WO2007093769A1 - Inhibiteurs de la biosynthèse des oligosaccharides - Google Patents

Inhibiteurs de la biosynthèse des oligosaccharides Download PDF

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Publication number
WO2007093769A1
WO2007093769A1 PCT/GB2007/000468 GB2007000468W WO2007093769A1 WO 2007093769 A1 WO2007093769 A1 WO 2007093769A1 GB 2007000468 W GB2007000468 W GB 2007000468W WO 2007093769 A1 WO2007093769 A1 WO 2007093769A1
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oligosaccharide
saccharide
hydroxyl group
group
chain terminating
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PCT/GB2007/000468
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English (en)
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Antony Fairbanks
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Isis Innovation Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/06—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing nitrogen as ring hetero atoms
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to a method of inhibiting oligosaccharide biosynthesis comprising the use of chain-terminating monosaccharide derivatives. Furthermore, this invention relates to a method of treating diseases or illnesses associated with oligosaccharide biosynthesis such as bacterial, viral, parasitic and fungal infections, cancer, lysozomal storage disorders, and inflammation. This invention also provides pharmaceutical compositions comprising chain terminating monosaccharide derivatives for the treatment of diseases or illnesses associated with oligosaccharide biosynthesis. Furthermore, this invention provides novel chain terminating monosaccharide derivatives and processes for synthesising chain terminating monosaccharide derivatives.
  • Oligosaccharide structures are made up of multiple monosaccharide units linked together by a hydroxyl group of one monosaccharide which is covalently joined to the anomeric centre of the next monosaccharide unit.
  • the precise mode of linking i.e. the regiochemistry and stereochemistry of the acetal linkages is defined b o stereochemical descriptors, and a regiochemical descriptor e.g. (1-6), (1-5), (1-4), (1-3), (1- 2) etc.
  • the two numbers refer to the number of atoms in each of the monosaccharide units, and thus a (1-4) linkage means that carbon 1 (the anomeric centre) of the monosaccharide unit is linked to the 4-hydroxyl unit of the next monosaccharide unit.
  • Oligosaccharide biosynthesis is essential for the replication and viability of cells associated with a number of diseases. Oligosaccharide biosynthesis is also associated with many intercellular recognition processes, which are involved in several disease states. The improper biosynthesis of oligosaccharides is also associated with several inherited genetic disorders.
  • the biosynthesis of oligosaccharide structures involves the sequential addition of several monomer units. Each monosaccharide unit has at least one hydroxyl group. However, only one hydroxyl group will be used to form a further link to another monosaccharide unit. At branch points in the oligosaccharide chain more than one hydroxyl group will be used for the attachment of further monosaccharide units.
  • the specific hydroxyl group to which further monosaccharide units are attached is referred to as the active hydroxyl group.
  • the addition of monosaccharide units to the proliferating oligosaccharide chain is controlled by a specific enzyme for the oligosaccharide.
  • the enzyme acts as a catalyst for the addition of the monosaccharide units to the oligosaccharide chain.
  • the monosaccharide units involved in oligosaccharide synthesis are generally activated nucleoside diphosphate derivatives of a monosaccharide.
  • the monosaccharide units may be other monosaccharide derivatives, such as polyprenol monophosphates for example.
  • a monosaccharide unit is transferred to a particular hydroxyl group of the growing oligosaccharide chain.
  • the transfer of the monosaccharide unit to the oligosaccharide is highly selective and is controlled by the relevant transferase. The transferase controls both the regio- and stereochemistry of the new covalent bond formation.
  • a glycosyl donor building block for example a monosaccharide containing an active hydroxyl group
  • the relevant transferase are required. It is known in the art that the substrate for the arabinosyl transferase is a polyprenol glycosyl phosphate arabinose derivative.
  • pathogens use carbohydrates including oligosaccharides on the surface of cells to recognise and interact with target host cells.
  • Infection of a host comprises several steps.
  • a critical early step in the initiation of infection is the adhesion of pathogens to proteins and glycoconjugates on the extracellular membrane of the plasma membrane of the host cell. Adhesion of the pathogen to the cell surface is a pre-requisite for intracellular pathogens to enter the cell. The pathogen must then be able to replicate in the host and spread to other hosts.
  • the virus targets the host cell by interacting with an oligosaccharide containing sialic acid extending from the glycoproteins or glycolipids on the cell surface. Attachment of the virus to the oligosaccharide enables the virus to penetrate the cells and replicate with them.
