WO2010049678A2 - Treatment of energy utilization diseases - Google Patents

Treatment of energy utilization diseases Download PDF

Info

Publication number
WO2010049678A2
WO2010049678A2 PCT/GB2009/002554 GB2009002554W WO2010049678A2 WO 2010049678 A2 WO2010049678 A2 WO 2010049678A2 GB 2009002554 W GB2009002554 W GB 2009002554W WO 2010049678 A2 WO2010049678 A2 WO 2010049678A2
Authority
WO
WIPO (PCT)
Prior art keywords
pyrrolidine
compound
hydroxymethyl
piperidine
optionally substituted
Prior art date
Application number
PCT/GB2009/002554
Other languages
French (fr)
Other versions
WO2010049678A3 (en
Inventor
Francis Xavier Wilson
Robert James Nash
Graeme Horne
Richard Storer
Jonathan Mark Tinsley
Alan Geoffrey Roach
Original Assignee
Summit Corporation Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0819941A external-priority patent/GB0819941D0/en
Priority claimed from GB0906161A external-priority patent/GB0906161D0/en
Priority claimed from GB0908702A external-priority patent/GB0908702D0/en
Priority claimed from GB0914471A external-priority patent/GB0914471D0/en
Application filed by Summit Corporation Plc filed Critical Summit Corporation Plc
Publication of WO2010049678A2 publication Critical patent/WO2010049678A2/en
Publication of WO2010049678A3 publication Critical patent/WO2010049678A3/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones

Definitions

  • This invention relates to certain compounds, in particular iminosugars, and to methods for the treatment of energy utilization diseases, in particular diabetes (including type 1 diabetes, type 2 diabetes and insulin resistance) and metabolic syndrome (including any disease or disorder associated therewith, for example central obesity and elevated levels of triglycerides) based on the use of these compounds.
  • diabetes including type 1 diabetes, type 2 diabetes and insulin resistance
  • metabolic syndrome including any disease or disorder associated therewith, for example central obesity and elevated levels of triglycerides
  • Energy utilization diseases encompass a wide range of diseases and include, for example, disorders of homeostasis, metabolic diseases, dysfunction of sugar metabolism and appetite disorders.
  • Examples of energy utilization diseases therefore include insulin resistance, various forms of diabetes, metabolic syndrome, obesity, wasting syndromes (for example, cancer associated cachexia), myopathies, gastrointestinal disease, growth retardation, hypercholesterolemia, atherosclerosis and age-associated metabolic dysfunction.
  • wasting syndromes for example, cancer associated cachexia
  • myopathies for example, gastrointestinal disease, growth retardation, hypercholesterolemia, atherosclerosis and age-associated metabolic dysfunction.
  • Energy utilization diseases also include conditions associated with metabolic syndrome, obesity and/or diabetes, including for example hyperglycaemia, glucose intolerance, hyperinsulinaemia, glucosuria, metabolic acidosis, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, macular degeneration, glomerulosclerosis, diabetic cardiomyopathy, insulin resistance, impaired glucose metabolism, arthritis, hypertension, hyperlipidemia, osteoporosis, osteopenia, bone loss, brittle bone syndromes, acute coronary syndrome, infertility, short bowel syndrome, chronic fatigue, eating disorders and intestinal motility dysfunction.
  • hyperglycaemia glucose intolerance
  • hyperinsulinaemia glucosuria
  • metabolic acidosis cataracts
  • diabetic neuropathy diabetic nephropathy
  • diabetic retinopathy macular degeneration
  • glomerulosclerosis diabetic cardiomyopathy
  • insulin resistance impaired glucose metabolism, arthritis, hypertension, hyperlipidemia, osteoporosis, osteopenia, bone loss
  • pancreatic ⁇ -cells sense increases in blood glucose levels and respond by secreting insulin.
  • Insulin promotes glucose uptake by tissues of the body, thereby restoring blood glucose concentration to the physiological range.
  • Glucagon acts reciprocally, increasing blood glucose levels under fasting conditions, primarily by stimulating glucose production in the liver.
  • Insulin resistance is characterized by a reduced action of insulin in skeletal muscle, adipocytes and hepatocytes so that normal amounts of insulin become inadequate to produce a normal insulin response from the cells of these tissues.
  • adipocytes insulin resistance results in hydrolysis of stored triglycerides, leading to elevated free fatty acids in the blood plasma.
  • insulin resistance reduces glucose uptake while in hepatocytes it reduces glucose storage. In both of the latter cases an elevation of blood glucose concentrations results.
  • Metabolic syndrome is a constellation of abnormalities and disorders that increase the risk of cardiovascular disease and diabetes. The incidence is very high in many developed countries: some studies indicate prevalence in the USA of up to 25% of the population. The disorder is also known as (metabolic) syndrome X, insulin resistance syndrome, Reaven's syndrome and CHAOS. Metabolic syndrome may be diagnosed by the presence of three or more of the following symptoms: central obesity (waist measurement of more than 40 inches for men and more than 35 inches for women); high levels of triglycerides (150 mg/dL or higher); low levels of HDL (below 40 mg/dL for men and below 50 mg/dL for women) and high blood pressure (130/85 mm Hg or higher). Associated diseases and signs are: fatty liver (often progressing to non-alcoholic fatty liver disease), polycystic ovarian syndrome, hemochromatosis (iron overload) and acanthosis nigricans (dark skin patches).
  • the first line treatment of metabolic syndrome is change of lifestyle (caloric restriction and physical activity). However, drug treatment is frequently required. Generally, the individual diseases that comprise the metabolic syndrome are treated separately (e.g. diuretics and ACE inhibitors for hypertension). Cholesterol drugs may be used to lower LDL cholesterol and triglyceride levels, if they are elevated, and to raise HDL levels if they are low. Use of drugs that decrease insulin resistance (e.g. metformin and thiazolidinediones is controversial). Cardiovascular exercise is therapeutic in less than 31% of cases and does not generally produce a decrease in fasting plasma glucose or insulin resistance.
  • Type 2 diabetes is a chronic disease that is characterised by persistently elevated blood glucose levels (hyperglycaemia). Insulin resistance together with impaired insulin secretion from the pancreatic ⁇ -cells characterizes the disease. The progression of insulin resistance to type 2 diabetes is marked by the development of hyperglycaemia after eating when pancreatic ⁇ -cells become unable to produce adequate insulin to maintain normal blood sugar levels (euglycemia).
  • Metformin is of the biguanide class of oral antihyperglycaemic agents.
  • Other biguanides include phenformin and buformin (now withdrawn).
  • Metformin works primarily by reducing liver release of blood glucose from glycogen stores, but also has some effect in increasing the uptake of glucose.
  • Other widely used drug classes include those of the sulfonylurea group (including glibenclamide and gliclazide). These drugs increase glucose stimulated insulin secretion by the pancreas.
  • Newer drug classes include thiazolidinediones (e.g.
  • rosiglitazone, pioglitazone, and troglitazone which act by binding to PPARs (peroxisome proliferator-activated receptors), a group of receptor molecules inside the cell nucleus.
  • PPARs peroxisome proliferator-activated receptors
  • Other classes include ⁇ -glucosidase inhibitors (acarbose), meglitinides (which stimulate insulin release and include nateglinide, repaglinide and their analogues), peptide analogs (e.g. incretin mimetics, which act as insulin secretagogues, glucagon-like peptide analogues (e.g. exenatide), dipeptidyl peptidase-4 (DPP-4) inhibitors (which increase incretin levels (e.g. sitagliptin) and amylin agonist analogues (which slow gastric emptying and suppress glucagon (e.g. pramlintide).
  • O-linked - ⁇ - ⁇ /-acetylglucosamine (O-GlcNAc) is a dynamic posttranslational modification that, analogous to phosphorylation, cycles on and off serine and/or threonine hydroxyl groups. Cycling of O-GlcNAc is regulated by the concerted actions of O-GlcNAc transferase and O-GlcNAcase.
  • GlcNAcylation is involved in the aetiology of glucose toxicity and chronic hyperglycemia-induced insulin resistance, a major hallmark of type 2 diabetes. Hexosaminidase activity has been shown to be elevated in the serum of diabetics (e.g. Agardh, CD. et al., 1982, Acta Med Scand. 212:39-41).
  • Type 1 diabetes (or insulin dependent diabetes) is characterized by loss of the insulin- producing beta cells of the islets of Langerhans in the pancreas, leading to a deficiency of insulin.
  • the main cause of this beta cell loss is a T-cell mediated autoimmune attack.
  • There is no known preventative measure that can be taken against type 1 diabetes which comprises up to 10% of diabetes mellitus cases in North America and Europe. Most affected people are otherwise healthy and of a healthy weight when onset occurs. Sensitivity and responsiveness to insulin are usually normal, especially in the early stages.
  • type 1 diabetes Even from the earliest stages, is replacement of insulin combined with careful monitoring of blood glucose levels using blood-testing monitors. Without insulin, ketosis and diabetic ketoacidosis can develop and coma or death will result. Apart from the common subcutaneous injections, it is also possible to deliver insulin by a pump, which allows continuous infusion of insulin 24 hours a day at preset levels, and the ability to program closes (a bolus) of insulin as needed at meal times. An inhaled form of insulin, Exubera, has recently been approved by the FDA.
  • 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
  • y 1 or 2
  • R 1 represents H; C1-15 alkyl, C1-15 alkenyl or C1-15 alkynyl, optionally substituted with one or more R 2 ; oxygen or an oxygen containing group such that the compound is an N-oxide; C(O)OR 3 ; C(O)NR 3 R 4 ; SO 2 NR 3 ; OH, OR 3 , or formyl
  • R 3 represents H; C1-6 alkyl, optionally substituted with one or more OH; aryl or C1- 3 alkyl optionally substituted with aryl; SiR 4 3 and
  • R 4 represents H; C1-6 alkyl, optionally substituted with one or more OH
  • R 3 and R 4 may optionally form a 4 to 8 membered ring, containing one or more O, SO x or NR 3 groups
  • x represents an integer from O to 2
  • the invention provides a compound of Formula (2)
  • p represents an integer from 1 to 2
  • z represents an integer from 1 to (p+7)
  • y 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 R 2
  • R 1 represents H; C1-15 alkyl, C1-15 alkenyl or C1-15 alkynyl, optionally substituted with one or more R 2 ; oxygen or an oxygen containing group such that the compound is an N-oxide; C(O)OR 3 ; C(O)NR 3 R 4 ; SO 2 NR 3 ; OH, OR 3 , or formyl
  • R 3 represents H; C1-6 alkyl, optionally substituted with one or more OH; aryl or C1-
  • R 4 represents H; C1-6 alkyl, optionally substituted with one or more OH
  • R 3 and R 4 may optionally form a 4 to 8 membered ring, containing one or more O,
  • x represents an integer from O to 2
  • the invention provides a compound of Formula (3)
  • 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
  • n represents an integer from 1 to 3 and the ring may also contain at least one unsaturated C-C bond
  • the endocyclic nitrogen atom may be bonded to an oxygen or an oxygen containing group such that the compound is an N-oxide
  • R 3 represents H; C1-6 alkyl, optionally substituted with one or more OH; aryl or C1- 3 alkyl optionally substituted with aryl; SiR 4 3 and
  • R 4 represents H; C1-6 alkyl, optionally substituted with one or more OH
  • R 3 and R 4 may optionally form a 4 to 8 membered ring, containing one or more O, SO x or NR 3 groups
  • x represents an integer from O to 2
  • the compound has three, four or more rings or pharmaceutically acceptable salt or derivative thereof, for the treatment of an energy utilization disease.
  • the invention provides an iminosugar as herein defined for the treatment of an energy utilization disease.
  • the invention provides a compound selected from compounds 1 to 892 of Table 1 , or a pharmaceutically acceptable salt or derivative thereof, for the treatment of an energy utilization disease.
  • the invention also contemplates adjunctive use of the compounds of the invention with various adjunctive agents.
  • the invention provides a composition comprising a compound or iminosugar of the invention and an adjunctive agent.
  • the invention provides a pharmaceutical kit of parts comprising a compound of the invention in combination with an adjunctive agent.
  • 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.
  • the term “comprising” is inclusive or open-ended and does not exclude additional, unrecited integers or method/process steps.
  • 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.
  • 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.
  • treatment 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).
  • the term is used synonymously with the term “therapy”.
  • treatment 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.
  • treatment is used synonymously with the term “prophylaxis”.
  • metabolic syndrome is used herein to define conditions characterized by the presence of three or more of the following symptoms: central obesity (waist measurement of more than 40 inches for men and more than 35 inches for women); high levels of triglycerides (150 mg/dL or higher); low levels of HDL (below 40 mg/dL for men and below 50 mg/dL for women) and high blood pressure (130/85 mm Hg or higher).
  • the term therefore includes conditions defined in accordance with the definition of metabolic syndrome by the World Health Organization: (a) fasting plasma glucose above 6.1 mmol/L; (b) blood pressure above140/90 mm Hg; and (c) one or more of the following: (i) plasma triglycerides above 1.7mmol/L; (ii) HDL below 0.9 and 1.0 mmol/L (for men and women, respectively); (iii) a body mass index above 30 kg/m 2 .
  • references herein to the treatment of metabolic syndrome are to be interpreted to include the treatment of any or all of the disorders associated with metabolic syndrome, including in particular obesity (e.g. central obesity) and elevated serum triglycerides.
  • references herein to the treatment of type 1 or type 2 diabetes are to be interpreted to include the treatment of type 1 and type 2 diabetes perse as well as pre-diabetes (incipient diabetes) and insulin resistance.
  • pre-diabetes or “incipient diabetes” defines conditions in which elevated levels of glucose or glycosylated haemoglobin are present in the absence of diabetes.
  • intervention is a term of art used herein to define any agency which effects a physiological change at any level.
  • 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.
  • 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.
  • the subject is a human.
  • 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.
  • 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.
  • 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).
  • adjunctive use of the materials of the invention is reflected in the formulation of the pharmaceutical compositions of the invention.
  • 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).
  • 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.
  • 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.
  • the terms “combined” and “combining” in this context are to be interpreted accordingly.
  • 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
  • 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);
  • 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.
  • 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.
  • 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).
  • 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.
  • dosing means e.g. measuring device
  • delivery means e.g. inhaler or syringe
  • 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.
  • the term "pharmaceutical pack” defines an array of one or more unit doses of a pharmaceutical composition, optionally contained within common outer packaging.
  • 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.
  • 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.
  • 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.
  • 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.
  • iminosugar acid defines mono- or bicyclic sugar acid analogues in which the ring oxygen is replaced by a nitrogen.
  • 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); pyrrolizidine; indolizidine and nortropane.
  • 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.
  • 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).
  • iminosugars typically have at least 3, 4, 5, 6 or 7 (preferably 3, 4 or 5) free hydroxyl groups on the ring system nucleus.
  • 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.
  • 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 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.
  • 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.
  • the ligands of the invention may bind the target and thereby result in 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).
  • 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.
  • 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.
  • 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.
  • the ligands of the invention may bind PRRs and thereby result in 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).
  • 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.
  • 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.
  • 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).
  • sila-substituted 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 Phvsiol Pharmacol. 77(2):79-88). In its broadest aspect, the present invention contemplates all bioisosteres (and specifically, all silicon bioisosteres) of the compounds of the invention.
  • the present invention contemplates all optical isomers, racemic forms and diastereoisomers of the compounds described herein.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • organic carboxylic acids for example acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic
  • 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.
  • alky defines a straight or branched saturated hydrocarbon chain.
  • C 1 -C 6 alkyl refers to a straight or branched saturated hydrocarbon chain having one to six carbon atoms.
  • C r C 9 alkyl refers to a straight or branched saturated hydrocarbon chain having one to nine carbon atoms.
  • C 1 -C 15 alkyl refers to a straight or branched saturated hydrocarbon chain having one to fifteen carbon atoms.
  • Preferred is C 1 -C 6 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.
  • alkenyl defines a straight or branched hydrocarbon chain having containing at least one carbon-carbon double bond.
  • C 1 -C 6 alkenyl refers to a straight or branched unsaturated hydrocarbon chain having one to six carbon atoms.
  • C 1 -C 9 alkenyl refers to a straight or branched unsaturated hydrocarbon chain having one to nine carbon atoms.
  • C 1 -C 15 alkenyl refers to a straight or branched unsaturated hydrocarbon chain having one to fifteen carbon atoms.
  • Preferred is C 1 -C 6 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.
  • alkynyl defines a straight or branched hydrocarbon chain having containing at least one carbon-carbon triple bond.
  • C 1 -C 6 alkynyl refers to a straight or branched unsaturated hydrocarbon chain having one to six carbon atoms.
  • C 1 -C 9 alkynyl refers to a straight or branched unsaturated hydrocarbon chain having one to nine carbon atoms.
  • C 1 -C 15 alkynyl refers to a straight or branched unsaturated hydrocarbon chain having one to fifteen carbon atoms.
  • Preferred is C 1 -C 6 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.
  • 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.
  • cycloalkyls Saturated carbocyclyl residues are preferred and are referred to herein as "cycloalkyls" and the term “cycloalkyl” is used herein to define a saturated 3 to 14 membered carbocyclic ring including fused bicyclic or tricyclic systems. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and also bridged systems such as norbomyl and adamantyl.
  • the cycloalkyl residues of the invention may be optionally substituted by one or more halogen atoms.
  • aryl defines a 5-14 (e.g.
  • 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.
  • halo refers to fluoro, chloro, bromo or iodo.
  • diseases which may be treated according to the invention include, for example, disorders of homeostasis, metabolic diseases, dysfunction of sugar metabolism and appetite disorders.
  • the invention finds application in the treatment of insulin resistance, various forms of diabetes, metabolic syndrome, obesity, wasting syndromes (for example, cancer associated cachexia), myopathies, gastrointestinal disease, growth retardation, hypercholesterolemia, atherosclerosis and age-associated metabolic dysfunction.
  • various forms of diabetes for example, metabolic syndrome, obesity, wasting syndromes (for example, cancer associated cachexia), myopathies, gastrointestinal disease, growth retardation, hypercholesterolemia, atherosclerosis and age-associated metabolic dysfunction.
  • the invention may also be used for the treatment of conditions associated with metabolic syndrome, obesity and/or diabetes, including for example hyperglycaemia, glucose intolerance, hyperinsulinaemia, glucosuria, metabolic acidosis, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, macular degeneration, glomerulosclerosis, diabetic cardiomyopathy, insulin resistance, impaired glucose metabolism, arthritis, hypertension, hyperlipidemia, osteoporosis, osteopenia, bone loss, brittle bone syndromes, acute coronary syndrome, infertility, short bowel syndrome, chronic fatigue, eating disorders, intestinal motility dysfunction and sugar metabolism dysfunction.
  • hyperglycaemia glucose intolerance
  • hyperinsulinaemia glucosuria
  • metabolic acidosis cataracts
  • diabetic neuropathy diabetic nephropathy, diabetic retinopathy
  • macular degeneration glomerulosclerosis
  • diabetic cardiomyopathy insulin resistance, impaired glucose metabolism, arthritis, hypertension, hyperlipidemia, osteoporos
  • the invention may also be used to suppress appetite. Particularly preferred is the treatment of insulin resistance, metabolic syndrome, obesity and diabetes (particularly type 2 diabetes).
  • Insulin resistance is characterized by a reduced action of insulin in skeletal muscle, adipocytes and hepatocytes so that normal amounts of insulin become inadequate to produce a normal insulin response from the cells of these tissues.
  • adipocytes insulin resistance results in hydrolysis of stored triglycerides, leading to elevated free fatty acids in the blood plasma.
  • insulin resistance reduces glucose uptake while in hepatocytes it reduces glucose storage. In both of the latter cases an elevation of blood glucose concentrations results. High plasma levels of insulin and glucose due to insulin resistance often progresses to metabolic syndrome and type 2 diabetes.
  • the invention finds application in the treatment of metabolic syndrome (as herein defined).
  • the disorder is also known as (metabolic) syndrome X, insulin resistance syndrome, Reaven's syndrome and CHAOS.
  • the invention finds application in the treatment of diseases associated with metabolic syndrome, including for example: fatty liver (often progressing to non-alcoholic fatty liver disease), polycystic ovarian syndrome, hemochromatosis (iron overload) and acanthosis nigricans (dark skin patches).
  • diseases associated with metabolic syndrome including for example: fatty liver (often progressing to non-alcoholic fatty liver disease), polycystic ovarian syndrome, hemochromatosis (iron overload) and acanthosis nigricans (dark skin patches).
  • Type 2 diabetes is a chronic disease that is characterised by persistently elevated blood glucose levels (hyperglycaemia). Insulin resistance together with impaired insulin secretion from the pancreatic ⁇ -cells characterizes the disease. The progression of insulin resistance to type 2 diabetes is marked by the development of hyperglycaemia after eating when pancreatic ⁇ -cells become unable to produce adequate insulin to maintain normal blood sugar levels (euglycemia)).
  • Type 1 diabetes The invention finds application in the treatment of Type 1 diabetes (or insulin dependent diabetes).
  • Type 1 diabetes is characterized by loss of the insulin-producing beta cells of the islets of Langerhans in the pancreas, leading to a deficiency of insulin.
  • the main cause of this beta cell loss is a T-cell mediated autoimmune attack.
  • There is no known preventative measure that can be taken against type 1 diabetes which comprises up to 10% of diabetes mellitus cases in North America and Europe. Most affected people are otherwise healthy and of a healthy weight when onset occurs. Sensitivity and responsiveness to insulin are usually normal, especially in the early stages.
  • the compounds of the invention may have antidiabetogenic virus activity.
  • Diabetogenic viruses are aetiological agents of type 1 diabetes, and so compounds having antidiabetogenic virus activity are particularly preferred for use in the treatment or prevention of type 1 diabetes and also: (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 ⁇ -cell lysis (e.g.
  • 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.
  • those compounds which are novel are claimed as compounds per se, 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).
  • 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)
  • those compounds are claimed for use as pharmaceuticals (for example in any of the particular medical uses described herein).
  • the compounds for use according to the invention may comprise a nucleus selected from those shown below and numbered (1), (2) and (3):
  • the compounds for use according to the invention may be of Formula (1)
  • 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 1 or 2
  • R 1 represents H; C1-15 alkyl, C1-15 alkenyl or C1-15 alkynyl, optionally substituted with one or more R 2 ; oxygen or an oxygen containing group such that the compound is an N-oxide; C(O)OR 3 ; C(O)NR 3 R 4 ; SO 2 NR 3 ; OH, OR 3 , or formyl
  • R 3 represents H; C1-6 alkyl, optionally substituted with one or more OH; aryl or C1-. 3 alkyl optionally substituted with aryl; SiR 4 3 and
  • R 4 represents H; C1-6 alkyl, optionally substituted with one or more OH
  • R 3 and R 4 may optionally form a 4 to 8 membered ring, containing one or more O, SO x or NR 3 groups
  • x represents an integer from O to 2 or a pharmaceutically acceptable salt or derivative thereof.
  • the compound of Formula (1) is selected from any one of the Formulae shown below:
  • r represents an integer from 1 to (n+4)
  • s represents an integer from 1 to (n+4)
  • n an integer from O to 2
  • R 3 represents H; C1-6 alkyl, optionally substituted with up to 4 OH; aryl or C1-3 alkyl optionally substituted with aryl
  • R 4 represents H; C1-6 alkyl, optionally substituted with up to 4 OH R 3 and R 4 may optionally form a 4 to 8 membered ring, containing O to 1 O, S or NR 3 groups.
  • the compounds for use according to the invention may be of Formula (2)
  • p represents an integer from 1 to 2
  • z represents an integer from 1 to (p+7)
  • y 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 R 2
  • R 1 represents H; C1-15 alkyl, C1-15 alkenyl or C1-15 alkynyl, optionally substituted with one or more R 2 ; oxygen or an oxygen containing group such that the compound is an N-oxide; C(O)OR 3 ; C(O)NR 3 R 4 ; SO 2 NR 3 ; OH 1 OR 3 , or formyl
  • R 3 represents H; C1-6 alkyl, optionally substituted with one or more OH; aryl or C1- 3 alkyl optionally substituted with aryl; SiR 4 3 and
  • R 4 represents H; C1-6 alkyl, optionally substituted with one or more OH
  • R 3 and R 4 may optionally form a 4 to 8 membered ring, containing one or more O, SO x or NR 3 groups
  • x represents an integer from O to 2
  • the compound of Formula (2) is selected from any one of the Formulae shown below:
  • 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
  • R 1 represents C1-9 alkyl, optionally substituted with up to 6 OH, NR 3 R 4 , aryl, O-C1- 3 alkyl, O-C1-3 alkenyl, CO 2 H, NH(NH)NH 2 , CONR 3 R 4 ; C(O)OR 3 ; C(O)NR 3 R 4 ; SO 2 NR 3
  • R 3 represents H; C1-6 alkyl, optionally substituted with up to 4 OH; aryl or C1-3 alkyl optionally substituted with aryl R 4 represents H; C1-6 alkyl, optionally substituted with up to 4 OH
  • R 3 and R 4 may optionally form a 4 to 8 membered ring, containing 0 to 1 O, S or
  • the compounds for use according to the invention may be of Formula (3)
  • 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
  • n represents an integer from 1 to 3 and the ring may also contain at least one unsaturated C-C bond
  • the endocyclic nitrogen atom may be bonded to an oxygen or an oxygen containing group such that the compound is an N-oxide
  • P(O)(OR 3 ) 2 C1-15 alkyl or alkenyl optionally substituted with one or more OH, OR 3 ,
  • R 3 represents H; C1-6 alkyi, optionally substituted with one or more OH; aryl or C1- 3 alkyl optionally substituted with aryl; SiR 4 3 and
  • R 4 represents H; C1-6 alkyl, optionally substituted with one or more OH
  • R 3 and R 4 may optionally form a 4 to 8 membered ring, containing one or more O, SO x or NR 3 groups
  • x represents an integer from O to 2
  • the compound of Formula (3) is selected from any one of the Formulae shown below:
  • r represents an integer from 1 to (n+m+4)
  • s represents an integer from 1 to (n+m+4)
  • n an integer from 1 to 3
  • n an integer from 1 to 3
  • R 3 represents H; C1-6 alkyl, optionally substituted with up to 4 OH; aryl or C1-3 alkyl optionally substituted with aryl
  • R 4 represents H; C1-6 alkyl, optionally substituted with up to 4 OH
  • R 3 and R 4 may optionally form a 4 to 8 membered ring, containing O to 1 O, S or
  • NR 3 groups the endocyclic nitrogen atom may be bonded to an oxygen or an oxygen containing group such that the compound is an N-oxide.
  • one or more endocyclic carbon atoms may be substituted with a sulphur, oxygen or nitrogen atom.
  • the compounds of Formula (1), (2) and (3) may comprise compounds having three, four or more rings.
  • oligomers e.g. dimers, trimers etc.
  • 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).
  • the compounds of Formula (1), (2) or (3) may be, but not necessarily are, iminosugars as defined in Section A(II) (below).
  • the compounds for use according to the invention may be iminosugars, as hereinbefore defined.
  • the compounds for use according to the invention may be selected from:
  • 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.
  • the iminosugar for use according to the invention is an azasugar as defined above, then the iminosugar may be selected from:
  • 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).
  • iminosugars as defined above for use according to the invention may be of any structural class or subclass, including the classes described below:
  • 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:
  • 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:
  • 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:
  • 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:
  • 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:
  • 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:
  • one or more endocyclic carbon atoms may be substituted with a sulphur, oxygen or nitrogen atom.
  • Piperidine iminosugars comprise the nucleus:
  • Pyrroline iminosugars comprise one of the following three nuclei:
  • Pyrrolidine iminosugars comprise the nucleus:
  • Pyrrolizidine iminosugars comprise the nucleus:
  • Indolizidine iminosugars comprise the nucleus:
  • Nortropane iminosugars comprise the nucleus:
  • dotted line represents a bridge containing 2 or 3 carbon atoms between any two different ring carbon atoms.
  • 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 nortropanes which have been reported to inhibit ⁇ -glucosidases, ⁇ -xylosidases and ⁇ -galactosidases (Asano et al., 1997, Glycobiology 7: 1085-1088).
  • the calystegines are common in foods belonging to the Solanaceae 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- ⁇ -D-glucopyranoside of 1 ⁇ ,2 ⁇ ,3 ⁇ ,6 ⁇ -tetrahydroxy-A7or- tropane (Calystegine B 1 ) (Griffiths, et al., 1996, Tetrahedron Letters 37: 3207-3208) can alter the glycosidase inhibition to include ⁇ -glucosidases and ⁇ -galactosidases.
  • These iminosugars comprise the nucleus:
  • Azepane imino sugars comprise the nucleus:
  • 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.
  • at least 2 preferably at least 3 or 4
  • hydroxyl groups or alkyl groups with one or more hydroxy substituent(s)
  • one or more endocyclic carbon atoms may be substituted with a sulphur, oxygen or nitrogen atom.
  • iminosugars comprising the various nuclei described in subsections (i) to (ix) may comprise compounds having three, four or more rings.
  • 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.
  • iminosugars for use according to the invention may therefore be further characterized on the basis of their structural subclass, for example being selected from:
  • 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) Phytochemistry 56: 265-295), the disclosure of which is incorporated herein by reference).
  • iminosugar acids selected from the following structural classes:
  • 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.
  • polyhydroxylated ISAs 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.
  • ISAs which are analogues of hydroxymethyl-substituted iminosugars in which one or more hydroxymethy! groups are replaced with carboxyl groups.
  • 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.
  • 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.
  • the ISA of the invention may be a pyrrolizidine ISA having at least 2 (preferably at least 3, 4 or 5) free hydroxyl (or hydroxyalkyl) groups on the ring system nucleus.
  • 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.
  • 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.
  • the compound of the invention may be as defined hereinin with the proviso that it is not an iminosugar acid, for example not a piperidine iminosugar acid (as hereinabove defined).
  • . 1 -/V-iminosugars (isoiminosugars) lsoimino sugars 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).
  • iminosugar conjugates are often conjugated to other biomolecules in vivo, including lipids, proteins, nucleosides and phosphate groups.
  • iminosugar conjugates include:
  • Iminosugar nucleotide analogues • Iminosugar glycolipid analogues (e.g. C- or N-alky) iminosugar derivatives)
  • 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:
  • 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.
  • 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 al. (2007) in Iminosugars From Synthesis to Therapeutic Applications: Compain, Philippe / Martin, Olivier R. (eds.) ISBN-13: 978-0-470-03391-3 - John Wiley & Sons) pages 87-130 the disclosure of which is hereby incorporated herein by reference.
  • they may be: (a) linear (1— >1)-C- linked; (b) linear (1 ⁇ ⁇ )-C-linked; or (c) branched (I ⁇ n)-C-Iinked (see Fig. 5.1 of Vogel et a/. (2007), op. c/..).
  • Iminosugar lactams for use according to the invention may for example comprise a nucleus selected from:
  • the iminosugars for use according to the invention may be a branched imino sugar.
  • 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.
  • two non-H substituents e.g. two alkyl groups, two hydroxyalkyl groups, a hydroxy and hydroxyalkyl group or a hydroxy and alkyl group
  • iminosugars with features characteristic of two or more of the foregoing subclasses (i) to (x) may also find application according to the invention.
  • 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).
  • 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:
  • 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.
  • 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.
  • the compound may be defined as a functional sugar mimetic (as discussed in more detail in Section B, below).
  • 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.
  • 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).
  • functional mimicry e.g. at the level of interaction with a biological target in vivo
  • 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.
  • 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.
  • the stereochemical comparison relates to consideration of contiguous C-het stereocentres (these being C-O, C-N etc.)
  • contiguous C-het stereocentres (these being C-O, C-N etc.)
  • two simple monocyclic iminosugars IS1 and IS2 shown below
  • the relative stereochemical relationship to the reference monosaccharide units D- arabinose and D-glucose respectively
  • IS1 is a D-arabinose mimetic while IS2 is a D-glucose mimetic.
  • D-arabinose can exist in the following cyclic forms:
  • 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.
  • the iminosugar IS4 exhibits the following stereochemical sequences:
  • the iminosugar IS5 exhibits the following stereochemical sequences:
  • the iminosugar IS6 exhibits the following stereochemical sequences:
  • an iminosugar may present more than one stereochemical sequence it is not necessarily a carbohydrate mimetic for each and every stereochemical sequence exhibited.
  • 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:
  • IS7 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.
  • iminosugar IS9 the mimetic properties of iminosugar IS9 can be analysed as follows: D
  • hydroxyl groups may also generates iminosugars which are mimetics of a monosaccaride.
  • IS10 is a D-arabinofuranose mimetic, as shown below:
  • the stereochemical configuration of the iminosugar matches one or more monosaccharides, but the group is not OH or an isostere (e.g. OBn, CO 2 H or N 3 ) this would also be considered a mimetic for the purposes of the present invention.
  • the iminosugar 1S11 is considered to be a mimetic of D- arabinofuranose, as shown below:
  • iminosugars may also be considered as mimics of di- or oligosaccharides.
  • the same general principles described above are applied, with the caveat being that the iminosugar must contain two or more non-overlapping carbohydrate mimics.
  • Iminosugars may mimic either D- or L- forms of sugars.
  • IS14 is a mimic of D-glucose
  • IS15 is a mimic of L- glucose. This principle is generally applicable.
  • 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 lminosugars of D- or L-galacto configuration; lminosugars of D- or L-manno configuration; lminosugars of D- or L-allo configuration; lminosugars of D- or L-altro configuration; lminosugars of D- or L-ido configuration; lminosugars of D- or L-gulo configuration; lminosugars of D- or L-talo configuration; lminosugars of D- or L-arabino configuration; lminosugars of D- or L-ribo configuration; lminosugars of D- or L-xylo configuration; and/or lminosugars of D- or L-lyxo configuration.
  • the iminosugars for use according to the invention may be classified according to their stereochemical configuration in combination
  • the compounds for use according to the invention 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.
  • 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.
  • 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:
  • amylases or • two or more of the foregoing enzyme classes.
  • 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
  • the compounds for use according to the invention preferably do not inhibit enzymes involved in metabolism of xenobiotics as this couid lead to drug-drug interactions.
  • 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).
  • 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:
  • 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
  • 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:
  • GTPases 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);
  • 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
  • the above enzyme 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; (Ni), a site outside the catalytic site; and/or (d) a site outside an allosteric site (see also Section III, below); or
  • 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.
  • They may act as ligands for a carbohydrate binding site of any protein (including, for example, any of the lectins hereinbefore described).
  • PAMPs pathogen-associated molecular patterns
  • PRRs pathogen-(orpattern-)recognition receptors
  • TLRs Toll-like receptor class
  • 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).
  • LPS lipopolysaccharide
  • TLR2 appears to have several ligands, including peptidoglycan 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 peptidoglycan.
  • 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).
  • CpGs cytosine-guanosine dinucleotides
  • 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)).
  • PRR Another major class of PRR are the C-type lectins (reviewed by Figdor et al. (2002) Nature Reviews Immunology 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).
  • CRD carbohydrate recognition domain
  • C-type lectins examples 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 ⁇ -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.
  • 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.
  • PRR ligands are PRR ligands (as defined herein).
  • 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.
  • 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.
  • 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.
  • PRR for example C-type lectin
  • DCs immune cells
  • the PRR ligands of the invention may bind any PRR, including any TLR, C-type lectin or NOD-protein.
  • 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.
  • the NOD-proteins 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.
  • LRRs C-terminal leucine-rich repeats
  • NOD central nucleotide- binding oligomerization domain
  • CARDs caspase recruitment domains
  • pyrin domains or a TIR domain.
  • TLR Toll-like receptor
  • the PRR ligands of the invention may bind to any TLR receptor.
  • the PRRs of the invention may bind to one or more of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10 and TLR11.
  • the TLR ligands for use according to the invention bind to:
  • an endosomal TLR e.g. TLR7, TLR8 and/or TLR9
  • an intracellular TLR e.g. TLR3
  • TLR9 or TLR4 ligands are particularly preferred.
  • 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 at. (2002) Nature Reviews Immunology 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:
  • MMR CD206, macrophage mannose receptor
  • l-type lectins for example, siglecs (sialic acid-binding immunoglobulin superfamily lectins); and/or
  • the PRR or lectin (for example C-type lectin) ligands 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.
  • the compounds of the invention may be ligands for chaperone proteins.
  • the compounds of the invention may be ligands for calnexin and/or calreticulin.
  • 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 compounds of the invention may be pharmacoperones as defined above.
  • 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).
  • the compounds for use according to the invention may be ASSCs as defined above.
  • the compounds or iminosugars of the invention are pharmacoperones of an enzyme which do not bind to a catalytic site of said enzyme.
  • the pharmacoperones of the invention need not be a competitive inhibitor of said enzyme, so removing the problems associated with chaperone:inhibitor ratios associated with known pharmacoperones.
  • the pharmacoperone for use according to the invention is an activator of said enzyme.
  • the pharmacoperone may specifically bind an activating allosteric site on the enzyme.
  • the pharmacoperone may be a non-competitive inhibitor of said enzyme.
  • the chaperone.-inhibitor ratio may be favourable in view of the availably of the catalytic site.
  • the pharmacoperone may specifically bind an inhibiting allosteric site on the enzyme.
  • the pharmacoperone of the invention does not bind to the enzyme at all, but acts as an indirect chaperone via a chaperone effect attendant on binding to a protein (e.g. enzyme) which itself acts as a chaperone or co-chaperone of the enzyme.
  • a protein e.g. enzyme
  • the pharmacoperones of the invention may bind to chaperone proteins such as calnexin and calreticulin and so influence protein trafficking through the Golgi apparatus.
  • the compounds of the invention may be immunomodulatory.
  • 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.
  • 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-translational modification, secretion, activation, shedding, stabilization or sequestration).
  • the stimulation comprises an increase in the production of the cytokine(s) by the PRR-bearing cell.
  • 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.
  • cytokine(s) for example, IL-12 production in dendritic cells
  • 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).
  • cytokines e.g. Th1 cytokines
  • 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
  • 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.
  • cytokines e.g. IL-12
  • 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.
  • the PRR ligands of the invention may bind a PRR as part of a cellular signalling cascade in which the PRR forms a part.
  • they may bind PRR in the context of some other aspect of cellular physiology.
  • 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.
  • 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).
  • 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.
  • PRR agonists or PRR precursors
  • the innate immune system appears to play a key role in promoting the response of autoreactive T cells triggering type 1 diabetes (see e.g. Zipris (2008) Innate immunity and its role in type 1 diabetes. Curr. Opin. Endocrinol Diabetes Obes 15: 326-331 ; Richer et a/. (2008) 57(5): 1302 - 1311).
  • compounds of the invention may interact with PRR bearing cells/C-type lectin receptors/Toll-like receptors or affect immune responses to infectious organisms in such a way as to give protection from development of diabetes type 1 or to reduce the proinflammatory responses causing autoimmune diabetes
  • 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.
  • PRR-bearing cell defines any cell which expresses one or more pathogen-(or pattern-) recognition receptors (PRRs).
  • 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).
  • PRR-bearing cells as described herein may comprise epithelial cells, macrophages, neutrophils, dendritic cells or other effector cells of the innate immune system.
  • the PRR-bearing cell for use in relation to the invention are dendritic cells or macrophages.
  • 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).
  • the PRR-bearing cells described herein are macrophages or dendritic cells.
  • 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.
  • 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).
  • cytokine stimulatory compounds for use according to the invention are PRR ligands (as herein defined).
  • the stimulation comprises an increase in the production of the cytokine(s) by the PRR-bearing cell.
  • 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.
  • various cytokines e.g. IL-12 and/or IL-2
  • immune cells e.g. dendritic cells and/or macrophages
  • 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.
  • the compound may stimulate one or more TM 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.
  • 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 TM response (and so increase the TM :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).
  • CTL endogenous dendritic cells
  • the induced expression of IL-2 may also indirectly potentiate a TM response (and so increase the TM :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).
  • CTL lymphocytes
  • 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 TM response). It induces natural killer (NK) cells to produce IFN- ⁇ as part of the innate immune response and promotes the expansion of CD4 + TM cells and cytotoxic CD8 + cells which produce IFN- ⁇ . It therefore increases T-cell invasion of tumours as well as the susceptibility of tumour cells to T-cell invasion.
  • 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).
  • cytokines for example one or more TM cytokines, e.g. IL-12 and/or IL-2
  • PRR-bearing cells e.g. neutrophils, macrophages or dendritic 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.
  • 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.
  • the cytokine stimulation profile is characterized by reference to the presence or absence of stimulation of one or more Th1 cytokines and/or one or more Th2 cytokines.
  • 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).
  • Th1 cytokine is a term of art used to define those cytokines produced by Th1 T-helper cells.
  • Th1 cytokines include, for example, IL2, IFN- ⁇ , IFN- ⁇ / ⁇ , IL12, IL-18, IL-27 and TNF- ⁇ .
  • Th 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.
  • 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- ⁇ 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.
  • 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- ⁇ via regulating production of IL-2 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- ⁇ produced becomes less active or inactive as proposed for deoxynojirimycin and ⁇ /-methyl-deoxynojirimycin in isolated splenocyte studies by Kosuge et a/. (2000) Biol. Pharm. Bull. 23 (1): 1-5.
  • Therapeutic improvements to iminosugars for therapeutic applications involving reduction of overproduction of IFN- ⁇ would be increased glycosidase specificity to avoid inhibition of off- target glucosidases caused by DNJ and N-methyl-DNJ.
  • 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 are compounds which share some or all of the functional properties of the sugar mimicked.
  • 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 a/. (1995) J. Med. Chem. 38: 2349-2356.
  • the functional sugar mimetic binds to a sugar receptor PRR.
  • Such binding per se 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.
  • the binding may occur in the context of some other aspect of cellular physiology.
  • 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.
  • 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).
  • 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.
  • 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.
  • DNJ 1,5-dideoxy- 1,5-imino-D-glucitol
  • DNJ deoxynojirimycin
  • 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.
  • 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.
  • 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.
  • preferred rhamnose mimetics for use according to the invention are iminosugars which exhibit inhibitory activity against one or more rhamnosidase enzyme(s).
  • preferred mannose mimetics for use according to the invention are iminosugars which exhibit inhibitory activity against one or more mannosidase enzyme(s).
  • preferred iminosugars may be rhamnose mimetics which bind to the rhamnose receptor PRR (see Grillon, Monsigny and Kieda (1990) Glycobiology 1(1): 33-8).
  • Such binding per se 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.
  • the binding may occur in the context of some other aspect of celMar physiology.
  • 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.
  • 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).
  • 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.
  • mannose mimetics which bind to the mannose receptor PRR. Again, such binding per se 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.
  • binding may occur in the context of some other aspect of cellular physiology.
  • 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.
  • 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).
  • 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.
  • the compounds for use according to the invention may be sodium-glucose cotransporter (SGLT) inhibitors.
  • SGLT sodium-glucose cotransporter
  • the kidney is important for the body's energy control. Glucose is reabsorbed from blood after filtration in the kidney proximal tubule. Two types of sodium-glucose cotransporters mediate this reabsorption of glucose.
  • the low-affinity sodium-glucose cotransporter (SGLT2) is found almost exclusively within the kidney and accounts for the majority of glucose reabsorption by the kidney. The remainder of the glucose is reabsorbed by the high-affinity sodium-glucose cotransporter (SGLT1).
  • SGLT1 is expressed to some extent in the kidney but is mainly expressed in the intestine where it is important in the absorption of glucose from the diet.
  • SGLT2 plays a dominant role in the control of glucose transport in the kidney with SGLT1 having a supporting role.
  • SGLT1 and/or 2 inhibitors can cause the excretion of excess glucose in the urine by inhibiting glucose reabsorption in the kidney. As a result, they can lower plasma glucose levels, remove glucose toxicity and thereby relieve many of the symptoms of diabetes.
  • SGLT1 inhibitors and/or mixed SGLT1/2 inhibitors may have utility in the treatment of obesity.
  • the sodium-glucose cotransporter SGLT3 like SGLT2 is a low affinity sugar transporter, and selectively transports D-glucose over D-galactose.
  • SGLT3 is expressed in the small intestine (plasma membranes of the cholinergic neurons within the autonomic neuronal plexus and neuroendocrine cells), skeletal muscle, kidney, spleen, liver.brain, uterus and testes.
  • SGLT3 has also been characterised as a glucose sensor in mammalian cells. SGLT3 responds to variations in extracellular glucose concentrations through changes in membrane potential and these glucose-induced electrical changes modulate the action of other cells via electrical or hormonal signals. Evidence also suggests the presence of the glucose sensor SGLT3 in hypothalamic neurons and in neuromuscular junctions in skeletal muscle. Inhibitors of SGLT3 may therefore modulate glucose sensitivity and so find application in the treatment of glucose intolerance, obesity and diabetes.
  • compounds of the invention which are SGLT inhibitors find particular application in the treatment of diabetes (and in particular, type 2 diabetes) and/or obesity.
  • Compounds of the invention which are SGLT inhibitors may be specific for SGLT1 , SGLT2 or SGLT3.
  • the compounds of the invention may be SGLT1 inhibitors or SGLT2 inhibitors or SGLT3 inhibitors.
  • compounds of the invention which are SGLT inhibitors may be mixed inhibitors.
  • the compounds of the invention may be dual SGLT1/3 inhibitors, dual SGLT2/3 inhibitors or dual SGLT1/2 inhibitors.
  • the compounds of the invention may be mixed SGLT1/2/3 inhibitors.
  • the compounds for use according to the invention may be sodium-glucose cotransporter (SGLT) modulators.
  • SGLT sodium-glucose cotransporter
  • the compounds may be agonists or antagonists for SGLT3.
  • Compounds of the invention which are SGLT3 modulators may find particular utility in the treatment of obesity and diabetes.
  • Compounds of the invention which are SGLT inhibitors may be of Formula 1, Formula 2 or Formula 3, as hereinbefore described.
  • compounds of the invention which are SGLT inhibitors may be selected from any one of the Formulae shown below:
  • r represents an integer from 1 to (n+4)
  • s represents an integer from 1 to (n+4)
  • n an integer from 0 to 2
  • R 1 represents C1-9 alkyl, optionally substituted with up to 6 OH, NR 3 R 4 , aryl, O-C1- 3 alkyl, O-C1-3 alkenyl, CO 2 H, NH(NH)NH 2 , CONR 3 R 4 ; C(O)OR 3 ; C(O)NR 3 R 4 ; SO 2 NR 3
  • R 3 represents H; C1-6 alkyl, optionally substituted with up to 4 OH; aryl or C1-3 alkyl optionally substituted with aryl R 4 represents H; C1-6 alkyl, optionally substituted with up to 4 OH
  • R 3 and R 4 may optionally form a 4 to 8 membered ring, containing 0 to 1 O, S or
  • 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
  • R 3 represents H; C1-6 alkyl, optionally substituted with up to 4 OH; aryl or C1-3 alkyl optionally substituted with aryl
  • R 4 represents H; C 1-6 alkyl, optionally substituted with up to 4 OH R 3 and R 4 may optionally form a 4 to 8 membered ring, containing O to 1 O, S or NR 3 groups;
  • 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
  • R 3 represents H; C1-6 alkyl, optionally substituted with up to 4 OH; aryl or C1-3 alkyl optionally substituted with aryl
  • R 4 represents H; C1-6 alkyl, optionally substituted with up to 4 OH
  • R 3 and R 4 may optionally form a 4 to 8 membered ring, containing O to 1 O, S or
  • the endocyclic nitrogen atom may be bonded to an oxygen or an oxygen containing group such that the compound is an N-oxide.
  • one or more endocyclic carbon atoms may be substituted with a sulphur, oxygen or nitrogen atom.
  • compounds of the invention which are SGLT inhibitors may be of Formula 1(a) as hereinbefore described:
  • r represents an integer from 1 to (n+4)
  • s represents an integer from 1 to (n+4)
  • n represents an integer from 0 to 2
  • R 1 represents C1-9 alkyl, optionally substituted with up to 6 OH, NR 3 R 4 , aryl, O-C1- 3 alky!, O-C1-3 alkenyl, CO 2 H, NH(NH)NH 2 , CONR 3 R 4 ; C(O)OR 3 ; C(O)NR 3 R 4 ; SO 2 NR 3
  • R 3 represents H; C1-6 alkyl, optionally substituted with up to 4 OH; aryl or C1-3 alkyl optionally substituted with aryl
  • R 4 represents H; C1-6 alkyl, optionally substituted with up to 4 OH
  • R 3 and R 4 may optionally form a 4 to 8 membered ring, containing O to 1 O, S or NR 3 groups.
  • r may be 3, n may be 1 , s may be 1 and R 2 may represent aryl, optionally substituted with up to 6 OH, NR 3 R 4 , aryl, 0-C1-3 alkyl, CONR 3 R 4 , C(O)OR 3 ; C(O)NR 3 R 4 ; SO 2 NR 3 ; NH(NH)NH 2 ; NR 4 C(O)R 3 ; NR 4 SO 2 R 3 ; N 3 ; F and Cl.
  • the SGLT inhibitors of Formula 1(a) may be of Formula 1 (a)(i):
  • R 2 may represent aryl, optionally substituted with up to 6 OH, NR 3 R 4 , aryl, 0-C1-3 alkyl, CONR 3 R 4 , C(O)OR 3 ; C(O)NR 3 R 4 ; SO 2 NR 3 ; NH(NH)NH 2 ; NR 4 C(O)R 3 ; NR 4 SO 2 R 3 ; N 3 ; F and Cl.
  • the compounds for use according to the invention may be glucose mimetics.
  • the SGLT inhibitors of Formula 1(a)(i) may be glucose mimetics of Formula 1 (a)(ii):
  • 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
  • R 1 represents C1-9 alky], optionally substituted with up to 6 OH, NR 3 R 4 , aryl, 0-C1-
  • alkyl O-C1-3 alkenyl, CO 2 H, NH(NH)NH 2 , CONR 3 R 4 ; C(O)OR 3 ; C(O)NR 3 R 4 ; SO 2 NR 3
  • NH(NH)NH 2 ; NR 4 C(O)R 3 ; NR 4 SO 2 R 3 ; N 3 ; F; Cl R 3 represents H; C1-6 alkyl, optionally substituted with up to 4 OH; aryl or C1-3 alkyl optionally substituted with aryl
  • R 4 represents H; C1-6 alkyl, optionally substituted with up to 4 OH R 3 and R 4 may optionally form a 4 to 8 membered ring, containing O to 1 O, S or
  • r represents an integer from 1 to (n+m+4)
  • s represents an integer from 1 to (n+m+4)
  • n an integer from 1 to 3
  • n an integer from 1 to 3
  • R 3 represents H; C1-6 alkyl, optionally substituted with up to 4 OH; aryl or C1-3 alkyl optionally substituted with aryl
  • R 4 represents H; C1-6 alkyl, optionally substituted with up to 4 OH R 3 and R 4 may optionally form a 4 to 8 membered ring, containing O to 1 O, S or
  • NR 3 groups the endocyclic nitrogen atom may be bonded to an oxygen or an oxygen containing group such that the compound is an N-oxide.
  • R 2 may represent an aryl group as hereinbefore defined.
  • aryl group may be an optionally substituted aryl group defined according to the following formula:
  • X represents a bond, O, S, NH or an alkyl linker such as CH 2 or CH 2 CH 2
  • Ar 1 represents a 5 to 10 membered mono- or bicyclic aromatic or heteroaromatic ring system, optionally substituted by 1 to 4 groups selected from halo, alkyl, OH, O-alkyl or S-a!kyl
  • Y represents a bond, O, S, NH or an alkyl linker (for example, CH 2 or CH 2 CH 2 )
  • Ar 2 represents a 5 to 10 membered mono- or bicyclic aromatic or heteroaromatic ring system, optionally substituted by 1 to 4 groups selected from halo, alkyl, OH,
  • O-alkyl or S-alkyl O-alkyl or S-alkyl.
  • R 2 may represent an aryl group as hereinbefore defined selected from those set out in the Table below:
  • the compounds of the invention preferably do not inhibit glucosidase activity (or do not inhibit glucosidase activity to a clinically-significant extent). Without wishing to be bound by any theory, it is thought that the compounds of the invention may stimulate, directly or indirectly, pancreatic ⁇ -cell activity and/or regeneration in vivo. Thus, preferred compounds for use according to the invention stimulate, directly or indirectly, pancreatic ⁇ -cell activity and/or regeneration in vivo. In such embodiments, the compounds find particular application in the treatment of type 1 (or insulin-dependent) diabetes, since the compound may promote functional regeneration of pancreatic ⁇ -cells.
  • the compounds may inhibit glucuronidases, iduronidase, sialidase or hexosaminidases. Reducing glucuronidase activity may for example improve beta cell function, directly or indirectly, via improved removal of toxins as glucuronides.
  • the compounds of the invention may have antidiabetogenic virus activity.
  • Diabetogenic viruses are aetiological agents of type 1 diabetes, and so compounds having antidiabetogenic virus activity are particularly preferred for use in the treatment or prevention of type 1 diabetes and in: (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 ⁇ -cell lysis (e.g.
  • the diabetogenic virus target of such compounds may be selected from viruses of the Picomavirus 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
  • ⁇ -herpesviridae for example, cytomegalovirus
  • Preferred diabetogenic viral targets are selected from enteroviruses, rubella, mumps, rotavirus, parvovirus and cytomegalovirus.
  • the compounds for use according to the invention 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.
  • the iminosugar may have a molecular weight of 100 to 400 Daltons, preferably 150 to 300 Daltons and most preferably 200 to 250 Daltons.
  • non-metabolizable iminosugars are also preferred. Such sugars may exhibit extended tissue residence durations, and so exhibit favourable pharmacokinetics.
  • AIIose Altrose Arabinose Galactose Glucose Gulose ldose Lyxose Mannose Ribose Talose Xylose

