EP0984974A1 - Glycoconjugues de substances opiacees - Google Patents

Glycoconjugues de substances opiacees

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Publication number
EP0984974A1
EP0984974A1 EP98924479A EP98924479A EP0984974A1 EP 0984974 A1 EP0984974 A1 EP 0984974A1 EP 98924479 A EP98924479 A EP 98924479A EP 98924479 A EP98924479 A EP 98924479A EP 0984974 A1 EP0984974 A1 EP 0984974A1
Authority
EP
European Patent Office
Prior art keywords
compound
group
formula
anyone
sugar
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98924479A
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German (de)
English (en)
Inventor
Gregorio Valencia
Raquel Emilia Rodriguez
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Rolabo SL
Original Assignee
Rolabo SL
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rolabo SL filed Critical Rolabo SL
Publication of EP0984974A1 publication Critical patent/EP0984974A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms

Definitions

  • the present invention relates to sugar derivatives of biologically active opiates and their use as analgesics, particularly to -sugar derivatives .
  • Morphine and its synthetic analogues eg. hydromorphone, diamorphine and oxymorphone are the most widely used pharmaceutical materials for the control of chronic pain. Codeine, dihydrocodeine and nalbuphine are also commonly employed for their milder analgesic properties. Morphine and its analogues will be referred to collectively herein as opiates, which term is intended to include all non-peptide substances which bind specifically to opioid receptors and which may be referred to elsewhere as opioids or opioid analgesics.
  • the present invention provides a compound being a sugar derivative of a biologically active opiate comprising at least one sugar residue coupled with at least one opiate residue through an ⁇ -glycosidic bond and salts, analogues and complexes thereof .
  • sugar residue and opiate residue may be coupled indirectly through a linker group (eg. an NHCO or HCS group) , preferably the residues are coupled directly and the ⁇ -glycosidic bond is an O-glycosidic bond.
  • a linker group eg. an NHCO or HCS group
  • the sugar residue is preferably a five or six membered ring, eg. a furanose or pyranose.
  • furanoses are also suitable.
  • the preferred furanoses are the aldopentoses such as ribose, arabinose, xylose, lyxose and 2-deoxy- ribose.
  • varous ketohexoses such as fructose, psicose, sorbose and tagatose, and ketopentoses such as ribulose and xylulose.
  • the compound according to the invention is of formula I :
  • n 0 or 1
  • R 2 is H when n is 1 and H or CH 2 OR 5 when n is 0 ;
  • R denotes the residue of a biologically active opiate of formula R-OH, wherein the OH group is either an alcoholic or phenolic OH group;
  • X denotes an O-glycosidic bond or a linker group
  • Ri denotes hydrogen, a CH 2 OR 5 , CH 2 OCOR 5 or COZ group
  • Z denotes an 0R 5 , NR 3 R 4 , 0(CO)R 5 , C J. _ J.B -alky1 or C J. _ J.8 - alkenyl group;
  • R 3 and R 4 independently denote hydrogen, a C ⁇ e- alkyl, or aryl group;
  • R 5 denotes hydrogen, a aryl, sulphate, phosphate or silyl group
  • R 6 independently denotes hydrogen, a C x _ 1B -alkenyl, aryl, COR 5 , phosphate, sulphate or silyl group) , while one or more 0R 6 groups may optionally be replaced by hydrogen atoms (eg. as in 2-deoxy-D-ribose) ; and the salts, analogues and complexes thereof.
  • a group is specified as C 1 _ 18 -alkyl or Cj .
  • _ 18 - alkenyl it is optionally hydroxylated, aminated, carboxylated, amidated, esterified, sulphated or phosphated and it is more preferably or Cj.g- alkenyl.
  • aryl is specified it is more preferably phenyl .
  • Preferred compounds of the invention are those in which R 6 denotes hydrogen, especially preferably those in which R 6 denotes hydrogen and R x denotes CH 2 0R 5 .
  • the ⁇ -sugar residue may be an ⁇ -D-furanose (eg. fructofuranose, ribofuranose or 2-deoxy-ribofuranose) or more preferably an ⁇ -D-pyranose eg. a glucose, galactose or mannose residue, preferably a galactose residue.
  • ⁇ -D-furanose eg. fructofuranose, ribofuranose or 2-deoxy-ribofuranose
  • ⁇ -D-pyranose eg. a glucose, galactose or mannose residue, preferably a galactose residue.