  • An enzyme called neuraminidase is required to enable release of the new virus from the host cell.
  • Drugs such as Tamiflu and Relenza bind to the active site of the enzyme in competition with the natural sugar therefore inhibiting release of the new virus from the infected cells. This is known as competitive inhibition.
  • ⁇ -lactam antibiotics inhibit the transpeptidiation; vancomycin binds to D- Ala-D-Ala residues and inhibits the cross linking of peptidoglycan; cycloserine inhibits Ala racemase and ligase; tunicamycin and bacitracin inhibit membrane translocation and phosphonmycin inhibits GIcNAc enolpyruvyl transferase.
  • certain strains of bacteria have developed resistance to these modes of antibiotic action.
  • jit is also known that major changes in carbohydrate expression occur during the onset and progression of diseases such as cancer and that malignant cells exhibit either incomplete or abnormal oligosaccharides on the surface of the cells.
  • Oligosaccharides also play a role in diseases associated with inflammation, such as rheumatoid arthritis.
  • Blood vessels which are wounded or infected exhibit a large number of carbohydrate-binding proteins called selectins on the surface of the endothelial cells.
  • Selectins bind to the carbohydrates on the surface of white blood cells causing the white blood cells to concentrate at a certain area within the blood vessel. Illnesses, such as toxic shock syndrome, may develop from an over development of carbohydrate binding proteins on the endothelial cells.
  • Oligosaccharides play an important role in numerous diseases and illnesses including bacterial, viral, parasitic and fungal infections, cancer and inflammation. Oligosaccharides are chains of monosaccharide units which are linked together by a hydroxyl group of one monosaccharide unit to the anomeric centre of the adjacent monosaccharide unit. At branch points several monosaccharide units are linked via their anomeric centre to different hydroxyls of another monosaccharide unit. Certain monosaccharide derivatives are already known. For example, WO 03/018598 discloses monosaccharide conjugates which are fibronectin and fibronectin receptor interaction antagonists. In addition to having anti-angiogenic and pro-angiogenic properties these compounds are reported to inhibit cell adhesion and signal transduction pathways.
  • EP 1157696 describes the use of oligosaccharides such as acarbose for treating acidosis in ruminant animals. This document does not refer to any inhibition of the biosynthetic pathway involved in the disease state however.
  • glycosaminoglycans such as heparin and heparan sulfate
  • glycosaminoglycans mediate numerous physiological processes.
  • this document concerns only an in vitro study and is not capable of providing a workable form of an in vivo treatment of a disease.
  • One reason for this is because GAGs bind to many proteins and it is known that drugs that promote or inhibit the binding of GAGs to proteins, such as the analogs of heparan sulfate, inevitably display a lack of selectivity in vivo. As such these drugs cannot be successfully used as specific agonists or antagonists for any one protein because of the risk of significant and unpredictable side effects.
  • Prior art treatments involving carbohydrates as the active agent are based on administration of the carbohydrate compound as the therapeutic agent which competes with the natural sugar. There is no disclosure in the prior art of any treatment involving inhibiting the biosynthesis of the natural sugar. Similarly, the prior art does not provide a method of treating a range of diseases in which oligosaccharide biosynthesis is implicated by terminating the biosynthetic pathway.
  • a related aim of the present invention is to provide novel pharmaceutical compositions for treating illnesses or diseases associated with oligosaccharide biosynthesis, jit is a further aim to provide a convenient, synthetically efficient process for the preparation of the chain terminating saccharides of the present invention, ideally which provides the compounds in good yield and for which avoids the use of unnecessary synthetic steps and /or purification steps.
  • Chain terminating carbohydrates are monomeric carbohydrate building blocks or partially complete oligosaccharide chains that have been modified at the hydroxyl group at which further carbohydrate units would otherwise be added, after such a modified building block has been added to the growing oligosaccharide chain.
  • These modified compounds are not inhibitors of the enzyme, the glycosyl transferase, which is responsible for oligosaccharide formation but are substrates for such an enzyme that are readily processed. The modified compounds thus function as chain-terminating units.
  • a process for preparing a therapeutically active chain terminating saccharide suitable for treating a disease state in a human or a non-human mammal comprising the steps:
  • step (b) optionally comparing the oligosaccharide identified in step (a) with known oligosaccharide biosynthetic pathways for the human or non-human mammal;
  • a chain terminating saccharide in medicine.
