WO2011083291A1 - Combinaisons comprenant un agent anti-inflammatoire et/ou un agent antibactérien et une glycosylamine et leur utilisation en médecine - Google Patents

Combinaisons comprenant un agent anti-inflammatoire et/ou un agent antibactérien et une glycosylamine et leur utilisation en médecine Download PDF

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Publication number
WO2011083291A1
WO2011083291A1 PCT/GB2010/051109 GB2010051109W WO2011083291A1 WO 2011083291 A1 WO2011083291 A1 WO 2011083291A1 GB 2010051109 W GB2010051109 W GB 2010051109W WO 2011083291 A1 WO2011083291 A1 WO 2011083291A1
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pharmaceutical composition
kit
group
glycosylamine
monosaccharide
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PCT/GB2010/051109
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English (en)
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Julian Manuel Galvez
Michael Peter Seed
Ivan Maurice Roitt
Michael Burnet
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Julian Manuel Galvez
Michael Peter Seed
Ivan Maurice Roitt
Michael Burnet
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Publication of WO2011083291A1 publication Critical patent/WO2011083291A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • 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
    • A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to pharmaceutical compositions and kits comprising an anti-inflammatory and/or an antibacterial agent, and a glycosylamine such as ⁇ , ⁇ - di-glucosylamine.
  • the anti-inflammatory is a COX inhibitor such as aspirin, ibuprofen, naproxen or a selective COX-2 inhibitor.
  • the compositions or kits may comprise precursor(s) of the glycosylamine such as glucose and/or ammonium salts.
  • the compositions and kits are suitable for use in the treatment or prevention of inflammation, pain, fever, cancer or cardiovascular disorders, and for use in the treatment of wounds.
  • the present invention also relates to uses of glycosylamines or precursors thereof to treat or prevent side effects associated with the administration of anti-inflammatories and/or antibacterial agents.
  • glycosylamines or precursors thereof can also substantially enhance the activity and reduce the side effects of other compounds used to treat inflammatory diseases, such as COX inhibitors. It has further now been discovered that glycosylamines and precursors thereof are also effective at enhancing the activity and reducing the side effects of antibacterial agents such as antibiotics. The present invention is based upon these findings.
  • a first aspect of the present invention relates to a pharmaceutical composition or kit comprising:
  • glycosylamine or one or more precursors thereof or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate of said glycosylamine or precursor (s).
  • a pharmaceutical 'composition' refers to a pharmaceutical wherein the components are present as a union, i.e. in a single dosage form, for example as a single tablet or powder containing the components.
  • a pharmaceutical 'kit' the components of that kit are not present as a single union, but are in separate dosage forms for administration simultaneously, separately, sequentially or at intervals to one and the same human or animal body.
  • the first aspect of the present invention relates to a pharmaceutical composition.
  • the anti-inflammatory is a COX inhibitor.
  • a 'COX inhibitor' refers to an inhibitor of cyclooxygenase.
  • the COX inhibitor is a non-steroidal antiinflammatory drug (NSAID).
  • NSAID is selected from: (a) an aminoarylcarboxylic acid derivative such as enfenamic acid, etofenamate, flufenamic acid, isonixin, meclofenamic acid, mefenamic acid, niflumic acid, talniflumate, terofenamate or tolfenamic acid;
  • an ai lacetic acid derivative such as aceclofenac, acemetacin, alclofenac, amfenac, amtolmetin guacil, bromfenac, bufexamac, diclofenac, etodolac, felbinac, fenclozic acid, fentiazac, glucametacin, ibufenac, indomethacin, isoxepac, lonazolac, metiazinic acid, mofezolac, nepafenac, oxametacine, proglumetacin, sulindac, tiaramide, tolmetin, tropesin or zomepirac;
  • an ai lacetic acid derivative such as aceclofenac, acemetacin, alclofenac, amfenac, amtolmetin guacil, bromfenac, bufexamac, diclofenac, etod
  • an aiylbutyric acid derivative such as bumadizon, butibufen, butixirate or fenbufen;
  • an arylpropionic acid derivative such as alminoprofen, bermoprofen, carprofen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, ketoprofen, loxoprofen, naproxen, oxaprozin, piketoprofen, pranoprofen, suprofen, tiaprofenic acid, ximoprofen or zaltoprofen;
  • arylpropionic acid derivative such as alminoprofen, bermoprofen, carprofen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, ketoprofen, loxoprofen, naproxen, oxaprozin, piketoprofen, pranoprofen, suprofen, tiaprofenic acid
  • a pyrazolone derivative such as apazone, feprazone, mofebutazone, morazone, oxyphenbutazone, phenylbutazone, pipebuzone, propyphenazone, ramiphenazone or suxibuzone;
  • a salicylic acid derivative such as acetaminosalol, aspirin, balsalazide, benorylate, diflunisal, fendosal, gentisic acid, glycol salicylate, imidazole salicylate, lysine acetylsalicylate, mesalamine, morpholine salicylate, 1-napthyl salicylate, olsalazine, parsalmide, phenyl acetylsahcylate, phenyl salicylate, salicylamide O- acetic acid, salicylsulphuric acid, salsalate, salicylic acid or sulfasalazine;
  • a salicylic acid derivative such as acetaminosalol, aspirin, balsalazide, benorylate, diflunisal, fendosal, gentisic acid, glycol salicylate, imidazole salicylate,
  • a thiazinecarboxamide derivative such as ampiroxicam, lornoxicam, meloxicam, piroxicam or tenoxicam;
  • a selective COX-2 inhibitor such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib or valdecoxib; or
  • NSAID another NSAID such as ⁇ -acetamidocaproic acid, S- adenosylmethionine, ajulemic acid, 3-amino-4-hydroxybutyric acid, bendazac, benzydamine, oc-bisabolol, bucolome, difenpiramide, ditazol, emorfazone, fepradinol, guaiazulene, lexipafant, licofelone, nabumetone, nimesulide, oxaceprol, perisoxal, proquazone, superoxide dismutase or tenidap.
  • NSAID such as ⁇ -acetamidocaproic acid, S- adenosylmethionine, ajulemic acid, 3-amino-4-hydroxybutyric acid, bendazac, benzydamine, oc-bisabolol, bucolome, difenpiramide
  • said NSAID is a salicylic acid derivative such as aspirin.
  • a typical unit dosage size is lOmg to 2000mg, more preferably 50mg to 1500mg, most preferably 75mg to 900mg.
  • said NSAID is an arylpropionic acid derivative such as ibuprofen or naproxen.
  • a typical unit dosage size is 50mg to 2000mg, more preferably lOOmg to 1500mg, most preferably 200mg to 600mg.
  • said NSAID is a selective COX-2 inhibitor.
  • a typical unit dosage size is 5mg to lOOOmg, more preferably lOmg to 500mg, most preferably 20mg to 250mg.
  • the anti-inflammatory is a steroid.
  • the steroid is a corticosteroid such as 21-acetoxypregnenolone, fludrocortisone, fluticasone furoate, fluticasone propionate, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, ciclesonide, clobestasol, clobetasone, clocortolone, cloprednol, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, etiprednol dicloacetate, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocorto
  • the steroid is selected from hydrocortisone, betamethasone, cortisone, deflazacort, dexamethasone, methylprednisolone, prednisolone, triamcinolone, fludrocortisone, beclomethasone, budesonide, ciclesonide, fluticasone furoate, mometasone furoate, flunisolide, flumethasone, fluorometholone or loteprednol etabonate.
