)-5-

(hydroxymethyl)pyrrolιdι ne-3,4-dιol

196 (2R,3R,4R,5S)-2- pyrrolidine

(hydroxymethyl)-5-(4- hydroxyphenyl)pyrrolidi ne-3,4-dιol

197 (1 R,2S,6S,7S,8R,8aR)- indolizidine

6- methyloctahydromdolizi ne-1 ,2,6,7,8-pentaol

198 (1 R,2S,6R,7R,8R,8aR)- indolizidine

D- methyloctahydroindolizi ne-1 ,2,6,7,8-pentaol

199 (2S,3S,4R)-1-benzyl-2- pyrrolidine r/j ((S)-1 , 2- dihydroxyethyl)pyrrolidin m e-3,4-dιol

C/) 200 (2S,3S,4R)-2-((R)-1 ,2- pyrrolidine dιhydroxyethyl)-4-

(hydroxymethyl)pyrrolιdι

C ne-3,4-dιol

H (2R 3R,4S,5R)-2- pipeπdine m 201

(hydroxymethyl)-5-

C/) methylpιpeπdιne-3,4,5-

Z tnol m (2S,3S,4S)-2,4- pyrrolidine m 202 bιs(hydroxymethyl)pyrro lιdιne-3,4-dιol jB 203 (2S,3S,4S)-2-((S)-1 ,2- pyrrolidine

C dιhydroxyethyl)-4- ι— (hydroxymethyl)pyrrolιdι m ne-3,4-dιol

N) 204 3-((2R,3R,4R,5S)-3,4,5- pipeπdine tπhydroxy-2-

(hydroxymethyl)pιpeπdι n-1-yl)propanoιc acid

205 (2S,3R,4R,5S)-butyl 1- piperidine butyl-3,4,5- tπhydroxypιpeπdιne-2- carboxylate

206 (1S,6R,7R,7aS)-7- pyrrol izidine

(methylamιno)hexahydr o-1 H-pyrrolιzιne-1 ,6-dιol

207 2-((2S,3S,4S,5S)-3,4- pyrrolidine dιhydroxy-2,5- bιs(hydroxymethyl)pyrro lιdιn-1-yl)acetιc acιd

208 (1R,2R)-1-((2R,3R,4S)- pyrrolidine

3,4-dιhydroxypyrrolιdιn-

2-yl)propane-1 ,2,3-tπol

209 (2S,3R,4R,5S)-3,4,5- pipeπdme tπhydroxy-1-(2- hydroxyethyl)pιpeπdιne-

2-carboxyiιc acid

210 2-((2R,3R,4R)-3,4- pyrrolidine dιhydroxy-2-

(hydroxymethyl)pyrrolιdι n-1-yl)acetιc acιd

211 (2S,3S,4R)-2-((R)-1 ,2- pyrrolidine dιhydroxyethyl)-4-

C/) methylpyrrolιdιne-3,4-

C diol

OO 212 (2S,3S,4R)-2- pyrrolidine

V) (hydroxymethyl)-4-

H methylpyrrolιdιne-3,4- diol

C 213 (1 S,5R,8S)-6-oxa-3- piperidine

H azabιcyclo[3 2 1]octane- m 1 ,8-dιol

C/) 214 2-((2R,3R,4R 5S)-3,4,5- pipeπdine

Z trιhydroxy-2- m (hydroxymethyl)pιperιdι m n-1-yl)acetιc acid

-H 215 (2R,3S,4R,5S)-2- piperidine

(hydroxym ethyl )pιpeπdι ne-3,4,5-tπol ι— 216 (2S,3S,4S,5R)-2- piperidine m (hydroxymethyl)pιpeπdι

N) ne-3,4,5-trιol σ> 217 (3aS,4R,6aR)-N-benzyl- pyrrolidine

2,2,4- trιmethyltetrahydro-3aH-

[1 ,3]dιoxolo[4,5- c]pyrrole-4-carboxamιde

218 (2R,3S,4R)-N-benzyl- pyrrolidine

3,4-dιhydroxy-2- methylpyrrolιdιne-2- carboxamide

219 (3R,4S,5S)-5- pipeπdine

(hydroxymethyl)pιpeπdι ne-3,4-dιol

220 (2S,3S,4R)-1-butyl-2- pyrrolidine

(hydroxymethyl)-2-

methylpyrrolιdιne-3,4- diol

221 (2S,3S,4S,5R)-2- pipeπdine

(hydroxymethyl)pιpβπdι ne-3,4,5-tπol

222 (2R,3R,4R,5R)-2-(3,4- pyrrolidine dιmethoxyphenyl)-5- (hydroxymethyl)pyrrolιdι ne-3,4-dιol

223 (2S,3R,4S,5R)-2- pipeπdine

(hydroxymethyl)pιperιdι ne-3,4,5-trιol 224 (3R,4R,5R,6S)-2,2- azepane

C/) bιs(hydroxymethyl)azep

C ane-3,4,5,6-tetraol DO 1 -hydroxy- 13- pyrrolidine C/) 225

((2R,3R,4S,5R)-4- hydroxy-5-

(hydroxym ethyl )-3-

(3 4 5-trιhydroxy-6- m (hydroxymethyl)tetrahyd

C/) ro-2H-pyran-2-

Z yloxy)pyrrolιdιn-2- m yl)tπdecan-5-one m 226 (R)-13-((2R,3R,4R,5R)- pyrrolidine

3,4-dιhydroxy-5- (hydroxymethyl)pyrrolιdι n-2-yl)-1,13- c dιhydroxytπdecan-5-one m 227 (2R,3S,4R,5S)-2- pipeπdine

(amιnomethyl)pιperιdιne

-3,4,5-tπol

- 228 (4S,5S)-phenyl 3- pipeπdine bromo-4,5- dιhydroxypιpeπdιne-1- carboxylate

229 (2R,3R,4R,5R)-2- pipeπdine

(hydroxymethyl)pιpeπdι ne-3,4,5-trιol 230 (4S,5S)-phenyl 3- pipeπdine bromo-4,5- dιhydroxypιpeπdιne-1- carboxylate

231 (3R,4s,5S)-1- pipeπdine nonylpιperιdιne-3,4,5- tπol

232 (3R,4r,5S)-1- pipeπdine butylpιpendιne-3,4,5- tπol

233 (3aS,4R,8R,8aS)-4,8- azepane dιhydroxy-2,2- dιmethyltetrahydro-3aH-

[1,3]dιoxolo[4,5- d]azepιn-5(4H)-one

234 (2S,3S,4S,5S)-4,5- piperidine bιs(tert- butyldιmethylsιlyloxy)-2-

((tert- butyldιmethylsιlyloxy)me

C/) thyl)pιpeπdιn-3-ol

C 235 1-((2S,3S,4S)-2-((S)- pyrrolidine

CD 1 ,2-dιhydroxyethyl)-3,4-

V) dιhydroxypyrrolιdιn-1-

H yljethanone

H 236 (2S,3R)-3,4- pyrrolidine

C dιhydroxypyrrolιdιne-2-

H carboxylic acid m 237 (3aR 6S.7S 7aR)-7- piperidine

C/) hydraxy 2,2 6- OC

Z tnmethyltetrahydro- m [1,3]dιoxolo[4,5- m c]pyrιdιn-4(3aH)-one

"H 238 (3aS,6R,7R,7aS)-6- piperidine

((tert-

C butyldιmethylsιlyloxy)me ι— thyl)-7-hydroxy-2,2- m dimethyltetrahydro-

N) [1,3]dιoxolo[4,5- σ> c]pyπdιn-4(3aH)-one

239 (S)-1-((2S,3S,4S)-3,4- pyrrolidine bιs(benzyloxy)pyrrolιdιn-

2-yl)ethane-1 ,2-dιol

240 1-((3aS,4S,8R,8aS)-8- azepane hydroxy-4,7-anhydro-

2,2,4-tπmethyl-3aH-

[1 ,3]dιoxolo[4,5- c]azepιn-

5(4H,6H,7H,8H,8aH)- yl)ethanone

241 (3aS,7R,8R,8aS)-7,8- azepane dιhydroxy-2,2- dιmethyltetrahydro-3aH-

[1,3]dιoxolo[4,5- c]azepιn-4(5H)-one

242 (3S,4S,5R)-3,4- pyrrolidine bιs(benzyloxy)-5-((S)-

1,2- dιhydroxyethyl)pyrτolιdιn

-2-one

243 (3S,4S,5R,6R)-3,4,5- pipeπdine trιhydroxy-6- methylpιperιdιn-2-one

244 (3aR,4S,7R,7aS)-6- pipeπdine

(hydroxymethyl)-2,2,4- tπmethylhexahydro-

V) [1,3]dιoxolo[4,5-

C c]pyrιdιn-7-ol

OO 245 (2R,3S,4R,5S,6R)-N- piperidine

C/) butyl-3,4,5-trιhydroxy-6- methylpιperιdιne-2- carboxamide

C -I 246 (2S,3R,4S,5R,6R)- piperidine m 3,4,5-tπhydroxy-6- (hydroxymethyl)-N-

C/) methylpιperιdιne-2-

Z m carboxamide m 247 (2R,3S,4R,5S,6R)-N- piperidine benzyl-3,4,5-trιhydroxy-

6-methylpιpeπdιne-2- carboxamide

C 248 (2S,3R,4S,5R,6R)- piperidine m 3,4,5-tπhydroxy-6-

(hydroxymethyl)pιperιdι ne-2-carboxylιc acid

249 (2R,3S,4R,5S,6R)- pipeπdine

3,4,5-trιhydroxy-N,6- dιmethylpιpeπdιne-2- carboxamide

250 methyl 2-((7R)-7- pipeπdine hydroxy-2,2-dιmethyl-4- oxohexahydro-

[1 ,3]dιoxolo[4,5- c]pyπdιn-6-yl)acetate

251 (3aS,4R,8R,8aR,8bS)- pyrrolizidine

4-(benzyloxymethyl)-8- hydroxy-2,2- dιmethyltetrahydro-3aH-

[1,3]dιoxolo[4,5-

a]pyrrolιzιn-6(4H)-one

252 (2S,3R,4R)-1-butyl-2- pipeπdine

(hydroxymethyl)pιpeπdι ne-3,4-dιol 253 (3R,4r,5S)-1- pipeπdine methylpιpeπdιne-3,4,5- tnol 254 (3R,4r,5S)-1- piperidine nonylpιperιdιne-3,4,5- tπol

255 (2S,3S,4S)-1-benzyl-2- pyrrolidine

((S)-L 2- V) dιhydroxyethyl)pyrrolιdιn e-3,4-dιol

S ²⁵⁶ (2S,5S)-2- pipeπdine

H (hydroxymethyl)-6- methylpιpeπdιne-3,4,5- H tπol ^ 257 (2S 3R 4S 5R)-2- pipeπdine m methylpιpeπdιne-3,4,5- tπol

£ 258 (2R,3S,4R,5S)-2- pipeπdine m methylpιperιdιne-3 4,5- m tnol

259 (2R,3R,4R,5R)-2- piperidine methylpιperιdιne-3,4,5- tπol

C 260 (3S,4S,5R,6S)-3,4,5- piperidine m trιhydroxy-6-

(hydroxymethyl)pιpeπdι n-2-one

2 261 (2R,4S,5R)-2-(2- pyrrolidine hydroxyethyl)-5-

(hydroxymethyl)pyrrolιdι ne-3,4-dιol

262 (2S,3R,4R)-3,4- pyrrolidine dιhydroxypyrrolιdιne-2- carboxylic acid 263 (2R,3S,4R,5S,6R)-2- piperidine

(hydroxymethyl)-6- methylpιpeπdιne-3,4,5- tπol

264 (2S,3S,4R,5S,6R)-2- piperidine

(hydroxymethyl)-6- methylpιpeπdιne-3,4,5-

tπol

265 (3S,4R,5S,6S)-N-butyl- pipeπdme

3,4,5-trιhydroxy-6- methylpιpeπdιne-2- carboxamide

266 (1R,2S,6R,7S,7ar)- pyrrol dine hexahydro-1 H- pyrrolιzιne-1 ,2,6,7- tetraol

267 (3S,4R,5S,6S)-N- piperidine benzyl-3,4,5-tπhydroxy-

6-methylpιperιdιne-2-

V) carboxamide

C 268 (2S,3S,4S,5S)-2- pipeπdine

DO methylpιperιdιne-3,4,5-

C/) tπol

269 (2S,3S,4R,5S,6S)-2- piperidine

H (hydroxymethyl)-6- methylpιperιdιne-3 4 5- m tnol

270 1- azepane

C/) ((1 R,2S 3S,4S,5S 7R)-

X m m 2,3,4-trιhydroxy-5- m methyl-7-

((2R,3S,4R,5S,6S)-

3,4,5-trιhydroxy-6-

TJ (hydroxymethyl)tetrahyd

C ro-2H-pyran-2-yloxy)-8- m oxa-6- azabιcyclo[3 2 1]octan-

6-yl)ethanone

271 (1 R,2R,3R,6S,7S,7aR)- pyrrolidine

5-gem-dιdeuteπo-3-

(hydroxymethyl)hexahy dro-1 H-pyrrolιzιne-

1 ,2,6,7-tetraol

272 (3S,4s,5R)-1- piperidine butylpιpeπdιne-3,4,5- tπo!

273 (3R,5R)-pιperιdιne- pipendine

3,4,5-tπol

274 ((2S,4S)-4- pyrrolidine azιdopyrrolιdιn-2- yl)methanol

275 ((2S,4S)-4-azιdo-1- pyrrolidine butylpyrrolιdιn-2- yl)methanol

276 (2R,3R,4R,5S)-1-(4- pipeπdine hydroxybutyl)-2-

(hydroxymethyl)pιpeπdι πe-3,4,5-tπol

277 2-((2S,4S)-4-azιdo-2- pyrrolidine

(hydroxymethyl)pyrrolιdι n-1-yl)ethanol

278 (2R,3R,3aR,5S,6R,7R,7 pipeπdine aS)-3-((R)-1- hydroxybutyl)-5- r/j (hydroxymethyl)octahyd rofuro[3,2-b]pyrιdιne-

DO 2,6,7-tπol

C/) 279 (3R,4R,5R)-5-

(hydroxym ethyl )pιperιdi ne-3,4-dιol

C 280 (3R 5S)-1-(2- pyrrolidine

H hydroxyethyl)-5- m (hydroxymethyl)pyrrolιdι

C/) n-3-ol

Z 281 (3R 5R)-3,4,5- pipeπdine m tπhydroxypιpeπdιne-1 - m carbaldehyde

282 (3S,5S)-pιpeπdιne- pipeπdine

3,4,5-tπol

C 283 (3R,5S)-5- pyrrolidine ι m~ (hydroxymethyl)pyrrolιdι

1 11 n-3-ol

N) ((2S,4S)-4-azιdo-1- pyrrolidine S) 284 nonylpyrrolιdιπ-2- yl)methaπol

285 (3R,5S)-5- pyrrolidine

(amιnomethyl)-1-(2- hydroxyethyl)pyιτolιdιπ-

3-ol

286 (3R,5S)-5- pyrrolidine

(azιdomethyl)-i- butylpyrrolιdιn-3-ol

287 (3R,5S)-5- pyrrolidine

(azιdomethyl)-1-(2- hydroxyethyl)pyrrolιdιn-

3-ol

288 (2R,3R,4R,5S)-2- pipeπdine

(hydroxymethyl)- 1 -(3- phenoxypropyl)pιpeπdιn e-3,4,5-trιol

289 (3R,5S)-5- pyrrolidine

(amιnomethyl)-i- butylpyrrolιdιn-3-ol

290 2-((2S,4S)-4-amιno-2- pyrrolidine y y

(hydroxymethyl)pyrrolιdι n-1-yl)ethanol

291 diethyl 3-((2S,4S)-4- pyrrolidine y y azιdo-2-

(hydroxymethyl)pyrrolιdι π-1-

C yl)propylphosphonate

CD 292 ((2S,4S)-4-amιno-1- pyrrolidine

C/) butylpyrrolιdιn-2-

H yl)methanol

H 293 (3R,5S)-1-(2- pyrrolidine

C hydroxyethyl)-5- m (morpholιnomethyl)pyrro lιdιn-3-ol

C/) 294 (3R,5S)-5- pyrrolidine

Z (hydroxymethyl)-i- m m nonylpyrrolιdιn-3-ol

295 ((2S,4S)-4-amιno-1- pyrrolidine y nonylpyrrolιdιn-2- yl)methanol

C 296 (3R,5R)-1- pipeπdine ι— y butylpιpeπdιne-3,4,5- m tnol

N) 297 (3R,5R)-1- piperidine y methylpιperιdιne-3,4,5- tπol

298 (3S,5S)-1- pipeπdine y butylpιpeπdιne-3,4,5- tπol

299 (3S,5S)-1- pipeπdine y methylpιpeπdιne-3,4,5- tnol

300 (2S,3S,4S,5S)-2- pyrrolidine

(hydroxymethyi)-5- methylpyrrolιdιne-3,4- diol

301 (3S,4s,5R)-pιpeπdιne- pipeπdine

3,4,5-tπol

302 (3S,5S)-1- piperidine y nonylpιpeπdιne-3,4,5- tπol

303 (3R,5R)-tert-butyl 3,4,5- pipeπdine y tπhydroxypιpeπdιne-1 - carboxylate

304 (2R,3S,4S)-1-(2- pyrrolidine hydroxyethyl)-2-

(hydroxymethyl)pyrrolιdι ne-3,4-dιol

305 (2R,3S,4S)-2- pyrrolidine y (hydroxymethyl)pyrrolιdι ne-3,4-dιol

^ 306 (2R,3S,4S)-1-butyl-2- pyrrolidine y

^ (hydroxymethyl)pyrrolιdι gg ne-3,4-dιol

C/) 307 (2R,3R,4S)-1-benzyl-2- pyrrolidine

H ((S)-1 ,2-

_| dihydroxyethyl)pyrrolιdιn

C e-3,4-dιol

H 308 (2S,3S 4S)-4-azιdo-1- pyrrolidine m benzyl-2

C/) (hydroxymethyl)pyrrolιdι

1 n-3-ol m 309 N-((3S,4R,5S)-1-benzyl- pyrrolidine

^ 4-hydroxy-5-

^""" (hydroxymethyl)pyrrolιdι

JQ n-3-yl)acetamιde

C 310 (2R,3R,4S)-2- pyrrolidine

|~ (hydroxymethyl)pyrrolιdι m ne-3,4-dιol

NJ 311 (2R,3R,4S)-1 -benzyl-2- pyrrolidine

2 (hydroxymethyl)pyrrolιdι ne-3,4-dιol

312 (2S,3R,4S)-4-amιno-1- pyrrolidine benzyl-2-

(hydroxymethyl)pyιτolιdι n-3-ol

313 (2S,3R,4S)-4- pyrrolidine acetamιdo-2-

(acetoxymethyl)-i- benzylpyrrolιdιn-3-yl acetate

314 (2S,3S,4R)-1-butyl-2- pyrrolidine

((R)-1 ,2- dihydroxyethyljpyrrolidin

e-3,₄-dιol

315 (2R,3R,4S)-2-((S)-1,2- pyrrolidine y dihydroxyethyljpyrrolidin e-3,4-dιol

316 (2S,3S,4R)-2-((R)-1 ,2- pyrrolidine y dιhydroxyethyl)-1- nonylpyrrolιdιne-3,4-dιol

317 (2R,3R,4S)-1-butyl-2- pyrrolidine

(hydroxymethyl)pyrrolιdι ne-3,4-dιol

318 N-((3S,4R,5S)-4- pyrrolidine hydroxy-5-

C/) (hydroxymethyl)pyrrolιdι

C n-3-yl)acetamιde

CD 319 N-((3S,4R,5S)-1-butyl- pyrrolidine

C/) 4-hydroxy-5-

^■H (hydroxymethyl)pyrrolιdι n-3-yl)acetamιde

_| 320 (2S,3R,4R)-1- pyrrolidine m (cyclohexylmethyl)-2-

(hydroxymethyl)pyrrolιdι

\J1 ne-3,4-dιol

J_ m 321 (2S,3R,4R)-1-(2- pyrrolidine m hydroxyethyl)-2-

(hydroxymethyl)pyrrolιdι

... ne-3,4-dιol

Ti 322 (1R,2R)-1-((2R,3R,4S)- pyrrolidine

C 1-butyl-3,4- m dιhydroxypyrrolιdιn-2- yl)propane-1 ,2,3-tπol

N) S) 323 (1R,2R)-1-((2R,3R,4S)- pyrrolidine

3,4-dιhydroxypyrrolιdιn-

2-yl)propane-1 ,2,3-tπol

324 (1S,2R)-1-((2R,3R,4S)- pyrrolidine y

3,4-dιhydroxy-1- nonylpyrrolιdιn-2- yl)propaπe-1 ,2,3-tπol

325 (1S,2R)-1-((2R,3R,4S)- pyrrolidine y

1-butyl-3,4- dιhydroxypyrrolιdin-2- yl)propane-1 ,2,3-tπol

326 (1S,2R)-1-((2R,3R,4S)- pyrrolidine y

3,4-dιhydroxy-1-(2- hydroxyethyl)pyrrolιdιn-

2-yl)propane-1 ,2,3-tπol

327 (1R,2R)-1-((2R,3R,4S)- pyrrolidine

3,4-dιhydroxy-1-(2- hydroxyethyl)pyrrolιdιn-

2-yl)propane-1 ,2,3-tπol

328 (1 R,2R)-1-((2R,3R,4S)- pyrrolidine

1-benzyl-3,4- dιhydroxypyrrolιdιn-2- yl)propane-1 ,2,3-trιol

329 (1S,2R)-1-((2R,3R,4S)- pyrrolidine y

1-benzyl-3,4- dιhydroxypyrrolιdιn-2- yl)propane-1 ,2,3-trιo!

330 ((2S,4S)-4-acetamιdo-1 - pyrrolidine

(2-

C acetoxyethyl)pyrrolιdιn-

DO 2-yl)methyl acetate

C/) 331 ((2S,4S)-4-acetamιdo-1- pyrrolidine y

H butylpyrrolιdιn-2-

H yl)methyl acetate

C 332 ((2S,4S)-4-acetamιdo-1- pyrrolidine y m nonylpyrrolιdιn-2- yl)methyl acetate

C/) 333 (1 R 2S,8R,8aR)- indolizidine y

Z octahydroindohzine- m m 1 ,2,8-trιol

334 (2S,3S,4R)-2-((R)-1 ,2- pyrrolidine

^■H y dιhydroxyethyl)-1-(2- hydroxyethyl)pyrrolιdιne

C -3,4-dιol ι— 3 N-((3S,4R,5S)-4- pyrrolidine m 35 hydroxy-1-(2-

N) hydroxyethyl)-5-

(hydroxymethyi)pyrrolιdι n-3-yl)acetamιde

336 (1S,2R)-1-((2S,3R,4S)- pyrrolidine y

3,4-dιhydroxypyrrolιdιn-

2-yl)propane-1 ,2,3-tπol

337 (1R,2S,8R,8aS)-1 ,2,8- indolizidine y tnhydroxyhexahydroind olιzιn-5(1 H)-one

338 N-((3S,4R,5S)-4- pyrrolidine hydroxy-5-

(hydroxymethyl)-i- nonylpyrrolιdιn-3- yllacetamide

339 (2R,3R,4S)-1-butyl-2- pyσolidine

((S)-1 ,2- dιhydroxyethyl)pyrrolιdιn θ-3,4-dιol

340 (2R,3R,4S)-2-((S)-1 ,2- pyrrolidine dιhydroxyethyl)-1-(2- hydroxyethyljpyrrolidine

-3,4-dιol

341 2-((2S,3S,4R)-2-((R)- pyrrolidine

1 ,2-dιhydroxyethyl)-3,4- dιhydroxypyrrolιdιn-1- yl)acetιc acid

342 (2S,3S,4R)-1-benzyl-2- pyrrolidine

(hydroxymethyl)pyrrolιdι

C ne-3,4-dιol

DO 343 (2R,3R,4R,5R)-2,5- pyrrolidine

C/) bιs(hydroxymethyl)-1 -(3-

H ρhenoxypropyl)pyrrolιdι

H ne-3,4-dιol

C 344 ((2S,4S)-4- pyrrolidine y amιnopyrrolιdιn-2- m yl)methanol

C/) 345 (2S,4S)-4- pyrrolidine

Z y azιdopyrrolιdιne-2- m m carboxylic acid

346 N-((3S,5S)-5- pyrrolidine y

(hydroxymethyl)pyrrolιdι n-3-yl)acetamιde

C 347 N-((3S,5S)-1-(2- pyrrolidine ι— y hydroxyethyl)-5- m (hydroxymethyl)pyrrolιdι

N) n-3-yl)acetamιde

0) 348 N-((3S,5S)-5- pyrrolidine

(hydroxymethyl)-i- nonylpyrrolιdιn-3- yl)acetamιde

349 (2R,3R,4R)-2- pyrrolidine

(hydroxymethyl)-1-(3- phenoxypropyl)pyrrolιdι ne-3,4-dιol

350 N-((3S,5S)-1-butyl-5- pyrrolidine

(hydroxymethyl)pyrrolιdι n-3-yl)acetamιde

351 (2S,3R,4S)-1-benzyl-2- pyrrolidine

((R)-1, 2- dιhydroxyethyl)pyrrolιdιn

e-3,4-dιol

352 (1S,2S,6S,7R,8R,8aR)- indolizidine octahydroindolizine-

1,2,6,7,8-pentaol

353 N-((3S,4R,5S)-4,5- pipeπdine y dιhydroxypιperιdιn-3- y yl)acetamιde

354 (3R,5R)-benzyl 3,4,5- piperidine y y trιhydroxypιpeπdιne-1- carboxylate

355 2-((2S,4S)-4-azιdo-2- pyrrolidine y

(hydroxymethyl)pyrrolιdι y

C/) n-1-yl)acetιc acid

C 356 (1 R,2S,3S,7R,7aR)-3- pyrrolidine OO (hydroxymethyl)hexahy C/) dro-1H-pyrrolιzιne-1 ,2,7- tnol

357 (2R,3S,4S)-2- pipeπdine (hydroxymethyl)pιpeπdι m ne-3,4-dιol

2-((2S,3R,4S)-4- pyrrolidine

C/) 358 OC acetamιdo-3-hydroxy-2-

Z m (hydroxymethyl)pyrrolιdι m n-1-yl)acetιc acid

359 2-((2R,3R,4S)-2-((S)- pyrrolidine

1 ,2-dιhydroxyethyl)-3,4-

73 dιhydroxypyrrolιdιn-1- c yl)acetιc acid m 360 (2S,3S,4R)-1-butyl-2- pyrrolidine y (hydroxymethyl)pyrrolιdι ne-3,4-dιol

361 2-((2R,3R,4S)-3,4- pyrrolidine dιhydroxy-2- y

(hydroxymethyl)pyrrolιdι n-1-yl)acetιc acιd

362 (2R,3S,4R)-4- pyrrolidine acetamιdo-2-

(acetoxymethyl)-i- benzylpyrrolιdιn-3-yl acetate

363 (2R,3R,4R)-4-azιdo-1- pyrrolidine benzyl-2-

(hydroxymethyl)pyrrolιdι n-3-ol

364 N-((3R,4S,5R)-1-benzyl- pyrrolidine

4-hydroxy-5-

(hydroxymethyl)pyrrolιdι n-3-yl)acetamιde

365 N-((3R,4S,5R)-4- pyrrolidine hydraxy-5-

(hydroxymβthyl)pyrrolιdι n-3-yl)acetamιde

366 2-((2R,3S,4R)-4- pyrrolidine acetamιdo-3-hydroxy-2-

(hydroxymethyl)pyrrolιdι n-1-yl)acetιc acid

367 N-((3R,4S,5R)-4- pyrrolidine hydroxy-5-

(hydroxymethyl)-i- m ιsopropylpyrrolιdιn-3-

C/) yl)acetamιde

368 2-((2S,3S,4R)-3,4- pyrrolidine dιhydroxy-2-

C (hydroxymethyl)pyrτolιdι

H n-1-yl)acetιc acιd m 369 N-((3R,4S,5R)-4- pyrrolidine

C/) hydroxy-1-(2-

Z hydroxyethyl)-5- m (hydroxymethyl)pyrrolιdι m n-3-yl)acetamιde

370 (2R,3S,4R)-4-amιno-1- pyrrolidine benzyl-2-

C (hydroxymethyl)pyrrolιdι

|— n-3-ol m 371 (2S,3S,4S,5S)-3,4- pyrrolidine

N) dιhydroxy-2,5- bιs(hydroxymethyl)pyrro lιdιne-1-carbaldehyde

372 N-((3R,4R,5S)-1-benzyl- pyrrolidine

4-hydroxy-5-

(hydroxymethyl)pyrrolιdι n-3-yl)acetamιde

373 (2S,3R,4R)-4-amιno-1- pyrrolidine benzyl-2-

(hydroxymethyl)pyrrolιdι n-3-ol

374 (2S,3S,4R)-4-azιdo-1- pyrrolidine benzyl-2-

(hydroxymethyl)pyrrolιdι n-3-ol

375 N-((3R,4R,5S)-4- pyrrolidine hydroxy-1-(2- hydroxyethyl)-5-

(hydroxymethyl)pyrrolιdι n-3-yl)acetamιde

376 (2S,3R,4R)-4- pyrrolidine acetamιdo-2- (acetoxymethyl)-i- benzylpyrrolιdιn-3-yl acetate

377 2-((2S,3R,4R)-4- pyrrolidine acetamido-3-hydroxy-2- (hydroxymethyl)pyrrolιdι

V) n-1-yl)acetιc acid

C 378 N-((3R,4R,5S)-4- pyrrolidine

DO hydroxy-5-

C/) (hydroxymethyl)pyrrolιdι

^H n-3-yl)acetamιde

H 379 N-((3R,4R,5S)-1 -butyl- pyσolidme

C 4-hydroxy-5-

—I (hydroxymethyl)pyrrolιdι m n-3-yl)acetamιde K.

C/) 380 (2R,3R,4S,5S,6S)-2- piperidine

Z (but-3-enyl)-6- m (hydroxymethyl)pιpeπdι m ne-3,4,5-trιol

H 381 (3R,5S)-5- pyrrolidine

(azιdomethyl)pyrrolιdιn-

C 3-ol ι 382 (2R,3R,4R,5S)-3,4,5- piperidine m— tnhydroxy-N-

N) methylpιperιdιne-2- carboxamide

383 (5R)-3-hydroxy-5- pyrrolidine

(hydroxymethyl)pyrrolιdι ne-3-carboxylιc acid

384 (2R,3S,4R)-2- pyrrolidine y

(hydroxymethyl)pyrrolιdι ne-3,4-dιol

385 (2R,3S,4R)-1 -benzyl-2- pyrrolidine y (hydroxymethyl)pyrrolιdι ne-3,4-dιol

386 (2S,3R,4S)-1-benzyl-2- pyrrolidine y (hydroxymethyl)pyrrolιdι ne-3,4-dιol

387 (3R,5R)-1- pipeπdine nonylpιperιdιne-3,4,5- tπol

388 (2R,3R,4R,5S)-2- pipeπdine methylpιpeπdιne-3,4,5- tπol

389 (2R,3S,4S)-4- pyrrolidine acetamιdo-2-

(acetoxymethyl)-i- benzylpyrrolιdιn-3-yl acetate

390 (2R,3S,4S)-4-amιnα-1- pyrrolidine benzyl-2-

C/) (hydroxymethyl)pyrrolιdι

C n-3-ol

CD 391 N-((3S,4S 5R)-1-butyl- pyrrolidine

C/) 4-hydroxy-5-

H (hydroxymethyl)pyrrolιdι

H n-3-yl)acetamιde

C 392 2-((2R 3S,4S)-4- pyrrolidine

H acetamιdo-3-hydroxy-2- m (hydroxymethyl)pyrrolιdι

C/) n-1-yl)acetic acid

Z 393 (R)-5-((1R,2S,3S)- pyrrolidine m 1 2,3,4- m tetrahydroxybutyl)pyrrolι dιn-2-one

394 (2R,3R,4S)-4-azιdo-1- pyrrolidine

C benzyl-2- ι— (hydroxymethyl)pyrrolιdι m n-3-ol

N) σ 395 N-((3S,4S,5R)-4- pyrrolidine > hydroxy-5-

(hydroxymethyl)pyrrolιdι n-3-yl)acetamιde

396 N-((3S,4S,5R)-1-benzyl- pyrrolidine

4-hydroxy-5-

(hydroxymethyl)pyrrolιdι n-3-yl)acetamιde

397 N-((3S,4S,5R)-4- pyrrolidine hydroxy-1-(2- hydroxyethyl)-5-

(hydroxymethyl)pyrrolιdι n-3-yl)acetamιde

398 2-((2S,3R,4S)-2-((R)- pyrrolidine

1 ,2-dιhydroxyethyl)-3,4-

dιhydroxypyrrolιdιn-1- yl)acetιc acid

399 (1R,2S,5S,8R,8aS)-5- indolizidine methyloctahydroindolizi ne-1 ,2,8-tπol 400 (1 R,2S,6S,7R,8R,8aR)- indolizidine y octahydroindolizine-

1,2,6,7,8-pentaol 401 (1R,2S,6R,7S,8R,8aR)- indolizidine y

1 ,2,6,7,8- pentahydroxyhexahydro ιndolιzιn-5(1 H)-one

402 (1 R,2S,8S,8aS)-1 ,2,8- indolizidine

C/) tnhydroxyhexahydroind

C olιzιn-5(1 H)-one 00 403 (2S,3R,4S)-1-butyl-2- pyrrolidine C/) ((R)-1 , 2- dιhydroxyethyl)pyrrolιdιn e-3,4-dιol

404 (1 R,2R)-1-((2R 3R,4S)- pyrrolidine m 3,4-dιhydroxy-1- nonylpyrrolιdιn-2- K.