Abstract

Described are various compounds, in particular iminosugars, for the treatment of energy utilization diseases, in particular diabetes (including type 1 diabetes, type 2 diabetes and insulin resistance) and metabolic syndrome (including any disease or disorder associated therewith, for example central obesity and elevated levels of triglycerides).

Description

TREATMENT OF ENERGY UTILIZATION DISEASES
Field of the Invention
This invention relates to certain compounds, in particular iminosugars, and to methods for the treatment of energy utilization diseases, in particular diabetes (including type 1 diabetes, type 2 diabetes and insulin resistance) and metabolic syndrome (including any disease or disorder associated therewith, for example central obesity and elevated levels of triglycerides) based on the use of these compounds.
Background of the Invention
Energy utilization diseases
Energy utilization diseases encompass a wide range of diseases and include, for example, disorders of homeostasis, metabolic diseases, dysfunction of sugar metabolism and appetite disorders.
Examples of energy utilization diseases therefore include insulin resistance, various forms of diabetes, metabolic syndrome, obesity, wasting syndromes (for example, cancer associated cachexia), myopathies, gastrointestinal disease, growth retardation, hypercholesterolemia, atherosclerosis and age-associated metabolic dysfunction.
Energy utilization diseases also include conditions associated with metabolic syndrome, obesity and/or diabetes, including for example hyperglycaemia, glucose intolerance, hyperinsulinaemia, glucosuria, metabolic acidosis, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, macular degeneration, glomerulosclerosis, diabetic cardiomyopathy, insulin resistance, impaired glucose metabolism, arthritis, hypertension, hyperlipidemia, osteoporosis, osteopenia, bone loss, brittle bone syndromes, acute coronary syndrome, infertility, short bowel syndrome, chronic fatigue, eating disorders and intestinal motility dysfunction.
Insulin resistance, metabolic syndrome and diabetes
In healthy individuals, blood glucose levels are maintained within a narrow range by two pancreatic hormones: insulin (produced by pancreatic β-cells) and glucagon (produced by pancreatic α-cells). Pancreatic β-cells sense increases in blood glucose levels and respond by secreting insulin. Insulin promotes glucose uptake by tissues of the body, thereby restoring blood glucose concentration to the physiological range. Glucagon acts reciprocally, increasing blood glucose levels under fasting conditions, primarily by stimulating glucose production in the liver.
Insulin resistance is characterized by a reduced action of insulin in skeletal muscle, adipocytes and hepatocytes so that normal amounts of insulin become inadequate to produce a normal insulin response from the cells of these tissues. In adipocytes, insulin resistance results in hydrolysis of stored triglycerides, leading to elevated free fatty acids in the blood plasma. In muscle, insulin resistance reduces glucose uptake while in hepatocytes it reduces glucose storage. In both of the latter cases an elevation of blood glucose concentrations results.
High plasma levels of insulin and glucose due to insulin resistance often progresses to metabolic syndrome and type 2 diabetes.
Metabolic syndrome is a constellation of abnormalities and disorders that increase the risk of cardiovascular disease and diabetes. The incidence is very high in many developed countries: some studies indicate prevalence in the USA of up to 25% of the population. The disorder is also known as (metabolic) syndrome X, insulin resistance syndrome, Reaven's syndrome and CHAOS. Metabolic syndrome may be diagnosed by the presence of three or more of the following symptoms: central obesity (waist measurement of more than 40 inches for men and more than 35 inches for women); high levels of triglycerides (150 mg/dL or higher); low levels of HDL (below 40 mg/dL for men and below 50 mg/dL for women) and high blood pressure (130/85 mm Hg or higher). Associated diseases and signs are: fatty liver (often progressing to non-alcoholic fatty liver disease), polycystic ovarian syndrome, hemochromatosis (iron overload) and acanthosis nigricans (dark skin patches).
The first line treatment of metabolic syndrome is change of lifestyle (caloric restriction and physical activity). However, drug treatment is frequently required. Generally, the individual diseases that comprise the metabolic syndrome are treated separately (e.g. diuretics and ACE inhibitors for hypertension). Cholesterol drugs may be used to lower LDL cholesterol and triglyceride levels, if they are elevated, and to raise HDL levels if they are low. Use of drugs that decrease insulin resistance (e.g. metformin and thiazolidinediones is controversial). Cardiovascular exercise is therapeutic in less than 31% of cases and does not generally produce a decrease in fasting plasma glucose or insulin resistance.
Thus, new and/or alternative treatments for metabolic syndrome are required, particularly treatments which are effective against obesity and/or elevated triglyceride levels.
Type 2 diabetes is a chronic disease that is characterised by persistently elevated blood glucose levels (hyperglycaemia). Insulin resistance together with impaired insulin secretion from the pancreatic β-cells characterizes the disease. The progression of insulin resistance to type 2 diabetes is marked by the development of hyperglycaemia after eating when pancreatic β-cells become unable to produce adequate insulin to maintain normal blood sugar levels (euglycemia).
The most important drug currently used to treat type 2 diabetes is metformin (Glucophage, Diabex, Diaformin, Fortamet, Riomet, Glumetza, Cidophage and others). Metformin is of the biguanide class of oral antihyperglycaemic agents. Other biguanides include phenformin and buformin (now withdrawn). Metformin works primarily by reducing liver release of blood glucose from glycogen stores, but also has some effect in increasing the uptake of glucose. Other widely used drug classes include those of the sulfonylurea group (including glibenclamide and gliclazide). These drugs increase glucose stimulated insulin secretion by the pancreas. Newer drug classes include thiazolidinediones (e.g. rosiglitazone, pioglitazone, and troglitazone), which act by binding to PPARs (peroxisome proliferator-activated receptors), a group of receptor molecules inside the cell nucleus. Other classes include α-glucosidase inhibitors (acarbose), meglitinides (which stimulate insulin release and include nateglinide, repaglinide and their analogues), peptide analogs (e.g. incretin mimetics, which act as insulin secretagogues, glucagon-like peptide analogues (e.g. exenatide), dipeptidyl peptidase-4 (DPP-4) inhibitors (which increase incretin levels (e.g. sitagliptin) and amylin agonist analogues (which slow gastric emptying and suppress glucagon (e.g. pramlintide).
However, no existing therapies for the different forms of type 2 diabetes seem to improve function of key intrinsic factors in the β-cells and all existing therapies fail to arrest progression of the disease and, over time, also fail to normalise glucose levels and/or prevent subsequent complications. The existing therapies are also associated with undesirable side effects. For example, insulin secretagogues and insulin injections may cause hypoglycaemia and weight gain. Patients may also become unresponsive to insulin secretagogues over time. Metformin and α-glucosidase inhibitors often lead to gastrointestinal problems and PPAR agonists tend to cause increased weight gain and oedema. Exenatide is also reported to cause nausea and vomiting.
Glycosylation has an important role in regulating properties of proteins and is associated with many diseases. Itoh, N. et al., 2007 (Am J Physiol Endocrinol Meiab 293: E1069- E1077) have reported the serum Λ/-glycan profile in human subjects with type 2 diabetes and found an increased amount of a biantennary Λ/-glycan that had an α1 ,6-fucose with a bisecting Λ/-acetylglucosamine. Copeland, R.J. et al., 2008 (Am J Physiol Endocrinol Metab 295: E17-E28) have reviewed the importance of O-linked N-acetylglucosamine in diabetes and concluded that there is a strong positive correlation between GlcNAcylation and the development of insulin resistance. O-linked -β-Λ/-acetylglucosamine (O-GlcNAc) is a dynamic posttranslational modification that, analogous to phosphorylation, cycles on and off serine and/or threonine hydroxyl groups. Cycling of O-GlcNAc is regulated by the concerted actions of O-GlcNAc transferase and O-GlcNAcase. GlcNAcylation is involved in the aetiology of glucose toxicity and chronic hyperglycemia-induced insulin resistance, a major hallmark of type 2 diabetes. Hexosaminidase activity has been shown to be elevated in the serum of diabetics (e.g. Agardh, CD. et al., 1982, Acta Med Scand. 212:39-41).
Type 1 diabetes (or insulin dependent diabetes) is characterized by loss of the insulin- producing beta cells of the islets of Langerhans in the pancreas, leading to a deficiency of insulin. The main cause of this beta cell loss is a T-cell mediated autoimmune attack. There is no known preventative measure that can be taken against type 1 diabetes, which comprises up to 10% of diabetes mellitus cases in North America and Europe. Most affected people are otherwise healthy and of a healthy weight when onset occurs. Sensitivity and responsiveness to insulin are usually normal, especially in the early stages.
The principal treatment of type 1 diabetes, even from the earliest stages, is replacement of insulin combined with careful monitoring of blood glucose levels using blood-testing monitors. Without insulin, ketosis and diabetic ketoacidosis can develop and coma or death will result. Apart from the common subcutaneous injections, it is also possible to deliver insulin by a pump, which allows continuous infusion of insulin 24 hours a day at preset levels, and the ability to program closes (a bolus) of insulin as needed at meal times. An inhaled form of insulin, Exubera, has recently been approved by the FDA.
The treatment of type 1 diabetes must be continued indefinitely. While treatment does not impair normal activities, great awareness, appropriate care, and discipline in testing and medication must be observed.
Thus, new and/or alternative antidiabetic drug treatments, particularly those that are able to restore β-cell function, are required. In particular, there is a real and substantial unmet clinical need for an effective drug that is capable of treating both type 2 and type 1 diabetes and associated conditions with fewer side effects than existing drug therapies.
Summary of the Invention
According to a first aspect of the present invention there is provided a compound of Formula (1)
Figure imgf000006_0001
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
2 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; =O; NH2; N3; SH; SOxR3; 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, SOxR3, 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, SOxR3, 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; 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
R3 and R4 may optionally form a 4 to 8 membered ring, containing one or more O, SOx or NR3 groups
x represents an integer from O to 2
or a pharmaceutically acceptable salt or derivative thereof, for the treatment of an energy utilization disease.
In a second aspect, the invention provides a compound of Formula (2)
Figure imgf000008_0001
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 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; SOxR3; 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, SOxR3, 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, SOxR3, 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)
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
R3 and R4 may optionally form a 4 to 8 membered ring, containing one or more O,
SOx or NR3 groups
x represents an integer from O to 2
or pharmaceutically acceptable salt or derivative thereof, for the treatment of an energy utilization disease.
In a third aspect, the invention provides a compound of Formula (3)
Figure imgf000009_0001
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 O to (n+2), provided that where z = O 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; =O; NH2; N3; SH; SOxR3; 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, SOxR3, 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, SOxR3, 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; 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
R3 and R4 may optionally form a 4 to 8 membered ring, containing one or more O, SOx or NR3 groups
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, for the treatment of an energy utilization disease.
In a further aspect, the invention provides an iminosugar as herein defined for the treatment of an energy utilization disease.
In a yet further aspect, the invention provides a compound selected from compounds 1 to 892 of Table 1 , or a pharmaceutically acceptable salt or derivative thereof, for the treatment of an energy utilization disease.
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.
Thus, in another aspect, the invention provides a composition comprising a compound or iminosugar of the invention and an adjunctive agent.
In another aspect, the invention provides a pharmaceutical kit of parts comprising a compound of the invention in combination with an adjunctive agent.
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 "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 "treatment" or "treating" refers to an intervention (e.g. the administration of an agent to a subject) which cures, ameliorates or lessens the symptoms of a disease or removes (or lessens the impact of) its cause(s). In this case, the term is used synonymously with the term "therapy". Additionally, the terms "treatment" or "treating" refers to an intervention (e.g. the administration of an agent to a subject) which prevents or delays the onset or progression of a disease or reduces (or eradicates) its incidence within a treated population. In this case, the term treatment is used synonymously with the term "prophylaxis".
The term "metabolic syndrome" is used herein to define conditions characterized by the presence of three or more of the following symptoms: central obesity (waist measurement of more than 40 inches for men and more than 35 inches for women); high levels of triglycerides (150 mg/dL or higher); low levels of HDL (below 40 mg/dL for men and below 50 mg/dL for women) and high blood pressure (130/85 mm Hg or higher).
The term therefore includes conditions defined in accordance with the definition of metabolic syndrome by the World Health Organization: (a) fasting plasma glucose above 6.1 mmol/L; (b) blood pressure above140/90 mm Hg; and (c) one or more of the following: (i) plasma triglycerides above 1.7mmol/L; (ii) HDL below 0.9 and 1.0 mmol/L (for men and women, respectively); (iii) a body mass index above 30 kg/m2.
References herein to the treatment of metabolic syndrome are to be interpreted to include the treatment of any or all of the disorders associated with metabolic syndrome, including in particular obesity (e.g. central obesity) and elevated serum triglycerides.
References herein to the treatment of type 1 or type 2 diabetes are to be interpreted to include the treatment of type 1 and type 2 diabetes perse as well as pre-diabetes (incipient diabetes) and insulin resistance. The term "pre-diabetes" or "incipient diabetes" defines conditions in which elevated levels of glucose or glycosylated haemoglobin are present in the absence of diabetes.
The term "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 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); pyrrolizidine; 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 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 result in 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 result in 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 Phvsiol 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 "alky!" 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 "CrC9 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 C1-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-C9 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-C15 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 bicyclic or tricyclic systems. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and also bridged systems such as norbomyl 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.
Medical uses of the compounds of the invention
The invention finds broad application in the treatment of any energy utilization disease. Thus, diseases which may be treated according to the invention include, for example, disorders of homeostasis, metabolic diseases, dysfunction of sugar metabolism and appetite disorders.
In preferred embodiments, the invention finds application in the treatment of insulin resistance, various forms of diabetes, metabolic syndrome, obesity, wasting syndromes (for example, cancer associated cachexia), myopathies, gastrointestinal disease, growth retardation, hypercholesterolemia, atherosclerosis and age-associated metabolic dysfunction.
The invention may also be used for the treatment of conditions associated with metabolic syndrome, obesity and/or diabetes, including for example hyperglycaemia, glucose intolerance, hyperinsulinaemia, glucosuria, metabolic acidosis, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, macular degeneration, glomerulosclerosis, diabetic cardiomyopathy, insulin resistance, impaired glucose metabolism, arthritis, hypertension, hyperlipidemia, osteoporosis, osteopenia, bone loss, brittle bone syndromes, acute coronary syndrome, infertility, short bowel syndrome, chronic fatigue, eating disorders, intestinal motility dysfunction and sugar metabolism dysfunction.
The invention may also be used to suppress appetite. Particularly preferred is the treatment of insulin resistance, metabolic syndrome, obesity and diabetes (particularly type 2 diabetes).
Insulin resistance, metabolic syndrome and diabetes
The invention finds application in the treatment of insulin resistance. Insulin resistance is characterized by a reduced action of insulin in skeletal muscle, adipocytes and hepatocytes so that normal amounts of insulin become inadequate to produce a normal insulin response from the cells of these tissues. In adipocytes, insulin resistance results in hydrolysis of stored triglycerides, leading to elevated free fatty acids in the blood plasma. In muscle, insulin resistance reduces glucose uptake while in hepatocytes it reduces glucose storage. In both of the latter cases an elevation of blood glucose concentrations results. High plasma levels of insulin and glucose due to insulin resistance often progresses to metabolic syndrome and type 2 diabetes.
The invention finds application in the treatment of metabolic syndrome (as herein defined). The disorder is also known as (metabolic) syndrome X, insulin resistance syndrome, Reaven's syndrome and CHAOS.
The invention finds application in the treatment of diseases associated with metabolic syndrome, including for example: fatty liver (often progressing to non-alcoholic fatty liver disease), polycystic ovarian syndrome, hemochromatosis (iron overload) and acanthosis nigricans (dark skin patches).
The invention finds application in the treatment of Type 2 diabetes. Type 2 diabetes is a chronic disease that is characterised by persistently elevated blood glucose levels (hyperglycaemia). Insulin resistance together with impaired insulin secretion from the pancreatic β-cells characterizes the disease. The progression of insulin resistance to type 2 diabetes is marked by the development of hyperglycaemia after eating when pancreatic β-cells become unable to produce adequate insulin to maintain normal blood sugar levels (euglycemia)).
Type 1 diabetes The invention finds application in the treatment of Type 1 diabetes (or insulin dependent diabetes). Type 1 diabetes is characterized by loss of the insulin-producing beta cells of the islets of Langerhans in the pancreas, leading to a deficiency of insulin. The main cause of this beta cell loss is a T-cell mediated autoimmune attack. There is no known preventative measure that can be taken against type 1 diabetes, which comprises up to 10% of diabetes mellitus cases in North America and Europe. Most affected people are otherwise healthy and of a healthy weight when onset occurs. Sensitivity and responsiveness to insulin are usually normal, especially in the early stages.
As explained below, the compounds of the invention may have antidiabetogenic virus activity. Diabetogenic viruses are aetiological agents of type 1 diabetes, and so compounds having antidiabetogenic virus activity are particularly preferred for use in the treatment or prevention of type 1 diabetes and also: (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 nonimmune 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.
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 per se, 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):
Figure imgf000026_0001
(i) Compounds of Formula (1)
The compounds for use according to the invention may be of Formula (1)
Figure imgf000026_0002
L 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; SOxR3; 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, SOxR3, 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, SOxR3, 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-su!fate; 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
R3 and R4 may optionally form a 4 to 8 membered ring, containing one or more O, SOx or NR3 groups
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:
Figure imgf000028_0001
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, 0-C1- 3 alkyl, O-C1-3 alkenyl, CO2H, NH(NH)NH2, CONR3R4; C(O)OR3; C(O)NR3R4; SO2NR3 R2 represents =O; 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
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 O to 1 O, S or NR3 groups.
(ii) Compounds of Formula (2)
The compounds for use according to the invention may be of Formula (2)
Figure imgf000029_0001
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 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; OH1 OR3, or formyl
R2 represents OH; OR3; =O; NH2; N3; SH; SOxR3; 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, SOxR3, 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, SOxR3, halo, CN1 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; 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
R3 and R4 may optionally form a 4 to 8 membered ring, containing one or more O, SOx or NR3 groups
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:
Figure imgf000031_0001
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 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.
(iii) Compounds of Formula (3)
The compounds for use according to the invention may be of Formula (3)
Figure imgf000032_0001
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; SOxR3; 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, SOxR3, halo, CN1 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, SOxR3, 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; C1-6 alkyi, 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, SOx or NR3 groups
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, the compound of Formula (3) is selected from any one of the Formulae shown below:
Figure imgf000034_0001
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, 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 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; (j) 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:
Figure imgf000037_0001
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:
Figure imgf000037_0002
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-^7 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:
Figure imgf000038_0001
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:
Figure imgf000038_0002
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:
Figure imgf000038_0003
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:
Figure imgf000039_0001
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:
Figure imgf000039_0002
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
Pyrrolizidine iminosugars comprise the nucleus:
Figure imgf000039_0003
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:
Figure imgf000040_0001
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:
Figure imgf000040_0002
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:
Figure imgf000040_0003
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 nortropanes which have been reported to inhibit β-glucosidases, β-xylosidases and α-galactosidases (Asano et al., 1997, Glycobiology 7: 1085-1088). The calystegines are common in foods belonging to the Solanaceae 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-A7or- tropane (Calystegine B1) (Griffiths, et al., 1996, Tetrahedron Letters 37: 3207-3208) can alter the glycosidase inhibition to include α-glucosidases and β-galactosidases.
(viii) 5-7 fused
These iminosugars comprise the nucleus:
Figure imgf000041_0001
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 imino sugars comprise the nucleus:
Figure imgf000041_0002
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.
Figure imgf000042_0001
(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) Phytochemistry 56: 265-295), 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
(f) 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 hydroxymethy! 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 pyrrolizidine iminosugar acids
The ISA of the invention may be a pyrrolizidine 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.
The compound of the invention may be as defined hereinin with the proviso that it is not an iminosugar acid, for example not a piperidine iminosugar acid (as hereinabove defined).
(ii) .1 -/V-iminosugars (isoiminosugars) lsoimino sugars 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 are iminosugar conjugates. These include:
• Iminosugar-based glycopeptide analogues
• Iminosugar phosphonate analogues
• Iminosugar nucleotide analogues • Iminosugar glycolipid analogues (e.g. C- or N-alky) iminosugar derivatives)
(iv) Iminosugar 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:
Figure imgf000045_0001
lminosugars of this structural subclass are described by Compain (2007) in lminosugars From Synthesis to Therapeutic Applications: Compain, Philippe / Martin, Olivier R. (eds.) ISBN-13: 978-0-470-03391-3 - John Wiley & Sons) pages 63-86 (the disclosure of which is hereby incorporated by reference). (v) N-substituted iminosuqars