  • the anti-inflammatory is an anti-interleukin-6 agent such as tocilizumab, anti-IL-6 chimeric monoclonal antibody, ALD518 or CNTO 136.
  • the anti-interleukin-6 agent is tocilizumab.
  • the anti-inflammatory is a sulphated saccharide such as those disclosed in WO 2008/152423, which is hereby incorporated herein by reference in its entirety.
  • the sulphated saccharide is sucrose octasulphate or sucralfate.
  • a second aspect of the present invention relates to a pharmaceutical composition or kit comprising:
  • the second aspect of the present invention relates to a pharmaceutical composition.
  • the antibacterial agent is an antibiotic.
  • the antibiotic may be selected from:
  • aminoglycosides such as amikacin, arbekacin, bambermycins, butirosin, dibekacin, dihydrostreptomycin, fortimicins, gentamicin, isepamicin, kanamycin, micronomicin, neomycin, netilmicin, paromomycin, ribostamycin, sisomicin, spectinomycin, streptomycin or tobramycin;
  • amphenicols such as azidamfenicol, chloramphenicol or thiamphenicol; ansamycins such as rifamide, rifampin, rifamycin SV, rifapentine or ⁇ -lactams including carbacephems such as loracarbef; carbapenems such as biapenem, doripenem, ertapenem, imipenem, meropenem or panipenem; cephalosporins such as cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefazolin, cefcapene pivoxil, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefmenoxime, cefodizime, cefonicid, cefoperazone, ceforanide, cefoselis, cefotaxime, cefotiam,
  • hncosamides such as clindamycin or lincomycin
  • macrolides such as azithromycin, cethromycin, clarithromycin, dirithromycin, erythromycin, erythromycin ethylsuccinate, erythromycin acistrate, erythromycin estolate, erythromycin glucoheptonate, erythromycin lactobionate, erythromycin propionate, erythromycin stearate, josamycin, leucomycins, midecamycins, miokamycin, oleandomycin, primycin, rokitamycin, rosaramicin, roxithromycin, spiramycin, telithiOmycin or troleandomycin;
  • polypeptides such as amphomycin, bacitracin, bacitracin zinc, capreomycin, colistin, dalbavancin, daptomycin, enduracidin, enviomycin, fusafungine, gramicidin (s), gramicidin S, iseganan, oritavancin, polymyxin, quinupiistin, ramoplanin, ristocetin, teicoplanin, telavancin, thiostrepton, tuberactinomycin, tyrocidine, tyrothricin, vancomycin or viomycin;
  • tetracyclines such as chlortetracycline, clomocycline, demeclocycline, doxycycline, guamecycline, lymecycline, meclocycline, mefhacycline, minocycline, oxytetracycline, pipacycline, rolitetracycline, tetracycline or tigecycline; or
  • antibiotics such as cycloserine, dalfopristin, fosfomycin, fusidic acid, mupirocin, pristinamycin or virginiamycin.
  • the antibiotic is selected from amikacin, gentamicin, neomycin, tobramycin, cefaclor, cefadroxil, cephalexin, cefixime, cefotaxime, cefpodoxime proxetil, cephradine, ceftazidime, ceftriaxone, cefuroxime, azithromycin, clarithromycin, erythromycin, erythromycin ethylsuccinate, erythromycin stearate, telithromycin, amoxicilhn, ampicillin, floxacillin, penicilUn G, penicillin V, piperacillin, ticarcillin, rifampin, demeclocycline, doxycycline, lymecycline, minocycline, oxytetracycline, tetracycline, aztreonam, chloramphenicol, clindamycin, colistin, daptomycin, doripenem, ertapenem, imi
  • the antibacterial agent is a synthetic antibacterial agent.
  • the synthetic antibacterial agent may be selected from:
  • nitrofurans such as furaltadone, furazolium chloride, nifuratel, nifurfoline, nifurpirinol, nifurtoinol or nitrofurantoin;
  • quinolones and analogs thereof such as balofloxacin, cinoxacin, ciprofloxacin, clinafloxacin, enoxacin, fleroxacin, flumequine, garenoxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin, miloxacin, moxifloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin, oxolinic acid, pazufloxacin, pefloxacin, pipemidic acid, piromidic acid, pruhfloxacin, rosoxacin, rufloxacin, sitafloxacin, sparfloxacin, tosufloxacin or trovafloxacin;
  • sulfonamides such as acetyl sulfamethoxypyrazine, chloramine-B, chloramine-T, dichloramine T, N 2 -formylsulfisomidine, mafenide, noprylsulfamide, phthalylsulfacetamide, phthalylsulfathiazole, salazosulfadimidine, succinylsulfathiazole, sulfabenzamide, sulfacetamide, sulfachloropyridazine, sulfachrysoidine, sulfacytine, sulfadiazine, sulfadicramide, sulfadoxine, sulfaethidole, sulfaguanidine, sulfaguanole, sulfalene, sulfaloxic acid, sulfamerazine, sulfameter, sulfamethazine
  • sulfones such as acediasulfone, dapsone, glucosulfone sodium, solasulfone, succisulfone, sulfanilic acid, p-sulfanilylbenzylamine, sulfoxone sodium or thiazolsulfone; or
  • the synthetic antibacterial agent is selected from metronidazole, tinidazole, ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, nalidixic acid, trimethoprim, sulfamethoxazole, linezolid or noxythiolin.
  • the antibacterial agent is a leprostatic agent such as clofazimine, dapsone, glucosulfone sodium, hydnocarpic acid, solasulfone, succisulfone or sulfoxone sodium.
  • the antibacterial agent is an anti-rickettsial agent such as p-aminobenzoic acid, chloramphenicol or tetracycline.
  • the antibacterial agent is a tuberculostatic agent such as p- amino salicylic acid, p-aminosalicylic acid hydrazine, benzoylpas, 5- bromosalicylhydroxamic acid, capreomycin, clofazimine, cyacetacide, cycloserine, dihydrostreptomycin, enviomycin, ethambutol, ethionamide, furonazide, glyconiazide, isoniazid, morphazinamide, openingazide, phenyl aminosalicylate, protionamide, pyrazinamide, rifabutin, rifalazil, rifampin, rifapentine, salinazid, streptomycin, sulfoniazide, thiacetazone, tuberactinomycin or viomycin.
  • a tuberculostatic agent such as p- amino salicylic acid, p-aminos
  • the antibacterial agent is an antibacterial adjunct.
  • the antibacterial adjunct is selected from:
  • ⁇ -lactamase inhibitors such as clavulanic acid, sulbactam, sultamicillin or tazobactam;
  • renal dipeptidase inhibitors such as cilastatin
  • renal protectants such as betamipron.
  • the antibacterial adjunct is selected from clavulanic acid, tazobactam or cilastatin.
  • any pharmaceutical composition or kit containing an anti-inflammatory or antibacterial agent contains a single unit dosage of said antiinflammatory or antibacterial agent or a fraction of a single unit dosage such as 1 /2, 1/3 or 1 /4.
  • any pharmaceutical composition or kit containing an anti-inflammatory or antibacterial agent contains a single unit dosage of said anti- inflammatory or antibacterial agent.
  • any pharmaceutical composition or kit containing a glycosylamine or one or more precursors thereof contains a single unit dosage of said glycosylamine or one or more precursors thereof, or a fraction of a single unit dosage such as 1 /2, 1/3 or 1/4.