C/) K. yl)propane-1 ,2,3-tπol

Z m 405 (2S,3R,4S)-2-((R)-1 ,2- pyrrolidine m dιhydroxyethyl)-1-(2- hydroxyethyl)pyrrolιdιne

-3,4-dιol

J2 406 (1R,2S,5R,8S,8aS)-5- indolizidine methyloctahydroindolizi m ne-1 ,2,8-tπol

407 (S)-5-((1S,2R,3R)- pyrrolidine

1 ,2,3,4- tetrahydroxybutyl)pyrτolι dιn-2-one

408 (S)-4-((2S,3R,4S)-1- pyrrolidine benzyl-3,4- dιhydroxypyrrolιdιn-2- yl)-4- hydroxybutanenitπle

409 (3aS,6R,9S,9aS,9bR)- indolizidine

2,2-dιethyl-6- methyloctahyd roll ,3]dιoxolo[4,5- a]ιndolιzιn-9-ol

410 (1R,2S,5R,8S,8aR)-8- indolizidine methoxy-5- methyloctahydroindolizi ne-1 ,2-dιol

411 (1R,2S,3S)-1-((R)-1- pyrrolidine butylpyrτolιdιn-2- yl)butane-1,2,3,4-tetraol

412 (3aR,5R,6R,6aS)-4- pyrrolidine benzyl-6-hydroxy-5-

(hydroxymethyl)hexahy dro-2H-furo[3,2-b]pyrrol-

2-one

413 (1 R,2S,3S)-1-((R)- pyrrolidine y r/j pyrrolιdιn-2-yl)butane-

1 ,2,3,4-tetraol

DO 414 (1 R,2S,3S)-1-((R)-1-(2- pyrrolidine y

V) hydroxyethyl )py rrol id in-

H 2-yl)butane-1 ,2,3,4- tetraol

C 415 (S)-5-((1R,2S,3S)- pyrrolidine

H 1 ,2,3,4- m tetrahydroxybutyl)pyrrolι K.

C/) dιn-2-one

Z 416 (1R,2S,3S)-1-((S)-1-(2- pyrrolidine m m hydroxyethyl)pyrrolιdιn-

2-yl)butane-1 ,2,3,4-

"H tetraol

TJ 417 N-((3S,4R,5S)-1-benzyl- pyrrolidine

C 4-hydroxy-5- ι— (hydroxymethyl)pyrrolιdι m n-3-yl)-2,2,2-

N) tnfluoroacetamide

418 (3S,4S,5S)-1-butyl-5- pipendine y

(hydroxym ethyl )pιpeπdι ne-3,4-dιol

419 (3R,4R,5R)-1-butyl-5- pipeπdme y

(hydroxymethyl)pιperιdι ne-3,4-dιol

420 (3R,4R,5R)-1-(2- pipendine y hydroxyethyl)-5-

(hydroxymethyl)pιpeπdι ne-3,4-dιol

421 (1 R,2S,3S)-1-((S)- pyrrolidine pyrrohdιn-2-yl)butane-

1,2,3,4-tetraol

422 (1S,2R,3R)-1-((S)- pyrrolidine pyrrolιdιn-2-yl)butane-

1 ,2,3,4-tetraol 423 (2S,3S,4R)-1-benzyl-2- pyrrolidine

((S)-1 ,2- dιhydroxyethyl)pyrrolιdιn e-3,4-dιol

424 (2R,3R,4R,5S)-tert-butyl piperidine

3,4,5-trιhydroxy-2- (hydroxym ethyl )pιpeπdι ne-1-carboxylate 425 (2S,3S,4R)-2-((S)-1 ,2- pyrrolidine dιhydroxyethyl)-1-(2-

C/) hydroxyethyl)pyrrolιdιne

C -3,4-dιol OO 426 (2S,3S,4R)-1-butyl-2- pyrrolidine C/) ((S)-1.2- dιhydroxyethyl)pyrrolιdιn e-3,4-dιol

427 (2S,3S,4R)-2-((S)-1 ,2- pyrrolidine dιhydroxyethyl)-1 - m nonylpyrrolιdιne-3,4-dιol K.

C/) 428 (2S,3S,4R)-2-((S)-1 ,2- pyrrolidine

Z dιhydroxyethyl)-1 - m methylpyrrolιdιne-3,4- m diol

429 (2S,3S,4R)-2-((S)-1 ,2- pyrrolidine

73 dihydroxyethyljpyrrolidin e-3,4-dιol

430 (3aR,4R,6aS)-4- pyrrolidine m (azιdomethyl)-5-benzyl- 2,2-dιmethyltetrahydro- 3aH-[1 ,3]dιoxolo[4,5- c]pyrrole

431 N-((3S,4R,5S)-1 -benzyl- pyrrolidine

4-hydroxy-5-

(hydroxymethyl)pyrrolιdι n-3-yl)butyramιde

432 (2R,3R,4S)-2- pyrrolidine

(azιdomethyl)-i- benzylpyrrolιdιne-3,4- diol

433 (2S,3S,4R)-2-((S)-1 ,2- pyrrolidine dιhydroxyethyl)-1-(9- hydroxynonyl)pyrrolιdιn e-3,4-dιol

434 2-((2S,3S,4R)-2-((S)- pyrrohdine

1 ,2-dιhydroxyethyl)-3,4- dιhydroxypyrrolιdιn-1- yl)acetonιtπle

435 (2S,3S,4R)-2-((S)-1,2- pyrrolidine dιhydroxyethyl)-1-(2-(2- methoxyethoxy)ethyl)py rrolιdιne-3,4-dιol

436 (3R,4R,4aR,7S,8R,8aR) pipeπdine

-octahydro-2H- pyrano[3,2-b]pyrιdιne-

3,4,7,8-tetrol

437 6-[(2S ,4R)-4-hydroxy-2- pyrrolidine

C/) (hydroxymethyi)pyrrolιdι

C n-1-yl]hexanoιc acid

OO 438 2-{[(2S,3S,4R,5S) A- pyrrolidine

V) hydroxy-5-

H (hydroxymethyl)-2-

H t(2S,4Z)-undec-4-ene-

C 1 ,2,11-trιol]pyrrolιdιn-3-

H yl]oxy}-6- m (hydroxymethyl)tetrahyd K.

C/) ro-2H-pyran-3,4,5-trιol

Z 3-[(2R,3R,4R)-3 4- pyrrolidine m 439 m dιhydroxy-2-

(hydroxymethyl)pyrrolιdι

^H n-1-yl]propaπoιc acιd

73 440 [(2S,3R,4R)-3,4- pyrrolidine

C dιhydroxy-2- ι— (hydroxymethyl)pyrrolιdι m n-1-yl]acetιc acid

N) (2S,4S,5S)-4,5- pipeπdine

S) 441 dιhydroxypιpeπdιne-2- carboxylic acid

442 (2R,3R,4R,5S)-3,4,5- pipeπdine trιhydroxypιpeπdιne-2- carboxyhc acid

443 (3aR,6R,7R,8R,8aS 8b pyrrolizidme

S)-7,8-dιhydroxy-6- v y

(hydroxymethyl)-2,2- dιmethylhexahydro-4H-

[1 ,3]dιoxolo[4,5- a]pyrrolιzιn-4-one

444 (2S,5S,6S,7S,8R,8aS)- indolizidine

6,7,8-tπhydroxy-5-

(hydroxymethyl)-3-

oxooctahydroindolizine-

2-carboxylιc acid

445 (2S,5R,6R,7R,8R,8aR)- indolizidine

6,7,8-trιhydroxy-5-

(hydroxymethyl)-3- oxooctahydroindolizme-

2-carboxylιc acid

446 (3S,4R,5S,6R)-3,4,5- pipeπdine trιhydroxy-6-

(hydroxymethyl)pιpeπdι n-2-one

447 (2R,3S,4S,5R)-2- pipeπdme y

(hydroxymethyl)pιperιdι

C/) ne-3,4,5-tnol

C 448 (1R,2S,5R,6S,7S,7aS)- pyrrolidine

OO y

1 ,2,6,7-tetrahydroxy-5-

C/) (hydroxymethyl)hexahy

^■H dro3H-pyπOlιzιn-3-one

449 (2R,3R,4R,5S)-benzyl pipeπdine

_| 3,4,5-trιhydroxy-2- m (hydroxymethyl)pιpeπdι ne-1-carboxylate K.

\Jt σ

^p 2-((3R,4R,5R)-3,4- pipeπdine

J- 450 m dιhydroxy-5- m (hydroxymethyl)pιpeπdι n-1-yl)acetιc acid

__, 451 2-((3S,4S,5S)-3,4- pipendine

7} dιhydroxy-5-

C (hydroxymethyl)pιperιdι m n-1-yl)acetιc acid

1 11

452 (2R,3S,4R)-3,4- pyrrolidine

N) S) dιhydroxy-2- methylpyrrolιdιne-2- carboxylic acid

453 8-Aza- nortropane bιcyclo[3,2,1]octan-3-ol

454 (R)-3-Hydroxypιpeπdιne pipeπdine

455 4-Hydroxypιpeπdιne pipendine

456 cιs-L-3-Hydroxyprolιne pyrrolidine

457 (R)-3- pyrrolidine

Hydroxypyrrolidine

458 cιs-4-Hydroxy-D-prolιne pyrrolidine

459 4-hydroxy-2- pyrrolidine Pyrrolidinecarboxamide

460 2-methyl-4-Pιperιdιnol pipeπdine

461 L-beta- pyrrolidine Homohydroxyproline

462 (R)-5-Hydroxy-pιperιdιn- pipeπdine 2-one pyrrolidine piperidine pipeπdine piperidine pipeπdine pyrrol dine

469 1-Deoxy-L- piperidine 73 idonojinmycin ι— 470 2,5-Anhydro-2,5-ιmιno- pyrrolidine m D-glucιtol

N) σ> 471 1 ,4-Dιdeoxy-1 ,4-ιmιno- pyrrolidine D-mannιtol

472 (2S.5S)- pyrrolidine Bishydroxymethyl- (3R.4R)- bishydroxypyrrolidine 473 4-hydroxy-2- pyrrolidine Pyrrolidinemethanol

474 (R)-3-Hydroxypιpeπdιne pipeπdine

475 cιs-L-3-Hydroxyprolιne pyrrolidine

476 (S)-3-Hydroxypyrrolιdιne pyrrolidine

477 trans-4-Hydroxy-D- pyrrolidine y proline

478 trans-4-Hydroxy-D- pyrrolidine y proline

479 (R)-(+)-4-Hydroxy-2- pyrrolidine pyrrolidinone

480 S)-3-Hydroxy-pyrrolιdιn- pyrrolidine

2-one

481 N-(((3aR,4R,6aS)-5- pyrrolidine r/j benzyl-2,2- dιmethyltetrahydro3aH-

OO [1 ,3]dιoxolo[4,5-c]pyrrol-

V) 4-yl)methyl)acetamιde

H 482 N-(((2R,3R,4S)-1- pyrrolidine

H benzyl-3,4-

C dιhydroxypyrrolιdιn-2-

H yl)methyl)acetamιde m 483 ((3aR 4R 6aS)-5- pyrrolidine K.

C/) benzyl-2,2- OC

Z dιmethyltetrahydro-3aH- m [1 ,3]dιoxolo[4,5-c]pyrrol- m 4-yl)methanamιne

484 N-(((2R,3R,4S)-3,4- pyrrolidine jB dιhydroxypyrrolιdιn-2-

C yl)methyl)acetamιde ι— 485 N-((3S,4R,5S)-1-benzyl- pyrrolidine m 4-hydroxy-5-

N) (hydroxymethyl)pyrrolιdι σ> n-3-yl)benzamιde

486 (2R,3R,4S)-2- pyrrolidine

(amιnomethyl)-i- benzylpyrrolιdιne-3,4- diol

487 2-((2S,3S,4R)-2-((S)- pyrrolidine

1 ,2-dιhydroxyethyl)-3,4- dιhydroxypyπrolιdιn-1- yl)acetιc acid

488 (2R,3R,4S,5R,6R)-2- pipeπdine butyl-6-

(hydroxymethyl)pιpeπdι ne-3,4,5-tπol

489 (1 R,2S,8R,8aR)-1 ,2,8- indolizidine tπhydroxy-6-(2- hydroxyethyl)hexahydro ιndolιzιn-5(1 H)-one

490 (1R,2S,8R,8aR)-1 ,2,8- indolizidine tπhydroxy-6- methylhexahydroindolizi n-5(1 H)-one

491 5-[(2R,3R,4R)-3,4- pyrrolidine dιhydroxy-2-

(hydroxymethyl)pyrrolιdι n-1-yl]pentanoιc acid

492 (1 R,2S,6R,8R,8aR)-6- indolizidine

C/) (2-

C hydroxyethyl)octahydroι

OO ndolιzιne-1,2,8-tπol

V) 493 (1R,2S,6S,8R,8aR)-6- indolizidine

H (2-

H hydroxyethyl)octahydroι

C ndolιzιne-1 ,2,8-tπol

H 3-[(2R,3R,4R,5R)-3,4- pyrrolidine m 494 dιhydroxy-2 5- K.

C/) bιs(hydroxymethyl)pyrro

Z lιdιn-1-yl]propanoιc acid m 495 (2S,3S,3aS,6S,7S,7aS) pyrrolidine m _| -2-(hydroxymethyl)-1 -

(methylsulfonyl)octahydr

73 opyrano[3,2-b]pyrrole-

C 3,6,7-tπol ι— (3S,3aS,5S,6R,7R,7aS) pyrrolidine m 496

-5-(hydroxymethyl)-1 -

N) (methylsulfonyl)octahydr opyrano[3,2-b]pyrrole-

3,6,7-tπol

497 3-[(2S,4R)-4-hydroxy-2- pyrrolidine y

(hydroxymethyl)pyrrolιdι n-1-yl]propanoιc acid

498 [(2S,4R)-4-hydroxy-2- pyrrolidine y

(hydroxymethyl)pyrrolιdι n-1-yl]acetιc acιd

499 4-[(2R,3R,4R)-3,4- pyrrolidine dιhydroxy-2-

(hydroxymethyl)pyrrolιdι n-1-yl]butanoιc acιd

500 (2S,3S,4S)-1-benzyl-2- pyrrolidine

(hydroxymethyl)pyrrolιdι

ne-3,4-dιol

501 (2S,3S,4S)-2- pyrrolidine

(hydroxymethyl)-2- methylpyrrolιdιne-3,4- diol

502 (2R,3S,4S)-N-benzyl- pyrrolidine

3,4-dιhydroxy-2- methylpyrrolιdιne-2- carboxamide

503 N-{[(3S,4S,5R)-1- piperidine benzyl-4,5- dιhydroxypιperιdιn-3-

CΛ yl]methyl}acetamιde

C 504 (2R,3S,4S)-3,4- pyrrolidine DO dιhydroxy-2- CΛ methylpyrrolιdιne-2- carboxylic acid

505 (3aR,4S,6aS)-4- pyrrolidine

(azιdomethyl)-5-benzyl- m 2,2-dιmethyltetrahydro-

CΛ 3aH-[1 ,3]dιoxolo[4,5- O.

Z c]pyrrole m 506 (2S,3R,4S)-2- pyrrolidine m (azιdomethyl)-i- benzylpyrrolιdιne-3,4- diol

73 c 507 ((3aR,4S,6aS)-5-benzyl- pyrrolidine ι— 2,2-dιmethyltetrahydro- m 3aH-[1 ,3]dιoxolo[4,5- c]pyrrol-4-

N) yl)methanamιne

- 508 N-(((3aR,4S,6aS)-5- pyrrolidine benzyl-2,2- dιmethyltetrahydro-3aH-

[1 ,3]dιoxolo[4,5-c]pyrrol-

4-yl)methyl)acetamιde

509 (2R,3R,4R,5S)-2- pipeπdine

(hydroxymethyl)-1-(2- morpholιnoethyl)pιpeπdι ne-3,4,5-tπol

510 (2R,3R,4R,5S)-1- pipeπdine benzyl-2-

(hydroxymethyl)pιpeπdι ne-3,4,5-tπol

511 N-(((2R,3R,4S)-3,4- pyrrolidine dιhydroxy-1-(9- hydroxynonyl)pyrrolιdιn-

2-yl)methyl)acetamιde

512 N-(((2R,3R,4S)-3,4- pyrrolidine dιhydroxy-1- nonylpyrrolιdιn-2- yl)methyl)acetamιde

513 (2R,3R,4S)-2- pyrrolidine

(amιnomethyl)pyrrolιdιn e-3,4-dιol

514 (2R 3R,4R,5R)-1- pyrrolidine benzyl-2,5- r/j bιs(hydroxymethyl)pyrro lιdιne-3,4-dιol

DO 515 (2R,3R,4R,5R)-2,5- pyrrolidine

V) bιs(hydroxymethyl)- 1 -

H methylpyrrolιdιne-3,4-

_ι diol

C 516 N-(((2R,3R,4S)-3,4- pyrrolidine

H dιhydroxy-1-(2-(2- m methoxyethoxy)ethyl)py

C/) rrolιdιn-2-

Z yl)methyl)acetamιde m m 517 N-(((2R 3R.4S) 3,4- pyrrolidine dιhydroxy-1-(2-

^H hydroxyethyl)pyrrolιdιn-

73 2-yl)methyl)acetamιde

C 518 N-(((2R 3R,4S)-1- pyrrolidine ι— (bιphenyl-4-ylmethyl)- m 3,4-dιhydroxypyrrolιdιn-

N) 2-yl)methyl)acetamιde

519 N-(((2R,3R,4S)-1-butyl- pyrrolidine

3,4-dιhydroxypyrrolιdιn-

2-yl)methyl)acetamιde

520 N-(((2R,3R,4S)-3,4- pyrrolidine dιhydroxy-1-(2- morpholιnoethyl)pyrrolιd ιn-2- yl)methyl)acetamιde

521 3-((2R,3R,4S)-2- pyrrolidine

(acetamιdomethyl)-3,4- dιhydroxypyrrolιdιn-1- yl)propanamιde

522 (1 R,2S,3S)-1- pyrrolidine

[(2R,3S,4S)-3,4-

dιhydroxypyrrolιdιn-2- yl]butane-1 ,2,3,4-tetrol

523 (2R,3R,4R,5S)-2- piperidine (hydroxymethyl)-i -(2-

(pιperιdιn-1- yl)ethyl)pιpeπdιne-3,4,5- tπol

524 (2R,3R,4R,5S)-1- piperidine (bιphenyl-4-ylmethyl)-2- (hydroxymethyl)pιpeπdι ne-3,4,5-tπol

525 (1R,2S,5R,8S,8aS)-5- indolizidine methyloctahydroindolizi

C/) ne-1 ,2,8-trιyl triacetate

C 526 (1 R,2S,3R)-1- pyrrolidine DO ((2R,3R,4R)-1-benzyl- C/) 3,4-dιhydroxypyrrolιdιn-

2-yl)butane-1 , 2,3,4- tetraol

527 (1 R,2S,3R)-1- pyrrolidine m ((2R,3R,4S)-3,4- dιhydroxy-1-

C/) K.

Z nonylpyrrolιdιn-2- m yl)butane-1 ,2,3,4-tetraol m 528 (1 R,2S,3R)-1- pyrrolidine ((2R,3R,4S)-1-

(bιphenyl-4-ylmethyl)-

3,4-dιhydroxypyrrolιdιn- c 2-yl)butane-1 , 2,3,4- m tetraol

529 (1 R,2S,3R)-1- pyrrolidine ((2R,3R,4S)-3,4- dιhydroxy-1-(9- hydroxynonyl)pyrrolιdιn- 2-yl)butane-1 ,2,3,4- tetraol

530 2-((2R,3R,4S)-3,4- pyrrolidine dιhydroxy-2-

((1R,2S,3R)-1, 2,3,4- tetrahydroxybutyl)pyrrolι dιn-1-yl)acetιc acid

531 (1 R,2S,3R)-1- pyrrolidine ((2R,3R,4S)-1butyl-3,4- dιhydroxypyrrolιdιn-2- yl)butane-1 ,2,3,4-tetraol

532 (1 R,2S,3R)-1- pyrrolidine ((2R,3R,4S)-1-benzyl- 3,4-dιhydroxypyrrolιdιn-

2-yl)butane-1 , 2,3,4- tetraol

533 (1 R,2S,3R)-1- pyrrolidine ((2R,3R,4S)-3,4- dιhydroxy-1-(2- hydroxyethyl)pyrrolidin-

2-yl)butane-1 ,2,3,4- tetraol

534 (1 R,2S,5R,6R,7S,8R,8a indolizidine

R)-5-

V) methyloctahydroindohzi

C πe-1 ,2,6,7,8-pentaol

DO 535 (1 R,2S,3R}-1- pyrrolidine

C/) ((2R,3R,4S)-3,4- dιhydroxypyrrolιdιn-2- yl)butane-1 ,2,3,4-tetraol

C

_| 536 (1 R,2S,3R)-1- pyrrolidine m ((2R 3R,4S)-3,4- dιhydroxy-1-(2-(2-

C/) methoxyethoxy)ethyl)py

Z m rrolιdιn-2-yl)butane- m 1 ,2,3,4-tetraol

537 N-(((2R,3R,4S)-3,4- pyrrolidine dιhydroxy-1-(2-

73 (pιpeπdιn-1-

C yl)ethyl)pyrrolιdιn-2-

^ I _^ yl)methyl)acetamιde m 538 N-butyl-2- pyrrolidine e Nni ((2R,3S,4R,5R)-3,4- dιhydroxy-5-

(hydroxymethyl)-i- nonylpyrrolιdιn-2- yl)acetamιde

539 2-((2R,3S,4R,5R)-1- pyrrolidine benzyl-3,4-dιhydroxy-5- (hydroxymethyl)pyrrolιdι n-2-yl)-N- butylacetamide

540 N-butyl-2- pyrrolidine ((2R,3S,4R,5R)-3,4- dιhydroxy-1-(2- hydroxyethyl)-5-

(hydroxymethyl)pyrrolιdι

BST_I SHEE_T SU

n-2-yl)acetamιde

541 N-butyl-2- pyrrolidine ((2R,3S,4R,5R)-1-butyl-

3,4-dιhydroxy-5-

(hydroxymethyl)pyrrolιdι n-2-yl)acetamιde

542 N-(((2R,3R,4S)-1-(2- pyrrolidine (dιmethylamιno)ethyl)- 3,4-dιhydroxypyrrolιdιn-

2-yl)methyl)acetamιde

543 N-butyl-2- pyrrolidine ((2R,3S,4R,5R)-3,4- dιhydroxy-5-

(hydroxymethyl)pyrrolιdι n-2-yl)acetamιde

544 2-((2R,3R,4S)-2- pyrrolidine

(acetamιdomethyl)-3,4- dιhydroxypyrrolιdιn-1-

C

—i yl)acetιc acid m 545 (3R.5S) 5 pyrrolidine

(acetamιdomethyl)-1-(2- 4- acetoxyethyl)pyrrolιdιn- 3-yl acetate

546 (3R,5S)-5- pyrrolidine

(acetamidomethyl)- 1 - butylpyrrolιdιn-3-yl

73 acetate

C 547 (3R,5S)-5- pyrrolidine m (acetamidomethyl)- 1 - nonylpyrrolιdιn-3-yl acetate

548 N-(((2S,4R)-4-hydroxy- pyrrolidine

1-(2- hydroxyethyl)pyrrolιdιn- 2-yl)methyl)acetamιde

549 N-(((2S 4R)-1-butyl-4- pyrrolidine hydroxypyrrolιdιn-2- yl)methyl)acetamιde

550 (2R,3R,4R,5S)-2- pipeπdme

(hydroxymethyl)-i- nonylpιpeπdιne-3,4,5- tπol 551 azetιdιn-3-ol other

552 (3S,4S)-tert-butyl 4- pipeπdine bromo-3- hydroxypιpeπdιne-1 - carboxylate

553 (R)-tert-butyl 3- pipeπdine

(hydroxymethyl)pιpeπdι ne-1 -carboxylate

554 (S)-tert-butyl 3- pipeπdine

(hydroxymethyl)pιpeπdι ne-1 -carboxylate

555 (2R,3R,4R,5R)-2,5- pyrrolidine bιs(hydroxymethyl)-1- nonylpyrrolιdιne-3,4-dιol r/j 556 (2R,3R,4R,5R)-1-(2- pyrrolidine

C (benzyloxy)ethyl)-2,5-

OO bιs(hydroxymethyl)pyrro

V) lιdιne-3,4-dιoi

H 557 (2R,3R,4R,5R)-2,5- pyrrolidine

H bιs(hydroxymethyl)-1 -(9-

C hydroxynonyl)pyrrolιdιn

H e-3,4-dιol m 558 (2R 3R,4R,5R)-1- pyrrolidine

C/) (bιphenyl-4-ylmethyl)-

Z 2,5- m m bιs(hydroxymethyl)pyrro lιdιne-3,4-dιol

"H

559 (2R,3R,4R,5R)-2,5- pyrrolidine

TJ bιs(hydroxymethyl)-1 -(2-

C moφholιπoethyl)pyrrolιd ι— ιne-3,4-dιol m 560 (2R,3R,4R,5R)-2,5- pyrrolidine

N) bιs(hydroxymethyl)-1 -(2-

(pιpeπdιn-1- yl)ethyl)pyrrolιdιne-3,4- diol

561 (2S,3S,4S,5S)-2-((R)-4- pyrrolidine amιnopentyl)-5-

(hydroxymethyl)pyrrolιdι ne-3,4-dιol

562 (2S,3S,4S,5S)-2-((S)-4- pyrrolidine amιnopentyl)-5-

(hydroxymethyl)pyrrolιdι ne-3,4-dιol

563 N-((3R,4S,5R)-4,5- pipeπdine dιhydroxypιpeπdιn-3- yhacetamide

564 (2R,3R,4R)-1-(bιphenyl- pyrrolidine

4-ylmethyl)-2-

(hydroxymethyl)pyrrolιdι ne-3,4-dιol

565 (R)-piperidιn-3- pipeπdine ylmethanol

566 (2R,3R,4R)-1-benzyl-2- pyrrolidine

(hydroxymethyl)pyrrolιdι ne-3,4-dιol

567 (2R,3R,4R,5R)-2,5- pyrrolidine bιs(hydroxymethyl)-1 -(2-

(2- methoxyethoxy)ethyl )py

C/) rrolιdιne-3,4-dιol

C 568 (2R,3R,4R)-2- pyrrolidine

OO (hydroxymethyl)-i-

C/) nonylpyrrolιdιne-3,4-dιol

^■H 569 (2R,3R,4R)-2- pyrrolidine

(hydroxymethyl)-i -(9- hydroxynonyl)pyrrolιdιn m e-3,4-dιol

570 ((3aS,4S,6aR)-5-benzyl- pyrrolidine σ

2,2-dιmethyltetrahydro-

J- m 3aH-[1 ,3]dιoxolo[4,5- m c]pyrrol-4-yl)methanol

571 (2R,3R,4R)-2- pyrrolidine

(hydroxymethyl)-i -(2-(2- methoxyethoxy)ethyl)py

C rrolιdιne-3,4-dιol r~ m 572 (2R,3R,4R)-2- pyrrolidine

(hydroxymethyl)-1-(2- σ> moφholιnoethyl)pyrrolιd ιne-3,4-dιol

573 (2R,3R,4R)-2- pyrrolidine

(hydroxymethyl)-1-(2-

(pipeπdin-i- yl)ethyl)pyrrolιdιne-3,4- diol

574 3-((2R,3R,4R)-3,4- pyrrolidine dιhydroxy-2-

(hydroxymethyl)pyrrolιdι n-1 -yl)propanamιde

575 (3aR,7R,7aR)-7- pipeπdine hydroxy-3a-

(hydroxymethyl)-2,2- dimethyltetrahydro

[1 ,3]dιoxolo[4,5- c]pyrιdιn-4(3aH)-one

576 (3aS,4R,7R,7aR)-4- pipeπdine (hydroxymethyl)-2,2- dimethylhexahydro-

[1 ,3]dιoxolo[4,5- c]pyrιdιn-7-ol

577 (3aR,4S,6aS)-N-benzyl- pyrrolidine

2,2,4,6a- tetramethyltetrahydro-

3aH-[1 ,3]dιoxolo[4,5- c]pyrrole-4-carboxamιde

578 (3aS,7S,7aR)-7- pipeπdine

C/) (azιdomethyl)-5-benzyl-

C 2,2,3a- DO tπmethylhexahydro- C/) [1 ,3]dιoxolo[4,5- cjpyndine

579 (3aS,4R,7R,7aR)-tert- pipeπdine butyl 7-hydroxy-2,2,4- m tπmethyltetrahydro-

[1 ,3]dιoxolo[4,5-

C/) c]pyπdιne-5(6H)-

Z m carboxylate m 580 tert-butyl 5-hydroxy-5,6- pipeπdine dιhydropyπdιne-1(2H)- carboxylate