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 al. (2007) in Iminosugars From Synthesis to Therapeutic Applications: Compain, Philippe / Martin, Olivier R. (eds.) ISBN-13: 978-0-470-03391-3 - John Wiley & Sons) pages 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 a/. (2007), op. c/..).
(vii) Iminosugar lactams
Iminosugar lactams for use according to the invention may for example comprise a nucleus selected from:
Figure imgf000046_0001
in which the =0 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 imino sugar.
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) Iminosugar 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 chira! centres 4 contiguous chiral centres
Figure imgf000048_0001
L-arabino or L-lyxo D-manno L-maπno
Figure imgf000048_0002
Figure imgf000048_0004
D- cr L-a)lo D- orL-galacto
Figure imgf000048_0003
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:
Figure imgf000049_0001
IS1 D-arablnose IS2 D-gluεass
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:
Figure imgf000049_0002
D-arabϊπofuranosB D-arabinopyranose
Exemplary iminosugar mimetics include the iminosugars IS1 and IS3, respectively, as shown below:
Figure imgf000049_0003
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 (S3 the stereochemistry represents that not just of D- arabinopyranose but also that of D-lyxose:
Figure imgf000050_0001
in
Figure imgf000050_0002
D-aratenopyra∞se D-Iyxopyranαse
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:
Figure imgf000050_0003
L-talo configuration L-talo configuration
The iminosugar IS5 exhibits the following stereochemical sequences:
Figure imgf000051_0001
IS5 D-gluco configuration L-gluco configuration
L-guIo configuration D-gulo configuration
The iminosugar IS6 exhibits the following stereochemical sequences:
Figure imgf000051_0002
IS6 D-altro configuration D-gluco configuration
D-ta Io configuration L-gulo configuration
Figure imgf000051_0003
L-altro configuration L-gϊυco configuration
L-tato 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:
Figure imgf000052_0001
Rotate 180
Figure imgf000052_0002
Figure imgf000052_0003
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.
Figure imgf000052_0004
J ;
D-g!ucofuranose D-gluco L-gulo L-gukrfuranose
(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
Figure imgf000053_0001
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:
Figure imgf000053_0002
D-arabino D-ørabinofυranose
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 1S11 is considered to be a mimetic of D- arabinofuranose, as shown below:
Figure imgf000053_0003
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:
Figure imgf000054_0001
D-arabino D-arabinofuranose
IS12
(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.
Figure imgf000054_0002
IS13 D-arabino co πfrqurat L-arabino configuration D-arabfno configuration
+ L-arabino configuration
(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- glucose. This principle is generally applicable.
Figure imgf000055_0001
(liydiOxymetliyl)piperidine-3,4,5-friol {liyclroxymethyl)piperidiiie-3,4.5-triol
Figure imgf000055_0002
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; lminosugars of D- or L-galacto configuration; lminosugars of D- or L-manno configuration; lminosugars of D- or L-allo configuration; lminosugars of D- or L-altro configuration; lminosugars of D- or L-ido configuration; lminosugars of D- or L-gulo configuration; lminosugars of D- or L-talo configuration; lminosugars of D- or L-arabino configuration; lminosugars of D- or L-ribo configuration; lminosugars of D- or L-xylo configuration; and/or lminosugars 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.
(1) 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 couid 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).
(II) Glycosyltransferase 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:
• 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; (Ni), 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 may act as a ligand for one or more G- protein coupled receptor(s) in vitro and/or in vivo.
They may act as ligands for a carbohydrate binding site of any protein (including, for example, any of the lectins hereinbefore described).
(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 peptidoglycan 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 peptidoglycan. 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 al. (2002) Nature Reviews Immunology 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 liqands
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 MyDδδ 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 at. (2002) Nature Reviews Immunology 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; έnd/or
(f) DC-SIGN; and/or
(g) BDCA-2; and/or (h) DCIR; and/or (i) DLEC; and/or
Q) 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.
(d) Other ligands The compounds of the invention may be ligands for chaperone proteins. For example, the compounds of the invention may be ligands for calnexin and/or calreticulin.
(V) Pharmacoperones
It has recently been discovered that certain small molecules can serve as a molecular scaffolding and cause otherwise-misfolded mutant proteins to fold and route correctly within the cell. Such molecules have been dubbed "chemical chaperones", "pharmaceutical chaperones" or "pharmacoperones".
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 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.
In other embodiments, the compounds or iminosugars of the invention are pharmacoperones of an enzyme which do not bind to a catalytic site of said enzyme.
Thus, the pharmacoperones of the invention need not be a competitive inhibitor of said enzyme, so removing the problems associated with chaperone:inhibitor ratios associated with known pharmacoperones. In preferred embodiments, the pharmacoperone for use according to the invention is an activator of said enzyme. In such embodiments, the pharmacoperone may specifically bind an activating allosteric site on the enzyme.
In other embodiments, the pharmacoperone may be a non-competitive inhibitor of said enzyme. In such embodiments, the chaperone.-inhibitor ratio may be favourable in view of the availably of the catalytic site. In such embodiments the pharmacoperone may specifically bind an inhibiting allosteric site on the enzyme.
In yet other embodiments, the pharmacoperone of the invention does not bind to the enzyme at all, but acts as an indirect chaperone via a chaperone effect attendant on binding to a protein (e.g. enzyme) which itself acts as a chaperone or co-chaperone of the enzyme. For example, the pharmacoperones of the invention may bind to chaperone proteins such as calnexin and calreticulin and so influence protein trafficking through the Golgi apparatus.
(Vl) 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-translational 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) intracellular^/, in which case they may act as molecular chaperones to increase the expression of active PRR. (b) PRR agonists
The innate immune system appears to play a key role in promoting the response of autoreactive T cells triggering type 1 diabetes (see e.g. Zipris (2008) Innate immunity and its role in type 1 diabetes. Curr. Opin. Endocrinol Diabetes Obes 15: 326-331 ; Richer et a/. (2008) 57(5): 1302 - 1311).
Without wishing to be bound by any theory, it is thought that compounds of the invention may interact with PRR bearing cells/C-type lectin receptors/Toll-like receptors or affect immune responses to infectious organisms in such a way as to give protection from development of diabetes type 1 or to reduce the proinflammatory responses causing autoimmune diabetes
Thus, 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.
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 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 TM 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 TM response (and so increase the TM :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 TM :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 TM response). It induces natural killer (NK) cells to produce IFN-γ as part of the innate immune response and promotes the expansion of CD4+ TM 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+ Th1 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 Th1 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 Th1 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 Th 2 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 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 a/. (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 a/. (1995) J. Med. Chem. 38: 2349-2356.
In yet other embodiments, the functional sugar mimetic binds to a sugar receptor PRR. Such binding per se 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) Mannose 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, Monsigny and Kieda (1990) Glycobiology 1(1): 33-8). Such binding per se 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 celMar 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 per se 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) Sodium-glucose cotransporter inhibitors
The compounds for use according to the invention may be sodium-glucose cotransporter (SGLT) inhibitors.
The kidney is important for the body's energy control. Glucose is reabsorbed from blood after filtration in the kidney proximal tubule. Two types of sodium-glucose cotransporters mediate this reabsorption of glucose. The low-affinity sodium-glucose cotransporter (SGLT2) is found almost exclusively within the kidney and accounts for the majority of glucose reabsorption by the kidney. The remainder of the glucose is reabsorbed by the high-affinity sodium-glucose cotransporter (SGLT1). SGLT1 is expressed to some extent in the kidney but is mainly expressed in the intestine where it is important in the absorption of glucose from the diet. Thus, SGLT2 plays a dominant role in the control of glucose transport in the kidney with SGLT1 having a supporting role. Thus, SGLT1 and/or 2 inhibitors (and SGLT2 and dual SGLT1/2 inhibitors in particular) can cause the excretion of excess glucose in the urine by inhibiting glucose reabsorption in the kidney. As a result, they can lower plasma glucose levels, remove glucose toxicity and thereby relieve many of the symptoms of diabetes. By virtue of the role of SGLT1 within the intestine, SGLT1 inhibitors and/or mixed SGLT1/2 inhibitors may have utility in the treatment of obesity.
The sodium-glucose cotransporter SGLT3, like SGLT2 is a low affinity sugar transporter, and selectively transports D-glucose over D-galactose. SGLT3 is expressed in the small intestine (plasma membranes of the cholinergic neurons within the autonomic neuronal plexus and neuroendocrine cells), skeletal muscle, kidney, spleen, liver.brain, uterus and testes. SGLT3 has also been characterised as a glucose sensor in mammalian cells. SGLT3 responds to variations in extracellular glucose concentrations through changes in membrane potential and these glucose-induced electrical changes modulate the action of other cells via electrical or hormonal signals. Evidence also suggests the presence of the glucose sensor SGLT3 in hypothalamic neurons and in neuromuscular junctions in skeletal muscle. Inhibitors of SGLT3 may therefore modulate glucose sensitivity and so find application in the treatment of glucose intolerance, obesity and diabetes.
Thus, compounds of the invention which are SGLT inhibitors find particular application in the treatment of diabetes (and in particular, type 2 diabetes) and/or obesity.
Compounds of the invention which are SGLT inhibitors may be specific for SGLT1 , SGLT2 or SGLT3. Thus, the compounds of the invention may be SGLT1 inhibitors or SGLT2 inhibitors or SGLT3 inhibitors.
Alternatively, compounds of the invention which are SGLT inhibitors may be mixed inhibitors. Thus, the compounds of the invention may be dual SGLT1/3 inhibitors, dual SGLT2/3 inhibitors or dual SGLT1/2 inhibitors.
Alternatively, the compounds of the invention may be mixed SGLT1/2/3 inhibitors.
The compounds for use according to the invention may be sodium-glucose cotransporter (SGLT) modulators. Thus, the compounds may be agonists or antagonists for SGLT3. Compounds of the invention which are SGLT3 modulators may find particular utility in the treatment of obesity and diabetes.
Compounds of the invention which are SGLT inhibitors may be of Formula 1, Formula 2 or Formula 3, as hereinbefore described. Thus, compounds of the invention which are SGLT inhibitors may be selected from any one of the Formulae shown below:
Figure imgf000077_0001
wherein:
r represents an integer from 1 to (n+4)
s represents an integer from 1 to (n+4)
n represents an integer from 0 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;
or from any one of the Formulae shown below:
Figure imgf000078_0001
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 alkyl, optionally substituted with up to 6 OH, NR3R4, aryl, 0-C1- 3 alkyl, O-C1-3 alkenyl, CO2H, NH(NH)NH2, CONR3R4; C(O)OR3; C(O)NR3R4; SO2NR3 R2 represents =O; 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
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 O to 1 O, S or NR3 groups;
or from any one of the Formulae shown below:
Figure imgf000079_0001
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 =O; 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
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 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.
Thus, compounds of the invention which are SGLT inhibitors may be of Formula 1(a) as hereinbefore described:
Figure imgf000080_0001
wherein:
r represents an integer from 1 to (n+4)
s represents an integer from 1 to (n+4) n represents an integer from 0 to 2
R1 represents C1-9 alkyl, optionally substituted with up to 6 OH, NR3R4, aryl, O-C1- 3 alky!, 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, O-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 O to 1 O, S or NR3 groups.
Thus, in the Formula 1(a), above, r may be 3, n may be 1 , s may be 1 and R2 may represent 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 and Cl.
Thus, the SGLT inhibitors of Formula 1(a) may be of Formula 1 (a)(i):
Figure imgf000081_0001
wherein R2 may represent 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 and Cl. As mentioned in the preceding section, the compounds for use according to the invention may be glucose mimetics. Thus, the SGLT inhibitors of Formula 1(a)(i) may be glucose mimetics of Formula 1 (a)(ii):
Figure imgf000082_0001
Compounds of the invention which are SGLT inhibitors may be of Formula 2(a) as hereinbefore described:
Figure imgf000082_0002
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, 0-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 O to 1 O, S or
NR3 groups.
Compounds of the invention which are SGLT inhibitors may be of Formula 3(a) as hereinbefore described:
Figure imgf000083_0001
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 =O; 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 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 the compounds of the invention which are SGLT inhibitors having any of the Formulae as described above (e.g. of Formula 1 , 1 (a), 1(a)(i), (1)(a)(ii), 2, 2(a), 3 and 3(a) as described above), R2 may represent an aryl group as hereinbefore defined.
Thus, the aryl group may be an optionally substituted aryl group defined according to the following formula:
-X-Ar1Y-Ar2
wherein:
X represents a bond, O, S, NH or an alkyl linker such as CH2 or CH2CH2
Ar1 represents a 5 to 10 membered mono- or bicyclic aromatic or heteroaromatic ring system, optionally substituted by 1 to 4 groups selected from halo, alkyl, OH, O-alkyl or S-a!kyl
Y represents a bond, O, S, NH or an alkyl linker (for example, CH2 or CH2CH2)
Ar2 represents a 5 to 10 membered mono- or bicyclic aromatic or heteroaromatic ring system, optionally substituted by 1 to 4 groups selected from halo, alkyl, OH,
O-alkyl or S-alkyl.
Thus, R2 may represent an aryl group as hereinbefore defined selected from those set out in the Table below:
Figure imgf000085_0001
Figure imgf000086_0001
(IX) Other functional attributes The compounds of the invention preferably do not inhibit glucosidase activity (or do not inhibit glucosidase activity to a clinically-significant extent). Without wishing to be bound by any theory, it is thought that the compounds of the invention may stimulate, directly or indirectly, pancreatic β-cell activity and/or regeneration in vivo. Thus, preferred compounds for use according to the invention stimulate, directly or indirectly, pancreatic β-cell activity and/or regeneration in vivo. In such embodiments, the compounds find particular application in the treatment of type 1 (or insulin-dependent) diabetes, since the compound may promote functional regeneration of pancreatic β-cells.
Without wishing to be bound by any theory, the compounds may inhibit glucuronidases, iduronidase, sialidase or hexosaminidases. Reducing glucuronidase activity may for example improve beta cell function, directly or indirectly, via improved removal of toxins as glucuronides.
(IX) Anti-viral activity
The compounds of the invention may have antidiabetogenic virus activity. Diabetogenic viruses are aetiological agents of type 1 diabetes, and so compounds having antidiabetogenic virus activity are particularly preferred for use in the treatment or prevention of type 1 diabetes and in: (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 nnsty be infected with a diabetogenic virus as described above. The diabetogenic virus target of such compounds may be selected from viruses of the Picomavirus 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.
C. General phvsicochemical 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
AIIose Altrose Arabinose Galactose Glucose Gulose ldose Lyxose Mannose Ribose Talose Xylose
(1R,2R,3S,6S,7R,7aS)- pyrrolizidine y y y y
3-
(hydroxymethyl)hexahy dro-1 H-pyrroliziπe-
1 ,2,6,7-tetraol
2 (2R,3R,4R)-2- pyrrolidine
(hydroxymethyl)pyrrolidi ne-3,4-diol 3 (2R,3R,4R,5S)-2- piperidiπe
(hydroxymethyl)-i- methylpiperidine-3,4,5- triol
4 (3R,4R)-4-hydroxy-1 ,1- pyrrolidine dimethylpyrrolidinium-3- 00 carboxylafe 5 (2R,3S,4S)-4-hydroxy- pyrrolidine
2-(4- methoxybenzyl)pyrrolidi n-3-yl acetate
6 (2S,4R)-4-hydro)q/-1,1- pyrrolidine dimethylpyrrolidinium-2- carboxylate
7 (2S,3R,4R,5S)-3,4,5- piperidine trihydroxypiperidine-2- carboxylic acid 8 (1R,5S,8R)-1 ,8- other y dihydroxy-6-oxa-3- azabicyclo[3.2.1 ]octan-
2-one
9 (3R,4R,5S)-3- piperidine y (hydroxymethyl)piperidi ne-3,4,5-trioI 10 (1S,2R,3S,4R,5S)-8- nortropane methyl-8- azabicyclo[3.2.1 Joctane- 1 ,2,3,4-tetraol
11 (2R,3R,4R,5R)-2-((R)- pyrrolidine 1 ,2-dihydroxyethyl)-5-
(hydroxymethyl)pyrrolidi ne-3,4-diol
12 (1S,7S,8S,8aR)- indoϋzidiπe y octahydroindolizine-
1,2,7,8-tetraol
13 (2R,3R,4R,5R)-2,5- pyrrolidine y bis(hydroxymethyl)pyrro lidine-3,4-diol
14 (1R,2R,3R,5R,7aR)-3- pyrrolizidine y
(hydroxymethyl)-5- methylhexahydro-1 H- pyrrolizine-1 ,2-diol
15 (2R,3S,4R,5R,6R)-2,6- piperidine y bis(hydroxymethyl)piperi dine-3,4,5-triol
16 (2R,3R,4S,5S,6R)-2- piperidine y
(hydroxymethyl)-6-
(((2R,3R,4S,5S,6R)-
3,4,5-trihydroxy-6-
(hydroxymethyl)tetrahyd ro-2H-pyran-2-
O yloxy)methyl)piperidine-
3,4,5-triol
17 (1 R,2R,3R,7S,7aS)-3- pyrrolizidine (hydroxymethyl)hexahy dro-1 H-pyrrolizine-1 ,2,7- triol
18 (3aR,3a1R,4R,5S,8aS)- pyrrolizidine
5-(hydroxymethyl)-2,2- dimethylhexahydro-
3aH-[1 ,3]dioxino[4,5,6- gh]pyrrolizin-4-ol
19 loline pyrrolizidine y
20 (1R,2S,3R,5R)-8- nortropane y azabicyclo[3.2.1]octane-
1 ,2,3-triol
21 (1R,2S,3R,4S,5R)-8- nortropane azabicyclo[3.2.1 ]octane-
1 ,2,3,4-tetraol
22 (1R,2R,3R,5S,7S,7aR)- pyrrolizidine
3-(hydroxymethyl)-5- methylhexahydro-1 H- pyrrolizine-1 ,2,7-triol
23 (2S,3R,4S,5S,6S)-2- piperidine ethyl-6-
(hydroxymethyl)piperidi ne-3,4,5-triol
24 (1S,2R,3R,5R,6S,7R,7a pyrrolizidine R)-3-(hydroxymethyl)-5- methylhexahydro-1 H- pyrrolizine-1 ,2,6,7- tetraol
25 (2R,3R,4R,5R)-1-(2- pyrrolidine hydroxyethyl)-2,5- bis(hydroxymethy[)pyrro lidine-3,4-diol
26 (2R,3R,4R,5R)-2-(3- pyrrolidine hydroxy-4- methoxyphenyl)-5-
(hydroxymethyl)pyrrolidi πe-3,4-diol
27 (2R,3R,4R,5R)-2- pyrrolidine (hydroxymethyl)-5-(4- hydroxyphenyl)pyrrolidi ne-3,4-diol
28 (1 R,2R,3R,6S,7S,7aS)- pyrrolizidine
3-(hydroxymethyl)-6-
(3,4,5-trihydroxy-6-
(hydroxymethyl)tetrahyd ro-2H-pyran-2- yloxy)hexahydro-1 H- pyrrolizine-1 ,2,7-triol
29 (2S,3S,4R)-1-(2- pyrrolidine hydroxyethyl)-2-
(hydroxymethyl)pyrrolidi ne-3,4-diol
30 (1R,2S,6R,7R,8R,8aR)- indolizidine octahydroindolizine- Y 1 ,2,6,7,8-pentaol
31 (1R,2R,3R,7aR)-3- pyrrolizidine (hydroxymethyl)-5- y
(3,10,11- trihydroxyundecyl)hexa hydro-1 H-pyrrolizine-
1,2,6-triol
32 (1S,6S,7R,8R,8aR)-8- indolizidine
(3,4,5-trihydroxy-6-
(hydroxymethyl)tetrahyd ro-2H-pyran-2-
yloxy)octahydroindolizin e-1,6,7-triol
33 (1 R,2S,3R,4S,5R,6R)-8- nortropane azabicyclo[3.2.1]octane-
1 ,2,3,4,6-pentaol
34 (2R,3R,4R,6R)-6-butyl- piperidine
2-
(hydroxymethyl)piperidi ne-3,4-diol
35 (1R,2R,3S,6S,7R,7aR)- pyrrolizidine
3-
(butyryloxymethyl)hexah ydro-1H-pyrrolizine-
1 ,2,6,7-tetrayl tetraborate
36 (1S,2R,8R,δaR)- indolizidine octahydroindolizine- y
1 ,2,8-triol
37 (1S,2R,6R,7S)- pyrrolizidine hexahydro-1 H- y pyrroliziπe-1 , 2,6,7- tetraol
38 (1R,2R,3S,6S,7R,7aR)- pyrrolizidine K)
7-amino-3-
(hydroxymethyl)hexahy dro-1 H-pyrrolizine-1 ,2,6- triol
39 (2R,3R,4R,5R)-2-((1 R)- pyrrolidine
2-(3,4-dihydroxy-4-
(hydroxymethyl)tetrahyd rofuran-2-yloxy)-1- hydroxyethyl)-5-
(hydroxymethyl)pyrrolidi ne-3,4-diol
40 (2R,3R,4R)-2- piperidine (hydroxymethyl)piperidi ne-3,4-diol
41 (1R,2S,6S,7R,8R,8aS)- indolizidine
2-(3,4,5-trihydroxy-6- (hydroxymethyl)tetrahyd ro-2H-pyran-2- yloxy)octahydroindoliziπ e-1,6,7,8-tetraol
42 (2R,3R,4R,5R)-2-((Z)-5- pyrrolidine hydrazono-4- iminopentyl)-5-
(hydroxymethyl)pyrrolidi ne-3,4-diol
43 (1S,2R,3S,5R)-8- nortropane y azabicyclo[3.2.1]octane- y
1 ,2,3,6-tetraol
44 (1S,3R,4R,5S)-8- nortropane y y azabicyclo[3.2.1 ]octaπe-
1 ,3,4-triol
45 (4R,5R,6S)-4,5- oxazilidine y dihydroxy-6- y
(hydroxymethyl)morphol in-2-ium
46 (1S,6S,7S,8R)-1 ,7,8- indolizidine trihydroxyoctahydroindo lizin-6-yl butyrate
47 (1 R,2R,3R,6S,7S,7aR)- pyrrolizidine
3-
(acetoxymethyl)hexahy dro-1 H-pyrrolizine-
1 ,2,6,7-tetrayl tetraacetate
48 (2R,3R,4S)-2-((R)-1 ,2- pyrrolidine dihydroxyethyl)-1 -(2- hydroxyethyl)pyrrolidine
-3,4-diol
49 (2R,3R,4R)-1-butyl-2- pyrrolidine y y (hydroxymethyl)pyrrolidi ne-3,4-diol
50 2-((2R,3R,4R)-3- piperidine y y hydroxy-2- (hydroxymethyl)piperidi n-4-yloxy)-6-
(hyd roxy methy i)tetrahyd ro-2H-pyran-3,4,5-triol
51 (2R,3R,4R,5S,6R)-2- piperidine
(hydroxymethyl)-6- methylpiperidine-3,4,5- triol
52 (2R,3R,4S,5S)-2,5- piperidine y bis(hydroxymethyl)piperi dine-3,4,5-triol
53 2-((S)-2-((2S,3S,4S,5S)- pyrrolidine y
3,4-dihydroxy-5- (hydroxymethyl)pyrrolidi n-2-yl)-2- hyd roxyethoxy)tetrahyd r
o-2H-pyran-3,4,5-triol
54 (1S,2R,3R,7aR)-3- pyrrolizidine (hydroxymethyl)hexahy dro-1 H-pyrrolizine-1 ,2- diol
55 (1R,2R,3R,6S,7S,7aR)- pyrrolizidine
3-((3,4,5-trihydroxy-6- (hyd roxymethyl)tetrahyd ro-2H-pyran-2- yloxy)methyl)hexahydro
-1 H-pyrrolizine-1 ,2,6,7- tetraol
56 (1 R,2R,3S,7S,7aR)- pyrrolizidine
1 ,2,7- trihydroxyhexahydro- 1 H-pyrrolizine-3- carboxylic acid
57 (2R,3S)-2- pyrrolidine (hydroxymethyl)pyrrolidi n-3-ol
58 (3S,4S,5R,6S)-3,4,5- piperidine trihydroxy-3,6- bis(hydroxymethyl)piperi din-2-one
59 (1S,2R,3R,5S,7aR)-5- pyrrolizidine
«1R)-1 ,3- dihydroxybutyl)-3-
(hydroxymethyl)hexahy dro-1 H-pyrrolizine-1 ,2- diol
60 (2S,3S,4S,5S)-2-(4- pyrrolidine aminopentyl)-5-
(hydroxymethyl)pyrrolidi ne-3,4-diol
61 4-((2S,3S,4R,5R)-3,4- piperidine dihydroxy-2-
(hydroxymethyl)-5-
(3,4,5-trihydroxy-6-
(hydroxymethyl)tetrahyd ro-2H-pyran-2- yloxy)piperidin-1- yl)butanoic acid
62 (2R,3R,4R,5R)-2- pyrrolidine (hydroxymethyl)-5-((R)-
1-
hydroxypropyl)pyrrolidin e-3,4-diol
63 (2R,3R,4R,5R)-2-((1 R)- pyrrolidine y 1 ,2-dihydroxypropyI)-5- (hydroxymethyi)pyrrolidi ne-3,4-diol
64 (2R,3R,4R,5R)-1-(2- pyrrolidine y acetoxyethyl)-2,5- bis(acetoxymethyl)pyrrol idine-3,4-diyl diacetate
65 (2S,4R)-4-hydroxy-1- pyrrolidine methylpyrrolidine-2- carboxylic acid
66 (1S,2R,3R,5R,6S,7aR)- pyrrolizidine
5-(3-hydroxybutyl)-3-
(hydroxymethyl)hexahy dro-1 H-pyrrolizine-1 ,2,6- triol
67 (1S,2R,3R,5S,7aR)-5- pyrrolizidine
(3-hydroxybutyl)-3-
(hydroxymethyl)hexahy dro-1 H-pyrrolizine-1 ,2- diol 'Jl
68 (1S,2R,3R,5S,7R,7aR)- pyrrolizidine
3,5- bis(hydroxymethyl)hexa hydro-1 H-pyrrolizine-
1 ,2,7-triol
69 (2S,3S,4S,5R,6S)-2- piperidine y y
(acetoxymethyl)-δ- ethylpiperidine-3,4,5- triyl triacetate
70 (2S,3R,4S)-2-((R)~1 ,2- pyrrolidine dihydroxyethyl)pyrrolidin e-3,4-diol
71 (2R,3S)-3-hydroxy-1 ,1- pyrrolidine dimethylpyrrolidinium-2- carboxylate
72 (2S,3S,4S,5R)-2- piperidine ethylpiperidine-3,4,5- triol
73 (2S,3S,4R)-1-benzyl-2- pyrrolidine
((RH ,2- dihydroxyethyl)pyrrolidiπ e-3,4-diol
74 (2S,3S,4R)-1-butyl-2- pyrrolidine (hydroxymethyl)pyrroltcli ne-3,4-dιol
75 (2S,3R,4S)-2-(1 ,2- pyrrolidine y dιhydroxypropyl)pyrrohdι ne-3,4-dιol
76 (2S,3S,4S,5S)-2-(3,6- pyrrolidine y dιhydroxyheptyl)-5-
(hydroxymethyl)pyrrolιdι ne-3,4-dιol
77 (2S,3R,4R,5R,6R)-5- piperidine
(3,4-dιhydroxy-2,5- bιs(hydroxymethy()tetra hy d rof uran-2-y loxy)-2 , 6- bιs(hydroxymethyl)pιpeπ dιne-3,4-dιol
78 (2R,3R,4R,5S)-2- piperidine ((3,4,5-trιhydroxy-6-
(hydroxymetnyl)tetrahyd ro-2H-pyran-2- yloxy)methyl)pιpeπdιne-
3,4,5-trιol
79 2-((2R,3R,4R,5R)-4- pyrrolidine hydroxy-2,5- bιs(hydroxymethyl)pyrro lιdιn-3-yloxy)-6-
(hydroxymethyl)tetrahyd ro-2H-pyran-3,4,5-trιol
80 (2S,3R,4R)-3,4- pyrrolidine dιhydroxy-1 ,1- dιmethylpyrrolιdιnιum-2- carboxylate
81 (1R,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- piperidine dimethylpipeπdine-
3,4,5-trιol
83 (3R,4R,5S)-3,4,5- piperidine trιhydroxy-3-
(hydroxymethyl)pιpeπdι n-2-oπe
84 (3R,4S)-2,2- pyrrolidine bιs(hydroxymethyl)pyrro
lidine-3,4-diol
85 (2S,4S)-4- pyrrolidine (hydroxymethyl)-i- methylpyrrolidine-2- carboxylic acid
86 (2R,3S,4R)-2-((S)-1,2- pyrrolidine dihydroxyethyl)-4- methylpyrrolidine-3,4- diol
87 (3R,4R,5R)-3,4,5- piperidine trihydroxypiperidine-3- carboxylic acid
88 (2R,3S,4S)-2-((S)-1- pyrrolidine hydroxyethyl)pyrrolidiπe
-3,4-diol
89 (3S,4R)-1-(allyloxy)-2,2- pyrrolidine bis(hydroxymethyl)pyrro lidine-3,4-diol
90 N-((1S,7aR)-hexahydro- pyrrolizidine
1 H-pyrrolizin-1 -yl)-2- methylbutanamide
91 (3S,4R)-2,2- pyrrolidine bis(hydroxymethyl)-1 - propoxypyrrolidine-3,4- diol
92 (2S,3S,4R)-2- pyrrolidine (hydroxymethyl)-2- methylpyrrolidine-3,4- diol
93 (1R,2S,6S,8S,8aS)-6- indolizidine methyloctahydroindolizi ne-1 ,2,8-triol
94 (2R,3R,4R)-3,4- pyrrolidine dihydroxy-1-(2- hydroxyethyl)-2-
(hydroxymethyl)pyrrolidi ne 1 -oxide
95 (2R,3R,4R)-1-butyl-3,4- pyrrolidine dihydroxy-2-
(hydroxymethyl)pyrrolidi ne 1 -oxide
96 (2S,3R,4S)-1-butyl-2- pyrrolidine
((S)-1 ,2- dihydroxyethyl)pyrrolidin e-3,4-diol
97 (S)-1-((3aS,4R,6aS)-6a- pyrrolidine
(hydroxymethyl)-2,2- dimethyItetrahydro-3aH- [1 ,3]dioxolo[4,5-c]pyrrol-
4-yl)ethane-1 ,2-diol