  • any pharmaceutical composition or kit containing a glycosylamine or one or more precursors thereof contains a single unit dosage of said glycosylamine or one or more precursors thereof.
  • each monosaccharide subunit independently is optionally substituted and/ or optionally modified
  • each hydrocarbyl group independently is a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton.
  • one R group is not hydrogen
  • one R group is a monosaccharide subunit and one R group is a hydrocarbyl group; and/ or
  • one R group is a monosaccharide subunit and one R group is hydrogen; and/ or
  • one R group is a hydrocarbyl group and one R group is hydrogen; and/ or
  • two R groups are independently hydrocarbyl groups; and/ or
  • one or two R groups are independently hydrogen, or an alkyl, acyl or alkoxycarbonyl group; and/or
  • one or two R groups are independently hydrogen, or a C C 6 alkyl, C 2 -C 6 acyl, C 2 -C 6 halo-acyl, or C j _ 20 alkoxycarbonyl group; and/ or
  • one or two R groups are independently a methyl, ethyl, acetyl, trifluoroacetyl, Boc, Fmoc, or Zervas group; and/ or
  • one R group is a hydrocarbyl group or a monosaccharide subunit and one R group is an acyl group.
  • the group is directly bonded to both monosaccharide subunits without any intervening atoms being present, such that the compound comprising the two monosaccharide subunits is or comprises a poly- or oligosaccharide.
  • the glycosidic -NR- group or the glycosidic -NR 2 + - group may be linked to one or both of the monosaccharide subunits by a glycosidic bond.
  • the glycosylamine comprises at least one monosaccharide subunit comprising a glycosidic -NR 2 group or a glycosidic -NR 3 + group.
  • the at least one monosaccharide subunit is not substituted with an -OR group, wherein R is any group comprising a further monosaccharide subunit.
  • the glycosylamine may contain 1-100, 1-20, 1-12, 2-10, 2-8, 2-6 or 2-4 monosaccharide subunits.
  • the glycosylamine may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more monosaccharide subunits.
  • the glycosylamine may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 monosaccharide subunits.
  • the glycosylamine may comprise a sequence of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more monosaccharide subunits.
  • the glycosylamines used in the present invention contain one to twelve monosaccharide subunits, preferably one to eight monosaccharide subunits, preferably one to six monosaccharide subunits, preferably two to four monosaccharide subunits, preferably two to three monosaccharide subunits.
  • the glycosylamines may contain, in total, including any further monosaccharide subunits, one monosaccharide subunit, or two monosaccharide subunits, or three monosaccharide subunits, or four monosaccharide subunits, or five monosaccharide subunits, or six monosaccharide subunits, or seven monosaccharide subunits, or eight monosaccharide subunits, or nine monosaccharide subunits, or ten monosaccharide subunits, or eleven monosaccharide subunits, or twelve monosaccharide subunits.
  • all the monosaccharide subunits are independently aldosyl or ketosyl monosaccharides.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or all monosaccharide subunits are independently triosyl, tetrosyl, pentosyl, hexosyl, heptosyl, octosyl or nonosyl monosaccharides.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or all monosaccharide subunits are independently glycerosyl, erythrosyl, threosyl, ribosyl, arabinosyl, xylosyl, lyxosyl, allosyl, altrosyl, glucosyl, mannosyl, gulosyl, idosyl, galactosyl, talosyl, rhamnosyl or fucosyl monosaccharides.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or all monosaccharide subunits are independently tetrosyl monosaccharides or higher, and the ring of those monosaccharides is furanosyl.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or all monosaccharide subunits are independently pentosyl monosaccharides or higher, and the ring of those monosaccharides is pyranosyl.
  • a 'saccharide' is any compound comprising at least one monosaccharide subunit, optionally substituted and/ or optionally modified.
  • a glycosylamine of the present invention is a saccharide.
  • a saccharide may be a mono-, oligo- or polysaccharide.
  • An 'oligosaccharide' may comprise between 2 and 10 monosaccharide subunits and may therefore be a disaccharide, trisaccharide, tetrasaccharide, pentasaccharide, hexasaccharide, heptasaccharide, octasaccharide, nonasacchaiide, or decasaccharide.
  • a 'polysaccharide' may comprise 11 or more monosaccharide subunits.
  • the term 'monosaccharide subunit' refers to a monosaccharide optionally substituted and/or optionally modified, which may or may not be part of a compound comprising more than one monosaccharide subunit.
  • the present invention covers compounds comprising just one monosaccharide subunit, such as monosaccharides.
  • a compound 'contains x monosaccharide subunits' this means that the compound has x monosaccharide subunits and no more, unless it is explicitly mentioned that the compound contains or comprises further monosaccharide subunits.
  • a compound 'comprises x monosaccharide subunits' this means that the compound has x or more monosaccharide subunits.
  • glycosidic bond The single bond between an anomeric carbon of a monosaccharide subunit and a substituent is called a glycosidic bond.
  • a glycosidic group is linked to the anomeric carbon of a monosaccharide subunit by a glycosidic bond.
  • an oc-glycosidic bond of a D-monosaccharide subunit emanates below the plane of the monosaccharide subunit and a ⁇ -glycosidic bond emanates above that plane, and vice versa for an L-monosaccharide subunit.
  • a 'glycosylamine' is any compound comprising at least one monosaccharide subunit with a glycosidic amine group.
  • a 'glucosylamine' is any compound comprising at least one glucose subunit with a glycosidic amine group.
  • a ' ⁇ , ⁇ -di-glucosylamine' is any compound comprising at least two glucose subunits linked by a ⁇ , ⁇ -glycosidic amine group.
  • a ⁇ , ⁇ -glycosidic amine group is linked to the anomeric carbons of two monosaccharide subunits, with both glycosidic bonds being ⁇ -glycosidic bonds.
  • All monosaccharide subunits are independently ring-closed or open-chain or a mixture of ring-closed and open-chain.
  • Ring-closed and open-chain monosaccharide subunits are tautomers of each other, which exist in their cyclic and acyclic forms respectively (with respect to the portion of the molecule referred to). For example, in the equilibrium below, A is the open-chain tautomer and B is the ring-closed tautomer:
  • any substituent that contains a hydrogen atom of moderate acidity may interact with the ⁇ -bond illustrated so as to establish the above equilibrium.
  • a 'hydrogen atom of moderate acidity' is defined as one with an approximate pK a (relative to water) of less than 40, preferably less than 30, preferably less than 25, preferably less than 20. It is also understood that in some cases it is not possible to establish the above equilibrium due to a lack of a suitable hydrogen atom and the relevant portion of the molecule is effectively 'locked' in its open-chain form.
  • the relevant portion of the molecule will exist predominantly in its ring-closed form with little or none of the open-chain form being detectable. It is also to be understood that more than one equilibrium may be established within a given portion of the molecule, for example, the scenario below may be established, wherein the molecule exists in two ring-closed forms C and E, and one open-chain form D.
  • a pyranosyl monosaccharide subunit is a cycHc saccharide with a six-membered ring.
  • Pyranosyl monosaccharide F shown below has been marked with substituent X in the 2-position relative to the anomeric carbon of the pyranosyl subunit:
  • a first group is located a to a second group
  • a first group is located ⁇ to a second group
  • a first group is located ⁇ to a second group
  • this means that the first group is attached to the furthest carbon atom removed, along a continuous chain of carbon atoms, from the carbon atom to which the second group is attached.