581 N-butyl-2- pyrrolidine c ((2R,3S,4R,5R)-3,4- m dιhydroxy-5-

(hydroxymethyl)-i -(2-(2- methoxyethoxy)ethyl)py rrolιdιn-2-yl)acetamιde

582 N-butyl-2- pyrrolidine ((2R,3S,4R,5R)-3,4- dιhydroxy-5-

(hydroxymethyl)-i -(9- hydroxynonyl)pyrrolιdιn-

2-yl)acetamιde

583 N-(((2S,3R,4S)-3,4- pyrrolidine dιhydroxy-1-(2-(2- methoxyethoxy)ethyl)py rrolιdιn-2- yl)methyl)acetamιde

584 N-(((2S,3R,4S)-1- pyrrolidine

(bιphenyl-4-ylmethyl)-

3,4-dιhydroxypyrrolιdιn-

2-yl)methyl)acetamιde

585 2-((2R,3S,4R,5R)-1- pyrrolidine

(bιphenyl-4-ylmethyl)-

3,4-dιhydroxy-5-

(hydroxymethyl)pyrrolιdι n-2-yl)-N- butylacetamide

586 N-(((2R,3R,4S)-1- pyrrolidine benzyl-3,4- dιhydroxypyrrolιdιn-2-

C/) yl)mβthyl)benzamιde

C 587 N-(((2S,3R,4S)-3,4- pyrrolidine

CD dιhydroxy-1-

V) nonylpyrrolιdιn-2-

H yl)methyl)acetamιde

H 588 ((3aS,4S,6aR)-2,2- pyrrolidine

C dιmethyltetrahydro-3aH-

H [1 ,3]dιoxolo[4,5-c]pyrrol- m 4-yl)methanol

C/) 589 (1R,2S,3R)-1-((3R,4R)- pyrrolidine OC

Z 3,4-dιhydroxy-1-(2- m m hydroxyethyl)pyrrolιdιn-

2-yl)butane-1 ,2,3,4- tetraol

590 (1R,2S,3R)-1-((3R,4R)- pyrrolidine

C 1 -(bιphenyl-4-ylmethyl)- ι— 3,4-dιhydroxypyrrolιdιπ- m 2-yl)butane-1 , 2,3,4-

N) tetraol

591 (1R,2S,3R)-1-((3R,4R)- pyrrolidine

3,4-dιhydroxy-1-(9- hydroxynonyl)pyrrolιdιn-

2-yl)butane-1 , 2,3,4- tetraol

592 (1 R,2S,3R)-1-((3R,4R)- pyrrolidine

3,4-dιhydroxy-1-(2-(2- methoxyβthoxy)ethyl)py rrolιdιn-2-yl)butane-

1 ,2,3,4-tetraol

593 (1R,2S,3R)-1-((3R,4R)- pyrrolidine

3,4-dιhydroxypyrrolιdιn-

2-yl)butane-1 ,2,3,4- tetraol

594 (1R,2S,3R)-1-((3R,4R)- pyrrolidine

1-butyl-3,4- dιhydroxypyrrolιdιn-2- yl)butane-1 ,2,3,4-tetraol

595 (1 R,2S,3R)-1-((3R,4R)- pyrrolidine

3,4-dιhydroxy-1- nonylpyrrolιdιn-2- yl)butane-1 ,2,3,4-tetraol

596 (5R,6R,7S,8R)-5- pipeπdine methyl-5,6,7,8- tetrahydrotetrazolo[1 ,5- a]pyrιdιne-6,7,8-trιol

597 N-(((2S,3R,4S)-1- pyrrolidine

C/) benzyl-3,4-

C dιhydroxypyrrolιdιn-2-

CD yl)methyl)benzamιde

C/) 598 N-(((2S,3R,4S)-1- pyrrolidine

H benzyl-3,4-

H dιhydroxypyrrolιdιn-2-

C yl)methyl)acetamιde m 599 N-(((3aR,4S 6aS)-5- pyrrolidine benzyl-2,2-

C/) dιmethyltetrahydro-3aH-

Z [1 ,3]dιoxolo[4,5-c]pyrrol- m m 4-yl)methyl)benzamιde

600 N-(((2S,3R,4S)-3,4- pyrrolidine dιhydroxy-1-(2- hydroxyethyl)pyrrolιdιn-

C 2-yl)methyl)acetamιde ι— N-(((2S,3R,4S)-3,4- pyrrolidine m 601 y dιhydroxypyrrolιdιn-2-

N) yl)methyl)acetamιde

602 N-(((2S,3R,4S)-3,4- pyrrolidine y dιhydroxypyrrolιdιn-2- yl)methyl)benzamιde

603 N-(((2S,3R,4S)-1-butyl- pyrrolidine y

3,4-dιhydroxypyrrolιdιn-

2-yl)methyl)acetamιde

604 (2S,3R,4S)-2- pyrrolidine y

(amιnomethyl)-i- benzylpyrrolιdιne-3,4- diol

605 ((3aS,4S,6aR)-5- pyrrolidine

(bιphenyl-4-ylmethyl)-

2,2-dιmethyltetrahydro-

3aH-[1,3]dιoxolo[4,5-

c]pyrrol-4-yl)methanol

606 (2S,3S,4R)-1-(t>iphenyl- pyrrolidine 4-ylmethyl)-2-((S)-1 ,2- dιhydroxyethyl)pyrτolιdιn e-3,4-dιol

607 N-(((2S,3R,4S)-1-butyl- pyrrolidine y y 3,4-dιhydroxypyrrolιdιn- 2-yl)methyl)benzamιde 608 N-(((3aR,4S,6aS)-5- pyrrolidine y y benzyl-2,2- dιmethyltetrahydro-3aH-

[1 ,3]dιoxolo[4,5-c]pyrrol-

C/) 4-yl)methyl)-2,2,2-

C tπfluoroacetamide

S ⁶⁰⁹ N-(((3aR,4S,6aS)-2,2- pyrrolidine dιmethyltetrahydro-3aH- [1 ,3]dιoxolo[4,5-c]pyrrol- 4-yl)methyl)acetamιde

610 N-(((3aR 4S 6aS)-5- pyrrolidine m (bιphenyl-4-ylmethyl)-

C/) 2,2-dιmethyltetrahydro-

Z 3aH-[1 ,3]dιoxolo[4,5- m c]pyrrol-4- m yl)methyl)acetamιde

611 N-(((3aR,4S,6aS)-2,2- pyrrolidine dιmethyltetrahydro-3aH- c [1 ,3]dιoxolo[4,5-c]pyrrol- ι— 4-yl)methyl)-2,2,2- m tπfluoroacetamide

612 N-(((2S,3R,4S)-3,4- pyrrolidine

N) dιhydroxy-1-(2-

(pιperιdιn-1- yl )ethy I )pyrrolιd ιn-2- yl)methyl)benzamιde

613 N-(((2S,3R,4S)-3,4- pyrrolidine dιhydroxy-1-(9- hydroxynonyl)pyrrolιdιn-

2-yl)methyl)benzamιde

614 N-(((2R,3R,4S)-3,4- pyrrolidine dιhydroxypyπOlιdιn-2- yl)methyl)benzamιde 615 N-(((2S,3R,4S)-1-(2- pyrrolidine

(dιmethylamιno)ethyl)-

3,4-dιhydroxypyrrolιdιn-

2-yl)methyl)acetamιde

616 N-(((2S,3R,4S)-3,4- pyrrolidine dιhydroxy-1-(2-

(pιperιdιn-1- yl)ethyl)pyrrolιdιn-2- yl)methyl)acetamιde

617 N-(((2R,3R,4S)-1-butyl- pyrrolidine

3,4-dιhydroxypyrrolιdιn-

2-yl)methyl)benzamιde

618 N-(((2S,3R,4S)-3,4- pyrrolidine dιhydroxy-1-(2- moφholιnoethyl)pyrrolιd ιn-2- yl)methyl)acetamιde r/j 619 N-(((2R,3R,4S)-1- pyrrolidine

C benzyl-3,4-

OO dιhydroxypyrrolιdιn-2-

V) yl)methyl)-2,2,2-

H tπfluoroacetamide

H 620 N-butyl-2- pyrrolidine

C ((2R,3S,4R,5R)-3,4-

H dιhydroxy-5- m (hydroxymethyl)-1-(2-

C/) morpholιnoethyl)pyrrolιd

Z ιn-2-yl)acetamιde m m 621 N-(((2S,3R,4S)-3,4- pyrrolidine dιhydroxy-1-(2-(2- methoxyethoxy)ethyl)py jB rrolιdιn-2-

C yl)methyl)benzamιde ι— 622 N-(((2S,3R,4S)-3,4- pyrrolidine m dιhydroxy-1-

N) nonylpyrrolιdιn-2- yl)methyl)benzamιde

623 (2S,3S,4R)-1-(bιphenyl- pyrrolidine

4-ylmethyl)-2-

(hydroxymethyl)pyrτolιdι ne-3,4-dιol

624 (1R,2S,3R)-1-((3R,4S)- pyrrolidine

3,4-dιhydroxy-1- methylpyrrolιdιn-2- yl)butane-1 ,2,3,4-tetraol

625 (1R,2S,3R)-1-((3R,4R)- pyrrolidine

3,4-dιhydroxy-1- methylpyrrolιdιn-2- yl)butane-1 ,2,3,4-tetraol

626 (1R,2S,3R)-1-((3R,4R)- pyrrolidine

3,4-dιhydroxy-1-(2- morpholιnoethyl)pyrrolιd ιn-2-yl)butane-1 , 2,3,4- tetraol

627 (1R,2S,3R)-1-((3R,4R)- pyrrolidine

3,4-dιhydroxy-1-(2-

(pιpeπdιn-1- yl)ethyl)pyrrolιdιπ-2- yl)butane-1 ,2,3,4-tetraol

628 N-(((2R,3R,4S)-3,4- pyrrolidine dιhydroxy-1- methylpyrrolιdin-2-

C/) yl)methyl)benzamιde

C 629 N-(((3aR,4S,6aS)-2,2- pyrrolidine

CD dιmethyltetrahydro-3aH-

C/) [1 ,3]dιoxolo[4,5-c]pyrrol-

H 4-yl)methyl)benzamιde

H 630 N-(((3aR,4S,6aS)-2,2- pyrrolidine

C dιmethyl-5-

H nonyltetrahydro-3aH- m [1 ,3]dιoxolo[4,5-c]pyrrol-

C/) 4-yl)methyl)acetamιde

Z 2,2,2-trιfluoroN- pyrrolidine m 631

(((3aR,4S,6aS)-5-(2-(2- m methoxyethoxy)ethyl)-

2,2-dιmethyltetrahydro-

3aH-[1,3]dιoxolo[4,5-

C c]pyrrol-4- ι— yl)methyl)acetamιde m 632 N-(((3aR,4S,6aS)-5- pyrrolidine

N) (biphenyl-4-ylmethyl)-

0) 2,2-dιmethyltetrahydro-

3aH-[1,3]dιoxolo[4,5- c]pyrrol-4-yl)methyl)-

2,2,2-tπfluoroacetamιdβ

633 N-(((2S,3R,4S)-3,4- pyrrolidine dιhydroxy-1-(2- moφholιnoettiyl)pyrrolιd ιn-2- yl)methyl)bβnzamιde

634 N-(((2S,3R,4S)-3,4- pyrrolidine dιhydroxy-1-(9- hydroxynonyl)pyrrolιdιn-

2-yl)methyl)acetamιde

635 (1S,2S,3S,6R,7R,7aR)- pyrrolizidine

1,6,7-tnhydroxy-3-

(hydroxymethyl)hexahy dro-1 H-pyrrolιzιn-2-yl methanesulfonate

636 (3R,4S,5S)-5- pipendine y

(amιnomethyl)pιpeπdιne

-3,4-dιol

637 N-{[(3R,4S,5R)-4,5- pipendme y dιhydroxypιpendιn-3- yl]methyl}acetamιde

638 (2S,4R)-4-hydroxy-1 ,1- pyrrolidine dιmethylpyrrolιdιnιum-2-

C/) carboxylate

C 639 N-((3R,4S,5R)-5- pipendine

DO (benzyloxy)-4-

V) hydroxypιpendιn-3-

H yl)acetamιde

H 640 (3S,4S,5S)-1-(2- pipendine

C hydroxy ethyl )-5-

—i r (hydroxymethyl)pιperιdι mπ ne-3,4-dιol

C/) 641 (3S,4S,5S)-5- pipendine

Z (hydroxym ethyl )pιperιdι m m ne-3,4-dιol

_ ^_^| 642 (1S,2R,3S,4R,5R)- other Y Y Y

2,3,4-tnhydroxy-N-(N'-

73 octylthιocarbamoyl)-6-

C oxa-nor-tropane ι— (5R,6R,7S,8R,8aR)- other Y Y m 643

5,6,7,8-Tetrahydroxy-3-

N) octylιmιno-2- oxaindolizidine

644 (1S,2R,3S,4R,5R)-N- other Y Y

(N'-Butylthιocarbamoyl)-

2,3,4-tnhydroxy-6-oxa- nor-tropane

645 (3Z,5R,6R,7S,8R,8aR)- other Y Y

3-

(octylιmιno)hexahydro[1

,3]thιazolo[3,4- a]pyrιdιne-5,6,7,8-tetrol

646 N-(((2R,3R,4S)-3,4- pyrrolidine dιhydroxy-1- nonylpyrrolιdin-2- yl)methyl)benzamιde

647 N-(((2R,3R,4S)-3,4- pyrrolidine dιhydroxy-1-(2- hydroxyethyl)pyrrolιdιn-

2-yl)methyl)benzamιde

648 N-(((2R,3R,4S)-3,4- pyrrolidine Y dιhydroxy-1-(9- hydroxynonyl)pyrrolιdιπ-

2-yl)methyl)benzamιde

649 N-(((2R,3R,4S)-1- pyrrolidine Y

(bιphenyl-4-ylmethyl)-

3,4-dιhydroxypyrrolιdιn-

2-yl)methyl)benzamιde

650 N-(((2R,3R,4S)-3,4- pyrrolidine Y

C/) dιhydroxy-1-(2-(2-

C methoxyethoxy)ethyl)py

OO rrolιdιn-2-

V) yl)methyl)benzamιde

H 651 N-(((2R,3R,4S)-3,4- pyrrolidine

H dιhydroxy-1-(2-

C moφholιnoethyl)pyrrolιd

H ιn-2- m yl)methyl)benzamιde 4-

C/) 652 N-(((3aR,4S,6aS)-5- pyrrolidine Y 4-

Z benzyl-2,2- m dιmethyltetrahydro-3aH- m [1 ,3]dιoxolo[4,5-c]pyrrol-

4-yl)methyl)bιphenyl-4- carboxamide

C 653 N-(((2R,3R,4S)-3,4- pyrrolidine ι— dιhydroxy-1-(2- m (pιpeπdιn-1-

N) yl)ethyl)pyrrolιdιπ-2-

S) yl)methyl)benzamιde

654 N-(((2R,3R,4S)-1-(2- pyrrolidine

(dιmethylamιno)ethyl)-

3,4-dιhydroxypyrrolιdιn-

2-yl)methyl)benzamιde

655 2-((2R,3R,4S)-2- pyrrolidine Y

(benzamιdomethyl)-3,4- dιhydroxypyrrolιdιn-1- yl)acetιc acid

656 N-(((2R,3R,4S)-3,4- pyrrolidine Y dιhydroxy-1- methylpyrrolιdιn-2- yl)methyl)acetamιde

_SUB_{STI SHEET}

657 N-(((2S,3R,4S)-1- pyrrolidine Y benzyl-3,4- dιhydroxypyrrolιdιn-2- yl)methyl)bιphenyl-₄- carboxamide

658 N-(((2S,3R,4S)-1-butyl- pyrrolidine Y 3,4-dιhydroxypyrrolιdιn- 2-yl)methyl)bιphenyl-4- carboxamide

659 N-(((2S,3R,4S)-3,4- pyrrolidine Y Y dιhydroxy-1- nonylpyrrolιdιn-2- yl)methyi)bιphenyl-4- carboxamide

660 N-(((2S,3R,4S)-3,4- pyrrolidine Y dιhydroxy-1-(9- hydroxynonyl)pyrrolιdιn- 2-yl)methyl)bιphenyl-4-

H carboxamide C N-(((3aR,4S,6aS)-5-(9- pyrrolidine

_| 661 Y m hydroxynonyl)-2,2- dιmethyltetrahydro-3aH-

[1 ,3]dιoxolo[4,5-c]pyrrol-

4-yl)methyl)benzamιde

662 N-(((3aR,4S,6aS)-5- pyrrolidine Y Y benzyl-2,2- dιmethyltetrahydro-3aH-

73 [1 ,3]dιoxolo[4,5-c]pyrrol-

C 4-yl)methyl)-2,2,2-

I tnfluoroacetamide m 663 2,2,2-trιfIuoro-N- pyrrolidine Y en (((3aR,4S,6aS)-5-(9- hydroxynonyl)-2,2- dιmethyltetrahydro-3aH-

[1 ,3]dιoxolo[4,5-c]pyrrol-

4-yl)methyl)acetamιde

664 N-(((2S,3R,4S)-1- pyrrolidine Y Y (bιphenyl-4-ylmethyl)-

3,4-dιhydroxypyrrolιdιn- 2-yl)methyl)benzamιde

665 3-((2S,3R,4S)-2- pyrrolidine Y (acetamιdomethyl)-3,4- dιhydroxypyrrolιdιn-1 - yl)propanamιde

666 N-(((2S,3R,4S)-1-(3- pyrrolidine Y Y amιno-3-oxopropyl)-3,4-

dιhydroxypyrrolιdιn-2- yl)methyl)benzamιde

667 N-(((2S,3R,4S)-1-(2- pyrrolidine Y Y (dιmethylamιno)ethyl)- 3,4-dιhydroxypyrrolιdιn- 2-yl)methyl)benzamιde

668 N-(((3aR,4R,6aS)-5- pyrrolidine Y benzyl-2,2- dιmethyltetrahydro-3aH- [1 ,3]dιoxolo[4,5-c]pyrrol- 4-yl)methyl)butyramιde

669 N-(((2R,3R,4S)-1- pyrrolidine benzyl-3,4-

C/) dιhydroxypyrrolιdιn-2-

C yl)methyl)butyramιde DO 670 N-(((2S,3R,4S)-3,4- pyrrolidine Y Y C/) dιhydroxypyrrolιdιn-2- yl)m ethyl )bιphenyl-4- carboxamide

671 (3aS,4R,6aR)-4- pyrrolidine Y Y m (azιdomethyl)-2,2- dιmethyltetrahydro-3aH-

C/) [1 ,3]dιoxolo[4,5-

Z m c]pyrrole m 672 N-(((3aR,4R,6aS)-5- pyrrolidine benzyl-2,2- dιmethyltetrahydro-3aH-

[1 ,3]dιoxolo[4,5-c]pyrrol- c 4-yl)methyl)bιphenyl-4- m carboxamide

673 N-(((2R,3R,4S)-1- pyrrolidine benzyl-3,4- dιhydroxypyrrolιdιn-2- yl)methyl)bιphenyl-4- carboxamide

674 N-(((2S,3R,4S)-3,4- pyrrolidine Y Y dιhydroxypyrrolιdιn-2- yl)methyl)-2,2,2- tnfluoroacetamide

675 N-(((3aR,4S,6aS)-2,2- pyrrolidine Y dιmethyl-5-(2- moφholinoethyljtetrahy dro-3aH-

[1 ,3]dιoxolo[4,5-c]pyrrol- 4-yl)methyl)-2,2,2- tπfluoroacetamid

676 N-(((3aR,4S,6aS)-5- pyrrolidine Y Y butyl-2,2- dιmethyltetrahydro-3aH- [1 ,3]dιoxolo[4,5-c]pyrrol-

4-yl)methyl)-2,2,2- tπfluoroacetamide

677 N-(((3aR,4S,6aS)-2,2- pyrrolidine dιmethyl-5-(2-(pιpeπdιn-

1 -yl)ethyl)tetrahydro-

3aH-[1,3]dιoxolo[4,5- c]pyrrol-4-yl)methyl)-

2,2,2-tπfluoroacetamιde

678 N-(((3aR,4S,6aS)-5-(2- pyrrolidine Y Y (dιmethylamιno)ethyl)-

C/)

C 2,2-dιmethyltetrarιydro- DO 3aH-[1,3]dιoxolo[4,5- C/) c]pyrrol-4-yl)methyl)-

2,2,2-tnfluoroacetamιde

679 N-(((2S,3R,4S)-3,4- pyrrolidine Y Y dιhydroxy-1- methylpyrrolιdιn-2- m yl)methyl)acetamide

C/) 680 (2S.3R 4R)-2- pyrrolidine Y Y

Z [(2R,3S,4R)-3,4- m dihydroxytetrahydrofura m n-2-yl]pyrrolιdιne-3,4- diol

Ti 681 (2R,3R,4R)-1-butyl-2- pipeπdine Y Y (hydroxymethyl)pιpeπdι ne-3,4-dιol m 682 N-(((2S,3R,4S)-1-butyl- pyrrolidine Y Y

3,4-dιhydroxypyrrolιdιn- 2-yl)methyl)-2,2,2- tnfluoroacetamide

683 N-(((2S,3R,4S)-3,4- pyrrolidine Y dιhydroxy-1-(2-

(pιpeπdιn-1- yl )ethyl )pyrrolιd ιn-2- yl)methyl)-2,2,2- tπfluoroacetamide

684 tert-butyl pyrrolidine Y ((3aR,4S,6aS)-5-(2- hydroxyethyl)-2,2- dιmethyltetrahydro-3aH-

[1 ,3]dιoxolo[4,5-c]pyrrol-

4-yl)methylcarbamate

685 dimethyl 1-(((2S,3R,4S)- pyrrolidine Y Y

1-benzyl-3,4- dιhydroxypyrrolιdιπ-2- yl)methyl)-1 H-1 ,2,3- tπazole-4,5- dicarboxylate

686 (2S,3R,4S)-2- pyrrolidine (amιnomethyl)-i-

(bιphenyl-4- ylmethyl)pyrrolιdιne-3,4- diol

687 (2R,3S,4R)-2- pyrrolidine Y (amιnomethyl)-i-

C/) benzylpyrrolιdιne-3,4-

C diol DO 688 N-(((2S,3R,4S)-3,4- pyrrolidine Y C/) dιhydroxy-1-(2-(2- methoxyethoxy)ethyl)py rrolιdιn-2- yl)methyl)bιphenyl-4- carboxamide m 689 N-(((2R,3R,4S)-1 -butyl- pyrrolidine Y

C/) 3,4-dιhydroxypyrrolιdιn- OC

Z 2-yl)methyl)butyramιde m m 690 (2R,3S,4R)-2- pyrrolidine Y (amιnomethyl)pyrrolιdιn e-3,4-dιol

691 N-((2R,3R)-3- pyrrolidine Y c ((2R,3R,4R)-3,4- dιhydroxypyrrolιdιn-2- m yl)-2,3- dιhydroxypropyl)acetam ide

692 (1R,2R)-1-((2R,3R,4R)- pyrrolidine Y Y Y

3,4-dιhydroxy-1- nonylpyrrolιdιn-2- yl)propaπe-1,2,3-tπol

693 (1 R,2R)-1-((2R,3R,4R)- pyrrolidine Y Y Y

3,4-dιhydroxy-1-(2-(2- methoxyethoxy)ethyl)py rrolιdιn-2-yl)propane-

1 ,2,3-tπol

694 tert-butyl 4- pyrrolidine Y Y (((2R,3R,4S)-3,4- dιhydroxy-2- ((1R,2S,3R)-1, 2,3,4-

tetrahydroxybutyl)pyrrolι dιn-1- yl)methyl)pιpeπdιne-1 - carboxylate

695 tert-butyl 4-(((3R,4R)- pyrrolidine Y Y Y

3,4-dιhydroxy-2-

((1R,2S,3R)-1 , 2,3,4- tetrahydroxybutyl)pyrτolι dιn-1- yl)methyl)pιpeπdιne-1 - carboxylate

696 (1R,2S,3R)-1-((3R,4R)- pyrrolidine Y Y Y

1-(2- r/j (dimethylamino)ethyl)-

3,4-dιhydroxypyrrolιdιπ-

OO 2-yl)butane-1 , 2,3,4-

C/) tetraol

697 N-((2R,3R)-3- pyrrolidine Y Y Y

((2S,3R,4R)-1-benzyl-

C 3,4-dιhydroxypyrrolιdιn-

H 2-yl)-2,3- m dιhydroxypropy[)acetam

C/) ide

Z (2S,3R,4R)-1-benzyl-2- pyrrolidine m 698 Y Y Y

((1 R,2R)-3- m (benzylamιno)-i ,2- dihydroxypropyljpyrrolidi ne-3,4-dιol

C 699 (1 R,2R)-1-((2R,3R,4R)- pyrrolidine Y Y Y ι— 3,4-dιhydroxypyιτolιdιn- m 2-yl)propane-1 ,2,3-tπol

N) 700 (2S,3R,4S)-1-bβnzyl-2- pyrrolidine Y

((S)-2-(benzylamιno)-1 - hydroxyethyl)pyrrolιdιne

-3,4-dιol

701 N-(((2S,3R,4S)-1- pyrrolidine Y Y

(bιphenyl-4-ylmethyl)-

3,4-dιhydroxypyrrolιdιn-

2-yl)methyl)bιphenyl-4- carboxamide

702 N-(((2S,3R,4S)-3,4- pyrrolidine Y dιhydroxy-1-(2- moφholιnoethyl)pyrrolιd ιn-2-yl)methyl)bιphenyl-

4-carboxamιde

703 (1R,2R)-1-((2R,3R,4R)- pyrrolidine Y Y Y

1-benzyl-3,4- dιhydroxypyrrolιdιn-2- yl)propane-1 ,2,3-trιol

704 (2R,3R,4R)-1-benzyl-2- pyrrolidine Y Y Y

((4R,5R)-5-

((benzylamιπo)methyl)-

2,2-dιmethyl-1 ,3- dιoxolan-4- yl)pyrrolιdιne-3,4-dιol

705 (1 R,2R)-1-((2R,3R,4R)- pyrrolidine Y Y

1-(2-

(dιmethylamιno)ethyl)-

C/) 3,4-dιhydroxypyrrolιdιn-

C 2-yl)propane-1 ,2,3-tπol

CD 706 (1 R,2R)-1-((2R,3R,4R)- pyrrolidine Y Y Y

V) 3,4-dιhydroxy-1-(2-

H hydroxyβthyl)pyrrolιdιn-

H 2-yl)propane-1 ,2,3-trιol

C 707 (2S,2'S,3R,3'R,4S,4'S)- pyrrolidine Y Y

H 2,2'-((1 R,1'R,2R,2'R)- m 3,3'-azanedιylbιs(1 2- 'J

C/) dιhydroxypropane-3, 1 -

Z dιyl))bιs(1- m m benzylpyrrolιdιne-3,4- diol)

708 (2S,3R,4S)-2-((S)-2- pyrrolidine amιno-1-

C hydroxyethyl)pyrrolιdιne ι— -3,4-dιol m 709 N-((S)-2-((2S,3R,4S)- pyrrolidine Y

N) 3,4-dιhydroxypyrrolιdιn-

2-yl)-2- hydroxyethyl)acetamιde

710 (2R,4S)-methyl 4- pyrrolidine Y Y hydroxypyrrolιdιne-2- carboxylate

711 (3R,4R,5R,6R)- azepane azepane-3,4,5,6-tetraol

712 N-butyl-2- pyrrolidine Y

((2R,3S,4R,5R)-3,4- dιhydroxy-5-

(hydroxymethyl)-1-(2-

(pipeπdιn-1- yl)ethyl)pyrrolιdιπ-2- yl)acetamιde

713 (2R,4S)-1-tert-butyl 2- pyrrolidine Y methyl 4- hydroxypyrrolιdιne-1 ,2- dicarboxylate

714 2-{[(2R,3R,6R)-6-ethyl- pipβπdine

3-hydroxypιpeπdιn-2- yl]methoxy}-6-

(hydroxymethyl)tetrahyd ro-2H-pyran-3,4,5-tπol

715 (1S,6R,7R,8S,8aR)- indolizidine octahydroindolizine-

1 ,6,7,8-tetraol

716 3-((2S,4S)-4-azιdo-2- pyrrolidine Y Y

C/) (hydroxymethyl)pyrrolιdι

C π-1-yl)propan-1-ol

DO 717 3-((2R,4R)-4-azιdo-2- pyrrolidine Y Y

C/) (hydroxymethyl)pyrrolιdι

H n-1-yl)propan-1-ol

H 718 N-(((3aR,4R 6aS)-2,2- pyrrolidine

C dιmethyltetrahydro-3aH- m [1 ,3]dιoxolo[4,5-c]pyrrol-

4-yl)methyl)butyramιde

C/) 719 (7S,8R,8aS)-methyl 7,8- other Y Y

Z dιhydroxy-4-oxo- m m 4,6,7,8,8a,9- hexahydropyrrolo[1 ,2-

^H d][1 ,2,3]tπazolo[1 ,5-

73 a]pyrazιne-3-

C carboxylate ι— 720 (2S,3R,4S)-2- pyrrolidine Y Y m (amιnomethyl)-1-(2-

N) hydroxyethyl)pyrrolιdιne

-3,4-dιol

721 (2R,3R,4R)-4-azιdo-1- pyrrolidine Y Y

(2-hydroxyethyl)-2-

(hydroxymethyl)pyrrolιdι n-3-ol

722 (2S,3S,4S)-4-azιdo-1- pyrrolidine Y Y

(2-hydroxyethyl)-2-

(hydroxymethyl)pyrrolιdι n-3-ol

723 2-((2R,4S)-4-azιdo-2- pyrrolidine Y Y

(hydroxymethyl)pyrrolιdι n-1-yl)ethanol

724 (2R,3R,4R,5S)-2- piperidine

(hydroxymethyl)-i -(9-

hydroxynonyl)pιpeπdιne -3,4,5-tπol

725 (2R,3R,4R,5S)-2- piperidine Y Y

(hydroxymethyl)-i -(2-(2- methoxyethoxy)ethyl)pι peπdιne-3,4,5-trιol

726 (2R,3R,4R,5S)-1-(2- pipeπdine Y Y

(dιmethylamιno)ethyl)-2- (hydroxymethyl)pιpeπdι ne-3,4,5-tπol

727 N-((3S,5S)-3,5- piperidine Y Y dιhydroxypιperιdιn-4-

'J

K.

