EP4577667A2 - Procédé de production de composés libérant des antagonistes des opioïdes et leur utilisation en tant que médicament - Google Patents

Procédé de production de composés libérant des antagonistes des opioïdes et leur utilisation en tant que médicament

Info

Publication number
EP4577667A2
EP4577667A2 EP23762393.9A EP23762393A EP4577667A2 EP 4577667 A2 EP4577667 A2 EP 4577667A2 EP 23762393 A EP23762393 A EP 23762393A EP 4577667 A2 EP4577667 A2 EP 4577667A2
Authority
EP
European Patent Office
Prior art keywords
conjugate
morphinan
naloxone
composition
naltrexone
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.)
Pending
Application number
EP23762393.9A
Other languages
German (de)
English (en)
Inventor
Thilo Fischer
Fong-Chin Huang
James Ferri
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.)
Biosynth GmbH
Virginia Commonwealth University
Original Assignee
Biosynth GmbH
Virginia Commonwealth University
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 Biosynth GmbH, Virginia Commonwealth University filed Critical Biosynth GmbH
Publication of EP4577667A2 publication Critical patent/EP4577667A2/fr
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/44—Preparation of O-glycosides, e.g. glucosides
    • C12P19/60—Preparation of O-glycosides, e.g. glucosides having an oxygen of the saccharide radical directly bound to a non-saccharide heterocyclic ring or a condensed ring system containing a non-saccharide heterocyclic ring, e.g. coumermycin, novobiocin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
    • C07D489/08—Oxygen atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/1048—Glycosyltransferases (2.4)
    • C12N9/1051—Hexosyltransferases (2.4.1)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/18—Preparation of compounds containing saccharide radicals produced by the action of a glycosyl transferase, e.g. alpha-, beta- or gamma-cyclodextrins
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y204/00—Glycosyltransferases (2.4)
    • C12Y204/01—Hexosyltransferases (2.4.1)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y204/00—Glycosyltransferases (2.4)
    • C12Y204/01—Hexosyltransferases (2.4.1)
    • C12Y204/01017—Glucuronosyltransferase (2.4.1.17)