98 (2R,3S,4S)-2-((S)-1 ,2- pyrrolidine dihydroxyethyl)-4-
(hydroxymethy[)pyrrolidi ne-3,4-diol
99 (2S,3S,4R)-1-(2- pyrrolidine hydroxyethyl)-2-
(hydroxymethyl)-2- methylpyrrolidine-3,4- diol
100 (2S,3R,4S,5R)-1 -butyl- piperidine 2,3-dimethylpiperidine-
3,4,5-triol
101 N-((3R,5R)-1-benzyl-5- pyrrolidine
((S)-1 ,2- dihydroxyethyl)pyrrolidin -3-yl)acetamide
102 (3R,4S,5R)-5,6- piperidine dimethyl-2,3,4,5-
90 tetrahydropyridine- 3,4,5-triol
103 (3R,4r,5S)-piperidine- piperidine
3,4,5-triol
104 (1S,6S,7R,8R,8aR)- indolizidine octahydroindolizine-
1 ,6,7,8-tetraol
105 (1R,2S,3S,4S,5R)-4- nortropane
(3,4,5-trihydroxy-6-
(hydroxymethyl)tetrahyd ro-2H-pyran-2-yloxy)-8- azabicyclo[3.2.1 Joctane-
1 ,2,3-triol
106 (1S,2S,3R,4S,5S)-5- nortropane methyl-8-oxa-6- azabicyclo[3.2.1]octane-
2,3,4-triol
107 (7aS,7a1 R,10aR,18aR, pyrrolizidine
18bS)-
2,2,6,6,13,13,17,17- octamethyltetradecahyd robis[1 ,5]dioxecino[2,3- b:2',3',4'-gh]pyrrolizine-
4,15(7aH,7a1H)-dione
108 (2S,3S,4R,5R,6R)-2- piperidine butyl-6-
(hydroxymethyl)piperidi ne-3,4,5-triol
109 (2R,3R,4S,5R)-2- piperidine methylpiperidine-3,4,5- triol
110 2-((2R,3R,4R,5S,6R)- piperidine
4,5-dihydroxy-2,6- y y bis(hydroxymethyl)piperi din-3-yloxy)-6-
(hydroxymethyl)tetrahyd ro-2H-pyran-3,4,5-triol
111 1-((2S,3R,4R,5R)-3,4- pyrrolidine dihydroxy-5-
(hydroxymethyl)pyrrolidi n-2-yl)-2-methoxy-1 H- imidazole-4,5-diol
112 (3S,4S,5R,6R)-3,4,5- piperidine trihydroxy-6-
(hydroxymefhyl)piperidi n-2-one
113 2-((1S,5R,6R,7R,7aS)- pyrrolizidine
6,7-dihydroxy-5-
(hydroxymethyl)hexahy dro-1 H-pyrrolizin-1- yloxy)-6-
(hydroxymethyl)tetrahyd ro-2H-pyran-3,4,5-trioI
114 (2S,3S,4R,5R,6R)-2- piperidine pentyl-6-((3,4,5- trihydroxytetrahydro-2H- pyran-2- yloxy)methyl)piperidine- 3,4,5-triol
115 (2R,4R)-2- piperidine carboxypiperidinium-4-yI sulfate
116 (1S,2R,3R,5R,7aR)-3,5- pyrrolizidine bis(hydroxymethyl)hexa hydro-1 H-pyrrolizine- 1,2-diol
117 (2R,3R,4R,5R)-3,4- pyrrolidine dihydroxy-2-methyl-1 - oxo-5- phenylpyrrolidinium
118 (2R,3R,4R,5S)-1 -butyl- piperidine
2-
(hydroxymethyl)piperidi ne-3,4,5-triol
119 (2S,3S,4S,5R)-2- pyrrolidine (hydroxymethyl)-5- methylpyrrolidine-3,4- diol
120 2-((2R,3R,4R,5S)-3,5- piperidine dihydroxy-2- (hydroxymethyl)piperidi n-4-yloxy)-6-
(hydroxymethyl)tetrahyd ro-2H-pyran-3,4, 5-triol
121 2-((3S,4S,5R,6R)-4,5- piperidine dihydroxy-6- (hydroxymethyl)piperidi n-3-yloxy)-6-
(hydroxymethyl)tetrahyd O ro-2H-pyran-3,4,5-triol O
122 2-((3S,4S,5R,6R)-4,5- piperidine dihydroxy-6- (hydroxymethyl)-i- methylpiperidin-3- y(oxy)-6-
(hydroxymethyl)tetrahyd ro-2H-pyraπ-3,4,5-triol
123 2-((3R,4R,5R)-4- pyrrolidine hydroxy-5- (hydroxymethyl)pyrrolidi n-3-yloxy)-6-
(hydroxymethyl)tetrahyd ro-2H-pyran-3,4,5-triol
124 (2R,3R,4R,5S,6R)-2,6- piperidine bis(hydroxymethyl)-1 - methylpiperidine-3,4,5- triol
125 (3aR,6S,7R,7aS)- piperidine hexahydrospiro[[1 ,3]dio xolo[4,5-b]pyridine-2, 1 '- cyclohexane]-6,7-diol
126 (3S)-2,3-dihydroxy-3- pyrrolidine
((2R,3R,4R)-2,3,4- trihydroxypyrrolidin-2- yl)propanoic acid
127 (1 R,2R,3S,7S,7aR)-3- pyrrolizidine (hydroxymethyl)hexahy dro-1 H-pyrrolizine-1 ,2,7- triol
128 (1 R,2R,3R,7S,7aR)-3- pyrrolizidine (hydroxymethyl)hexahy dro-1 H-pyrrolizine-1 ,2,7- triol
129 (1R,2R,3S,6S,7S,7aR)- pyrrolizidine
3-
(hydroxymethyl)hexahy dro-1 H-pyrrolizine-
1 ,2,6,7-tetraol
•J 30 (1S,2S,6S,7S,8S,8aS)- indolizidine y y octahydroindolizine- 1 ,2,6,7,8-pentaol
131 (1R,2R,3S,6R,7R,7aR)- pyrrolizidine y y
3-
(hydroxymethyl)hexahy dro-1 H-pyrrolizine-
1 ,2,6,7-tetraol
132 (1 R,2R,3R,6S,7S,7aR)- pyrrolizidine
3-
(butyryloxymethyl)hexah ydro-1 H-pyrrolizine-
1 ,2,6,7-tetrayl tetrabutyrate
133 (2R,3S,4S,5S,6R)-2- piperidine
(hydroxymethyl)-6- methylpiperidine-3,4, 5- triol
134 (2R,3R,4R,5R,6S)-2- piperidine
(hydroxymethyl)-6- methylpiperidine-3,4,5- triol
135 (2S,3R,4S,5S)-2,5- piperidine y y bis(hydroxymethyl)piperi dine-3,4,5-triol
136 (1R,2R,3S,6S,7S,7aR)- pyrrolizidine y y
3-
(acetoxymethyl)hexahy dro-1 H-pyrrolizine-
1 ,2,6,7-tetrayl tetraacetate
137 (1R,2R,3R,6S,7S,7aR)- pyrrolizidine
3-
(hydroxymethyl)hexahy dro-1 H-pyrrolizine-
1 ,2,6,7-tetraol
138 (1 R,2R,3R,4S,5R)-8- nortropane azabicyclo[3.2.1 ]octane-
1 ,2,3,4-tetraol
139 (1S,2R,3R,7S,7aR)-3- pyrrolizidine (hydroxymethyl)hexahy dro-1 H-pyrrolizine-1 ,2,7- triol
140 (2R,3R,4S)-2- piperidine (hydroxymethyl)piperidi ne-3,4-diol
141 (1R,2S,3R,4R,5R)-8- nortropane y y azabicyclo[3.2.1 ]octane-
1 ,2,3,4-tetraol
142 (2R,3R,4R)-1-(2- pyrrolidine y y hydroxyethyl)-2-
(hydroxymethyJ)pyrrolidi O K) ne-3,4-diol
143 (1S,2R,3R,5R,7R,7aR)- pyrrolizidine
3-(hydroxymethyl)-5- methylhexahydro-1 H- pyrrolizine-1 ,2,7-triol
144 (1 R,2R,3S,6S,7R,7aR)- pyrrolizidine
3-
(acetoxymethyl)hexahy dro-1 H-pyrrolizine-
1 ,2,6,7-tetrayl tetraacetate
145 (2R,3S,4R)-2-((S)-1 ,2- pyrrolidine dihydroxyethyl)-1-(2- hydroxyethyl)pyrrolidine
-3,4-diol
146 (1R,2R,3S,6S,7R,7aS)- pyrrolizidine
3-
(acetoxymethyl)hexahy dro-1 H-pyrrolizine-
1,2,6,7-tetrayl tetraacetate
147 (1S,2S,3S,6R,7R,7aS)- pyrrolizidine
3-
(hydroxymethyl)hexahy dro-1 H-pyrroliziπe-
1 ,2,6,7-tetraol
148 (1S,2S,3S,6S,7S,7aS)- pyrrolizidine
3-
(hydroxymethyl)hexahy dro-1 H-pyrroliziπe-
1 ,2,6,7-tetraol
149 (1S,2R,3R,5S,7R,7aR)- pyrroiizidine
3-(hydroxymethyl)-5- methylhexahydro-1 H- pyrrolizine-1 ,2,7-triol
150 (1S,2R,3R,5R,7aR)-3- pyrrolizidine y
(hydroxymethyl)-5- methylhexahydro-1 H- pyrrolizine-1 ,2-diol
151 (1 R,2S,3R,5R,7aR)-3- pyrrolizidine y
(hydroxymethyl)-5- methylhexahydro-1 H- pyrrolizine-1 ,2-diol
152 (1S,2R,3R,5S,6R,7S,7a pyrrolizidine y O R)-3-(hydroxymethyl)-5- methylhexahydro-1 H- pyrrolizine-1 ,2,6,7- tetraol
153 (1R,2S,8S,8aS)- indolizidine octahydroindolizine-
1 ,2,8-triol
154 (2R,3R,4S)-1-(2- pyrrolidine hydroxyethyl)-2-
(hydroxymethyl)pyrrolidi ne-3,4-diol
155 (2S,3R,4S)-2-((S)-1 ,2- pyrrolidine dihydroxyethyl)pyrrolidin e-3,4-diol
156 (2S,3S,4R)-2-((R)-1 ,2- pyrrolidine dihydroxyethyl)pyrrolidin e-3,4-diol
157 (2S,3R,4R)-1-butyl-2- pyrrolidine (hydroxymethyl)pyrrolidi ne-3,4-diol
158 (1R,2S,3R,5S,7S,7aR)- pyrrolizidine
3-(hyd roxymethy l)-5- methylhexahydro-1 H-
pyrrolizine-1 ,2,7-triol
159 (2S,3R,4S)-1-benzyl-2- pyrrolidine
((S)-1 ,2- dihydroxyethyl)pyrrolidin e-3,4-diol
160 (2S,3S,4S)-2- pyrrolidine y y (hydroxymethyl)pyrrolidi ne-3,4-diol
161 (2S,3S,4S)-1-(2- pyrrolidine y y hydroxyethyl)-2-
(hydroxymethyl)pyrrolidi ne-3,4-diol
162 (2S,3R,4S)-1-butyl-2- pyrrolidine y y (hydroxymethyl)pyrrolidi ne-3,4-diol
163 (2S,3S,4S)-1-butyl-2- pyrrolidine y y (hydroxymethyl)pyrrolidi ne-3,4-diol
164 (1S,2R,3S,5S,7S,7aR)- pyrrolizidine
3-(hydroxymethyl)-5- methylhexahydro-1 H- pyrrolizine-1 ,2,7-triol
165 (1 S,2R,3S,4S)-1 -butyl- pyrrolidine
3,4-dihydroxy-2-
(hydroxymethyl)pyrrolidi ne 1 -oxide
166 (2S,3S,4R)-2- pyrrolidine (hydroxymethyl)pyrrolidi ne-3,4-diol
167 (2S,3R,4S)-2- pyrrolidine (hydroxymethyl)pyrrolidi ne-3,4-diol
168 (2R,3R,4S,5R)-1-(2- pyrrolidine hydroxyethyl)-2,5- bis(hydroxymethyl)pyrro lidine-3,4-diol
169 (1R,2R,3R,6S,7S,7aR)- pyrrolizidine 1 ,2,6,7-tetrahydroxy-3-
(hydroxymethyl)octahyd ropyrrolizine 4-oxide
170 (3R,4R,5R)-3,4,5- piperidine trihydroxy-3-
(hydroxymethyl)piperidi n-2-one
171 (2S,3R,4R)-2- pyrrolidine (hydroxymethyOpyrroϋdi ne-3,4-diol
172 (1R,2S,3S,7S,7aR)-3- pyrrolizidine (hydroxymethyl)hexahy dro-1 H-pyrrolizine-1 ,2,7- triol
173 (1 R,2S,3R,5R,7S,7aR)- pyrrolizidine
3-(hydroxymethyl)-5- methylhexahydro-1 H- pyrrolizine-1 ,2,7-triol
174 (2S,4R)-4- pyrrolidine (hydroxymethyl)-i- methylpyrrolidine-2- carboxylic acid
■J 75 (1 R,2S,6R,8S,8aS)-6- indolizidine methyloctahydroindolizi ne-1,2,8-triol ■J 76 (2S,3R,4S)-2-((S)-1,2- pyrrolidine dihydroxyethyl)-1 -(2- hydroxyethyl)pyrrolidine
-3,4-diol
177 (1 R,2R,3S,6S,7R,7aS)- pyrrolizidine O 1 ,2,6,7-tetrahydroxy-3- Ul
(hydroxymethyl)octahyd ropyrrolizine 4-oxide
178 (1 R,2S,3R,4R)-1 -butyl- pyrrolidine
3,4-dihydroxy-2-
(hydroxymethyl)pyrrolidi ne 1 -oxide
179 (2S,3S,4S)-2-((S)-1 ,2- pyrrolidine dihydroxyethyl)-4-
(hydroxymethyl)pyrrolidi ne-3,4-diol
180 (2S,3S,4R,5S)-2,3- piperidine dimethylpiperidine-
3,4,5-triol
181 (2R,3S,4R,5S)-2,3- piperidine dimethylpiperidine-
3,4,5-triol
182 (2R,3R,4S,5R)-2,3- piperidine y y dimethylpiperidine-
3,4,5-triol
183 (2R,3R,4S,5R)-2,5- pyrrolidine y y bis(hydroxymethyl)pyrro lidine-3,4-diol
184 (2R,3R,4S,5R,6R)-2- piperidine
(hydroxymef.hyl)-6- methylpiperidine-3,4,5- triol
185 (1 R,2R,3R,7R,7aR)-3- pyrrolizidiπe (hydroxymethyl)hexahy dro-1 H-pyrrolizine-1 ,2,7- triol
186 (1S,6R,7R,8R,8aR)- indolizidiπe octahydroindolizine-
1 ,6,7,8-tetraol
187 (2R,3R,4S,5S)-2- piperidine (hydroxymethyl)piperidi ne-3,4,5-triol
188 (2R,3R,4R,5S,6S)-2- piperidine
(hydroxymethyl)-6- methylpiperidine-3,4,5-
MoI
189 (2R,3S,5S,6R)-2,6- piperidine bis(hydroxymethyl)piperi dine-3,4,5-triol
190 (2R,3R,4R,5R)-2- pyrrolidine (hydroxymethyl)-5- O methylpyrrolidine-3,4- diol
191 (1R,2R,3R,5R,7R,7aR)- pyrrolizidine
3-(hydroxymethyl)-5- methylhexahydro-1 H- pyrroliziπe-1,2,7-triol
192 (1R,2R,3S,6S,7R,7aR)- pyrrolizidine
3-
(hydroxymethyl)hexahy dro-1 H-pyrrolizine-
1,2,6,7-tetraoI
193 (2R,3R,4R,5S)-2- piperidine (hydroxymethyl)piperidi ne-3,4,5-triol
194 (2R,3R,4R,5R)-2-(2- pyrrolidine hydroxyethyl)-5-
(hydroxymethyl)pyrrolidi ne-3,4-diol
195 (2S,3R,4R,5R)-2-(3- pyrrolidine hydroxy-4- methoxyphenyl)-5-
(hydroxymethyl)pyrrolidi ne-3,4-diol
196 (2R,3R,4R,5S)-2- pyrrolidine (hydroxymethyl)-5-(4- hydroxyphenyl)pyrrolidi ne-3,4-diol
197 (1 R,2S,6S,7S,8R,8aR)- indolizidine
6- methyloctahydroindolizi ne-1 ,2,6,7,8-pentaol
198 (1 R,2S,6R,7R,8R,8aR)- indolizidine
6- methyloctahydroindolizi ne-1 ,2,6,7,8-pentaol
199 (2S,3S,4R)-1-benzyl-2- pyrrolidine
((S)-1 ,2- dihydroxyethyl)pyrrolidin e-3,4-diol
200 (2S,3S,4R)-2-((R)-1 ,2- pyrrolidine dihydroxyethyl)-4-
(hydroxymethyl)pyrrolidi ne-3,4-diol
201 (2R,3R,4S,5R)-2- piperidine (hydroxymethyl)-5- methylpiperidine-3,4,5- O triol
202 (2S,3S,4S)-2,4- pyrrolidine bis(hydroxymethyl)pyrro lidine-3,4-diol
203 (2S,3S,4S)-2-((S)-1 ,2- pyrrolidine dihydroxyethyl)-4-
(hydroxymethyl)pyrrolidi ne-3,4-diol
204 3-((2R,3R,4R,5S)-3,4,5- piperidine trihydroxy-2-
(hydroxymethyl)piperidi n-1-yl)propanoic acid
205 (2S,3R,4R,5S)-butyl 1- piperidine butyl-3,4,5- trihydroxypiperidine-2- carboxylate
206 (1S,6R,7R,7aS)-7- pyrrolizidine (methylamino)hexahydr o-1 H-pyrrolizine-1 ,6-diol
207 2-((2S,3S,4S,5S)-3,4- pyrrolidine dihydroxy-2,5- bis(hydroxymethyl)pyrro
Iidin-1-yl)acetic acid
208 (1 R,2R)-1-((2R,3R,4S)- pyrrolidine
3,4-dihydroxypyrrolidin-
2-yI)propane-1 ,2,3-triol
209 (2S,3R,4R,5S)-3,4,5- piperidine trihydroxy-1-(2- hydroxyethyl)piperidine-
2-carboxylic acid
210 2-((2R,3R,4R)-3,4- pyrrolidine dihydroxy-2-
(hydroxymethyl)pyrrolidi n-1-yl)acetic acid
211 (2S,3S,4R)-2-((R)-1 ,2- pyrrolidine dihydroxyethyl)-4- methylpyrrolidine-3,4- diol
212 (2S,3S,4R)-2- pyrrolidine
(hydroxymethyl)-4- methylpyrrolidine-3,4- diol
213 (1S,5R,8S)-6-oxa-3- piperidine azabicyclo[3.2.1 ]octane-
1,8-diol
214 2-((2R,3R,4R,5S)-3,4,5- piperidine O trihydroxy-2- 90
(hydroxymethyl)piperidi n-1-yl)acetic acid
215 (2R,3S,4R,5S)-2- piperidine
(hydroxymethyl)piperidi πe-3,4,5-trio(
216 (2S,3S,4S,5R)-2- piperidine
(hydroxymethyl)piperidi ne-3,4,5-triol
217 (3aS ,4R,6aR)-N-benzyl- pyrrolidine
2,2,4- trimethyltetrahydro-3aH-
[1 ,3]dioxolo[4,5- c]pyrroIe-4-carboxamide
218 (2R,3S,4R)-N-benzyI- pyrrolidine
3,4-dihydroxy-2- methylpyrrolidine-2- carboxamide
219 (3R,4S,5S)-5- piperidine
(hydroxymethyl)piperidi ne-3,4-diol
220 (2S,3S,4R)-1-butyl-2- pyrrolidine
(hyd roxymethy I)-2-
methylpyrrolidine-3,4- diol
221 (2S,3S,4S,5R)-2- piperidine (hydroxymethyl)piperidi ne-3,4,5-triol
222 (2R,3R,4R,5R)-2-(3,4- pyrrolidine dimethoxyphenyl)-5-
(hydroxymethyl)pyrrolidi ne-3,4-diol
223 (2S,3R,4S,5R)-2- piperidine (hydroxymethyl)piperidi ne-3,4,5-triol
224 (3R,4R,5R,6S)-2,2- azepane bis(hydroxymethyl)azep ane-3,4,5,6-tetraol
225 1-hydroxy-13- pyrrolidine ((2R,3R,4S,5R)-4- hydroxy-5-
(hydroxymethyl)-3-
(3,4,5-trihydroxy-6-
(hydroxymethyl)tetrahyd ro-2H-pyran-2- yloxy)pyrrolidin-2- O yl)tridecan-5-one
226 (R)-13-((2R,3R,4R,5R)- pyrrolidine
3,4-dihydroxy-5- (hydroxymethyl)pyrrolidi n-2-yl)-1 ,13- dihyd roxytridecan-5-one
227 (2R,3S,4R,5S)-2- piperidine (aminomethyl)piperidine
-3,4,5-triol
228 (4S,5S)-phenyl 3- piperidine bromo-4,5- dihydroxypiperidine-1 - carboxylate
229 (2R,3R,4R,5R)-2- piperidine (hydroxymethyl)piperidi ne-3,4,5-triol
230 (4S,5S)-phenyI 3- piperidine bromo-4,5- dihydroxypiperidine-1 - carboxylate
231 (3R,4s,5S)-1- piperidine nonylpiperidine-3,4,5- triol
232 (3R,4r,5S)-1- piperidine butylpiperidiπe-3,4,5- triol
233 (3aS,4R,8R,8aS)-4,8- azepaπe dihydroxy-2,2- dimethyltetrahydro-3aH-
[1 ,3]dioxolo[4,5- d]azepin-5(4H)-one
234 (2S,3S,4S,5S)-4,5- piperidine bis(tert- butyldimethylsilyloxy)-2-
((tert- butyldimethylsilyloxy)me thyl)piperidin-3-ol
235 1-((2S,3S,4S)-2-((S)- pyrrolidine 1 ,2-dihydroxyethyl)-3,4- dihydroxypyrrolidin-1- yl)ethanone
236 (2S,3R)-3,4- pyrrolidine dihydroxypyrrolidine-2- carboxylic acid
237 (3aR,6S,7S,7aR)-7- piperidine hydroxy-2,2,6- trimethyltetrahydro-
[1 ,3]dioxolo[4,5- c]pyridin-4(3aH)-one
238 (3aS,6R,7R,7aS)-6- piperidine
((tert- butyldimethy(silyloxy)me thyl)-7-hydroxy-2,2- dimethyltetrahydro-
[1 ,3]dioxolo[4,5- c]pyridin-4(3aH)-one
239 (S)-1-((2S,3S,4S)-3,4- pyrrolidine bis(benzyloxy)pyrrolidin-
2-yl)ethane-1 ,2-diol
240 1-((3aS,4S,8R,8aS)-8- azepane hydroxy-4,7-anhydro- 2,2,4-trimethyl-3aH-
[1 ,3]dioxolo[4,5- c]azepin-
5(4H,6H,7H,8H,8aH)- yl)ethanone
241 (3aS,7R,8R,8aS)-7,8- azepane dihydroxy-2,2- dimethyItetrahydro-3aH-
[1 ,3]dioxolo[4,5- c]azepiπ-4(5H)-oπe
242 (3S,4S,5R)-3,4- pyrrolidine bis(benzyloxy)-5-((S)-
1 ,2- dihydroxyethyl)pyrrolidin -2-one
243 (3S,4S,5R,6R)-3,4,5- piperidine trihydroxy-6- methylpiperidin-2-one
244 (3aR,4S,7R,7aS)-6- piperidine (hydroxymethyl)-2,2,4- trimetπylhexahydro-
[1,3]dioxolo[4,5- c]pyridin-7-ol
245 (2R,3S,4R,5S,6R)-N- piperidine butyl-3,4,5-trihydroxy-6- methylpiperidine-2- carboxamide
246 (2S,3R,4S,5R,6R)- piperidine 3,4,5-trihydroxy-6- (hydroxymethyl)-N- methylpiperidine-2- carboxamide
247 (2R,3S,4R,5S,6R)-N- piperidine benzyl-3,4,5-trihydroxy-
6-methy[piperidine-2- carboxamide
248 (2S,3R,4S,5R,6R)- piperidine 3,4,5-trihydroxy-6-
(hydroxymethyl)piperidi ne-2-carboxylic acid
249 (2R,3S,4R,5S,6R)- piperidine 3,4,5-trihydroxy-N,6- dimethylpiperidine-2- carboxamide
250 methyl 2-((7R)-7- piperidine hydroxy-2,2-dimethyl-4- oxohexahydro-
[1 ,3]dioxolo[4,5- c]pyridin-6-yl)acetate
251 (3aS,4R,8R,8aR,8bS)- pyrrolizidine 4-(benzyloxymethyl)-8- hydroxy-2,2- dimethyltetrahydro-3aH-
[1 ,3]dioxolo[4,5-
a]pyrroIizin-6(4H)-one
252 (2S,3R,4R)-1-butyl-2- piperidine
(hydroxymethyl)piperidi ne-3,4-diol
253 (3R,4r,5S)-1- piperidine y methylpiperidine-3,4,5- triol
254 (3R,4r,5S)-1- piperidine y nonylpiperidine-3,4,5- triol
255 (2S,3S,4S)-1-benzyl-2- pyrrolidine
((S)-1 ,2- dihydroxyethyl)pyrrolidin e-3,4-diol
256 (2S,5S)-2- piperidine
(hydroxymethyl)-6- methylpiperidine-3,4,5- triol
257 (2S,3R,4S,5R)-2- piperidine y methylpiperidine-3,4,5- triol
258 (2R,3S,4R,5S)-2- piperidine y methylpiperidine-3,4,5- triol
259 (2R,3R,4R,5R)-2- piperidine methylpiperidine-3,4,5- triol
260 (3S,4S,5R,6S)-3,4,5- piperidine trihydroxy-6-
(hydroxymethyl)piperidi n-2-one
261 (2R,4S,5R)-2-(2- pyrrolidine hydroxyethyl)-5-
(hydroxymethyl)pyrrolidi ne-3,4-diol
262 (2S,3R,4R)-3,4- pyrrolidine dihydroxypyrrolidine-2- carboxylic acid
263 (2R,3S,4R,5S,6R)-2- piperidine
(hydroxymethyl)-6- methylpiperidine-3,4,5- triol
264 (2S,3S,4R,5S,6R)-2- piperidine
(hydroxymethyl)-6- methylpiperidine-3,4,5-
triol
265 (3S,4R,5S,6S)-N-butyl- piperidine
3,4,5-trihydroxy-6- methylpiperidine-2- carboxamide
266 (1R,2S,6R,7S,7ar)- pyrralizidine hexahydro-1 H- pyrrolizine-1 ,2,6,7- tetraol
267 (3S,4R,5S,6S)-N- piperidine benzyl-3,4,5-trihydroxy-
6-methylpiperidine-2- carboxamide
268 (2S,3S,4S,5S)-2- piperidine y methylpiperidine-3,4,5- triol
269 (2S,3S,4R,5S,6S)-2- piperidine y
(hydroxymethyl)-6- methylpiperidiπe-3,4,5- triol
270 1- azepane ((1R,2S,3S,4S,5S,7R)-
2,3,4-trihydroxy-5- methyl-7-
((2R,3S,4R,5S,6S)-
3,4,5-trihydroxy-6-
(hydroxymethyl)tetrahyd ro-2H-pyran-2-yloxy)-8- oxa-6- azabicyclo[3.2.1 ]octan- 6-yl)ethanone
271 (1 R,2R,3R,6S,7S,7aR)- pyrrolizidine
5-gem-dideuterio-3-
(hydroxymethyl)hexahy dro-1 H-pyrrolizine-
1 ,2,6,7-tetraol
272 (3S,4s,5R)-1- piperidine butylpiperidine-3,4,5- triol
273 (3R,5R)-piperidine- piperidine y y
3,4,5-triol
274 ((2S,4S)-4- pyrrolidine y y azidopyrrolidin-2- yl)methano!
275 ((2S,4S)-4-azido-1- pyrrolidine butylpyrroIidin-2- yl)methanol
276 (2R,3R,4R,5S)-1-(4- piperidine hydroxybutyl)-2-
(hydroxymethyl)piperidi πe-3,4,5-triol
277 2-((2S,4S)-4-azido-2- pyrrolidine
(hydroxym ethyl)py rro lid i n-1-yl)ethanol
278 (2R,3R,3aR,5S,6R,7R,7 piperidine aS)-3-((R)-1- hydroxybutyl)-5-
(hydroxymethyl)octahyd rofuro[3,2-b]pyridine-
2,6,7-triol
279 (3R,4R,5R)-5- y
(hydroxymethyl)piperidi ne-3,4-diol
280 (3R,5S)-1-(2- pyrrolidine y hydroxyethyl)-5-
(hydroxymethyl)pyrrolidi n-3-ol
281 (3R,5R)-3,4,5- piperidine y trihydroxypiperidine-1 - carbaldehyde
282 (3S,5S)-piperidine- piperidine y
3,4,5-triol
283 (3R,5S)-5- pyrrolidine
(hydroxymethyl)pyrrolidi n-3-ol
284 ((2S,4S)-4-azido-1- pyrrolidine nonylpyrrolidin-2- yl)methanol
285 (3R,5S)-5- pyrrolidine
(aminomethyl)-1-(2- hydroxyethyl)pyrrolidin-
3-ol
286 (3R,5S)-5- pyrrolidine y y
(azidomethyl)-i- butylpyrrolidin-3-oI
287 (3R,5S)-5- pyrrolidine y y
(azidomethyl)-1-(2- hydroxyethyl)pyrrolidin-
3-ol
288 (2R,3R,4R,5S)-2- piperidine (hydroxymethy!)-1 -(3- phenoxypropyl)piperidin e-3,4,5-triol
289 (3R,5S)-5- pyrrolidine (aminomethyl)-i- butylpyrrolidiπ-3-ol
290 2-((2S,4S)-4-amino-2- pyrrolidine y y (hydroxymethyl)pyrrolidi n-1-yl)ethanol
291 diethyl 3-((2S,4S)-4- pyrrolidine y y azido-2- (hydroxymethyl)pyrrolidi n-1- yl)propylphosphonate
292 ((2S,4S)-4-amino-1- pyrrolidine butylpyrrolidin-2- yl)methanol
293 (3R,5S)-1-(2- pyrrolidine hydroxyethyl)-5-
(morpholinomethyl)pyrro lidin-3-ol
294 (3R,5S)-5- pyrrolidine y ~ (hydroxymethyl)-i- nonylpyrrolidin-3-oI
295 ((2S,4S)-4-amino-1- pyrrolidine y y nonylpyrrolidin-2- yl)methanol
296 (3R,5R)-1- piperidine y y butylpiperidine-3,4,5- triol
297 (3R,5R)-1- piperidine y y methylpiperidine-3,4,5- triol
298 (3S,5S)-1- piperidine y y butylpiperidine-3,4,5- triol
299 (3S,5S)-1- piperidine y y methylpiperidine-3,4,5- triol
300 (2S,3S,4S,5S)-2- pyrrolidine (hydroxymethyl)-5- methylpyrrolidine-3,4- diol
301 (3S,4s,5R)-piperidine- piperidine
3,4,5-triol
302 (3S,5S)-1- pipendiπe y y noπylpιpeπdιne-3,4,5- tπol
303 (3R,5R)-tert-butyI 3,4,5- piperidine y y tπhydroxypipeπdine-i - carboxylate
304 (2R,3S,4S)-1-(2- pyrrolidine hydroxyethyl)-2-
(hydroxymethyl)pyrrolιdi πe-3,4-dιol
305 (2R,3S,4S)-2- pyrrolidine (hydroxymethyl)pyrrolιdι ne-3,4-diol
306 (2R,3S,4S)-1-butyl-2- pyrrolidine (hydroxymethyl)pyrrolιdι ne-3,4-dιol
307 (2R,3R,4S)-1-benzyl-2- pyrrolidine
((S)-1 ,2- dιhydroxyethyl)pyrrolιdιn e-3,4-dιol
308 (2S,3S,4S)-4-azιdo-1- pyrrolidine benzyl-2-
(hydroxymethyl)pyrrohdι n-3-ol
309 N-((3S,4R,5S)-1 -benzyl- pyrrolidine
4-hydroxy-5- (hydroxymethyl)pyrrolιdι n-3-yl)acetamιde
3-(O (2R,3R,4S)-2- pyrrolidine y
(hydroxymethyl)pyrrolιdι ne-3,4-dιol
311 (2R,3R,4S)-1-benzyl-2- pyrrolidine y (hydroxymethyl)pyrrolidi ne-3,4-dιol
312 (2S,3R,4S)-4-amιno-1- pyrrolidine benzyl-2-
(hydroxymethyl)pyrrolιdι n-3-ol
313 (2S,3R,4S)-4- pyrrolidine acetamido-2-
(acetoxymethyl)-i- benzylpyrrolιdιn-3-yl acetate
314 (2S,3S,4R)-1-butyl-2- pyrrolidine
((RM ,2- dιhydroxyethyl)pyrrolιdin
e-3,4-diol
315 (2R,3R,4S)-2-((S)-1 ,2- pyrrolidine y dihydraxyethyl)pyrrolidin e-3,4-dioI
316 (2S,3S,4R)-2-((R)-1 ,2- pyrrolidine y dihydroxyethyl)-1- nonylpyrrolidine-3,4-diol
317 (2R,3R,4S)-1-butyl-2- pyrrolidine (hydroxymethyl)pyrrolidi ne-3,4-diol
318 N-({3S,4R,5S)-4- pyrrolidine hydroxy-5-
(hydroxymethyl)pyrrolidi n-3-yl)acetamide
319 N-((3S,4R,5S)-1 -butyl- pyrrolidine
4-hydroxy-5-
(hydroxymethyl)pyrrolidi n-3-yl)acetamide
320 (2S,3R,4R)-1- pyrrolidine (cyclohexylmethyl)-2-
(hydroxymethyl)pyrrolidi ne-3,4-diol
321 (2S,3R,4R)-1-(2- pyrrolidine hydroxyethyl)-2-
(hydroxymethyl)pyrrolidi ne-3,4-diol
322 (1R,2R)-1-((2R,3R,4S)- pyrrolidine y
1-butyl-3,4- dihydroxypyrrolidin-2- yl)propane-1 ,2,3-triol
323 (1 R,2R)-1-((2R,3R,4S)- pyrrolidine y 3,4-dihydroxypyrrolidin- 2-yl)propane-1 ,2,3-triol
324 (1S,2R)-1-((2R,3R,4S)- pyrrolidine
3,4-dihydroxy-1- nonylpyrrolidin-2- yl)propane-1 ,2,3-triol
325 (1S,2R)-1-((2R,3R,4S)- pyrrolidine
1-butyl-3,4- dihydroxypyrrolidin-2- yl)propane-1 ,2,3-triol
326 (1S,2R)-1-((2R,3R,4S)- pyrrolidine
3,4-dihydroxy-1-(2- hydroxyethyl)pyrrolidin- 2-yl)propane-1 ,2,3-triol
327 (1R,2R)-1-((2R,3R,4S)- pyrrolidine
3,4-d/hydroxy-1-(2- hydroxyethyl)pyrrolidin- 2-yl)propane-1 ,2,3-trioI
328 (1 R,2R)-1-((2R,3R,4S)- pyrrolidine
1-benzyl-3,4- dihydroxypyrrolidin-2- yl)propane-1 ,2,3-trioI
329 (1S,2R)-1-((2R,3R,4S)- pyrrolidine
1-benzyl-3,4- dihydroxypyrrolidin-2- yl)propane-1 ,2,3-trioI
330 ((2S,4S)-4-acetamido-1- pyrrolidine
(2- acetoxyethyl)pyrrolidin- 2-yl)methyl acetate
331 ((2S,4S)-4-acetamido-1- pyrrolidine y butylpyrrolidiπ-2- yl)methyl acetate
332 ((2S,4S)-4-acetamido-1- pyrrolidine y πonylpyrrolidin-2- yl)methyl acetate
333 (1R,2S,8R,8aR)- indolizidine y octahydroindolizine-
1 ,2,8-triol
334 (2S,3S,4R)-2-((R)-1 ,2- pyrrolidine y dihydroxyethyl)-1-(2- hydroxyethyl)pyrrolidine
-3,4-diol
335 N-((3S,4R,5S)-4- pyrrolidine hydroxy-1-(2- hydroxyethyl)-5-
(hydroxymethyl)pyrrolidi n-3-yl)acetamide
336 (1S,2R)-1-((2S,3R,4S)- pyrrolidine y 3,4-dihydroxypyrrolidin- 2-yl)propane-1 ,2,3-trioI
337 (1R,2S,8R,8aS)-1 ,2,8- indolizidine y trihydroxyhexahydroind olizin-5(1 H)-one
338 N-((3S,4R,5S)-4- pyrrolidine hydroxy-5-
(hydroxymethyl)-i- nonylpyrrolidiπ-3- yl)acetamide
339 (2R,3R,4S)-1-butyl-2- pyrrolidine
((SM ,2- dihydroxyethyl)pyrrolidin e-3,4-diol
340 (2R,3R,4S)-2-((S)-1 ,2- pyrrolidine dihydroxyethyl)-1-(2- hydroxyethyl)pyrrolidine
-3,4-diol
341 2-((2S,3S,4R)-2-((R)- pyrrolidine 1 ,2-dihydroxyethyl)-3,4- dihydroxypyrrolidin-1 - yl)acetic acid
342 (2S,3S,4R)-1-benzyl-2- pyrrolidine (hydroxymethyl)pyrrolidi ne-3,4-diol
343 (2R,3R,4R,5R)-2,5- pyrrolidine bis(hydroxymethyl)-1-(3- pheπoxypropyl)pyrrolidi ne-3,4-dioI
344 ((2S,4S)-4- pyrrolidine y y aminopyrrolidin-2- yl)methanol
345 (2S,4S)-4- pyrrolidine y y azidopyrrolidine-2- carboxylic acid
346 N-((3S,5S)-5- pyrrolidine y y (hydroxymethyl)pyrrolidi n-3-yl)acetamide
347 N-((3S,5S)-1-(2- pyrrolidine y y hydroxyethyl)-5-
(hydroxymethyl)pyrrolidi n-3-yl)acetamide
348 N-((3S,5S)-5- pyrrolidine (hydroxymethyl)-i - nonylpyrrolidin-3- yl)acetamide
349 (2R,3R,4R)-2- pyrrolidine (hydroxymethyl)-i -(3- pheπoxypropyl)pyrrolidi ne-3,4-diol
350 N-((3S,5S)-1-butyl-5- pyrrolidine (hydroxymethyl)pyrrolidi n-3-yl)acetamide
351 (2S,3R,4S)-1-benzyl-2- pyrrolidine
((RM ,2- dihydroxyethyl)pyrrolidin
e-3,4-diol
352 (1S,2S,6S,7R,8R,8aR)- indolizidine octahydroindolizine- 1 ,2,6,7,8-pentaol
353 N-((3S,4R,5S)-4,5- piperidine y y dihydroxypiperidin-3- yl)acetamide
354 (3R,5R)-benzyl 3,4,5- piperidine y y trihydroxypiperidine-1- carboxylate
355 2-((2S,4S)-4-azido-2- pyrrolidine y y (hydroxymethyl)pyrrolidi n-1-yl)acetic acid
356 (1 R,2S,3S,7R,7aR)-3- pyrrolizidine (hydroxymethyl)hexahy dro-1 H-pyrrolizine-1 ,2,7- triol
357 (2R,3S,4S)-2- piperidine (hydroxymethyl)piperidi ne-3,4-diol
358 2-((2S,3R,4S)-4- pyrrolidine acetamido-3-hydroxy-2-
O (hydroxymethyl)pyrrolidi n-1-yl)acetic acid
359 2-((2R,3R,4S)-2-((S)- pyrrolidine 1 ,2-dihydroxyethyl)-3,4- dihydroxypyrrolidin-1 - yl)acetic acid
360 (2S,3S,4R)-1-butyl-2- pyrrolidine y (hydroxymethyl)pyrrolidi ne-3,4-diol
361 2-((2R,3R,4S)-3,4- pyrrolidine y dihydroxy-2-
(hydroxymethyl)pyrrolidi n-1-yl)acetic acid
362 (2R,3S,4R)-4- pyrrolidine acetamido-2-
(acetoxymethyl)-i - benzylpyrrolidin-3-yl acetate
363 (2R,3R,4R)-4-azido-1- pyrrolidine benzyl-2-
(hydroxymethyl)pyrrolidi n-3-ol
364 N-((3R,4S,5R)-1 -benzyl- pyrrolidine
4-hydroxy-5-
(hydroxymethyl)pyrrolidi n-3-yl)acetamide
365 N-((3R,4S,5R)-4- pyrrolidine hydroxy-5-
(hydroxymethyl)pyrrolidi n-3-yl)acetamide
366 2-((2R,3S,4R)-4- pyrrolidine acetamido-3-hydroxy-2- (hydroxymethyl)pyrrolidi n-1-yl)acetic acid
367 N-((3R,4S,5R)-4- pyrrolidine nydroxy-5-
(hydroxymethyl)-i- isopropylpyrrolidin-3- yl)acetamide
368 2-((2S,3S,4R)-3,4- pyrrolidine dihydroxy-2-
(hydroxymethyl)pyrrolidi n-1-yl)acetic acid
369 N-((3R,4S,5R)-4- pyrrolidine hydroxy-1-(2- hydroxyethyl)-5-
(hydroxymethyl)pyrrolidi n-3-yl)acetamide
370 (2R,3S,4R)-4-amino-1- pyrrolidine benzyl-2-
(hydroxymethyl)pyrrolidi n-3-ol
371 (2S,3S,4S,5S)-3,4- pyrrolidine dihydroxy-2,5- bis(hydroxymethyl)pyrro lidine-1 -carbaldehyde
372 N-((3R,4R,5S)-1 -benzyl- pyrrolidine
4-hydroxy-5-
(hydroxymethyl)pyrrolidi n-3-yl)acetamide
373 (2S,3R,4R)-4-amino-1- pyrrolidine benzyl-2-
(hydroxymethyl)pyrrolidi n-3-ol
374 (2S,3S,4R)-4-azido-1- pyrrolidine benzyl-2-
(hydroxymethyl)pyrrolidi 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)pyrrolidι n-1-yl)acetιc acιd
378 N-((3R,4R,5S)-4- pyrrolidine hydroxy-5-
(hydroxymethyl)pyrrolιdι n-3-yl)acetamιde
379 N-((3R,4R,5S)-1 -butyl- pyrrolidine
4-hydroxy-5-
(hydroxymethyl)pyrrolιdι n-3-yl)acetamιde
380 (2R,3R,4S,5S,6S)-2- pipendine
(but-3-enyl)-6-
(hydroxymethyl)pιperιdι ne-3,4,5-tπol
381 (3R,5S)-5- pyrrolidine (azidomethyl)pyrrolιdιn-
3-ol
382 (2R,3R,4R,5S)-3,4,5- pipendine tπhydroxy-N- methylpιpeπdιne-2- carboxamide
383 (5R)-3-hydroxy-5- pyrrolidine (hydroxymethyl)pyrrolιdι ne-3-carboxylιc acid
384 (2R,3S,4R)-2- pyrrolidine y y (hydroxymethyl)pyrrolιdi ne-3,4-dιol
385 (2R,3S,4R)-1-benzyl-2- pyrrolidine y y (hydroxymethyl)pyrrolidi ne-3,4-dιol
386 (2S,3R,4S)-1-benzyl-2- pyrrolidine y y (hydroxymethyl)pyrrolιdι ne-3,4-dιoI
387 (3R,5R)-1- pipeπdine nonylpιperιdine-3,4,5- tπol
388 (2R,3R,4R,5S)-2- piperidine methylpiperιdιne-3,4,5- tπol
389 (2R,3S,4S)-4- pyrrolidine acetamido-2-
(acetoxymethyl)-i- benzylpyrrohdιn-3-yl acetate
390 (2R,3S,4S)-4-amιno-1- pyrrolidine benzyl-2-
(hydroxymethyl)pyrrolιdι n-3-ol
391 N-((3S,4S,5R)-1-butyl- pyrrolidine
4-hydroxy-5-
(hydroxymethyl)pyrrolιdι n-3-yl)acetamιde
392 2-((2R,3S,4S)-4- pyrrolidine acetamιdo-3-hydroxy-2- (hydroxymethyl)pyrrolιdι n-1-yl)acetιc acιd
393 (R)-5-((1R,2S,3S)- pyrrolidine
1 ,2,3,4- tetrahydroxybutyl)pyrrolι dιn-2-one
394 (2R,3R,4S)-4-azido-1- pyrrolidine beπzy(-2-
(hydroxymethyl)pyrrolιdι n-3-ol
395 N-((3S,4S,5R)-4- pyrrolidine hydroxy-5-
(hydroxymethyl)pyrrolidι n-3-yl)acetamιde
396 N-((3S,4S,5R)-1 -benzyl- pyrrolidine
4-hydroxy-5-
(hydroxymethyl)pyrrolιdi 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-
dihydroxypyrrolidin-1 - yOacetic acid
399 (1R,2S,5S,8R,8aS)-5- indolizidine methyloctahydroindolizi ne-1 ,2,8-triol
400 (1 R,2S,6S,7R,8R,8aR)- indolizidine y y y octahydroindoϋzine- 1 ,2,6,7,8-pentaol
401 (1 R,2S,6R,7S,8R,8aR)- indolizidine y y y
1 ,2,6,7,8- pentahydroxyhexahydro indolizin-5(1 H)-one
402 (1 R,2S,8S,8aS)-1 ,2,8- indolizidine y trihydroxyhexahydroind olizin-5(1 H)-one
403 (2S,3R,4S)-1-butyl-2- pyrrolidine y
((R)-1 ,2- dihydroxyethyl)pyrrolidin e-3,4-diol
404 (1 R,2R)-1-((2R,3R,4S)- pyrrolidine
3,4-dihydroxy-1- nonylpyrrolidin-2- yl)propane-1 ,2,3-triol
405 (2S,3R,4S)-2-((R)-1 ,2- pyrrolidine dihydroxyethyl)-1-(2- hydroxyethyl)pyrrolidine
-3,4-diol
406 (1 R,2S,5R,8S,8aS)-5- indolizidine methyloctahydroindolizi ne-1 ,2,8-triol
407 (S)-5-((1S,2R,3R)- pyrrolidine