736 (3R,4S,5R,6S)-1- azepane Y nonylazepane-3,4,5,6- tetraol

737 (3R,4S,5R,6S)-1-(9- azepane Y hydroxynonyl)azepane-

3,4,5,6-tetraol 738 (3R,4S,5R,6S)-1- azepane Y

(bιphenyl-4- ylmethyljazepane-

3,4,5,6-tetraol

739 (3R,4S,5R,6S)-1-(2- azepane Y

(dιmethylamιno)ethyl)az epane-3,4,5,6-tetraol 740 (3R,4S,5R,6S)-1- azepane Y benzylazepane-3,4,5,6- tetraol

C/) 741 (R)-(I -butylpιpeπdιn-3- azepane

C yl)methanol 00 742 (3R,4S,5R,6S)- azepane C/) azepane-3,4,5,6-tetraol

743 (2R,3R,4R,5R)-1-(2- pyrrolidine Y

(dιmethylamιno)ethyl)-

2,5- m bιs(hydroxymethyl)pyrro it lιdιne-3,4-dιol

774444 (R)-2-(3- pipeπdine

(hydroxym ethyl )pιpeπdι n-1-yl)ethanol

745 (2R,3R,4R,5R)-1-butyl- pyrrolidine

73 2,5-

C bιs(hydroxymethyl)pyrro r~ lιdιne-3,4-dιol m 746 (R)-(I -nonylpipendin-3- pipeπdine

N) yl)methanol σ>

747 (R)-(1-(2-(2- pipeπdine methoxyethoxy)ethyl)pι peπdιn-3-yl)methanol

748 1-(bιphenyl-4- other ylmethyl)azetιdιn-3-ol 749 1-(9- other hydroxynonyl)azetιdιn-

3-ol

750 (1R,4S,7R)-2-oxa-5- pyrrolidine Y Y azabιcyclo[2 2 1]heptan

-7-ol 751 (7S,8R,8aR)- pyrrolidine octahydropyrrolo[1 ,2- a]pyrazιne-7,8-dιol

752 (2S,3R,4S,5R)-1,2- pipeπdine Y dimethylpipeπdine-

3,4,5-tπol

753 (6S,7R,8R,8aR)-6,7,8- pipeπdine Y Y trιhydroxytetrahydro-1 H- oxazolo[3,4-a]pyπdιn- 3(5H)-one

754 (2R,3R,4R)-1-(2- piperidine Y Y hydroxyethyl)-2-

(hydroxym ethyl )pιpeπdι ne-3,4-dιol

755 (2R,3R,4R)-2- piperidine (hydroxymethyl)-1-(2- f#» methoxyethyl)pιperιdιne

C -3,4-dιol

DO 756 (2R,3R,4R,5S)-1-ethyl- piperidine Y Y

CΛ 2-

H (hydroxymethyl)pιpeπdι

—I ne-3,4,5-tπol

C 757 (1R,2R,3R,4R)-1-butyl- pipeπdine Y

H 3,4-dιhydroxy-2- rπ (hydroxymethyl)pιpeπdι 'J

C/) ne 1 -oxide

Z 758 (2S,4S,5S)-4,5- pipeπdine Y Y Y

IT! dιhydroxy-1-

[J] methylpιpeπdιne-2-

I^ carboxylic acid

_/O 759 (4aR,7S,8R,8aR)-5- pipeπdine Y Y

C benzyl-2,2- l~ dιmethylhexahydro-4H- m [1 ,3]dιoxιno[5,4-

NJ b]pyrιdιne-7,8-dιol

2 760 (2R,4aR,7S,8R,8aR)- pipeπdine benzyl 7,8-dιhydroxy-2- phenyltetrahydro-4H- [1,3]dιoxιno[5,4- b]pyπdιne-5(4aH)- carboxylate

761 (3R,4R,5R,6R)-1-(2-(2- azepane Y methoxyethoxy)ethyl)az epane-3,4,5,6-tetraol

762 (3R,4R,5R,6R)-1- azepane Y

(bιphenyl-4- ylmethyl)azepane-

3,4,5,6-tetraol

763 (3R,4R,5R,6R)-1-(9- azepane Y hydroxynonyl)azepane-

3,4,5,6-tetraol

764 (3R,4R,5R,6R)-1- azepane Y butylazepane-3,4,5,6- tetraol

765 2-((3R,4R,5R,6R)- azepane Y

3,4,5,6- telrahydroxyazepan-1 - yl)acetιc acid

766 (3R,4R,5R,6R)-1-(5- azepane

(adamantan-1-yl- methoxy)-

C/) pentyl)azepane-3,4,5,6- tetraol

DO 767 ((2R,4S)-4- pyrrolidine Y Y

C/) azιdopyrrolιdιn-2-

H yl)methanol

H 768 (2R,4S)-tert-butyl 4- pyrrolidine Y Y

C azιdo-2-

H (hydroxymethyl)pyrrolιdι m ne-1-carboxytate 'J

C/) 769 (3R,4R,5S,6R)-3,4,5,6- azepane Y Y

Z tetrahydroxyazepan-2- m one m 770 (3R,4S,5S,6S)- azepane Y Y azepaπe-3,4,5,6-tetraol

771 N-((3R,5R)-3,5- pipeπdine Y Y

C dιhydroxypιpeπdιn-4- ι~ m yl)acetamιde

772 N-((3R,4S,5S)-4,5- pipeπdine Y

N) dιhydroxy-1- O) methylpιperιdιn-3- yl)acetamιde

773 N-((3R,4S,5S)-1-butyl- pipeπdine Y

4,5-dιhydroxypιpeπdιn-

3-yl)acetamιde

774 N-((3R,4S,5S)-4,5- pipeπdine Y dιhydroxy-1- nonylpιpeπdιn-3- yljacetamide

775 N-((3S,5S)-3,5- pipeπdine Y Y dιhydroxy-1- methylpιpeπdιn-4- yl)acetamιde

776 N-((3S,5S)-1-butyl-3,5- pipeπdine Y Y dιhydroxypιpeπdιn-4- yl)acetamιde

111 N-((3S,5S)-3,5- pipeπdine Y Y dιhydroxy-1- nonylpιpeπdιπ-4- yljacetamide

778 N-((3S,4R,5R)-4,5- pipeπdine Y dιhydroxy-1- methylpιperιdιn-3- yl)acetamιde

779 N-((3S,4R,5R)-1 -butyl- pipeπdine Y 4,5-dιhydroxypιpeπdιn-

V) 3-yl)acetamιde

C 780 N-((3S,4R,5R)-4,5- pipeπdine Y

00 dιhydroxy-1-

V) nonylpιpeπdιn-3- yl)acetamιde

H 781 N-((3R,5R)-3,5- pipeπdine Y dιhydroxy-1-

Hm methylpιperιdιn-4- yl)acetamιde 'J

Sg 782 N-((3R,5R)-1-butyl-3,5- pipendine Y Y σ m dιhydroxypιpeπdιn-4- yl)acetamιde

_l 783 N-((3R,5R)-3,5- pipendine Y Y dιhydroxy-1- 73 nonylpιpeπdιn-4- yljacetamide 7⁸⁴ N-((3R,4S,5R)-1-butyl- pipendine 4,5-dιhydroxypιpendιn-

3-yl)acetamιde

2 785 N-((3S,4r,5R)-3,5- pipendine Y dιhydroxypιpeπdιn-4- yl)acetamιde 786 N-((3S,4r,5R)-3,5- pipendine Y dihydroxy-1- methylpιperιdιn-4- yl)acetamιde

787 N-((3S,4r,5R)-1 -butyl- pipendine Y

3,5-dιhydroxypιpendιn-

4-yl)acetamιde 788 (2R,3S,4R,5R)-2- pyrrolidine Y

(hydroxymethyl)-5- methylpyrrolιdιne-3,4- diol

789 N-((3S,4r,5R)-3,5- pipendine dιhydroxy-1- nonylpιperιdιn-4- yljacetamide

790 N-((3R,4R,5S)-3- pipeπdine Y

(benzyloxy)-i -butyl-5- hydroxypιpeπdιn-4- yl)acetamιde

791 (2S,3R,4S,5S)-2- piperidine Y

(hydroxymethyl)pιpeπdι ne-3,4,5-tπol

792 (2R,3R,4R,5S)-1-(5- pipendine Y Y

(adamantan-1-yl- r/j methoxy)-peπtyl)2-

(hydroxymethyl)-

DO pιperιdιne-3,4,5-tnol

C/) 793 (3R,4R,5R,6R)-3,4,5,6- azepane Y

H tetrahydroxyazepan-2- one

C 794 (3R,4R,5R,6R)-1- azepane Y

H nonylazepane-3,4,5,6- m tetraol

C/) 795 (2R,3R,4S,5R)-2- pyrrolidine Y Y

Z benzyl-5- m (hydroxymethyl)pyrrolιdι m ne-3,4-dιol

796 (2S,3S,4R)-2-((R)-1 ,2- pyrrolidine Y dιhydroxyethyl)-1-

C methylpyrrolιdιne-3,4-

|— diol m 797 (2S,3R,4S,5R,6R)- pipendine Y Y Y Y

N) 3,4,5-tπhydroxy-2,6- bιs(hydroxymethyl)pιperι dinium chloride

798 (2S,3R,4R,5R,6R)-2- pipendine Y Y ethyl-6-

(hydroxymethyl)pιpeπdι πe-3,4,5-tπol

799 (2R,3S,4R)-1-benzyl-2- pyrrolidine Y

((S)-1 ,2- dιhydroxyethyl)pyrrolιdιn e-3,4-dιol

800 (1S,2R,7R,7aR)- pyrrol dine Y hexahydro-1 H- pyrrolιzιnθ-1 ,2,7-tπol

801 (2R,3S,4R)-2-((R)-1- pyσolidine Y hydroxyethyl)pyrrolιdιne

-3,4-dιol

802 N-((3S,4R,5R,6R)-4,5- piperidine Y Y dιhydroxy-6-

(hydroxymethyl)pιpeπdι n-3-yl)acetamιde

803 (2S,3S,4R)-2-((S)-2- pyrrolidine fluoro-1- hydroxyethyl)pyrrolιdιne

-3,4-dιol

804 (2S,3R,4R,5S)-1- pyrrolidine Y benzyl-2,5-

C/) bιs(hydroxymethyl)pyrro

C lιdιne-3,4-dιol

DO 805 (1S,2S,3S,5R,8aS)-3- indolizidine Y

V) (hydroxymethyl)-5-

H methyloctahydroindolizi

H ne-1 ,2-dιol

C 806 (2S,3R,4R,5R)-2- pipeπdme Y Y

H (hydroxymethyl)pιpeπdι m ne-3,4,5-tπol 'J

C/) 807 (2R,3R,4R)-1-(4- pyrrolidine Y OC

Z chlorobenzyl)-2- m m (hydroxymethyl)pyrrolιdι ne-3,4-dιol

808 (2R,3R,4R)-2- pyrrolidine Y Y

(hydroxymethyl)-i -(3-

C phenylpropyl)pyrrolιdιne ι— -3,4-dιol m 809 (2R,3R,4S)-2-((R)-1 ,2- pyrrolidine Y Y

N) dιhydroxyethyl)pyrrolιdιn

0) e-3,4-dιol

810 (2R,3R,4S)-1-beπzyl-2- pyrrolidine Y Y

((R)-1 ,2- dιhydroxyethyl)pyrrolιdιn e-3,4-dιol

811 (2R,3R,4R,5S)-2- pipeπdine Y

(hydroxymethyl)-5- methylpιperιdιne-3,4,5- tπol

812 (2S,3R,4R)-1-benzyl-2- pyrrolidine Y

((S)-1 ,2- dιhydroxyethyl)pyrrolιdιn e-3.4-dιol

813 (2S,3R,4R)-2-((S)-1 ,2- pyrrolidine dihydroxyethyl)pyrrolidin e-3,4-dιol

814 (1 R,4S,7R)-2-benzyl- pyrrolidine Y Y

2,5- dιazabιcyclo[22 1]hepta n-7-ol

815 (3S,4S,5S,6S)- azepane Y azepane-3,4,5,6-tetraol

816 (2R,3S,4S)-1-butyl-2- pipeπdine

(hydroxymethyl)pιperιdι ne-3,4-dιol

817 (2R,3S,4R)-2-((R)-1,2- pyrrolidine Y Y

V) dιhydroxyethyl)pyrrolιdιn

C e-3,4-dιol

DO 818 (3R,4S,5R,6R)- azepane Y

C/) azepane-3,4,5,6-tetraol

13 819 (2S,3S,4S)-2- pyrrolidine Y Y

(hydroxymethyl)-1-(3-

H pheπylpropyl)pyrrolιdιne m -3,4-dιol 'J

C/) 820 (2S,3R,4R)-1-butyl-2- pyrrolidine Y

Z «S)-1 ,2- m dιhydroxyethyl)pyrτolιdιn m e-3,4-dιol

821 (2S,3R,4R)-2-((S)-1 ,2- pyrrolidine Y

T dιhydroxyethyl)-1-(2-

^Jl hydroxyethyl)pyrrolιdιne

-3,4-dιol m 822 (2R,3R,4R,5S)-1-hexyl- pipeπdine Y

N) 2- (hydroxymethyl)pιpeπdι ne-3,4,5-tπol

823 (2S,3R,4S)-2- pyrrolidine Y Y

(hydroxymethyl)-1-(4- methoxybenzyl)pyrrolιdι ne-3,4-dιol

824 (3R,4S,5S,6R)- azepane Y azepane-3,4,5,6-tetraol

825 (2R,3S,4S)-1-benzyl-2- pyrrolidine Y

((R)-1 ,2- dιhydroxyethyl)pyrrolιdιn e-3,4-dιol

826 (2R,3S,4S,5R)-2,5- pyrrolidine bιs(hydroxymethyl)pyrro

lιdιne-3,4-dιol

827 N-((3S,4S,5R)-4,5- piperidine Y dιhydroxypιpeπdιn-3- yl)acetamιde 828 N-((3R,4R,5S)-4,5- pipeπdine Y dιhydroxypιpeπdιn-3- yl)acetamιde 829 (1S,2S,3R,6S,9aS)-6- quinolizidin Y methyloctahydro-1 H- e quιnolιzιne-1 ,2,3-tπol

830 N-((3S,4S,5R)-4,5- piperidine Y dιhydroxy-1-

C/) methylpιperιdιn-3-

C yl)acetamιde 00 N-((3S,4S,5R)-4,5- piperidine Y C/) 831 dιhydroxy-1- nonylpιpeπdιn-3- yljacetamide

832 N-((3R,4R,5S)-4,5- piperidine Y m dιhydroxy-1- methylpιperιdιn-3- σ

C/)

Z yl)acetamιde m 833 N-((3R,4R,5S)-1-butyl- pipeπdine Y m 4,5-dιhydroxypιpeπdιn-

3-yl)acetamιde

834 N-((3S,4S,5R)-1-butyl- pipeπdine Y

73 4,5-dιhydroxypιpeπdιn-

C ι~ 3-yl)acetamιde m 835 (3R,4S,5S)-5- pipeπdine Y amιnopιpeπdιnθ-3,4-dιol

N) σ> 836 2-((3R,4r,5S)-3,4,5- pipeπdine Y tπhydroxypιpeπdιn-1- yl)acetonιtπle

837 (3R,4r,5S)-1-(2- piperidine Y hydroxyethyl)pιpeπdιne-

3,4,5-tπol 838 (3R,4r,5S)-1-(2-(2- pipeπdine Y methoxyethoxy)ethyl)pι peπdιne-3,4,5-trιol 839 (2R,3R,4R,5R)-2-((R)- pipeπdine Y

1,2- dιhydroxyethyl)pipeπdιn e-3,4,5-trιol

840 (2R,3R,4S,5R)-2-((R)- pipeπdine Y

1 ,2- dιhydroxyethyl)pιpeπdιn e-3,4 5-tπol

841 (2R,3R,4R,5S)-2- pyrrolidine Y Y

(hydroxymethyl)-5- methylpyrrolιdιne-3,4- diol

842 (2R,3S,4R)-2-((S)-1 ,2- pyrrolidine Y dιhydroxyethyl)-1- methylpyrrolιdιne-3,4- diol

843 (3R,4R,5R)-3- piperidine Y Y

C/) (hydroxymethyl)pιperazι

C ne-4,5-dιol

CD 844 (4R,5R,6R)-6- pipeπdine Y Y

C/) (hydroxymethyl)-i-

H methylpιperazιne-4,5-

H diol

C 845 retronecine N-oxide pyrrol izidine m

846 1-((3R,4R,5R)-4,5- piperidine

\J1 Y Y

T dιhydroxy-3- m (hydroxymethyl)pιperazι m n-1-yl)ethanone

847 (2S,3R,4R,5R)-2-((R)- piperidine Y Y

1 ,2-

73 dιhydroxyethyl)pιpeπdιπ e-3,4,5-trιol m 848 (2R,3S,4S)-2-((R)-1 ,2- pyrrolidine dιhydroxyethyl)pyrrolιdιn σ> e-3,4-dιol

849 (1S,2S,8R,8aS)- indolizidine Y octahydroindohzine-

1 ,2,8-tπol

850 N-((3R,4R,5R,6R)-4,5- pipeπdine Y dιhydroxy-6-

(hydroxymethyl)-2- oxopιpeπdιn-3- yl)acetamιde

851 (2R,3S,4R,5R)-2-((S)- pyσolidine Y Y

1 ,2-dιhydroxyethyl)-5-

(hydroxymethyl)pyrrolιdι ne-3,4-dιol

852 (3R,5R)-1- pipeπdine Y hexylpιpendιne-3,4,5- tπol

853 (3R,4r,5S)-1- pipeπdine Y hexylpιpeπdιne-3,4,5- tπol

854 (1R,2R,3R,7S,7aR)-3- pyσohzidine Y Y

((allylamιno)methyl)hex ahydro-1 H-pyrrolιzιne-

1 ,2,7-tnol

855 2-((1R,2R,3R,7S,7aR)- pyrrolizidiπe Y Y Y Y Y

1 ,2,7- tπhydroxyhexahydro-

C/) 1 H-pyrrolιzιn-3-

C yl)acetonιtπle

DO 856 (3S,5S)-1- pipendine Y Y

C/) hexylpιpeπdιne-3,4,5-

H tπol

H 857 (1R,2R,3R,7S,7aR)-3- pyrrolizidine Y Y Y Y Y Y

C ((benzylamιno)methyl)h exahydro-1 H- m pyrrolιzιne-1 ,2,7-tnol σ

C/) 858 (2R,3S,4R,5S)-1-(2- pipendine Y K.

Z hydraxyethyl)-2- m methylpιpendιne-3,4,5- m tπol

859 (2R,3S,4R,5S)-1-butyl- pipeπdine Y

2-methylpιpeπdιne-

C 3,4,5-tπol ι— 860 (2R,3S,4R,5S)-1-(2-(2- pipeπdine Y m methoxyethoxy)ethyl)-2-

N) methylpιperιdιne-3,4,5- σ> tπol

861 2-((2R,3S,4R,5S)-3,4,5- pipeπdine Y trιhydroxy-2- methylpιperιdιn-1- yl)acetιc acid

862 (2R,3S,4R,5S)-1-(6- pipeπdine hydroxyhexyl)-2- methylpιperιdιne-3,4,5- tπol

863 (2R,3S,4R,5S)-2- pipeπdine methyl-1-(2- morpholιnoethyl)pιpeπdι ne-3,4,5-tnol

864 (2R,3S,4R,5S)-2- pipeπdine Y methyl-1 -(2-(pιpeπdιn-1 - yl)ethyl)pιperιdιne-3,4,5- tπol

865 (2R,3S,4R,5S)-1-(2- pipeπdme Y

(dιmethylamιno)ethyl)-2- methylpιpeπdιne-3,4,5- tπol

866 (2R,3S,4R,5S)-1-(6- pipeπdine Y

(2,5- dιmethylphenoxy)hexyl)

-2-methylpιperιdιne-

3,4,5-tπol r/j 867 (2R,3S,4R,5S)-2- pipβπdine Y

C methyl-1-(6-((1r,4R)-4-

OO methylcyciohexyloxy)he

V) xyl)pιpeπdιne-3,4,5-tnol

H 868 2-((3R,4r,5S)-3,4,5- piperidine Y

H trιhydroxypιpeπdιn-1 -

C yl)acetιc acid

869 N-((3R,4S,5S)-4,5- pipeπdine m Y dιhydroxypιpeπdιn-3-

C/) yl)acetamιde

Z 870 N-((3S,4R,5S)-4,5- pipeπdine Y Y m dιhydroxy-1- m

^ __^| methylpιperιdιn-3- yl)acetamide

73 871 N-((3S,4R,5S)-1-butyl- pipeπdine Y Y

C 4,5-dιhydroxypιpeπdιn- ι— 3-yl)acetamιdβ m 872 (2S,3S,4S,5S)-2-(4- pipeπdine

N) methoxyphenyl)pιpeπdι

S) ne-3,4,5-tπol

873 (2S,3S,4S,5S)-2-(4- pipeπdine hydroxyphenyl)pιpeπdιn e-3,4,5-trιol

874 (2S,3S,4S,5S)-2- pipeπdine phenylpιperιdιne-3,4,5- tπol

876 (2S,4S,5S)-4,5- pipeπdine dιhydroxy-1- nonylpιpeπdιne-2- carboxylic acid

877 (2R,3S,4S,5S)-3,4- pyrrolidine dιhydroxy-5-

(hydroxymethyl)-i- methylpyrrolιdιne-2- carboxylic acid

878 (2R,3S,4S,5S)-1-butyl- pyrrolidine

3,4-dιhydroxy-5-

(hydroxymethyl)pyrrolιdι ne-2-carboxylιc acid

879 (2R,3S,4S,5S)-3,4- pyrrolidine dιhydroxy-5-

(hydroxymethyl)-i- nonylpyrrolιdιne-2-

C/) carboxylic acid

C 880 (2S,3R,4R,5S)-3,4,5- pipeπdme

OO tπhydroxy-1-

V) nonylpιpeπdιne-2-

H carboxylic acid

H 881 (2S,3S,4S,5S)-2,5- pyrrolidine

C bιs(hydroxymethyl)-1-

H methylpyrrolιdιne-3,4- m diol σ

C/) 882 (2S,3S,4S,5S)-1-butyl- pyrrolidine

Z 2,5- m bιs(hydroxymethyl)pyrro m lιdιne-3,4-dιol

883 (2S,3S,4S,5S)-2,5- pyrrolidine bιs(hydroxymethyl)- 1 -

C nonylpyrrolιdιne-3,4-dιol ι— 884 (2S,3R,4R,5S)-1-ethyl- pipeπdine m 3,4,5-

N) tπhydroxypιpeπdιne-2- carboxylic acid

885 (2S,3R,4R,5S)-3,4,5- pipeπdine tπhydroxy-1- propylpιperιdιne-2- carboxylic acid

886 (2S,3R,4R,5S)-3,4,5- pipeπdine tπhydroxy-1- pentylpιperιdιne-2- carboxylic acid

887 (3R,4R,5S)-1-(6- pipeπdine

((1r,4R)-4- methylcyclohexyloxy)he xy1)pιpeπdιne-3,4,5-tnol

888 (2S,3R,4R,5S)-3,4,5- pipeπdiπe tπhydroxy-1- methylpιpeπdιne-2- carboxyhc acid hydrochloride

889 (2S,3R,4R,5S)-1-butyl- pipeπdine

3,4,5- tπhydroxypιpeπdιne-2- carboxylic acid hydrochloride

890 (2S,3R,4R,5S)-3,4,5- pipeπdine y y trιhydroxypιperιdιne-2- carboxamide ry> 891 (2S,3R,4R,5S)-3,4,5- pipeπdine y y

C tπhydroxy-N- 00 methylpιpeπdιne-2- carboxamide d 892 (1 R,2S,3R,5R,8aR)-3- indolizidine

(hydroxyme(hyl)-5- methyloctahydroindolizi ne-1 ,2-dιol m

C/)

Z m m

C ι— m

E. Chemical synthesis

I. General considerations

Generally applicable strategies for the synthesis of iminosugars and iminosugar libraries are described by La Ferla et al. (2007) in "Iminosugars: From synthesis to therapeutic applications", Wiley ISBN 978-0-470-03391-3; Compain and Martin (Eds.) pp25-61. These general techniques find application in the synthesis of a wide range of compounds for use according to the invention, including monocyclics, 1-N-iminosugars, bicyclic compounds and iminosugar conjugates. This disclosure is hereby incorporated herein by reference.

II. Synthesis of iminosugar C-qlycosides

Generally applicable strategies for the synthesis of iminosugar C-glycosides are described by Compain (2007) in "Iminosugars: From synthesis to therapeutic applications", Wiley ISBN 978-0-470-03391-3; Compain and Martin (Eds.) pp63-86. These general techniques find application in the synthesis of a wide range of iminosugar C-glycosides for use according to the invention and the disclosure is hereby incorporated herein by reference.

III. Synthesis of imino-C-disaccharides and analogues

Generally applicable strategies for the synthesis of imino-C-disaccharides and various analogues are described by Vogel et al. (2007) in "Iminosugars: From synthesis to therapeutic applications", Wiley ISBN 978-0-470-03391-3; Compain and Martin (Eds.) pp87-130 the disclosure of which is hereby incorporated herein by reference.

IV. Synthesis of polyhydroxylated iminosugars

The synthesis of polyhydroxylated iminosugars can be carried out by protecting or differentiating the reactivity of the oxygen functions. Bell et al. (1997) Tetrahedron Letters

SUBSTITUTE SHEET (RULE 261 Ib /

38(33): 5869-72 describe the synthesis of four diastereoisomers of casuarine from eight carbon sugar lactones by reduction of open chain azidodimesylates by Suzuki-Takaoka reduction to allow the formation of the pyrrolizidine nucleus by bicyclisation.

Another approach is based on tandem [4+2]/[3+2] nitroalkene cycloadditions. It has been used for the synthesis of several pyrrolizidine and indolizidines iminosugars with up to four contiguous stereogenic centres (see Denmark and Hurd (1999) Organic Letters 1 (8): 1311- 14). The method was later extended by the same workers to the synthesis of (+)-casuarine by the intermolecular [3+2] cycloaddition of a suitable substituted dipolarophile and a flexible, heavily substituted nitronate.

WO2006/008493 (the content of which relating to synthetic schemes for producing iminosugars is hereby incorporated by reference) describes the synthesis of polyhydroxylated pyrrolizidine and indolizidine compounds without protecting all of the free hydroxyl groups, so achieving considerably shortened synthetic schemes. Moreover, the use of intermediates having free hydroxyl groups provides a mechanism for controlling the product distribution, stereospecificity and yield via complex formation at the free hydroxyl groups.

According to WO2006/008493, polyhydroxylated bicyclic (for example pyrrolizidine, indolizidine or quinolizidine) iminosugars can be produced by cyclisation of a pyrrolidine or piperidine intermediate having three or more free hydroxyl groups. The application of a cyclisation step to an intermediate having three or more free hydroxyl groups eliminates the need for selective protection, deprotection and/or activation at these sites.

V. Synthesis of iminosugar acids

The ISAs described herein may be made by conventional methods. Methods of making heteroaromatic ring systems are well known in the art. In particular, methods of synthesis are discussed in Taylor et al. (2005) Tetrahedron: 61 (40) 9611-9617 and in Comprehensive Heterocyclic Chemistry, Vol. 1 (Eds.: AR Katritzky, CW Rees), Pergamon Press, Oxford, 1984 and Comprehensive Heterocyclic Chemistry II: A Review of the Literature 1982-1995 The Structure, Reactions, Synthesis, and Uses of Heterocyclic IbS

Compounds, Alan R. Katritzky (Editor), Charles W. Rees (Editor), E.F.V. Scriven (Editor), Pergamon Pr, June 1996.

Other general resources which would aid synthesis of the compounds of interest include March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley- Interscience; 5th edition (January 15, 2001).

Some exemplary synthetic schemes for producing ISAs for use according to the invention are shown below:

SUBSTITUTE SHEET (RULE 261 Vl. Synthesis of nortropanes

Generally applicable strategies for the synthesis of nortropanes are described by Skaanderup and Madsen (2003) Journal of Organic Chemistry 68(6): 2115-2122 the disclosure of which is hereby incorporated herein by reference.

VII. Synthesis of azepanes

Generally applicable strategies for the synthesis of azepanes are described by Li et al. (2007) Chemical Communications (Cambridge, United Kingdom) (2): 183-185 the disclosure of which is hereby incorporated herein by reference.

VIII. Synthesis of pyrrolidines

Generally applicable strategies for the synthesis of pyrrolidines are described by Rountree et al. (2007) Tetrahedron Letters 48: 4287-4291 and Behr and Guillerm (2007) Tetrahedron Letters 48(13), 2369-2372 the disclosure of which is hereby incorporated herein by reference.

SUBSTITUTE SHEET (RULE 261 IX. Synthesis of piperidines

Generally applicable strategies for the synthesis of piperidines are described by Mane et al. (2008) Journal of Organic Chemistry 73 (8): 3284 -3287 and Rengasamy et al. (2008) Journal of Organic Chemistry 73(7): 2898-2901 the disclosure of which is hereby incorporated herein by reference.

X. Synthesis of pyrrolidines

Generally applicable strategies for the synthesis of pyrrolidines are described in Pyrrolidine Alkaloids, pp617-653, in The Way of Synthesis, Tomas Hudlicky and Josephine W. Reed, 2007, Wiley, ISBN: 978-3-527-31444-7 and by Van Ameijde et al. (2006) Tetrahedron: Asymmetry 17: 2702-2713, the disclosure of which is hereby incorporated herein by reference.

XI. Synthesis of indolizidines

Generally applicable strategies for the synthesis of indolizidines are described in Abrams et a/. (2008) Journal of Organic Chemistry 73 (5): 1935 -1940 and Kumar et al. (2008) Organic & Biomolecular Chemistry 6(4): 703-711 , the disclosure of which is hereby incorporated herein by reference.

XII. Synthesis of quinolizidines

Generally applicable strategies for the synthesis of quinolizidines are described in Pasniczek et al. (2007) Journal of Carbohydrate Chemistry 26(3): 195-211 and Kumar et al. (2008) Organic & Biomolecular Chemistry 6(4): 703-711 , the disclosure of which is hereby incorporated herein by reference.

XIII. Synthesis of 4-membered monocycles

Generally applicable strategies for the synthesis of 4-membered monocycles are described in Evans et al. (2008) Journal of Medicinal Chemistry 51(4): 948-956, the disclosure of which is hereby incorporated herein by reference. XIV. Synthesis of 9-membered monocvcles

Generally applicable strategies for the synthesis of 9-membered monocycles are described in Leonard and Swann (1952) Journal of the American Chemical Society 74: 4620-4, the disclosure of which is hereby incorporated herein by reference.

XV. Synthesis of 10-membered monocvcles

Generally applicable strategies for the synthesis of 10-membered monocycles are described by Arata and Kobayashi (1972) Chemical & Pharmaceutical Bulletin 20(2): 325- 9, the disclosure of which is hereby incorporated herein by reference.

XVI. Synthesis of 4,6 fused bicyclics

Generally applicable strategies for the synthesis of 4,6 fused bicyclics are described in Pandey et al. (2006) Tetrahedron Letters 47(45): 7923-7926, the disclosure of which is hereby incorporated herein by reference.

XVII. Synthesis of 4.7 fused bicvclics

Generally applicable strategies for the synthesis of 4,7 fused bicyclics are described in Alcaide and Saez (2005) European Journal of Organic Chemistry (8): 1680-1693, the disclosure of which is hereby incorporated herein by reference.

XVIII. Synthesis of 5,7 fused bicvclics

Generally applicable strategies for the synthesis of 5,7 fused bicyclics are described in Bande et al. (2007) Tetrahedron: Asymmetry 18(10): 1176-1182, the disclosure of which is hereby incorporated herein by reference.

XIX. Synthesis of 1,2 piperazines

Generally applicable strategies for the synthesis of 1 ,2-piperazines are described in Ernholt et al. (1999) Synlett. 701-704, Liang et al (1999) J. Org. Chem., 64 (23), 8485-8488, Ernholt et al. (2000) Chem. Eur. J., 6(2) 278-287, Jensen et al. (2001) J. Chem. Soc, Perkin Trans. 1 , 905 - 909 and Jensen et al. (2002) J. Chem. Soc, Perkin Trans. 1 , 1190- 1198 the disclosure of which is hereby incorporated herein by reference.

F. Purification from botanic sources

I. General

Botanic and microbial sources for a wide range of different iminosugars are described in Watson et al. (2001) Phytochemistry 56: 265-295. lminosugar acids also have a wide distribution in plants such as in Stevia, Gymnema, Citrus, Lycium species, leguminous spp.e.g. Aspalanthus linearis (Rooibos), Lotus species and Castanospermum australe ' (Fabaceae), Cucurbitaceae species and Andrographis paniculata (Acanthaceae). The distribution of iminosugar acids in microorganisms is not known but they are likely to be present.

II. Purification of iminosugars and iminosugar acids from botanic sources

The compounds described herein for use according to the invention may be isolated from natural sources. For example, plant material from botanic sources such as Stevia species can be used as starting material for the isolation and purification of both iminosugars and iminosugar acids for use according to the invention. Microorganisms such as Bacillus, Streptomyces and Metarrhizium species can be used for isolation of iminosugars. The natural iminosugars and iminosugar acids of the invention are water-soluble and can be concentrated by using strongly acidic cation exchange resins to which they bind with the iminosugar acids then concentrated subsequently by binding them to strongly basic anion exchange resins. The iminosugars are not strongly retained on the anion exchange resins whereas the iminosugar acids are. Purification of the iminosugars and iminosugar acids can then be achieved by using a series of cation and anion exchange resins selected by those experienced in the art. Size exclusion methods can also be used to concentrate them. Thus, it will be appreciated that those skilled in the art can readily purify and isolate the iminosugar and iminosugar acids of the invention using standard techniques.

Adjunctive agents for use with the compounds of the present invention I. General

In addition to the compound and/or imino sugar of the invention, the invention also contemplates the use of one or more of the following adjunctive agents as further components of the invention.

Thus, the invention provides compositions comprising the compound of the invention in combination with one or more adjunctive agents selected from those described below.

II. Antiviral adjunctive agents

(a) General

The combinations preferably further comprise one or more auxiliary antiviral agent(s). Such auxiliary antiviral agents may be selected from one or more of: (a) viral enzyme inhibitors (for example selected from (i) protease inhibitors, (ii) helicase inhibitors and (iii) polymerase inhibitors); (b) nucleoside/nucleotide reverse transcriptase inhibitors; (c) non- nucleoside reverse transcriptase inhibitors; (d) integrase inhibitors; (e) maturation inhibitors; (f) cytokines or cytokine stimulatory factors; (g) viral entry inhibitors, for example selected from: (i) an attachment inhibitor; (ii) a co-receptor binding inhibitor; and (iii) a membrane fusion inhibitor.