Definitions

  • glycoside conjugate compounds [001] The subject matter disclosed herein relates to glycoside conjugate compounds, methods for preparing them, and methods for their use.
  • Morphinan compounds including opiates from the opium poppy (Papaver somniferum), have been used medicinally as analgesics and antidiarrheal drugs for a long time (Dhawan et al. 1996, International Union of Pharmacology XII. Classification of Opiate Receptors, Pharmacological Reviews 48 (4), 567-592).
  • O-methyl-morphine, analgesic, antitussive) and diacetylmorphine (heroin) have been developed for medical purposes (Dhawan et al. 1996).
  • codeine is activated by the Cyp450 enzyme and oxidative demethylation to morphine (SH Snyder and GW Pasternak, 2003, Trends in Pharmacological Sciences, 24 (4), 198-205).
  • the opioid receptors are G-protein coupled and the binding of agonists is synergistically positively influenced by GTP and Na + ion (Snyder and Pasternak 2003).
  • B-D-glucosides can be cleaved by B-glycosidases. These enzymes occur in humans and their microbiome.
  • the present disclosure offers a solution to the problem above; the present inventors have found that, of many possible substitutions which could achieve a releaseretarding effect, the selection of a glycosyl group is particularly favorable.
  • glycosylation of a morphinan compound is thought to inhibit or prevent the binding of the MC to its receptor, and so control of such derivatization by enzymatic synthesis of the conjugate by a cell-free system or in cell culture, or hydrolysis of the conjugate in situ for release of the active agent MC, can be used to modulate the timing of release or pharmacologic profile of a MC active agent.
  • a “glycoside” is a chemical combination of an alcohol with a carbohydrate. Glycosides can also be joined via N, S and C atoms (thus also “N-”, “S-”, and “C-glycosides”). Typically, when forming a glycoside conjugate, a morphinan group is attached to a glycoside via an oxygen atom, but morphinan compounds can also be conjugated to glycosides via N or S atoms.
  • a distinction can be made between a- and B-D-glycosides, depending on the position of the oxygen bridge atom in relation to the carbohydrate in the normal projection (a-gly cosides: oxygen is from the ring downwards, with B-glycosides upwards).
  • a “glycosyl transferase” or “glycosyltransferase” is an enzyme having a biological activity of attaching the saccharide part of an activated saccharide or oligosaccharide to a nucleophilic acceptor group on an organic compound, typically via an oxygen atom on the substrate compound provided by a hydroxyl group.
  • the nucleophile can be carbon-, nitrogen-, or sulfur-based.
  • Naltrexone is a specific compound; IUPAC name (5R, 9R, 13S, 14S) -17- Cyclopropylmethyl-3,14-dihydroxy-4,5-epoxymorphinan-6-one.
  • patient refers to any human or animal subject and are not intended to limit the systems or methods to human use.
  • a first aspect of the present disclosure relates to a method for producing a purified morphinan-glycoside conjugate (m-g conjugate) comprising: a) contacting a morphinan compound with an activated saccharide or activated oligosaccharide and a glycosyltransferase in a reaction mixture under conditions, including any co-factors necessary for glycosyltransferase activity, effective to produce a m-g conjugate; and b) purifying the conjugate m-g conjugate from the reaction mixture to obtain the isolated m-g conjugate.
  • a morphinan compound used in such method can be one having a core bridged heteropoly cyclic framework, as in Formula I.
  • Ra can be any group, which group can include additional rings, or any two Ra groups can also join to form additional rings, which additional rings may contain at least one further heteroatom.
  • two Ra groups might form a 5- or 6-member epoxy group, a 5- or 6- member thioexpoxy group, a pyrrolidine or a piperidine group, n can be from 0 to 8.
  • Each Ra can be the same or different.
  • Each Ra can be further specified as Rl, R2, R3, etc. as convenience or specificity of description might require.
  • alkyl such as methyl or ethyl, alkenyl, alkynl, allyl, azine
  • the 7 and 8 carbons can be joined by a double bond.
  • the 4 and 5 positions are joined by an epoxy ring.
  • a “morphinan compound” can also include additional heteroatoms, either in the polycyclic bridged core, or in substituents appended to the core, or in both.
  • a “morphinan compound” is preferably one that has appended a hydroxyl group that is sterically accessible to a glycosyl transferase enzyme.
  • the morphinan group can be one that is substituted at least one position by a hydroxyl, thiol, or amine group, for example a morphinan compound wherein at least the 3 -position of the morphinan compound is so substituted.
  • the morphinan compound can be one wherein neither of the 9 or 13 positions are substituted.
  • a morphinan compound used to prepare a conjugate can be one such as Naloxone, Naltrexone, Naloxonazine, Naloxonbenzoylhydrazone, or a derivative of one of these.
  • Ra is a methyl-cylcopropyl group.
  • a morphinan compound is codeine (Formula IV)
  • one Ra is a methoxy group
  • one Ra is a hydroxyl group
  • two Ra groups form a 5-member epoxy ring joining the 4 and 5 positions
  • one Ra is a methyl group
  • the 7 and 8 carbons are joined by a double bond.
  • the morphinan compound can further be one of Formula VI
  • Rj is H, OH or O (i.e., an oxygen atom bound by a double bond to the carbon atom).
  • the morphinan compound of formula VII is more preferably a compound of formula VIII Formula VIII wherein:
  • the morphinan compound of formula VIII is still more preferably a compound of formula IX wherein:
  • the morphinan compound of formula IX is yet more preferably a compound of formula X or XI wherein:
  • the morphinan compound can have various biochemical activities, for example as an opioid receptor antagonist or as an opioid receptor agonist.
  • a morphinan compound “active agent,” for instance released from a m-g conjugate as described elsewhere herein, can have such agonist or antagonist activity selectively for one of the mu, kappa, delta, or epsilon subtype of opioid receptor. For instance, in treating acute opioid overdose, it might be preferable that the opioid receptor antagonist have selectivity for the mu receptor subtype.
  • the activated saccharide can be an activated form of fructose, glucose, galactose, mannose, ribose, or another monosaccharide, or an activated oligosaccharide of one or more of these.
  • the saccharide or oligosaccharide can be one that is activated by an O-linked ester, for example a methyl or ethyl ester, or that is activated by an O-linked phosphoester such as a uridine diphosphate phosphoester (O-UDP).
  • the glycosyltransferase can be an isolated UDP-carbohydrate-dependent glycosyltransferase.
  • an embodiment can be one wherein the glycosyltransferase uses UDP-glucose as the activated saccharide and the m-g conjugate product is the corresponding B-D- glucoside.
  • a gene encoding a glycosyl transferase is “heterologously expressed” if one or more of the following are true in respect of the system by which the glycosyl transferase gene is expressed: a) the promoter of the expression cassette has a nucleotide sequence of a promoter of a gene in a first species whereas the nucleotide sequence of the structural gene of the expression cassette is of a gene of a second species; or b) the host cell used in the expression system is of a species different from the species from which at least one nucleotide sequence of an element of the expression cassette (e.g., promoter, structural gene, enhancer, and the like) are derived.
  • an element of the expression cassette e.g., promoter, structural gene, enhancer, and the like
  • the m-g conjugate product can be the corresponding B-D-glucoside.
  • the UDP-glucose-dependent glycosyltransferase can be one derived from a plant of the genus Arabidopsis, Fragaria or Mentha, or from a bacterium of the genus Bacillus or Lactobacillus.
  • the morphinan group is preferably conjugated at the 3-position with the glycoside.
  • a second aspect of the disclosure lies in a method for purifying a glycoside conjugate of a morphinan compound (“m-g conjugate”) from a reaction mixture comprising: a) adjusting the pH of the reaction mixture to from 7 to 10.5, or preferably to from 8 to 10 or from 9 to 10, to convert m-g conjugate acetate in the reaction mixture to m-g conjugate; b) neutralizing the reaction mixture and contacting it with a lipophilic solid phase to obtain immobilized m-g conjugate and washing the immobilized m-g conjugate; c) eluting the m-g conjugate from the solid phase with an alcohol; d) drying the eluate, redissolving the dried eluate in water or a buffer to obtain an aqueous solution; e) optionally back extracting the aqueous solution with a polar organic solvent to remove any remaining morphinan compound and recovering the aqueous solution; f) drying the aqueous solution to obtain the solid m-
  • a third aspect of the disclosure is a method for purifying a morphinan compound O-glycoside conjugate from a biological culture comprising: a) removing cells from the culture to obtain a supernatant containing m-g conjugate and m-g conjugate acetate; b) adjusting the pH of the supernatant to from 7 to 10.5, preferably to from 8 to 10 or from 9 to 10, to convert m-g conjugate acetate in the supernatant to m-g conjugate; c) neutralizing the supernatant and contacting it with a lipophilic solid phase to obtain immobilized m-g conjugate and washing the immobilized m-g conjugate; d) eluting the m-g conjugate from the solid phase with an alcohol; e) drying the eluate, redissolving the dried eluate in water or a buffer to obtain an aqueous solution; f) optionally back extracting the aqueous solution with a polar organic solvent to
  • the solid phase can be a lipohilic solid phase, an AmberliteTM polymeric adsorbent resin, a PuroliteTM polymeric adsorbent resin, or a mixture of any two or more of these.
  • a fourth aspect of the disclosure is a compound Nal oxone-3 -O-B-D-glucoside, Naltr exone-3 -O-B-D-glucoside, or an ester thereof, or an acetal, semiacetal derivative thereof or an ester of any of these.
  • a m-g conjugate of the fifth aspect of the disclosure can be one wherein the morphinan group further comprises at least one additional N, O or S heteroatom.
  • a m-g conjugate can be one wherein the morphinan group comprises a radical of a substituted morphinan compound of Formula I: (Formula I), wherein: n can be from 1 to 8, or from 2 to 8, or from
  • the morphinan compound of Formula I can be as defined above.
  • EE23 A method for purifying a morphinan compound O-glycoside conjugate (m- g conjugate) from a biological culture comprising: a) removing cells from the culture to obtain a supernatant containing m-g conjugate and m-g conjugate acetate; b) adjusting the pH of the supernatant to from 7 to 10.5, or to from 8 to 10 or from 9 to 10, to convert m-g conjugate acetate in the supernatant to m-g conjugate; c) neutralizing the supernatant and contacting it with a lipophilic solid phase to obtain immobilized m-g conjugate and washing the immobilized m-g conjugate; d) eluting the m-g conjugate from the solid phase with an alcohol; e) drying the eluate, redissolving the dried eluate in water or a buffer to obtain an aqueous solution; f) optionally back extracting the aqueous solution with a polar