  • Preferred compounds are those of formula II
  • R l t R 3 , R, R 5 , R 6 X and Z are as hereinbefore defined
  • the salts and analogues thereof especially those of formula II in which R 6 denotes hydrogen, particularly those in which R 6 denotes hydrogen and R x denotes CH 2 OR 5 .
  • Especially preferred compounds according to the invention are 6-morphinyl ⁇ -D-mannopyranoside acetate and 6-morphinyl ⁇ -D-galactopyranoside acetate and salts, analogues and complexes thereof .
  • biologically active opiate is meant compounds having pharmacological and therapeutic activities in relation to analgesia, cough, dysponea, constipation, anesthesia, sedation or diarrhea or which stimulate or inhibit such activity. This includes full agonists, partial agonists, mixed agonist-antagonists and antagonists.
  • biologically active opiates include opiate substances isolated from nature or synthesized and their salts and analogues.
  • opiates morphine, codeine, hydromorphone, diamorphone, oxymorphone, naloxone, nalbuphine, buprenorphine , pholcodine, meperidine, loperamide, sufentanil, methadone, pethidine, oxycodone, levorphanol, fentanyl, alfentanil, butorphanol, propoxyphene, metazocine, dezocine phenazocine and pentazocine.
  • Preferred sugars or carbohydrates may be, for example, any known mono- or oligosaccharide, especially a mono-, di- or trisaccharide or analogues thereof (eg. an amino and/or carboxylic acid and/or reduced and/or esterified and/or sulfated and/or phosphated analogue thereof) .
  • opiates In formulae I and II, only one sugar moiety per opiate is denoted. However, the invention also covers ⁇ -sugar derivatives of opiates having more than one free hydroxyl group on the opiate residue and therefore these structures may contain 2 or more sugar residues per opiate residue. Preferably opiates contain 1 to 3 monosaccharide units which may also be joined to the active molecule as a disaccharide or trisaccharide. Similarly a single sugar residue linked to more than one opiate residue is within the scope of the invention.
  • the sinuous line ( —_- ) indicates that the stereochemistry at a particular carbon of the sugar residue is undefined and that the formulae is intended to cover both epimers .
  • residues may be mentioned as specific ⁇ -sugar residues: glucosyl , galactosyl, mannosyl, allosyl, altrosyl, talosyl, gulosyl, idosyl, xylosyl, glucosaminyl , N-acetyl-glucosaminyl , octylglucopyranosyl , cyclohexylglucopyranosyl , benzylglucopyranosyl , glucosyl sulfate, glucosyl phosphate, glucosaminyl sulfate, N-acetyl -glucosaminyl sulfate, lactosyl, gentiobiosyl, chitobiosyl, N-acetyl-lactosaminyl, cellobiosyl, maltosyl, melibiosyl and L
  • Preferred compounds of the invention are ⁇ -sugar derivatives of opiates structurally related to morphine eg. opiates of morphinan structure and their analogues. Particularly preferred are the ⁇ -sugar derivatives of compounds of formula III:
  • x is a hydroxyl, methoxy, ethoxy, acetoxy or -0CH 2 CH 2 N ) group
  • M 2 is hydrogen, a hydroxyl, oxy, acetoxy, methoxy or methene group
  • M 3 is a methyl, methylene cyclopropyl, methylene cyclobutyl or allyl group
  • M 4 is hydrogen or a hydroxyl group; the bond between carbon atoms in positions 6-7 and 7-8 can be either single or double; and the ether function between position 4 and 5 can be either present or not present on the molecule) .
  • Compounds of formula III can exist either in the form of levo or dextrorotatory isomers as well as salts, analogues and complexes thereof.
  • Preferred compounds of formula III are those in which M : and M 2 are hydroxyl, M 3 is methyl, M 4 is hydrogen and a double bond exists between positions 7-8 and an ether function between positions 4-5 (ie. morphine) and in which Mi is hydroxyl, M 2 is oxy, M 3 is allyl, M 4 is hydroxyl and a single bond exists between positions 7-8 and an ether function between positions 4-5 (ie. naloxone) .
  • definitions for codeine, heroin, hydromorphone, hydrocodone, oxymorphone, oxycodone, levorphanol, dextromethorphan, nalorphine, naltrexone, levallorphan, thebacone, ethyl morphine, dihydrocodeine, nalmefene, nalbuphine, butorphanol and pholcodine may be deduced from formula III.