  • the chain terminating saccharide may be used in the treatment of a disease selected from the group comprising: a bacterial infection, a fungal infection, a parasitic infection, an inflammatory disease and a proliferative disorder.
  • the disorder is caused by or is manifested as a fungal infection.
  • the saccharide derivatives of the present invention may either act as pro-drugs, or as the active drug themselves in the treatment of disease.
  • a preferred group of compunds which show good activity are compounds of Formula (A).
  • the present invention thus relates to a compound of Formula (A):
  • Rl is selected from the group comprising: OAc, OBz and OH;
  • R2 is selected from the group comprising: OAc, OBz and OH;
  • R3 is C 1-6 alkyl or Ci- ⁇ haloalkyl
  • X is an isostere of the hydroxyl group which satisfies one or both of the following conditions: (a) that it is of a similar size to or smaller than the hydroxyl group, and (b) that it is able to either donate or accept hydrogen bonds.
  • Rl is OAc or OBz.
  • R2 is OAc or OBz.
  • Rl and R2 are identical.
  • R3 is methyl or ethyl. Most preferably R3 is methyl.
  • the isostere is smaller than the hydroxyl group.
  • X is selected from the group comprising: hydrogen, azide, fluorine, C 1-6 alkoxy (such as methoxy), C 1-6 haloalkoxy (such as trifluoromethoxy), C 1-6 amino (such as methylamino), C 1-6 amido (such as formamido), thio, C 1-6 alkylthio (such as methylthio), C ⁇ - ⁇ carboxylate (such as acetate), and cyano, and aryl carboxylate (such as benzoate).
  • Compounds of Formula (A) are expected to be particularly advantageous as therapeutic agents.
  • the present invention also relates to the use of a compound of Formula (A) in medicine.
  • the present invention also relates to the use of a compound of Formula (A) in the preparation of a medicament for the treatment of a disease selected from the group comprising: a bacterial infection, a fungal infection, a parasitic infection, an inflammatory disease and a proliferative disorder.
  • a chain terminating saccharide as identified in the above process in the preparation of a medicament for the treatment of a disease selected from the group comprising: invasive breast cancer, pancreatic cancer, progressive multifocal leukoencephalopathy, Karposis-sarcoma, prostrate cancer, testicular cancer, endocrine related cancers, ovarian cancer, neuroblastoma, human-malignant mesothelioma, renal cell carcinoma, leukemia, gastric carcinoma, fibromatosis, lung cancer, carcinoma of the bladder, non-Hodgkin's lymphoma, colo-rectal cancer; Gaucher' s disease, Fabry's disease, Tay-Sachs disease and other lyszomal storage diseases; benign prostatic hyperplasia, venous neointimal hyperplasia, intimal hyperplasia, atherosclerosis and human coronary heart disease, chronic myocardial ischemia, rheumato
  • viral infections treatable according to the present invention include AIDS, adenoviridae infections, alphavirus infections, arbovirus infections, borna disease, bunyaviridae infections, caliciviridae infections, chicken pox, coronaviridae infections, coxsackie virus, cytomegalovirus, dengue, DNA virus infections, ecthyma, encephalitis arbovirus, erythema infectiosum, hantavirus, hemorrhagic fevers, hepatitis, herpes simple, herpes zoster, herpes viridae, infectious mononucleousis, influenza, lassa fever, measles, molluscum contagoisum, mumps, paramyxoviridae infections, phlebotomus fever, rabies, respiratory syncytial virus infections, rift valley fever, RNA virus infections, rubella, slow virus diseases, small pox, subacute sclerosing panencepha
  • Examples of bacterial infections treatable according to the present invention include actinomycosis, anthrax, boils, brucellosis, buruli ulcer, Campylobacter infections, cat scratch disease, cellulitis, chancroid, chlamydia, cholera, Clostridium perfringens, diptheria, ecthyma, enterobacterial infections, erlichiosis, erysipelas, escherichia coli, gangrene, glanders, gonorrhea, haemophilus influenzae serotype, Helicobacter pylori, impetigo, klebsiella, legionellosis, leprosy, leptospirosis, listeria, lyme, melioidosis, meningitis, paratyphoid fever, paronychia, pasteurella infections, plague, pneumococcal, pneumonia, proteus infections, psuedomonas, p
  • Fungal infections treatable according to the present invention include aspergillosis, blastomycosis, candidiasis, chromoblastomycosis, coccidioiodmycosis, cryptococcosis, histoplasmosis, mucormycosis, onychomycosis, paracoccidionmycosis, phaeohyphomycosis, Pneumocystis carinii, rhinosporidiosis, sporotrichosis, tinea and zygomycosis.