1 ,2,3,4- tetrahydroxybutyl)pyrroli din-2-oπe
408 (S)-4-((2S,3R,4S)-1- pyrrolidine benzyl-3,4- dihydroxypyrrolidin-2- yl)-4- hydroxybutanenitrile
409 (3aS,6R,9S,9aS,9bR)- indolizidine
2,2-diethyl-6- methyloctahydro-
[1 ,3]dioxolo[4,5- ajindolizin-9-ol
410 (1R,2S,5R,8S,8aR)-8- indolizidine methoxy-5- methyloctahydroindolizi ne~1,2-diol
411 (1 R,2S,3S)-1-((R)-1- pyrrolidine butylpyrrolidin-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 (1R,2S,3S)-1-((R)- pyrrolidine y y pyrrolidin-2-yl)butane-
1 ,2,3,4-tetraol
414 (1 R,2S,3S)-1-((R)-1-(2- pyrrolidine y y hydroxyethyl)pyrrolidin-
2-yl)butane-1 ,2,3,4- tetraol
415 (S)-5-((1 R,2S,3S)- pyrrolidine
1 ,2,3,4- tetrahydroxybutyOpyrroli din-2-one
416 (1 R,2S,3S)-1-((S)-1-(2- pyrrolidine Ul hydroxyethyl)pyrrolidin-
2-yl)butane-1 ,2,3,4- tetraol
417 N-((3S,4R,5S)-1 -benzyl- pyrrolidine
4-hydroxy-5- (hydroxymethyl)pyrrolidi n-3-yl)-2,2,2- trifluoroacetamide
418 (3S,4S,5S)-1-butyl-5- piperidine y (hydroxymethyl)piperidi ne-3,4-diol
419 (3R,4R,5R)-1-butyl-5- piperidine y (hydroxymethyl)piperidi ne-3,4-diol
420 (3R,4R,5R)-1-(2- piperidine y hydroxyethyl)-5-
(hydroxymethyl)piperidi ne-3,4-diol
421 (1R,2S,3S)-1-((S)- pyrrolidine pyrrolidin-2-yl)butane-
1,2,3,4-tetraol
422 (1S,2R,3R)-1-((S)- pyrrolidine pyrrolidin-2-yl)butane-
1 ,2,3,4-tetraol
423 (2S,3S,4R)-1-benzyl-2- pyrrolidine
((S)-1 ,2- dihydroxyethyl)pyrrolidin e-3,4-diol
424 (2R,3R,4R,5S)-tert-butyl piperidine
3,4,5-trihydroxy-2-
(hydroxymethyl)piperidi ne-1-carboxylate
425 (2S,3S,4R)-2-((S)-1 ,2- pyrrolidine dihydroxyethyl)-1-(2- hydroxyethyl)pyrrolidine
-3,4-diol
426 (2S,3S,4R)-1-butyl-2- pyrrolidine
«S)-1 ,2- dihydroxyethyl)pyrrolidin e-3,4-diol
427 (2S,3S,4R)-2-((S)-1 ,2- pyrrolidine y y dihydroxyethyl)-1- nonylpyrrolidine-3,4-diol
428 (2S,3S,4R)-2-((S)-1 ,2- pyrrolidine y y dihydroxyethyl)-1- methylpyrrolidine-3,4- diol
429 (2S,3S,4R)-2-((S)-1 ,2- pyrrolidine dihydroxyethyl)pyrrolidin e-3,4-dio!
430 (3aR,4R,6aS)-4- pyrrolidine (azidomethyl)-5-benzyl- 2,2-dimethyltetrahydro-
3aH-[1 ,3]dioxolo[4,5- c]pyrrole
431 N-((3S,4R,5S)-1-benzyl- pyrrolidine
4-hydroxy-5-
(hydroxymethyl)pyrrolidi n-3-yl)butyramide
432 (2R,3R,4S)-2- pyrrolidine (azidomethyl)-i- benzylpyrroiidine-3,4- diol
433 (2S,3S,4R)-2-((S)-1 ,2- pyrrolidine dihydroxyethyl)-1-(9- hydroxynonyl)pyrrolidin e-3,4-diol
434 2-((2S,3S,4R)-2-((S)- pyrrolidine 1 ,2-dihydroxyethyl)-3,4- dihydroxypyrrolidin-1 - yl)acetonitrile
435 (2S,3S,4R)-2-((S)-1 ,2- pyrrolidine dihydroxyethyl)-1-(2-(2~ methoxyethoxy)ethyl)py rrolidine-3,4-diol
436 (3R,4R,4aR,7S,8R,8aR) piperidine
-octahydro-2H- pyrano[3,2-b]pyridine-
3,4,7,8-tetrol
437 6-[(2S,4R)-4-hydroxy-2- pyrrolidine (hydroxymethyl)pyrrolidi n-1-yl]hexanoic acid
438 2-{[(2S,3S,4R,5S)-4- pyrrolidine hydroxy-5-
(hydroxymethyl)-2-
[(2S,4Z)-undec-4-ene-
1 ,2,11-triol]pyrrolidin-3- yl]oxy}-6-
(hydroxymethyl)tetrahyd ro-2H-py ran-3,4, 5-triol
439 3-[(2R,3R,4R)-3,4- pyrrolidine dihydroxy-2-
(hydroxymethyl)pyrrolidi n-1-yl]propanoic acid
440 [(2S,3R,4R)-3,4- pyrrolidine dihydroxy-2-
(hydroxymethyl)pyrrolidi n-1-yl]acetic acid
441 (2S,4S,5S)-4,5- piperidine dihydroxypiperidine-2- carboxylic acid
442 (2R,3R,4R,5S)-3,4,5- piperidine trihydroxypiperidine-2- carboxylic acid
443 (3aR,6R,7R,8R,8aS,8b pyrrolizidine y y
S)-7,8-dihydroxy-6-
(hydroxymethyl)-2,2- dimethylhexahydro-4H-
[1 ,3]dioxolo[4,5- a]pyrrolizin-4-one
444 (2S,5S,6S,7S,8R,8aS)- indolizidiπe
6,7,8-trihydroxy-5- (hyd roxymethy l)-3-
oxooctahydroindolizine- 2-carboxy!ic acid
445 (2S,5R,6R,7R,8R,8aR)- indolizidiπe
6,7,8-trihydroxy-5-
(hyd roxy methy l)-3- oxooctahydroindolizine-
2-carboxy!ic acid
446 (3S,4R,5S,6R)-3,4,5- piperidine trihydroxy-6-
(hydroxymethyl)piperidi π-2-one
447 (2R,3S,4S,5R)-2- piperidine y (hydroxymethyl)piperidi ne-3,4,5-triol
448 (1R,2S,5R,6S,7S,7aS)- pyrrolizidine y 1 ,2,6,7-tetrahydroxy-5- (hydroxymethyl)hexahy dro-3H-pyrrolizin-3-one
449 (2R,3R,4R,5S)-benzyl piperidine
3,4,5-trihydroxy-2-
(hydroxymethyi)piperidi ne-1-carboxylate
450 2-((3R,4R,5R)-3,4- piperidine 90 dihydroxy-5-
(hydroxymethyl)piperidi n-1-yl)acetic acid
451 2-((3S,4S,5S)-3,4- piperidine dihydroxy-5-
(hydroxymethyl)piperidi n-1-yl)acetic acid
452 (2R,3S,4R)-3,4- pyrrolidine dihydroxy-2- methylpyrrolidine-2- carboxylic acid
453 8-Aza- nortropane bicyclo[3,2,1]octan-3-oI
454 (R)-3-Hydroxypiperidine piperidine
455 4-Hydroxypiperidine piperidine
456 cis-L-3-Hydroxyproline pyrrolidine
457 (R)-3- pyrrolidine Hydroxypyrrolidine
458 cis-4-Hydroxy-D-proline pyrrolidine
459 4-hydroxy-2- pyrrolidine
Pyrrolidinecarboxamide
460 2-methyl-4-PiperidinoI piperldlne
461 L-beta- pyrrolidine
Homohydroxyproline
462 (R)-5-Hydroxy-piperidin- piperidine
2-one
463 (S)-(-)-4-Hydroxy-2- pyrrolidine pyrrolidinone
464 Nojirimycin-1 -Sulfonic piperidine
Acid
465 Siastatin B microbial piperidine
466 D-Glucaro-delta-lactam piperidine
467 4-hydroxy-4- piperidine
Piperidinecarboxylic acid
468 Laburnine pyrrolizidine
469 1-Deoxy-L- piperidine idonojirimycin
470 2,5-Anhydro-2,5-imino- pyrrolidine
D-glucitol
471 1 ,4-Dideoxy-1 ,4-imino- pyrrolidine
D-manπitol
472 (2S.5S)- pyrrolidine
Bishydroxymethyl-
(3R.4R)- bishydroxypyrrolidine
473 4-hydroxy-2- pyrrolidine
Pyrrolidinemethaπol
474 (R)-3-Hydroxypiperidine piperidine
475 cis-L-3-Hydroxyproline pyrrolidine
476 (S)-3-Hydroxypyrrolidine pyrrolidine
477 trans-4-Hydroxy-D- pyrrolidine y y proline
478 trans-4-Hydroxy-D- pyrrolidine y y proline
479 (R)-(+)-4-Hydroxy-2- pyrrolidine pyrrolidinone
480 S)-3-Hydroxy-pyrrolidin- pyrrolidine
2-one
481 N-(((3aR,4R,6aS)-5- pyrrolidine benzyl-2,2- dimethyltetrahydro-3aH-
[1 ,3]dioxolo[4,5-c]pyrrol-
4-yl)methyl)acetamide
482 N-(((2R,3R,4S)-1- pyrrolidine benzyl-3,4- dihydroxypyrrolidin-2- yl)methyl)acetamide
483 ((3aR,4R,6aS)-5- pyrrolidine benzyl-2,2- Ul dimethyltetrahydro-3aH- O
[1 ,3]dioxolo[4,5-c]pyrrol-
4-yl)methanamine
484 N-(((2R,3R,4S)-3,4- pyrrolidine dihydroxypyrrolidin-2- yl)methyl)acetamide
485 N-((3S,4R,5S)-1-benzyl- pyrrolidine
4-hydroxy-5-
(hydroxymethyl)pyrrolidi n-3-yl)benzamide
486 (2R,3R,4S)-2- pyrrolidine (aminomethyl)-i- benzylpyrrolidine-3,4- diol
487 2-((2S,3S,4R)-2-((S)- pyrrolidine 1 ,2-dihydroxyethyl)-3,4- dihydroxypyrrolidin-1 - yl)acetic acid
488 (2R,3R,4S,5R,6R)-2- piperidine butyl-6-
(hydroxymethyl)piperidi ne-3,4,5-triol
489 (1 R,2S,8R,8aR)-1 ,2,8- indolizidine y trihydroxy-6-(2- hydroxyethyl)hexahydro indolizin-5(1H)-one
490 (1R,2S,8R,8aR)-1 ,2,8- indolizidine y trihydroxy-6- methylhexahydroindolizi n-5(1H)-one
491 5-[(2R,3R,4R)-3,4- pyrrolidine dihydroxy-2-
(hydroxymethyl)pyrrolidi n-1-yl]pentanoic acid
492 (1 R,2S,6R,8R,8aR)-6- indolizidine y
(2- hyd roxy ethyl) octahyd roi ndolizine-1 ,2,8-triol
493 (1 R,2S,6S,8R,8aR)-6- indolizidine y
(2- hydroxyethyl)octahydroi ndolizine-1 ,2,8-triol
494 3-[(2R,3R,4R,5R)-3,4- pyrrolidine dihydroxy-2,5- bis(hydroxymethyl)pyrro Ul Iidin-1-yl]propanoic acid
495 (2S,3S,3aS,6S,7S,7aS) pyrrolidine
-2-(hydroxymethyi)-1 -
(methylsulfonyl)octahydr opyrano[3,2-b]pyrrole-
3,6,7-triol
496 (3S,3aS,5S,6R,7R,7aS) pyrrolidine y
-5-(hydroxymethyl)-1 -
(methylsulfonyl)octahydr opyrano[3,2-b]pyrrole-
3,6,7-triol
497 3-K2S,4R)-4-hydroxy-2- pyrrolidine y (hydroxymethyl)pyrrolidi n-1-yl]propanoic acid
498 [(2S,4R)-4-hydroxy-2- pyrrolidine y (hydroxymethyl)pyrrolidi n-1-yl]acetic acid
499 4-[(2R,3R,4R)-3,4- pyrrolidine dihydroxy-2-
(hydroxymethyl)pyrrolidi n-1-yl]butanoic acid
500 (2S,3S,4S)-1-benzyl-2- pyrrolidine (hydroxymethyl)pyrrolidi
ne-3,4-diol
501 (2S,3S,4S)-2- pyrrolidine (hydroxymethyl)-2- methylpyrrolidine-3,4- diol
502 (2R,3S,4S)-N-beπzyl- pyrrolidine
3,4-dihydroxy-2- methylpyrrolidine-2- carboxamide
503 N-{[(3S,4S,5R)-1- piperidine benzyl-4,5- dihydroxypiperidin-3- yl]methyl}acetamide
504 (2R,3S,4S)-3,4- pyrrolidine dihydroxy-2- methylpyrrolidine-2- carboxylic acid
505 (3aR,4S,6aS)-4- pyrrolidine (azidomethyl)-5-benzyl- 2,2-dimethyltetrahydro-
3aH-[1 ,3]dioxolo[4,5- c]pyrrole Ul K)
506 (2S,3R,4S)-2- pyrrolidine (azidomethyl)-i- benzylpyrrolidine-3,4- diol
507 ((3aR,4S,6aS)-5-benzyl- pyrrolidine 2,2-dimethyltetrahydro-
3aH-[1 ,3]dioxolo[4,5- c]pyrrol-4- yl)methanamine
508 N-(((3aR,4S,6aS)-5- pyrrolidine benzyl-2,2- dimethyltetrahydro-3aH-
[1 ,3]dioxolot4,5-c]pyrrol-
4-yl)methyl)acetamide
509 (2R,3R,4R,5S)-2- piperidine y y (hydroxymethyl)-i -(2- morpholinoethyl)piperidi ne-3,4,5-triol
510 (2R,3R,4R,5S)-1- piperidine y y benzyl-2-
(hydroxymethyl)piperidi ne-3,4,5-triol
511 N-(((2R,3R,4S)-3,4- pyrrolidine dihydroxy-1-(9- hydroxynonyl)pyrrolidin- 2-yl)methyl)acetamide
512 N-(((2R,3R,4S)-3,4- pyrrolidine dihydroxy-1- nonylpyrrolidin-2- yl)methyl)acetamide
513 (2R,3R,4S)-2- pyrrolidine (aminomethyl)pyrrolidin e-3,4-diol
514 (2R,3R,4R,5R)-1- pyrrolidine benzyl-2,5- bis(hydroxymethyl)pyrro lidιne-3,4-diol
515 (2R,3R,4R,5R)-2,5- pyrrolidine bιs(hydroxymethyl)-1 - methylpyrrolidine-3,4- diol
516 N-(((2R,3R,4S)-3,4- pyrrolidine dihydroxy-1-(2-(2~ methoxyethoxy)ethyl)py rrolidin-2- Ul yl)methyl)acetamide
517 N-(((2R,3R,4S)-3,4- pyrrolidine dihydroxy-1-(2- hydroxyethyl)pyrrolidin- 2-yl)methyl)acetamide
518 N-(((2R,3R,4S)-1- pyrrolidine (biphenyl-4-ylmethyl)-
3,4-dihydroxypyrrolidin- 2-yl)methyl)acetamide
519 N-(((2R,3R,4S)-1 -butyl- pyrrolidine y 3,4-dihydroxypyrrolidin- 2-yl)methyl)acetamide
520 N-(((2R,3R,4S)-3,4- pyrrolidine y dihydroxy-1-(2- morpholinoethyl)pyrrolid in-2- yl)methy[)acetamide
521 3-((2R,3R,4S)-2- pyrrolidine (acetamidomethyl)-3,4- dihydroxypyrrolidin-1 - yl)propanamide
522 (1R,2S,3S)-1- pyrrolidine [(2R,3S,4S)-3,4-
dihydroxypyrroIidin-2- yl]butane-1 ,2,3,4-tetroI
523 (2R,3R,4R,5S)-2- piperidine (hydroxymethy!)-1 -(2-
(piperidin-1- yl)ethyl)piperidine-3,4,5- triol
524 (2R,3R,4R,5S)-1- piperidine (biphenyl-4-ylmethyl)-2- (hydroxymethyl)piperidi ne-3,4,5-triol
525 (1 R,2S,5R,8S,8aS)-5- indolizidine methyloctahydroindolizi y ne-1 ,2,8-triyl triacetate
526 (1 R,2S,3R)-1- pyrrolidine ((2R,3R,4R)-1-benzyl- y
3,4-dihydroxypyrrolidin-
2-yl)butane-1 ,2,3,4- tetraol
527 (1R,2S,3R)-1- pyrrolidine ((2R,3R,4S)-3,4- dihydroxy-1- nonylpyrrolidin-2- Ul yl)butane-1 ,2,3,4-tetraol
528 (1 R,2S,3R)-1- pyrrolidine ((2R,3R,4S)-1-
(biphenyl-4-ylmethyl)- 3,4-dihydroxypyrrolidin- 2-yl)butane-1 ,2,3,4- tetraol
529 (1 R,2S,3R)-1- pyrrolidine ((2R,3R,4S)-3,4- dihydroxy-1-(9- hydroxyπonyl)pyrrolidiπ- 2-yl)butane-1 ,2,3,4- tetraol
530 2-((2R,3R,4S)-3,4- pyrrolidine dihydroxy-2-
((1R,2S,3R)-1 ,2,3,4- tetrahydroxybutyl)pyrroli din-1-yl)acetic acid
531 (1R,2S,3R)-1- pyrrolidine ((2R,3R,4S)-1butyl-3,4- dihydroxypyrrolidin-2- yl)butane-1 ,2,3,4-tetraol
532 (1R,2S,3R)-1- pyrrolidine ((2R,3R,4S)-1-beπzyl-
3,4-dihydroxypyrrolidin-
2-yl)butane-1 ,2,3,4- tetraol
533 (1R,2S,3R)-1- pyrrolidine ((2R,3R,4S)-3,4- dihydroxy-1-(2- hydroxyethyl)pyrrolidin-
2-yl)butaπe-1 , 2,3,4- tetraol
534 (1 R,2S,5R,6R,7S,8R,8a indolizidine
R)-5- methyloctahydroindolizi ne-1 ,2,6,7,8-peπtaol
535 (1 R,2S,3R)-1- pyrrolidine ((2R,3R,4S)-3,4- dihydroxypyrrolidin-2- yl)butane-1 ,2,3,4-tetraol
536 (1 R,2S,3R)-1- pyrrolidine ((2R,3R,4S)-3,4- dihydroxy-1-(2-(2- methoxyethoxy)ethyl)py Ul rrolidin-2-yl)butane- Ul
1 ,2,3,4-tetraol
537 N-(((2R,3R,4S)-3,4- pyrrolidine dihydroxy-1-(2-
(piperidin-1- yl)ethyl)pyrrolidin-2- yl)methyl)acetamide
538 N-butyl-2- pyrrolidine ((2R,3S,4R,5R)-3,4- dihydroxy-5-
(hydroxymefhyl)-i- nonylpyrrolidin-2- yl)acetamide
539 2-((2R,3S,4R,5R)-1- pyrrolidine benzyl-3,4-dihydroxy-5- (hydroxymethyl)pyrrolidi n-2-yl)-N- butylacetamide
540 N-butyl-2- pyrrolidine ((2R,3S,4R,5R)-3,4- dihydroxy-1-(2- hydraxyethyl)-5-
(hydroxymethyl)pyrrolidi
π-2-yl)acetamide
541 N-butyl-2- pyrrolidine ((2R,3S,4R,5R)-1-butyl-
3,4-dihydroxy-5-
(hydroxymethyl)pyrrolidi n-2-yl)acetamide
542 N-(((2R,3R,4S)-1-(2- pyrrolidine (dimethylamino)ethyl)- 3,4-dihydroxypyrrolidin- 2-yl)methyl)acetamide
543 N-butyl-2- pyrrolidine ((2R,3S,4R,5R)-3,4- dihydroxy-5-
(hydroxymethyl)pyrrolidi n-2-yl)acetamide
544 2-((2R,3R,4S)-2- pyrrolidine (acetamidomethyl)-3,4- dihydroxypyrrolidin-1- yl)acetic acid
545 (3R,5S)-5- pyrrolidine (acetamidomethyl)-i -(2- acetoxyethyl)pyrrolidin- Ul
3-yl acetate
546 (3R,5S)-5- pyrrolidine (acetamidomethyl)-i - butylpyrrolidin-3-yl acetate
547 (3R,5S)-5- pyrrolidine (acetamidomethyl)-i - nonylpyrrolidin-3-yl acetate
548 N-(((2S,4R)-4-hydroxy- pyrrolidine
1-(2- hydroxyethyl)pyrrolidin- 2-yl)methyl)acetamide
549 N-(((2S,4R)-1-butyl-4- pyrrolidine hydroxypyrrolidin-2- yl)methyl)acetamide
550 (2R,3R,4R,5S)-2- piperidine (hydroxymethyl)-i- nonylpiperidine-3,4,5- triol
551 azetidin-3-ol other
552 (3S,4S)-tert-butyl 4- piperidine bromo-3- hydroxypiperidine-1 - carboxylate
553 (R)-tert-butyl 3- piperidine (hydroxymethyl)piperidi ne-1 -carboxylate
554 (S)-tert-butyl 3- piperidine (hydroxymethyl)piperidi ne-1 -carboxylate
555 (2R,3R,4R,5R)-2,5- pyrrolidine y bis(hydroxymethyl)-1 - nony(pyrrolidine-3,4-diol
556 (2R,3R,4R,5R)-1-(2- pyrrolidine y (benzyloxy)ethyl)-2,5- bis(hydroxymethyl)pyrro lidine-3,4-diol
557 (2R,3R,4R,5R)-2,5- pyrrolidine bis(hydroxymethyl)-1 -(9- hydroxynonyl)pyrrolidin e-3,4-diol
558 (2R,3R,4R,5R)-1- pyrrolidine (biphenyl-4-ylmethyl)- Ul
2,5- bis(hydroxymethyl)pyrro lidine-3,4-diol
559 (2R,3R,4R,5R)-2,5- pyrrolidine bis(hydroxymethyl)-1 -(2- morpholinoethyl)pyrrolid ine-3,4-diol
560 (2R,3R,4R,5R)-2,5- pyrrolidine bis(hydroxymethyl)-1 -(2-
(piperidin-1- yl)ethyl)pyrrolidine-3,4- diol
561 (2S,3S,4S,5S)-2-((R)-4- pyrrolidine aminopentyl)-5-
(hydroxymethyl)pyrrolidi ne-3,4-diol
562 (2S,3S,4S,5S)-2-((S)-4- pyrrolidine aminopentyl)-5-
(hydroxymethyl)pyrrolidi ne-3,4-diol
563 N-((3R,4S,5R)-4,5- piperidine dihydroxypiperidin-3- yl)acetamide
564 (2R,3R,4R)-1-(biphenyl- pyrrolidine
4-ylmethyl)-2-
(hydroxymethyl)pyrrolidi ne-3,4-diol
565 (R)-piperidin-3- piperidiπe ylmethanol
566 (2R,3R,4R)-1-benzyl-2- pyrrolidine (hydroxymethyl)pyrrolidi ne-3,4-diol
567 (2R,3R,4R,5R)-2,5- pyrrolidine bis(hydroxymethyl)-1 -(2-
(2- methoxyethoxy)ethyl)py rrolidine-3,4-diol
568 (2R,3R,4R)-2- pyrrolidine y y (hydroxymethyl)-i- nonylpyrrolidine-3,4-diol
569 (2R,3R,4R)-2- pyrrolidine y y (hydroxymethyl)-i -(9- hydroxynonyl)pyrrolidin e-3,4-diol
570 ((3aS,4S,6aR)-5-benzyl- pyrrolidine 2,2-dimethyltetrahydro- Ul
3aH-[1 ,3]dioxolo[4,5- 90 c]pyrrol-4-yl)methanol
571 (2R,3R,4R)-2- pyrrolidine (hydroxymethyl)-i -(2-(2- methoxyethoxy)ethyl)py rrolidine-3,4-diol
572 (2R,3R,4R)-2- pyrrolidine (hydroxymethyl)-i -(2- morpholinoethyl)pyrrolid ine-3,4-diol
573 (2R,3R,4R)-2- pyrrolidine (hydroxymethyl)-i -(2-
(piperidin-1- yl)ethyl)pyrrolidine-3,4- diol
574 3-((2R,3R,4R)-3,4- pyrrolidine dihydroxy-2-
(hydroxymethyl)pyrrolidi n-1 -yOpropanamide
575 (3aR,7R,7aR)-7- piperidine hydroxy-3a- (hydroxymethyl)-2,2- dimethyltetrahydro-
[1 ,3]dioxolo[4,5- c]pyridin-4(3aH)-one
576 (3aS,4R,7R,7aR)-4- piperidine (hydroxymethyl)-2,2- dimethylhexahydro-
[1,3]dioxolo[4,δ- c]pyridin-7-ol
577 (3aR,4S,6aS)-N-benzyl- pyrrolidine
2,2,4,6a- tetramethyltetrahydro-
3aH-[1 ,3]dioxolo[4,5- c]pyrrole-4-carboxamide
578 (3aS,7S,7aR)-7- piperidine (azidomethyl)-5-benzyl-
2,2,3a- trimethylhexahydro-
[1 ,3]dioxolo[4,5- c]pyridine
579 (3aS,4R,7R,7aR)-tert- piperidine butyl 7-hydroxy-2,2,4- trimethyltetrahydro-
[1 ,3]dioxolo[4,5- c]pyridine-5(6H)- Ul carboxylate
580 tert-butyl 5-hydroxy-5,6- piperidine dihydropyridine-1 (2H)- carboxylate
581 N-butyl-2- pyrrolidine ((2R,3S,4R,5R)-3,4- dihydroxy-5-
(hydroxymethyl)-i -(2-(2- methoxyethoxy)ethyl)py rrolidin-2-yl)acetamide
582 N-butyl-2- pyrrolidine ((2R,3S,4R,5R)-3,4- dihydroxy-5-
(hydroxymethyl)-1-(9- hydroxynonyl)pyrrolidin-
2-yl)acetamide
583 N-(((2S,3R,4S)-3,4- pyrrolidine dihydroxy-1-(2-(2- methoxyethoxy)ethyl)py rrolidin-2- y/)methyl)acetamide
584 N-(((2S,3R,4S)-1- pyrrolidine (biphenyl-4-ylmethyl)-
3,4-dihydroxypyrrolidin- 2-yl)methyl)acetamide
585 2-((2R,3S,4R,5R)-1- pyrrolidine (biphenyl-4-ylmethyl)-
3,4-dihydroxy-5- (hydroxymethyl)pyrrolidi n-2-yl)-N- butylacetamide
586 N-(((2R,3R,4S)-1- pyrrolidine benzyl-3,4- dihydroxypyrrolidin-2- yl)methyl)benzamide
587 N-(((2S,3R,4S)-3,4- pyrrolidine dihydroxy-1- nonylpyrrolidin-2- yl)methy])acetamide
588 ((3aS,4S,6aR)-2,2- pyrrolidine dimethyltetrahydro-3aH-
[1 ,3]dioxolo[4,5-c]pyrrol- 4-yl)methanol
589 (1 R,2S,3R)-1-((3R,4R)- pyrrolidine
3,4-dihydroxy-1-(2- hydroxyethyl)pyrrolidin-
2-yl)butane-1 ,2,3,4- tetraol
590 (1R,2S,3R)-1-((3R,4R)- pyrrolidine 1 -(biphenyl-4-ylmethyl)- 3,4-dihydroxypyrrolidin-
2-yl)butane-1 , 2,3,4- tetraol
591 (1R,2S,3R)-1-((3R,4R)- pyrrolidine
3,4-dihydroxy-1-(9- hydroxynonyl)pyrrolidin-
2-yl)butane-1 , 2,3,4- tetraol
592 (1R,2S,3R)-1-((3R,4R)- pyrrolidine
3,4-dihydroxy-1-(2-(2- methoxyethoxy)ethyl)py rrolidin-2-yl)butane-
1 ,2,3,4-tetraol
593 (1R,2S,3R)-1-((3R,4R)- pyrrolidine 3,4-dihydroxypyrrolidin-
2-yl)butane-1, 2,3,4- tetraol
594 (1R,2S,3R)-1-((3R,4R)- pyrrolidine
1-butyl-3,4- dihydroxypyrrolidin-2- yl)butane-1 ,2,3,4-tetraoI
595 (1R,2S,3R)-1-((3R,4R)- pyrrolidine
3,4-dihydroxy-1- nonylpyrrolidin-2- yl)butane-1 ,2,3,4-tetraoI
596 (5R,6R,7S,8R)-5- piperidine methyl-5,6,7,8- tetrahydrotetrazolo[1 ,5- a]pyridine-6,7,8-triol
597 N-(((2S,3R,4S)-1- pyrrolidine benzyl-3,4- dihydroxypyrrolidin-2- yl)methyl)benzamide
598 N-(((2S,3R,4S)-1- pyrrolidine benzyl-3,4- dihydroxypyrrolidin-2- yl)methyl)acetamide
599 N-(((3aR,4S,6aS)-5- pyrrolidine benzyl-2,2- dimethyltetrahydro-3aH- [1 ,3]dioxolo[4,5-c]pyrrol- 4-yl)methyl)benzamide
600 N-(((2S,3R,4S)-3,4- pyrrolidine dihydroxy-1-(2- hydroxyethyl)pyrrolidin- 2-yl)methyl)acetamide
601 N-(((2S,3R,4S)-3,4- pyrrolidine y y dihydroxypyrrolidin-2- yl)methyl)acetamide
602 N-(((2S,3R,4S)-3,4- pyrrolidine y y dihydroxypyrrolidin-2- yl)methyl)benzamide
603 N-(((2S,3R,4S)-1-butyl- pyrrolidine y y 3,4-dihydroxypyrrolidin- 2-yl)methyl)acetamide
604 (2S,3R,4S)-2- pyrrolidine y y (aminomethyl)-i- benzylpyrrolidine-3,4- diol
605 ((3aS,4S,6aR)-5- pyrrolidine (biphenyl-4-ylmethyl)-
2,2-dimethyltetrahydro- 3aH-t1 ,3]dioxolo[4,5-
c]pyrrol-4-yl)methanol
606 (2S,3S,4R)-1-(biphenyl- pyrrolidine
4-ylmethyl)-2-((S)-1 ,2- dihydroxyethyl)pyrrolidin e-3,4-dioi
607 N-(((2S,3R,4S)-1-butyl- pyrrolidine y y 3,4-dihydroxypyrrolidin- 2-yl)methyl)benzamide
608 N-(((3aR,4S,6aS)-5- pyrrolidine y y benzyl-2,2- dimethyltetrahydro-3aH- [1 ,3]dioxolo[4,5-c]pyrrol-
4-yl)methyi)-2,2,2- trifluoroacetamide
609 N-(((3aR,4S,6aS)-2,2- pyrrolidine dimethyltetrahydro-3aH-
[1 ,3]dioxolo[4,5-c]pyrrol- 4-yl)methyl)acetamide
610 N-(((3aR,4S,6aS)-5- pyrrolidine (biphenyl-4-ylmethyl)-
2,2-dimethyltetrahydro- 3aH-[1,3]dioxolo[4,5- c]pyrrol-4- yl)methyl)acetamide
611 N-(((3aR,4S,6aS)-2,2- pyrrolidine dimethyltetrahydro-3aH-
[1 ,3]dioxolo[4,5-c]pyrrol- 4-yl)methyl)-2,2,2- trifluoroacetamide
612 N-(((2S,3R,4S)-3,4- pyrrolidine dihydroxy-1-(2-
(piperidin-1- yl)ethyl)pyrrolidin-2- yl)methyl)benzamide
613 N-(((2S,3R,4S)-3,4- pyrrolidine dihydroxy-1-(9- hydroxynonyl)pyrrolidin- 2-yl)methyl)benzamide
614 N-(((2R,3R,4S)-3,4- pyrrolidine dihydroxypyrrolidin-2- yl)methyl)benzamide
615 N-(((2S,3R,4S)-1-(2- pyrrolidine (dimethylamino)ethyl)- 3,4-dihydroxypyrroiidin- 2-yl)methyl)acetamide
616 N-(((2S,3R,4S)-3,4- pyrrolidine dihydroxy-1-(2-
(piperidin-1- yI)ethyl)pyrrolidin-2- yl)methyl)acetamide
617 N-(((2R,3R,4S)-1 -butyl- pyrrolidine 3,4-dihydroxypyrrolidin- 2-yl)methyl)benzamide
618 N-(((2S,3R,4S)-3,4- pyrrolidine dihydroxy-1-(2- morpholinoethyl)pyrrolid in-2- yl)methyl)acetamide
619 N-(((2R,3R,4S)-1- pyrrolidine benzyl-3,4- dihydroxypyrrolidin-2- yl)methyl)-2,2,2- trifluoroacetamide
620 N-butyl-2- pyrrolidine ((2R,3S,4R,5R)-3,4- dihydroxy-5-
(hydroxymethyl)-i -(2- morpholinoethyl)pyrrolid in-2-yl)acetamide
621 N-(((2S,3R,4S)-3,4- pyrrolidine dihydroxy-1-(2-(2- methoxyethoxy)ethyl)py rrolidin-2- yl)methyl)benzamide
622 N-(((2S,3R,4S)-3,4- pyrrolidine dihydroxy-1- nonylpyrrolidin-2- yl)methyl)benzamide
623 (2S,3S,4R)-1-(biphenyl- pyrrolidine
4-ylmethyl)-2-
(hydroxymethyl)pyrrolidi ne-3,4-diol
624 (1 R,2S,3R)-1-((3R,4S)- pyrrolidine
3,4-dihydroxy-1- methylpyrrolidin-2- yl)butane-1 ,2,3,4-tetraol
625 (1R,2S,3R)-1-((3R,4R)- pyrrolidine
3,4-dihydroxy-1- mefhylpyrrolidin-2- yl)butaπe-1 ,2,3,4-tetraol
626 (1 R,2S,3R)-1-((3R,4R)- pyrrolidine
3,4-dihydroxy-1-(2- morpholinoethyl)pyrroiid in-2-yl)butane-1 ,2,3,4- tetraol
627 (1 R,2S,3R)-1-((3R,4R)- pyrrolidine
3,4-dihydroxy-1-(2-
(piperidin-1- yl)ethyl)pyrrolidin-2- yl)butaπe-1 ,2,3,4-tetraol
628 N-(((2R,3R,4S)-3,4- pyrrolidine dihydroxy-1- methylpyrrolidiπ-2- yl)methyl)benzamide
629 N-(((3aR,4S,6aS)-2,2- pyrrolidine dimethyltetrahydro-3aH-
[1 ,3]dioxolo[4,5-c]pyrrol- 4-yl)methyl)benzamide
630 N-(((3aR,4S,6aS)-2,2- pyrrolidine dimethyl-5- nonyltetrahydro-3aH-
[1 ,3]dioxolo[4,5-c]pyrrol-
4-yl)methyl)acetamide
631 2,2,2-trifluoro-N- pyrrolidine (((3aR,4S,6aS)-5-(2-(2- methoxyethoxy)ethyl)- 2,2-dimethyltetrahydro-
3aH-[1 ,3]dioxolo[4,5- c]pyrrol-4- yl)methyl)acetamide
632 N-(((3aR,4S,6aS)-5- pyrrolidine (biphenyl-4-ylmethyl)-
2,2-dimethyltetrahydro-
3aH-[1 ,3]dioxolo[4,5- c]pyrrol-4-yl)methyl)- 2,2,2-trifluoroacetamide
633 N-(((2S,3R,4S)-3,4- pyrrolidine dihydroxy-1-(2- morpholinoethyl)pyrrolid in-2- yl)methyl)benzamide
634 N-(((2S,3R,4S)-3,4- pyrrolidine dihydroxy-1-(9- hydroxynonyl)pyrrolidin- 2-yl)methyl)acetamide
635 (1S,2S,3S,6R,7R,7aR)- pyrrolizidine
1,6,7-trihydroxy-3-
(hydroxymethyl)hexahy dro-1 H-pyrrolizin-2-yl methanesulfonate
636 (3R,4S,5S)-5- piperidine y (aminomethyl)piperidine
-3,4-diol
637 N-{[(3R,4S,5R)-4,5- piperidine y dihydroxypiperidin-3- yl]methyl}acetamide
638 (2S,4R)-4-hydroxy-1 ,1- pyrrolidine dimethylpyrrolidinium-2- carboxylate
639 N-((3R,4S,5R)-5- piperidine
(benzyloxy)-4- hydroxypiperidin-3- yl)acetamide
640 (3S,4S,5S)-1-(2- piperidine hydroxyethyl)-5-
(hydroxymethyl)piperidi ne-3,4-diol
641 (3S,4S,5S)-5- piperidine (hydroxymethyl)piperidi ne-3,4-diol
642 (1 S,2R,3S,4R,5R)- other Y Y Y 2,3,4-trihydroxy-N-(N'- octylthiocarbamoyl)-6- oxa-nor-tropaπe
643 (5R,6R,7S,8R,8aR)- other Y Y Y 5,6,7,8-Tetrahydroxy-3- octylimino-2- oxaindolizidine
644 (1S,2R,3S,4R,5R)-N- other Y Y Y (N'-Butylthiocarbamoyl)-
2,3,4-trihydroxy-6-oxa- nor-tropane
645 (3Z,5R,6R,7S,8R,8aR)- other Y Y
3- (octylimino)hexahydro[1
,3]thiazolo[3,4- a]pyridine-5,6,7,8-tetrol
646 N-(((2R,3R,4S)-3,4- pyrrolidine Y dihydroxy-1- nonylpyrrolidin-2- yl)methyl)benzamide
647 N-(((2R,3R,4S)-3,4- pyrrolidine dihydroxy-1-(2- hydroxyethyl)pyrrolidin- 2-yl)methyl)benzamide
648 N-(((2R,3R,4S)-3,4- pyrrolidine Y dihydroxy-1-(9- hydroxynonyl)pyrrolidin- 2-yl)methyl)benzamide
649 N-(((2R,3R,4S)-1- pyrrolidine (biphenyl-4-ylmethyl)-
3,4-dihydroxypyrrolidin- 2-yl)methyl)benzamide
650 N-(((2R,3R,4S)-3,4- pyrrolidine Y dihydroxy-1-(2-(2- methoxyethoxy)ethyl)py rrolidin-2- yl)methyl)benzamide
651 N-(((2R,3R,4S)-3,4- pyrrolidine Y dihydroxy-1-(2- morpholinoethyl)pyrrolid in-2- yl)methyl)benzamide
652 N-(((3aR,4S,6aS)-5- pyrrolidine Y Y benzyl-2,2- dimethyltetrahydro-3aH-
[1 ,3]dioxolo[4,5-c]pyrrol-
4-yl)methyl)biphenyl-4- carboxamide
653 N-(((2R,3R,4S)-3,4- pyrrolidine Y dihydroxy-1-(2-
(piperidin-1- yl)ethyl)pyrrolidin-2- yl)methyl)benzamide
654 N-(((2R,3R,4S)-1-(2- pyrrolidine (dimethylamino)ethyl)- 3,4-dihydroxypyrrolidin- 2-yl)methyl)benzamide
655 2-((2R,3R,4S)-2- pyrrolidine Y (benzamidomethyl)-3,4- dihydroxypyrrolidin-1- yl)acetic acid
656 N-(((2R,3R,4S)-3,4- pyrrolidine Y dihydroxy-1- methylpyrrolidin-2- yl)methyl)acetamide
657 N-(((2S,3R,4S)-1- pyrrolidine Y beπzyl-3,4- dihydroxypyrrolidin-2- yl)methyl)biphenyl-4- carboxamide
658 N-(((2S,3R,4S)-1 -butyl- pyrrolidine Y 3,4-dihydroxypyrrolidin- 2-yl)methyl)biphenyl-4- carboxamide
659 N-(((2S,3R,4S)-3,4- pyrrolidine Y Y dihydroxy-1- nonylpyrrolidin-2- yI)methyl)biphenyl-4- carboxamide
660 N-(((2S,3R,4S)-3,4- pyrrolidine Y Y dihydroxy-1-(9- hydroxynonyl)pyrrolidin-
2-yl)methyl)biphenyl-4- carboxamide
661 N-(((3aR,4S,6aS)-5-(9- pyrrolidine Y Y hydroxynonyl)-2,2- dimethyltetrahydro-3aH- [1 ,3]dioxolo[4,5-c]pyrrol- 4-yl)methyl)benzamide
662 N-(((3aR,4S,6aS)-5- pyrrolidine Y Y benzyl-2,2- dimethyltetrahydro-3aH- [1 ,3]dioxolo[4,5-c]pyrrol-
4-y[)methyl)-2,2,2- trifluoroacetamide
663 2,2,2-trifluoro-N- pyrrolidine Y Y (((3aR,4S,6aS)-5-(9- hydroxynonyl)-2,2- dimethyltetrahydro-3aH-
[1 ,3]dioxolo[4,5-c]pyrrol-
4-yl)methyl)acetamide
664 N-(((2S,3R,4S)-1- pyrrolidine Y (biphenyl-4-ylmethyl)-
3,4-dihydroxypyrrolidin- 2-yl)methyl)benzamide
665 3-((2S,3R,4S)-2- pyrrolidine Y Y (acetamidomethyl)-3,4- dihydroxypyrrolidin-1 - yl)propanamide
666 N-(((2S,3R,4S)-1-(3- pyrrolidine Y Y amino-3-oxopropyl)-3,4-
dihydroxypyrroIidin-2- yl)methyl)benzamide
667 N-(((2S,3R,4S)-1-(2- pyrrolidine Y (dimethylamino)ethyl)- 3,4-dihydroxypyrrolidin- 2-yI)methyl)benzamide
668 N-(((3aR,4R,6aS)-5- pyrrolidine Y benzyl-2,2- dimethyltetrahydro-3aH- [1 ,3]dioxolo[4,5-c]pyrrol- 4-yl)methyl)butyramide
669 N-(((2R,3R,4S)-1- pyrrolidine Y benzyl-3,4- dihydroxypyrrolidin-2- yl)methyl)butyramide
670 N-(((2S,3R,4S)-3,4- pyrrolidine Y Y dihydroxypyrrolidin-2- yl)methyl)bipheny!-4- carboxamide
671 (3aS,4R,6aR)-4- pyrrolidine Y Y (azidomethyl)-2,2- dimethyltetrahydro-3aH-
[1 ,3]dioxolo[4,5- c]pyrrole
672 N-(((3aR,4R,6aS)-5- pyrrolidine Y benzyl-2,2- dimethyltetrahydro-3aH-
[1 ,3]dioxolo[4,5-c]pyrrol-
4-yl)methyl)biphenyl-4- carboxamide
673 N-(((2R,3R,4S)-1- pyrrolidine Y beπzyl-3,4- dihydroxypyrrolidin-2- yl)methyl)biphenyl-4- carboxamide
674 N-(((2S,3R,4S)-3,4- pyrrolidine Y Y dihydroxypyrrolidin-2- yl)methyl)-2,2,2- trifluoroacetamide
675 N-(((3aR,4S,6aS)-2,2- pyrrolidine Y Y dimethyl-5-(2- morpholinoethyl)tetrahy dro-3aH-
[1 ,3]dioxolo[4,5-c]pyrrol- 4-yl)methyl)-2,2,2- trifluoroacetamid
676 N-(((3aR,4S,6aS)-5- pyrrolidine Y butyl-2,2- dimethyltetrahydro-3aH- [1 ,3]dioxolo[4,5-c]pyrrol-
4-yl)methyI)-2,2,2- trifluoroacetamide
677 N-(((3aR,4S,6aS)-2,2- pyrrolidine Y dimethyl-5-(2-(piperidin-
1-yl)ethyl)tetrahydro-
3aH-[1 ,3]dioxolo[4,5- c]pyrrol-4-yl)methyl)-
2,2,2-trif[uoroacetamide
678 N-(((3aR,4S,6aS)-5-(2- pyrrolidine Y Y (dimethylamino)ethyl)- 2,2-dimethyltetrahydro-
3aH-[1 ,3]dioxolo[4,5- c]pyrrol-4-yl)methyl)-
2,2,2-trifluoroacetamide
679 N-(((2S,3R,4S)-3,4- pyrrolidine Y Y dihydroxy-1- methylpyrrolidin-2- yl)methyl)acetamide
680 (2S,3R,4R)-2- pyrrolidine Y [(2R,3S,4R)-3,4- dihydroxytetrahydrofura n-2-yl]pyrrolidiπe-3,4- diol
681 (2R,3R,4R)-1-butyl-2- piperidine Y Y (hydroxymethyl)piperidi ne-3,4-diol
682 N-(((2S,3R,4S)-1 -butyl- pyrrolidine Y Y 3,4-dihydroxypyrrolidin-
2-yl)methyl)-2,2,2- trifluoroacetamide
683 N-(((2S,3R,4S)-3,4- pyrrolidine Y Y dihydroxy-1-(2-
(piperidin-1 - yl)ethyl)pyrrolidin-2- yl)methyl)-2,2,2- trifluoroacetamide
684 tert-butyl pyrrolidine Y ((3aR,4S,6aS)-5-(2- hydroxyethyl)-2,2- dimethyltetrahydro-3aH-
[1 ,3]dioxolo[4,5-c]pyrrol-
4-yI)methyIcarbamate
685 dimethyl 1-(((2S,3R,4S)- pyrrolidine Y
1-beπzyl-3,4- dihydroxypyrrolidin-2- yl)methyl)-1H-1 ,2,3- triazole-4,5- dicarboxylate
686 (2S,3R,4S)-2- pyrrolidine Y Y (aminomethyl)-i-
(biphenyl-4- ylmethyl)pyrrolidine-3,4- diol
687 (2R,3S,4R)-2- pyrrolidine Y (aminomethyl)-i- benzylpyrrolidine-3,4- diol
688 N-(((2S,3R,4S)-3,4- pyrrolidine Y dihydroxy-1-(2-(2- methoxyethoxy)ethyl)py rrolidin-2- yl)methyl)biphenyl-4- carboxamide
689 N-(((2R,3R,4S)-1 -butyl- pyrrolidine Y 3,4-dihydroxypyrrolidin- Ul 2-yl)methyl)butyramide O
690 (2R,3S,4R)-2- pyrrolidine Y Y (aminomethyl)pyrrolidin e-3,4-diol