  • Other analogues such as metopon and buprenorphine that may not be deduced from formula III directly are also preferred morphinan compounds .
  • More preferred sugar derivatives of morphinan structure are those which have an ⁇ -sugar residue on either positions C-3 and C-6 of the morphinan backbone.
  • Particularly preferred compounds are the 3- and 6- derivatives of morphine, codeine and naloxone.
  • Further preferred compounds of the invention are ⁇ - sugar derivatives of opiates of the meperidine (pethidine) series ie. of the phenylpiperidine type and their complexes and analogues, including piperidine type structures in which radicals have been modified to introduce suitable functions such as hydroxyl groups that may allow further coupling reactions with sugar residues .
  • pethidine meperidine
  • phenylpiperidine type and their complexes and analogues including piperidine type structures in which radicals have been modified to introduce suitable functions such as hydroxyl groups that may allow further coupling reactions with sugar residues .
  • Ej . is a methyl, phenylethyl, p-phenylethylamine, -(CH 2 ) 3 -NH-C 6 H 5 , -(CH 2 ) 2 -C(C 6 H 5 ) 2 -CN, ⁇
  • E 2 is hydrogen, a phenyl , m-hydroxyphenyl, p-chlorophenyl, methylenemetoxide or piperidinyl group;
  • E 3 is a hydroxyl, ethylcarbonyl , carboxamide, ethyloxycarbonyl, ethylcarboxyl or -N (C 6 H 5 ) -CO-CH 2 -CH 3 group) .
  • More preferred compounds of formula IV are those in which Ej . is methyl, E 2 is phenyl, and E 3 is ethoxycarbonyl (ie. meperidine) and in which Ej . is
  • E 2 is phenyl and E 3 is ethoxycarbonyl (ie. diphenoxylate) .
  • definitions for loperamide, fentanyl, sufentanil, alfentanil, cetobemidon, piritramide, anileridine, piminodine may be deduced directly from formula IV.
  • Other analogues such as alphaprodine, ' fenpipramide, ethoheptazine, tilidin and nefopam which may not be deduced from formula IV are also preferred.
  • Especially preferred ⁇ -glycosilated opiates of the meperidine type are those which are glycosilated on one hydroxyl group already present or introduced for binding purposes on radicals E 2 and E 3 of formula IV, most especially those of meperidine, loperamide and cetobemidon.
  • Further preferred compounds of the invention are the ⁇ -sugar derivatives of opiates of the methadone type and their complexes and analogues ie .
  • opiates which are structurally closely related to methadone.
  • Analogues of methadone include structures in which radicals have been modified with functions such as hydroxyl groups to allow coupling with ⁇ -sugar residues.
  • Dj is a phenyl or benzyl group
  • D 2 is a -CH 2 -CH(CH 3 ) -, -CH (CH 3 ) -CH 2 - or -(CH 2 ) 2 - group;
  • D 3 is an ethylcarbonyl, ethylcarboxyl or -CH(OCOCH 3 ) -CH 2 -CH 3 group).
  • More preferred compounds of formula V are those in which Dj . is phenyl, D 2 is -CH 2 -CH (CH 3 ) - and D 3 is ethylcarbonyl (ie. methadone) or in which Dj . is benzyl, D 2 is -CH(CH 3 ) -CH 2 - and D 3 is ethylcarboxyl (ie. propoxyphene) .
  • Particularly preferred ⁇ -sugar derivatives of opiates of the methadone type are those which are glycosilated on a hydroxyl group which has been introduced for coupling purposes on radicals D x and D 3 of formula V, especially those of methadone.
  • Further preferred compounds of the invention are the ⁇ -sugar derivatives of opiates of the benzomorphane group and their complexes and analogues ie. compounds with structures which correspond to the benzomorphane motif.
  • analogues such as dezocine and meptazinol which may -not be deduced directly from formula VI are also preferred opiates of the benzomorphane group of compounds .
  • the ⁇ -sugar derivatives of opiates of the benzomorphane group are preferably those which are glycosilated on the phenol function of formula VI, especially those of methazocine, pentazocine and cyclazocine.
  • ⁇ -sugar residues may be coupled to appropiate residues of a biologically active opiate.
  • the sugar residue is attached to an hydroxyl group of the opiate residue by - lo an ⁇ -O-glycosidic bond.
  • This group of compounds of the invention may be prepared by any of the known methods of ⁇ -O-glycosidic bond formation, eg., the Koenigs-Knorr reaction, Helferich, Hannessian or Schmidt procedures. Coupling through a linker group (X) may equally be achieved conventionally.