  • Parasitic infections treatable according to the present invention include acanthamoeba, african trypanosomiasis, alveolar hydatid disease, amebiasis, babesiosis, blastocystosis, chagas disease, cryptosporidosis, cyclosporiasis, proamoeba fragilis infection, dracunculiasis, giardiasis, anchylostomiasis, leishmaniasis, pediculosis, lice, lymphatic filariasis, malaria, naegleria infection, nonpathogenic intestinal amebae, parasitic roundworm diseases, pinworms, onchocerciasis, toxocariasis, ascariasis, baylisascaris, scabies, schistosomiasis, cercarial dermatitis, cysticercosis, toxoplasmosis, trichinosis and trichurias
  • the present invention provides process for the preparation of the chain terminating saccharides of the present invention wherein the reactive hydroxyl group of a mono- or oligosaccharide precursor identified in the process described above is replaced by isosteres including hydrogen, azide, fluorine, lower alkoxy such as methoxy, lower haloalkoxy such as trifluoromethoxy, amino, lower amino such as methylamino, lower amido such as formamido, thio, lower thio such as methyl thio, lower carboxylate such as acetate, and cyano, or a pharmaceutically, veterinarily or agriculturally acceptable salt thereof, or a pharmaceutically, veterinarily or agriculturally acceptable solvate (including hydrate) of either entity.
  • isosteres including hydrogen, azide, fluorine, lower alkoxy such as methoxy, lower haloalkoxy such as trifluoromethoxy, amino, lower amino such as methylamino, lower amido such as formamido, thio
  • the comparison effected in step (b) enables an oligosaccharide associated with the disease state to be identified which is not present in a healthy non- human or human object. Synthesis of the appropriate chain-terminating saccharide thus leads to a therapeutically active agent which has the major advantage of being potentially free of damaging side effects.
  • the design of a chain terminating saccharide requires knowledge of the structure of the oligosaccharide structure that one intends to inhibit the biosynthesis of. Knowledge of the identity of the monomelic units, and of the active hydroxyl group by which units are linked, immediately identifies the potential chain terminating saccharide species.
  • an oligosaccharide consists of galactose residues linked together by the 4- hydroxyl group (the active hydroxyl group)
  • the chain terminating saccharide which may stop the biosynthesis of this oligosaccharide structure, is identified as a galactose monomeric unit which is modified at the position of the 4-hydroxyl.
  • chain terminating saccharide can be a simple mono- or oligosaccharide derivative, or whether it will have to be the activated phosphate donor is difficult to predict a priori but is easily determined by experiment. Some kinases accept modified monosaccharide units and so one may expect a simple monosaccharide derivative to be an acceptable pro-drug.
  • Each monosaccharide which is incorporated into a oligosaccharide chain is recognised by a specific transferase.
  • the chain terminating saccharides of the present invention are transferred onto the terminus of the growing oligosaccharide chain.
  • the active hydroxyl group of the mono- or oligosaccharide unit is no longer present in the chain terminating saccharides of the present invention because of the synthetic modification to the molecule at the active hydroxyl group.
  • the chain termmating saccharides of the present invention once incorporated at the terminus of an oligosaccharide chain are unable to form links to further monosaccharide units.
  • the chain terminating saccharides of the present invention therefore inhibit further elongation of the oligosaccharide chain and therefore result in chain termination of the oligosaccharide chain.
  • each monosaccharide has a specific transferase which is capable of transferring the monosaccharide onto the terminus of an oligosaccharide.
  • the isostere which replaces the active hydroxyl group is compatible with and does not disrupt the enzyme so that the chain terminating saccharide is incorporated into the oligosaccharide and so that chain termination can then occur J
  • galactose is transferred onto an elongating oligosaccharide by galactosyl transferase. It is therefore essential that any modification of the saccharide, such as substitution of the active hydroxyl group by an isostere or other suitable group which is tolerated, does not have a significant effect on the structure and/or the electronic properties of the saccharide unit.
  • the specific transferase for that saccharide is unlikely to recognise the chain terminating saccharides of the present invention and therefore the chain terminating saccharides of the present invention will not be transferred onto the elongating oligosaccharide chain.