  • Formula G has been marked with substituents X in the -, ⁇ -, ⁇ -, ⁇ - and ⁇ -positions relative to the group Y:
  • the term 'directly bonded' used in relation to a monosaccharide subunit comprising a group means that the group is bonded to the carbon backbone of the monosaccharide subunit without any intervening atoms being present.
  • Each monosaccharide subunit independently may be substituted and/or modified.
  • -R a - is independently a chemical bond, or a substituted or unsubstituted alkylene, alkenylene or alkynylene group which optionally includes one or more heteroatoms in its carbon skeleton and preferably comprises 1 -10 carbon atoms;
  • -R b is independently hydrogen, an optionally substituted monosaccharide subunit, or a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton and preferably comprises 1-15 carbon atoms;
  • -R c - is independently a chemical bond, or a substituted or unsubstituted alkylene, alkenylene or alkynylene group which optionally includes one or more heteroatoms in its carbon skeleton and preferably comprises 1-10 carbon atoms; and
  • M is a metal
  • the monosaccharide subunit comprises at least one -OR b ,
  • any substituted monosaccharide subunit comprises at least one, at least two, at least three or at least four -OR b , -OSOR , -OS0 2 R b , -OS0 3 R b , -OSi(R b ) 3 , -OCOR b , -OC0 2 R b , or -OM. More preferably any substituted monosaccharide subunit comprises at least one, at least two, at least three or at least four -OR b or -OM.
  • the ring oxygen of the modified monosaccharide subunit is replaced with -S- or -NR b -, wherein -R is independently hydrogen, an optionally substituted monosaccharide subunit, or a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton and preferably comprises 1-15 carbon atoms.
  • Each hydrocarbyl group independently may be a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally comprises 1-15 carbon atoms and optionally includes one or more heteroatoms in its carbon skeleton.
  • a hydrocarbyl group comprises 1-12, 1-6 or 1-4 carbon atoms.
  • -R - is independently a chemical bond, or a substituted or unsubstituted alkylene, alkenylene or alkynylene group which optionally includes one or more heteroatoms in its carbon skeleton and preferably comprises 1-10 carbon atoms; and -R b is independently hydrogen, an optionally substituted monosaccharide subunit, or a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton and preferably comprises 1-15 carbon atoms.
  • each R group that is not hydrogen contains 1-25 or 1-20 carbon atoms. In another embodiment, each R group that is not hydrogen contains 1-12 carbon atoms. For instance, each R group that is not hydrogen may contain 1-7, 1-6, 1-5 or 1-4 carbon atoms.
  • one R group that is not hydrogen contains 1-25 or 1-20 carbon atoms. In another embodiment of the present invention, one R group that is not hydrogen contains 1-12 carbon atoms. For instance, one R group that is not hydrogen may contain 1-7, 1-6, 1-5 or 1-4 carbon atoms. Preferably said R group is a hydrocarbyl group. All monosaccharide subunits are independently in the D- or L-configuration.
  • each glycosidic bond is independently a or ⁇ .
  • the glycosylamine is not a nucleoside and/ or not a nucleotide. In yet another embodiment, the glycosylamine does not comprise a ribose subunit comprising a glycosidic tertiary amine.
  • none of the monosaccharide subunits is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit.
  • none of the monosaccharide subunits is -NH-hydrocarbyl substituted a to the anomeric carbon.
  • none of the monosaccharide subunits is iV-substituted a to the anomeric carbon.
  • none of the monosaccharide subunits is pyranosyl with a -C0 2 Q group attached to the 5-position relative to the anomeric carbon of the pyranosyl subunit, wherein Q is hydrogen or a hydrocarbyl group.
  • none of the monosaccharide subunits has a -C0 2 Q group attached to the 5-position and/ or the ⁇ -position relative to the anomeric carbon of the monosaccharide subunit.
  • none of the monosaccharide subunits is substituted with a -C0 2 Q group.
  • the glycosylamine contains no sulphate groups.
  • Preferred glycosylamines for use in the invention include:
  • the glycosylamine further comprises at least one sulphate group, wherein a sulphate group is a -0-S0 2 -OR , -NR -S0 2 -OR , -0-S0 2 -N(R) 2 or -NR -S0 2 -N(R) 2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit, or a hydrocarbyl group.
  • the glycosylamine comprises at least two or at least three sulphate groups.
  • the glycosylamine comprising at least one sulphate group may be any as described in WO 2008/059003, which is hereby incorporated herein by reference in its entirety.
  • the sulphate groups are selected from -0-S0 2 -OR , -NR -S0 2 -OR or -0-S0 2 -N(R) 2 groups. More preferably the sulphate groups are -OS0 3 R groups.
  • the glycosylamine comprises at least two monosaccharide subunits, each of which is substituted with at least one sulphate group.
  • 1-50, or 2-30, or 3-15, or 6-12, or all the hydroxyl groups on the monosaccharide subunits independently have been replaced with a sulphate group.
  • the specified range relates to the total number of hydroxyl groups that have been replaced with a sulphate group across all the monosaccharide subunits within the compound.
  • 1-9, or 2-8, or 3-4 hydroxyl groups on each of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 or all monosaccharide subunits independently have been replaced with a sulphate group.
  • the specified range relates to the number of hydroxyl groups that have been replaced with a sulphate group per individual monosaccharide subunit within the compound, and the specified number relates to the number of monosaccharide subunits on which the specified replacement has occurred.
  • each R is independently hydrogen, a metal, or a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton.
  • each R is independently hydrogen, an alkali metal, an alkali earth metal, copper, silver, zinc, or a C C 6 alkyl group.
  • R ' is a metal
  • typically -OS0 3 R ' is -OS0 3 " Li + , -OS0 3 " Na + , -OS0 3 " K + , -OS0 3 " Cu + , -OS0 3 ⁇ Ag + , -OS0 3 ⁇ (Al 2 (OH) 5 ) +
  • two -OS0 3 R ' together are (-OS0 3 ⁇ ) 2 Mg 2+ , (-OS0 3 ⁇ ) 2 Ca 2+ , (-OS0 3 " ) 2 Cu 2+ , or (-OS0 3 ⁇ ) 2 Zn 2+
  • three -OS0 3 R together are (-OS0 3 ⁇ ) 3 Al 3+ ; typical -NR -S0 2 -OR groups comprise the same metal cations.
  • Examples of preferred sulphated glycosylamines for use in the present invention include:
  • glycosylamine has formula (I):
  • R is H, Ac, Me, Et, COCF 3 , or COPh
  • each R is S0 3 R or H;
  • each R ' is H, Li, Na or K
  • R is Ac and all R are H;
  • R is H and all R " are H.
  • glycosylamine the formula (II):
  • R is H, Ac, Me, Et, COCF 3 , or COPh
  • each R is S0 3 R or H;
  • each R ' is H, Li, Na or K
  • the glycosylamine has the formula (III):
  • R is H, CHO or COMe
  • R is S0 3 R or H
  • R ' is H, Li, Na or K
  • glycosylamine the formula (IV):
  • R is H, Ac, Me, Et, COCF 3 , or COPh
  • each R is S0 3 R or H;
  • each R is H, Li, Na or K;
  • R is H or Ac and all R are H.
  • the pharmaceutical composition or kit comprises a glycosyl-precursor and/ or an amine- precursor of a glycosylamine according to any of the preceding embodiments of the present invention.
  • a pharmaceutical composition or kit further comprises a glycosylamine according to any of the preceding embodiments of the present invention.