  • the present invention provides a process for preparing the compounds according to the invention, said process comprising the following steps: a) reacting an optionally protected opiate (acyl acceptor) having a free hydroxyl group with an optionally protected, activated reducing ⁇ -sugar derivative (acyl donor) in the presence of a promoter; and b) subsequently removing any protecting groups.
  • the process of the invention may require the use of one or more suitable protecting groups for reactive functions in both the ⁇ -sugar and the opiate reagent to prevent them hindering the reaction. These may be added and removed by known techniques.
  • step (a) When a modification on the sugar molecule is to be introduced, a separate reaction step is required ⁇ either before or after step (a) and may involve other reaction procedures such as phosphate or sulphate bonding, or ester or amide bond formation which may be carried out by conventional procedures using reagents such as acid halides, carbodiimides, phosphonium or uronium salts, active esters and symmetrical anhydrides.
  • reagents such as acid halides, carbodiimides, phosphonium or uronium salts, active esters and symmetrical anhydrides.
  • Step (a) may be carried out by conventional glycosidic bond formation.
  • the promoter may be conveniently an Ag + or Hg ++ compound (eg. silver triflate or AgC0 3 ) or a Lewis acid such as BF 3 OEt 2 or LiOH.
  • a tertiary organic amine may be added.
  • the reaction is preferably carried out in a solvent such as dichloromethane, acetonitrile, methanol or methylene chloride, at temperatures in the range -100°C to reflux temperature, preferably in the range -40°C to room temperature .
  • the compounds according to the invention may be converted into salts thereof, more particularly for pharmaceutical use into physiologically acceptable salts thereof with inorganic or organic acids (eg. sulphuric acid, hydrochloric acid, acetic acid, tartaric acid.
  • inorganic or organic acids eg. sulphuric acid, hydrochloric acid, acetic acid, tartaric acid.
  • the invention seeks to provide compounds which facilitate blood-brain barrier passage.
  • the compounds have improved analgesic potency and a longer lasting analgesic effect.
  • the present invention provides the use of a compound according to the invention as an analgesic.
  • the present invention provides a composition for use as an analgesic comprising a compound according to the invention or a salt or complex thereof together with one or more pharmaceutically acceptable carriers or diluents.
  • the present invention provides the use of a compound according to the invention or a salt or complex thereof for the manufacture of an analgesic medicament .
  • the present invention provides a method of treatment of the human or non-human, preferably mammalian, body to combat pain, said method comprising administering to said body a compound according to the invention or a physiologically acceptable salt or complex thereof.
  • the compounds according to the invention or their pharmaceutical compositions may be used to combat cancer pain, central pain, labour pain, mycardial infarction pain, pancreatic pain, colic pain, postoperative pain and pain associated with intensive care. More generally, they may be used to combat conditions relating to cough, dysponea, constipation or diarrhea and in anesthesia or sedation.
  • the active compound may be formulated with other analgesics including non-opioids (eg. paracetemol or aspirin) or with weak or strong opioid analgesics, with adjuvants to increase analgesia or reduce side effects (eg. antiemetics) and optionally with conventional carriers or excipients.
  • analgesics including non-opioids (eg. paracetemol or aspirin) or with weak or strong opioid analgesics, with adjuvants to increase analgesia or reduce side effects (eg. antiemetics) and optionally with conventional carriers or excipients.
  • Formulation aids such as flavouring agents, antioxidants, os olality adjusting agents, solubilizing agents, emulsifiers, buffers, viscosity enhancing agents, preservatives and stabilisers may also be present .