  • the isostere must be of a similar size to or smaller than the hydroxyl group. Preferably, the isostere is smaller than the hydroxyl group.
  • the isostere must be able to either donate or accept hydrogen bonds.
  • such groups may be selected from hydrogen, azide, fluorine, lower alkoxy such as methoxy, lower haloalkoxy such as trifluoromethoxy, amino, lower amino such as methylamino, lower amido such as formamido, thio, lower alkylthio such as methylthio, lower carboxylate such as acetate, and cyano.
  • Another suitable group is aryl carboxylate such as benzoate.
  • Suitable synthetic reagents capable of introducing these groups are well known in the art. The skilled person will recognize that term 'lower' in lower alkyl, lower alkoxy etc. refers to a group in which the carbon chain usually has not more than 10 carbon atoms, and preferably not more than 6 carbon atoms.
  • the present invention provides a method for treating diseases or illnesses in the human or animal body associated with oligosaccharide biosynthesis.
  • diseases may for example include viral, bacterial, parasitic and fungal infections, cancer and inflammation.
  • the chain terminating saccharides for use with the method of the present invention may be derivatives of any naturally occurring monosaccharide including, but not limited to, such as, for example, glucose, glucosamine and derivatives thereof, fructose, ribose, deoxyribose, galactose, galactosamine and derivatives thereof, mannose, sialic acid, arabinose, muramic acid, and xylose.
  • An arabinose derivative of formula (I) may be prepared by protecting all of the hydroxy groups except for the active hydroxy group of arabinose (II) with ter/butyldiphenylsilyl chloride in the presence of imidazole in DMF, followed by sequential treatment with acetic anhydride in pyridine and HF pyridine complex.
  • the active hydroxy group at the 4-position is substituted by an isostere by reacting a protected arabinose derivative of formula (I) either with tosyl chloride and a species capable of forming an anion of the isostere, for example sodium azide, or with methyl triflate and a base, for example difer/butylmethylpyridine, to form an arabinose derivative of formula (III).
  • a protected arabinose derivative of formula (I) either with tosyl chloride and a species capable of forming an anion of the isostere, for example sodium azide, or with methyl triflate and a base, for example difer/butylmethylpyridine, to form an arabinose derivative of formula (III).
  • the deprotected arabinose derivative (IV) may be prepared by reacting a compound of formula (III) with sodium methoxide.
  • the present invention provides a method for preparing pharmaceutically acceptable salts of the arabinose derivatives of formula (V) by reacting a protected arabinose derivative of formula (III) with either hydrazine or benzylamine to form an arabinose derivative of formula (V) wherein the 1 -hydroxy substituent has been deprotected.
  • decaprenol phosphodiester derivative of formula (VII) is formed by reacting the arabinose derivative of formula (VI) with iodine in the presence of THF. Methanolic ammonia is then introduced to provide the polyprenol phosphodiester derivative of formula
  • the arabinose derivative of formula (III) is reacted sequentially with (i) trimethylsilyl bromide in dichloromethane; (ii) dibenzyl phosphate and triethylamine in toluene; (iii) hydrogen gas in the presence of palladium.
  • Decaprenol phosphate derivative of formula (VII) is also formed by reacting the phosphate salt derivative of formula (VIII) sequentially with (i) decaprenol trichloroacetimidate; (ii) cyclohexylarnine in methanol.
  • the arabinose derivative of formula (V) is reacted sequentially with (i) lithium diisopropylamide and tetrabenzylpyrophosphate in tetrahydrofuran; (ii) hydrogen gas in the presence of palladium hydroxide; (iii) cyclohexylamine in methanol.
  • This procedure may be used to prepare any chain terminating saccharides of the present invention or phosphate or polyprenol phosphate derivatives thereof.
  • the structure and biosynthesis of the tuberculosis cell wall is well known in the art (Besra, G. S. et al; Biochemistry, 1995, 34, 4257-4266).
  • the tuberculosis cell wall comprises polymeric arabinose (II) and galactose (X) structures forming the arabinogalalctan component. It is well known in the art that the arabinogalactan component does not occur naturally within mammalian systems and that the arabinogalactan component is crucial for the survival of the bacteria.
  • the present invention therefore provides a method of inhibiting the biosynthesis of the arabinogalactan component in the cell walls of tuberculosis cells in vivo or in vitro comprising the step of administering at least one derivative of either arabinose (II) and galactose (X) or a combination thereof, wherein the active hydroxy! group is substituted by an isostere.