  • EE24 The method of EE22 or 23, wherein the solid phase is a lipohilic solid phase, an AmberliteTM polymeric adsorbent resin, a PuroliteTM polymeric adsorbent resin, or a mixture of any two or more of these.
  • EE26 The method of any one of EEs22-25, wherein the polar organic solvent is ethyl acetate, a C4 alcohol, a C5 alcohol, among the latter n-butanol, or 2-methyl-l -butanol.
  • the polar organic solvent is ethyl acetate, a C4 alcohol, a C5 alcohol, among the latter n-butanol, or 2-methyl-l -butanol.
  • EE30 The m-g conjugate of EE29, wherein the morphinan group is a radical
  • Ra groups can also join to form additional rings, which additional rings may contain at least one further heteroatom.
  • EE33 The m-g conjugate of any one of EEs28-32, wherein the morphinan group is conjugated by an O, S or N atom.
  • EE34 The m-g conjugate of EE33, wherein the 3-position of the morphinan group is conjugated.
  • EE36 A composition comprising a) at least one morphinan-gly coside conjugate of any one of EEs27-35 or an acetal, semiacetal or ester-derivative thereof; and b) at least one glycosidase, and/or at least one microorganism that produces a one or more glycosidases.
  • EE38 The composition of EE36 or 37, wherein the m-g conjugate is a Naloxone- or Naltrexone-3-O-B-D-glucoside.
  • EE39 The composition of any one of EEs36-38, wherein the glycosidase is a 13- glucosidase, or a mixture of 13-glucosidases.
  • EE40 The composition of any one of EEs36-39 in which the glycosidase is a 13- glucosidase, or a mixture of 13-glucosidases, derived from bacteria of genus Lactobacillus.
  • EE44 The pharmaceutical composition of EE43, that is formulated for oral administration, administration by transdermal patch, or for administration by intravenous injection or infusion, for administration by intramuscular injection or for administration for subcutaneous injection.
  • EE45 A method for increasing the rate of hydrolysis of a morphinan-gly coside conjugate of any one of EEs27-35, or an acetal, semiacetal or ester-derivative thereof; comprising contacting said morphinan compound-glycoside conjugate or an acetal, semiacetal or esterderivative thereof with at least one glycosidase, and/or at least one microorganism that produces one or more glycosidases.
  • EE48 A method for producing a purified morphinan compound-O-glycoside conjugate comprising: a) contacting a morphinan compound with an activated saccharide or activated oligosaccharide and a glycosyltransferase in a reaction mixture under conditions, including any co-factors necessary for glycosyltransferase activity, effective to produce a morphinan O-glycoside conjugate (m-g conjugate); and b) purifying the m-g conjugate from the reaction mixture to obtain the isolated m-g conjugate.
  • m-g conjugate morphinan O-glycoside conjugate
  • EE49 The method of EE48 in which the contacting step is performed in a cultured medium in which the glycosyltransferase is heterologously expressed by a host cell, and wherein said host cell also produces the activated saccharide or activated oligosaccharide as a metabolic product.
  • EE50 The method of EE48 or 49, wherein the activated saccharide is UDP- glucose, or the activated oligosaccharide is an oligosaccharide comprising UDP-glucose.
  • EE51 The method of EE50, wherein the m-g conjugate product is the corresponding B-D-glucoside.
  • EE52 The method of any one of EEs49-51, in which the glycosyltransferase is a
  • UDP-glucose-dependent glycosyltransferase from a plant or a bacterium.
  • EE55 The method of EE54, wherein a topical formulation is a cream or gel, or an enteric formulation is a solid formulation for oral administration to the intestinal tract, or as a solid formulation for suppository administration to the colon or vagina.
  • EE56 The method of EE54 or EE55, wherein both of the compositions a) and b) are included in the dosage form.
  • EE58 The use of EE57, that includes transdermal administration of the m-g conjugate or release of the morphinan compound active agent from a m-g conjugate to the skin of a subject via a transdermal patch dosage form.
  • EE59 The use of EE57, that comprises administering the m-g conjugate or a composition comprising the m-g conjugate, to a subject via inhalation or intravenous injection or intramuscular injection or subcutaneous injection.
  • EE60 Use of the compound of any one of EEs27-35 or of the composition of any one of EEs36-44 to prepare a medicament comprising mixing the compound or composition with one or more pharmaceutically acceptable carriers and/or excipients.
  • EE61 The use of EE60, wherein the medicament is formulated for administration to a subject via inhalation or intravenous injection or intramuscular injection or subcutaneous injection, or for application to the skin of a subject as a topical formulation or via a transdermal patch.
  • the subject invention has been illustrated and described in detail in the drawings and foregoing description, the disclosed EEsare illustrative and not restrictive in character. All changes and modifications that come within the scope of the invention are desired to be protected.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Addiction (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Psychiatry (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