  • composition in liquid form eg. formulated as syrup, solution, dispersion, suspension or linctus in an appropriate solvent such as water or aqueous vehicle such as sodium chloride solution, Ringers solution, dextrose solution, lactated Ringers solution, it may be combined with ethanol, glycerol, sorbitol, polyethylene-glycol or propyleneglycol and optionally filled into capsules.
  • an appropriate solvent such as water or aqueous vehicle such as sodium chloride solution, Ringers solution, dextrose solution, lactated Ringers solution
  • ethanol glycerol, sorbitol, polyethylene-glycol or propyleneglycol and optionally filled into capsules.
  • compositions according to the invention are formulated in solid form eg. as granules, tablets, coated tablets, capsules, powders or pellets, preferably for sustained release, optionally together with diluents or excipients such as lactose, starch and derivatives thereof, microcrystalline cellulose or derivatives thereof, cornstarch, glucose, magnesium polyvinylpyrrolidone, citric acid, tartaric acid, fatty substances and adjuvants such as binders and lubricants.
  • diluents or excipients such as lactose, starch and derivatives thereof, microcrystalline cellulose or derivatives thereof, cornstarch, glucose, magnesium polyvinylpyrrolidone, citric acid, tartaric acid, fatty substances and adjuvants such as binders and lubricants.
  • the dosage of active compound and its administration route will vary according to the level and type of pain. Typically it may be administered rectally, subcutaneously, intraspinally, intramuscularly, intranasally or intraveneously, but more desirably orally. Parenteral doses may be administered as bolus injections or continuous or intermittent infusions adjusted to analgesic requirements. Dosages may vary from 50 ⁇ g to more than 2500 mg every 4 hours, although more typically 100 mg or less, preferably 0.05 to 20 mg, every 4 hours if administered orally and generally less if administered parenterally. Preferably the active ingredient is administered in a sustained release form.
  • the intermediate product was prepared as follows. a) 6- (3-O-acetvl) -morphinyl- ⁇ -D-mannopyranoside tetraacetate
  • the intermediate products can be prepared as follows.
  • 3 -O-acetyl-morphine (0.43 g) is dried by azeotropic distillation with benzene. Under argon atmosphere, a solution is prepared with the morphine derivative and 10 ml of dry dichloromethane . Tetra-O- benzyl- ⁇ -D-galactopyranosyl trichloroacetimidate (0.9 g) , borontrifluoride diethyl etherate complex (0.18 g) and 4 A molecular sieves are added. After stirring at room temperature overnight, the reaction mixture is diluted with methylene chloride, washed with aqueous bicarbonate, dried over sodium sulfate and the solvent evaporated. The residue is purified on a silica gel column eluted with a chloroform/methanol mixture (20:1 to 8:2) yielding 0.67 g of the title compound.
  • the corresponding glucopyranosyl analogue is prepared by a similar procedure as described for the galactosyl analogue following a procedure such as the one of Example 2 using a trichloroacetimidate intermediate of glucose .
  • the glucu onic acid analogue is synthesized by the method described for the galactoside analogue of Example 2.
  • Example 2 is also followed for the analogous preparation of the corresponding glucuronamide analogue of morphine.
  • Example 7 is also followed for the analogous preparation of the corresponding glucuronamide analogue of morphine.
  • the title compound is prepared from methadol following an analogous procedure to the one described for 6- morphinyl- ⁇ -D-mannopyranoside acetate (Example 1) .
  • the corresponding glucopyranosyl analogue is prepared by a similar procedure as described in Example 2 using a glucose intermediate.
  • the glucuronic acid analogue of methadol is synthesized by an analogous method to that used to prepare the compound of Example 2.
  • This analogue is prepared from pentazocine by a similar reaction pathway as for the corresponding morphine analogue of Example 1.
  • the pentazocine analogue of the morphine compound of Example 2 is also prepared analogously to Example 2 from the corresponding galactose trichloroacetimidate.