691 N-((2R,3R)-3- pyrrolidine Y ((2R,3R,4R)-3,4- dihydroxypyrrolidin-2- yl)-2,3- dihydroxypropyl)acetam ide
692 (1R,2R)-1-((2R,3R,4R)- pyrrolidine Y Y Y
3,4-dihydroxy-1- nonylpyrrolidin-2- yl)propane-1 ,2,3-triol
693 (1 R,2R)-1-((2R,3R,4R)- pyrrolidine Y Y Y
3,4-dihydroxy-1-(2-(2- methoxyethoxy)ethyl)py rrolidin-2-yl)propane-
1 ,2,3-triol
694 tert-butyl 4- pyrrolidine Y Y (((2R,3R,4S)-3,4- dihydroxy-2- ((1R,2S,3R)-1 ,2,3,4-
tetrahydroxybutyl)pyrroli din-1- yl)methyl)piperidine-1- carboxylate
695 tert-butyl 4-(((3R,4R)- pyrrolidine Y Y Y Y
3,4-dihydroxy-2-
((1 R,2S,3R)-1 ,2,3,4- tetrahydroxybutyl)pyrroli din-1- yl)methyl)piperidine-1 - carboxylate
696 (1R,2S,3R)-1-((3R,4R)- pyrrolidine Y Y Y Y
1-(2-
(dimethylamino)ethyl)-
3,4-dihydroxypyrrolidin-
2-yl)butane-1 ,2,3,4- tetraol
697 N-((2R,3R)-3- pyrrolidine Y Y Y ((2S,3R,4R)-1-benzyl-
3,4-dihyd roxy py rro lid i n-
2-yl)-2,3- dihydroxypropyl)acetam ide Ul
698 (2S,3R,4R)-1-benzy(-2- pyrrolidine Y Y Y
((1 R,2R)-3-
(benzylamino)-i ,2- dihydroxypropyl)pyrrolidi ne-3,4-diol
699 (1R,2R)-1-((2R,3R,4R)- pyrrolidine Y Y Y 3,4-dihydroxypyrrolidin- 2-yl)propane-1 ,2,3-triol
700 (2S,3R,4S)-1-benzyl-2- pyrrolidine Y ((S)-2-(benzylamino)-1 - hydroxyethyl)pyrrolidine
-3,4-diol
701 N-(((2S,3R,4S)-1- pyrrolidine Y (biphenyl-4-ylmethyl)-
3,4-dihydroxypyrrolidin-
2-yl)methyl)biphenyl-4- carboxamide
702 N-(((2S,3R,4S)-3,4- pyrrolidine Y dihydroxy-1-(2- morpholinoethyl)pyrrolid in-2-yl)methyl)biphenyl-
4-carboxamide
703 (1R,2R)-1-((2R,3R,4R)- pyrrolidine Y Y
1-benzyl-3,4- dihydroxypyrrolidin-2- yl)propane-1 ,2,3-triol
704 (2R,3R,4R)-1-benzyl-2- pyrrolidine Y Y Y
((4R,5R)-5-
((benzylamino)methyl)- 2,2-dimethyl-1 ,3- dioxolan-4- yl)pyrrolidine-3,4-diol
705 (1R,2R)-1-((2R,3R,4R)- pyrrolidine Y Y Y
1-(2-
(dimethylamino)ethyl)- 3,4-dihydroxypyrrolidin- 2-yl)propane-1 ,2,3-triol
706 (1 R,2R)-1-((2R,3R,4R)- pyrrolidine Y Y Y
3,4-dihydroxy-1-(2- hydroxyethyl)pyrrolidin- 2-yl)propane-1 ,2,3-triol
707 (2S,2'S,3R,3'R,4S,4'S)- pyrrolidine Y Y
2,21-((1 R,1'R,2R,2'R)- 3,3'-azanediylbis(1 ,2- dihydroxypropane-3,1- Ul diyl))bis(1- K) benzylpyrrolidine-3,4- diol)
708 (2S,3R,4S)-2-((S)-2- pyrrolidine Y amino-1- hydroxyethyl)pyrrolidine -3,4-diol
709 N-((S)-2-((2S,3R,4S)- pyrrolidine Y 3,4-dihydroxypyrrolidin-
2-yl)-2- hyd roxyethy I) acetam ide
710 (2R,4S)-methyl 4- pyrrolidine Y hydroxypyrrolidine-2- carboxylate
711 (3R,4R,5R,6R)- azepane Y azepane-3,4,5,6-tetraol
712 N-butyl-2- pyrrolidine Y ((2R,3S,4R,5R)-3,4- dihydroxy-5- (hydroxymethyl)-i -(2-
(piperidin-1- yl)ethyl)pyrrolidin-2- yl)acetamide
713 (2R,4S)-1-tert-butyl 2- pyrrolidine Y Y methyl 4- hydroxypyrrolιdιne-1 ,2- dicarboxylate
714 2-{[(2R,3R,6R)-6-ethyI- piperidine
3-hydroxypιperιdιn-2- yl]methoxy}-6-
(hydroxymethyl)tetrahyd ro-2H-pyran-3,4,5-trιol
715 (1 S,6R,7R,8S,8aR)- indolizidine octahydroindoliziπe-
1 ,6,7,8-tetraol
716 3-((2S,4S)-4-azιdo-2- pyrrolidine Y Y (hydroxymethyl)pyrrolιdι n-1-yl)propan-1-ol
717 3-((2R,4R)-4-azιdo-2- pyrrolidine Y Y (hydroxymethyl)pyrrolιdι n-1-yl)propan-1-ol
718 N-(((3aR,4R,6aS)-2,2- pyrrolidine dιmethyltetrahydro-3aH-
[1 ,3]dιoxolo[4,5-c]pyrrol- 4-yl)methyl)butyramιde
719 (7S,8R,8aS)-methyl 7,8- other Y Y Ul dιhydroxy-4-oxo-
4,6,7,8,8a,9- hexahydropyrrolo[1 ,2- d][1 ,2,3]trιazolo[1 ,5- a]pyrazιne-3- carboxylate
720 (2S 3R,4S)-2- pyrrolidine Y (amιnomethyl)-1-(2- hydroxyethyl)pyrrolιdιne -3,4-dιol
721 (2R,3R,4R)-4-azιdo-1- pyrrolidine Y Y
(2-hydroxyethyl)-2-
(hydroxymethyl)pyrrolιdi n-3-ol
722 (2S,3S,4S)-4-azιdo-1- pyrrolidine Y Y
(2-hydroxyethyI)-2-
(hydroxymethyl)pyrrolιdι n-3-ol
723 2-((2R,4S)-4-azido-2- pyrrolidine Y (hydroxymethyl)pyrrolιdι n-1-yl)ethano(
724 (2R,3R,4R,5S)-2- piperidine Y (hydroxymethyl)-1-(9-
hydroxynonyl)piperidine -3,4,5-trio!
725 (2R,3R,4R,5S)-2- piperidine Y Y (hydroxymethyl)-i -(2-(2- methoxyethoxy)ethyl)pi peridine-3,4,5-triol
726 (2R,3R,4R,5S)-1-(2- piperidine Y (dimethylamino)ethyl)-2- (hydroxymethyi)piperidi ne-3,4,5-triol
727 N-((3S,5S)-3,5- piperidine Y Y dihydroxypiperidin-4- yl)acetamide
728 (2S,3S,4S,5S)-2-butyl- pyrrolidine Y
5-
(hydroxymethyl)pyrrolidi πe-3,4-diol
729 (2S,3S,4S,5S)-2,5- pyrrolidine Y Y bis(hydroxymethyl)pyrro lidine-3,4-diol
730 N-((3R,4S,5R)-4,5- piperidine Y Y dihydroxy-1- methylpiperidin-3- Ul yl)acetamide
731 N-((3R,4S,5R)-4,5- piperidine Y Y dihydroxy-1- nonylpiperidin-3- yl)acetamide
732 (2S,3S,4S,5S)-2-ethyl- pyrrolidine Y
5-
(hydroxymethyl)pyrrolidi ne-3,4-diol
733 N-((3S,4R,5R)-4,5- piperidine Y dihydroxypiperidin-3- yl)acetamide
734 (3R,4S,5R,6S)-1-(2- azepane Y hydroxyethyl)azepane-
3,4,5,6-tetraol
735 (3R,4S,SR,6S)-1- azepane Y butylazepane-3,4,5,6- tetraol
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-tetraoi
738 (3R,4S,5R,6S)-1- azepane Y
(bιphenyl-4- ylmethyl)azepane-
3,4,5,6-tetraol
739 (3R,4S,5R,6S)-1-(2- azepane Y
(dimethylamιno)ethyl)az epane-3,4,5,6-tetraol
740 (3R,4S,5R,6S)-1- azepane Y benzylazepane-3,4,5,6- tetraol
741 (R)-(I -butylpιpeπdιn-3- azepane yl)methanol
742 (3R,4S,5R,6S)- azepane Y azepane-3,4,5,6-tetraol
743 (2R,3R,4R,5R)-1-(2- pyrrolidine Y
(dιmethylamιno)ethyl)-
2,5- bιs(hydroxymethyl)pyrro lιdine-3,4-diol
Ul
744 (R}-2-(3- pipeπdme Ul
(hydroxymethyl)pιpeπdι n-1-yl)ethanol
745 (2R,3R,4R,5R)-1 -butyl- pyrrolidine Y
O £ bιs(hydroxymethyl)pyrro lιdιne-3,4-dιol
746 (R)-(I -πonylpιpeπdιn-3- piperidine yl)methanol
747 (R)-(I -(2-(2- piperidine methoxyethoxy)ethyl)pi perιdιn-3-yl)methanoI
748 1-(bιphenyl-4- other ylmethyl)azetιdιn-3-ol
749 1-(9- other hydroxynonyl)azetιdιn-
3-ol
750 (1 R,4S,7R)-2-oxa-5- pyrrolidine Y Y azabιcyclo[2 2 1]heptan
-7-ol
751 (7S,8R,8aR)- pyrrolidine Y 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- piperidine Y trihydroxytetrahydro-1 H- oxazolo[3,4-a]pyπdιn- 3(5H)-one
754 (2R,3R,4R)-1-(2- pipeπdine Y Y hydroxyethy[)-2-
(hydroxymethyl)pιpeπdι ne-3,4-dιol
755 (2R,3R,4R)-2- pipeπdine Y (hydroxymethyl)-i -(2- methoxyethyl)pιpeπdιne -3,4-dιol
756 (2R,3R,4R,5S)-1 -ethyl- piperidine Y Y
2-
(hydroxymethyl)pιpeπdι ne-3,4,5-tπol
757 (1 R,2R,3R,4R)-1 -butyl- pipeπdine Y Y
3,4-dιhydroxy-2-
(hydroxymethyl)pιpeπdι ne 1 -oxide Ul
758 (2S,4S,5S)-4,5- piperidine Y Y Y dιhydroxy-1- methylpιpeπdιne-2- carboxylic acid
759 (4aR,7S,8R,8aR)-5- piperidine Y Y benzyl-2,2- dιmethylhexahydro-4H-
[1 ,3]dιoxιno[5,4- b]pyrιdιne-7,8-dιol
760 (2R,4aR,7S,8R,8aR)- piperidine Y Y benzyl 7,8-dιhydroxy-2- phenyItetrahydro-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 hydroxynony!)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- tetrahydroxyazepaπ-1 - yl)acetic acid
766 (3R,4R,5R,6R)-1-(5- azepane Y
(adamantan-1-yl- methoxy)- pentyl)azepane-3, 4,5,6- tetraol
767 ((2R,4S)-4- pyrrolidine Y Y azidopyrrolidin-2- yl)methanol
768 (2R,4S)-tert-buty[ A- pyrrolidine Y Y azido-2-
(hydroxymethyl)pyrrolidi ne-1-carboxylate
769 (3R,4R,5S,6R)-3,4,5,6- azepane Y Y Ul tetrahyd roxyazepan-2- one
770 (3R,4S,5S,6S)- azepane Y Y azepaπe-3,4,5,6-tetraol
771 N-((3R,5R)-3,5- piperidine Y Y dihydroxypiperidin-4- yl)acetamide
772 N-((3R,4S,5S)-4,5- piperidine dihydroxy-1- methylpiperidin-3- yl)acetamide
773 N-((3R,4S,5S)-1-butyl- piperidine Y
4,5-dihydroxypiperidin-
3-yl)acetamide
774 N-((3R,4S,5S)-4,5- piperidine Y dihydroxy-1- nonylpiperidin-3- yl)acetamide
775 N-((3S,5S)-3,5- piperidine Y Y dihydroxy-1- methylpipeιϊdin-4- yl)acetamide
776 N-((3S,5S)-1-butyl-3,5- piperidine Y Y dihydroxypiperidiπ-4- yl)acetamide
777 N-((3S,5S)-3,5- piperidine Y Y dihydroxy-1- nonylpiperidin-4- yl)acetamide
778 N-((3S,4R,5R)-4,5- piperidine Y dihydroxy-1- methylpiperidin-3- yl)acetamide
779 N-((3S,4R,5R)-1-butyl- piperidine Y 4,5-dihydroxypiperidin-
3-yl)acetamide
780 N-((3S,4R,5R)-4,5- piperidine Y dihydroxy-1- nonylpiperidin-3- yl)acetamide
781 N-((3R,5R)-3,5- piperidine Y Y dihydroxy-1- methylpiperidin-4- yl)acetamide
782 N-((3R,5R)-1-butyl-3,5- piperidine Y Y Ul dihydroxypiperidin-4- 90 yl)acetamide
783 N-((3R,5R)-3,5- piperidine Y Y dihydroxy-1- nonylpiperidin-4- yl)acetamide
784 N-((3R,4S,5R)-1-butyl- piperidine Y Y 4,5-dihydroxypiperidin-
3-yl)acetamide
785 N-((3S,4r,5R)-3,5- piperidine Y dihydroxypiperidin-4- yl)acetamide
786 N-((3S,4r,5R)-3,5- piperidine Y dihydroxy-1- methylpiperidin-4- yl)acetamide
787 N-((3S,4r,5R)-1 -butyl- piperidine Y 3,5-dihydroxypiperidin-
4-yl)acetamide
788 (2R,3S,4R,5R)-2- pyrrolidine Y (hydroxymethyl)-5- methylpyrrolidine-3,4- diol
789 N-((3S,4r,5R)-3,5- piperidine dihydroxy-1- nonylpiperidin-4- yl)acetamide
790 N-((3R,4R,5S)-3- piperidine (benzyloxy)-i -butyl-5- hydroxypiperidin-4- yl)acetamide
791 (2S,3R,4S,5S)-2- piperidine Y (hydroxymethyl)piperidi ne-3,4,5-triol
792 (2R,3R,4R,5S)-1-(5- piperidine Y Y
(adamantan-1-yl- methoxy)-pentyl)2-
(hydroxymethyl)- piperidine-3,4,5-triol
793 (3R,4R,5R,6R)-3,4,5,6- azepane Y tetrahydroxyazepan-2- one
794 (3R,4R,5R,6R)-1- azepane Y nonylazepane-3,4,5,6- tetraol
795 (2R,3R,4S,5R)-2- pyrrolidine Y Y Ul benzyl-5-
(hydroxymethyl)pyrroiidi ne-3,4-diol
796 (2S,3S,4R)-2-((R)-1 ,2- pyrrolidine Y dihydroxyethyl)-1- methylpyrrolidiπe-3,4- diol
797 (2S,3R,4S,5R,6R)- piperidine Y Y Y 3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperi dinium chloride
798 (2S,3R,4R,5R,6R)-2- piperidine Y ethyl-6-
(hydroxymethyl)piperidi ne-3,4,5-triol
799 (2R,3S,4R)-1-benzyl-2- pyrrolidine
((S)-1 ,2- dihydroxyethyl)pyrrolidin e-3,4-diol
800 (1S,2R,7R,7aR)- pyrrolizidine hexahydro-1 H- pyrrolizine-1 ,2,7-triol
801 (2R,3S,4R)-2-((R)-1- pyrrolidine hydroxyethyl)pyrrolidine
-3,4-diol
802 N-((3S,4R,5R,6R)-4,5- piperidine Y Y dihydroxy-6-
(hydroxymethyl)piperidi n-3-yl)acetamide
803 (2S,3S,4R)-2-((S)-2- pyrrolidine fluoro-1- hydroxyethyl)pyrrolidiπe -3,4-diol
804 (2S,3R,4R,5S)-1- pyrrolidine Y benzyl-2,5- bis(hydroxymethyl)pyrro lidine-3,4-diol
805 (1S,2S,3S,5R,8aS)-3- indolizidine Y
(hydroxymethyl)-5- methyloctahydroindolizi ne-1 ,2-diol
806 (2S,3R,4R,5R)-2- piperidine Y Y (hydroxymethyl)piperidi ne-3,4,5-triol
807 (2R,3R,4R)-1-(4- pyrrolidine Y chlorobenzyl)-2- O
(hydroxymethyl)pyrrolidi ne-3,4-diol
808 (2R,3R,4R)-2- pyrrolidine Y Y (hydroxymethyl)-i -(3- phenylpropyl)pyrrolidiπe -3,4-diol
809 (2R,3R,4S)-2-((R)-1 ,2- pyrrolidine Y Y dihydroxyethyl)pyrrolidin e-3,4-diol
810 (2R,3R,4S)-1-benzyl-2- pyrrolidine Y Y
((R)-1 ,2- dihydroxyethyl)pyrrolidin e-3,4-diol
811 (2R,3R,4R,5S)-2- piperidine (hyd roxy methy l)-5- methylpiperidine-3,4,5- triol
812 (2S,3R,4R)-1-benzyl-2- pyrrolidine Y
((SH ,2- dihydroxyethyl)pyrrolidin e-3,4-diol
813 (2S,3R,4R)-2-((S)-1 ,2- pyrrolidine dihydroxyethyl)pyrrolidin e-3,4-diol
814 (1R,4S,7R)-2-benzyl- pyrrolidine Y Y
2,5- diazabicyclo[2.2.1 ]hepta n-7-ol
815 (3S,4S,5S,6S)- azepane Y azepane-3,4,5,6-tetraol
816 (2R,3S,4S)-1-butyl-2- piperidine Y (hydroxymethyl)piperidi ne-3,4-diol
817 (2R,3S,4R)-2-((R)-1 ,2- pyrrolidine Y Y dihydroxyethyl)pyrrolidin e-3,4-diol
818 (3R,4S,5R,6R)- azepane Y Y azepane-3,4,5,6-tetraol
819 (2S,3S,4S)-2- pyrrolidine Y Y (hydroxymethyl)-i -(3- phenylpropyl)pyrrolidine -3,4-diol
820 (2S,3R,4R)-1-butyl-2- pyrrolidine Y
((S)-1 ,2- CK dihydroxyethyl)pyrrolidin e-3,4-diol
821 (2S,3R,4R)-2-((S)-1 ,2- pyrrolidine Y dihydroxyethyl)-1-(2- hydroxyethyl)pyrrolidine
-3,4-diol
822 (2R,3R,4R,5S)-1-hexyl- piperidine Y Y
2-
(hydroxymethyl)piperidi ne-3,4,5-triol
823 (2S,3R,4S)-2- pyrrolidine Y Y (hydroxymethyl)-1-(4- methoxybenzyl)pyrrolidi ne-3,4-diol
824 (3R,4S,5S,6R)- azepane Y azepaπe-3,4,5,6-tetraol
825 (2R,3S,4S)-1-benzyl-2- pyrrolidine Y
((R)-1 ,2- dihydroxyethyl)pyrrolidin e-3,4-diol
826 (2R,3S,4S,5R)-2,5- pyrrolidine Y bis(hydroxymethyl)pyrro
!idine-3,4-diol
827 N-((3S,4S,5R)-4,5- piperidiπe Y dihydroxypiperidin-3- yl)acetamide
828 N-((3R,4R,5S)-4,5- piperidine Y dihydroxypiperidin-3- yl)acetamide
829 (1S,2S,3R,6S,9aS)-6- quinolizidin Y Y methyloctahydro-1 H- e quinolizine-1 ,2,3-triol
830 N-((3S,4S,5R)-4,5- piperidine Y dihydroxy-1- methylpiperidin-3- yl)acetamide
831 N-((3S,4S,5R)-4,5- piperidine Y dihydroxy-1- nonylpiperidin-3- yl)acetamide
832 N-((3R,4R,5S)-4,5- piperidine Y dihydroxy-1- methylpiperidin-3- yl)acetamide
833 N-((3R,4R,5S)-1-butyl- piperidine Y K)
4,5-dihydroxypiperidin-
3-yl)acetamide
834 N-((3S,4S,5R)-1-butyl- piperidine Y
4,5-dihydroxypiperidin-
3-yl)acetamide
835 (3R,4S,5S)-5- piperidine Y aminopiperidine-3,4-diol
836 2-((3R,4r,5S)-3,4,5- piperidine Y trihydroxypiperidiπ-1 - yl)acetonitrile
837 (3R,4r,5S)-1-(2- piperidine Y hydroxyethyl)piperidine-
3,4,5-triol
838 (3R,4r,5S)-1-(2-(2- piperidine Y methoxyethoxy)ethyl)pi peridine-3,4,5-triol
839 (2R,3R,4R,5R)-2-((R)- piperidine Y Y
1 ,2- dihydroxyethyOpiperidin e-3,4,5-triol
840 (2R,3R,4S,5R)-2-((R)- piperidine Y Y
1,2- dihydroxyethyl)piperidin e-3,4,5-triol
841 (2R,3R,4R,5S)-2- pyrrolidine Y Y (hydroxymethyl)-5- methylpyrrolidine-3,4- diol
842 (2R,3S,4R)-2-((S)-1 ,2- pyrrolidine Y dihydroxyethyl)~1- methylpyrrolidine-3,4- diol
843 (3R,4R,5R)-3- piperidine Y Y (hydroxymethyl)piperazi ne-4,5-diol
844 (4R,5R,6R)-6- piperidine Y Y (hydroxymethyl)-i- methylpiperaziπe-4,5- diol
845 retronecine N-oxide pyrrolizidine
846 1-((3R,4R,5R)-4,5- piperidine Y dihydroxy-3- M
(hydroxymethyl)piperazi n-1-yl)ethanone
847 (2S,3R,4R,5R)-2-((R)- piperidine Y Y
1 ,2- dihydroxyethyl)piperidin e-3,4,5-triol
848 (2R,3S,4S)-2-((R)-1 ,2- pyrrolidine Y dihydroxyethyl)pyrrolidin e-3,4-diol
849 (1S,2S,8R,8aS)- indolizidine Y octahydroiπdolizine-
1 ,2,8-triol
850 N-((3R,4R,5R,6R)-4,5- piperidine Y Y dihydroxy-6-
(hydroxymethyl)-2- oxopiperidin-3- yl)acetamide
851 (2R,3S,4R,5R)-2-((S)- pyrrolidine Y Y Y 1 ,2-dihydroxyethyl)-5-
(hydroxymethyl)pyrrolidi ne-3,4-diol
852 (3R,5R)-1- piperidine Y hexylpiperidiπe-3,4,5- triol
853 (3R,4r,5S)-1- piperidine Y hexylpiperidine-3,4,5- triol
854 (1 R,2R,3R,7S,7aR)-3- pyrrolizidiπe Y Y Y Y Y Y ((allylamino)methyl)hex ahydro-1 H-pyrrolizine- 1 ,2,7-triol
855 2-((1 R,2R,3R,7S,7aR)- pyrrolizidine Y Y Y Y Y Y
1 ,2/7- trihydroxyhexahydro-
1 H-pyrrolizin-3- yl)acetonitrile
856 (3S,5S)-1- piperidine Y Y hexylpiperidine-3,4,5- triol
857 (1R,2R,3R,7S,7aR)-3- pyrrolizidine Y Y Y Y Y Y ((benzylamino)methyl)h exahydro-1 H- pyrrolizine-1 ,2,7-triol
858 (2R,3S,4R,5S)-1-(2- piperidine Y CK hydroxyethyl)-2- methylpiperidine-3,4,5- triol
859 (2R,3S,4R,5S)-1-butyl- piperidine Y
2-methylpiperidine- 3,4,5-triol
860 (2R,3S,4R,5S)-1-(2-(2- piperidine Y methoxyethoxy)ethyl)-2- methylpiperidine-3,4,5- triol
861 2-((2R,3S,4R,5S)-3,4,5- piperidine Y trihydroxy-2- methylpiperidin-1- yl)acetic acid
862 (2R,3S,4R,5S)-1-(6- piperidine Y hydroxyhexyl)-2- methylpiperidine-3,4,5- triol
863 (2R,3S,4R,5S)-2- piperidine Y methyl-1-(2- morpholinoethyl)piperidi ne-3,4,5-triol
864 (2R,3S,4R,5S)-2- piperidine Y methyl-1 -(2-(piperidin-1 - yl)ethyl)piperidine-3,4,5- triol
865 (2R,3S,4R,5S)-1-(2- piperidine Y (dimethylamino)ethyl)-2- methylpiperidine-3,4,5- triol
866 (2R,3S,4R,5S)-1-(6- piperidine Y
(2,5- dimethylphenoxy)hexyl)
-2-methylpiperidine-
3,4,5-friol
867 (2R,3S,4R,5S)-2- piperidine Y methyl-1 -(6-((1 r,4R)-4- methylcyclohexyloxy)he xyl)piperidine-3,4,5-triol
868 2-((3R,4r,5S)-3,4,5- piperidine Y trihydroxypiperidin-1- y[)acetic acid
869 N-((3R,4S,5S)-4,5- piperidine Y dihydroxypiperidin-3- yl)acetamide
870 N-((3S,4R,5S)-4,5- piperidine Y Y Ul dihydroxy-1- methylpiperidin-3- yl)acetamide
871 N-((3S,4R,5S)-1-butyl- piperidine Y Y 4,5-dihydroxypiperidiπ-
3-yl)acetamide
872 (2S,3S,4S,5S)-2-(4- piperidine methoxyphenyl)piperidi y ne-3,4,5-triol
873 (2S,3S,4S,5S)-2-(4- piperidine hydroxyphenyl)piperidin y e-3,4,5-triol
874 (2S,3S,4S,5S)-2- piperidine phenylpiperidine-3,4,5- y triol
875 (2S,4S,5S)-1-butyl-4,5- piperidine dihydroxypiperidine-2- carboxylic acid
876 (2S,4S,5S)-4,5- piperidine dihydroxy-1- nonylpiperidine-2- carboxylic acid
877 (2R,3S,4S,5S)-3,4- pyrrolidine dihydroxy-5-
(hydroxymethyl)-i- methylpyrrolidine-2- carboxylic acid
878 (2R,3S,4S,5S)-1-butyl- pyrrolidine
3,4-dihydroxy-5-
(hydroxymethyl)pyrrolidi ne-2-carboxylic acid
879 (2R,3S,4S,5S)-3,4- pyrrolidine dihydroxy-5-
(hydroxymethyl)-i- nonylpyrrolidine-2- carboxylic acid
880 (2S,3R,4R,5S)-3,4,5- piperidine trihydroxy-1- nonylpiperidine-2- carboxylic acid
881 (2S,3S,4S,5S)-2,5- pyrrolidine bis(hydroxymethyl)-1 - methylpyrrolidine-3,4- diol
882 (2S,3S,4S,5S)-1-butyl- pyrrolidine
2,5- bis(hydroxymethyl)pyrro lidine-3,4-diol
883 (2S,3S,4S,5S)-2,5- pyrrolidine bis(hydroxymethyl)-1- πoπylpyrrolidiπe-3,4-diol
884 (2S,3R,4R,5S)-1 -ethyl- piperidine
3,4,5- trihydroxypiperidine-2- carboxylic acid
885 (2S,3R,4R,5S)-3,4,5- piperidine trihydroxy-1- propylpiperidine-2- carboxylic acid
886 (2S,3R,4R,5S)-3,4,5- piperidine trihydroxy-1- pentylpiperidine-2- carboxylic acid
887 (3R,4R,5S)-1-(6- piperidine
((1r,4R)-4- methylcyclohexyloxy)he xyl)piperidine-3,4,5-triol
888 (2S,3R,4R,5S)-3,4,5- pipeπdine tπhydrσxy-1- methylpιperιdιne-2- carboxylic 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- piperidine y y tπhydroxypiperιdιπe-2- carboxamide
891 (2S,3R,4R,5S)-3,4,5- pipeπdine y y tπhydroxy-N- methylpιpeπdιne-2- carboxamide
892 (1R,2S,3R,5R,8aR)-3- (πcfolizidiπe
(hydroxymethyl)-5- methyloctahydroindolizi ne-1 ,2-dιol
9\ -3
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.) pages 25-61. 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.) pages 63-86. 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.) pages 87 -130 the disclosure of which is hereby incorporated herein by reference.
IV. Synthesis of polvhydroxylated 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 Lett. 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 (Bell et al. (1997) Tetrahedron Lett. 38(33): 5869-72).
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 Lett. 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 iminosuqar 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 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-lnterscience; 5th edition (January 15, 2001). Some exemplary synthetic schemes for producing ISAs for use according to the invention are shown below:
Figure imgf000171_0001
Figure imgf000171_0002
VI. Synthesis of nortropanes
Generally applicable strategies for the synthesis of nortropanes are described by Skaanderup and Madsen (2003) J. Org. Chem. 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 a/.
(2007) Chem. Comm. (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 Lett. 48: 4287-4291 and Behr and Guillerm (2007) Tetrahedron Lett. 48(13), 2369-2372 the disclosure of which is hereby incorporated herein by reference.
IX. Synthesis of piperidines
Generally applicable strategies for the synthesis of piperidines are described by Mane et a/. (2008) J. Org. Chem. 73 (8): 3284 -3287 and Rengasamy ef a/. (2008) J. Org. Chem. 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 pyrrolizidines are described in Pyrrolizidine Alkaloids, in The Way of Synthesis, Tomas Hudlicky and Josephine W. Reed, 2007, Wiley, ISBN: 978-3-527-31444-7, pages 617-653 and by Van Ameijde et al. (2006) Tetrahedron: Asymm. 17: 2702-2713, the disclosure of which is hereby incorporated herein by reference.
Xl. Synthesis of indolizidines
Generally applicable strategies for the synthesis of indolizidines are described in Abrams et al. (2008) J. Org. Chem. 73 (5): 1935 -1940 and Kumar et al. (2008) Org. Biomol. Chem. 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) J. Carbohydrate Chem. 26(3): 195-211 and Kumar et al. (2008)
Org. Biomol. Chem. 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) J. Med. Chem. 51 (4): 948-956, the disclosure of which is hereby incorporated herein by reference.
XIV. Synthesis of 9-membered monocycles
Generally applicable strategies for the synthesis of 9-membered monocycles are described in Leonard and Swann (1952) J. Am. Chem. Soc. 74: 4620-4, the disclosure of which is hereby incorporated herein by reference.
XV. Synthesis of 10-membered monocycles
Generally applicable strategies for the synthesis of 10-membered monocycles are described by Arata and Kobayashi (1972) Chem. Pharm. Bull. 20(2): 325-9, the disclosure of which is hereby incorporated herein by reference.
XVI. Synthesis of 4,6 fused tricyclics
Generally applicable strategies for the synthesis of 4,6 fused bicyclics are described in Pandey et al. (2006) Tetrahedron Lett. 47(45): 7923-7926, the disclosure of which is hereby incorporated herein by reference.
XVII. Synthesis of 4,7 fused tricyclics
Generally applicable strategies for the synthesis of 4,7 fused bicyclics are described in Alcaide and Saez (2005) Eur. J. Org. Chem. (Issue 8): 1680-1693, the disclosure of which is hereby incorporated herein by reference.
XVIII. Synthesis of 5,7 fused bicyclics
Generally applicable strategies for the synthesis of 5,7 fused bicyclics are described in Bande et al. (2007) Tetrahedron: Asymm. 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. G. Adjunctive agents for use according to the invention
In addition to the compound and/or imino sugar of the invention, the invention also contemplates the use of one or more of various adjunctive agents as further components of the invention. The adjunctive agent may be an agent useful in the treatment of an energy utilization diseases, in particular diabetes (including type 1 diabetes, type 2 diabetes and insulin resistance) and metabolic syndrome (including any disease or disorder associated therewith, for example central obesity and elevated levels of triglycerides).
Thus, when used adjunctively, the compounds of the invention may be formulated for use with one or more other drug(s). In particular, the compounds of the invention may be used in combination with one or more adjunctive agent(s) selected from those listed below:
• Anti-atherogenic agents • Anti-hypertensive agents
• Anti-diabetic agents
• Antithrombotic agents
• Anti-obesity agents
Preferred anti-atherogenic agents include: (a) HMG-CoA reductase inhibitors (a.k.a. statins, for example atorvastatin, fluvastatin, lovastatin and simvastatin); (b) cholesterol absoption blockers (e.g. ezetimibe); (c) bile-acid sequestrants (e.g. cholestyramine, colestipol and colesevelam); (d) nicotinic acid; (e) peroxisome proliferator-activated receptor α (PPARα) agonists (e.g. fibrates such as bezafibrate, ciprofibrate, clofibrate, gemfibrozil and fenofibrate); (f) dual PPARy/ PPARα agonists and (f) torcetrabib; and (g) squalene synthetase inhibitors.
Preferred anti-hypertensive agents include: (a) diuretics (e.g. furosamide and hydrochlorothiazide); (b) beta-blockers (e.g. propranolol, metaprolol and atenolol); (c) angiotensin converting enzyme (ACE) inhibitors (e.g. captopril and enalapril); (d) angiotensin Il receptor antagonists (e.g. losartan, candesartan and olmesartan); (e) dual angiotensin Il receptor antagonists/ PPARy agonists (e.g. telmisartan); (f) calcium channel blockers (e.g. nitrendipine, nicardapine, felodipine, verapamil and diltiazem) and (g) alpha- blockers; and (h) imidazoline receptor antagonists (e.g. moxonidine and rilmenidine). Preferred anti-diabetic agents include: (a) insulin secretagogues; (b) metformins; (c) insulin sensitizers/antihyperglycaemic agents; (d) PPARy agonists (e.g. thiazolidinones such as rosiglitazone and pioglitazone); (d) glitazones (e.g. thiazolidinediones, such as pioglitazone and rosiglitazone); (e) insulin and insulin mimetics; (f) prandial glucose regulators; (g) selective peroxisome proliferator-activated receptor modulators (SPPARMs); (h) glitazars; (i) incretin mimetics (e.g. glucagon-like peptide analogues and analogues of GLP-1 , such as liraglutide, exenatide, GSK716155, AVE0010, R1583 and CJC-1134-PC); 0) 11 β-hydroxysteroid dehydrogenase 1 inhibitors (a.k.a. 11 β HSD inhibitors) (e.g. INCB13739); (k) dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g. sitagliptin, saxagliptin, alogliptin and vildagliptin); (I) inhibitors of low affinity sodium glucose cotransporter (SGLT2) (e.g. sergliflozin, dapagliflozin and remogliflozin etabonate); (m) glucokinase modulators (e.g. R-1511 , piragliatin, AZD-1656, AZD-6370, TTP-355, NN-9101 , PSN-010 and TTP-399); (n) glycogen phosphorylase inhibitors (e.g. JTT-651 , FR-258900, ingliforib and PSN-357) and (o) G protein-coupled receptor 119 (GPR119) agonists (e.g. PSN821 and APD668).
Preferred insulin secretagogues include: (a) sulphonylureas (e.g. glipizide, glibenclamide, gliclazide, glibornuride and glimepiride); (b) meglitinides (e.g. nateglinide, repaglinide and their analogues); and (c) imidazoline insulin secretagogues (e.g. afaroxan and tolbutamide). Preferred anti-thrombotic agents include: (a) aspirin; (b) clopidogrel.
Preferred anti-obesity agents include: (a) food absorption inhibitors (e.g. α-glucosidase inhibitors such as acarbose, miglitol and emiglitate); (b) CNS-active agents; (c) energy expenditure promoters (e.g. β3-adrenoceptor agonists, thyroid hormone receptor β-subtype agonists and peroxisome proliferator-activated receptor-δ (PPARδ agonists) and (d) G protein-coupled receptor 119 (GPR119) agonists (e.g. PSN821 and APD668). Preferred CNS-active anti-obesity agents include: (a) serotonin (5-hydroxytryptamine) agents; (b) D- fenfluramine; (c) sibutramine; (d) leptin-like agents; (e) agonists for melanocortin 3 and 4 receptors; (f) gastrointestinal hormone analogues; (g) peptide YY analogues; (h) ghrelin antagonists; (i) cholecystokinin receptor agonists; (j) somatostatin receptor antagonists (e.g. octreotide); (k) pancreatic amylin and amylin agonists (e.g. pramlintide); (I) cannabinoid receptor antagonists (e.g. rimonabant and SR-147778); (m) antiepilepsy agents (e.g. topiramate and zonisamide) and (n) antidepressants (e.g. bupropion). Preferred food absorption inhibiting anti-obesity agents include orlistat.
Posology 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 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-alkylimidazoline quarternary 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 hydrophϋe-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.
Example 1 : N-acetylhexosaminidase and β-glucuronidase Inhibitors
Many plants with claims as therapies for diabetes or weight control contain iminosugars or acids which show inhibition of glycosidases (e.g. Gymnema sylvestre, Citrus species, Stevia rebaudiana, Cissus quadrangularis, Rooibos (Aspalanthus linearis), Soya, Chamomile).
Without wishing to be bound by theory we propose that some compounds of the invention may have utility in energy utilization disorders through being functional analogues of N- acetylglucosamine and interfering with the activity of hexosaminidase activity or the activity of hexosamine transferases. Hexosaminidase activity has been shown to be elevated in the serum of diabetics (e.g. Agardh, CD. et al., 1982, Acta Med Scand. 212:39-41). In diabetes there appears to be a strong correlation increased O-linked /V-acetylglucosamine and the development of insulin resistance (reviewed by Copeland, R.J. et al., 2008, Am J Physiol Endocrinol Metab 295: E17-E28). Attachment of Λ/-acetylglucosamine is involved in the aetiology of glucose toxicity and chronic hyperglycemia-induced insulin resistance, a major hallmark of type 2 diabetes. Itoh, N. et al., 2007 (Am J Physiol Endocrinol Metab 293: E1069-E1077) reported that the serum /V-glycan profile in human subjects with type 2 diabetes has an increased amount of a biantennary /V-glycan that had an α1 ,6-fucose with a bisecting Λ/-acetylglucosamine.