  • the glycosyl-precursor comprises:
  • the glycosyl-precursor may for instance be a monosaccharide, such as glucose and in particular D-glucose, or a poly- or oligosaccharide, such as starch, maltose, glycogen and lactose.
  • the amine-precursor may be for instance NH 3 , NH 2 R, NHR 2 or NR 3 , wherein R is as defined above, with the proviso that R is not hydrogen.
  • an acid addition salt of the amine-precursor is used.
  • the amine-precursor may for instance be an ammonium salt, such as ammonium carbonate, ammonium bicarbonate, ammonium sulphate and ammonium magnesium sulphate.
  • the glycosyl-precursor and the amine-precursor together can generate a glycosylamine according to the present invention.
  • the glycosyl-precursor when used without an amine-precursor can generate a glycosylamine according to the present invention together with a nitrogen source already present in the patient to be treated.
  • the amine-precursor when used without a glycosyl-precursor can generate a glycosylamine according to the present invention together with a saccharide source already present in the patient to be treated.
  • a pharmaceutical composition or kit of the present invention comprises both a glycosyl-precursor and an amine-precursor
  • said precursors may form part of the same or separate pharmaceutical compositions.
  • Preferably said precursors form part of the same pharmaceutical composition.
  • a third aspect of the present invention relates to a pharmaceutical composition of the first or second aspects of the present invention, further comprising a third active pharmaceutical ingredient, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.
  • a fourth aspect of the present invention relates to a pharmaceutical kit comprising a pharmaceutical composition of the first or second aspects of the present invention, and a third active pharmaceutical ingredient, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.
  • a fifth aspect of the present invention relates to a pharmaceutical kit of the first or second aspects of the present invention, further comprising a third active pharmaceutical ingredient, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.
  • a pharmaceutical kit of the first, second, fourth or fifth aspects of the present invention in the pharmaceutical kit of the first, second, fourth or fifth aspects of the present invention:
  • the anti-inflammatory or antibacterial agent or pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof may form part of a first pharmaceutical composition
  • glycosylamine or precursor(s) thereof, or pharmaceutically acceptable tautomer, salt, prodrug or hydrate of said glycosylamine or precurso (s), may form part of a second pharmaceutical composition;
  • the third active pharmaceutical ingredient or pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof may form part of a third pharmaceutical composition.
  • the third active pharmaceutical ingredient may be any other antiinflammatory or antibacterial agent, such as those listed in relation to the first and second aspects of the present invention.
  • the pharmaceutical composition or kit comprises an anti-inflammatory or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof
  • the third active pharmaceutical ingredient may be selected from antibacterial agents or pharmaceutically acceptable tautomers, salts, prodrugs and hydrates thereof.
  • the third active pharmaceutical ingredient is selected from antibiotics, synthetic antibacterial agents, or pharmaceutically acceptable tautomers, salts, prodrugs and hydrates thereof.
  • the third active pharmaceutical ingredient is an antibiotic or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.
  • the pharmaceutical composition or kit comprises an antibacterial agent or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof
  • the third active pharmaceutical ingredient may be selected from anti-inflammatories or pharmaceutically acceptable tautomers, salts, prodrugs and hydrates thereof.
  • the third active pharmaceutical ingredient is selected from COX- inhibitors, steroids, anti-interleukin-6 agents, sulphated saccharides or pharmaceutically acceptable tautomers, salts, prodrugs and hydrates thereof.
  • the third active pharmaceutical ingredient is a COX-inhibitor such as aspirin, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.
  • the third active pharmaceutical ingredient may be a second anti- inflammatory or pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.
  • the first anti-inflammatory is a COX-inhibitor such as aspirin, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof
  • said second anti-inflammatory is selected from steroids, anti-interleukin-6 agents, sulphated saccharides or pharmaceutically acceptable tautomers, salts, prodrugs and hydrates thereof.
  • the third active pharmaceutical ingredient may be a second antibacterial agent or pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.
  • the first antibacterial agent is an antibiotic or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof
  • said second antibacterial agent may be selected from synthetic antibacterial agents or pharmaceutically acceptable tautomers, salts, prodrugs and hydrates thereof.
  • said second antibacterial agent may selected from antibacterial adjuncts or pharmaceutically acceptable tautomers, salts, prodrugs and hydrates thereof.
  • any compound such as the glycosylamine, precursor, antiinflammatory, antibacterial agent and/ or third active pharmaceutical ingredient used in the present invention may be a pharmaceutically acceptable salt.
  • the compounds can be used both, in their free base form and their acid addition salt form.
  • a 'salt' of a compound of the present invention can be an acid addition salt.
  • Acid addition salts are preferably pharmaceutically acceptable, non-toxic addition salts with suitable acids, including but not limited to inorganic acids such as hydrohalogenic acids (for example, hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid) or other inorganic acids (for example, nitric, perchloric, sulphuric or phosphoric acid); or organic acids such as organic carboxylic acids (for example, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, salicylic, succinic, malic or hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, mucic or galactaric, gluconic, pantothenic or pamoic acid), organic sulphonic acids (for example, methanesulphonic, trifluoromethanesulphonic, ethanesulphonic, 2-hydroxyethanesulphonic, benzenesulphonic, toluene-p-sulphonic
  • the compounds can also be used both, in their free acid form and their salt form.
  • a 'salt' of a compound of the present invention can also be formed between a carboxylic acid, sulphate, or other suitable functionality of a compound of the present invention and a suitable cation.
  • Suitable cations include, but are not limited to, alkali metal cations such as lithium, sodium and potassium cations, alkali earth metal cations such as magnesium and calcium cations, transition metal cations such as zinc, copper, zirconium, titanium, manganese, osmium and iron cations, aluminium cations such as [Al 2 (OH) 5 ] + , carbocations, and ammonium cations such as ammonium, HOCH 2 CH 2 NH 3 + , (HOCH 2 CH 2 ) 2 NH 2 + , (HOCH 2 CH 2 ) 3 NH + , NI 3 ⁇ 4 , H + _ NH 2 AND QUATEMARY ammonium cations such as choline cation.
  • Preferred cations include sodium, potassium, magnesium, calcium, ammonium and choline cations.
  • the salt may be a mono-, di-, tri-, tetra- or multi-salt, or a mixture thereof
  • the salt of a sulphated glycosylamine is a multi-sodium, potassium, magnesium, calcium, aluminium, ammonium or choline salt. More preferably the salt is a multi-potassium salt.
  • each sulphate group of a compound of the present invention exists in its salt form.
  • the present invention encompasses the use of pharmaceutically acceptable salts, derivatives, solvates, clathrates and/or hydrates (including anhydrous forms) of the compounds used in the present invention.
  • the present invention also encompasses the use of quaternary ammonium salts of the glycosylamines used in the present invention, wherein the nitrogen of the glycosidic amine group is further substituted by a substituent other than hydrogen, resulting in a positive charge on the nitrogen, balanced by a suitable counter-anion.
  • the substituent is alkyl, preferably methyl or ethyl.
  • Suitable counter- anions include any of those formed in the process of generating acid addition salts as discussed above.
  • the present invention does not use quaternary ammonium salts of glycosylamines.
  • any compound or pharmaceutically acceptable salt form of any compound used in any aspect of the present invention is water soluble.
  • the term 'water soluble' refers to a form wherein at least 1 g of said compound or pharmaceutically acceptable salt will dissolve in 10 hires of water, preferably at a pH of 10 or less.