  • the present invention provides a method for treating tuberculosis in humans or animals comprising administering a pharmaceutical effective dose of a pharmaceutical composition comprising at least one derivative of either arabinose (II) and galactose (X) or a combination thereof, wherein the active hydroxyl group is substituted by an isostere.
  • the arabinogalactan component comprises multiple repeats of the arabinose (II) and galactose (X) components.
  • the monosaccharide derivatives of the present invention being incorporated into the elongating oligosaccharide chain.
  • Suitable derivatives for inhibiting biosynthesis of the arabinogalactan component in tuberculosis cell walls are the arabinose derivatives (III) and the galactose derivatives (XI) wherein the active hydroxyl group has been replaced by hydrogen (Illb and XIa) 5 a methoxy group (IIIc and XIb), fluorine (HId and XIc) or an azide group (HIe and XId).
  • arabinose derivatives (III), the 1 -phosphate salts (JX), and the polyprenol phosphodiester salts (VII) are capable of inhibiting the elongation of the oligosaccharide present in the cell wall of tuberculosis cells.
  • Galactofuranose is also present in the cell wall of a tuberculosis cell.
  • the following galactopyranose and/or galactofuranose derivatives are also capable of inhibiting the elongation of the oligosaccharide present in the cell wall of tuberculosis cells, for example the galactopyranosese derivatives (XI), the pyranose 1 -phosphate salts (XII), the pyranose UDP salts (XIII), and the furanose UDP salts (XIV).
  • Chitin is a polymer of ⁇ (l-4)GlcNAc and is also a vital component in fungal cell walls and insect exoskeletons. This oligosaccharide is not present within mammalian systems.
  • the present invention provides a method for inhibiting the biosynthesis of chitin in fungal cell walls and in cell walls of insect exoskeletons comprising administering a GIcNAc monosaccharide derivative wherein the active hydroxyl group is substituted by an isostere.
  • the present invention therefore provides a method for treating fungal infections comprising administering a GIcNAc monosaccharide derivative wherein the active hydroxyl group is substituted by an isostere.
  • the present invention provides pharmaceutical anti-fungal and insecticidal compositions.
  • Suitable acetylamine substituted glucose derivatives which may be used with the methods of the present invention to inhibit biosynthesis of chitin and to treat fungal infections include acetylamine substituted glucose derivatives (XV), phosphate derivatives (XVI- XVII), and oxazoline derivatives (XVIII).
  • Particularly effective compounds are those of formula (XVIII) in which R is OAc or Bz.
  • R is OAc or Bz.
  • the efficacy of these compounds can be seen from Figures 1 and 2.
  • the methods of the present invention may be used to inhibit bacterial peptidoglycan biosynthesis.
  • Bacterial peptidoglycan biosynthesis is essential for bacterial cell wall synthesis.
  • the oligosaccharide portion of bacterial peptidoglycan consists of repeat oligomers of N-acetylmuramic acid linked ⁇ (l-4) to N-acetylglucosamine.
  • the present invention therefore provides a method of inhibiting peptidoglycan biosynthesis synthesis comprising administering an N-acetylglucosamine or muramic acid derivative wherein the active hydroxyl group is substituted by an isostere.
  • the present invention therefore provides a method of treating bacterial infections comprising administering an N- acetylglucosamine derivative wherein the active hydroxyl group is substituted by an isostere.
  • the methods of the present invention have the advantage that they do not cause bacterial strains to mutate and to become resistant to the drugs.
  • Suitable chain terminating monosaccharides for inhibiting bacterial peptidoglycan biosynthesis and for treating bacterial infections include N-acetylglucosamine derivatives such as (XV) to (XVIII) and muramic acid derivative (XIX).
  • a doubling dilution of the putative inhibitors was prepared across a 96- well plate, starting at ImM concentration, in lOO ⁇ l 0.1% keratin broth per well. lOO ⁇ l spore suspension was then added to each well, making the final volume 200 ⁇ l. There were 4 replicate wells for each test. Plates were incubated at 3O 0 C for 24 hours, before being emptied and washed 3 times with water. lOO ⁇ l 0.05% crystal violet solution were added to each well and incubated at room temperature for 15 minutes. Plates were then washed again 3 times in water, leaving the stain within the fungal material remaining on the plate.