Table 2 below gives examples of compounds from the invention that inhibit mammalian (bovine) hexosaminidase. These compounds were very selective amongst hexosaminidases showing no inhibition of the hexosaminidases from Rice or Jack bean.
Of particular interest is the ability of acids of the imino sugar glucosidase inhibitors such as DAB (1 ,4-dideoxy-1 ,4-imino-D-arabinitol) (Cpd 205) and DNJ (1-deoxynojirimycin) (Cpd 204 and Cpd 214) to inhibit the mammalian hexosaminidase which the parent compounds do not. Elevated levels of this enzyme activity has been shown to occur in urine of diabetic patients (Yamanouchi et al.,1998, Diabetes Care 21 : 619-624) but it may be that the inhibition of the enzyme activity helps to control metabolic disturbances seen in diabetics. The inhibition of the alpha-glucosidases (not shown here) was also reduced by addition of the acid substituent to the imino sugars (e.g. Cpd 204, Cpd 205 and Cpd 214).
It is also of interest that compounds of the invention could inhibit bovine β-glucuronidase since this enzyme can be significantly elevated in diabetes (see for example, Koh, M.S. et al., 1983, Clinical and Experimental Dermatology 8: 299-304).
Table 2
Figure imgf000182_0001
Figure imgf000183_0001
IC50 value of compounds. NI = less than 50% inhibition at top concentration of 0.8mM
The results were obtained using commercially available glycosidases and p-nitrophenyl- substrates using standard methods described for example by Watson et al (1997) Phytochemistry 46 255-259. All enzymes and substrates were bought from Sigma. Enzyme and substrate solutions were made using sodium phosphate buffers at the pH optima values. All enzymes were used with the appropriate p-nitrophenyl substrates (5mM).
In addition to inhibition of hexosaminidase by the iminosugar acids above we have also shown other compounds of the invention can selectively and potently inhibit hexosaminidases and therefore may have utility in treatment of disorders of energy metabolism. The IC50 values as μg/ml are shown in Table 3 (below). The glycosidase assay conditions were as described previously.
Table 3
Figure imgf000183_0002
Example 2: Detection of Cpd 7 in Gvmnema
Gymnema sylvestre is a liana or climbing plant with stems up to 8 m in length. It grows in open woods and bushland at an altitude of 100-1000 m in India, China, Indonesia, Japan, Malaysia, Sri Lanka, Vietnam and South Africa: Both the leaf and root are used in Ayurvedic medicine. Because of its property of abolishing the taste of sugar it was given the Hindi names of Gurmar and Madhunashini meaning 'sugar destroying.' The herb is traditionally used for the treatment of metabolic syndrome and Gymnema extracts are sold in Japan for the control of obesity.
A controlled study on insulin-dependent diabetics found that a water-soluble Gymnema extract (400 mg/day) reduced insulin requirements (by about 50%) (Shanmugasundaram et al.,1990, J Ethnopharmacol. 30:281-294). Over the duration of treatment Gymnema lowered fasting mean blood glucose (by about 35%), glycosylated haemoglobin and glycosylated plasma protein levels from baseline values. Cholesterol was significantly reduced and brought to near normal levels. Triglycerides, free fatty acids and serum amylase were also lowered. The treatment period ranged from 6-30 months. The significant decrease in glycosylated haemoglobin occurred after 6-8 months of Gymnema treatment but remained significantly higher than normal values. None of these reductions was observed in control patients on insulin therapy alone who were studied over a period of 10-12 months. The authors suggested that Gymnema enhanced endogenous insulin production, possibly by pancreatic regeneration, as levels of C-peptide, a by-product of the conversion of proinsulin to insulin, were apparently raised (in comparison to both the insulin alone group and normal subjects).
A second study by the same research group found that the same Gymnema preparation (400 mg/day) produced similar results for non-insulin-dependent diabetics (Baskaran et al.,1990, J Ethnopharmacol. 30:295-300). Fasting blood glucose, glycosylated haemoglobin and glycosylated plasma protein were significantly reduced compared to baseline values (pθ.001) after 18-20 months of treatment. None of these reductions was observed in patients receiving conventional therapy alone who were studied over a period of 10-12 months. By the end of the treatment period cholesterol, triglycerides, phospholipids and free fatty acid levels were also significantly reduced compared to baseline values in those receiving Gymnema (p<0.001). Control patients receiving only conventional therapy achieved reductions in cholesterol, triglycerides and free fatty acids (pO.05-pO.001). Fasting and post-prandial serum insulin levels were significantly increased in the Gymnema group compared to those taking only conventional drugs (pθ.01). Twenty-one of the 22 patients were able to reduce their intake of hypoglycaemic drugs; 5 of these discontinued hypoglycaemic drugs entirely and maintained their blood glucose homeostasis with Gymnema extract alone. The authors' suggestion of beta cell regeneration or repair facilitated by Gymnema was supported by the higher insulin levels in the serum of patients after Gymnema supplementation. Gymnema administration to healthy volunteers did not produce any acute reduction in fasting blood glucose level.
Figure 1A is the GC-MS chromatogram trace of Gymnema water extract showing the Cpd 7 of this invention (as the trimethylsilyl derivative) as a major component at 9.26 minutes after removal of sugars.
Example 3. Uptake of Cpd 7 after oral administration of Gymnema sylvestre
In a preliminary experiment on one male volunteer to determine if Cpd 7 was readily absorbed from the gastrointestinal tract, a water extract of Gymnema leaves obtained commercially containing 7mg of Cpd 7 was drunk and urine monitored for Cpd 7 over 4 hours (0-2 hours and 2-4 hours). An internal standard of 1mg of castanospermine was added to the two samples of urine prior to applying to a cation exchange resin (IR120 in the H+ form). After washing the resin with copious water, the bound material was displaced using excess 2M NH4 + solution and dried for GC-MS analysis. The samples were derivatised using Pierce Tri-Sil to produce trimethyl-silyl-derivatives of the imino sugars and imino sugar acids. GC-MS was carried out on a Perkin Elmer TurboMass Gold mass spectrometer, with a quadrupole ion filter system, which was run at 250°C constantly during analysis. The detector mass range was set to 100 to 650 amu. The temperature of the transfer line (GC to MS) was held at 2500C. The GC column was a high polarity fused- silica column (Varian 'Factor Four' VF-5ms column, 25 m x 0.25 mm Ld., 0.25 μm phase thickness). The carrier gas (helium) flow rate was 1 ml min-1. Cpd 7 gives a characteristic mass spectrum as the tms derivative and was well resolved allowing quantification. Cpd 7 was detected in the urine at both time periods and the 7mg appeared to be recovered within the four hours. Figure 1 B shows the characteristic mass spectrum (TMS) of imino sugar acid Cpd 7.
Example 4: Inhibition of glvcosidase enzymes by Cpd 7 of the invention
DNJ (Cpd 193) is a potent inhibitor of a wide range of α-glucosidases and inhibits digestive glucosidases with Ki values in the low or sub-μM range (Watson et a/., 2001 , Phytochemistry 56: 265-295). Anti-diabetic drugs (Glyset and Miglitol) were derived from Cpd 193 by Bayer and these function by reducing uptake of glucose into the blood but they also have side effects such as disturbance of the digestive tract. In contrast Cpd 7 of the invention is a very weak inhibitor of α-glucosidases only just reaching 50% inhibition at nearly mM concentration and so is unlikely to function in the same way (see Table 4, below). Cpd 7 has also been reported to be a weak inhibitor of glucuronidase and iduronidase (Booth et al., 2007, Acta Crystalographica Section E63, o3783-o3784 and references therein). Inhibition of these enzymes could be involved in weight control or control of metabolic syndrome. The iminosugar fagomine (Cpd 40) has been shown to potentiate insulin release but the mechanism is unknown and might be via glucosidase inhibition (Taniguchi et al.,1998, Horm. Metab. Res. 30: 679-683).
Although there is interest in compounds such as Cpd 193 and Cpd 40 as potential antidiabetic agents, it may well be that the glucosidase inhibition is in fact not important for some of the in vivo anti-diabetic activity of these imino sugars; formation of small amounts of the acids in vivo may result in compounds showing glucuronidase inhibition.
Without wishing to be bound by any theory, inhibition of the glucuronidase activity elevated in metabolic syndrome may aid removal of toxins and improve regulation of metabolism generally and specifically beta cell function and growth. Thus, preferred compounds for use according to the invention may be glucuronidase inhibitors. Particularly preferred may be compounds which are glucuronidase inhibitors and which do not inhibit α-glucosidase (or which are weak inhibitors thereof).
Table 4
Figure imgf000187_0001
% inhibition of compounds tested at O.δmM
Italics = IC50 (the concentration of compound giving 50% inhibition of the enzyme)
NI = no inhibition
Example 5: Increase in plasma insulin levels in vivo by Cpd 7
The study started with 42 male ob/ob mice, 10 weeks of age. The mice were fed a normal chow diet during the whole study. After 1 week of acclimatization, mice were matched on basis of body weight, plasma glucose and insulin (after 4h-fasting) and divided in 3 groups of 10 animals (t = 0 days). For the next 6 days, mice received vehicle (control group 1) or 5 mg/kg/day (group 2) or 50 mg/kg/day (group 3) of the Cpd 7 of the invention (test compound) around 12.00 h by gavage (5 ml/kg mouse). On the 7th day, mice were fasted at 8.00 h and received the last gavage (vehicle for group 1 or 5 mg/kg/day, test compound for group 2 or 50 mg/kg/day test compound for group 3) at 12.00 h. At 13.00 h the mice subsequently received a glucose bolus (2g/kg mouse, 5 ml/kg mouse) by gavage as start of the oral glucose tolerance test (OGTT). Measurement of blood glucose and plasma collection was at t=0 Gust before gavage of glucose) and at t=5, 15, 30, 45, 60 and 120 min after glucose bolus. After the OGTT, mice were sacrificed with CO2 and additional blood was collected in heparin-coated tubes via heart puncture (> 100 μl plasma was obtained) and heparin- plasma samples were analysed.
On day 0 mice were randomized on body weight and 4h fasted plasma glucose and insulin levels. Twelve out of 42 mice were excluded, to create more homogenous groups with respect to body weight, plasma glucose and insulin. Both body weight and food intake were not significantly changed after treatment with 5 mg/kg/day or 50 mg/kg/day Cpd 7, when compared to the control (vehicle) group.
When compared to the control group, plasma insulin levels at 0 min (just before the oral load of glucose) seemed to be reduced somewhat in both test compound treatment groups, although this reduction was not significant. No significant changes were seen between 3 groups at 15, 30, 45 and 60 min. Two hours after the glucose bolus, plasma insulin concentrations were significantly increased in the 5 mg/kg and the 50 mg/kg test compound treated groups when compared to the control group.
The data showed that plasma insulin levels were significantly increased in both test compound treatment groups 120 min after the oral bolus of glucose, possibly as a result of an improved pancreatic β-cell function. The mice appeared to show high insulin resistance which will have to some extent reduced the chances of seeing a strong activity but the conclusion was that extending the treatment period might have given a stronger effect on both insulin and blood glucose regulation, particularly if beta cell regeneration and improved function is involved.
Example 6: Properties of the Cpd 7 of the invention
Chemical Properties
Cpd 7 of the invention is an iminosugar acid of molecular weight 177. It is freely soluble in water. The compound is stable under all normal laboratory storage conditions. Occurrence and Exposure Data
The Cpd 7 is a natural product that occurs in polar extracts of a range of plants that are known in Ayurveda and the European plant pharmacopoeia. The present inventors have detected the compound at concentrations ca. 0.2 mg/mL in several herbal medicinal products used in the management of obesity and diabetes in humans. Such products are generally regarded as safe and, at typical doses, exposure to the Cpd 7 from their consumption is around 1 mg/day.
The anti-diabetic and anti-obesity effects of one herbal formulation has been verified in an experimental animal model, in which hyperlipidaemic Wistar rats received either a single dose equivalent to 0.6 mg compound 7 /Kg or 10 daily doses up to 0.4 mg/Kg. No toxicity was reported and the results indicated the herbal formulation's ability to reduce body weight gain, and lower concentrations of plasma triglycerides, and fasting and postprandial blood glucose in animals on a high energy diet. In other studies, herbal extracts have been administered daily to rats at doses estimated to be equivalent to 5 - 50 mg/Kg for up to 52 weeks with no observable toxic effect.
Predictive Toxicology Screen
Cpd 7 was screened for toxicity liabilities using a validated Acute Toxicity assay. Fertilized eggs were obtained from breeding pairs of adult Tuebingen (Tu) zebrafish and arrayed at the 2-4 cell stage of development into 24-well culture plates containing fresh 0.3X Danieau's solution. Plates were incubated at 28.5°C in a humidity controlled environment prior to assessment. Stock concentrations of Cpd 7 were produced by serial dilution in 100% DMSO (final concentration exposed to larvae, 0.5%). Screening was performed at seven doses (1 , 5, 25, 50, 100, 200 and 50OmM) alongside Summit internal controls and vehicle. Dosing of Cpd 7 took place at 72h post fertilisation (hpf; at which point embryogenesis is complete) with visual assessment of lethality and gross morphology at 96hpf (24h incubation). 14 larvae were exposed to each dose of Cpd 7 giving a total of 84 larvae assessed (excluding controls). At 96hpf, larvae were observed and screened using a dissecting stereomicroscope for the presence or absence of: (1) heartbeat; (2) circulation; (3) necrosis; and (4) motility (touch response). If all four criteria were satisfied, a larva would be classified as dead. The compound was screened blind. Results obtained at concentrations of 1 mM, 5mM, 25mM, 5OmM, 10OmM, 20OmM, 50OmM showed that Cpd 7 did not cause acute toxicity to zebrafish larvae when exposed via an aqueous dose.
Example 7: N-acetylhexosamine and Uronic Acid Analogues
Without wishing to be bound by theory we propose that compounds of the invention may have utility in energy utilization disorders through interfering with the activity of hexosaminidase activity or the activity of hexosamine transferases. The table below gives examples of compounds from the invention that inhibit bovine hexosaminidase activity. These compounds were very selective amongst hexosaminidases showing no inhibition of enzymes from Rice or Jack bean.
Of particular interest is the ability of acids of the imino sugar glucosidase inhibitors such as DAB (1 ,4-dideoxy-1 ,4-imino-D-arabinitol) and DNJ (1-deoxynojirimycin) to inhibit the mammalian hexosaminidase which the parent compounds do not. Elevated levels of this enzyme activity has been shown to occur in urine of diabetic patients (Yamanouchi et al. (1998) Diabetes care 21 : 619-624) but it may be that the inhibition of the enzyme activity helps to control metabolic disturbances seen in diabetics. The inhibition of the alpha- glucosidases (not shown here) was also reduced by addition of the acid substituent to the imino sugars (DMDP, DAB and DNJ).
It was also of interest that compounds of the invention could inhibit bovine β-glucuronidase since this enzyme can be significantly elevated in diabetes (see for example, Koh, M.S. et al., 1983, Clinical and Experimental Dermatology 8: 299-304). The results are shown in Table 5 (below).
Table 5
Figure imgf000190_0001
Figure imgf000191_0001
% inhibition with compounds tested at 0.8mM. NI = less than 50% inhibition at top concentration. Values given = IC50.
The results were obtained using commercially available glycosidases and p-nitrophenyl- substrates using standard methods described for example by Watson et al (1997) Phytochemistry 46 255-259. All enzymes and substrates were bought from Sigma. Enzyme and substrate solutions were made using sodium phosphate buffers at the pH optima values. All enzymes were used with the appropriate p-nitrophenyl substrates (5mM).
In addition to inhibition of hexosaminidase by the iminosugar acids above we have also shown other compounds of the invention can selectively and potently inhibit hexosaminidases and therefore may have utility in treatment of disorders of energy metabolism, including for example Cmpd 246, Cmpd 309; Cmpd 318; Cmpd 319; Cmpd 335; Cmpd 338 and Cmpd 358.
Example 8: Insulin release from Min6c4 β-cells
Insulinoma cell culture
Mouse Min6c4 insulinoma cells, selected for high insulin secretion licensed from Prof. Junichi Miyazaki (Osaka University Medical School, Japan). Min6c4 cells were cultured in Dulbecco's modified Eagle's medium containing 10% (v/v) heat-inactivated foetal bovine serum, 4.5 g/L glucose and L-glutamine, 0.0005% (v/v) β-mercaptoethanol, 100 U/ml penicillin and 100 ug/ml streptomycin in a humidified atmosphere of 5% CO2 at 370C.
Insulin secretion
The HTRF® insulin assay was used to test for insulinotropic molecules. The HTRF® insulin assay is a sandwich immunoassay involving two monoclonal antibodies labelled with Eu3+-
Cryptate (Eu-K) and XL665, that recognise distinct insulin epitopes. FRET occurs between
EU-K/XL665 when in close proximity. The HTRF® signal is proportional to the insulin concentration. Min6c4 were seeded at a density of 60,000 cells per well in 96 well plates and left to adhere for 3 days in a humidified atmosphere of 5% CO2 at 370C before use (until -80% confluence achieved). The cells were washed twice with Krebs-Ringer bicarbonate buffer (KRBH) containing CaCI2 1.26mM, KCI 5.4mM, KH2PO4 0.44mM, MgCI2 • 6H2O 0.5mM, MgSO4'7H2O 0.4mM, NaCI 14OmM, NaHCO3 4.1 mM, Na2HPO4 0.34mM and HEPES 2OmM (pH 7). Cells were then rested in KRBH buffer containing 2.5mM glucose at 370C for 30 min. After resting, cells were washed twice more with KRBH buffer before dosing with or without compounds in KRBH buffer containing glucose at 370C for 2 hrs. After this time the cell supernatant was removed and diluted to the desired dilution in KRBH buffer before transferring to the detection plate. The antibody pre-mixes were added to detection plate according to manufacturer's instructions (Cisbio International, 62INSPEC) and incubated at 2 hrs at room temperature. The HTRF® signal was read on a fluorometer (OPTIMA, BMG) at 655nm (XL665 emission) and 620nm (Eu-K emission) in a time- resolved manner.
HTRF® signal, expressed as % of delta F (DF%) was calculated using the fluorescence ratios ((655/620)x10,000) from each well using the following equation:
% of Delta F = ((665/620) sample - (665/620)blank)/(665/620)blank x100
The level of insulin in a well was calculated from the HTRF® signal to insulin ratios obtained from the insulin standard curve.
In the aforementioned protocol, Compound 7 from Table 1 , (2S,3R,4R,5S)-3,4,5- trihydroxypiperidine-2-carboxylic acid, exhibited the activity shown in Figure 2. The following compounds also demonstrated activity (raised level of insulin as compared to control):
Compound No Name
207 2-((2S,3S,4S,5S)-3,4-dihydroxy-2,5-bis(hydroxymethyI)pyrrolidin-1-yI)acetic acicl
214 2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)acetic acid
442 (2R,3R,4R,5S)-3,4,5-trihydroxypiperidine-2-carboxylic acid
466 D-Glucaro-delta-Iactam 888 (2S,3R,4R,5S)-3,4,5-trihydroxy-1-methylpiperidine-2-carboxylic acid hydrochloride
890 (2S,3R,4R,5S)-3,4,5-trihydroxypiperidine-2-carboxamide 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)
Figure imgf000194_0001
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; SOxR3; 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, SOxR3, 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, SOxR3, 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)
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
R3 and R4 may optionally form a 4 to 8 membered ring, containing one or more O, SOx or NR3 groups
x represents an integer from O to 2
or a pharmaceutically acceptable salt or derivative thereof, for the treatment of an energy utilization disease.
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)
Figure imgf000195_0001
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 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; SOxR3; 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, SOxR3, 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, SOxR3, 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; 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 R3 and R4 may optionally form a 4 to 8 membered ring, containing one or more O, SOx or NR3 groups
x represents an integer from 0 to 2
or pharmaceutically acceptable salt or derivative thereof, for the treatment of an energy utilization disease.
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)
Figure imgf000197_0001
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; SOxR3; 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, SOxR3, 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, SOxR3, halo, CN, NO2, NR3R4, (NR3)NR3R4, NH(NR3)NR3R4, CO2R4, OC(O)R3, CONR3R4, NR4C(O)R3, NR4SO2R3, P(O)(OR3)2, C 1-9 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 alkyl, optionally substituted with one or more OH; aryl or C1- 3 alkyl optionally substituted with aryf; 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, SOx or NR3 groups
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, for the treatment of an energy utilization disease.
11. 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 an energy utilization disease.
21. The compound or iminosugar as defined in any one of the preceding claims which is selected from compounds 1 to 892 of Table 1 , or a pharmaceutically acceptable salt or derivative thereof.
22. The compound or iminosugar of any one of the preceding claims wherein the energy utilization disease is selected from: (a) disorders of homeostasis; (b) metabolic diseases; (c) dysfunction of sugar metabolism; (d) appetite disorders; (e) insulin resistance; (f) diabetes (e.g. type 1 or type 2 diabetes); (g) pre-diabetes; (h) metabolic syndrome; (i) obesity; (j) wasting syndromes (for example, cancer associated cachexia); (k) myopathies; (I) gastrointestinal disease; (m) growth retardation; (n) hypercholesterolemia; (o) atherosclerosis; (p) age-associated metabolic dysfunction; (q) hyperglycaemia; (r) glucose intolerance; (s) hyperinsulinaemia; (t) glucosuria; (u) metabolic acidosis; (v) cataracts; (w) diabetic neuropathy; (x) diabetic nephropathy; (y) diabetic retinopathy; (z) macular degeneration; (aa) glomerulosclerosis; (bb) diabetic cardiomyopathy; (cc) impaired glucose metabolism; (dd) arthritis; (ee) hypertension; (ff) hyperlipidemia; (gg) osteoporosis; (hh) osteopenia; (ii) bone loss; (jj) brittle bone syndromes; (kk) acute coronary syndrome; (II) infertility; (mm) short bowel syndrome; (nn) chronic fatigue; (oo) eating disorders; (pp) intestinal motility dysfunction; (qq) sugar metabolism dysfunction; (rr) fatty liver; (ss) polycystic ovarian syndrome; (tt) hemochromatosis; and (uu) acanthosis nigricans.
23. A composition comprising a compound or iminosugar as defined in any one of claims 1 to 21 in combination with an adjunctive agent selected from one or more of: (a) an antiatherogenic agent; (b) an anti-hypertensive agent; (c) an anti-diabetic agent; (d) an antithrombotic agent; and/or (e) an anti-obesity agent.
24. 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 claim 23.
25. The 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 claim 23.
26. A combination comprising a compound or iminosugar as defined in any one of claims 1 to 21 and an adjunctive agent as defined in claim 23.
27. The combination of claim 26 wherein the compound or iminosugar and adjunctive agent are physically associated.
28. The combination of claim 27 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).
29. The combination of claim 26 wherein the compound or iminosugar and adjunctive agent are non-physically associated.
30. The combination of claim 29 wherein the combination comprises: (a) at least one of the compound and adjunctive agent together with instructions for their extemporaneous association to form a physical association; or (b) at least one of the compound and adjunctive agent together with instructions for combination therapy with the inhibitor and adjunctive agent; or (c) at least one of the compound and adjunctive agent together with instructions for administration to a patient population in which either the compound or adjunctive agent have been (or are being) administered; or (d) at least one of the compound and adjunctive agent in an amount or in a form which is specifically adapted for use in combination.
31. The combination as defined in any one of claims 26 to 30: (a) in the form of a pharmaceutical pack, kit or patient pack; (b) in a pharmaceutical excipient; or (c) in unit dosage form.
32. A pharmaceutical composition comprising the combination as defined in any one of claims 26 to 31.
33. A combination according to any one of claims 26 to 32 for use in therapy or prophylaxis (e.g. for use in the treatment of an energy utilization disorder).
34. The compound or iminosugar as defined in any one of claims 1 to 21 for the treatment of a subject undergoing treatment with one or more of the adjunctive agents defined in claim 23.
35. A method for the treatment of an energy utilization disease comprising administering an effective amount of a compound or iminosugar as defined in any one of claims 1 to 21 to said subject.
PCT/GB2009/002554 2008-10-31 2009-10-27 Treatment of energy utilization diseases WO2010049678A2 (en)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
GB0819941.6 2008-10-31
GB0819941A GB0819941D0 (en) 2008-10-31 2008-10-31 Treatment of energy utilization diseases
GB0906161.5 2009-04-09
GB0906161A GB0906161D0 (en) 2009-04-09 2009-04-09 Treatment for energy utilization diseases
GB0908702.4 2009-05-20
GB0908702A GB0908702D0 (en) 2009-05-20 2009-05-20 Treatment of energy utilization diseases
GB0914471A GB0914471D0 (en) 2009-08-19 2009-08-19 Treatment of energy utilization diseases
GB0914471.8 2009-08-19