  • at least 1 g of said compound or pharmaceutically acceptable salt will dissolve in 1 litre, 100 ml, 30 ml, 10 ml or more preferably 1 ml of water.
  • the compounds used in the present invention may contain one or more chiral centres. The compounds may therefore exist in two or more stereoisomeric forms.
  • the present invention independently encompasses the use of racemic mixtures of each of the compounds as well as enantiomerically enriched and substantially enantiomerically pure isomers of each of the compounds.
  • a 'substantially enantiomerically pure' isomer of a compound comprises less than 5% of other isomers of the same compound, preferably less then 3%, preferably less than 2%, preferably less than 1%, preferably less than 0.5%.
  • an 'alkyP group is defined as a monovalent saturated hydrocarbon, which may be straight-chained or branched, or be or include cyclic groups.
  • alkyl groups are methyl, ethyl, //-propyl, /-propyl, //-butyl, /-butyl, /'-butyl and //-pentyl groups.
  • an alkyl group is straight-chained or branched and does not include any heteroatoms in its carbon skeleton.
  • an alkyl group is a C r C 12 alkyl group, which is defined as an alkyl group containing from 1 to 12 carbon atoms. More preferably an alkyl group is a Cj-C 6 alkyl group, which is defined as an alkyl group containing from 1 to 6 carbon atoms.
  • An alkyl group may also be a C C 4 alkyl group, which is defined as an alkyl group containing from 1 to 4 carbon atoms.
  • An 'alkylene' group is similarly defined as a divalent alkyl group.
  • An 'alkenyl' group is defined as a monovalent hydrocarbon, which comprises at least one carbon-carbon double bond, which may be straight-chained or branched, or be or include cyclic groups.
  • alkenyl groups are vinyl, allyl, but-l-enyl and but-2-enyl groups.
  • an alkenyl group is straight-chained or branched and does not include any heteroatoms in its carbon skeleton.
  • an alkenyl group is a C 2 -C 12 alkenyl group, which is defined as an alkenyl group containing from 2 to 12 carbon atoms.
  • an alkenyl group is a C 2 -C 6 alkenyl group, which is defined as an alkenyl group containing from 2 to 6 carbon atoms.
  • An alkenyl group may also be a C 2 -C 4 alkenyl group, which is defined as an alkenyl group containing from 2 to 4 carbon atoms.
  • An 'alkenylene' group is similarly defined as a divalent alkenyl group.
  • An 'alkynyl' group is defined as a monovalent hydrocarbon, which comprises at least one carbon-carbon triple bond, which may be straight-chained or branched, or be or include cyclic groups.
  • alkynyl groups are ethynyl, propargyl, but- 1-ynyl and but-2-ynyl groups.
  • an alkynyl group is straight- chained or branched and does not include any heteroatoms in its carbon skeleton.
  • an alkynyl group is a C 2 -C 12 alkynyl group, which is defined as an alkynyl group containing from 2 to 12 carbon atoms. More preferably an alkynyl group is a C 2 -C 6 alkynyl group, which is defined as an alkynyl group containing from 2 to 6 carbon atoms.
  • alkynyl group may also be a C 2 -C 4 alkynyl group, which is defined as an alkynyl group containing from 2 to 4 carbon atoms.
  • An 'alkynylene' group is similarly defined as a divalent alkynyl group.
  • An 'acyP group is defined as a -COR x group, wherein R x is hydrogen, or an optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group.
  • R x is hydrogen, or an optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group.
  • acyl groups are formyl, acetyl, trifluoroacetyl, propanoyl and benzoyl groups.
  • an acyl group is straight-chained or branched and does not include any heteroatoms in its carbon skeleton.
  • an acyl group is a Q-C ⁇ acyl group, which is defined as an acyl group containing from 1 to 15 carbon atoms. More preferably an acyl group is a C 1 -C n acyl group, which is defined as an acyl group containing from 1 to 12 carbon atoms. More preferably an acyl group is a Q-Q acyl group, which is defined as an acyl group containing from 1 to 6 carbon atoms. An acyl group may also be a Q-C 4 acyl group, which is defined as an acyl group containing from 1 to 4 carbon atoms. An acyl group may also contain 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • An 'aryl' group is defined as a monovalent aromatic hydrocarbon. Examples of aryl groups are phenyl, naphthyl, anthracenyl and phenanthrenyl groups. Preferably an aryl group does not include any heteroatoms in its carbon skeleton. Preferably an aryl group is a C 4 -C 14 aryl group, which is defined as an aryl group containing from 4 to 14 carbon atoms. More preferably an aryl group is a C 6 -C 10 aryl group, which is defined as an aryl group containing from 6 to 10 carbon atoms. An 'arylene' group is similarly defined as a divalent aryl group.
  • arylalkyl arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl
  • the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.
  • a typical example of an arylalkyl group is benzyl.
  • -R p - is independently a chemical bond, or a substituted or unsubstituted alkylene, alkenylene or alkynylene group, optionally including one or more heteroatoms in its carbon skeleton.
  • -R Y is independently hydrogen, or a substituted or unsubstituted alkyl or aryl group, optionally including one or more heteroatoms in its carbon skeleton.
  • Optional substituent(s) are not taken into account when calculating the total number of carbon atoms in the parent group substituted with the optional substituent(s).
  • the total number of carbon atoms in any given -R Y or -R p - group, including any further substitution on that group is 1-50, preferably 1-20, preferably 1-10, preferably 1-6.
  • a substituted group comprises 1, 2 or 3 substituents, preferably 1 or 2 substituents, preferably 1 substituent. Any optional substituent, for example on a monosaccharide subunit or on a hydrocarbyl group, may be protected. Suitable protecting groups for protecting optional substituents are known in the art, for example from 'Protective Groups in Organic Synthesis' by Theodora W. Greene and Peter G. M. Wuts (Wiley- Interscience, 4th edition, 2006).
  • a heteroatom is preferably a B, Si, N, P, O or S atom; more preferably a heteroatom is a N, O or S atom.
  • Any pharmaceutical composition or kit in any of the above aspects of the present invention may independently optionally comprise one or more pharmaceutically acceptable excipients.
  • any pharmaceutical composition or kit in any of the above aspects of the present invention may independently be for oral, parenteral (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural), transdermal, airway (aerosol), rectal, vaginal or topical (including buccal, mucosal and sublingual) administration.
  • at least one pharmaceutical composition is for topical or transdermal administration. Every pharmaceutical composition may be for topical or transdermal administration.
  • each pharmaceutical composition for topical or transdermal administration is independently in the form of an ointment, cataplasm (poultice), paste, powder, dressing, cream, plaster or patch.
  • composition may comprise an antibacterial agent such as an antibiotic, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.
  • said composition may comprise an anti-inflammatory such as a COX inhibitor or a steroid, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.
  • said composition comprises both an antibacterial agent and an anti- inflammatory, or pharmaceutically acceptable tautomers, salts, prodrugs or hydrates thereof.
  • At least one pharmaceutical composition is for oral administration. Every pharmaceutical composition may be for oral administration.
  • each pharmaceutical composition for oral administration is independently a tablet, capsule, caplet, troche, lozenge, or is in the form of a powder, granules, an aqueous solution, suspension or dispersion.
  • Most preferably each pharmaceutical composition for oral administration is a tablet.
  • Tablets for oral use may include the active pharmaceutical ingredient(s) 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.
  • Com starch and alginic acid are suitable disintegrating agents.
  • Binding agents may include starch and gelatine.