The use of adjunctive agents is particularly advantageous in the case where the invention is applied to the treatment of infection with HCV (Hepatitis C). Thus, in another aspect, the invention provides a composition comprising a compound of the invention in combination with: (a) compounds which inhibit the binding to and/or infection of cells by HCV. These include antibodies (e.g. monoclonal antibodies) against, for example, HCV E1 and/or E2 proteins) and glucosaminoglycans (such as heparan sulphate and suramin); (b) compounds which inhibit the release of viral RNA from the viral capsid or the function of HCV gene products, including inhibitors of the IRES, protease (e.g. serine protease) inhibitors, helicase inhibitors and inhibitors of the viral polymerase/replicase; (c) compounds which perturb cellular functions involved in or influencing viral replication, including inhibitors of inosine monophosphate dehydrogenase (e.g. Ribavirin, mycophenolic acid and VX497) and inhibitors of glycoprotein processing such as DNJ and its derivatives; (d) compounds which act to alter immune function (e.g. thymosin alpha and interferons such as α interferons and β interferons) and (e) compounds which act to modulate the symptoms and effects of HCV infection (e.g. antioxidants such as the flavinoids).

In addition the invention provides a composition comprising a compound of the invention in combination with compounds used in the treatment of frequently found co-infections (such as hepatitis B virus and the human retroviruses such as human immunodeficiency viruses types 1 and 2 and human T-cell lymphotrophic viruses types 1 and 2). Examples of such compounds include nucleotide/nucleoside RT inhibitors (e.g. Lamivudine (3TC), zidovudine, stavudine, didanosine, adefovir dipivoxil and abacavir), non-nucleoside RT inhibitors (e.g. nevirapine) and and protease inhibitors (e.g. saquinavir, indinavir and ritonavir).

Preferably, the interferon is interferon-α (IFN-α), though other interferons may also be used (for example an interferon produced by expression of a cloned human interferon gene).

The use of adjunctive agents is also particularly advantageous in the case where the invention is applied to the treatment of HIV infection (AIDS). In the following list, the trade name, the various generic name(s) and drug code(s) are listed, together with the manufacturing pharmaceutical company.

(b) Protease Inhibitors (PIs)

One or more of the following protease inhibitors may be used:

(a) Agenerase® amprenavir APV 141 W94 or VX-478 (GlaxoSmithKline)

(b) Aptivus® tipranavir TPV PNU-140690 (Boehringer Ingelheim)

(c) Crixivan® indinavir IDV MK-639 (Merck & Co)

(d) Fortovase® saquinavir (Soft Gel Cap) SQV (SGC) (Hoffmann-La Roche) (e) Invirase® saquinavir SQV Ro-31-8959 (Hoffmann-La Roche)

(f) Kaletra® lopinavir + ritonavir LPV ABT-378/r (Abbott Laboratories)

(g) Lexiva® fosamprenavir FPV GW-433908 or VX-175 (GlaxoSmithKline) (h) Norvir® ritonavir RTV ABT-538 (Abbott Laboratories)

(i) Reyataz® atazanavir ATZ BMS-232632 (Bristol-Myers Squibb) (j) Viracept® nelfinavir NFV AG-1343 (Pfizer) (k) Brecanavir™ GW640385 or VX-385 (GlaxoSmithKline) (I) Darunavir™ TMC-114 (Tibotec)

(c) Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

One or more of the following NRTIs may be used:

(a) Combivir® zidovudine + lamivudine AZT + 3TC (GlaxoSmithKline)

(b) Emtriva® emtricitabine FTC (Gilead Sciences)

(c) Epivir® lamivudine 3TC (GlaxoSmithKline) (d) Epzicom™ abacavir + lamivudine ABC + 3TC (GlaxoSmithKline)

(e) Hivid® zalcitabine ddC (Hoffmann-La Roche)

(f) Retrovir® zidovudine AZT or ZDV (GlaxoSmithKline)

(g) Trizivir® abacavir + zidovudine + lamivudine ABC + AZT + 3TC (GlaxoSmithKline) (h) Truvada® tenofovir DF + emtricitabine TDF + FTC (Gilead Sciences) (i) Videx® didanosine: buffered versions ddl BMY-40900 (Bristol-Myers Squibb)

O-) Videx® EC didanosine: delayed-release capsules ddl (Bristol-Myers Squibb)

(k) Viread® tenofovir disoproxil fumarate (DF) TDF or Bis(POC) PMPA (Gilead Sciences)

(I) Zerit® stavudine d4T BMY-27857 (Bristol-Myers Squibb) (m) Ziagen® abacavir ABC 1592U89 (GlaxoSmithKline)

(n) Reverset™ dexelvucitabine DFC (Pharmasset and Incyte)

(o) Alovudine™ MIV-310 (Boehringer Ingelheim)

(p) Amdoxovir™ DAPD (Gilead Sciences)

(q) Elvucitabine™ Beta-L-Fd4C ACH-126,443 (Achillion Pharmaceuticals)

(d) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

One or more of the following NNRTIs may be used:

(a) Rescriptor® delavirdine DLV U-90152S/T (Pfizer) (b) Sustiva® efavirenz EFV DMP-266 (Bristol-Myers Squibb)

(c) Viramune® nevirapine nivirapine NVP BI-RG-587 (Boehringer Ingelheim)

(d) (+)-calanolide A (Sarawak Medichem)

(e) etravirine TMC-125 (Tibotec)

(f) TMC-278 (Tibotec) (g) BMS-561390 or DPC-083 (Bristol-Myers Squibb) (e) Immune-Based Therapies

One or more of the following may also be used: (a) Proleukin® aldesleukin, or lnterleukin-2 IL-2 (Chiron Corporation)

(b) Remune® HIV-1 Immunogen, or SaIk vaccine AG1661 (The Immune Response Corporation)

(c) One or more interferons.

(f) Other Classes of Anti-HIV Drugs

(a) lntegrase Inhibitors: e.g. MK-0518 (Merck & Company)

(b) Maturation Inhibitors: e.g. PA-457 (Panacos Pharmaceuticals)

(c) Cellular Inhibitors: e.g. Droxia® hydroxyurea HU (Bristol-Myers Squibb)

(g) Viral entry inhibitors

Viral entry is an attractive target for therapeutic or prophylactic intervention, since drug activity is independent of intracellular access. The extracellular site of action renders such agents unsusceptible to cellular efflux transporters that lower the intracellular concentration of other classes of antiviral drugs and is thought to confer a low toxicity profile. Moreover, the distinct site of action relative to intracellularly-acting agents in other classes minimizes cross-resistance when entry inhibiting drugs are used with such other classes.

Each of the three discrete steps of viral entry described infra (attachment, co-receptor binding and fusion) represents a unique drug target and a large number of drugs have now been developed in each class.

For example, and in the case of HIV-1 , several attachment inhibitors have been produced that block the binding of gp120 to the CD4 receptor and a number are in pre-clinical or clinical development (including BMS-806, BMS-043, PRO 2000, TNX-35525 and PRO 542). Agents that act as chemokine co-receptor binding inhibitors are in various stages of development. These inhibitors include those that block the CCR5 receptor (e.g. TAK-779, SCH-C and SCH-D, PRO-140, UK-427 (Maraviroc™ , Celsentri™), GW873140 and AMD887) and others which block the CXCR4 receptor (e.g. AMD310039 and AMD070). The third and final step in the viral entry process, fusion, is particularly attractive as a target, since it combines a virus-specific target with an extracellular mode of action. Toxicity is therefore likely to be inherently lower because the target is exclusively viral and elements of the host cell receptor systems (in the case of HIV-1 , elements of the host immune system) are not targeted.

Fusion inhibitors can be designed as peptide mimetics of an essential region within viral fusion proteins that block the structural rearrangements by forming a complex with the pre- fusion conformation so preventing adoption of the post-fusion conformation and blocking membrane fusion. The first fusion inhibitor to be approved for clinical use is Enfuvirtide™ (FUZEON™, formerly known as T-20 or DP178), which blocks the entry of HIV-1. Enfuvirtide is a peptide homologous to a segment of the HR2 region of gp41 and binds to the HR1 region, so blocking the formation of the six-helix bundle necessary for fusion. Enfuvirtide exhibits potent and selective inhibition of HIV-1 both in vitro and in vivo.

Other fusion inhibitors include T-1249 (a slightly longer peptide than Enfuvirtide™) which is active against HIV-1 and HIV-2 as well as simian immunodeficiency virus. Several other fusion inhibitor therapeutics have been developed, most of them being peptide mimetics. These include T-649 (which blocks hairpin structure formation in a similar way to Enfuvirtide™; C34 peptide; D-peptide, a cyclic molecule designed to bind pocket region within the six-helix structure, DP-107 and DP-178. Other fusion inhibitors include 5-helix and RPR103611 , a non-peptide triterpene compound that targets the loop region linking the two halves of the gp41 leucine zipper so disrupting the association of gp120-gp41 in CXCR4-tropic HIV viruses.

In embodiments where HIV infection (AIDS) is treated or prevented by the compounds of the invention, two or more auxiliary antiviral agents independently selected from two or more distinct classes (viz. PIs, NRTIs and NNRTIs) are preferably used. Thus, if desired, a glycosylation modulator and a membrane fusion inhibitor may be used in further combination with other anti-HIV therapeutics such as, but not limited to, zidovudine, lamivudine, nelfinavir, indinavir and efavirenz.

In embodiments where HIV infection (AIDS) is treated or prevented by the compounds of the invention, the use of the combinations of the invention may advantageously form part of a HAART or E-HAART treatment regimen (combination of several (typically three or four) antiretroviral drugs is known as Highly Active Anti-Retroviral Therapy (HAART). Where one or more of these drugs acts extracellularly, then the regimen is known as E-HAART).

III. Antibacterial adjunctive agents

The compounds of the invention may be used in combination with various antibacterial agents, including, but not limited to one or more antibiotic(s) selected from the following:

• Aminoglycosides (for example amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin and paromomycin).

• Ansamycins (for example geldanamycin and herbimycin).

• Carbacephems (for example loracarbef).

• Carbapenems (for example ertapenem, doripenem, imipenem/cilastatiή and meropenem) • Cephalosporins (first generation), including for example cefadroxil, cefazolin, cefalotin/cefalothin and cephalexin).

• Cephalosporins (second generation), including for example cefaclor, cefamandole, cefoxitin, cefprozil and cefuroxime.

• Cephalosporins (third generation), including for example cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone and cefdinir.

• Cephalosporins (fourth generation), including for example cefepime.

• Glycopeptides (for example vancomycin and teicoplanin).

• Macrolides (for example azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin and spectinomycin).

• Monobactams (for example aztreonam).

• Penicillins (for example amoxicillin, ampicillin, azlocillin, carbenicillin, cloxaciilin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, penicillin, piperacillin and ticarcillin).

• Polypeptides (for example bacitracin, polymixin B and colistin). • Quinolones (for example ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin and trovafloxacin).

• Sulfonamides (for example mafenide, prontosil, sulfacetamide, sulfamethizole, sulfanamide, sulfasalazine, sulfisoxazole, trimethoprim, trimethoprim- sulfamethoxazole (co-trimoxazole, TMP-SMX)). W 2

179 ^'

• Tetracyclines (for example demeclocycline, doxycycline, minocycline, oxytetracycline and tetracycline).

• Aminocoumarins (for example novobiocin, albamycin, coumermycin and clorobiocin). • Oxazolidinones (for example linezolid and AZD2563).

Other suitable antibiotics useful as adjunctive agents include one or more antibiotic(s) selected from the following: arsphenamine, chloramphenicol, clindamycin, lincoamycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, metronidazole, mupirocin, nitrofurantoin, platensimycin, pyrazinamide, quinupristin/dalfopristin, rifampin/rifampicin and tinidazole.

Thus, the compounds of the invention may be used in combination with one or more antibiotics selected from: penicillin, cloxacillin, dicloxacillin, methicillin, nafcillin, oxacillin, ampicillin, amoxicillin, bacampicillin, capreomycin, cycloserine, azlocillin, carbenicillin, mezlocillin, piperacillin, ticarcillin, azithromycin, clarithromycin, clindamycin, erythromycin, lincomycin, demeclocycline, doxycycline, ethambutol, ethionamide, minocycline, oxytetracycline, tetracycline, quinolone, cinoxacin, nalidixic acid, fluoroquinolones (for example levofloxacin, moxafloxacin and gatifloxacin, ciprofloxacin, enoxacin, grepafloxacin), kanamycin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, p- aminosalicylic acid, sparfloxacin, trovafloxacin, bacitracin, colistin, polymyxin B, sulfonamide, trimethoprim- sulfamethoxazole, co-amoxyclav, cephalothin, cefuroxime, ceftriaxone, vancomycin, gentamicin, amikacin, metronidazole, chloramphenicol, streptomycin, nitrofurantoin, co- trimoxazole, rifamycin and derivatives thereof (for example rifampicin, rifabutin and rifapentine), isoniazid, pyrazinamide, kirromycin, thiostrepton, micrococcin, fusidic acid, thiolactomycin and fosmidomycin.

Other suitable antibacterial adjunctive agents may be selected from those listed in the table below:

IV. Antifungal adjunctive agents

The compounds of the invention may be used in combination with various antifungal agents (antimycotics).

For example, the compounds of the invention may be used in combination with an antifungal adjunctive agent selected from:

(a) a griseofulvin

(b) an azole (e.g. an imidazole or triazole);

(c) a polyene;

(d) an allylamine (e.g. terbinafine);

(e) a candin (e.g. caspofungin, micafungin and anidulafungin); and

(f) a morpholine (e.g. amorolfine).

Particularly preferred are adjunctive antimycotics selected from: imidazoles (such as miconazole, ketoconazole and clotrimazole); triazoles (such as fluconazole, posaconazole, voriconazole and ravuconazole, azaconazole, bromuconazole bitertanol, propiconazole, difenoconazole, diniconazole, cyproconazole, epoxiconazole, fluquinconazole, flusilazole.flutriafol, hexaconazole, itraconazole, imazalil, imibenconazole, ipconazole, tebuconazole, tetraconazole, fenbuconazole, metconazole, myclobutanil, perfurazoate, penconazole, pyrifenox, prochloraz, terconazole, triadimefon, triadimenol, triflumizole, and triticonazole).

Preferred adjunctive antimycotics for use with the compounds of the invention include fluconazole, itraconazole, ketoconazole, posaconazole, ravuconazole, voriconazole, clotrimazole, econazole miconazole, oxiconazole, sulconazole, terconazole, tioconazole, nikkomycin Z, caspofungin, micafungin (FK463), anidulafungin (LY303366), amphotericin B (AmpB), AmpB lipid complex, AmpB colloidal dispersion, liposomal AmpB, liposomal nystatin, nystatin, pimaricin, lucensomycin, griseofulvin, ciclopirox olamine, haloprogin, tolnaftate, undecylenate, gentamicin, amikacin, kanamycin, framycetin, neomycin, netilmicin, streptomycin, tobramycin, silver sulfadiazine, sodium sulfacetamide, sulfamethoxazole, sulfanilamide sulfasalazine, sulfisoxazole, trimethoprim, sulfamethoxazole, triple sulfa, amrolfine, fenpropimorph, butenafine and flucytosine.

Yet other preferred adjunctive antimycotics for use according to the invention include, but are not limited to: amorolfine; ciclopiroxolamine; flucytosine; griseofulvin; haloprogrin; potassium iodide sodium pyrithione; undecylenic acid; imidazole derivatives (including without limitation bifonazole, butoconazole, clotrimazole, econazole, ketoconazole, miconazole, oxiconazole and sulconazole); allylamines (including without limitation naftifine and terbinafine); polyene antifungal antibiotics (including amphotericin B and nystatin) and antifungal organic acids (including without limitation benzoic acid, salicylic acid, propionic acid, and caprylic acid).

V. Antiprotozoal adjunctive agents

The compounds of the invention may be used in combination with various antiprotozoal agents, including but not limited to, chloroquine, doxycycline, mefloquine, metronidazole, eplomithiηe, furazolidone, hydroxychloroquine, iodoquinol, pentamidine, mebendazole, piperazine, halofantrine, primaquine, pyrimethamine sulfadoxine, doxycycline, clindamycin, quinine sulfate, quinidine gluconate, quinine dihydrochloride, hydroxychloroquine sulfate, proguanil, quinine, clindamycin, atovaquone, azithromycin, suramin, melarsoprol, eflomithine, nifurtimox, amphotericin B, sodium stibogluconate, pentamidine isethionate, trimethoprim- sulfamethoxazole, pyrimethamine and sulfadiazine. Vl. Other adjunctive agents

The compounds of the invention may be co-administered with a variety of other co- therapeutic agents which treat or prevent side effects arising from the antiinfective treatment and/or presenting as sequelae of the infection. Adjunctive agents of this type may or may not have antiinfective activity.

For example (and particularly in the treatment of HIV infection (AIDS)), co-therapeutic agents which treat or prevent any of the following side effects may be used as part of the same treatment regimen as the compounds of the invention: (a) lipodystrophy and wasting; (b) facial lipoatrophy; (c) hyperlipidemia; (d) fatigue; (e) anemia; (f) peripheral neuropathy; (g) nausea; (h) diarrhoea; (i) hepatotoxicity; (j) osteopenia and (k) osteoporosis.

The compounds of the invention may be co-administered with a variety of antimicrobial agents as co-therapeutic agents which treat or prevent opportunistic infections arising from the anti-viral treatment and/or presenting as sequelae of the viral infection. For example (and particularly in the treatment of HIV infection (AIDS), antimicrobial agents which treat or prevent bacterial, fungal, metazoan or protozoan infections may be used as part of the same treatment regimen as the compounds of the invention.

The adjunctive agent for use according to the invention may be a glycosylation inhibitor. Any agent which can alter N-linked or O-linked oligosaccharide structures on viral glycoproteins (particularly viral envelope glycoproteins) can be used in the combinations of the invention. Preferred glycosylation modulators are pharmaceutical agents which alter (e.g. eliminate, truncate or debranch) N-linked or O-linked oligosaccharide structures on viral envelope glycoproteins. Most preferably, the glycosylation modulator is a glycosylation inhibitor. The glycosylation inhibitors of the invention may eliminate, truncate or debranch oligosaccharide structures on viral envelope proteins.

The glycosylation modulators may modulate the activity of one or more glycosidase(s). Preferred are glycosylation inhibitors which inhibit the activity of one or more glycosidase(s). Particularly preferred are glycosylation modulators or inhibitors which modulate or inhibit the activity of glycosidase I (particularly glucosidase I). Particularly preferred glycosylation inhibitors for use in the combinations of the invention are glycovirs, and more particularly glucovirs (as described and defined herein)

Glycosylation modulators may be identified by standard enzymological assay. Preferred are agents which specifically inhibit ER α-glucosidases (for example, which specifically inhibit ER α-glucosidase I and/or ER α-glucosidase II, relative to other mammalian , glycosidase enzymes). Most preferably, the glycosylation modulators of the invention inhibit ER α-glucosidase I and/or ER α-glucosidase Il with a degree of specificity such that gastrointestinal toxicity via disaccharidase inhibition on administration at antiviral concentrations in humans is absent (or present at clinically acceptable or subtoxic levels).

The preferred glycosylation modulators for use according to the invention are commonly derived from plants or microorganisms. Novel sugars have been synthesised and naturally occurring ones have also been modified. The common structural feature is that they are analogues of monosaccharides with the ring oxygen replaced by nitrogen. They include polyhydroxylated derivatives of piperidine (netromycin, deoxynojiromycin, N- butyldeoxynojiromycin, deoxymannojiromycin), pyrrolidines (DMDP, LAB), indolizidines (swainsonine, castanospermine, 6-O-butanoylcastanospermine) and pyrolizidines (Australine).

It is conjectured that the mechanism of action of the glycosylation modulators in HIV-1 infection is that of glucosidase I inhibition. A number of imino sugars are inhibitors of glucosidase I in vitro and also act as anti-HIV-1 agents, whereas mannosidase inhibitors, such as deoxymannojiromycin and swainsonine, display no anti-viral activity. There is structural evidence that glucosidase I inhibition occurs at the in vitro anti-viral concentration of 0.5 mM Bu-DNJ (Karlsson et al., (1993), J. Biol. Chem., 268: 570-576). Recombinant gp120/gp41 was expressed in CHO cells with Bu-DNJ present at 0.5 mM. The gp120 produced contained altered N-linked oligosaccharide structures with the terminal sequence Glcα1 ,2Glcα1 ,3Glcα1 ,3 being present. The three structures found on gp120 were Glc₃Man₉, Glc₃Man₈ and Glc₃Man₇. Other experiments have more directly suggested inhibition of the post-virion binding membrane fusion event as the anti-HIV mechanism of the imino sugars (Gruters et al., (1987), Nature, 330: 74-77; Walker et al., (1987), Proc. Nat. Acad. ScL, 84: 8120-8124). Virus particles produced in the presence of both castanospermine and deoxynojiromycin (two imino sugars related to Bu-DNJ) could still bind to the HIV-1 receptor CD4, but the infectivity of virions was reduced. This implicates the inhibition of a post-CD4 binding event, such as the necessary membrane fusion event.

Thus, the compounds of the present invention may be used in combination with an adjunctive agent selected from one or more of: Bu-DNJ and 6-BuCS (BuCast), in combination with a membrane fusion inhibitor which interferes with, modulates or otherwise has a biological effect on post virion-binding membrane fusion events. Such compounds which modulate fusion events include, but are not limited to, Enfuvirtide. The biological effect of co-administration of, for instance, Bu-DNJ and Enfuvirtide may be synergistic.

The treatment or prophylaxis may comprise the administration of a compound as defined herein as an adjunctive to one or more of the following treatments or interventions:

(a) Cancer therapy; (b) AIDS therapy;

(c) Immunosuppressive interventions;

(d) Post-transplantation graft/implant management;

(e) Onychomycotic nail surgery or debridement;

(f) Topical antimycotic therapy (for example with an antimycotic agent selected from azoles, allyiamines (e.g. terbinafine) or a morpholine (e.g. amorolfine);

(g) Systemic antimycotic therapy; (h) Antibacterial therapy;

(i) Antiviral therapy;

G) Anti-inflammation therapy (e.g. with steroids); (k) Analgesic administration;

(I) Antipruritic administration; or (m)Skin grafting.

Thus, the invention may comprise the treatment or prophylaxis of a patient population in which one or more of the treatment or interventions (a) to (m) are being (or have been) carried out.

VII. Adjunctive treatments The treatment or prophylaxis may comprise the administration of a compound as defined herein as an adjunctive to one or more of the following treatments or interventions:

I . Cancer therapy; 2. Immunosuppressive interventions;

3. lmmunostimulatory interventions;

4. Post-transplantation graft/implant management;

5. Onychomycotic nail surgery or debridement;

6. Anti-inflammation therapy (e.g. with steroids); 7. Analgesic administration;

8. Antipruritic administration;

9. Surgery;

10. Cell or tissue ablation;

I 1. Radiotherapy; 12. Cryotherapy; or

13. Skin grafting.

Thus, the invention may comprise the treatment or prophylaxis of a patient population in which one or more of the treatment or interventions (1) to (13) are being (or have been) carried out.

Infectious agent and disease targets of the compounds of the invention

I. General

The compounds of the present invention may have antiinfective (e.g. pathostatic or pathocidal) activity against any infective agent. The compounds of the invention may therefore target (i.e. have activity against) a wide range of different infectious agents. Thus, the invention finds broad application in the treatment or prevention of any infection or infectious disease, including infectious diseases in which viral, bacterial, fungal, protozoal, prion or metazoan agents are implicated.

Thus, the invention finds broad application in the treatment or prevention of viral infection; the treatment or prevention of bacterial infection; the treatment or prevention of protozoal infection; the treatment or prevention of fungal infection; the treatment or prevention of prion infection; and/or the treatment or prevention of metazoan (e.g. helminth) infection or infestation. The compounds of the invention may also find application in the treatment or prevention of chroni, dormant or latent viral, bacterial, protozoal, fungal, prion or metazoan (e.g. helminth) infections or infestations.

• Viral targets are discussed in detail in a separate section below, and so include the following viruses (or virus classes): Retroviridae (e.g. the human immunodeficiency viruses, including HIV-1); Picornaviridae (e.g. polio viruses, hepatitis A virus; enteroviruses, human Coxsackie viruses, rhinoviruses, echoviruses); Calciviridae (e.g. strains that cause gastroenteritis); Togaviridae (e.g. equine encephalitis viruses, rubella viruses); Flaviridae (e.g. dengue viruses, encephalitis viruses, yellow fever viruses); Coronoviridae (e.g. coronaviruses); Rhabdoviradae (e.g. vesicular stomatitis viruses, rabies viruses); Filoviridae (e.g. ebola viruses); Paramyxoviridae (e.g. parainfluenza viruses, mumps virus, measles virus, respiratory syncytial virus); Orthomyxoviridae (e.g. influenza viruses); Bungaviridae

(e.g. Hantaan viruses, bunga viruses, phleboviruses and Nairo viruses); Arena viridae (hemorrhagic fever viruses); Reoviridae (e.g. reoviruses, orbiviurses and rotaviruses); Birnaviridae; Hepadnaviridae (Hepatitis B virus); Parvoviridae (parvoviruses); Papovaviridae (papilloma viruses, polyoma viruses); Adenoviridae (most adenoviruses); Herpesviridae (herpes simplex virus (HSV) 1 and 2, varicella zoster virus, cytomegalovirus (CMV), herpes virus; Poxviridae (variola viruses, vaccinia viruses, pox viruses); and Iridoviridae (e.g. African swine fever virus); and unclassified viruses (e.g. the etiological agents of Spongiform encephalopathies, the agent of delta hepatitis (thought to be a defective satellite of hepatitis B virus), the HCV virus (causing non-A, non-B hepatitis); Norwalk and related viruses, and astroviruses). Of the foregeoing, particularly preferred are HIV, Hepatitis A, Hepatitis B, Hepatitis C, rabies virus, poliovirus, influenza virus, meningitis virus, measles virus, mumps virus, rubella, pertussis, encephalitis virus, papilloma virus, yellow fever virus, respiratory syncytial virus, parvovirus, chikungunya virus, haemorrhagic fever viruses and Herpes viruses, particularly, varicella, cytomegalovirus and Epstein-Barr virus.

• Bacterial targets are discussed in detail in a separate section below, and so include both Gram-negative and Gram-positive bacteria. Examples of bacteria which may be targeted by the compounds of the invention include but are not limited to: Helicobacter pylori, Borelia burgdorferi, Legionella pneumophilia, Mycobacterium spp (e.g. M. tuberculosis, M. leprae, M. avium, M. intracellular, M. kansaii and M. gordonae), Staphylococcus aureus, Neisseria gonorrhoeae, Neisseria meningitidis, Listeria monocytogenes, Streptococcus pyogenes (Group A Streptococcus), Streptococcus agalactiae (Group B Streptococcus), Streptococcus viridans,

Streptococcus faecalis, Streptococcus bovis, any anaerobic species of the genus Streptococcus, Streptococcus pneumoniae, Campylobacter spp., Enterococcus spp., Haemophilus influenzae, Bacillus anthracis, Corynebacterium spp. (including C. diphtheriae), Erysipelothrix rhusiopathiae, Clostridium perfringens, Clostridium tetani, Enterobacter aerogenes, Klebsiella spp (including K. pneumoniae),

Pasturella multocida, Bacteroides spp., Fusobacterium nucleatum, Streptobacillus monilijormis, Treponema pallidium, Treponema pertenue, Leptospira spp., Rickettsia spp. and Actinomyces spp. (including A. israelii).

• Fungal targets are discussed in detail in a separate section below, and so include but are not limited to Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, Chlamydia trachomatis and Candida albicans.

• Protozoal targets include but are not limted to Plasmodium spp. (including

Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale and Plasmodium vivax), Toxoplasma spp. (including T. gondii and T. cruzii), Leishmania spp., Cryptosporidium spp. (including C. parvum), Cyclospora spp. (including C. cayetanensis), Entamoeba (including E. histolytica) and Giardia spp. (including G. lamblia).

• Metazoan targets include parasites or pathogens, such as helminths (e.g. Schistosoma spp.).

Thus, it can be seen that the compositions and vaccines of the invention find application in the treatment or prophylaxis of various infections, including bacterial, viral, fungal, protozoan and metazoan infections. For example, the vaccines may be used in the treatment or prophylaxis of infection with respiratory syncytial virus (RSV)₁ Epstein-Barr, hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex type 1 and 2, herpes genitalis, herpes keratitis, herpes encephalitis, herpes zoster, human immunodeficiency virus (HIV), influenza A virus, hantann virus (hemorrhagic fever), human papilloma virus (HPV), tuberculosis, leprosy and measles. Particularly preferred is the treatment or prophylaxis of infections in which the pathogen occupies an intracellular compartment or causes the expression of neoantigens by host cells, including HIV/AIDS, leishmania, influenza, tuberculosis and malaria.

Certain microbial compounds produced during infection can arrest dendritic cells (DCs) in their immature state and/or instruct (or prime) them on maturation to initiate an immune response that is polarized towards a T_REG type. The resultant immunological tolerance benefits the pathogen and can permit chronic infection. Many eukaryotic pathogens (including protozoa, helminths, fungi and ectoparasites) can act in this way.

Examples of pathogens which subvert the host immune response by arresting DCs in the immature state or otherwise inhibiting DC activation or function include Plasmodium falciparum (by binding to CD36 and CD52), Mycobacterium spp. (which can bind to DC- SIGN via mannosylated lipoarabinomannan), hepatitis C virus (HCV), herpes simplex virus (HSV), cytomegalovirus, Bacillus anthracis, lymphocytic choriomeningitis virus (LCMV), lymphocytic choriomeningitis virus (LCMV) and lymphocytic choriomeningitis virus (LCMV). Examples of pathogens which instruct or prime DCs to initiate an immune response that is polarized towards a T_REG type include Bordatella pertussis and Schistosoma mansoni.

The invention may therefore find application in the treatment of chronic infection or infestation caused by any of the foregoing pathogens.

Certain pathogens may also induce neutropenia. Neutrophils are short lived, professional phagocytic cells which are important in host resistance to microbial invasion. They play a protective role in challenges by Candida albicans, Salmonella enteric subspecies, Tyhipimurium, Yersinia enterocolitica, Chlymadia trachomatis and Toxoplasma gondii. Some of these are known to have rhamnose as a key cell wall component. Neutropenia - depleted levels of circulating neutrophils - is a risk associated with the above mentioned infections. Evidence has shown that impaired protective acquired immunity is correlated to neutropenia, hence the importance of neutrophil presence during immune responses. During infection with Toxoplasma gondii, for example, neutrophil depletion leads to impaired immunity and lethal systemic pathology (Bennouna et ai, 2003). Thus, the invention finds application in the treatment or prophylaxis of pathogen-mediated neutropenia, for example in the treatment or prophylaxis of the clinical sequelae of infection with a pathogen selected from Candida albicans, Salmonella enteric subspecies, Tyhipimurium, Yersinia enterocolitica, Chlymadia trachomatis and Toxoplasma gondii.