  • T. rubrum conidia were harvested, and spore suspensions adjusted to the appropriate density. Test compounds were diluted with the spore suspension to obtain concentrations of up to ImM of each test compound. The resulting suspensions were pipetted with the appropriate number of replicates onto 0.1% keratin agar and incubated for 24 hours at 3O 0 C. After incubation images were taken of the germinated spores to allow assessment of germ tube formation. A sample of 30 sets of 10 spores was counted to quantify germ tube initiation.
  • Scheme 1 illustrates some target compounds that were prepared in accordance with the invention.
  • the method used involved deallylation of the anomeric position, followed by subsequent acetylation with acetic anhydride and further cyclisation using TMSBr.
  • the deallylation of compounds 3, 5 and 7 was carried out in good yields using Pd(Pb_ 3 ) 4 in AcOH at 80°C (Scheme 7).
  • the anomeric acetylated compounds 14-17 were achieved by reacting compounds 10-13 with Ac 2 O in Py. The cyclisation reaction was carried out at room temperature and proceeded in -55% yield. Deprotection of benzoyl groups was achieved with sodium methoxide and anhydrous methanol in -85% yield 25 (Scheme 9).
  • Scheme 10 illustrates the synthesis of oxazoline derivatives 38-41.
  • oxazolines 38-41 firstly the benzoyl groups were removed using NaOMe in MeOH, and then the anomeric position was liberated using Pd(O) for compounds 26-28 and PdCl for compound 29. The three free OH groups were acetylated (Ac 2 OZPy) subsequent cyclisation occurred using TMSBr. (Scheme 10).
  • BF 3 -OEt 2 (1.43 mL, 11.30 rnmol, 0.25 eq) was added to a suspension of iV-acetyl- ⁇ -D- glucosamine (10 g, 45.21 mmol, 1 eq) in allyl alcohol (100 mL) and the resulting mixture was heated at 90 0 C for 5 h. The allyl alcohol was evaporated under reduced pressure and the residue dissolved of water (100 mL). Do wex5 OWXS- ⁇ OOH + (15 g) was added and the resulting suspension was heated at 70 0 C. After 24h, TLC showed complete hydrolysis of the ⁇ -product. The mixture was filtered and was evaporated to dryness.
  • Benzoyl chloride (5.41 mL, 46.62 mmol, 2.1 eq) was added over a period of 60 minutes to a solution of compound 1 (5.80 g, 22.20 mmol, 1 eq) in dry pyridine (50 mL) and dichloromethane (DCM) (10OmL) cooled to -20 0 C (NaCl + ice). The resulting mixture was kept for 2h at that temperature and then MeOH were added until a clear solution was obtained. The mixture was evaporated to dryness.
  • DCM dichloromethane
  • Tributyltinhydride (3.43 mL, 12.37 mrnol, 1.5 eq) and 2,2'-azo-bisisobutyle nitrile (0.135 g, 0.82 mmol, 0.1 eq.) were added to a solution of compound 4 (4.78 g, 8.25 mmol, 1 eq) in dry freshly degassed toluene (75 mL) and the xesulting mixtuxe was xefluxed in the dark. After 1 h, the mixture was evaporated to dryness.
  • n-Buthyllithium (1.6M in hexanes) (0.053 mL, 0.02 mmol) was added to a degassed solution of Wilkinson's catalyst (39.88mg, 0.044mmol) in dry THF (4 mL). This mixture was stirred for lOmin before being added to a refluxing solution of compound 3 (lOOmg, 0.20mmol) in dry THF (3mL) and the resulting mixture was stirred for 2Oh at 72°C. The mixture was cooled to room temperature before the addition of dichloromethane (5OmL) and concentration in vacuo.
  • Tetrakis(triphenylphosphme)paUadiurn (3.96 g, 3.44 mmol, 0.5 eq) was added to a solution of compound 3 (3.32 g, 6.87 mmol, 1 eq) in AcOH (40 mL) and the resulting mixture was heated at 80 0 C. After 4 h, the mixture was evaporated to dryness.
  • Tetrakis(triphenylphosphine)palladium (4.84 g, 4.19 mmol, 0.5 eq) was added to a solution of compound 5 (3.8 g, 8.38 mmol, 1 eq) in AcOH (30 mL) and the resulting mixture was heated at 80 0 C. After 2 h, the mixture was evaporated to dryness.