  • the lubricating agent if present, may 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 gelatine capsules in which the active ingredient is mixed with a solid diluent, and soft gelatine capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
  • a pharmaceutical composition for oral administration may comprise an enteric coating.
  • any pharmaceutical composition comprising the anti-inflammatory and/ or antibacterial agent, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof, comprises an enteric coating.
  • Preferably 50%, 75%, 90%, 95%, 99% or all of the anti-inflammatory and/or antibacterial agent, or pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof, present within a pharmaceutical composition is encompassed by an enteric coating.
  • any pharmaceutical composition comprising the glycosylamine or one or more precursors thereof, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate of said glycosylamine or precursor(s), comprises an enteric coating.
  • an enteric coating Preferably 50%, 75%, 90%, 95%, 99% or all of the glycosylamine or one or more precursors thereof, or pharmaceutically acceptable tautomer, salt, prodrug or hydrate of said glycosylamine or precursor(s), present within a pharmaceutical composition is encompassed by an enteric coating.
  • a pharmaceutical composition comprises a glycosyl-precursor of a glycosylamine, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate of said precursor
  • said pharmaceutical composition also comprises an enteric coating. More preferably, 50%, 75%, 90%, 95%, 99% or all of said glycosyl-precursor, or pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof, is encompassed by the enteric coating.
  • a pharmaceutical composition comprises an amine-precursor of a glycosylamine, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate of said precursor
  • said pharmaceutical composition also comprises an enteric coating. More preferably, 50%, 75%, 90%, 95%, 99% or all of said amine-precursor, or pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof, is encompassed by the enteric coating.
  • any pharmaceutical composition comprising any active pharmaceutical ingredient comprises an enteric coating.
  • Preferably 90%, 95%, 99% or all of the active pharmaceutical ingredients present within a pharmaceutical composition are encompassed by an enteric coating.
  • Each enteric coating may be selected from acrylic copolymers such as methacrylic acid-methacrylic acid ester and methacrylic acid-acrylic acid ester copolymers; polyvinyl acetate phthalate; hydroxypropyl methylcellulose phthalate; cellulose acetate phthalate; cellulose acetate trimellitate; cellulose acetate succinate; carboxymethyl ethylcellulose; hydroxypropyl methylcellulose acetate succinate; a mixture of sodium alginate and stearic acid; formalin treated gelatin; shellac; and mixtures thereof.
  • each enteric coating is selected from acrylic copolymers.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate, or presented as an enema with a suitable solution or gel comprising, for example, alginates, modified celluloses (such as hydroxypropyl methylcellulose), starches or poloxamers.
  • 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.
  • the active pharmaceutical ingredients of the present invention will generally be provided in a sterile aqueous solution or suspension, buffered to an appropriate pH and isotonicity.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride or glucose.
  • 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 active pharmaceutical ingredients of the invention may also be presented as liposome formulations.
  • Suitable powders, suspensions and solutions can be used in inhalers for airway (aerosol) administration.
  • a sixth aspect of the present invention relates to a pharmaceutical composition or kit according to any of the preceding aspects of the present invention, for use in medicine.
  • the pharmaceutical composition or kit of the sixth aspect of the present invention is for use in the treatment or prevention of inflammation, pain, fever, cancer or a cardiovascular disorder.
  • the pharmaceutical composition or kit of the sixth aspect of the present invention is for use in the treatment of a wound.
  • said treatment aids wound healing.
  • the wound is chronic, and/or has arisen from trauma, decubitis, cosmetic surgery, surgical therapy, organ or tissue transplantation, an insect bite or a burn.
  • a seventh aspect of the present invention relates to a method of treating or preventing inflammation, pain, fever, cancer or a cardiovascular disorder, comprising administering a therapeutically or prophylactically effective amount of a pharmaceutical composition or kit according to any of the preceding aspects of the present invention to a patient in need thereof.
  • the inflammation, pain, fever, cancer or cardiovascular disorder is selected from arthropathies such as rheumatoid arthritis, osteoarthritis, gout, ankylosing spondylitis, psoriatic arthritis or Reiter's syndrome; oedema; proctitis; ileus; dysmenorrhoea; metastatic bone pain; muscoskeletal disorders; backache; rheumatic and/ or muscular pain; sprains; strains; peri-articular disorders; neuralgia; headache; migraine; common cold; sore throat; postoperative pain; pain due to tissue injury such as soft tissue injury; renal colic; rheumatic fever; Kawasaki disease; colorectal cancer; pancreatic cancer; lung cancer; cancer of the upper gastrointestinal tract; myocardial infarction; cerebrovascular disease such as stroke; platelet aggregation; thrombus formation; pericarditis or coronary artery disease.
  • arthropathies such as rheumato
  • An eighth aspect of the present invention relates to a method of treating a wound comprising administering a therapeutically or prophylactically effective amount of a pharmaceutical composition or kit according to any of the preceding aspects of the present invention to a patient in need thereof.
  • said treatment aids wound healing.
  • the wound is chronic, and/ or has arisen from trauma, decubitis, cosmetic surgery, surgical therapy, organ or tissue transplantation, an insect bite or a burn.
  • a ninth aspect of the present invention relates to a glycosylamine or one or more precursors thereof, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate of said glycosylamine or precursor(s), for use in the treatment or prevention of one or more side effects associated with the administration of an anti- inflammatory or antibacterial agent, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.
  • a tenth aspect of the present invention relates to a method of treating or preventing one or more side effects associated with the administration of an anti-inflammatory or antibacterial agent, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof, comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of a glycosylamine or one or more precursors thereof, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate of said glycosylamine or precursor(s).
  • said one or more side effects are selected from:
  • gastrointestinal disorders such as a gastrointestinal ulcer, ulcer perforation, gastrointestinal bleeding, irritable bowel syndrome, pancreatitis, dyspepsia, nausea, vomiting, diarrhoea, flatulence or other irritation of the gastrointestinal tract;
  • urinary disorders such as urinary tract infection, oliguria, nocturia, dysuria, cystitis or haematuria; hyperkalaemia; hypokalaemia; or hypertonia; or
  • respiratory disorders such as upper respiratory tract infection, bronchospasm, chest pain, allergic alveolitis, pulmonary eosinophilia, alveolar osteitis or pharyngitis.
  • said anti-inflammatory or antibacterial agent, or pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof is as defined in relation to the first or second aspects of the present invention.
  • said anti-inflammatory is a COX inhibitor or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.
  • the anti-inflammatory or antibacterial agent is for the treatment or prevention of inflammation, pain, fever, cancer or a cardiovascular disorder, such as a disorder listed in relation to the sixth or seventh aspects of the present invention.
  • the anti-inflammatory or antibacterial agent may also be for the treatment of a wound, such as a wound listed in relation to the sixth or eighth aspects of the present invention.
  • said glycosylamine or precursor(s) thereof, or pharmaceutically acceptable tautomer, salt, prodrug or hydrate of said glycosylamine or precursor(s), is as defined in relation to the first or second aspects of the present invention, or is part of a pharmaceutical composition or kit as defined in relation to any of the preceding aspects of the present invention.
  • the subject to be treated may be a human or animal. Preferably the subject to be treated is a human.
  • any embodiment of a given aspect of the present invention may occur in combination with any other embodiment of the same aspect of the present invention.
  • any preferred or optional embodiment of any aspect of the present invention should also be considered as a preferred or optional embodiment of any other aspect of the present invention.