II. Exemplary viral targets of the compounds of the invention

(a) General

The compounds of the present invention may have antiviral (e.g. virostatic or virocidal) activity against any virus. Thus, the invention finds broad application in the treatment or prevention of any viral infection, including for example infections, diseases and disorders in which any of the following viruses (or virus classes) are implicated:

Retroviridae (e.g. the human immunodeficiency viruses, including HIV-1); Picornaviήdae (e.g. polio viruses, hepatitis A virus; enteroviruses, human Coxsackie viruses, rhinoviruses, echoviruses); Calciviridae (e.g. strains that cause gastroenteritis); Togaviridae (e.g. equine encephalitis viruses, rubella viruses); Flaviridae (e.g. dengue viruses, encephalitis viruses, yellow fever viruses); Coronoviridae (e.g. coronaviruses, including SARS coronavirus); Rhabdoviradae (e.g. vesicular stomatitis viruses, rabies viruses); Filoviridae (e.g. ebola viruses); Paramyxoviridae (e.g. parainfluenza viruses, mumps virus, measles virus, respiratory syncytial virus); Orthomyxoviridae (e.g. influenza viruses); Bungaviridae (e.g. Hantaan viruses, bunga viruses, phleboviruses and Nairo viruses); Arena viridae (hemorrhagic fever viruses); Reoviridae (e.g. reoviruses, orbiviurses and rotaviruses); Birnaviridae; Hepadnaviridae (Hepatitis B virus); Parvoviridae (parvoviruses);

Papovaviridae (papilloma viruses, polyoma viruses); Adenoviridae (most adenoviruses); Herpesviridae (herpes simplex virus (HSV) 1 and 2, varicella zoster virus, cytomegalovirus (CMV), herpes virus; Poxviridae (variola viruses, vaccinia viruses, pox viruses); and Iridoviridae (e.g. African swine fever virus); and unclassified viruses (e.g. the etiological agents of Spongiform encephalopathies, the agent of delta hepatitis (thought to be a defective satellite of hepatitis B virus), the HCV virus (causing non-A, non-B hepatitis); Norwalk and related viruses, and astroviruses). Of the foregeoing, particularly preferred are HIV, Hepatitis A, Hepatitis B, Hepatitis C, rabies virus, poliovirus, influenza virus (including influenza A and influenza B virus), meningitis virus, measles virus, mumps virus, rubella, pertussis, encephalitis virus, papilloma virus, yellow fever virus, respiratory syncytial virus, parvovirus, chikungunya virus, haemorrhagic fever viruses and Herpes . viruses, particularly, varicella, cytomegalovirus and Epstein-Barr virus.

The invention finds particular application in the treatment or prevention of infections mediated by enveloped viruses. Examples of enveloped virus families and some human species within the families include Poxviridae, e.g. vaccinia and smallpox, Iridoviridae, Herpesviridae, e.g. Herpes simplex, Varicella virus, cytomegalovirus and Eppstein-Barr virus, Togaviridae, e.g. Yellow fewer virus, thick-borne encephalitis virus, Rubella virus and tropical encephalitis virus, Coronaviridae, e.g. Human coronovirus, Paramyxoviridae, e.g. Parainfluenza, mumps virus, measles virus and respiratory syncytial virus, Rabdoviridae, e.g. vesicular stomatitis virus and rabies virus, Filoviridae, e.g. Marburg virus and Ebola virus, Orthomyxoviridae, e.g. Influenza A, B and C viruses, Bunyaviridae, e.g. Bwamba virus, California encephalitis virus, sandfly fever virus and Rift Valley fever virus, Arenaviridae, e.g. LCM virus, Lassa virus and Juni virus, Hepnadnaviridae, e.g. hepatitis B- virus, and Retroviridae, e.g. HTLV and HIV-1 and HIV-2; Flaviviridae; Rhabdoviridae. These viruses and others are responsible for such diseases as encephalitis, intestinal infections, immunosuppressive disease, respiratory disease, hepatitis and pox infections. The Paramyxoviridae are enveloped viruses that include, among others, mumps virus, measles virus, Sendai virus, Newcastle disease virus (NDV), human respiratory syncytial virus (RSV), parainfluenza virus 5 (SV5) and human parainfluenza viruses 1-4 (hPIV)1. Many members of this viral family are significant human and animal pathogens, and newly emergent deadly paramyxoviruses (Nipah and Hendra viruses) have been identified.

The flavivirus group (family Flaviviridae) comprises the genera Flavivirus, Pestivirus and Hepacivirus and includes the causative agents of numerous human diseases and a variety of animal dieases which cause significant losses to the livestock industry. The family Flaviviridae (members of which are referred to herein as flaviviruses) include the genera Flavivirus (e.g. yellow fever virus, dengue viruses, Japanese encephalitis virus, Murray Valley encephalitis virus, West Nile fever virus, Rocio virus, St. Louis encephalitis virus, Louping ill virus, Powassan virus, Omsk hemorrhagic fever virus, Kyasanur forest disease virus and tick-borne encephalitis virus), Pestivirus (e.g. bovine viral diarrhoea virus, rubella virus, classical swine fever virus, hog cholera virus and border disease virus), Hepacivirus (hepatitis C virus) and currently unclassified members of the Flaviviridae (e.g. GB virus types A, B and C). The compounds of the invention find general application in the treatment of infections with any virus, including for example viruses of the family Flaviviridae (i.e. a flavivirus, as herein defined). The invention therefore contemplates the use of the compounds of the invention for the treatment of any disease arising from infection with any virus, including those of the family Flaviviridae.

Thus, the invention finds application in the treatment of infection with (and disease caused by) any virus, including those of the family Flaviviridae including for example any virus from the genera Flavivirus, Pestivirus and Hepacivirus. Thus, the invention finds application in the treatment of numerous human viral diseases and a variety of animal viral diseases which cause significant losses to the livestock industry.

Thus, the invention finds application in the treatment of infection with (and disease caused by) a virus selected from the genera Flavivirus (e.g. yellow fever virus, dengue viruses, Japanese encephalitis virus, Murray Valley encephalitis virus, West Nile fever virus, Rocio virus, St. Louis encephalitis virus, Louping ill virus, Powassan virus, Omsk hemorrhagic fever virus, Kyasanur forest disease virus and tick-borne encephalitis virus), Pestivirus (e.g. bovine viral diarrhoea virus, rubella virus, classical swine fever virus, hog cholera virus and border disease virus), Hepacivirus (hepatitis C virus) and currently unclassified members of the Flaviviridae (e.g. GB virus types A, B and C).

In preferred embodiments, the compound of the invention is for the treatment of infection with (and disease caused by) a member of the genus Hepacivirus. In a particularly preferred embodiment the hepacivirus is the hepatitis C virus (HCV). In such embodiments, the HCV virus may be selected from genotype 1 , 2, 3, 4, 5 or 6). Any and all subtypes and quasispecies may be treated according to the invention, but particularly preferred is the treatment of infection with HCV genotypes 1a, 1b, 2a, 2b, 2c, 3a, 4 and/or 5.

Thus, the compounds of the invention may find application in the treatment of a disease selected from hepatitis C, yellow fever, dengue fever, Japanese encephalitis, Murray Valley encephalitis, Rocio virus infection, West Nile fever, St. Louis encephalitis, tick-borne encephalitis, Louping ill virus infection, Powassan virus infection, Omsk hemorrhagic fever, Kyasanur forest disease, bovine diarrhoea, classical swine fever, border disease and hog cholera. The full list of members of the Flaviviridae are defined in detail by the International Committee on Taxonomy of Viruses (the currently accepted taxanomic definition is described in: Virus Taxonomy: The Classification and Nomenclature of Viruses. The Seventh Report of the International Committee on Taxonomy of Viruses (M.H.V. van Regenmortel, CM. Fauquet, D. H. L. Bishop, E. B. Carstens, M. K. Estes, S. M. Lemon, J. Maniloff, M.A. Mayo, D.J. McGeoch, CR. Pringle, R.B. Wickner (2000). Virus Taxonomy, Vllth report of the ICTV. Academic Press, SanDiego), the content of which relating to the constitution of the family Flaviviridae is hereby incorporated by reference.

The study of HCV has been hampered by the inability to propagate the virus efficiently in cell culture. However, in the absence of a suitable cell culture system able to support replication of human HCV, BVDV is an accepted cell culture model. HCV and BVDV share a significant degree of local protein homology, a common replication strategy and probably the same subcellular location for viral envelopment.

The invention therefore finds particular application in the treatment or prevention of HCV infection (e.g. in the treatment or prevention of hepatitis C).

The combination therapy of the invention may therefore be applied to other viral infections involving glycosylated envelope proteins, such as Hepatitis A, B and C, Herpes Simplex virus 1 and 2, Epstein Barr Virus, Herpes zoster virus, other Herpesviridiae, Influenza virus and Newcastle disease virus infections. Particularly preferred is the treatment or prophylaxis of HIV (particularly HIV-1) infection, influenza A and B, SARS coronavirus and HCV. The invention may be of particular use in the treatment of HIV-infected patients, in particular such patients who have previously been treated with other known anti-HIV therapies (and where for example the viral infection has not been effectively controlled by the existing treatment regime, for example because of viral resistance).

Thus, the invention finds broad application in the treatment or prevention of all viral infections, including for example infections, diseases and disorders in which any of the following viruses (or virus classes) are implicated:

Retroviridae (e.g. the human immunodeficiency viruses, including HIV-1); Picornaviridae (e.g. polio viruses, hepatitis A virus; enteroviruses, human Coxsackie viruses, rhinoviruses, echoviruses); Calciviridae (e.g. strains that cause gastroenteritis); Togaviridae (e.g. equine encephalitis viruses, rubella viruses); Flaviridae (e.g. dengue viruses, encephalitis viruses, yellow fever viruses); Coronoviridae (e.g. coronaviruses); Rhabdoviradae (e.g. vesicular stomatitis viruses, rabies viruses); Filoviridae (e.g. ebola viruses); Paramyxoviridae (e.g. parainfluenza viruses, mumps virus, measles virus, respiratory syncytial virus); Orthomyxoviridae (e.g. influenza viruses); Bungaviridae (e.g. Hantaan viruses, bunga viruses, phleboviruses and Nairo viruses); Arena viridae (hemorrhagic fever viruses); Reoviridae (e.g. reoviruses, orbiviurses and rotaviruses); Birnaviridae; Hepadnaviridae (Hepatitis B virus); Parvoviridae (parvoviruses); Papovaviridae (papilloma viruses, polyoma viruses); Adenoviridae (most adenoviruses); Herpesviridae (herpes simplex virus (HSV) 1 and 2, varicella zoster virus, cytomegalovirus (CMV), herpes virus; Poxviridae (variola viruses, vaccinia viruses, pox viruses); and Iridoviridae (e.g. African swine fever virus); and unclassified viruses (e.g. the etiological agents of Spongiform encephalopathies, the agent of delta hepatitis (thought to be a defective satellite of hepatitis B virus), the HCV virus (causing non-A, non-B hepatitis); Norwalk and related viruses, and astroviruses).

Of the foregeoing, particularly preferred are HIV, Hepatitis A, Hepatitis B, Hepatitis C, rabies virus, poliovirus, influenza virus (including influenza A and influenza B virus), meningitis virus, measles virus, mumps virus, rubella, pertussis, encephalitis virus, papilloma virus, yellow fever virus, respiratory syncytial virus, parvovirus, chikungunya virus, haemorrhagic fever viruses and Herpes viruses, particularly, varicella, cytomegalovirus and Epstein-Barr virus. In particular, the invention finds application in the treatment or prevention of infections mediated by:

(a) a virus which acquires its envelope from a membrane associated with the intracellular membrane of an infected cell; and/or

(b) a virus which replicates via cooperation with the endoplasmic reticulum (or the membrane surrounding the lumen of the endoplasmic reticulum) in the host cell; and/or (c) a virus which replicates via cooperation with the Golgi apparatus (or the membrane of the lumen of the Golgi apparatus) in the host cell; and/or

(d) a virus which encodes one or more glycoproteins which depend on calnexin and/or calreticulin interaction for proper folding; and/or

(e) a p7-viroporin virus (as hereinbefore defined); and/or (T) a virus which requires neuraminidase for pathogenicity.

(b) Viruses of classes (a)-(d)

The invention finds broad application in the treatment or prevention of any infection mediated by viruses of these classes. In particular, the invention finds application in the treatment or prevention of infections involving flaviviruses.

The flavivirus group (family Flaviviridae) comprises the genera Flavivirus, Pestivirus and HepacMrus and includes the causative agents of numerous human diseases and a variety of animal dieases which cause significant losses to the livestock industry.

The family Flaviviridae (members of which are referred to herein as flaviviruses) include the genera Flavivirus (e.g. yellow fever virus, dengue viruses, Japanese encephalitis virus, Murray Valley encephalitis virus, West Nile fever virus, Rocio virus, St. Louis encephalitis virus, Louping ill virus, Powassan virus, Omsk hemorrhagic fever virus, Kyasanur forest disease virus and tick-borne encephalitis virus), Pestivirus (e.g. bovine viral diarrhoea virus, rubella virus, classical swine fever virus, hog cholera virus and border disease virus), HepacMrus (hepatitis C virus) and currently unclassified members of the Flaviviridae (e.g. GB virus types A, B and C). One particularly important flavivirus is the hepatitis C virus (HCV). HCV is an enveloped plus-strand RNA virus belonging to the Flaviviridae family, but classified as a distinct genus Hepacivirus. It was first identified in 1989 and it has since become clear that this virus is responsible for most cases of post-transfusion non-A, non-B hepatitis. Indeed, HCV is now recognised as one of the commonest infections causing chronic liver disease and The

(c) P7-viroporin viruses of class (e)

The invention finds broad application in the treatment or prevention of any infection mediated by p7-viroporin viruses, which include pestiviruses and hepaciviruses. Thus, the invention finds particular application in the treatment or prevention of infections involving members of the genera Pestivirus and Hepacivirus (including the HCV and BVDV viruses, as discussed above).

(d) Neuraminidase viruses of class (f)

Influenza virus neuraminidase (NA) is a subtype-specific, transmembrane glycoprotein of the class Il type and, like haemagglutinin (HA)₁ undergoes antigenic variation. Neuraminidase is also functionally important for the removal of sialic acid residues from various glycoproteins on the host-cell surface that potentially bind viral glycoproteins and hence restrict virion egress. NA activity is necessary to prevent clumping and allow the release of virus progeny from the host cell. Thus, NA is a potential target in the treatment of influenza virus infection and NA inhibitors have recently found application in the treatment of influenza virus infection.

Diabetogenic viruses

The invention finds broad application in the treatment or prevention of any infection mediated by a diabetogenic virus. Such viruses are aetiological agents of type 1 diabetes.

The diabetogenic virus target may be selected from viruses of the Picornavirus family (including enteroviruses, such as coxsackie A and B, echoviruses and polioviruses as well as encephalomyocarditis virus).

The diabetogenic virus target may also be selected from viruses of the:

• Togavirus family (for example, Rubella);

• Paramyxovirus family (for example, mumps);

• Reovirus family (for example, Rotavirus);

• Parvovirus family (for example, Parvovirus);

• β-herpesviridae (for example, cytomegalovirus).

Preferred diabetogenic viral targets are selected from enteroviruses, rubella, mumps, rotavirus, parvovirus and cytomegalovirus.

III. Exemplary target viral diseases

The invention finds broad application in the treatment or prevention of any viral disease, including for example diseases in which any of the following viruses (or virus classes) are implicated:

Retroviridae (e.g. the human immunodeficiency viruses, including HIV-1); Picornaviridae (e.g. polio viruses, hepatitis A virus; enteroviruses, human Coxsackie viruses, rhinoviruses, echoviruses); Calciviridae (e.g. strains that cause gastroenteritis); Togaviridae (e.g. equine encephalitis viruses, rubella viruses); Flaviridae (e.g. dengue viruses, encephalitis viruses, yellow fever viruses); Coronoviridae (e.g. coronaviruses, including SARS coronavirus); Rhabdoviradae (e.g. vesicular stomatitis viruses, rabies viruses); Filoviridae (e.g. ebola viruses); Paramyxoviridae (e.g. parainfluenza viruses, mumps virus, measles virus, respiratory syncytial virus); Orthomyxoviridae (e.g. influenza viruses); Bungaviridae (e.g. Hantaan viruses, bunga viruses, phleboviruses and Nairo viruses); Arena viridae (hemorrhagic fever viruses); Reoviridae (e.g. reoviruses, orbiviurses and rotaviruses); Birnaviridae; Hepadnaviridae (Hepatitis B virus); Parvoviridae (parvoviruses);

Papovaviridae (papilloma viruses, polyoma viruses); Adenoviridae (most adenoviruses); Heφesviridae (herpes simplex virus (HSV) 1 and 2, varicella zoster virus, cytomegalovirus (CMV), herpes virus; Poxviridae (variola viruses, vaccinia viruses, pox viruses); and Iridoviridae (e.g. African swine fever virus); and unclassified viruses (e.g. the etiological agents of Spongiform encephalopathies, the agent of delta hepatitis (thought to be a defective satellite of hepatitis B virus), the HCV virus (causing non-A, non-B hepatitis); Norwalk and related viruses, and astroviruses). Of the foregeoing, particularly preferred are HIV, Hepatitis A, Hepatitis B, Hepatitis C, rabies virus, poliovirus, influenza virus (including influenza A and influenza B virus), meningitis virus, measles virus, mumps virus, rubella, pertussis, encephalitis virus, papilloma virus, yellow fever virus, respiratory syncytial virus, parvovirus, chikungunya virus, haemorrhagic fever viruses and Herpes viruses, particularly, varicella, cytomegalovirus and Epstein-Barr virus.

The flavivirus group (family Flaviviridae) comprises the genera Flavivirus, Pestivirus and Hθpacivirus and includes the causative agents of numerous human diseases and a variety of animal dieases which cause significant losses to the livestock industry. The family Flaviviridae (members of which are referred to herein as flaviviruses) include the genera Flavivirus (e.g. yellow fever virus, dengue viruses, Japanese encephalitis virus, Murray Valley encephalitis virus, West Nile fever virus, Rocio virus, St. Louis encephalitis virus, Louping ill virus, Powassan virus, Omsk hemorrhagic fever virus, Kyasanur forest disease virus and tick-borne encephalitis virus), Pestivirus (e.g. bovine viral diarrhoea virus, rubella virus, classical swine fever virus, hog cholera virus and border disease virus), Hepacivirus (hepatitis C virus) and currently unclassified members of the Flaviviridae (e.g. GB virus types A, B and C).

The invention therefore finds particular application in the treatment or prevention of HCV infection (e.g. in the treatment or prevention of hepatitis C). The combination therapy of the invention may therefore be applied to other viral infections involving glycosylated envelope proteins, such as Hepatitis A, B and C, Herpes Simplex virus 1 and 2, Epstein Barr Virus, Herpes zoster virus, other Herpesviridiae, Influenza virus and Newcastle disease virus infections.

Particularly preferred is the treatment or prophylaxis of HIV (particularly HIV-1) infection, influenza A and B, SARS coronavirus and HCV. The invention (and in particular the combined use of a glycosylation modulator and a membrane fusion inhibitor) will be of particular use in the treatment of HIV-infected patients, in particular such patients who have previously been treated with other known anti-HIV therapies (and where for example the viral infection has not been effectively controlled by the existing treatment regime, for example because of viral resistance).

The invention finds application in the treatment of diabetogenic viral infection. Thus, the invention finds application: (a) in the treatment of virus-induced type 1 diabetes; (b) in the delay or prevention of viral diabetogenesis; (c) the treatment of type 1 diabetes; (d) the treatment or prevention of virus-induced β-cell lysis (e.g. by non-immune cytolysis or by immune-mediated cytolysis); (e) the prevention, reduction or elimination of virus-mediated endogenous interferon production; (f) the prevention, reduction or elimination of virus- mediated bystander activation of autoreactive T cells targeted to β-cells; (g) the prevention, reduction or elimination of viral activation and/or expansion of autoreactive T cells targeted to β-cells; and/or (h) the prevention or reduction of virus-mediated loss of regulatory T cells exposing β-cells to immune-mediated cytolysis.

Such applications find particular utility in the treatment of subjects having islet autoantibodies, since such patients are at high risk of progression to type 1 diabetes and may be infected with a diabetogenic virus as described above.

IV. Exemplary bacterial targets of the compounds of the invention

The compounds of the present invention may have antibacterial (e.g. bacteriostatic or bacteriocidal) activity against any bacterium.

Thus, the compounds of the invention may target: (a) Gram-positive, Gram-negative and/or Gram-variable bacteria; (b) spore-forming bacteria; (c) non-spore forming bacteria; (d) filamentous bacteria; (e) intracellular bacteria; (f) obligate aerobes; (g) obligate anaerobes; (h) facultative anaerobes; (i) microaerophilic bacteria and/or (f) opportunistic bacterial pathogens.

In certain embodiments, the compounds of the invention target one or more bacteria of the following genera: Acinetobacter (e.g. A. baumannii); Aeromonas (e.g. A. hydrophila); Bacillus (e.g. B. anthracis); Bacteroides (e.g. B. fragilis); Bordetella (e.g. B. pertussis); Borrelia (e.g. B. burgdorferi); Brucella (e.g. B. abortus, B. canis, B. melitensis and B. suis); Burkholdeήa (e.g. B. cepacia complex); Campylobacter (e.g. C. jejuni); Chlamydia (e.g. C. trachomatis, C. suis and C. muridarum); Chlamydophila (e.g. (e.g. C. pneumoniae, C. pecorum, C. psittaci, C. abortus, C. felis and C. caviae); Citrobacter (e.g. C. freundii); Clostridium (e.g. C. botulinum, C. difficile, C. perfringens and C. tetani); Corynebacterium (e.g. C. diphteriae and C. glutamicum); Enterobacter (e.g. E. cloacae and E. aerogenes); Enterococcus (e.g. E. faecalis and E. faecium); Escherichia (e.g. E. colϊ); Flavobacterium; Francisella (e.g. F. tularensis); Fusobacterium (e.g. F. necrophorum); Haemophilus (e.g. H. somnus, H. influenzae and H. parainfluenzae); Helicobacter (e.g. H. pylori); Klebsiella (e.g. K. oxytoca and K. pneumoniae), Legionella (e.g. L pneumophila); Leptospira (e.g. L interrogans); Listeria (e.g. L. monocytogenes); Moraxella (e.g. M. catarrhalis); Morganella (e.g. M. morganii); Mycobacterium (e.g. M. leprae and M. tuberculosis); Mycoplasma (e.g. M. pneumoniae); Neisseria (e.g. Λ/. gonorrhoeae and /V. meningitidis); Pasteurella (e.g. P. multocida); Peptostreptococcus; Prevotella; Proteus (e.g. P. mirabilis and P. vulgaris), Pseudomonas (e.g. P. aeruginosa); Rickettsia (e.g. R rickettsii); Salmonella (e.g. S. fyp/7/ and S. typhimurium); Serratia (e.g. S. marcesens); Shigella (e.g. S. flexnaria, S. dysenteriae and S. sonnei); Staphylococcus (e.g. S. aureus, S. haemolyticus, S. intermedius, S. epidermidis and S. saprophytics); Stenotrophomonas (e.g. S. maltophila); Streptococcus (e.g. S. agalactiae, S. mutans, S. pneumoniae and S. pyogenes); Treponema (e.g. 7^". pallidum); Vibrio (e.g. V. cholerae) and Yersinia (e.g. V. pestis).

The compounds of the invention may be used to target multi-drug resistant bacteria, including, but not limited to penicillin-resistant, methicillin-resistant, quinolone- resistant, macrolide-resistant, and/or vancomycin-resistant bacterial strains, including for example penicillin-, methicillin-, macrolide-, vancomycin-, and/or quinolone- resistant Streptococcus pneumoniae; penicillin-, methicillin-, macrolide-, vancomycin-, and/or quinolone-resistant Staphylococcus aureus; penicillin-, methicillin-, macrolide-, vancomycin-, and/or quinolone- resistant Streptococcus pyogenes; and penicillin-, methicillin- , macrolide-, vancomycin-, and/or quinolone-resistant enterococci.

Thus, the compounds of the invention may also be used to target MRSA, for example selected from any of C-MSRA1 , C-MRSA2, C-MRSA3, C-MSRA4, Belgian MRSA₁ Swiss MRSA and any of the EMRSA strains.

The compounds of the invention may be used to target high G+C Gram-positive bacteria. The term "high G+C Gram-positive bacteria" is a term of art defining a particular class of evolutionary related bacteria. The class includes Micrococcus spp. (e.g. M. luteus), Mycobacterium spp. (for example a fast- or slow-growing mycobacterium, e.g. M. tuberculosis, M. leprae, M. smegmatis or M. bovis), Streptomyces spp. (e.g. S. rimosus and S. coelicoloή and Corynebacterium spp. (e.g. C. glutamicum).

The compounds of the invention may be used to target low G+C Gram-positive bacteria. The term "low G+C Gram-positive bacteria" is a term of art defining a particular class of evolutionarily related bacteria. The class includes members of the Firmicutes phylum, including for example Staphylococcus spp. and Bacillus spp.

V. Exemplary target bacterial diseases

Any bacterial disease may be treated using the compounds of the invention.

Thus, the compounds of the invention find application in the treatment or prophylaxis of a bacterial disease selected from: anthrax (e.g. cutaneous anthrax, pulmonary anthrax and gastrointestinal anthrax); bacterial pneumonia; whooping cough; Lyme disease; brucellosis; acute enteritis; botulism; tetanus; diphtheria; tularemia; Lemierre's syndrome; Legionnaire's Disease; leprosy (Hansen's disease); tuberculosis, meningitis, syphilis, gas gangrene, scarlet fever, erysipelas, rheumatic fever, streptococcal pharyngitis, toxic shock syndrome, listeriosis, Whipple's disease, erythrasma, nocardiosis, maduromycosis, Ghon's complex, Pott's disease, Rich focus, scrofula, Bazin disease, lupus vulgaris, Lady Windermere syndrome, Buruli ulcer, yaws, relapsing fever, trench mouth, rat-bite fever, leptospirosis, mycoplasmal pneumonia, ureaplasmal infection, psittacosis, chlamydia, lymphogranuloma venereum, trachoma, rickettsioses, typhus, spotted fever, Rocky Mountain spotted fever, Boutonneuse fever, Rickettsial pox, ehrlichiosis (including human granulocytic ehrlichiosis and human monocytic ehrlichiosis), Q fever, bartonella, orientia, bacillary angiomatosis, Waterhouse-Friderichsen syndrome, gonorrhoea, burkholderiales, glanders, melioidosis, pertussis, typhoid fever, paratyphoid fever, salmonellosis, rhinoscleroma, donovanosis, shigellosis, pasteurellosis, Brazilian purpuric fever, chancroid, actinobacillosis, cholera, campylobacteriosis, bronchitis, sinusitis, laryngitis, otitis media, bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, bronchitis, C. difficile colitis, cervicitis, septicemia, skin and soft tissue infections, urinary tract infections, sepsis (including catheter-related sepsis), hospital-acquired pneumonia (HAP), gynecological infection, respiratory tract infection (RTI), sexually transmitted disease, urinary tract infection, acute exacerbation of chronic bronchitis (ACEB), acute otitis media, acute sinusitis, an infection caused by drug resistant bacteria, skin and skin structure infection, febrile neutropenia, gonococcal cervicitis, upper and lower respiratory tract infections, skin and soft tissue infections, hospital-acquired lung infections, bone and joint infections, respiratory tract infections, acute bacterial otitis media, pyelonephritis, intra-abdominal infections, deep-seated abcesses, central nervous system infections, bacteremia, wound infections, peritonitis, infections after burn, urogenital tract infections, gastro-intestinal tract infections, pelvic inflammatory disease; intravascular infections and plague.

The compopunds of the invention may be used to treat multi-drug resistant bacterial infections, including infections caused by penicillin-resistant, methicillin-resistant, quinolone- resistant, macrolide-resistant, and/or vancomycin-resistant bacterial strains. The multi-drug resistant bacterial infections to be treated using the methods of the invention include, for example, infections by penicillin-, methicillin-, macrolide-, vancomycin-, and/or quinolone- resistant Streptococcus pneumoniae; penicillin-, methicillin-, macrolide-, vancomycin-, and/or quinolone-resistant Staphylococcus aureus; penicillin-, methicillin-, macrolide-, vancomycin-, and/or quinolone-resistant Streptococcus pyogenes; and penicillin-, methicillin- , macrolide-, vancomycin-, and/or quinolone-resistant enterococci.

The compounds of the invention may also be used to treat diseases arising from infection with MRSA, for example selected from any of C-MSRA1 , C-MRSA2, C-MRSA3, C-MSRA4, Belgian MRSA, Swiss MRSA and any of the EMRSA strains. Accordingly, the invention therefore finds utility in the treatment or prophylaxis of infections mediated by drug- resistant bacteria and in the treatment or prophylaxis of nosocomial infections. The compounds of the invention may also be used to treat mycobacterial diseases. The term "mycobacterial disease" defines any disease, disorder, pathology, symptom, clinical condition or syndrome in which bacteria of the genus Mycobacterium (i.e. mycobacteria) act as aetiological agents or in which infection with mycobacteria is implicated, detected or involved. Any mycobacterial infection may be treated, including those in which bacteria of the Mycobacterium avium complex (MAC) is involved. This term defines a class of genetically-related bacteria belonging to the genus Mycobacterium and includes Mycobacterium avium subspecies avium (MAA), Mycobacterium avium subspecies hominis (MAH), and Mycobacterium avium subspecies paratuberculosis (MAP) together with the genetically distinct Mycobacterium avium intracellulare (MAI).

The term therefore includes the various forms of tuberculosis (TB), leprosy, paediatric lymphadenitis and mycobacterial skin ulcers. The term therefore covers mycobacterial conditions arising from or associated with infection by nontuberculous mycobacteria as well as tuberculous mycobacteria.

Thus, the invention finds particular application in the treatment and prophylaxis of a mycobacterial condition selected from:

• AIDS-related mycobacterial infection

• Mycobacterial infection in immunocompromised patients (e.g. attendant on malignancy, receipt of an organ transplant, immunoablation or administration of steroids) • Pulmonary TB

• Extra-pulmonary TB (including but not limited to miliary TB, central nervous system TB, pleural TB, pericardital TB, genitourinary TB, gastrointestinal TB, peritonital TB and TB of the bones and joints).

• Latent (persistent or asymptomatic) mycobacterial infection • Active mycobacterial disease

• MDR-TB (multidrug resistant TB)

• XDR-TB (Extensive Drug Resistant TB or Extreme Drug Resistance TB): this is a recently recognized class of MDR-TB that displays resistance to three or more of the six principal classes of second-line drugs. The compounds of the invention may therefore be used in combination with one or more additional compounds useful for the treatment of TB. Examples of such compounds include but are not limited to, isoniazid, rifamycin and derivatives thereof, pyrazinamide, ethambutol, cycloserine, ethionamide, streptomycin, amikacin, kanamycin, capreomycin, p- aminosalicylic acid, and fluoroquinolones such as levofloxacin, moxafloxacin or gatifloxacin. Examples of rifamycin derivatives include rifampin, rifabutin and rifapentine.

Other infections which may be treated according to the invention include those involving Corynebacterium spp. (including Corynebacterium diphtheriae), Tropherymawhippθlii, Nocardia spp. (including Nocardia asteroides and Nocardia brasiliensis), Streptomyces spp. (including Streptomyces griseus, Streptomyces paraguayensis and Streptomyces somaliensis), Actinomadura spp., Nocardiopsis spp., Rhodococcus spp., Gordona spp. Jsukamurella spp. and Oerskovia spp. as well as other pathogenic organisms from the group referred to as high G+C Gram-positive bacteria. Other infections which may be treated include those involving pathogenic low G + C Gram-positive bacteria.

Vl. Exemplary fungal targets of the compounds of the invention

The compounds of the invention may be antimycotics. They may, for example, be fungistatic or fungicidal.