Publications (2)

Publication Number Publication Date
WO2010049678A2 true WO2010049678A2 (en) 2010-05-06
WO2010049678A3 WO2010049678A3 (en) 2010-08-26

Family

ID=41820684

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2009/002554 WO2010049678A2 (en) 2008-10-31 2009-10-27 Treatment of energy utilization diseases

Country Status (1)

Country Link
WO (1) WO2010049678A2 (en)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011058975A1 (en) * 2009-11-11 2011-05-19 国立大学法人富山大学 Agent for ameliorating postprandial hyperglycemia, and pyrrolidine iminosugar or salt thereof
CN102659787A (en) * 2011-03-29 2012-09-12 中国科学院化学研究所 Fluoro polyhydroxy pyrrole pyrrolizidine, and preparation method and application thereof
CN103265476A (en) * 2013-05-16 2013-08-28 中国科学院化学研究所 Azasugar quaternary ammonium salt compound and preparation method and application thereof
WO2014032185A1 (en) * 2012-08-31 2014-03-06 Alectos Therapeutics Inc. Glycosidase inhibitors and uses thereof
WO2014032187A1 (en) * 2012-08-31 2014-03-06 Alectos Therapeutics Inc. Glycosidase inhibitors and uses thereof
WO2014032188A1 (en) * 2012-08-31 2014-03-06 Alectos Therapeutics Inc. Glycosidase inhibitors and uses thereof
WO2014032184A1 (en) * 2012-08-31 2014-03-06 Alectos Therapeutics Inc. Glycosidase inhibitors and uses thereof
CN105503687A (en) * 2015-12-03 2016-04-20 广东药学院 Multi-membered ring polyhydroxylated alkaloid compound and application thereof
CN105541854A (en) * 2016-01-11 2016-05-04 中国科学院化学研究所 Swainsonine, preparing method for intermediate thereof, swainsonine derivative and preparing method and application of swainsonine derivative
US20160213733A1 (en) * 2013-07-29 2016-07-28 Phytoquest Limited Characterization of rice
WO2017064193A1 (en) * 2015-10-15 2017-04-20 Boehringer Ingelheim International Gmbh Sglt-2 inhibitor for use in the treatment of a metabolic myopathy
US9695197B2 (en) 2012-10-31 2017-07-04 Alectos Therapeutics Inc. Glycosidase inhibitors and uses thereof
US9718854B2 (en) 2011-03-31 2017-08-01 Alectos Therapeutics Inc. Selective glycosidase inhibitors and uses thereof
US9815861B2 (en) 2010-12-23 2017-11-14 Alectos Therapeutics, Inc. Selective glycosidase inhibitors and uses thereof
US9949998B2 (en) 2013-04-05 2018-04-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US9949997B2 (en) 2013-04-05 2018-04-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US9980947B2 (en) 2014-12-18 2018-05-29 Genentech, Inc. Tetrahydro-pyrido[3,4-b]indole estrogen receptor modulators and uses thereof
CN110128315A (en) * 2019-04-02 2019-08-16 中国科学院化学研究所 Compound and the preparation method and application thereof, glycosidase inhibitor
WO2020115475A1 (en) * 2018-12-04 2020-06-11 Phytoquest Limited Bioactive phytochemicals in zizyphus and guarana
US10906904B2 (en) 2015-07-02 2021-02-02 Horizon Orphan Llc ADO-resistant cysteamine analogs and uses thereof
US10954234B2 (en) 2018-06-21 2021-03-23 Genentech, Inc. Solid forms of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol and processes for preparing fused tricyclic compounds comprising a substituted phenyl or pyridinyl moiety, including methods of their use
CN115089578A (en) * 2022-07-25 2022-09-23 山西医科大学 Compound and composition for non-alcoholic fatty liver disease and application thereof
US11666590B2 (en) 2013-04-18 2023-06-06 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11813275B2 (en) 2013-04-05 2023-11-14 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997009040A1 (en) * 1995-09-08 1997-03-13 Novo Nordisk A/S 2-alkylpyrrolidines
WO1998050359A1 (en) * 1997-05-06 1998-11-12 Novo Nordisk A/S Novel heterocyclic compounds
JP2000044589A (en) * 1998-08-03 2000-02-15 Kikkoman Corp Maltooligosaccharide derivative and its use
JP2001002648A (en) * 1999-06-17 2001-01-09 Kikkoman Corp N-substituted azepan derivative and salt thereof
WO2004064715A2 (en) * 2003-01-23 2004-08-05 M N L Pharma Limited Polyhydroxylated pyrrolizidine
WO2006008493A1 (en) * 2004-07-23 2006-01-26 Mnl Pharma Limited Synthesis of polyhydroxylated alkaloids
WO2009152665A1 (en) * 2008-06-20 2009-12-23 湖南希尔天然药业有限公司 A pharmaceutical composition for treating diabetes

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997009040A1 (en) * 1995-09-08 1997-03-13 Novo Nordisk A/S 2-alkylpyrrolidines
WO1998050359A1 (en) * 1997-05-06 1998-11-12 Novo Nordisk A/S Novel heterocyclic compounds
JP2000044589A (en) * 1998-08-03 2000-02-15 Kikkoman Corp Maltooligosaccharide derivative and its use
JP2001002648A (en) * 1999-06-17 2001-01-09 Kikkoman Corp N-substituted azepan derivative and salt thereof
WO2004064715A2 (en) * 2003-01-23 2004-08-05 M N L Pharma Limited Polyhydroxylated pyrrolizidine
WO2006008493A1 (en) * 2004-07-23 2006-01-26 Mnl Pharma Limited Synthesis of polyhydroxylated alkaloids
WO2009152665A1 (en) * 2008-06-20 2009-12-23 湖南希尔天然药业有限公司 A pharmaceutical composition for treating diabetes

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
ANTIGNY ET AL: "Calcium homeostasis is abnormal in cystic fibrosis airway epithelial cells but is normalized after rescue of F508del-CFTR" CELL CALCIUM (EDINBURGH), CHURCHILL LIVINGSTONE MEDICAL JOURNALS, EDINBURGH, GB, vol. 43, no. 2, 19 January 2008 (2008-01-19), pages 175-183, XP022425997 ISSN: 0143-4160 *
BIJL NORA ET AL: "Reduction of Glycosphingolipid Biosynthesis Stimulates Biliary Lipid Secretion In Mice" HEPATOLOGY, vol. 49, no. 2, February 2009 (2009-02), pages 637-645, XP8120682 ISSN: 0270-9139 *
CASIROLA ET AL: "alpha-Glucosidase inhibitors prevent diet-induced increases in intestinal sugar transport in diabetic mice" METABOLISM, CLINICAL AND EXPERIMENTAL, W.B. SAUNDERS CO., PHILADELPHIA, PA, US, vol. 55, no. 6, 1 June 2006 (2006-06-01), pages 832-841, XP005437629 ISSN: 0026-0495 *
COX, TIMOTHY M. ET AL: "Medicinal use of iminosugars" IMINOSUGARS , 295-326. EDITOR(S): COMPAIN, PHILIPPE; MARTIN, OLIVIER R. PUBLISHER: JOHN WILEY & SONS LTD., CHICHESTER, UK. CODEN: 69KIVU; ISBN: 978-0-470-03391-3, 2007, XP8120616 *
KIMURA, MASAYASU ET AL: "Antihyperglycemic effects of N-containing sugars derived from mulberry leaves in streptozocin-induced diabetic mice" WAKAN IYAKUGAKU ZASSHI , 12(3), 214-19 CODEN: WIZAEL; ISSN: 1340-6302, 1995, XP8120663 *
KONG, WON-HO ET AL: "Antiobesity Effects and Improvement of Insulin Sensitivity by 1-Deoxynojirimycin in Animal Models" JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY , 56(8), 2613-2619 CODEN: JAFCAU; ISSN: 0021-8561, 2008, XP8120627 *
MARTIN O: "Iminosugars: current and future therapeutic applications" ANNALES PHARMACEUTIQUES FRANCAISES, MASSON, PARIS, FR, vol. 65, no. 1, 1 January 2007 (2007-01-01), pages 5-13, XP008105411 ISSN: 0003-4509 *
NOREZ CAROLINE ET AL: "A Cystic Fibrosis Respiratory Epithelial Cell Chronically Treated by Miglustat Acquires a Non-Cystic Fibrosis-Like Phenotype" AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, AMERICAN LUNG ASSOCIATION, NEW YORK, NY, US, vol. 41, no. 2, 1 August 2009 (2009-08-01), pages 217-225, XP008111572 ISSN: 1044-1549 *

Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011058975A1 (en) * 2009-11-11 2011-05-19 国立大学法人富山大学 Agent for ameliorating postprandial hyperglycemia, and pyrrolidine iminosugar or salt thereof
US9815861B2 (en) 2010-12-23 2017-11-14 Alectos Therapeutics, Inc. Selective glycosidase inhibitors and uses thereof
CN102659787B (en) * 2011-03-29 2015-04-01 中国科学院化学研究所 Fluoro polyhydroxy pyrrole pyrrolizidine, and preparation method and application thereof
CN102659787A (en) * 2011-03-29 2012-09-12 中国科学院化学研究所 Fluoro polyhydroxy pyrrole pyrrolizidine, and preparation method and application thereof
US9718854B2 (en) 2011-03-31 2017-08-01 Alectos Therapeutics Inc. Selective glycosidase inhibitors and uses thereof
WO2014032188A1 (en) * 2012-08-31 2014-03-06 Alectos Therapeutics Inc. Glycosidase inhibitors and uses thereof
US9522883B2 (en) * 2012-08-31 2016-12-20 Alectos Therapeutics Inc. Glycosidase inhibitors and uses thereof
US9809537B2 (en) 2012-08-31 2017-11-07 Alectos Therapeutics Inc. Glycosidase inhibitors and uses thereof
US20150218147A1 (en) * 2012-08-31 2015-08-06 Alectos Therapeutics Inc. Glycosidase inhibitors and uses thereof
US20150218097A1 (en) * 2012-08-31 2015-08-06 Merck Sharp & Dohme Corp. Glycosidase inhibitors and uses thereof
WO2014032187A1 (en) * 2012-08-31 2014-03-06 Alectos Therapeutics Inc. Glycosidase inhibitors and uses thereof
WO2014032185A1 (en) * 2012-08-31 2014-03-06 Alectos Therapeutics Inc. Glycosidase inhibitors and uses thereof
US9670195B2 (en) * 2012-08-31 2017-06-06 Alectos Therapeutics Inc. Glycosidase inhibitors and uses thereof
WO2014032184A1 (en) * 2012-08-31 2014-03-06 Alectos Therapeutics Inc. Glycosidase inhibitors and uses thereof
US9695197B2 (en) 2012-10-31 2017-07-04 Alectos Therapeutics Inc. Glycosidase inhibitors and uses thereof
US11090323B2 (en) 2013-04-05 2021-08-17 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11813275B2 (en) 2013-04-05 2023-11-14 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11833166B2 (en) 2013-04-05 2023-12-05 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US10258637B2 (en) 2013-04-05 2019-04-16 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11918596B2 (en) 2013-04-05 2024-03-05 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US9949998B2 (en) 2013-04-05 2018-04-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US9949997B2 (en) 2013-04-05 2018-04-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11666590B2 (en) 2013-04-18 2023-06-06 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
CN103265476B (en) * 2013-05-16 2015-09-09 中国科学院化学研究所 Azasugar quaternary ammonium salt compound and preparation method thereof and application
CN103265476A (en) * 2013-05-16 2013-08-28 中国科学院化学研究所 Azasugar quaternary ammonium salt compound and preparation method and application thereof
US20160213733A1 (en) * 2013-07-29 2016-07-28 Phytoquest Limited Characterization of rice
US10966963B2 (en) 2014-12-18 2021-04-06 Genentech, Inc. Tetrahydro-pyrido[3,4-b]indole estrogen receptor modulators and uses thereof
US9980947B2 (en) 2014-12-18 2018-05-29 Genentech, Inc. Tetrahydro-pyrido[3,4-b]indole estrogen receptor modulators and uses thereof
US10906904B2 (en) 2015-07-02 2021-02-02 Horizon Orphan Llc ADO-resistant cysteamine analogs and uses thereof
US11505550B2 (en) 2015-07-02 2022-11-22 Horizon Orphan Llc ADO-resistant cysteamine analogs and uses thereof
EP3362055B1 (en) 2015-10-15 2023-01-18 Boehringer Ingelheim International GmbH Sglt-2 inhibitor for use in the treatment of a metabolic myopathy
JP2018530592A (en) * 2015-10-15 2018-10-18 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング SGLT-2 inhibitor for use in the treatment of metabolic myopathy
WO2017064193A1 (en) * 2015-10-15 2017-04-20 Boehringer Ingelheim International Gmbh Sglt-2 inhibitor for use in the treatment of a metabolic myopathy
CN105503687A (en) * 2015-12-03 2016-04-20 广东药学院 Multi-membered ring polyhydroxylated alkaloid compound and application thereof
CN105541854A (en) * 2016-01-11 2016-05-04 中国科学院化学研究所 Swainsonine, preparing method for intermediate thereof, swainsonine derivative and preparing method and application of swainsonine derivative
US11780834B2 (en) 2018-06-21 2023-10-10 Genentech, Inc. Solid forms of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3- yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol and processes for preparing fused tricyclic compounds comprising a substituted phenyl or pyridinyl moiety, including methods of their use
US10954234B2 (en) 2018-06-21 2021-03-23 Genentech, Inc. Solid forms of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol and processes for preparing fused tricyclic compounds comprising a substituted phenyl or pyridinyl moiety, including methods of their use
WO2020115475A1 (en) * 2018-12-04 2020-06-11 Phytoquest Limited Bioactive phytochemicals in zizyphus and guarana
CN110128315B (en) * 2019-04-02 2021-08-20 中国科学院化学研究所 Compound, preparation method and application thereof, and glycosidase inhibitor
CN110128315A (en) * 2019-04-02 2019-08-16 中国科学院化学研究所 Compound and the preparation method and application thereof, glycosidase inhibitor
CN115089578B (en) * 2022-07-25 2023-08-25 山西医科大学 Compound and composition for non-alcoholic fatty liver disease and application thereof
CN115089578A (en) * 2022-07-25 2022-09-23 山西医科大学 Compound and composition for non-alcoholic fatty liver disease and application thereof

Also Published As

Publication number Publication date
WO2010049678A3 (en) 2010-08-26

Similar Documents

Publication Publication Date Title
WO2010049678A2 (en) Treatment of energy utilization diseases
US20110237538A1 (en) Treatment of lysosomal storage disorders and other proteostatic diseases
US20110195929A1 (en) Compounds for the treatment of flaviviral infections
WO2010029313A1 (en) Antiinfective compounds
US8853385B2 (en) Combination therapy comprising SGLT inhibitors and DPP4 inhibitors
CA2652958C (en) Deoxynojirimycin and d-arabinitol analogs and methods of using
EP2498599B1 (en) Analgesic that binds filamin a
KR20170012449A (en) Preparation and use of crystalline beta-d-nicotinamide riboside
JP2014525413A (en) Morphinan derivatives for the treatment of diabetes and related disorders
WO2010116141A2 (en) Drug combination for the treatment of proteostatic diseases
AU2014342593B2 (en) N-(1-hydroxy-3-(pyrrolidinyl)propan-2-yl)pyrrolidine-3-carboxamide derivatives as glucosylceramide synthase inhibitors
Pawar et al. Quaternary indolizidine and indolizidone iminosugars as potential immunostimulating and glycosidase inhibitory agents: synthesis, conformational analysis, biological activity, and molecular docking study
Kato et al. Isolation and SAR studies of bicyclic iminosugars from Castanospermum australe as glycosidase inhibitors
WO2014055474A1 (en) Mannose derivatives for treating bacterial infections
WO2021045159A1 (en) Therapeutic or prophylactic method for diabetes using combination medicine
CA3037766C (en) Dextrorphan-derivatives with suppressed central nervous activity
AU2016275361B2 (en) Mannose derivatives for treating bacterial infections
Yan et al. α-Glucosidase-inhibitory iminosugars from the leaves of Suregada glomerulata
CN111171020A (en) Hexa-membered and hexa-membered heterocyclic compounds and application thereof as protein receptor kinase inhibitors
KR20200027994A (en) Benzoxazole and benzofuran compounds substituted as PDE7 inhibitors
WO2013115294A1 (en) Diazaspiro urea derivative and pharmaceutical use thereof
KR101850142B1 (en) 1-(3-aminopropyl) substituted cyclic amine compounds, preparation method therefor, and pharmaceutical compositions and uses thereof
EP2561866A1 (en) Morphinan-derivatives for treating diabetes and related disorders
KR20220021912A (en) Heterocyclic derivatives and uses thereof
RU2481106C2 (en) Combined therapy including sglt inhibitors and dpp4 inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09763990

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09763990

Country of ref document: EP

Kind code of ref document: A2