  • Figure 1 shows the effect of TNBS on weight loss in mice subjected to various intra-rectal treatment regimes.
  • Figure 2 shows the effect of TNBS on weight loss in mice subjected to various intra-rectal treatment regimes.
  • CD-I mice were subjected intra-rectally to TNBS and then treated either with a vehicle enema, an enema that generates a glycosylamine or an enema that generates a glycosylamine and comprises an antibacterial agent, and bodyweight and diarrhoea were monitored.
  • Figure 5 shows the effect of monolateral CFA injection on paw withdrawal latency and the effect of treatment with a glycosylamine generating solution compared with treatment with diclofenac combined with the glycosylamine generating solution.
  • Example 1 Use of an enema that generates a glycosylamine to treat rectal disorders.
  • Various rectal and proximal colon disorders may be treated with rectal enemas.
  • Signs of disorders like proctitis may be reproduced in animals using intra-rectal insult, e.g. by the administration of an irritant like trinitrobenzenesulphonic acid (TNBS) in ethanol.
  • TNBS trinitrobenzenesulphonic acid
  • the animals were randomly assigned to 3 groups: (1) vehicle (1% hydroxypropyl methylcellulose in isotonic saline); (2) 5% glucose with equimolar (NH 4 ) 2 C0 3 in 1% hydroxypropyl methylcellulose incubated for 1 hour prior to use; or (3) 5% glucose with equimolar (NH 4 ) 2 C0 3 in 1% hydroxypropyl methylcellulose mixed just prior to use. Treatments were applied intra-rectally, 5 ml/kg once daily.
  • Example 2 Use of an enema that generates a glycosylamine and optionally comprises an antibacterial agent to treat rectal disorders.
  • Various rectal and proximal colon disorders may be treated with rectal enemas.
  • the inventors combined in an enema an antibacterial agent, azithromycin, with a glycosylamine generating solution.
  • vehicle 1% hydroxypropyl methylcellulose in isotonic sahne
  • Example 3 Use of an enterically coated capsule containing a glycosylamine generating solution and optionally a NSAID to treat systemic inflammatory disease.
  • Acute oedema is associated with many diseases and is not always a normal response to injury but rather a pathological state associated with excessive response to a local irritation (e.g. osteoarthritis). These phenomena may be reproduced in animals by the supply of a local irritant.
  • Capsules were filled with either of the following: (1) vehicle (microcrystalline cellulose 20 ⁇ ); (2) a mixed powder of glucose : ammonium carbonate (1.8 : 0.5); or (3) a mixed powder of glucose : ammonium carbonate : diclofenac (1.8 : 0.5 : 0.4).
  • the capsule filling powder was weighed into a vessel in the appropriate amounts and then mixed on a ball mill to obtain a uniform mixed powder.
  • the capsules were filled according to the directions of the manufacturer (Torpac, New Jersey) and the total filled weight was recorded.
  • the capsules were filled according the approximate weight of the rats designated for study (ca. 195-220 g). After filling, the capsules were matched to the rats to gain as similar as possible a dose regime. Approximately 2-fold more capsules were made than required for the study. After filling, the capsules were rendered resistant to digestion in the stomach using a standard polymer coating material (Eudragit, Evonik Industries, Darmstadt) according to the manufacturer's instructions.
  • the inventors used a double spray coating process in which the capsules were sprayed in multiple orientations to obtain a uniform coat, allowed the capsules to dry separately, and re-sprayed the capsules.
  • the capsules were maintained in separate containers to maintain identity.
  • the target dose of glucose was 100 mg/kg and the target dose of diclofenac was 10 mg/kg.
  • Rats female, Wistar, ca. 200 g were injected on the plantar surface of one paw with 20 ⁇ of complete Freund's adjuvant (CFA) containing 2 mg/ml mycobacterium. The animals were monitored for paw thickness, thermal hyperalgesia and spontaneous mobility at baseline and at various times after CFA injection. The capsules were provided at -0.5, 5 and 21 hours.
  • CFA complete Freund's adjuvant
  • Spontaneous mobility was determined by placing the rat in a container on its own and monitoring movement by video recording. The video recordings were then automatically tracked using software image analysis (Stoelting, Anymaze tm) to determine the movement parameters, notably distance travelled and time in motion. Animals with a paw injury tend to minimally explore the enclosure before resting in one corner of the enclosure. Animals with this specific lesion tend to carry or drag the paw and are generally slower and less likely to move than fully healthy animals.
  • the results are summarised in Figure 4.
  • Thermal hyperalgesia was determined by the time required for a rat to remove its paw from a diode heat source, the time being automatically determined by a light switch. Increase in the latency time is indicative of analgesia.
  • the results are summarised in Figure 5. As can be seen from Figures 3 to 5, the use of a glycosylamine generating solution and a NSAID together is more effective at treating inflammatory disease than the use of a glycosylamine generating

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Abstract

La présente invention concerne des compositions pharmaceutiques et des trousses comprenant un agent anti-inflammatoire et/ou un agent antibactérien, et une glycosylamine telle que la β,β-di-glucosylamine. De préférence l'anti-inflammatoire est un inhibiteur de COX tel que l'aspirine, l'ibuprofène, le naproxène ou un inhibiteur sélectif de COX-2. En variante, au lieu de ou en plus de la glycosylamine, les compositions ou trousses peuvent comprendre un/des précurseur(s) de glycosylamine tel(s) que le glucose et/ ou des sels d'ammonium. Les compositions et trousses sont adaptées pour utilisation dans le traitement ou la prévention de l'inflammation, la douleur, la fièvre, le cancer ou les troubles cardiovasculaires, et pour utilisation dans le traitement de plaies. La présente invention concerne en outre des utilisations de glycosylamines ou des précurseurs de celles-ci pour traiter ou prévenir les effets secondaires associés à l'administration d'agents anti-inflammatoires et/ou antibactériens.
PCT/GB2010/051109 2010-01-07 2010-07-05 Combinaisons comprenant un agent anti-inflammatoire et/ou un agent antibactérien et une glycosylamine et leur utilisation en médecine WO2011083291A1 (fr)

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Cited By (3)

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CN103054965A (zh) * 2013-02-01 2013-04-24 张冠军 一种治疗痹症的外用止痛膏及其制备方法
CN107106690A (zh) * 2015-01-13 2017-08-29 方济各安吉利克化学联合股份有限公司 用于治疗真菌病的药物组合物
CN112858690A (zh) * 2021-01-21 2021-05-28 宁波职业技术学院 一种尿白蛋白/尿肌酐复合质控品及其制备方法

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103054965A (zh) * 2013-02-01 2013-04-24 张冠军 一种治疗痹症的外用止痛膏及其制备方法
CN103054965B (zh) * 2013-02-01 2014-06-18 张冠军 一种治疗痹症的外用止痛膏及其制备方法
CN107106690A (zh) * 2015-01-13 2017-08-29 方济各安吉利克化学联合股份有限公司 用于治疗真菌病的药物组合物
CN107106690B (zh) * 2015-01-13 2020-11-10 方济各安吉利克化学联合股份有限公司 用于治疗真菌病的药物组合物
CN112858690A (zh) * 2021-01-21 2021-05-28 宁波职业技术学院 一种尿白蛋白/尿肌酐复合质控品及其制备方法
CN112858690B (zh) * 2021-01-21 2023-11-10 宁波职业技术学院 一种尿白蛋白/尿肌酐复合质控品及其制备方法

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