  • Tetrakis(triphenylphosphine)palladium (0.897 g, 0.78 mmol, 0.5 eq) was added to a solution of compound 7 (0.73 g, 1.55 mmol, 1 eq) in AcOH (12 mL) and the resulting mixture was heated at 80 °C. After 2 h, the mixture was evaporated to dryness.
  • the perbenzoylated glucopyranose 43 (1.00 g, 1.56 mmol, 1 eq) was dissolved in a cooled (0°C) solution of ammonia in THF (35 mL) and MeOH (15 mL) (this solution was prepared by bubbling ammonia gas through the mixture of solvents at 0 0 C for 20 min). The obtained mixture is stirred until the starting material has consumed (6 h) while it is allowed to warm up to room temperature. The mixture was evaporated to dryness and the residue was purified by flash column chromatography (pentane: EtOH.
  • Scheme 14 illustrates the synthesis of the different phosphate ditriethylammonium salts.
  • the use of LDA and tetrabenzyl pyrophosphate in dry THF gave the desired phosphates as single ⁇ -anomers.
  • CMAW CHCl 3 (60)/MeOH (30)/AcOH (3)/Water (5)
  • TEAB triethylammonium bicarbonate buffer.
  • NEt 3 H + ⁇ oIm W-X2 cation exchange column
  • the NEt 3 H + ⁇ oIm is prepared be passing 1 L of a 0.1 M aqueous solution of NEt 3 through the column (the resin gets darker) and then rninirnum 1 L of water (the resin gets lighter again) until pH ⁇ 7.
  • the product is eluted with water and collected in 1-2 mL fractions (tl.c. eluted with CMAW).
  • the H + -form of the resin is regenerated by passing 1 L of 1 M HCl and then 1 L (minimum) of water until pH ⁇ 7.
  • the resin can be used several times but must be stored in the H ⁇ -form.

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Abstract

La présente invention concerne une méthode d'inhibition in vivo et in vitro de la biosynthèse des oligosaccharides, ladite méthode comprenant les étapes d'administration d'au moins un dérivé de monosaccharide, le groupement hydroxy qui joue le rôle d'accepteur de glycosyle (c'est-à-dire le groupement hydroxy actif) du ou des monosaccharides étant substitué par un groupement ou un isostère adapté. La présente invention concerne également une méthode de traitement de maladies ou d'affections associées à la biosynthèse des oligosaccharides dans les organismes humains ou animaux. En outre, la présente invention concerne des compositions pharmaceutiques comprenant des dérivés de monosaccharide. De plus, la présente invention concerne de nouveaux dérivés de monosaccharide et des procédés de synthèse desdits dérivés de monosaccharide.
PCT/GB2007/000468 2006-02-13 2007-02-09 Inhibiteurs de la biosynthèse des oligosaccharides WO2007093769A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104961778A (zh) * 2015-07-22 2015-10-07 中国农业大学 甘露糖基噻唑啉化合物及其制备方法与应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0561523A2 (fr) * 1992-03-03 1993-09-22 Japan Tobacco Inc. Composés de sucre et leur utilisation comme inhibiteurs de la biosynthèse de sialyl-sucres, procédé pour leur préparation et composés intermédiaires
JPH07145191A (ja) * 1993-11-24 1995-06-06 Japan Tobacco Inc ガラクトシルホスフォネート誘導体
US20040242532A1 (en) * 2002-01-22 2004-12-02 Christopher Meyer Method for the treatment of microorganism infections by inhibiting energy storage and utilization

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0561523A2 (fr) * 1992-03-03 1993-09-22 Japan Tobacco Inc. Composés de sucre et leur utilisation comme inhibiteurs de la biosynthèse de sialyl-sucres, procédé pour leur préparation et composés intermédiaires
JPH07145191A (ja) * 1993-11-24 1995-06-06 Japan Tobacco Inc ガラクトシルホスフォネート誘導体
US20040242532A1 (en) * 2002-01-22 2004-12-02 Christopher Meyer Method for the treatment of microorganism infections by inhibiting energy storage and utilization

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FUJITA, M. ET AL: "A novel disaccharide substrate having 1,2-oxazoline moiety for detection of transglycosylating activity of endoglycosidases", BIOCHIMICA ET BIOPHYSICA ACTA, GENERAL SUBJECTS , 1528(1), 9-14 CODEN: BBGSB3; ISSN: 0304-4165, 2001, XP002431618 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104961778A (zh) * 2015-07-22 2015-10-07 中国农业大学 甘露糖基噻唑啉化合物及其制备方法与应用

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