The term antimycotic is used herein to indicate fungistatic and/or fungicidal activity and the terms antimycotic (when used as a noun) and antimycotic agent are to be interpreted accordingly. The terminology is extended to agents with more specific antimycotic activities by replacing the -mycotic suffix with those relating to particular fungal groups or taxa. In this way the terms antidermatophytic and anticandidal define activities/agents with fungistatic or fungicidal activity against inter alia dermatophytes and Candida spp., respectively. It should be noted that these latter terms do not necessarily preclude a broader spectrum of activity but merely indicate that the relevant agents have activity against at least one representative of the relevant fungal grouping. Thus, preferred antidermatophytic compounds for use according to the invention have fungistatic or fungicidal activity against at least one representative of the dermatophyte grouping (typically being active against Microsporum spp., Trichophyton spp. and/or Epidermophyton spp.) as well as activity against other non-dermatophytes (such as Candida and/or Aspergillus spp.). Antimycotic activity may be expressed in terms of the minimum inhibitory concentration (MIC) of the test compound required to produce a fungistatic effect in vitro. In general, MIC values of less than 10 μg/ml (preferably less than 1 μg/ml, most preferably less than 0.1 μg/ml) define thresholds that identify antimycotic activity. The in vitro tests typically involve serial dilution and liquid culture or the impregnation of absorbent discs with various concentrations of test agent followed by zone clearing tests with the discs on solid media. In the former case, the tests are typically broth microdilution tests performed according to the National Committee for Clinical Laboratory Standards (NCCLS) method using RPMI 1640 as the test medium or its European equivalent , the AFST-EUCAST procedure (see Cuenca-Estrella et al. (2002) Antimicrobial Agents and Chemotherapy, 46(11): 3644-3647 and the methods described herein). In the latter case, the assay format typically involves a series of agar plates, each having the test compound incorporated at a particular concentration. The plates are then inoculated with a standard culture of, for example, a dermatophyte and the plates then incubated for 48 hours at 37^°C. The plates are then examined for the presence or absence of growth of the fungus. Both of these assay formats are common general knowledge in the art. Preferred antimycotic compounds for use according to the invention have MIC values of less than 10 μg/ml (preferably less than 1 μg/ml, most preferably less than 0.1 μg/ml) in broth microdilution tests against at least one species of dermatophyte.

The compounds of the invention may be fungicidal or fungistatic. For example, they may be antidermatophytic and/or anticandidal. Thus, the compounds may be fungicidal or fungistatic for dermatophytes and/or yeasts (including for example yeasts selected from Candida spp. (e.g. C. albicans); Malassezia spp. (e.g. M. furfur, Geotrichum spp. (e.g. G. candidum) and Sporothrix spp. (e.g. S. schenkii).

Preferably, the compound for use according to the invention is active against species of any or all of the genera Microsporum, Trichophyton and Epidermophyton.

In preferred embodiments, the compound for use according to the invention is active against species of any or all of the genera Acremonium, Alternaria, Aspergillus, Botryodiplodia (e.g. B. theobromae), Fusarium, Onycochola (e.g. O. canadensis), Pyrenochaeta (e.g. P. unguis-hominis), Scytalidium (e.g. S. dimidiatum, S. scopulariopsis and S. hyalimum) and Candida. In preferred embodiments, the compound for use according to the invention is active against one or more species of all of the genera Microsporum, Trichophyton and Epidermophyton as well as Candida spp. (e.g. C. albicans). In such embodiments, particularly preferred are compounds that also show activity against species of one or more of the genera Acremonium, Alternaria, Aspergillus, Botryodiplodia (e.g. β. theohromae), Fusarium, Onycochola (e.g. O. canadensis), Pyrenochaeta (e.g. P. unguis-hominis), Scytalidium (e.g. S. dimidiatum, S. scopulariopsis and S. hyalimum) and Candida.

The compound for use according to the invention may therefore be active against yeasts (including for example yeasts selected from Candida spp. (e.g. C. albicans); Malassezia spp. (e.g. M. furfur, Geotrichum spp. (e.g. G. candidum) and Sporothrix spp. (e.g. S. schenkii). Particularly preferred are compounds having an activity spectrum which includes the taxa Microsporum, Trichophyton, Epidermophyton and Candida.

Other fungal targets include: Absidia corymbifera, Acremonium falciforme, Acremonium kiliense, Acremonium recifei, Ajellomyces dermatitidis, Ajellomyces capsulata, Aspergillus spp. (for example selected from A. flavus, A. fumigatus, A. nidulans, A. niger and A. terreus), Candida spp. (for example selected from C. albicans, C. glabrata, C. guillermondii, C. krusei, C. parapsilosis, C. kefyr and C. tropicalis), Cryptococcus spp. (for example selected from C. neoformans, C. gattii and C. grubii), Cunninghamella elegans, Emmonsia parva, Epidermophyton floccosum, Exophiala dermitidis, Exophiala werneckii, Exophiala jeanselmei, Exophiala spinifera, Exophiala richardsiae, Filobasidiella neoformans, Fonsecaea compacta, Fonsecaea pedrosoi, Histoplasma capsulatum, Leptoshaeria senegarlensis, Madurella mycetomatis, Madurella grisea, Malassezia furfur, Microsporum spp, Neotestudina rosatii, Paracoccidioides brasiliensis, Penicillium marneffei, Phialophora verrucosa, Piedraia hortae, Pneumocystis spp., Pseudallescheria boydii, Pyrenochaeta romeroi, Rhizomucor pusillus, Sporothrix schenckii, Trichophyton spp, Trichosporon beigelii, Wangiella dermatitidis and Xylohypha bantiana.

VII. Exemplary target fungal diseases

The invention finds broad application in the treatment or prevention of any fungal disease, including for example: (a) systemic and/or invasive infections (e.g. aspergillosis and candidiasis); (b) mucosal infections (e.g. oral and vaginal thrush); and (c) cutaneous infections (infections of the keratinised tissues of the skin, hair and nails, e.g. athlete's foot and ringworm).

In preferred embodiments, the fungal disease is selected from dermatophytosis, onychomycosis and dermatomycosis.

Preferred dermatophytoses which may be treated or prevented according to the invention includes any or all of: tinea capitis; tinea favosa; tinea corporis; tinea axillaris; tinea faciei; tinea imbricata; tinea pedis; tinea manuum; tinea cruris/inguinalis; tinea circinata; tinea profunda; Majocchi's granuloma; bullous tinea corporis; tinea unguium; tinea barbae/sycosis; tinea tonsurans and tinea incognito.

The fungal infection to be treated or prevented may be caused by a dermatophyte or a non-dermatophyte (e.g. a yeast). The application finds particular application in the treatment of terbinafine-resistant fungi (e.g. terbinafine-resistant dermatophytes) and/or azole-resistant fungi (e.g. azole-resistant dermatophytes).

The fungal infection to be treated or prevented according to the invention may involve superinfection or co-infection with one or more microorganism(s). In such embodiments, the superinfecting or co-infecting microorganism(s) may be selected from: (a) dermatophytes; (b) non-dermatophytes; (c) yeasts (including for example yeasts selected from Candida spp. (e.g. C. albicans); Malassezia spp. (e.g. M. furfur, Geotrichum spp. (e.g. G. candidum) and Sporothrix spp. (e.g. S. schenkii) and (d) bacteria (e.g. Gram- positive bacteria, Gram-negative bacteria or mycoplasmas).

The invention finds particular application in the treatment or prevention of mixed fungal infections (as defined herein). Here, the mixed infection may comprise infection with two or more distinct species of dermatophytes, or may comprise infection with two or more pathogens selected from dermatophytes, bacteria (e.g. Gram-positive bacteria, Gram- negative bacteria or mycoplasmas) and non-dermatophytes (for example yeasts, e.g. Candida spp.).

In embodiments where onychomycosis is treated or prevented according to the invention, the onychomycosis may involve infection with a dermatophyte selected from Epidermophyton spp. (e.g. E. floccosum) and Trichophyton spp. (e.g. T. mentagrophytes or T. rubrum). Alternatively, or in addition, the onychomycosis treated or prevented may involve infection with a non-dermatophyte selected from the genera: Acremonium; Alternaria; Aspergillus; Botryodiplodia (e.g. B. theobromae); Fusarium; Onycochola (e.g. O. canadensis); Pyrenochaeta (e.g. P. unguis-hominis); Scytalidium (e.g. S. dimidiatum, S. scopulariopsis and S. hyalimum) and Candida (e.g. C. albicans).

In particularly preferred embodiments, the onychomycosis to be treated or prevented according to the invention is caused by C. albicans and involves: (a) paronychial candidiasis; (b) Candida granuloma; or (c) Candida onycholysis.

In embodiments where tinea unguium or onychomycosis is treated or prevented according to the invention, the condition may involve: distal subungual onychomycosis (DSO); proximal subungual onychomycosis (PSO) or white superficial onychomycosis (WSO).

Other target fungal infections include those caused by Absidia corymbifera, Acremonium falciforme, Acremonium kiliense, Acremonium recifei, Ajellomyces dermatitidis, Ajellomyces capsulata, Aspergillus spp. (for example selected from A. flavus, A. fumigatus, A. nidulans, A. nigerand A. terreus), Candida spp. (for example selected from C. albicans, C. glabrata, C. guillermondii, C. krusei, C. parapsilosis, C. kefyrand C. tropicalis), Cryptococcus spp. (for example selected from C. neoformans, C. gattii and C. grubii), Cunninghamella elegans, Emmonsia pan/a, Epidermophyton floccosum, Exophiala dermitidis, Exophiala werneckii, Exophiala jeanselmei, Exophiala spinifera, Exophiala richardsiae, Filobasidiella neoformans, Fonsecaea compacta, Fonsecaea pedrosoi, Histoplasma capsulatum, Leptoshaeria senegarlensis, Madurella mycetomatis, Madurella grisea, Malassezia furfur, Microsporum spp, Neotestudina rosatii, Paracoccidioides brasiliensis, Penicillium marneffei, Phialophora verrucosa, Piedraia hortae, Pneumocystis spp., Pseudallescheria boydii, Pyrenochaeta romeroi, Rhizomucor pusillus, Sporothrix schenckii, Trichophyton spp, Trichosporon beigelii, Wangiella dermatitidis and Xylohypha bantiana.

Fungal infections that can be treated using the methods of the invention include tinea capitis, tinea corporis, tinea pedis, tinea barbae, tinea cruris, tinea versicolor, onychomycosis, perionychomycosis, pityriasis versicolor, tinea unguium, oral thrush, vaginal candidosis, respiratory tract candidosis, biliary candidosis, eosophageal candidosis, urinary tract candidosis, systemic candidosis, mucocutaneous candidosis, mycetoma, cryptococcosis, aspergillosis, mucormycosis, chromoblastomycosis, paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis and sporotrichosis.

Treatment or prophylaxis of tinea pedis according to the invention may comprise the treatment or prophylaxis of the following subtypes of tinea pedis: intertriginous tinea pedis; papulosquamous tinea pedis; vesiculo- or vesiculobullous tinea pedis and ulcerative tinea pedis.

The invention may find application in the treatment or therapy of a disease or condition selected from: endothrix; ectothrix; intertrigo and folliculitis.

In embodiments where the invention is used in the treatment or prophylaxis of dermatomycosis, the condition or disease may be selected from: tinea versicolor; tinea nigra; intertigo (e.g. candidal intertrigo) and pityriasis amiantacea (tinea amiantacea).

Veterinary applications

The invention not only finds application in the field of human therapy and prophylaxis, but also in the treatment and/or prophylaxis of infections in any non-human animal. Such veterinary applications are described in more detail below.

• Domesticated animals. The development of vaccines for prophylactic or therapeutic use with domesticated animals is of great importance, not only because the market for such vaccines for use with domestic pets is extremely large but also because the close proximity of animal and human in such situations leads to an increased risk of pathogen transmission from animal to human. Such "cross- species jumping" has been responsible for the evolution of many important human pathogens, including measles, HIV, SARS and dengue fever. The influenza A virus jumped from birds into humans to produce devastating pandemics in 1918, 1957 and 1968. Thus, the invention finds application in the treatment or prophylaxis of domesticated animals. Domesticated animals include pets (such as dogs, cats, mice, rats, gerbils, hamsters, monkeys, ferrets, fish, pigeons, parrots and other birds) as well as working animals such as horses, dogs, donkeys and goats. • Cattle. Infection of cattle and livestock can produce severe economic losses, as shown by the recent outbreaks of foot and mouth in the United Kingdom. Thus, vaccines for use with cattle and livestock (including cows, horses, donkeys, pigs, sheep, and goats) are extremely important.

• Birds. Modern farming practice often houses birds in large numbers in very close proximity under closed conditions. Such conditions foster the rapid spread of infectious disease, and the control of infection in birds is a major concern. Also, hatchlings are particularly vulnerable to infection. Particularly preferred is the treatment of birds selected from chicken, pigeon, turkey, duck, geese, pheasant and quail.

• Fish and other aquatic animals. The high density of aquatic animals in hatchery tanks, fish farms or other types of marine or freshwater farming enclosures puts the aquaculture industry at particular risk from infections and infestations. Viral, bacterial and parasitic diseases pose a serious problem for the aquaculture industry. Thus, the invention finds application in the treatment or prophylaxis of fish and other aquatic animals, including fish and shellfish (including clams, lobster, shrimp, crab and oysters). Particularly preferred is the treatment or prophylaxis of bony or cartilaginous fish, including salmonids, carp, catfish, yellowtail, seabream, and seabass. Particularly preferred is the treatment of trout, salmon and char.

Posologv

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

The amount 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.

Moreover, the compounds of the invention can be used in conjunction with other agents known to be useful in the treatment of diseases or disorders arising from protein folding abnormalities (as described infra) and in such embodiments the dose may be adjusted accordingly.

In general, the effective amount of the compound administered will generally range from about 0.01 mg/kg to 500 mg/kg daily. A unit dosage may contain from 0.05 to 500 mg of the compound, and can be taken one or more times per day. The compound can be administered with a pharmaceutical carrier using conventional dosage unit forms either orally, parenterally, or topically, as described below.

The preferred route of administration is oral administration. In general a suitable dose will be in the range of 0.01 to 500 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 50 mg per kilogram body weight per day and most preferably in the range 1 to 5 mg per kilogram body weight per day.

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.

Formulation

The compound for use according to the invention may take any form. It may be synthetic, purified or isolated from natural sources.

When isolated from a natural source, the compound for use according to the invention may be purified. In embodiments where the compound is formulated together with a pharmaceutically acceptable excipient, any suitable excipient may be used, including for example inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. The pharmaceutical compositions may take any suitable form, and include for example tablets, elixirs, capsules, solutions, suspensions, powders, granules and aerosols.

The pharmaceutical composition may take the form of a kit of parts, which kit may comprise the composition of the invention together with instructions for use and/or a plurality of different components in unit dosage form.

Tablets for oral use may include the compound for use according to the invention, mixed with pharmaceutically acceptable excipients, such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract. Capsules for oral use include hard gelatin capsules in which the compound for use according to the invention is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.

The compounds of the invention may also be presented as liposome formulations. For oral administration the compound can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, granules, solutions, suspensions, dispersions or emulsions (which solutions, suspensions dispersions or emulsions may be aqueous or non-aqueous). The solid unit dosage forms can be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and cornstarch.

In another embodiment, the compounds of the invention are tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders such as acacia, cornstarch, or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, lubricants intended to improve the flow of tablet granulations and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example, talc, stearic acid, or magnesium, calcium, or zinc stearate, dyes, coloring agents, and flavoring agents intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.

Suitable excipients for use in oral liquid dosage forms include diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptably surfactant, suspending agent or emulsifying agent.

The compounds of the invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally.

In such embodiments, the compound is provided as injectable doses in a physiologically acceptable diluent together with a pharmaceutical carrier (which can be a sterile liquid or mixture of liquids). Suitable liquids include water, saline, aqueous dextrose and related sugar solutions, an alcohol (such as ethanol, isopropanol, or hexadecyl alcohol), glycols (such as propylene glycol or polyethylene glycol), glycerol ketals (such as 2,2-dimethyl-1 ,3- dioxolane-4-methanol), ethers (such as poly(ethylene-glycol) 400), an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant (such as a soap or a detergent), suspending agent (such as pectin, carhomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose), or emulsifying agent and other pharmaceutically adjuvants. Suitable oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum, and mineral oil. Suitable fatty acids include oleic acid, stearic acid, and isostearic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.

Suitable soaps include fatty alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamines acetates; anionic detergents, for example, alkyl, aryl, and olefin sulphonates, alkyl, olefin, ether, and monoglyceride sulphates, and sulphosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkyIimidazoline quartemary ammonium salts, as well as mixtures.

The parenteral compositions of this invention will typically contain from about 0.5 to about 25% by weight of the compound for use according to the invention in solution. Preservatives and buffers may also be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5 to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB. Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.

The compound for use according to the invention may also be administered topically, and when done so the carrier may suitably comprise a solution, ointment or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Topical formulations may contain a concentration of the compound from about 0.1 to about 10% w/v (weight per unit volume). When used adjunctively, the compound for use according to the invention may be formulated for use with one or more other drug(s). Thus, adjunctive use may be reflected in a specific unit dosage designed to be compatible (or to synergize) with the other drug(s), or in formulations in which the compound is admixed with one or more enzymes.

Adjunctive uses may also be reflected in the composition of the pharmaceutical kits of the invention, in which the compounds of the invention is co-packaged (e.g. as part of an array of unit doses) with the enzymes. Adjunctive use may also be reflected in information and/or instructions relating to the co-administration of the compound and/or enzyme.

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.

BVDV Plaque Assay: In the absence of a suitable cell culture system able to support replication of human HCV, bovine diarrhoea virus (BVDV) is an accepted cell culture model. HCV and BVDV share a significant degree of local protein homology, a common replication strategy and probably the same subcellular location for viral envelopment. The ability of a compound of the invention to exert a direct anti-BVDV effect in vitro can therefore be tested and activity demonstrated in a BVDV plaque inhibition assay (as detailed below).

The materials and procedures were as described in Whitby et a/. (2004) Antiviral Chemistry and Chemotherapy 15: 141-151. In brief, MDBK cells were seeded in 96 well plates and allowed to reach confluency. Monolayers were exposed to between 14 and 45 plaque forming units of BVDV and adsorption allowed to take place. Infected monolayers were then exposed to the test compound, medium added containing low gelling-point agarose and allowed to set. The plates were then incubated for 4 days post infection, fixed in 5% formalin and stained with 0.5% neutral red after removal of the agarose layer. Anti-viral activity was measured by determination of plaque inhibition and expressed as IC₅₀ values. Castanospermine, a known viral inhibitor, was used as a positive control. Examples 1-3: Anti-BVDV activity

The hepatitis C virus (HCV) was first identified in 1989 and it has since become clear that this virus is responsible for most cases of post-transfusion non-A, non-B hepatitis.^' Indeed, HCV is now recognised as one of the commonest infections causing chronic liver disease and The World Health Organisation estimates that 170 million people are chronically infected. HCV infection results in a chronic infection in 85% of infected patients and approximately 20-30% of these will progress to cirrhosis and end stage liver disease, frequently complicated by hepatocellular carcinoma.

The study of HCV has been hampered by the inability to propagate the virus efficiently in cell culture. However, in the absence of a suitable cell culture system able to support replication of human HCV, bovine diarrhoea virus (BVDV) is an accepted cell culture model. HCV and BVDV share a significant degree of local protein homology, a common replication strategy and probably the same subcellular location for viral envelopment.

The ability of various compounds of the invention to exert a direct anti-BVDV effect in vitro was therefore tested and activity demonstrated in a BVDV plaque inhibition assay (as detailed below).

For these assays a confluent monolayer of MDBK cells is produced in a flat bottomed well of a tissue culture plate. The monolayer is infected with BVDV. Sufficient virus is added to eventually form approximately 20-30 plaques. After allowing approximately 1 hr for the virus to infect, the cells are washed and liquid agar is added and allowed to set as a thin layer over the cell surface (the 'overlay'). The infected cells are then left for a period of days to allow the virus to replicate and cells to shed virus, detach or lyse. Cells in the immediate vicinity of the initial virus infection are therefore infected - localized by the agar layer. Hence a clear plaque devoid of cells is eventually formed which after staining uninfected cells around it with neutral red is visible and can be scored.

The test compound is added at appropriate dilutions with the virus. An antiviral effect of the compound is scored by the reduction of plaque number or size. The concentration of compound required to produce a 50% (IC₅₀) reduction of plaque number or size is noted. Controls of no compound added are included. A control of a known antiviral compound (castanospermine) is carried out to calibrate the antiviral activity. Castanospermine (Compound 104), a known viral inhibitor (see infra), was used as a positive control. The following data was obtained:

Example 4: Toxicity assay

The compounds tested above were assayed for toxicity using a standard 'XTT' colorimetric assay. In this assay the test compound, in the absence of virus was added to the cell monolayer. The cells and compound (and controls of cells without compound) were incubated for a period equivalent to the time required for viral plaques to be formed in the standard antiviral assay. XTT reagents are then added. XTT is metabolized by the mitochondria of viable cells producing an increase in absorbance at 450 nm. The effect of toxic compounds is to reduce this metabolism and generate less absorbance at 450 nm.

All compounds assayed at 200μg/ml showed approximately 15% reduction in absorbance with respect to no compound controls. This is in the range of a designation of 'not toxic¹ in this assay.

Example 5: Anti-BVDV activity

The hepatitis C virus (HCV) was first identified in 1989 and it has since become clear that this virus is responsible for most cases of post-transfusion non-A, non-B hepatitis. Indeed, HCV is now recognised as one of the commonest infections causing chronic liver disease and The World Health Organisation estimates that 170 million people are chronically infected. HCV infection results in a chronic infection in 85% of infected patients and approximately 20-30% of these will progress to cirrhosis and end stage liver disease, frequently complicated by hepatocellular carcinoma.

The ability of compound 23 of the invention to exert a direct anti-BVDV effect in vitro was therefore tested and activity demonstrated in a BVDV plaque inhibition assay (as detailed below).

Plaque Assay: The materials and procedures were as described in Whitby et a/. (2004) Antiviral Chemistry and Chemotherapy 15: 141-151.

In brief, MDBK cells were seeded in 96 well plates and allowed to reach confluency. Monolayers were exposed to between 14 and 45 plaque forming units of BVDV and adsorption allowed to take place. Infected monolayers were then exposed to the test compound, medium added containing low gelling-point agarose and allowed to set. The plates were then incubated for 4 days post infection, fixed in 5% formalin and stained with 0.5% neutral red after removal of the agarose layer. Anti-viral activity was measured by determination of plaque inhibition and expressed as IC₅₀ values. Castanospermine (Compound 104), a known viral inhibitor, was used as a positive control.

Results:

The results show that the test compound of the invention exhibits good antiviral activity against BVDV. No cytotoxicity was noted.

Example 6: Inhibition of glvcosidase activity

Inhibition of the N-linked glycan trimming enzymes alpha-Glucosidases I and Il or alpha- Mannosidases I and Il are thought to be related to the anti-viral activity of castanospermine (Compound 104) and 1-deoxynojirimycin (Compound 193). Glycosidase assays were conducted on iminosugars exhibiting anti-viral activity. The data suggest that anti-viral activity can also be independent of inhibition of the above trimming glycosidases. All enzymes were purchased from Sigma, as were the appropriate p-nitrophenyl substrates. Assays were carried out in microtitre plates. Enzymes were assayed in 0.1 M citric acid/0.2M di-sodium hydrogen phosphate (Mcllvaine) buffers at the optimum pH for the enzyme. All assays were carried out at 2O⁰C. For screening assays the incubation assay consisted of 10 μl of enzyme solution, 10 μl of inhibitor solution (made up in water at 5mM) and 50 μl of the appropriate 5 mM p-nitrophenyl substrate (3.57mM final cone.) made up in Mcllvaine buffer at the optimum pH for the enzyme. W

220

The reactions were stopped with 0.4M glycine (pH 10.4) during the exponential phase of the reaction, which was determined at the beginning of the assay using blanks with water, which were incubated for a range of time periods to measure the reaction rate using 5 mM substrate solution. Endpoint absorbances were read at 405nm with a Bio-rad microtitre plate reader (Benchmark). Water was substituted for the inhibitors in the blanks.

The enzymes tested are shown in the table below.

The results (% inhibition) for these anti-BVDV compounds (all at 1mg/ml) are shown in the table below:

Example 7: Interference with mycobacterial cell wall formation

The compounds of the invention may selectively interfere with the formation of the cell walls pathogens and parasites. Examples are the rhamnose analogues that may be predicted to interfere selectively with microorganisms that use rhamnose in their cell walls such as mycobacteria, E. coli and Salmonella spp. whilst not affecting humans that do not incorporate rhamnose into glycans. Mycobacteria attach arabino-galactan to rhamnose and preliminary results show that Compound 70 and Compound 153 alter arabinose-galactose ratios in Mycobacterium aurum grown in vitro. The growth of the cells is not affected despite cell wall glycosylation changes; however, in vivo these effects could be significant in altering pathogen cell/host interactions and may also make existing anti-bacterial drugs more effective by improving uptake. Immune responses to the organisms might also be expected to be altered.

The Mycobacterium aurum (strain A+) used was CiP104482 from the Pasteur Institute, Paris. 1. Mycobacteria were transferred from frozen stocks to 5% horse blood Columbia agar slants using a flame-sterilised loop and incubated at 37⁰C for 3 days.

2. For assays, microrganisms were subcultured once to a freshly prepared 5% horse blood Columbia agar slant and incubated for a further 3 days at 37⁰C. 3. lnocula were prepared by transferring colonies to saline (0.9%w/v NaCI) in a glass vial containing some glass beads.

4. Bacterial suspensions were mixed vigorously to disrupt visible clumps and left to settle for 5 minutes.

5. Supernatants, containing dispersed bacterial cells, were diluted to match the turbidity of McFarland 0.5 standard.

6. The suspension (55μl) was transferred to a tube of cation-adjusted Mueller-Hinton broth (11 ml) and mixed thoroughly.

7. Cultures of 4ml containing 5 x 10⁵ CFU/ml and 0.5mg/ml of the iminosugars were incubated at 37⁰C for 3 days.

Preparation of mycobacterial cells for cell wall analysis

The isolation and fractionation of the cell wall was done as described by Nikaido et a/. (Molecular Microbiol. 1993, 8, 1025-1030).

1. Suspensions of M. aurum were centrifuged at 2000 x g (5 min) followed by 3500 x g (5 min).

2. The supernatant was discarded and distilled water was added. After mixing, the preparation was centrifuged again at 3500 x g for another 5 min to wash the cells. 3. The supernatant was discarded and the sediment was rinsed out into four glass test tubes with ethanol (5ml).

4. The ethanol suspension was sonicated for 10 min and this was followed by a centrifugation step at 35000 x g for 5 min. The ethanol was discarded.

5. Cells were extracted twice with 3ml of CHCI₃/CH₃OH (2:1 ,v/v) for 60 minutes at 5O⁰C.

6. After centrifugation at 10,000 x g for 30 minutes, the supernatants were discarded.

7. The pellets were transferred to glass test-tubes using 4ml of pre-prepared 12g/50ml of trifluoroacetic acid (16ml/100ml of TFA in HPLC grade water).

8. The suspensions (4ml) were heated on a heating block at 9O⁰C for 4 hours. 9. The hydrolysed cell walls in TFA were blown to dryness under nitrogen gas. 10. The blown-dried samples were then weighed and dissolved in HPLC grade water to give concentrations of approx. 1mg/ml.

11. The sample solutions were vortexed to ensure homogenous suspension and filtered through 0.22μm filter units to remove particulates in the sample solutions. 12. The filtered sample solutions were then vortexed and ready for HPLC (ligand exchange chromatography with pulsed amperometric detection). 13. A set of standard solutions: sucrose, galactose, arabinose and mannose were prepared for qualitative analysis and a set of calibration curves for galactose and arabinose were generated for the quantitative analysis.

Analysis of M. aurum cell wall sugars was conducted using a Dionex HPLC system using a DIONEX Pulsed Amperometry Detector with wave form of 1 ; range at 2 μC and using 0.3 M potassium hydroxide. The injection volume was 20μl with a mobile phase of HPLC grade water. The column was a PL Hi-Plex Ca column (sulphonated styrene/ divinylbenzene copolymer in calcium form, crosslink content 8%, particle size 8 μm, 300 x 7.7mm with a flow rate of 0.5-0.6 ml/min, temperature 85⁰C and operating pressure of < 24 bar).

Table showing mean concentration (n = 3) of galactose over arabinose ratios in cell wall of M. aurum grown in the presence or absence of rhamnose analogues

These results suggest that the presence of both of the rhamnose-like iminosugars in the medium of M. aurum affect the cell wall formation and hence alter the sugar compositions (as shown here by the ratios of galactose and arabinose). This effect would be expected to be due to interference with the attachment of arabinogalactan to the key rhamnose linker. Both compounds have the potential ability to alter the M. aurum cell wall permeability barrier and hence make the cells less resistant to drug treatment and may also alter the immune response to the organism.

Example 8: Anti-HCV activity Anti-HCV activity was assessed using the internally quenched 5-FAM/QXLTM520 Fluorescence Resonance Energy Transfer (FRET) assay described in Yu et a/. (2009) Development of a Cell-Based Hepatitis C Virus (HCV) Infection FRET Assay for High Throughput Antiviral Compound Screening Antimicrob Agents Chemother. doi: 10.1128/AAC.00495-09 (and see also Zhong et at. (2005) Robust hepatitis C virus infection in vitro Proc Natl Acad Sci U S A.: 102(26):9294-9).

The peptide substrate for the NS3 protease FRET assay is an internally quenched peptide with a fluorescent donor (FAM) and acceptor (QXL) on opposing sides of the NS3 protease cleavage site. The donor absorbs energy at 480nm and emits energy (i.e. fluorescence) at 520nm. However, when in close contact on an intact peptide, the acceptor absorbs the 52OnM energy emitted by the donor preventing fluorescence. Cleavage of the peptide increases the distance between the fluorophores resulting in proportional FAM fluorescence.

Synchronized, non-dividing human hepatoma-derived DMSO-Huh7 cells were infected with HCV at 0.05 ffu/cell. Compounds were added co-infection and were replenished every 2 days over the 6 day assay. Day 6 p. L, cultures assayed for HCV NS3 protein levels by FRET. Cells infected with increasing doses of HCV at day 3 p.i. exhibited FRET signals proportional to multiplicity of infection (MOI).

The following compounds exhibited anti-HCV activity in the screen described above:

TABLE 2: Anti-HCV compounds

Key: +++++ ≥ 80%

++++ 60 - 79%

+++ 40 - 59%

++ 20 - 39%

+ ≤ 19%

Example 9: Anti-RSV activity

Anti-RSV activity was measured as follows:

Hep2 cells were maintained as an adherent cell line in Dulbecco's Modified Eagle Medium with phenol red (DMEM; American Tissue Culture Type), supplemented with 10% Fetal Bovine Serum (FBS; Atlanta Biologicals), and 1% L-glutamine (Gibco), at 37⁰C in a humidified 5% CO₂ atmosphere. Cells were passaged as needed and harvested from flasks using 0.25% trypsin-EDTA (Gibco). Cells were counted and viability was determined by Propidium Iodide using the Coulter Epics XL-MLC. Hep2 cells were dispensed into black, clear-bottom, 96-well plates (Coming) at a density, of 10,000 cells/well in 50μl assay medium, and incubated overnight at 37⁰C, 5% CO₂, with . high humidity prior to drug treatment. The next day, 25μl of control drug and test compounds was added to ceils using the BIO-TEK Precision™ Microplate Pipetting System. Plates were maintained in the BSL-2 facility, where the cells were infected with 100 TCID₅₀ RSV. Controls consisted of wells containing media only, cells only, control compound(s), and virus and cells. Plates were then allowed to incubate at 37° C, 5% CO₂.

Cells are observed daily for virus-specific cytopathic effect (CPE). When CPE involving greater than 50% of cells is observed in control wells (Cells plus virus alone), the effect of treatment is determined. 100 μl of Cell Titer GIo was added to each well. Plates were shaken for 2 minutes at speed 5 on a Fisher shaker incubator (room temperature). Luminescence was then measured using a Bio-Tek Synergy plate reader.

Reduction in virus specific CPE compared to "untreated" control cells is determined calculating the number of viable cells. A software package is utilised to calculate the percent of CPE reduction of the virus-infected wells and the percentage cell viability of uninfected (treated and untreated) control wells.