L'invention concerne un procédé de production d'un conjugué morphinane-glycoside purifié. Le procédé comprend les étapes consistant à mettre en contact un composé morphinane avec un saccharide activé ou un oligosaccharide activé et une glycosyltransférase dans un mélange réactionnel dans des conditions, y compris tout co-facteur nécessaire à l'activité glycosyltransférase, efficace pour produire un conjugué morphinane-glycoside; et à purifier le conjugué morphinane-glycoside du mélange réactionnel pour obtenir le conjugué morphinane-glycoside isolé. L'invention concerne également des composés, des compositions, des conjugués et des procédés pour leur utilisation.
EP23762393.9A 2022-08-25 2023-08-25 Procédé de production de composés libérant des antagonistes des opioïdes et leur utilisation en tant que médicament Pending EP4577667A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263400998P 2022-08-25 2022-08-25
PCT/EP2023/073401 WO2024042226A2 (fr) 2022-08-25 2023-08-25 Procédé de production de composés libérant des antagonistes des opioïdes et leur utilisation en tant que médicament

Publications (1)

Publication Number Publication Date
EP4577667A2 true EP4577667A2 (fr) 2025-07-02

Family

ID=87886720

Family Applications (1)

Application Number Title Priority Date Filing Date
EP23762393.9A Pending EP4577667A2 (fr) 2022-08-25 2023-08-25 Procédé de production de composés libérant des antagonistes des opioïdes et leur utilisation en tant que médicament

Country Status (3)

Country Link
EP (1) EP4577667A2 (fr)
CA (1) CA3265713A1 (fr)
WO (1) WO2024042226A2 (fr)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6716452B1 (en) * 2000-08-22 2004-04-06 New River Pharmaceuticals Inc. Active agent delivery systems and methods for protecting and administering active agents
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
JP5266492B2 (ja) * 2004-05-28 2013-08-21 ヒューマン バイオモレキュラル リサーチ インスティテュート 代謝安定性鎮痛薬、疼痛薬物療法及び他の物質の合成
CL2008000905A1 (es) * 2007-03-29 2008-08-22 Progenics Pharm Inc Compuestos derivados de morfina, antagonistas del receptor opioide periferico; metodo de preparacion; composicion farmaceutica; y uso para reducir los efectos de la actividad opioide endogena.

Also Published As

Publication number Publication date
CA3265713A1 (fr) 2024-02-29
WO2024042226A2 (fr) 2024-02-29
WO2024042226A3 (fr) 2024-04-18

Similar Documents

Publication Publication Date Title
Matsuda et al. Antidiabetic principles of natural medicines. III. Structure-related inhibitory activity and action mode of oleanolic acid glycosides on hypoglycemic activity
CA2423568C (fr) Derives de glucopyranosiloxybenzylbenzene et compositions therapeutiques contenant ces composes
WO2013123824A1 (fr) Conjugué de polyglycol et de naloxone, composition pharmaceutique et leur utilisation
EP3137081A1 (fr) Dimère de la buprénorphine et son utilisation dans le traitement de troubles gastro-intestinaux
US4774230A (en) Glucuronic acid derivatives of opioid antagonists
CN115279915A (zh) 依托泊苷糖苷、其制备方法及其作为抗癌药物的用途
JPH08231581A (ja) アントラサイクリン誘導体
EP4577667A2 (fr) Procédé de production de composés libérant des antagonistes des opioïdes et leur utilisation en tant que médicament
CN104447893B (zh) 吡喃葡萄糖基衍生物及其在医药上的应用
EP0816375A1 (fr) Glycoconjugues de substances opiacees
EP0324212B1 (fr) Dérivés de l'acide glucuronique des antagonistes d'opiöides
WO2014049356A1 (fr) Dérivés de kétolides d'érythromycine portant des modifications en c-10
Dash et al. Biologically active carbohydrate-containing macrocycles
Zhang et al. Amoenucles A− F, novel nucleoside derivatives with TNF-α inhibitory activities from Aspergillus amoenus TJ507
CN114262354B (zh) 一种化合物及其用途
JP6376702B2 (ja) オピオイド鎮痛剤
CN1285338C (zh) 抗肺腺癌药物，其制备方法和其应用
CN102079763B (zh) 二氧杂双环辛烷化合物及其制备方法和用途
Baker et al. Methods for the treatment of Mycobacterium infections
JPH0551598B2 (fr)
WO2006124720A1 (fr) Anthracyclines anticancereuses multiresistantes aux medicaments
WO2024051666A1 (fr) Composé glycoside de dibenzylbutyrolactone, son procédé de préparation et son utilisation
CA1302265C (fr) Derives d'acide glycuronique d'antagonistes d'opioides
AU594855B2 (en) Glucuronic acid derivatives of opioid antagonists
CN121405627A (zh) 一种四氢异喹啉类化合物的合成方法及应用

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20250313

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC ME MK MT NL NO PL PT RO RS SE SI SK SM TR

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)