Abstract

On a découvert que des alpha -glycosides d'opiacés possèdent des propriétés pharmacologiques intéressantes, en particulier, des propriétés analgésiques. L'invention concerne un composé qui est un dérivé de sucre d'un opiacé biologiquement actif comprenant au moins un résidu de sucre couplé à au moins un résidu d'opiacé par l'intermédiaire d'une liaison alpha -glycosidique, ainsi que ses sels, analogues et complexes.
EP98924479A 1997-05-29 1998-05-29 Glycoconjugues de substances opiacees Withdrawn EP0984974A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9711118 1997-05-29
GBGB9711118.1A GB9711118D0 (en) 1997-05-29 1997-05-29 Compound
PCT/GB1998/001578 WO1998054196A1 (fr) 1997-05-29 1998-05-29 Glycoconjugues de substances opiacees

Publications (1)

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EP0984974A1 true EP0984974A1 (fr) 2000-03-15

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EP (1) EP0984974A1 (fr)
GB (1) GB9711118D0 (fr)
WO (1) WO1998054196A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2324330A1 (fr) * 1999-11-08 2001-05-08 Ssp Co., Ltd. Derives de la 4-hydroxy-4-phenylpiperidine et produits pharmaceutiques a base de ceux-ci
US6740641B2 (en) 2001-07-27 2004-05-25 Euro-Celtique, S.A. Sugar derivatives of hydromorphone, dihydromorphine and dihydromorphine, compositions thereof and uses for treating or preventing pain
FR2907121B1 (fr) * 2006-10-12 2012-05-04 Neorphys Nouveaux derives morphiniques
US8173666B2 (en) 2007-03-12 2012-05-08 Nektar Therapeutics Oligomer-opioid agonist conjugates
US10512644B2 (en) 2007-03-12 2019-12-24 Inheris Pharmaceuticals, Inc. Oligomer-opioid agonist conjugates

Family Cites Families (4)

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Publication number Priority date Publication date Assignee Title
US3647806A (en) * 1966-04-18 1972-03-07 Syntex Corp Tetrahydropyranyl and tetrahydro-furanyl benzomorphan ethers
GB9116909D0 (en) * 1991-08-06 1991-09-18 Salford Ultrafine Chem & Res Morphine derivatives
FR2680786B1 (fr) * 1991-09-04 1995-03-10 Irepa Procede de synthese de glucuronides d'epoxy-4,5 morphinanes.
CA2211596A1 (fr) * 1995-11-29 1997-06-19 Gregori Valencia Parera Glycoconjugues de substances opiacees

Non-Patent Citations (1)

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Title
See references of WO9854196A1 *

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GB9711118D0 (en) 1997-07-23

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