The following compounds exhibited anti-RSV activity in the screen described above at 100μM or 10μM:

TABLE 3: Anti-RSV compounds

N-(((2R₎3R,4S)-1-(2-(dimethylamino)ethyi)-3,4-dihydroxypyrrolidin-

654 2-yl)methyl)benzamide +++

N-(((2S,3R,4S)-3,4-dihydroxy-1-nonylpyrrolidin-2-

659 yl)methyl)biphenyl-4-carboxamide ++++

N-(((2S,3R,4S)-1-(biphenyl-4-ylmethyl)-3,4-dihydroxypyrrolidin-2-

664 yl)methyl)benzamide +++

N-(((3aR,4R,6aS)-5-benzyl-2,2-dimethyltetrahydro-3aH-

672 [1 ,3]dioxolo[4,5-c]pyrrol-4-yl)methyl)biphenyl-4-carboxamide +++

(2S,2^lS,3R,3^lR,4S,4'S)-2,2'-((1 R, 1¹R,2R,2'R)-3,3'-azanediylbis(1 ,2-

707 dihydroxypropane-3, 1 -diyl))bis(1 -benzylpyrrolidine-3,4-diol) ++

747 (R)-(1-(2-(2-methoxyethoxy)ethyl)piperidin-3-yl)methanol ++

784 N-((3R,4S,5R)-1-butyl-4,5-dihydroxypiperidin-3-yl)acetamide +++

785 N-((3S,4r,5R)-3,5-dihydroxypiperidin-4-yl)acetamide ++

786 N-((3S,4r,5R)-3,5-dihydroxy-1-methylpiperidin-4-yi)acetamide +++

Key: ++++ > 90% @10μM +++ ≥ 90% @100μM ++ 70 - 89% @100μM

+ 50 - 69% @100μM

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

1. A compound of Formula (1)

in which

z represents an integer from 1 to (n+2)

y represents 1 or 2

R² represents OH; OR³; =O; NH₂; N₃; SH; SO_xR³; halo; CN; NO₂; NR³R⁴; (NR³)NR³R⁴; NH(NR³)NR³R⁴; CO₂R⁴; OC(O)R³; CONR³R⁴; NR⁴C(O)R³; NR⁴SO₂R³;

P(O)(OR³)₂; C1-15 alkyl or alkenyl optionally substituted with one or more OH, OR³, =0, NH₂, N₃, SH, SO_xR³, halo, CN, NO_2, NR³R⁴, (NR³)NR³R⁴, NH(NR³)NR³R⁴, CO₂R⁴, OC(O)R³, CONR³R⁴, NR⁴C(O)R³, NR⁴SO₂R³, P(O)(OR³)₂, aryl or carbocyclyl groups; carbocyclyl or aryl, either of which is optionally substituted with one or more OH, OR³, =0, NH₂, N₃, SH, SO_xR³, halo, CN, NO₂, NR³R⁴,

(NR³)NR³R⁴, NH(NR³)NR³R⁴, CO₂R⁴, OC(O)R³, CONR³R⁴, NR⁴C(O)R³, NR⁴SO₂R³, P(O)(OR³)₂, C1-9 alkyl optionally substituted with one or more OH, OR³, =0, NH₂, N₃, halo, CN₁ NO₂, NR³R⁴, CO₂R⁴, CONR³R⁴, aryl or carbocyclyl groups; O- glycosyl; C-glycosyl; O-sulfate; O-phosphate or a group which together with the endocyclic carbon forms a spiro ring, with the provisos that: (a) two OH groups may not be attached to the same endocyclic carbon atom; (b) where there is only one R² substituent it contains an oxygen atom directly bonded to an endocyclic carbon atom; and (c) where z>1 any two R² substituents may together form an optionally heterocyclic ring (for example a carbocycle, cyclic ether or acetal)

R⁴ represents H; C1-6 alkyl, optionally substituted with one or more OH

x represents an integer from O to 2

or a pharmaceutically acceptable salt or derivative thereof, for the treatment of: (a) an infection with, or disease caused by, respiratory syncytial virus (RSV); or (b) an infection with, or disease caused by, an infectious agent.

2. The compound of claim 1 wherein n = 1 to 5, for example 2 or 3.

3. The compound of claim 1 having three, four or more rings.

4. The compound of any one of the preceding claims wherein z = 2 to (n + 2).

5. The compound of any one of claims 1 to 3 wherein z = n + 2.

6. A compound of Formula (2)

in which p represents an integer from 1 to 2

z represents an integer from 1 to (p+7)

y represents 1 or 2

(NR³)NR³R⁴; NH(NR³)NR³R⁴; CO₂R⁴; OC(O)R³; CONR³R⁴; NR⁴C(O)R³; NR⁴SO₂R³; P(O)(OR³)₂; C1-15 alkyl or alkenyl optionally substituted with one or more OH, OR³, =0, NH₂, N₃, SH, SO_xR³, halo, CN, NO₂, NR³R⁴, (NR³)NR³R⁴, NH(NR³)NR³R⁴, CO₂R⁴, OC(O)R³, CONR³R⁴, NR⁴C(O)R³, NR⁴SO₂R³, P(O)(OR³)₂, aryl or carbocyclyl groups; carbocyclyl or aryl, either of which is optionally substituted with one or more OH, OR³, =0, NH₂, N₃, SH, SO_xR³, halo, CN, NO₂, NR³R⁴, (NR³)NR³R⁴, NH(NR³)NR³R⁴, CO₂R⁴, OC(O)R³, CONR³R⁴, NR⁴C(O)R³, NR⁴SO₂R³, P(O)(OR³)₂, C1-9 alkyl optionally substituted with one or more OH, OR³, =0, NH₂, N₃, halo, CN, NO₂, NR³R⁴, CO₂R⁴, CONR³R⁴, aryl or carbocyclyl groups; O- glycosyl; C-glycosyl; O-sulfate; O-phosphate or a group which together with the endocyclic carbon forms a spiro ring, with the provisos that: (a) two OH groups may not be attached to the same endocyclic carbon atom; (b) where there is only one R² substituent it contains an oxygen atom directly bonded to an endocyclic carbon atom; and (c) where z>1 any two R² substituents may together form an optionally heterocyclic ring (for example a carbocycle, cyclic ether or acetal)

R⁴ represents H; C1-6 alkyl, optionally substituted with one or more OH R³ and R⁴ may optionally form a 4 to 8 membered ring, containing one or more O, SO_x or NR³ groups

x represents an integer from O to 2

7. The compound of any one of the preceding claims wherein: (a) y = 1 ; or (b) y = 2, the endocyclic nitrogen atom being quaternary.

8. The compound of any one of the preceding claims having three, four or more rings.

9. The compound of any one of claims 1 to 6 wherein R¹ = H.

10. A compound of Formula (3)

in which

z represents an integer from 0 to (n+2), provided that where z = 0 then y ≥ 1 y represents an integer from 0 to (m+2), provided that where y = 0 then z ≥ 1

R² represents OH; OR³; =0; NH₂; N₃; SH; SO_xR³; halo; CN; NO₂; NR³R⁴; (NR³)NR³R⁴; NH(NR³)NR³R⁴; CO₂R⁴; OC(O)R³; CONR³R⁴; NR⁴C(O)R³; NR⁴SO₂R³; P(O)(OR³)₂; C1-15 alkyl or alkenyl optionally substituted with one or more OH, OR³, =O, NH₂, N₃, SH, SO_xR³, halo, CN, NO₂, NR³R⁴, (NR³)NR³R⁴, NH(NR³)NR³R⁴, CO₂R⁴, OC(O)R³, CONR³R⁴, NR⁴C(O)R³, NR⁴SO₂R³, P(O)(OR³)₂, aryl or carbocyclyl groups; carbocyclyl or aryl, either of which is optionally substituted with one or more OH, OR³, =0, NH₂, N₃, SH, SO_xR³, halo, CN, NO₂, NR³R⁴, (NR³)NR³R⁴, NH(NR³)NR³R⁴, CO₂R⁴, OC(O)R³, CONR³R⁴, NR⁴C(O)R³, NR⁴SO₂R³, P(O)(OR³)₂, C1-9 alkyl optionally substituted with one or more OH, OR³, =0, NH₂, N₃, halo, CN, NO₂, NR³R⁴, CO₂R⁴, CONR³R⁴, aryl or carbocyclyl groups; O- glycosyl; C-glycosyl; O-sulfate; O-phosphate or a group which together with the endocyclic carbon forms a spiro ring, with the provisos that: (a) two OH groups may not be attached to the same endocyclic carbon atom; (b) where there is only one R² substituent it contains an oxygen atom directly bonded to an endocyclic carbon atom; and (c) where z>1 any two R² substituents may together form an optionally heterocyclic ring (for example a carbocycle, cyclic ether or acetal)

R⁴ represents H; C1-6 alkyl, optionally substituted with one or more OH

x represents an integer from O to 2

optionally wherein the compound has three, four or more rings or a pharmaceutically acceptable salt or derivative thereof, for the treatment of infection with, or a disease caused by, an infectious agent.

1 1. The compound of claim 10 wherein n = 2.

12. The compound of claim 10 wherein n = 3.

13. The compound of any one of claims 10 to 12 wherein m = 1.

14. The compound of any one of claims 10 to 12 wherein m = 2.

15. The compound of any one of claims 10 to 14 wherein (z + y) = 2 to ((n + m) + 4).

16. The compound of any one of claims 10 to 14 wherein (z + y) = 3 to ((n + m) + 4).

17. The compound of any one of claims 10 to 14 wherein (z + y) = 4 to ((n + m) + 4).

18. The compound of any one of the preceding claims wherein one or more endocyclic carbon atom(s) is replaced with a sulphur, oxygen or nitrogen heteroatom.

19. The compound of any one of the preceding claims having at least two R² substituents, one being OH and the other being hydroxymethyl.

20. An iminosugar as hereinbefore defined for the treatment of infection with, or a disease caused by, an infectious agent.

21. The compound or iminosugar as defined in any one of the preceding claims which is selected from: (a) compounds 1 to 892 of Table 1 , or a pharmaceutically acceptable salt or derivative thereof; or (b) the anti-HCV compounds listed in Table 2, or a pharmaceutically acceptable salt or derivative thereof; or (c) the anti-RSV compounds listed in Table 3, or a pharmaceutically acceptable salt or derivative thereof.

22. The invention of any one of the preceding claims wherein the infectious agent is a virus, for example a virus selected from: Retroviridae (e.g. the human immunodeficiency viruses, including HIV-1); Picornaviridae (e.g. polio viruses, hepatitis A virus; enteroviruses, human Coxsackie viruses, rhinoviruses, echoviruses); Calciviridae (e.g. strains that cause gastroenteritis); Togaviridae (e.g. equine encephalitis viruses, rubella viruses); Flaviridae (e.g. dengue viruses, HCV, encephalitis viruses, yellow fever viruses); Coronoviήdae (e.g. coronaviruses); Rhabdoviradae (e.g. vesicular stomatitis viruses, rabies viruses); Filoviridae (e.g. ebola viruses); Paramyxoviridae (e.g. parainfluenza viruses, mumps virus, measles virus, respiratory syncytial virus); Orthomyxoviridae (e.g. influenza viruses); Bungaviridae (e.g. Hantaan viruses, bunga viruses, phleboviruses and Nairo viruses); Arena viridae (hemorrhagic fever viruses); Reoviridae (e.g. reoviruses, orbiviurses and rotaviruses); Birnaviridae; Hepadnaviridae (Hepatitis B virus); Parvoviridae (parvoviruses); Papovaviridae (papilloma viruses, polyoma viruses); Adenoviridae (most adenoviruses); Herpesviridae (herpes simplex virus (HSV) 1 and 2, varicella zoster virus, cytomegalovirus (CMV), herpes virus; Poxviήdae (variola viruses, vaccinia viruses, pox viruses); Iridoviridae (e.g. African swine fever virus) and diabetogenic viruses, for example of the Picornavirus family (including enteroviruses, such as coxsackie A and B, echoviruses and polioviruses as well as encephalomyocarditis virus), the Togavirus family (for example, Rubella); the Paramyxovirus family (for example, mumps); the Reovirus family (for example, Rotavirus); the Parvovirus family (for example, Parvovirus) and the β-herpesviridae (for example, cytomegalovirus).

23. The invention of claim 22 wherein the virus is selected from HIV, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, rabies virus, poliovirus, influenza virus (including influenza A and influenza B virus), meningitis virus, measles virus, mumps virus, rubella, pertussis, encephalitis virus, papilloma virus, yellow fever virus, respiratory syncytial virus, parvovirus, chikungunya virus, haemorrhagic fever viruses and Herpes viruses, particularly, varicella, cytomegalovirus and Epstein-Barr virus.

24. The invention of any one of claims 1 to 21 wherein the virus is an enveloped viruses, for example an enveloped virus selected from the following virus families of groups: Poxviridae, e.g. vaccinia and smallpox; Iridoviridae; Herpesviridae, e.g. Herpes simplex; Varicella virus, cytomegalovirus and Eppstein-Barr virus, Togaviridae, e.g. Yellow fewer virus; thick-borne encephalitis virus; Rubella virus; tropical encephalitis virus; Coronaviridae, e.g. Human coronovirus; Paramyxoviridae; Rabdoviridae, e.g. vesicular stomatitis virus; rabies virus; Filoviridae, e.g. Marburg virus and Ebola virus; Orthomyxoviridae, e.g. Influenza A, B and C viruses; Bunyaviridae, e.g. Bwamba virus; California encephalitis virus; sandfly fever virus; Rift Valley fever virus; Arenaviridae, e.g. LCM virus, Lassa virus and Juni virus; Hepnadnaviridae, e.g. hepatitis B-virus; Retroviridae, e.g. HTLV and HIV-1 and HIV-2; Flaviviridae and Rhabdoviridae.

25. The invention of claim 24 wherein the virus is a member of the Paramyxoviridae selected from mumps virus, measles virus, Sendai virus, Newcastle disease virus (NDV), human respiratory syncytial virus (RSV), parainfluenza virus 5 (SV5), human parainfluenza viruses 1-4 (hPIV)1 and paramyxoviruses (for example Nipah and Hendra viruses).

26. The invention of any one of claims 1 to 21 wherein the disease caused is selected from encephalitis, intestinal infections, immunosuppressive disease, respiratory disease, hepatitis, pox infections and type 1 diabetes.

27. The invention of any one of claims 1 to 21 wherein the virus is a flavivirus.

28. The invention of claim 27 wherein the flavivirus is a member of the genus Pestivirus or Flavivirus.

29. The invention of claim 27 wherein the flavivirus is a member of the genus Hepacivirus.

30. The invention of claim 29 wherein the virus is HCV, for example selected from HCV genotypes 1 , 2, 3, 4, 5 and 6.

31. The invention of claim 27 wherein the flavivirus is selected from yellow fever virus, dengue viruses, Japanese encephalitis virus and tick-borne encephalitis virus.

32. The invention of claim 27 wherein the flavivirus is an animal virus.

33. The invention of claim 32 wherein the animal virus is selected from bovine viral diarrhoea virus (BVDV), classical swine fever virus and border disease virus.

34. The invention of any one of claims 27 to 33 wherein the disease is selected from:

a. hepatitis C; b. yellow fever; c. dengue fever; d. Japanese encephalitis; e. Murray Valley encephalitis; f. Rocio virus infection; g. West Nile fever; h. St. Louis encephalitis; i, tick-borne encephalitis; j. Louping ill virus infection; k. Powassan virus infection; i. Omsk hemorrhagic fever; m. Kyasanur forest disease; n. bovine diarrhoea; o. classical swine fever (hog cholera); and p. border disease.

35. A composition comprising a compound as defined in any one of claims 1 to 21 in combination with an adjunctive agent selected from:

(a) compounds which inhibit the binding to and/or infection of cells by HCV; and/or

(b) compounds which inhibit the release of viral RNA from the viral capsid or the function of HCV gene products, optionally selected from inhibitors of the

IRES, protease (e.g. serine protease) inhibitors, helicase inhibitors and inhibitors of the viral polymerase/replicase; and/or

(c) compounds which perturb cellular functions involved in or influencing viral replication; and/or (d) compounds which act to alter immune function; and/or

(e) compounds which act to modulate the symptoms and effects of HCV infection (e.g. antioxidants such as the flavinoids); and/or (T) compounds used in the treatment of hepatitis B virus and/or human retroviruses (for example nucleotide RT inhibitors, non-nucleoside RT inhibitors and protease inhibitors).

36. The composition of claim 35 wherein in (d) the compound which alters immune function is interferon-α (IFN-α).

37. The composition of claim 35 wherein in (c) the compound which perturbs cellular functions involved in or influencing viral replication is ribavirin.

38. A composition comprising a compound as defined in any one of claims 1 to 21 in combination with an adjunctive agent selected from: (a) viral enzyme inhibitors (for example selected from (i) protease inhibitors, (ii) helicase inhibitors and (iii) polymerase inhibitors); (b) nucleoside/nucleotide reverse transcriptase inhibitors; (c) non-nucleoside reverse transcriptase inhibitors; (d) integrase inhibitors; (e) maturation inhibitors; (f) cytokines or cytokine stimulatory factors; (g) viral entry inhibitors, for example selected from: (i) an attachment inhibitor; (ii) a co-receptor binding inhibitor; and (iii) a membrane fusion inhibitor.

39. A compound as defined in any one of claims 1 to 21 for use in combination therapy with interferon-α.

40. A compound as defined in any one of claims 1 to 21 for use in combination therapy with ribavirin (for example with ribavirin and interferon-α).

41. The invention of any one of claims 1 to 21 wherein the infectious agent is a bacterium, for example one or more bacteria of the following genera: Acinetobacter (e.g. A. baumannii); Aeromonas (e.g. A. hydrophila); Bacillus (e.g. B. anthracis); Bacteroides (e.g.

B. fragilis); Bordetella (e.g. B. pertussis); Borrelia (e.g. B. burgdorferi); Brucella (e.g. B. abortus, B. cam^'s, B. melitensis and B. suis); Burkholderia (e.g. β. cepacia complex); Campylobacter (e.g. C. jejuni); Chlamydia (e.g. C. trachomatis, C. suis and C. muridarum); Chlamydophila (e.g. (e.g. C. pneumoniae, C. pecorum, C. psittaci, C. abortus, C. felis and

C. caviae); Citrobacter (e.g. C. freundii); Clostridium (e.g. C. botulinum, C. difficile, C. perfringens and C. tetani); Corynebacterium (e.g. C. diphteriae and C. glutamicum); Enterobacter (e.g. E. cloacae and E. aerogenes); Enterococcus (e.g. E. faecalis and E. faecium); Escherichia (e.g. E. coli); Flavobacterium; Francisella (e.g. F. tularensis); Fusobacterium (e.g. F. necrophorum); Haemophilus (e.g. H. somnus, H. influenzae and H. parainfluenzae); Helicobacter (e.g. H. pylori); Klebsiella (e.g. K. oxytoca and K. pneumoniae), Legionella (e.g. L pneumophila); Leptospira (e.g. L interrogans); Listeria

(e.g. L monocytogenes); Moraxella (e.g. M. catarrhalis); Morganella (e.g. M. morganii);

Mycobacterium (e.g. M. leprae and M. tuberculosis); Mycoplasma (e.g. M. pneumoniae); Neisseria (e.g. N. gonorrhoeae and N. meningitidis); Pasteurella (e.g. P. multocida); Peptostreptococcus; Prevotella; Proteus (e.g. P. mirabilis and P. vulgaris), Pseudomonas (e.g. P. aeruginosa); Rickettsia (e.g. R. rickettsii); Salmonella (e.g. S. typhi and S. typhimurium); Serratia (e.g. S. marcesens); Shigella (e.g. S. flexnaria, S. dysenteriae and S. sonnei); Staphylococcus (e.g. S. aureus, S. haemolyticus, S. intermedius, S. epidermidis and S. saprophytics); Stenotrophomonas (e.g. S. maltophila); Streptococcus (e.g. S. agalactiae, S. mutans, S. pneumoniae and S. pyogenes); Treponema (e.g. T. pallidum); Vibrio (e.g. V. cholerae) and Yersinia (e.g. Y. pestis).

42. The invention of any one of claims 1 to 21 wherein the disease is selected from: anthrax (e.g. cutaneous anthrax, pulmonary anthrax and gastrointestinal anthrax); bacterial pneumonia; whooping cough; Lyme disease; brucellosis; acute enteritis; botulism; tetanus; diphtheria; tularemia; Lemierre's syndrome; Legionnaire's Disease; leprosy (Hansen's disease); tuberculosis, meningitis, syphilis, gas gangrene, scarlet fever, erysipelas, rheumatic fever, streptococcal pharyngitis, toxic shock syndrome, listeriosis, Whipple's disease, erythrasma, nocardiosis, maduromycosis, Ghon's complex, Pott's disease, Rich focus, scrofula, Bazin disease, lupus vulgaris, Lady Windermere syndrome, Buruli ulcer, yaws, relapsing fever, trench mouth, rat-bite fever, leptospirosis, mycoplasmal pneumonia, ureaplasmal infection, psittacosis, chlamydia, lymphogranuloma venereum, trachoma, rickettsioses, typhus, spotted fever, Rocky Mountain spotted fever, Boutonneuse fever, Rickettsial pox, ehrlichiosis (including human granulocytic ehrlichiosis and human monocytic ehrlichiosis), Q fever, bartonella, orientia, bacillary angiomatosis, Waterhouse-Friderichsen syndrome, gonorrhoea, burkholderiales, glanders, melioidosis, pertussis, typhoid fever, paratyphoid fever, salmonellosis, rhinoscleroma, donovanosis, shigellosis, pasteurellosis, Brazilian purpuric fever, chancroid, actinobacillosis, cholera, campylobacteriosis, bronchitis, sinusitis, laryngitis, otitis media, bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, prostatitis, bronchitis, C. difficile colitis, cervicitis, septicemia, skin and soft tissue infections, urinary tract infections, sepsis (including catheter-related sepsis), hospital-acquired pneumonia (HAP), gynecological infection, respiratory tract infection (RTI), sexually transmitted disease, urinary tract infection, acute exacerbation of chronic bronchitis (ACEB), acute otitis media, acute sinusitis, an infection caused by drug resistant bacteria, skin and skin structure infection, febrile neutropenia, gonococcal cervicitis, upper and lower respiratory tract infections, skin and soft tissue infections, hospital-acquired lung infections, bone and joint infections, respiratory tract infections, acute bacterial otitis media, pyelonephritis, intra-abdominal infections, deep-seated abcesses, central nervous system infections, bacteremia, wound infections, peritonitis, infections after burn, urogenital tract infections, gastro-intestinal tract infections, pelvic inflammatory disease; intravascular infections and plague.

43. A composition comprising a compound as defined in any one of claims 1 to 21 in combination with an antibacterial adjunctive agent selected from: Aminoglycosides (for example amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin and paromomycin); Ansamycins (for example geldanamycin and herbimycin); Carbacephems (for example loracarbef); Carbapenems (for example ertapenem, doripenem, imipenem/cilastatin and meropenem); Cephalosporins (first generation), for example cefadroxil, cefazolin, cefalotin/cefalothin and cephalexin; Cephalosporins (second generation), for example cefaclor, cefamandole, cefoxitin, cefprozil and cefuroxime; Cephalosporins (third generation), for example cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone and cefdinir; Cephalosporins (fourth generation), for example cefepime; Glycopeptides (for example vancomycin and teicoplanin); Macrolides (for example azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin and spectinomycin); Monobactams (for example aztreonam); Penicillins (for example amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, penicillin, piperacillin and ticarcillin); Polypeptides (for example bacitracin, polymixin B and colistin); Quinolones (for example ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin and trovafloxacin); Sulfonamides (for example mafenide, prontosil, sulfacetamide, sulfamethizole, sulfanamide, sulfasalazine, sulfisoxazole, trimethoprim, trimethoprim- sulfamethoxazole (co-trimoxazole, TMP-SMX)); Tetracyclines (for example demeclocycline, doxycycline, minocycline, oxytetracycline and tetracycline); Aminocoumarins (for example novobiocin, albamycin, coumermycin and clorobiocin); Oxazolidinones (for example linezolid and AZD2563) and other antibacterial agents selected from arsphenamine, chloramphenicol, clindamycin, lincoamycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, metronidazole, mupirocin, nitrofurantoin, platensimycin, pyrazinamide, quinupristin/dalfopristin, rifampin/rifampicin and tinidazole.

44. The invention of any one of claims 1 to 21 wherein the infectious agent is a fungus.

45. The invention of claim 44 wherein the compound or iminosugar is antidermatophytic and/or anticandidal.

46. The invention of claim 45 wherein the compound or iminosugar is active against; (a) Microsporum spp.; and/or

(b) Trichophyton spp.; and/or

(c) Epidermophyton spp..

47. The invention of claim 44 wherein the compound or iminosugar is active against: (a) Acremonium spp.; and/or

(b) Alternaria spp.; and/or

(c) Aspergillus spp.; and/or

(d) Botryodiplodia spp. (e.g. B. theobromae); and/or

(e) Fusarium spp.; and/or (f) Onycochola spp. (e.g. O. canadensis); and/or

(g) Pyrenochaeta spp. (e.g. P. unguis-hominis); and/or

(h) Scytalidium spp. (e.g. S. dimidiatum, S. scopulariopsis and S. hyalimum); and/or (i) a yeast, for example selected from Candida spp. (e.g. C. albicans); Malassezia spp. (e.g. M. furfur, Geotrichum spp. (e.g. G. candidum) and Sporothrix spp. (e.g. S. schenkii).

48. The invention of any one of claims 1 to 21 wherein the disease is selected from:

(a) dermatophytosis;

(b) onychomycosis; (c) dermatomycosis;

(d) candidiasis; and

(e) aspergillosis.

49. The invention of claim 48(a) wherein the dermatophytosis is selected from: (a) tinea capitis;

(b) tinea favosa;

(c) tinea corporis;

(d) tinea axillaris;

(e) tinea faciei; (f) tinea imbricata; (g) tinea pedis; (h) tinea manuum; (i) tinea cruris/inguinalis; (j) tinea circinata; (k) tinea profunda;

(I) Majocchi's granuloma; (m) bullous tinea corporis; (n) tinea unguium; (o) tinea barbae/sycosis; (p) tinea tonsurans; and

(q) tinea incognito.

50. The invention of any one of claims 1 to 21 wherein the infection involves superinfection or co-infection with one or more microorganisms.

51. The invention of claim 50 wherein the superinfecting or co-infecting microorganism(s) are selected from one or more of:

(a) a dermatophyte;

(b) a non-dermatophyte; (c) a yeast (e.g. a Candida spp., e.g. C. albicans);

(d) an Aspergillus sp.; and

(e) a bacterium (e.g. a Gram-positive bacterium, a Gram-negative bacterium or a mycoplasma).

52. The invention of any one of claims 1 to 21 wherein the infection is refractory fungal infection, a mixed infection, and opportunistic infection or a nosocomial infection.

53. The invention of claim 48(b) wherein the onychomycosis involves infection with a dermatophyte selected from: (a) Epidermophyton spp. (e.g. E. floccosum); and

(b) Trichophyton spp. (e.g. T. mentagrophytes or T. rubrum).

54. The invention of claim 48(b) wherein the onychomycosis involves infection with a non- dermatophyte selected from the genera: (a) Acremonium; (b) Alternaria;

(c) Aspergillus;

(d) Botryodiplodia (e.g. B. theobromae);

(e) Fusarium; (f) Onycochola (e.g. O. canadensis);

(g) Pyrenochaeta (e.g. P. unguis-hominis);

(h) Scytalidium (e.g. S. dimidiatum, S. scopulariopsis and S. hyalimum); (i) Candida (e.g. C. albicans); Q) Malassezia spp. (e.g. M. ft/Afur); (k) Geotrichum spp. (e.g. G. candidum); and

(I) Sporothrix spp. (e.g. S. schenkii).

55. The invention of any one of claims 1 to 21 wherein the disease is selected from: (a) endothrix; (b) ectothrix;

(c) intertrigo; and

(d) folliculitis.

56. A composition comprising a compound as defined in any one of claims 1 to 21 in combination with an adjunctive agent selected from: (a) griseofulvin; (b) an azole (e.g. an imidazole or triazole); (c) a polyene; (d) an allylamine (e.g. terbinafine); (e) a candin (e.g. caspofungin, micafungin and anidulafungin); and (T) a morpholine (e.g. amorolfine).

57. A composition comprising a compound as defined in any one of claims 1 to 21 in combination with an adjunctive agent selected from: imidazoles (such as miconazole, ketoconazole and clotrimazole); triazoles (such as fluconazole, posaconazole, voriconazole and ravuconazole), azaconazole, bromuconazole bitertanol, propiconazole, difenoconazole, diniconazole, cyproconazole, epoxiconazole, fluquinconazole, flusilazole.flutriafol, hexaconazole, itraconazole, imazalil, imibenconazole, ipconazole, tebuconazole, tetraconazole, fenbuconazole, metconazole, myclobutanil, perfurazoate, penconazole, pyrifenox, prochloraz, terconazole, triadimefon, triadimenol, triflumizole, and triticonazole.

58. The invention of any one of claims 1 to 21 wherein the infectious agent is a protozoan, for example a protozoan selected from: Plasmodium spp. (for example Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale and Plasmodium v/Vax); Toxoplasma spp. (for example T. gondii and T. cruzii); Leishmania spp.; Cryptosporidium spp. (for example C. parvum); Cyclospora spp. (for example C. cayetanensis); Entamoeba (for example E. histolytica) and Giardia spp. (for example G. lamblia). .

59. A composition comprising a compound as defined in any one of claims 1 to 21 in combination with an adjunctive agent selected from: chloroquine, doxycycline, mefloquine, metronidazole, eplornithine, furazolidone, hydroxychloroquine, iodoquinol, pentamidine, mebendazole, piperazine, halofantrine, primaquine, pyrimethamine sulfadoxine, doxycycline, clindamycin, quinine sulfate, quinidine gluconate, quinine dihydrochloride, hydroxychloroquine sulfate, proguanil, quinine, clindamycin, atovaquone, azithromycin, suramin, melarsoprol, eflornithine, nifurtimox, amphotericin B, sodium stibogluconate, pentamidine isethionate, trimethoprim- sulfamethoxazole, pyrimethamine and sulfadiazine.

60. The invention of any one of claims 1 to 21 wherein the infectious agent is a metazoan, for example a metazoan selected from helminths (e.g. Schistosoma spp.).

61. A combination comprising a compound or iminosugar as defined in any one of claims 1 to 21 and an adjunctive agent as defined in any one of claims 35 to 38, 43, 56-57 and 59 (for example, interferon-α and/or ribavirin).

62. The combination of claim 61 wherein the compound or iminosugar and adjunctive agent are physically associated.

63. The combination of claim 62 wherein the compound or iminosugar and adjunctive agent 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).

64. The combination of claim 62 or claim 63 wherein the compound or iminosugar and adjunctive agent are non-physically associated.

65. The combination of claim 64 wherein the combination comprises: (a) at least one of the compound or iminosugar and adjunctive agent together with instructions for their extemporaneous association to form a physical association; or (b) at least one of the compound or iminosugar and adjunctive agent together with instructions for combination therapy with the inhibitor and adjunctive agent; or (c) at least one of the compound or iminosugar and adjunctive agent together with instructions for administration to a patient population in which either the compound or iminosugar or adjunctive agent have been (or are being) administered; or (d) at least one of the compound or iminosugar and adjunctive agent in an amount or in a form which is specifically adapted for use in combination.

66. The combination as defined in any one of claims 61 to 65: (a) in the form of a pharmaceutical pack, kit or patient pack; (b) in a pharmaceutical excipient; or (c) in unit dosage form.

67. A pharmaceutical composition comprising the combination as defined in any one of claims 61 to 65.

68. A combination according to any one of claims 61 to 65 for Use in therapy or prophylaxis, for example the treatment or prophylaxis of an infection).

69. The compound or iminosugar as defined in any one of claims 1 to 21 for the treatment of a subject undergoing treatment with an antiinfective agent.

70. A compound or iminosugar as defined in any one of claims 1 to 21 for use in combination therapy with an adjunctive agent as defined in any one of claims 35 to 38, 43, 56-57 and 59.

71. The compound or iminosugar of claim 69 wherein the antiinfective agent is selected from the adjunctive agents defined in any one of claims 35 to 38, 43, 56-57 and 59.

72. A method for the treatment of an infection with, or disease caused by, an infective agent in a subject, comprising administering an effective amount of a compound or iminosugar as defined in any one of claims 1 to 21 to said subject.